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METHOD OF SYNTHESIZING INDOLE COMPOUNDS

20240059653 ยท 2024-02-22

    Inventors

    Cpc classification

    International classification

    Abstract

    A method of synthesizing indole compounds. The method may include allyllating an indole compound, oxidizing the resulting -indolepropene, and reductively aminating the resulting indoleacetaldehyde, providing a tryptamine. The indole compound may be substituted with a functional group on the indole ring or may be unsubstituted indole. The method may include substitution, oxidation or other derivatization of the indole ring of the indole compound, of tryptophan, of the tryptamine, or of intermediates. The method may include oxidizing tryptophan or a ring-substituted tryptophan analogue and reductively aminating the resulting indoleacetaldehyde, providing a tryptamine. The method may be applied in a telescoped approach without isolation of intermediates. The method may be applied to production of indoles, -indolepropenes, indole propyl diols, indoleacetaldehydes and tryptamines. Compounds from each of these classes of compounds are also provided herein.

    Claims

    1. A method of synthesizing a tryptamine comprising: allyllating a substituted indole compound comprising an indole ring and a functional group on the indole ring to provide a ring-substituted -indolepropene; oxidizing the -indolepropene to provide a ring-substituted indoleacetaldehyde; and reductively aminating the indoleacetaldehyde to provide the tryptamine.

    2. The method of claim 1 wherein the functional group is selected from the group consisting of OH, OR, NH.sub.2, NHR, NR.sub.2, NHCOR, N(R.sub.3)*, NO.sub.2, CN, N.sub.3, COR, CO.sub.2H, CO.sub.2R, CHO, RCHO, R, B(OR).sub.2, B(F.sub.3).sup., F, Cl, Br, I, At, PO.sub.4, PO.sub.2(OR).sub.2, SO.sub.2Cl, SH, SR, SO.sub.3F, SiH.sub.3, SiRH.sub.2, SiR.sub.2H and SiR.sub.3, wherein R is selected from the group consisting of alkyl, acyl, vinyl, propargyl, phenyl and benzyl, and each separate R group may be identical to other R groups or distinct from other R groups.

    3. The method of claim 2 wherein the functional group is selected from the group consisting of COCH.sub.3, PO.sub.2(OR).sub.2 wherein R is benzyl, and SO.sub.3F.

    4. The method of any one of claims 1 to 3 wherein the functional group is located on position 4 of the indole ring, using the numbering of tryptamine.

    5. The method of any one of claims 1 to 4 wherein the functional group is located on position 5 of the indole ring, using the numbering of tryptamine.

    6. The method of any one of claims 1 to 5 wherein the functional group is located on position 6 of the indole ring, using the numbering of tryptamine.

    7. The method of any one of claims 1 to 6 wherein the functional group is located on position 7 of the indole ring, using the numbering of tryptamine.

    8. The method of any one of claims 1 to 7 wherein oxidizing the -indolepropene comprises: oxidizing the -indolepropene to provide an indole propyl diol; and oxidizing the indole propyl diol to provide the indoleacetaldehyde.

    9. The method of claim 8 wherein allyllating the substituted indole compound and oxidizing the -indolepropene to provide the indole propyl diol are effected without isolation of intermediates.

    10. The method of claim 8 or 9 wherein oxidizing the -indolepropene to provide the indole propyl diol and oxidizing the indole propyl diol are effected without isolation of intermediates.

    11. The method of any one of claims 8 to 10 wherein oxidizing the indole propyl diol and reductively aminating the indoleacetaldehyde are effected without isolation of intermediates.

    12. The method of any one of claims 1 to 11 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with dimethylamine.

    13. The method of any one of claims 1 to 11 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with an amine selected from the group consisting of methylamine, ethylamine, isopropylamine, diethylamine, diisopropylamine, methylethylamine, methylisopropylamine and ethylisopropylamine.

    14. The method of any one of claims 1 to 11 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with a cyclic secondary amine and the tryptamine comprises a cyclic tertiary amine.

    15. The method of claim 14 wherein the cyclic secondary amine is pyrrolidine.

    16. The method of any one of claims 1 to 8 and 12 to 15 wherein allyllating the substituted indole compound and oxidizing the -indolepropene are effected without isolation of intermediates.

    17. The method of any one of claims 1 to 8 and 12 to 16 wherein oxidizing the -indolepropene and reductively aminating the indoleacetaldehyde are effected without isolation of intermediates.

    18. The method of any one of claims 1 to 17 further comprising substituting a functional group on the indole ring for another functional group.

    19. A method of synthesizing a tryptamine comprising: allyllating an unsubstituted indole to provide -indolepropene; oxidizing the -indolepropene to provide indoleacetaldehyde; and reductively aminating the indoleacetaldehyde to provide the tryptamine.

    20. The method of claim 19 wherein oxidizing the -indolepropene comprises: oxidizing the -indolepropene to provide an indole propyl diol; and oxidizing the indole propyl diol to provide the indoleacetaldehyde.

    21. The method of claim 20 wherein allyllating the substituted indole compound and oxidizing the -indolepropene to provide the indole propyl diol are effected without isolation of intermediates.

    22. The method of claim 20 or 21 wherein oxidizing the -indolepropene to provide the indole propyl diol and oxidizing the indole propyl diol are effected without isolation of intermediates.

    23. The method of any one of claims 20 to 22 wherein oxidizing the indole propyl diol and reductively aminating the indoleacetaldehyde are effected without isolation of intermediates.

    24. The method of any one of claims 19 to 23 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with dimethylamine.

    25. The method of any one of claims 19 to 23 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with an amine selected from the group consisting of methylamine, ethylamine, isopropylamine, diethylamine, diisopropylamine, methylethylamine, methylisopropylamine and ethylisopropylamine.

    26. The method of any one of claims 19 to 23 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with a cyclic secondary amine and the tryptamine comprises a cyclic tertiary amine.

    27. The method of claim 26 wherein the cyclic secondary amine is pyrrolidine.

    28. The method of any one of claims 19 and 24 to 27 wherein allyllating the substituted indole compound and oxidizing the -indolepropene are effected without isolation of intermediates.

    29. The method of any one of claims 19 and 24 to 28 wherein oxidizing the -indolepropene and reductively aminating the indoleacetaldehyde are effected without isolation of intermediates.

    30. A method of synthesizing a ring-substituted -indolepropene comprising: allyllating a substituted indole compound comprising an indole ring and a functional group on the indole ring to provide the -indolepropene.

    31. The method of claim 30 wherein the functional group is selected from the group consisting of OH, OR, NH.sub.2, NHR, NR.sub.2, NHCOR, N(R.sub.3).sup.+, NO.sub.2, CN, N.sub.3, COR, CO.sub.2H, CO.sub.2R, CHO, RCHO, R, B(OR).sub.2, B(F.sub.3).sup., F, Cl, Br, I, At, PO.sub.4, PO.sub.2(OR).sub.2, SO.sub.2Cl, SH, SR, SO.sub.3F, SiH.sub.3, SiRH.sub.2, SiR.sub.2H and SiR.sub.3, wherein R is selected from the group consisting of alkyl, acyl, vinyl, propargyl, phenyl and benzyl, and each separate R group may be identical to other R groups or distinct from other R groups.

    32. The method of claim 31 wherein the functional group is selected from the group consisting of COCH.sub.3, PO.sub.2(OR).sub.2 wherein R is benzyl, and SO.sub.3F.

    33. The method of any one of claims 30 to 32 wherein the functional group is located on position 4 of the indole ring, using the numbering of tryptamine.

    34. The method of any one of claims 30 to 33 wherein the functional group is located on position 5 of the indole ring, using the numbering of tryptamine.

    35. The method of any one of claims 30 to 34 wherein the functional group is located on position 6 of the indole ring, using the numbering of tryptamine.

    36. The method of any one of claims 30 to 35 wherein the functional group is located on position 7 of the indole ring, using the numbering of tryptamine.

    37. A method of synthesizing an indole propyl diol comprising: oxidizing a ring-substituted -indolepropene comprising an indole ring and a functional group on the indole ring to provide the indole propyl diol.

    38. The method of claim 37 wherein the -indolepropene is prepared by a method comprising: allyllating a substituted indole compound to provide the -indolepropene.

    39. The method of claim 38 wherein allyllating the substituted indole compound and oxidizing the -indolepropene are effected without isolation of intermediates.

    40. The method of any one of claims 37 to 39 wherein the functional group is selected from the group consisting of OH, OR, NH.sub.2, NHR, NR.sub.2, NHCOR, N(R.sub.3)+, NO.sub.2, CN, N.sub.3, COR, CO.sub.2H, CO.sub.2R, CHO, RCHO, R, B(OR).sub.2, B(F.sub.3).sup., F, Cl, Br, I, At, PO.sub.4, PO.sub.2(OR).sub.2, SO.sub.2Cl, SH, SR, SO.sub.3F, SiH.sub.3, SiRH.sub.2, SiR.sub.2H and SiR.sub.3, wherein R is selected from the group consisting of alkyl, acyl, vinyl, propargyl, phenyl and benzyl, and each separate R group may be identical to other R groups or distinct from other R groups.

    41. The method of claim 40 wherein the functional group is selected from the group consisting of COCH.sub.3, PO.sub.2(OR).sub.2 wherein R is benzyl, and SO.sub.3F.

    42. The method of any one of claims 37 to 41 wherein the functional group is located on position 4 of the indole ring, using the numbering of tryptamine.

    43. The method of any one of claims 37 to 42 wherein the functional group is located on position 5 of the indole ring, using the numbering of tryptamine.

    44. The method of any one of claims 37 to 43 wherein the functional group is located on position 6 of the indole ring, using the numbering of tryptamine.

    45. The method of any one of claims 37 to 44 wherein the functional group is located on position 7 of the indole ring, using the numbering of tryptamine.

    46. A method of synthesizing a tryptamine comprising: reductively aminating a ring-substituted indoleacetaldehyde comprising an indole ring and a functional group on the indole ring to provide the tryptamine.

    47. The method of claim 46 wherein the indoleacetaldehyde is prepared by a method comprising: oxidizing a ring-substituted -indolepropene to provide the indoleacetaldehyde.

    48. The method of claim 47 wherein oxidizing the -indolepropene and reductively aminating the indoleacetaldehyde are effected without isolation of intermediates.

    49. The method of claim 47 wherein oxidizing the -indolepropene comprises: oxidizing the -indolepropene to provide an indole propyl diol; and oxidizing the indole propyl diol to provide the indoleacetaldehyde.

    50. The method of claim 49 wherein oxidizing the -indolepropene to provide the indole propyl diol and oxidizing the indole propyl diol are effected without isolation of intermediates.

    51. The method of claim 49 or 50 wherein oxidizing the indole propyl diol and reductively aminating the indoleacetaldehyde are effected without isolation of intermediates.

    52. The method of any one of claims 47 to 51 wherein the -indolepropene is prepared by a method comprising: allyllating a substituted indole compound to provide the -indolepropene.

    53. The method of claim 52 wherein allyllating the substituted indole compound and oxidizing the -indolepropene are effected without isolation of intermediates.

    54. The method of any one of claims 46 to 53 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with dimethylamine.

    55. The method of any one of claims 46 to 53 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with an amine selected from the group consisting of methylamine, ethylamine, isopropylamine, diethylamine, diisopropylamine, methylethylamine, methylisopropylamine and ethylisopropylamine.

    56. The method of any one of claims 46 to 53 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with a cyclic secondary amine and the tryptamine comprises a cyclic tertiary amine.

    57. The method of claim 56 wherein the cyclic secondary amine is pyrrolidine.

    58. The method of any one of claims 46 to 57 wherein the functional group is selected from the group consisting of OH, OR, NH.sub.2, NHR, NR.sub.2, NHCOR, N(R.sub.3)+, NO.sub.2, CN, N.sub.3, COR, CO.sub.2H, CO.sub.2R, CHO, RCHO, R, B(OR).sub.2, B(F.sub.3), F, Cl, Br, I, At, PO.sub.4, PO.sub.2(OR).sub.2, SO.sub.2Cl, SH, SR, SO.sub.3F, SiH.sub.3, SiRH.sub.2, SiR.sub.2H and SiR.sub.3, wherein R is selected from the group consisting of alkyl, acyl, vinyl, propargyl, phenyl and benzyl, and each separate R group may be identical to other R groups or distinct from other R groups.

    59. The method of claim 58 wherein the functional group selected from the group consisting of COCH.sub.3, PO.sub.2(OR).sub.2 wherein R is benzyl, and SO.sub.3F.

    60. The method of any one of claims 46 to 59 wherein the functional group is located on position 4 of the indole ring, using the numbering of tryptamine.

    61. The method of any one of claims 46 to 60 wherein the functional group is located on position 5 of the indole ring, using the numbering of tryptamine.

    62. The method of any one claims 46 to 61 wherein the functional group is located on position 6 of the indole ring, using the numbering of tryptamine.

    63. The method of any one claims 46 to 62 wherein the functional group is located on position 7 of the indole ring, using the numbering of tryptamine.

    64. A method of synthesizing a tryptamine comprising: oxidizing tryptophan to provide indoleacetaldehyde; and reductively aminating the indoleacetaldehyde to provide the tryptamine; wherein oxidizing the tryptophan and reductively aminating the indoleacetaldehyde are effected without isolation of intermediates.

    65. The method of claim 64 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with dimethylamine.

    66. The method of claim 64 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with an amine selected from the group consisting of methylamine, ethylamine, isopropylamine, diethylamine, diisopropylamine, methylethylamine, methylisopropylamine and ethylisopropylamine.

    67. The method of claim 64 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with a cyclic secondary amine and the tryptamine comprises a cyclic tertiary amine.

    68. The method of claim 67 wherein the cyclic secondary amine is pyrrolidine.

    69. The method of any one of claims 64 to 68 further comprising oxidizing an indole ring of the tryptamine to provide a ring-substituted tryptamine comprising a functional group on the indole ring.

    70. The method of claim 69 wherein oxidizing the indole ring comprises application of Fenton chemistry and the ring-substituted tryptamine comprises a tryptamine substituted on the indole ring with OH.

    71. The method of claim 69 wherein the functional group is selected from the group consisting of OH, OR, NH.sub.2, NHR, NR.sub.2, NHCOR, N(R.sub.3).sup.+, NO.sub.2, CN, N.sub.3, COR, CO.sub.2H, CO.sub.2R, CHO, RCHO, R, B(OR).sub.2, B(F.sub.3).sup., F, Cl, Br, I, At, PO.sub.4, PO.sub.2(OR).sub.2, SO.sub.2Cl, SH, SR, SO.sub.3F, SiH.sub.3, SiRH.sub.2, SiR.sub.2H and SiR.sub.3, wherein R is selected from the group consisting of alkyl, acyl, vinyl, propargyl, phenyl and benzyl, and each separate R group may be identical to other R groups or distinct from other R groups.

    72. The method of any one of claims 69 to 71 wherein the functional group is located on position 4 of the indole ring, using the numbering of tryptamine.

    73. The method of any one of claims 69 to 72 wherein the functional group is located on position 5 of the indole ring, using the numbering of tryptamine.

    74. The method of any of claims 69 to 73 wherein the functional group is located on position 6 of the indole ring, using the numbering of tryptamine.

    75. The method of any of claims 69 to 74 wherein oxidizing the tryptophan, reductively aminating the indoleacetaldehyde and oxidizing the indole ring of the tryptamine are effected without isolation of intermediates.

    76. A method of synthesizing a ring-substituted tryptamine comprising: oxidizing an indole ring of tryptophan to provide a ring-substituted tryptophan analogue comprising a functional group on the indole ring; oxidizing the tryptophan analogue to provide a ring-substituted indoleacetaldehyde; and reductively aminating the indoleacetaldehyde to provide the tryptamine.

    77. The method of claim 76 wherein oxidizing the indole ring comprises oxidizing the indole ring by application of Fenton chemistry and the tryptophan analogue comprises a tryptophan analogue substituted on the indole ring with OH.

    78. The method of claim 72 wherein the functional group is selected from the group consisting of OH, OR, NH.sub.2, NHR, NR.sub.2, NHCOR, N(R.sub.3N).sup.+, NO.sub.2, CN, N.sub.3, COR, CO.sub.2H, CO.sub.2R, CHO, RCHO, R, B(OR).sub.2, B(F.sub.3).sup., F, Cl, Br, I, At, PO.sub.4, PO.sub.2(OR).sub.2, SO.sub.2Cl, SH, SR, SO.sub.3F, SiH.sub.3, SiRH.sub.2, SiR.sub.2H and SiR.sub.3, wherein R is selected from the group consisting of alkyl, acyl, vinyl, propargyl, phenyl and benzyl, and each separate R group may be identical to other R groups or distinct from other R groups.

    79. The method of any one of claims 76 to 78 wherein the functional group is located on position 4 of the indole ring, using the numbering of tryptamine.

    80. The method of any one of claims 76 to 79 wherein the functional group is located on position 5 of the indole ring, using the numbering of tryptamine.

    81. The method of any of claims 76 to 80 wherein the functional group is located on position 6 of the indole ring, using the numbering of tryptamine.

    82. The method of any one of claims 76 to 81 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with dimethylamine.

    83. The method of any one of claims 76 to 81 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with an amine selected from the group consisting of methylamine, ethylamine, isopropylamine, diethylamine, diisopropylamine, methylethylamine, methylisopropylamine and ethylisopropylamine.

    84. The method of any one of claims 76 to 81 wherein reductively aminating the indoleacetaldehyde comprises reductive amination with a cyclic secondary amine and the tryptamine comprises a cyclic tertiary amine.

    85. The method of claim 84 wherein the cyclic secondary amine is pyrrolidine.

    86. The method of any one of claims 76 to 85 wherein oxidizing the indole ring of the tryptophan and oxidizing the tryptophan analogue are effected without isolation of intermediates.

    87. The method of any one of claims 76 to 86 wherein oxidizing the tryptophan analogue and reductively aminating the indoleacetaldehyde are effected without isolation of intermediates.

    88. The method of any one of claims 76 to 85 wherein oxidizing the indole ring of the tryptophan, oxidizing the tryptophan analogue and reductively aminating the indoleacetaldehyde are effected without isolation of intermediates.

    89. An indole compound having the general formula (I): ##STR00038## wherein R is selected from the group consisting of allyl, ##STR00039##

    90. An indole compound having the general formula (II): ##STR00040## wherein R is selected from the group consisting of H, allyl, ##STR00041##

    91. An indole compound having the general formula (III): ##STR00042## wherein R is selected from the group consisting of allyl, ##STR00043## and CH.sub.2CH.sub.2NR.sup.1R.sup.2, R.sup.1 is C1 to C6 alkyl, R.sup.2 is C1 to C6 alkyl; and X is selected from the group consisting of H, COR, CO.sub.2R, CONR.sub.2, PO(OR).sub.2, SiR.sub.3, SO.sub.2(OR), and SO.sub.2F, wherein R is selected from the group consisting of alkyl, acyl, vinyl, propargyl, phenyl and benzyl, and each separate R group may be identical to other R groups or distinct from other R groups.

    92. The indole compound of claim 91 wherein R is CH.sub.2CH.sub.2NR.sup.1R.sup.2; and R.sup.1 and R.sup.2 are one continuous alkyl group forming a cyclic tertiary amine.

    93. The indole compound of claim 91 or 92 wherein X is SO.sub.2F.

    Description

    BRIEF DESCRIPTION OF THE FIGURES

    [0069] Embodiments of the present disclosure will now be described, by way of example only, with reference to the attached Figures.

    [0070] FIG. 1 shows reaction schemes for synthesis of ring-substituted and unsubstituted tryptamines from tryptophan;

    [0071] FIG. 2 shows tryptamines that may be synthesized by the method shown in FIG. 1;

    [0072] FIG. 3 shows synthesis of a pyrrolidinyl tryptamine from tryptophan;

    [0073] FIG. 4 shows synthesis of a ring-substituted tryptophan analogue from tryptophan;

    [0074] FIG. 5 shows synthesis of a ring-substituted tryptamine from dimethyltryptamine;

    [0075] FIG. 6 shows synthesis of ring-substituted tryptophan analogues and tryptamines from tryptophan and ring substituted tryptamines from unsubstituted tryptamines;

    [0076] FIG. 7 shows synthesis of multiple ring-substituted pyrrolidinyl tryptamines from pyrrolidinyl tryptamine;

    [0077] FIG. 8 shows tryptamines that may be synthesized in accordance with the method of FIG. 7;

    [0078] FIG. 9 shows synthesis of a ring-substituted carbamate analogue of a tryptamine;

    [0079] FIG. 10 shows tryptamines that may be synthesized in accordance with the method of FIG. 9;

    [0080] FIG. 11 shows synthesis of a tryptamine from a ring-substituted indole;

    [0081] FIG. 12 shows synthesis of 4-acetyl-2-allylindole (or 5-acetyl-3-allylindole counting from the indole nitrogen as position 1),

    [0082] FIG. 13 synthesis of a constrained pyrrolidine tryptamine from 4-acetyl-2-allylindole (or 5-acetyl-3-allylindole counting from the indole nitrogen as position 1);

    [0083] FIG. 14 shows tryptamines that may be synthesized in accordance with the method of FIGS. 12 and 13;

    [0084] FIG. 15 shows synthesis of 4-acetyl-2-allylindole and 4-acetyl-N-allylindole from 4-acetylindole;

    [0085] FIG. 16 shows synthesis of 1H-indol-4-yl acetate from 4-hydroxyindole;

    [0086] FIG. 17 shows synthesis of dibenzyl (1H-indol-4-yl) phosphate from 4-hydroxyindole;

    [0087] FIG. 18 shows synthesis of 3-allyl-1H-indol-4-yl acetate from 4-acetylindole;

    [0088] FIG. 19 shows synthesis of 3-allyl-1H-indol-4-yl dibenzyl phosphate from dibenzyl (1H-indol-4-yl) phosphate;

    [0089] FIG. 20 shows synthesis of 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate from 3-allyl-1H-indol-4-yl acetate;

    [0090] FIG. 21 shows synthesis of 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate from 1H-indol-4-yl acetate in a telescoped reaction;

    [0091] FIG. 22 shows synthesis of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl acetate from 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate in a telescoped reaction;

    [0092] FIG. 23 shows synthesis of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol from 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate in a telescoped reaction;

    [0093] FIG. 24 shows synthesis of a mixture of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl acetate and 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol from 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate in a telescoped reaction;

    [0094] FIG. 25 shows synthesis of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol from a mixture of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl acetate and 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol;

    [0095] FIG. 26 shows synthesis of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol from 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate in a telescoped reaction;

    [0096] FIG. 27 shows synthesis of 1H-indol-4-yl sulfurofluoridate from 4-hydroxyindole;

    [0097] FIG. 28 shows synthesis of 1-(fluorosulfonyl)-3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl sulfurofluoridate from 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol;

    [0098] FIG. 29 shows synthesis of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl sulfurofluoridate from 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol;

    [0099] FIG. 30 shows synthesis of dibenzyl (3-(2,3-dihydroxypropyl)-1H-indol-4-yl) phosphate from 3-allyl-1H-indol-4-yl dibenzyl phosphate; and

    [0100] FIG. 31 shows synthesis of dibenzyl (3-(2,3-dihydroxypropyl)-1H-indol-4-yl) phosphate from dibenzyl (1H-indol-4-yl) phosphate in a telescoped reaction.

    DETAILED DESCRIPTION

    [0101] Generally, the present disclosure provides a method for synthesizing tryptamines and other indole compounds. The method may be applied to ring-substituted or unsubstituted tryptamines and other compounds. Ring-substituted tryptamines and other compounds include functional groups on the indole ring of tryptamine such as OH, OR, NH.sub.2, NHR, NR.sub.2, NHCOR, R.sub.3N.sup.+, NO.sub.2, CN, N.sub.3, COR, CO.sub.2H, CO.sub.2R, CHO, RCHO, R, B(OR).sub.2, B(F.sub.3).sup., F, Cl, Br, I, At, PO.sub.4, PO.sub.2(OR).sub.2, SO.sub.2Cl, SH, SR, SO.sub.3F, SiH.sub.3, SiRH.sub.2, SiR.sub.2H, SiR.sub.3, wherein R is selected from the group consisting of alkyl, acyl, vinyl, propargyl, phenyl, benzyl, or other suitable groups, and each separate R group may be identical to other R groups or distinct from other R groups. The method may be applied to tryptamines or other indole compounds lacking functional groups on the indole ring and to tryptamines or other indole compounds with ring substitutions. The tryptamines may be alkylated on the terminal amine group with any suitable alkylation pattern. Alkylation patterns on the terminal amine may include methyl, ethyl, isopropyl, dimethylamine diethyl, diisopropyl, methylethyl, methylisopropyl and ethylisopropyl. Alkylation patterns on the terminal amine group may be cyclic tertiary amine groups, including an unconjugated pyrrolyl group with entirely sp3 orbital configuration on the alkyl amine. Other cyclic tertiary amines, whether conjugated or not, may also be applied to create cyclic tertiary amines (e.g. aromatic pyrrolyl, piperidinyl, pyridinyl, etc.).

    [0102] The method may be applied through two separate and related reactions. Oxidative decarboxylation of tryptophan or of a ring-substituted analog of tryptophan followed by reductive amination of the resulting aldehyde may be applied to synthesize a tryptamine. Oxidative decarboxylation of tryptophan or of a ring-substituted analog of tryptophan followed by reductive amination of the resulting aldehyde may be carried out in a single telescoped reaction without isolation of any intermediates. There is no previous report of a direct oxidation of tryptophan that is fed directly to reductive amination of an aldehyde without workup or isolation of intermediates. This telescoped sequence provides efficiencies. The switch from oxidative to reductive with effective coupling of the two reaction conditions is facilitated by close monitoring and control of reaction conditions. Selective or non-selective oxidation of the indole ring on tryptophan may provide a ring-substituted tryptophan analogue. Selective or non-selective oxidation of the indole ring on a tryptamine may provide a ring-substituted tryptamine. This approach allows use of tryptophan as a starting material, which may provide economic or other operational advantages relative to syntheses using other starting materials.

    [0103] Oxidative decarboxylation of tryptophan followed by reductive amination of the resulting aldehyde may be applied to tryptophan to provide a tryptamine without substitutions on the indole ring (e.g. N,N-dimethyltryptamine (DMT), N,N-diethyltryptamine (DET), N,N,methylethyltryptamine (MET), N,N,methylisopropyltryptamine (MiPT), N,N-diisopropyltryptamine (DiPT), etc.).

    [0104] Selective or non-selective oxidation of the indole ring on either tryptophan or the tryptamine results in a hydroxylated indole ring, which may be subsequently phosphorylated or otherwise derivatized, and whether maintained as a hydroxyl or otherwise derivatized, providing a ring-substituted tryptamine (e.g. 3-[2-(dimethylamino)ethyl]-4-phosphoryloxyindole (psilocybin), 3-[2-(dimethylamino)ethyl]-4-hydroxyindole (psilocin), 3-[2-(dimethylamino)ethyl]-4-acetoxyindole (4-acetyl-DMT), 3-[2-(trimethylamino)ethyl]-4-phosphoryloxyindole (aeruginascin), 3-[2-(methylamino)ethyl]-4-phosphoryloxyindole (baeocystin), 3-[2-(methylamino)ethyl]-4-hydroxyindole, 3-[2-(amino)ethyl]-4-hydroxyindole (norpsilocin), 3-[2-(amino)ethyl]-4-phosphoryloxyindole (norbaeocystin), 5-methoxy-dimethyltryptamine (bufotenin), 5-methoxy-diisopropyltryptamine (5-MeO-DiPT), N-acetyl-5-methoxy tryptamine (melatonin), 5-hydroxy tryptamine (serotonin), 5-methoxy-dimethyltryptamine (5-MeO-DMT), and 5-hydroxy-tryptophan (5-HTP).

    [0105] The method may be applied to adding alkyl functionality to a ring-substituted indole compound. The nucleophilic character of the 3-position of the indole ring may facilitate attaching a dimethylaminoethyl at the 3-position, resulting in tryptamine. An allyl group is added to the substituted indole compound. The resulting ring-substituted -indolepropene is oxidized to an indoleacetaldehyde. The resulting indoleacetaldehyde is reductively aminated to a tryptamine.

    [0106] The allyl group may be bonded to the indole ring, oxidized to an indole propyl diol, oxidized to an aldehyde, and reduced to a dialkylamino, or other amine group (e.g. dimethylamino-, diethylamino-, diisopropylamino-, methylethylamino-, pyrolidine or other group). By beginning with 4-hydroxy-indole or another 4-substituted indole, using the same numbering as on tryptamines, psilocin or another a 4-substituted tryptamine results from alkylation. By beginning with 5-hydroxy-indole or another 5-substituted indole, using the same numbering as on tryptamines, bufotenine or another a 5-substituted tryptamine results from alkylation.

    [0107] Synthesis of hydroxylated ring-substituted tryptamines (e.g. psilocin) as an initial step may in turn facilitate synthesis of phosphorylated, acetylated or other ring-substituted indole compounds (e.g. psilocybin, 4-acetyl-DMT, etc.), which may facilitate diversity in the number of tryptamines that can be synthesized by facilitating application of a variety of indole compound starting materials. Phosphorylation or other derivatization of hydroxylated ring-substituted indole compound may be completed through a number of organic chemistry or biosynthetic methods. Psilocybin is a prodrug of psilocin. Analogues of psilocybin in which the phosphate is substituted by bio-convertible groups may provide new chemical entities with different pharmacokinetics than psilocybin.

    [0108] Analogues of psilocybin where the alkylation pattern is not dimethyl may provide new chemical entities with different pharmacokinetics, pharmacodynamics or other properties, compared with psilocybin. Analogues of psilocybin where the ring substituent is a different functional group, is located at a different position on the ring or both may also be produced with the method. Other bio-convertible groups could potentially provide advantages such as longer or shorter duration of effect, extended release, specialized therapeutic indication, or other advantages. The flexibility of the methods provided herein to synthesize ring-substituted tryptamines with a variety of functional groups on the indole ring, and unsubstituted tryptamines, each with a variety of alkylation patterns, may provide advantages in drug discovery, and other aspects of research and development of therapeutic products.

    [0109] FIG. 1 shows two reaction pathways: (a) oxidative decarboxylation and reductive amination shown at Steps 1 to 2 and Steps 5 to 6 and (b) oxidation of the indole ring at Step 3 and Step 4. Step 4 may precede Steps 5 to 6. Steps 1 to 2 may precede Step 3.

    [0110] In FIG. 1, Steps 1 to 2 and 5 to 6 include tryptamine synthesis from amino acid in one telescoped series of reactions that includes sequential oxidative decarboxylation and reductive amination without isolation of any intermediates. In the example of FIG. 1, the tryptamine is N,N-DMT, but other tryptamines may be synthesized by varying the amine used for reductive amination of indoleacetaldehyde. The amino acid may be tryptophan (steps 1 and 2) or ring-substituted tryptophan analogues (steps 5 and 6). While only 4-substituted tryptamines and tryptophan analogues are shown in FIG. 1, other ring substitution patterns may also be applied in the method.

    [0111] The two telescoped steps of oxidative decarboxylation and reductive amination could be completed on either tryptophan (step 1 and 2 in FIG. 1) or 4-hydroxy tryptophan (steps 5 and 6 in FIG. 1). The conditions where oxidative decarboxylation and reductive amination overlap is a narrow window of reaction conditions. Timing of the reaction is important There is a narrow conditional window and a narrow kinetic window where the indoleacetaldehyde is present in high relative abundance and has not been oxidatively degraded. Increasing pH or otherwise changing solvent conditions to improve the nucleophilic character of the solvent, or adding an additional reagent as aminating nucleophile, during this conditional window and kinetic window, facilitates reductive amination. Managing the reaction sequence to allow these reaction conditions in a telescoped sequence may be facilitated by real-time reaction monitoring to balance maximizing the amount of the intermediate aldehyde available for reductive amination with minimizing the extent of indole ring destruction from oxidative hydrolysis. Real-time reaction monitoring may be accomplished by a combination of high-performance liquid chromatography (HPLC) and mass spectrometry (MS; the combination of HPLC and MS being called HPLC-MS), by proton nuclear magnetic resonance (1H-NMR) or other suitable real-time analytical techniques. Sampling of the reaction for real-time monitoring may be facilitated by automated sampling during the reaction (Chung, 2017); (Daponte, 2019); (Malig, 2020a); (Malig, 2020b); (Sato, 2021).

    [0112] Telescoping is the execution of multiple transformations (including quenches and other workup operations) without isolation of intermediates. Telescoped solutions of intermediates can be extracted, filtered (as long as the product remains in the filtrate), and solvent exchanged, but intermediates are held in solution throughout and carried forward to the subsequent transformation. Telescoping reactions together facilitates effective synthesis by carrying out several synthetic transformations and bond-forming steps without work up or purification. Telescoped reactions may be performed as one-pot reactions. Where sufficient monitoring and control are available, telescoped reactions may thus provide efficiencies in terms of chemical waste, time, and simplicity (Hayashi, 2016). Telescoped reactions may also be referred to as cascade, domino or tandem reactions. Approaches to synthesis in which one-pot or telescoped reactions are applied may be effected without isolation of intermediates.

    [0113] In FIG. 1, Steps 3 and 4 are oxidation of the indole ring, which may be carried out on the amino acid or on the tryptamine, and either before (Steps 4, 5 and 6) or after (Steps 1, 2 and 3) synthesis of the tryptamine. An aryl group may be used to add a hydroxyl group at basic pH, which is less toxic and more cost effective than using thallium. This approach may include CH functionalization to install an aryl boron as an intermediate before oxidation.

    [0114] In FIG. 1, the amino acid may be subject to oxidative decarboxylation followed by reductive amination to provide a tryptamine. The solvent or reagent used for reductive amination will determine the N-alkylation pattern of tryptamines that are synthesized using the method of FIG. 1. For example, reductive amination with dimethylamine provides DMT or other unsubstituted tryptamines, or provides psilocin or other ring-substituted tryptamines. Using other alkylated amines may provide other suitable alkylation at the amine group of the resulting tryptamine, whether substituted or not on the indole ring.

    [0115] FIG. 2 shows tryptamines that may be synthesized in accordance with the method of FIG. 1. In FIG. 2, positions 1, 2, 3, 4, 5, 6, and 7 on the indole ring of tryptamine, and positions a and P on the side chain of tryptamine, are labelled. Where the numbering of tryptamine is referred to herein, the numbering of positions as shown in FIG. 2 is being referenced. Carbons between positions 3 and 4, and between positions 1 and 7, are tertiary sp2 carbons and cannot carry functional groups, so these positions are excluded from the ring numbering of tryptamine used herein.

    [0116] In FIG. 2, Each of R.sub.1 to R.sub.4 may be H, and each of R.sub.5 and R.sub.6 may be methyl, showing conversion of tryptophan to DMT. R.sub.1 may be OH, each of R.sub.2 to R.sub.4 may be H, and R.sub.5 and R.sub.6 may be methyl, showing conversion of 4-OH-tryptophan to psilocin. Each of R.sub.1 to R.sub.4 may be any suitable functional group (e.g. OH, OR, NH.sub.2, NHR, NR.sub.2, NHCOR, R.sub.3N.sup.+, NO.sub.2, CN, N.sub.3, COR, CO.sub.2H, CO.sub.2R, CHO, RCHO, R, B(OR).sub.2, B(F.sub.3).sup., F, Cl, Br, I, At, PO.sub.4, PO.sub.2(OR).sub.2, SO.sub.2Cl, SH, SR, SO.sub.3F, SiH.sub.3, SiRH.sub.2, SiR.sub.2H, SiR.sub.3, etc. wherein R is selected from the group consisting of alkyl, acyl, vinyl, propargyl, phenyl, benzyl, or other suitable groups, and each separate R group may be identical to other R groups or distinct from other R groups).

    [0117] Tryptamines synthesized in accordance with the method disclosed herein may be alkylated on the terminal amine group with any suitable alkylation pattern. In FIG. 2, each of R.sub.5 and R.sub.6 may be any suitable H or any suitable alkyl group, and each of R.sub.5 and R.sub.6 may be the same substituent or may be distinct substituents. For example, alkylation patterns on the terminal amine may include methyl, ethyl, isopropyl, dimethyl, diethyl, diisopropyl, methylethyl, methylisopropyl and ethylisopropyl. Alkylation patterns on the terminal amine group may be cyclic tertiary amine groups, including an unconjugated pyrrolyl group with entirely sp3 orbital configuration on the alkyl amine. Other cyclic tertiary amines, whether conjugated or not, may also be applied to create cyclic tertiary amines (e.g. aromatic pyrrolyl, piperidinyl, pyridinyl, etc.).

    [0118] FIG. 3 shows an example of oxidative decarboxylation followed by reductive amination in which pyrroline is used as a nucleophilic dialkylamine to provide a tryptamine that includes a tertiary amine. The tertiary amine in in FIG. 3 is cyclic as the pyrroline that was used a nucleophile was also cyclic. FIG. 3 shows 3-[2-(pyrrolidin-1-yl)ethyl]-1H-indole, or N,N-tetramethylenetryptamine, which is an unconjugated pyrrolyl tryptamine with entirely sp3 orbital configuration on the alkyl amine group. Other cyclic tertiary amines, whether conjugated or not, may also be applied to create cyclic tertiary amines (e.g. aromatic pyrrolyl groups, piperidinyl groups, pyridinyl groups, etc.).

    [0119] Tryptophan is decarboxylated with sodium hypochlorite to oxidize the amine to an aldehyde. Sodium phosphate is then added to deprotonate the pyrrolidine to produce a nucleophilic pyrroline, and the aldehyde is reductively aminated with a weak reducing agent.

    [0120] In FIG. 3, Tryptophan was dissolved in a pH 7 phosphate buffer and reacted with sodium hypochlorite to oxidatively decarboxylate the tryptophan to provide indol-3-ylacetaldehyde (reaction 1 in FIG. 1). After decarboxylation of tryptophan, tryptamine is formed as an intermediate. The sodium hypochlorite oxidizes the amine of tryptamine to move CN single to CN* to CN. Put otherwise, the resulting primary amine from decarboxylation becomes a carbon bonded to N as primary imine. From the primary imine, CN reacts with nucleophilic OH.sup. to provide a primary alcohol, which in turn oxidizes to an aldehyde. Sodium ascorbate is then added to react with the remaining sodium hypochlorite to prevent excess oxidation and destruction of the indole ring. If the reaction with sodium hypochlorite were allowed to proceed, the indole ring would be cleaved by base. To prevent loss of indole, the solution is pushed into reductive conditions by adjusting the pH to between 7 and 9.

    [0121] After elimination of excess sodium hypochlorite, methanol was added to dilute the reaction mixture. Pyrrolidine was then added as a solution in water and the pH was adjusted to between 7 and 9 to push the reaction mixture into reductive conditions where pyrrolidine acts as a nucleophile. At this pH range, the indole ring will remain stable and will not be hydrolyzed. At this pH range, which is below the pKa of pyrrolidine (11.3), pyrrolidine will be predominantly deprotonated, increasing its nucleophilicity. The mixture is then treated with sodium triacetoxyhydroborate to reductively aminate the aldehyde with pyrrolidine, resulting in 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indole.

    [0122] The weak reducing agent sodium triacetoxyhydroborate allows formation of the bond between the alpha carbon and the secondary amine in pyrrolidine without reducing the aldehyde to a primary alcohol, which would occur with stronger reducing agents.

    [0123] With techniques to monitor abundance of the indoleacetaldehyde, as the tryptophan becomes less abundant and the indoleacetaldehyde becomes more abundant, an amine is added to the reaction mixture and the pH is adjusted to the range where the amine becomes sufficiently nucleophilic to react at the aldehyde, or the reaction conditions are otherwise modified to increase nucleophilicity of the amine. Monitoring of the indoleacetaldehyde abundance may be through HPLC-MS, 1H-NMR or any suitable real-time analytical technique. Sampling of the reaction for real-time monitoring may be facilitated by automated sampling during the reaction.

    [0124] The nucleophilic amine may also be provided as the solvent, such as use of pyridine in Examples I, and for the method of FIG. 11, Examples V and XX to XXVI. Any alkyl substitution pattern on the secondary amine may be applied with different nucleophilic amine groups. Propanal may be used as a longer chain surrogate to formaldehyde to provide DiPT and 4-OH-DiPT.

    [0125] There is no previous report of a direct oxidation of tryptophan that is fed directly to reductive amination of an aldehyde without isolation of intermediates. This telescoped sequence provides efficiencies. The switch from oxidative to reductive with effective coupling of the two reaction conditions is facilitated by close monitoring and control of reaction conditions.

    [0126] Oxidative decarboxylation of tryptophan has been reported with isolation of an intermediate indoleacetaldehyde (Maresh et al, 2014), (Fawzy, 2016), (Brown, 1952), (Gray, 1959). Previous reaction conditions have been optimized to deliver the resultant indoleacetaldehyde as the sole isolable product. If previous approaches were used prior to reductive amination, then isolation and purification of the indoleacetaldehyde would be required to purge solvent and other potential reaction impurities or reagents before reductive amination. Residual oxidative reagents that facilitate decarboxylation may destroy an alkyl amine and also the borohydride reducing agent. These reactions also require a chemoselective reaction at the amino acid fragment to avoid reaction on the indole ring. This selection process relies on precise and stringent kinetic control set an optimal time frame and provide reaction conditions to allow for only the amino acid, and not the indole ring, to undergo functional group conversion.

    [0127] The approach shown in FIG. 1 may be carried out with real-time reaction analytics to both visualize the rate and selectivity of the chemical reaction, allowing optimal process decision to be controlled. The process optimization may include timing on transitioning the reaction and the stoichiometry of oxidant. The approach shown in FIG. 1 requires execution of two antagonistic reactions in sequence and in the same reaction vessel. The approach shown in FIG. 1 facilitates seamless execution of step-to-step telescoping between oxidation and reduction amination, which may be carried out in one reaction vessel. Step-to-step telescoping between oxidation and reductive amination may mitigate potential byproducts and uncertainty in the procedure, and may also mitigate potential for error or loss during workup, such as when purifying, when transferring between reaction vessels or at other steps of the procedure.

    [0128] Reductive amination of indole aldehydes of various substitution and complexity with dialkyl amines have also been reported. (Dethe, 2016) (Shultz, 2011) (Dethe, 2013) and WO2007/017289. In addition to the complications discussed in relation to (Maresh et al, 2014), (Fawzy, 2016), (Brown, 1952) and (Gray, 1959), the amination is further complicated by the need for the reaction to adopt a narrow pH range. The narrow pH range would improve nucleophilicity of the incoming amine while also preventing indole hydrolysis and competing aldol condensation or Mannich coupling at the alkyl aldehyde center. Real-time reaction analytics may facilitate process optimization to identify and maintain conditions, facilitating a challenging manufacturing step of proceeding from allylation under oxidative conditions to alkylation by reductive amination. Monitoring of the indoleacetaldehyde abundance may be through HPLC-MS, 1H-NMR or any suitable real-time analytical technique. Sampling of the reaction for real-time monitoring may be facilitated by automated sampling during the reaction.

    [0129] Oxidation of the indole ring is shown in steps 3 and 4 of FIG. 1. Direct oxidation is possible with classical Fenton chemistry, which is highly unselective giving mixed oxidation at positions 4, 5, 6 and 7 of the indole ring and poly hydroxylation (Julia, 1969). Without selective synthesis by intentionally targeting high production without selectivity, a simple reaction with high conversion but low chemical selectivity could be applied with selective crystallization in continuously stirred tank reactor (CSTR) and multistage continuous mixed-suspension, mixed-product removal (MSMPR) techniques could be applied to resolve the compounds. This approach allows foregoing selectivity by separating during different products using purification. This approach has further value as many different hydroxylated tryptamines may each be valuable themselves or as precursors to neurotransmitters (serotonin, melatonin, etc.).

    [0130] FIGS. 4 and 5 show borylation used to add CH functionalization by installing a pinacolato boron (BPin) group on the indole ring. A BPin group has the general formula B(OR).sub.2. An aryl boron or other suitable group may also be added. The BPin, aryl boron or other group is then oxidatively hydrolyzed to a hydroxyl group on the indole ring. In FIG. 4, this approach is applied to tryptophan (Step 4 in the series of Steps 4 to 6 shown in FIG. 1). In FIG. 5, this approach is applied to DMT (Step 3 in the series of Steps 1 to 3 shown in FIG. 1).

    [0131] The two steps of each of FIGS. 3 and 4 (i.e. first borylation or other functionalization, then oxidation) may be telescoped without isolation of any intermediates. When applied to DMT rather than tryptophan, the tertiary amine provides as a directing group to position 4 on the indole ring and greater regioselectivity in the borylation than with tryptophan. There is no previous report of functionalization on the indole ring that is fed directly to oxidation of the functionalized tryptophan, which is in turn fed directly to reductive amination of the indoleacetaldehyde, without isolation of intermediates. This telescoped sequence provides efficiencies. To carry out the needed switch from oxidative to reductive with effective coupling of the two reaction conditions requires close monitoring and control of reaction conditions. Monitoring of the indoleacetaldehyde abundance may be through HPLC-MS, 1H-NMR or any suitable real-time analytical technique. Sampling of the reaction for real-time monitoring may be facilitated by automated sampling during the reaction. Control of reaction conditions may be effected by increasing the pH of the solvent, by adding amines or both.

    [0132] FIGS. 3 and 4 may include application of a carbamate protecting group on the amino nitrogen, an example of which is provided in Example III (FIG. 9). With the correct protecting groups this approach may select for 4-substituted tryptamines as an abundant product. Chelation control may be responsible for this result as suggested by earlier work on other systems (Lv, 2019). Sequential reaction (borylation followed by hydrolysis) facilitates hydroxylation at C-4 of indole. There are currently no published reports of this approach reaction access compound relating to tryptamines.

    [0133] Applying chelation control to functionalize the indole CH at C-4 is reported with a route employing thallium (Somei, 1998) to synthesize psilocin. Thallium is highly toxic and cannot be used in GMP manufacture of active pharmaceutical ingredients.

    [0134] FIG. 6 shows decarboxylation, for example by benzaldehyde in MeOH at high temperature, which efficiently yields tryptamine, or any suitable method. The tryptamine may be alkylated using reductive amination or any suitable method. Tryptophan, tryptamine or alkylated tryptamines were separately treated with FeSO.sub.4 and hydrogen peroxide to oxidize the indole ring. By selecting tryptophan, tryptamine or alkylated tryptamine as precursors, a ring-substituted tryptophan analogue, a ring-substituted tryptamine or a ring-substituted alkylated tryptamine may be prepared, each of which presented as a mixture of mono and polyhydroxylated materials after 2 to 3 hours (as shown in a generalized sense in FIG. 8).

    [0135] Direct oxidation at the aromatic center by the approach shown in FIG. 6 is facilitated where hydrogen peroxide is added gradually over time. Single administration and syringe pump addition over 20 min were each evaluated. The overall reaction of indole starting materials was higher when adding hydrogen peroxide gradually. In some cases, a conversion of about 60 to 80% was observed by adding hydrogen peroxide over 20 minutes compared with about 10 to 15% conversion when adding the hydrogen peroxide in a single bolus. This is consistent with a significant degree of unproductive peroxide decomposing and is common to this class of Fenton chemistry.

    [0136] In some cases, shortly after addition of hydrogen peroxide, the 4-OH isomer was observed as the major regioisomer. After 20 to 30 minutes, both the 5- and 6-substituted products began to appear. At longer reaction times (2 to 3 hours) the desired 4-OH products began to be consumed to give polyhydroxylated byproducts. Of the three aromatic precursors, the N,N dialkylated tryptamine was found in the highest relative abundance, and the N,N dialkylated compound did not show any 5-, or 6 hydroxylated products at the time point assessed. This selectivity may indicate a favorable NFe interaction at play directing the reaction toward the proximal CH relative to the coordination site, in this case, the 4 position on the indole ring, using the numbering of tryptamine.

    [0137] Application of coordinate iron complexes, such as the White-Chen catalyst, effectively suppress polyhydroxylation. This early study proved that by identifying an appropriate ligand system for the iron center it should be possible to select for only monohydroxylated species. Preferential continuous crystallization could then be applied to separate the position 4, position 5 and position 6 aromatic isomers.

    [0138] FIG. 7 shows synthesis of multiple ring-substituted pyrrolidinyl tryptamines from pyrrolidinyl tryptamine. The ring oxidation may be undertaken by classical Fenton chemistry, which is highly unselective giving mixed directed oxidation at positions 4, 5 and 6, and also polyhydroxylation.

    [0139] FIG. 8 shows tryptamines that may be synthesized in accordance with the method of FIG. 7, and applied as Step 3 of FIG. 1. R.sub.4 and R.sub.5 may be each be methyl, and R.sub.6 may be H, showing conversion of tryptophan to psilocin. R.sub.4 and R.sub.5 may be any suitable alkyl group, including a cycloalkyl group or other ring structure. R.sub.6 may be any suitable functional group (e.g. OH, OR, NH.sub.2, NHR, NR.sub.2, NHCOR, R.sub.3N.sup.+, NO.sub.2, CN, N.sub.3, COR, CO.sub.2H, CO.sub.2R, CHO, RCHO, R, B(OR).sub.2, B(F.sub.3).sup., F, Cl, Br, I, At, PO.sub.4, PO.sub.2(OR).sub.2, SO.sub.2Cl, SH, SR, SO.sub.3F, SiH.sub.3, SiRH.sub.2, SiR.sub.2H, SiR.sub.3, etc. wherein R is selected from the group consisting of alkyl, acyl, vinyl, propargyl, phenyl, benzyl, or other suitable groups, and each separate R group may be identical to other R groups or distinct from other R groups). Where a hydroxyl group will be added to the indole ring, R.sub.6 is H, alkyl or another low-reactivity group to preserve reactivity on the indole ring rather than substitution at R.sub.6. From among the range of substitution sites on the indole ring, the 4-substituted tryptamine may be selectively separated and isolated through application of continuous crystallization, fractional crystallization or other suitable isolation techniques. Tryptamines substituted on other portions of the indole ring may also be selectively separated and isolated.

    [0140] FIG. 9 shows synthesis of a ring-substituted carbamate analogue of tryptophan. Methyl (ethoxycarbonyl)-L-tryptophanate is reacted with boron tribromide, then quenched with pyridine and pinacol to provide methyl (S)-2-((ethoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)propanoate. The method of FIG. 9 may be applied as step 3 in the method of FIG. 1, and is an example of directed oxidation being applied to synthesizing tryptamines.

    [0141] FIG. 10 shows tryptamines that may be synthesized in accordance with the method of FIG. 9, or step 3 of FIG. 1. Each of R.sub.1 to R.sub.3 may be H, each of R.sub.4 and R.sub.5 may be methyl, showing conversion of tryptamine to psilocin. Each of R.sub.1 to R.sub.3 and R.sub.6 may be any suitable functional group (e.g. OH, OR, NH.sub.2, NHR, NR.sub.2, NHCOR, R.sub.3N.sup.+, NO.sub.2, CN, N.sub.3, COR, CO.sub.2H, CO.sub.2R, CHO, RCHO, R, B(OR).sub.2, B(F.sub.3).sup., F, Cl, Br, I, At, PO.sub.4, PO.sub.2(OR).sub.2, SO.sub.2Cl, SH, SR, SO.sub.3F, SiH.sub.3, SiRH.sub.2, SiR.sub.2H, SiR.sub.3, etc. wherein R is selected from the group consisting of alkyl, acyl, vinyl, propargyl, phenyl, benzyl, or other suitable groups, and each separate R group may be identical to other R groups or distinct from other R groups). Each of R.sub.4 and R.sub.5 may be any suitable alkyl group, including a cycloalkyl group or other ring structure. Where a hydroxyl group will be added to the indole ring, R.sub.6 is H, alkyl or another low-reactivity group to preserve reactivity on the indole ring rather than substitution at R.sub.6.

    [0142] FIG. 11 shows synthesis of tryptamines from substituted indole by allylating the indole ring with an allyl group and substituting a protecting group to the 4-hydroxyl (step 1), oxidizing to an indoleacetaldehyde (step 2), then reductive amination to provide a tryptamine (step 3). Nucleophilic substitution may be effected by solvent molecules.

    [0143] The reaction scheme shown in FIG. 11 leverages synthetic manipulations on an appropriately protected hydroxy-indole core (e.g. acetylated, phosphorylated, silylated, halogenated, etc.). In this approach, aromatic manipulations would be carried out using 4-hydroxy indole as a starting point. While 4-hydroxy indole is a stable precursor, 4-hydroxy indole will preferentially react via nucleophilic aromatic substitution at the 2-position, opening up numerous synthetic pathways based on classical Friedel-Crafts acylation and alkylation chemistry, such as using oxalyl chloride.

    [0144] The reaction scheme shown in FIG. 11 eliminates the need to oxidizing or otherwise derivatizing the tryptophan indole ring or the tryptamine ring indole ring by starting with 4-hydroxindole. 4-hydroxindole is an inexpensive commodity chemical. Allylation of the substituted indole is followed by oxidative scission of the resulting alkene to provide an aldehyde and reductive amination of the aldehyde to provide an amine. The hydroxyl group at the 4-position of the resulting tryptamine may be substituted for another functional group (e.g. OH, OR, NH.sub.2, NHR, NR.sub.2, NHCOR, R.sub.3N.sup.+, NO.sub.2, CN, N.sub.3, COR, CO.sub.2H, CO.sub.2R, CHO, RCHO, R, B(OR).sub.2, B(F.sub.3).sup., F, Cl, Br, I, At, PO.sub.4, PO.sub.2(OR).sub.2, SO.sub.2Cl, SH, SR, SO.sub.3F, SiH.sub.3, SiRH.sub.2, SiR.sub.2H, SiR.sub.3, etc. wherein R is selected from the group consisting of alkyl, acyl, vinyl, propargyl, phenyl, benzyl, or other suitable groups, and each separate R group may be identical to other R groups or distinct from other R groups). Substituting hydroxyl for another functional group may be carried out using any suitable nucleophilic, electrophilic, oxidative, reductive or other substitution technique.

    [0145] The method of FIG. 11 may include direct formation of aldehyde, telescoped into the reductive amination to install the dimethylamine (combine step 2 and 3 in FIG. 11). Monitoring of the indoleacetaldehyde abundance may be through HPLC-MS, 1H-NMR or any suitable real-time analytical technique. Sampling of the reaction for real-time monitoring may be facilitated by automated sampling during the reaction. Reductive amination of 4-oxo-indoleacetaldehydes (step 3) has not been previously reported, whether telescoped or not.

    [0146] While the methods of FIGS. 1 to 10 also provide an aldehyde as an intermediate, the steps leading to the aldehyde in FIGS. 1 to 10 are different than those in the method shown in FIG. 11. The steps from the aldehyde to the amine are similar in both FIGS. 1 to 10 and in FIG. 11. In each case, there are different oxidants, and in each case timing matters to ensure that there is a large amount of aldehyde but without loss of indole to oxidative cleavage. This approach may also be applied to DMT or other tryptamines that have no substitution on the indole ring.

    [0147] The approach shown in FIG. 11 could be used for other alkylation patterns or other functional groups, similarly to the approach of FIGS. 1 to 10. FIG. 14 illustrates a variety of ring-substituted tryptamines that may be prepared using the method of FIG. 11.

    [0148] Allylation of a C-4 hydroxylated indole or similarly 4-substituted indole with functionality that can be readily reconverted to psilocin has not been previously demonstrated. The added electron density and possible steric occlusion near the C-3 position resulting from functionality at C-4 may drive allyl addition to favor the indole nitrogen over the nucleophilic, enamine-like center located at C-3. The method of FIG. 11 provides a highly regioselective allylation using a Tsuji-Trost like functionalization, which may result from a Pd-allyl cationic intermediate (Kimura, 2005).

    [0149] FIG. 12 is an example of the process shown in FIG. 11. Acetyl-indole may be reacted with allyl acetate with a palladium catalyst to provide 4-acetyl-2-allylindole or 5-acetyl-3-allylindole, using the numbering of tryptamine and counting from the indole nitrogen as position 1 as shown in FIG. 2.

    [0150] FIG. 13 shows 4-acetyl-2-allylindole reacted with salcomine (cobalt-salen) in the presence of peroxide, reducing the allyl group to an aldehyde 4-acetyl-2-ethal-indole (not shown). The aldehyde is combined with pyrrolidine and treated with sodium triacetoxyhydroborate to reductively aminate the aldehyde with pyrrolidine, resulting in the 4-acetylated analogue of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indole.

    [0151] Conversion of an indole with C-3 alkene to an aldehyde has been reported in (Brown, 1952) and (Chen, 2017), each of which include a two-step sequence. First, dihydroxylation using OsO.sub.4 or similar high valence transition state metal catalyst. This approach applies a metalperoxo-catalyzed transfer, which has been demonstrated on simple substrates in (Mi, 2015) and (Tamami, 2011). The method of FIG. 13 may be applied with real-time reaction progress profiling to control reaction conditions, target certain chemicals and minimize production of byproducts. Concentrations, temperature and the addition rate of the hydrogen peroxide may be precisely controlled. Precise control mitigates overoxidation of the aldehyde to subsequent carboxylic acid or derivatization of the indole ring.

    [0152] Analogous in some respects to the approach of FIGS. 1 to 5, the methods of FIGS. 11 to 13 include conversion of a terminal alkene to an amine by reductive amination of an intermediate aldehyde without any requirement for isolation and workup between a ring-substituted tryptophan analogue and a ring-substituted tryptamine. A telescoped sequence including oxidative functional group rearrangement followed by CN bond formation by reductive amination involves sequential application of two antagonistic and mutually exclusive reaction conditions. Managing the sequence to allow these reaction conditions in a telescoped sequence may be facilitated by real-time reaction sampling and monitoring to balance maximizing the amount of the intermediate aldehyde available for reductive amination with minimizing the extent of indole ring destruction from oxidative hydrolysis.

    [0153] Reactions similar to step 2 of FIG. 11 have not been previously demonstrated for compounds functionalized with oxygen, halide, other electron-rich substituents, or other substituents on the indole ring (e.g. OH, OR, NH.sub.2, NHR, NR.sub.2, NHCOR, R.sub.3N.sup.+, NO.sub.2, CN, N.sub.3, COR, CO.sub.2H, CO.sub.2R, CHO, RCHO, R, B(OR).sub.2, B(F.sub.3).sup., F, Cl, Br, I, At, PO.sub.4, PO.sub.2(OR).sub.2, SO.sub.2Cl, SH, SR, SO.sub.3F, SiH.sub.3, SiRH.sub.2, SiR.sub.2H, SiR.sub.3, etc. wherein R is selected from the group consisting of alkyl, acyl, vinyl, propargyl, phenyl, benzyl, or other suitable groups, and each separate R group may be identical to other R groups or distinct from other R groups).

    [0154] FIG. 14 shows tryptamines that may be synthesized in accordance with the method of FIGS. 12 and 13. R.sub.1 may be H, each of R.sub.2 to R.sub.4 may be H, each of R.sub.5 and R.sub.6 may be H and each of R.sub.7 and R.sub.8 may be methyl, showing conversion of 4-hydroxyindole to psilocin. R.sub.1 may be any acyl or silyl group. Each of R.sub.2 to R.sub.4 may be any suitable functional group (e.g. OH, OR, NH.sub.2, NHR, NR.sub.2, NHCOR, R.sub.3N.sup.+, NO.sub.2, CN, N.sub.3, COR, CO.sub.2H, CO.sub.2R, CHO, RCHO, R, B(OR).sub.2, B(F.sub.3).sup., F, Cl, Br, I, At, PO.sub.4, PO.sub.2(OR).sub.2, SO.sub.2Cl, SH, SR, SO.sub.3F, SiH.sub.3, SiRH.sub.2, SiR.sub.2H, SiR.sub.3, etc. wherein R is selected from the group consisting of alkyl, acyl, vinyl, propargyl, phenyl, benzyl, or other suitable groups, and each separate R group may be identical to other R groups or distinct from other R groups). Each of R.sub.5 and R.sub.6 may be H or any suitable alkyl. Each of R.sub.7 and R.sub.8 may be any suitable alkyl.

    [0155] FIG. 15 shows synthesis of 4-acetyl-2-allylindole and 4-acetyl-N-allylindole from 4-acetylindole.

    [0156] 4-hydroxyindole may be used as a starting point for synthesizing other 4-substituted indole compounds, such as acetylated or dibenzylphosphorylated indole compounds, as shown in FIGS. 16 and 17.

    [0157] FIG. 16 shows synthesis of 1H-indol-4-yl acetate from 4-hydroxyindole. Examples of this process are shown in Examples VII, XIII and IX.

    [0158] FIG. 17 shows synthesis of dibenzyl (1H-indol-4-yl) phosphate from 4-hydroxyindole. Dibenzyl (1H-indol-4-yl) phosphate has not been previously reported and may be a valuable precursor for other compounds, as illustrated by FIG. 19.

    [0159] Indole compounds, including 4-substituted indole compounds, such as 4-acetyl or 4-dibenzyl phosphate indole compounds, may be allylated through catalysis by palladium as shown in FIG. 12. Two examples are shown in FIGS. 18 and 19.

    [0160] FIG. 18 shows synthesis of 3-allyl-1H-indol-4-yl acetate from 4-acetylindole. 3-allyl-1H-indol-4-yl acetate may provide a reagent for synthesis of 4-substituted diols, tryptamines or other compounds. Example XI and Example XII provide illustrations of application of this method.

    [0161] FIG. 19 shows synthesis of 3-allyl-1H-indol-4-yl dibenzyl phosphate from dibenzyl (1H-indol-4-yl) phosphate. As exemplified by Example XIII, FIG. 19 shows a method that facilitates direct allylation on a pseudo halide, PO.sub.2(OR).sub.2.

    [0162] FIG. 20 shows synthesis of 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate from 3-allyl-1H-indol-4-yl acetate. 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate may provide a precursor that may facilitate synthesis of 4-substituted tryptamines, as exemplified in Examples XIV, XV and XVI.

    [0163] FIG. 21 shows synthesis of 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate from 1H-indol-4-yl acetate in a telescoped reaction without isolation of any intermediates. Allylation of 4-acetyl-indole and oxidation of the 3-allyl-1H-indol-4-yl acetate together without isolation of any intermediates may facilitate synthesis of 4-substituted tryptamines or provide compounds with therapeutic or other applications without reductive amination to a tryptamine. Application of the method of FIG. 21 is illustrated by Examples XVII, XVIII and XIX.

    [0164] FIG. 22 shows synthesis of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl acetate from 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate in a telescoped reaction without isolation of any intermediates. A weak reducing agent, NaBH(OAc).sub.3, is used to reduce the 3-allyl-1H-indol-4-yl acetate to 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl acetate rather than to 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol. Application of the method of FIG. 21 is illustrated by Examples XX, XXI and XXII.

    [0165] FIG. 23 shows synthesis of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol from 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate in a telescoped reaction without isolation of any intermediates. Heat is used to complete a three-step telescoped sequence beyond the 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-acetate generated in FIG. 22. FIG. 23, which is exemplified by Example XXIII, shows oxidizing an indole propyl diol to provide a ring-substituted indoleacetaldehyde, reductively aminating the ring-substituted indoleacetaldehyde to provide an acetylated tryptamine, and reducing the acetylated tryptamine to provide a hydroxylated tryptamine. The tryptamines may be alkylated on the terminal amine group with any suitable alkylation pattern. Alkylation patterns on the terminal amine may include methyl, ethyl, isopropyl, dimethylamine diethyl, diisopropyl, methylethyl, methylisopropyl and ethylisopropyl. Alkylation patterns on the terminal amine group may be cyclic tertiary amine groups, including an unconjugated pyrrolyl group with entirely sp3 orbital configuration on the alkyl amine. Other cyclic tertiary amines, whether conjugated or not, may also be applied to create cyclic tertiary amines (e.g. aromatic pyrrolyl, piperidinyl, pyridinyl, etc.)

    [0166] FIG. 24 shows synthesis of a mixture of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl acetate and 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol from 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate in a telescoped reaction without isolation of any intermediates. As with FIG. 26, a variety of alkylation patterns may be applied to the method of FIG. 24, which is exemplified by Example XXIV.

    [0167] FIG. 25 shows synthesis of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol from a mixture of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl acetate and 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol. A stronger reducing agent than NaBH(OAc).sub.3, NaBH.sub.4, is used to complete a three-step telescoped sequence without isolation of any intermediates (in contrast with application of heat in FIG. 23). As with FIG. 26, a variety of alkylation patterns may be applied to the method of FIG. 25, which is exemplified by Example XXV.

    [0168] FIG. 26 shows synthesis of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol from 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate in a telescoped reaction incorporating the reactions shown in both FIG. 24 and FIG. 25 without isolation of any intermediates. A stronger reducing agent than NaBH(OAc).sub.3, NaBH.sub.4, is used to complete a three-step telescoped sequence without isolation of any intermediates (in contrast with application of heat in FIG. 23). FIG. 26, which is exemplified by Example XXVI, shows oxidizing an indole propyl diol to provide a ring-substituted indoleacetaldehyde, reductively aminating the ring-substituted indoleacetaldehyde to provide an acetylated tryptamine, and reducing the acetylated tryptamine to provide a hydroxylated tryptamine. The tryptamines may be alkylated on the terminal amine group with any suitable alkylation pattern. Alkylation patterns on the terminal amine may include methyl, ethyl, isopropyl, dimethylamine diethyl, diisopropyl, methylethyl, methylisopropyl and ethylisopropyl. Alkylation patterns on the terminal amine group may be cyclic tertiary amine groups, including an unconjugated pyrrolyl group with entirely sp3 orbital configuration on the alkyl amine. Other cyclic tertiary amines, whether conjugated or not, may also be applied to create cyclic tertiary amines (e.g. aromatic pyrrolyl, piperidinyl, pyridinyl, etc.).

    [0169] FIG. 27 shows synthesis of 1H-indol-4-yl sulfurofluoridate from 4-hydroxyindole. Example XXVII illustrates conditions under which the SO.sub.3F group is substituted for the hydroxyl group at the 4-position of 4-hydroxyindole. 1,1,sulfonyldiimidazole was reacted with the 4-hydroxyindole to produce 1H-indol-4-yl sulfurofluoridate.

    [0170] FIG. 28 shows synthesis of 1-(fluorosulfonyl)-3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl sulfurofluoridate from 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol. Example XXVIII illustrates conditions under which regioselectivity for positions 1 and 4 by the SO.sub.3F group when added to 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol. 1,1,sulfonyldiimidazole was reacted with 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol.

    [0171] FIG. 29 shows synthesis of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl sulfurofluoridate from 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol. Example XXIX illustrates conditions under which regioselectivity for position 4 by the SO.sub.3F group is facilitated.

    [0172] FIG. 30 shows synthesis of dibenzyl (3-(2,3-dihydroxypropyl)-1H-indol-4-yl) phosphate from 3-allyl-1H-indol-4-yl dibenzyl phosphate. Example XXX illustrates oxidation of dibenzyl (3-(2,3-dihydroxypropyl)-1H-indol-4-yl) phosphate. Phosphate surrogate may also provide a direct route to psilocybin or other 4-substituted tryptamines.

    [0173] FIG. 31 shows synthesis of dibenzyl (3-(2,3-dihydroxypropyl)-1H-indol-4-yl) phosphate from dibenzyl (1H-indol-4-yl) phosphate in a telescoped reaction without isolation of any intermediates. FIG. 31 shows telescoped allylation and hydroxylation on a phosphate-substituted indole compound. Example XXXI illustrates compatibility of the methods disclosed herein with a variety of substrates to which the method may be telescoped to exclude workup or isolation of any intermediates. Oxidation of the dibenzyl (3-(2,3-dihydroxypropyl)-1H-indol-4-yl) and reductive amination of the resulting aldehyde may follow as illustrated elsewhere in this specification.

    Example 1

    [0174] The method shown in FIG. 3 was carried out. The reagents were mixed into a total volume of 427 mL, including 250 mL of water and 100 mL of methanol, with a reaction molarity of 11.7 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 1A and Table 1B. Details of the products are shown in Table 1C and Table 1D

    TABLE-US-00001 TABLE 1A Physical Properties of Reagents Reagent Formula MM (g/mol) L-tryptophan C.sub.11H.sub.12N.sub.2O.sub.2 204.23 pyrrolidine C.sub.4H.sub.9N 71.12 sodium triacetoxyhydroborate C.sub.6H.sub.10BNaO.sub.6 211.94 sodium hypochlorite NaClO 74.44 sodium phosphate, dibasic HNa.sub.2O.sub.4P 141.96

    TABLE-US-00002 TABLE 1B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes L-tryptophan 1.0 1.02 5.00 N/A pyrrolidine 2.3 2.04 11.50 2 mL vol 1 g/mL density 40% Wt sodium triacetoxyhydroborate 2.0 2.12 10.00 N/A sodium hypochlorite 1.5 0.558 7.50 0.1 molar 75.0 mL 1.206 g/mL sodium phosphate, dibasic 2.5 1.77 12.50 N/A

    TABLE-US-00003 TABLE 1C Physical Properties of Products Product Formula MM (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indole C.sub.14H.sub.18N.sub.2 214.31

    TABLE-US-00004 TABLE 1D Relative Amounts of Products Product Theoretical Actual Yield 3-(2-(pyrrolidin-1- 1.07 g (5 mmol) 0.111 g (0.521 mmol) 10.4% yl)ethyl)-1H-indole

    [0175] L-tryptophan (1.02 g, 1 Eq, 5.00 mmol) was dissolved in water (250 mL) containing sodium phosphate, dibasic (1.77 g, 2.5 Eq, 12.5 mmol) (pH adjusted to 7 using a 5M solution of hydrochloric acid/sodium hydroxide as needed). This sample was stirred vigorously and treated with a solution of sodium hypochlorite (558 mg, 75.0 mL, 0.1 molar, 1.5 Eq, 7.50 mmol), and the rate of sodium hypochlorite addition was below 1 mmol sodium hypochlorite per min. The rate of addition may be adjusted based on reaction component analysis by real-time HPLC-MS. The sample was allowed to stir for 2 hours at 25 C. and then excess sodium hypochlorite was destroyed by addition of sodium ascorbate in water.

    [0176] Without isolation, the solution was diluted by MeOH (100 mL) and pyrrolidine (2.04 g, 2 mL, 2.3 Eq, 11.5 mmol) was added as a solution in water. The mixture was then treated with sodium triacetoxyhydroborate (2.12 g, 2 Eq, 10.0 mmol)added in four equal portions of solid. The mixture was stirred overnight to allow the reaction to complete.

    [0177] The pH of the solution was adjusted to 7.5 using sodium carbonate. The solution was then extracted into dichloromethane (450 mL), washed with brine (225 mL), dried over MgSO.sub.4, and the solvent removed under reduced pressure.

    [0178] The product, shown as VI in FIG. 3, was 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indole, with a molecular formula of C.sub.14H.sub.18N.sub.2, a molecular weight of 214.31 g/mol and an empirical mass of 214.14700 g/mol. At 100% yield, this would provide a theoretical mass of 1.07 g (5.00 mmol) of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indole. The actual yield of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indole was 153 mg (714 mol), which is a yield of 14.3%.

    Example II

    [0179] The method shown in FIG. 7 was carried out. The reagents and products included a total volume of 420 mL, including 200 mL of water, with a reaction molarity of 26 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 2A and Table 2B. Details of the products are shown in Table 2C and Table 2D.

    TABLE-US-00005 TABLE 2A Physical Properties of Reagents Reagent Formula MM (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)-1H- C.sub.14H.sub.18N.sub.2 214.31 indole EDTA disodium salt dihydrate C.sub.10H.sub.18N.sub.2Na.sub.2O.sub.10 372.24 urea hydrogen peroxide C.sub.6N.sub.2O.sub.3 94.07 ascorbic acid C.sub.6H.sub.8O.sub.6 176.12 iron(II) sulfate heptahydrate FeH.sub.14O.sub.11S 278.01

    TABLE-US-00006 TABLE 2B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 3-(2-(pyrrolidin-1-yl)ethyl)-1H- 1 2.4 11 N/A indole EDTA disodium salt dihydrate 1 4.1 11 N/A urea hydrogen peroxide 1 1.0 11 0.05 molar 0.22 L ascorbic acid 2 3.9 22 N/A iron(II) sulfate heptahydrate 0.05 0.15 0.55 N/A

    TABLE-US-00007 TABLE 2C Physical Properties of Products Product Formula MM (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)-1H- C.sub.14H.sub.18N.sub.2O 230.31 indol-4-ol 3-(2-(pyrrolidin-1-yl)ethyl)-1H- C.sub.14H.sub.18N.sub.2O 230.31 indol-5-ol 3-(2-(pyrrolidin-1-yl)ethyl)-1H- C.sub.14H.sub.18N.sub.2O.sub.2 246.31 indole-5,6-diol 3-(2-(pyrrolidin-1-yl)ethyl)-1H- C.sub.14H.sub.18N.sub.2O.sub.2 246.31 indole-4,5-diol

    TABLE-US-00008 TABLE 2D Relative Amounts of Products Product Theoretical Actual Yield 3-(2-(pyrrolidin-1-yl)ethyl)- 2.5 g (11 mmol) 0.11 g 4.3% 1H-indol-4-ol (0.48 mmol) 3-(2-(pyrrolidin-1-yl)ethyl)- 2.5 g (11 mmol) 0.19 g 7.5% 1H-indol-5-ol (0.82 mmol) 3-(2-(pyrrolidin-1-yl)ethyl)- 2.7 g (11 mmol) 0.05 g 2.0% 1H-indole-5,6-diol (0.20 mmol) 3-(2-(pyrrolidin-1-yl)ethyl)- 2.5 g (11 mmol) 0.07 g 3.0% 1H-indole-4,5-diol (0.30 mmol)

    [0180] 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indole (2.4 g, 1 Eq, 11 mmol) was suspended in water (200 mL) with ethylenediaminetetraacetic acid (EDTA) disodium salt dihydrate (4.1 g, 1 Eq, 11 mmol) and the pH was adjusted to above 9. iron(II) sulfate heptahydrate (0.15 g, 0.05 Eq, 0.55 mmol) and ascorbic acid (3.9 g, 2 Eq, 22 mmol) were then charged followed by dropwise addition of a solution of urea hydrogen peroxide (1.0 g, 0.22 L, 0.05 molar, 1 Eq, 11 mmol) in water over 1 hour.

    [0181] A mixture of regioisomers was formed. The crude solid was taken up in ethanol/water to produce a crude mixture of crystals including primarily 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol (0.11 g, 0.48 mmol, 4.3%) and 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indole-5-ol (0.19 g, 0.82 mmol, 7.5%). Testing shows results indicative that fractional crystallization may facilitate separation and isolation of the different regioisomers.

    Example III

    [0182] The method shown in FIG. 9 was carried out. The reagents were mixed into a total volume of 5 mL, including 5 mL of dichloromethane, with a reaction molarity of 200 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 3A and Table 3B.

    TABLE-US-00009 TABLE 3A Physical Properties of Reagents Reagent Formula MM (g/mol) methyl (ethoxycarbonyl)- C.sub.15H.sub.18N.sub.2O.sub.4 290.32 L-tryptophanate pyridine C.sub.5H.sub.5N 79.10 pinacol C.sub.6H.sub.14O.sub.2 118.18 boron tribromide BBr.sub.3 250.52

    TABLE-US-00010 TABLE 3B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes methyl (ethoxycarbonyl)-L- 1 0.3 1 N/A tryptophanate dichloromethane N/A N/A N/A 5 mL pyridine 1.5 0.1 2 0.1 mL 0.978 g/mL pinacol 1.5 0.2 2 N/A boron tribromide 1.1 0.3 1 0.1 mL 2.650 g/mL

    TABLE-US-00011 TABLE 3C Physical Properties of Products Product Formula MM (g/mol) methyl (S)-2-((methoxycarbonyl)amino)-3- C.sub.20H.sub.27BN.sub.2O.sub.6 402.25 (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-indol-3-yl)propanoate

    TABLE-US-00012 TABLE 3D Relative Amounts of Products Product Theoretical Actual Yield methyl (S)-2-((methoxycarbonyl)- 0.402 g 0.09 g 22.3% amino)-3-(4-(4,4,5,5-tetramethyl- (1 mmol) (0.223 mmol) 1,3,2-dioxaborolan-2-yl)-1H-indol- 3-yl)propanoate

    [0183] Methyl (ethoxycarbonyl)-L-tryptophanate (0.3 g, 1 Eq, 1 mmol) was dissolved in dry degassed dichloromethane (5 mL) under argon gas. Boron tribromide (0.3 g, 0.1 mL, 1.1 Eq, 1 mmol) was added in one charge and left to stir for 9 hours at 25 C.

    [0184] The reaction was quenched by charging pyridine (0.1 g, 0.1 mL, 1.5 Eq, 2 mmol) and pinacol (0.2 g, 1.5 Eq, 2 mmol).

    [0185] The product, shown as V in FIG. 9, was methyl (S)-2-((ethoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)propanoate, with a molecular formula of C.sub.21H.sub.29BN.sub.2O.sub.6, a molecular weight of 416.28 g/mol and an empirical mass of 416.21187 g/mol. At 100% yield, this would provide a theoretical mass of 0.4 g (1.00 mmol) of methyl (S)-2-((ethoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)propanoate. The actual yield of methyl (S)-2-((ethoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)propanoate was 0.09 g (0.3 mmol), which is a yield of 20.0%.

    Example IV

    [0186] The method shown in FIG. 12 was carried out. The reagents were mixed into a total volume of 10 mL tetrahydrofuran, with a reaction molarity of 100 mmolar at a temperature of 45 C. Details of the reagents are shown in Table 4A and Table 4B.

    TABLE-US-00013 TABLE 4A Physical Properties of Reagents Reagent Formula MM (g/mol) 1H-indol-4-yl acetate C.sub.10H.sub.9NO.sub.2 175.19 allyl acetate C.sub.5H.sub.8O.sub.2 100.12 tetrakis(triphenylphosphine) C.sub.72H.sub.60P.sub.4Pd 1155.59 palladium

    TABLE-US-00014 TABLE 4B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 1H-indol-4-yl acetate 1 0.2 1 N/A allyl acetate 1 0.1 1 N/A tetrakis(triphenylphosphine) 0.01 0.01 0.01 N/A palladium

    TABLE-US-00015 TABLE 4C Physical Properties of Products Product Formula MM (g/mol) 3-allyl-1H-indol-4-yl acetate C.sub.13H.sub.13NO.sub.2 215.25

    TABLE-US-00016 TABLE 4D Relative Amounts of Products Product Theoretical Actual Yield 3-allyl-1H-indol-4-yl acetate 0.01 g 0.002 g 22% (0.05 mmol) (0.01 mmol)

    [0187] 1H-indol-4-yl acetate (0.2 g, 1 Eq, 1 mmol) is dissolved in dry THF (10 mL) and treated sequentially with allyl acetate (0.1 g, 1 Eq, 1 mmol) and Pd(PPh.sub.3).sub.4 (0.01 g, 0.01 Eq, 0.01 mmol). The sample is sealed and heated under N.sub.2 for 2 hrs.

    [0188] The resulting crude mixture was purified by column chromatography. The product, shown in FIG. 12, was 3-allyl-1H-indol-4-yl acetate, with a molecular formula of C.sub.13H.sub.13NO.sub.2, a molecular weight of 215.25 g/mol and an empirical mass of 215.09463 g/mol. At 100% yield, this would provide a theoretical mass of 0.2 g (1.00 mmol) of 3-allyl-1H-indol-4-yl acetate. The actual yield of 3-ally-1H-indol-4-yl acetate was 0.18 g (0.84 mmol), which is a yield of 80.0%.

    Example V

    [0189] The method shown in FIG. 13 was carried out as a sequential telescoped reaction without isolation of intermediates. The reagents were mixed into a total volume of 10 mL, including 10 mL of tert-butanol, with a reaction molarity of 5 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 5A and Table B.

    TABLE-US-00017 TABLE 5A Physical Properties of Reagents Reagent Formula MM (g/mol) pyrrolidine C.sub.4H.sub.9N 71.12 3-allyl-1H-indol-4-yl acetate C.sub.13H.sub.13NO.sub.2 215.25 tert-butanol C.sub.4H10O 74.12 Co-salen C.sub.16H.sub.14CoN.sub.2O.sub.2 325.23 sodium triacetoxyhydroborate C.sub.6H.sub.10BNaO.sub.6 211.94 hydrogen peroxide H.sub.2O.sub.2 34.01

    TABLE-US-00018 TABLE 5B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes pyrrolidine 2 0.007 0.10 9 L 0.75 g/mL 3-allyl-1H-indol-4-yl 1 0.010 0.05 N/A acetate tert-butanol N/A N/A N/A 10 mL Co-salen 0.01 0.0002 0.0005 N/A sodium 3 0.030 0.20 N/A triacetoxyhydroborate hydrogen peroxide 2 0.010 0.10 Volume 0.01 mL Density 1.110 g/mL 25% Wt in water

    TABLE-US-00019 TABLE 5C Physical Properties of Products Product Formula MM (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)-1H- C.sub.16H.sub.20N.sub.2O.sub.2 272.35 indol-4-yl acetate

    TABLE-US-00020 TABLE 5D Relative Amounts of Products Product Theoretical Actual Yield 3-(2-(pyrrolidin-1-yl)ethyl)- 0.01 g (0.05 0.002 g (0.01 20% 1H-indol-4-yl acetate mmol) mmol)

    [0190] 3-allyl-1H-indol-4-yl acetate (0.01 g, 1 Eq, 0.05 mmol) was dissolved in tert-butanol (10 mL) and then treated with Co-salen (0.2 mg, 0.01 Eq, 0.5 mol). The mixture was then treated via dropwise addition of hydrogen peroxide (0.01 g, 0.01 mL, 25% Wt, 2 Eq, 0.1 mmol) over 1 hr. After the reaction was completed the solution was treated with sodium sulphite and then pyrrolidine (7 mg, 9 L, 2 Eq, 0.1 mmol) was added as a solution in water. The pH was adjusted to 8-9 using sodium carbonate. The reaction was then treated with sodium triacetoxyhydroborate (0.03 g, 3 Eq, 0.2 mmol) and allowed to react for thirty minutes. The crude mixture was evaporated to dryness and then immediately purified by column chromatography (DCM:MeOH) to give 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl acetate 0.002 g (0.01 mmol, 20.0% yield)

    Example VI

    [0191] The method shown in FIG. 15 was carried out. The reagents and products included a total volume of 21 mL, including 20 mL of toluene, with a reaction molarity of 220 mmolar at a temperature of 45 C. Details of the reagents are shown in Table 6A and Table 6B. Details of the products are shown in Table 6C and Table 6D.

    TABLE-US-00021 TABLE 6A Physical Properties of Reagents Reagent Formula MM (g/mol) 1H-indol-4-yl acetate C.sub.10H.sub.9NO.sub.2 175.19 3-bromoprop-1-ene C.sub.3H.sub.5Br 120.98 copper (II) acetate C.sub.4H.sub.6CuO.sub.4 181.63 1,8-diazabicyclo[5.4.0]undec-7-ene C.sub.9H.sub.16N.sub.2 152.24

    TABLE-US-00022 TABLE 6B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 1H-indol-4-yl acetate 1 0.79 4.5 N/A 3-bromoprop-1-ene 1 0.54 4.5 N/A copper (II) acetate 1 0.82 4.5 N/A 1,8-diazabicyclo[5.4.0]undec-7- 1 0.69 4.5 Volume ene 0.68 mL Density 1.010 g/mL

    TABLE-US-00023 TABLE 6C Physical Properties of Products Product Formula MM (g/mol) 3-allyl-1H-indol-4-yl acetate C.sub.13H.sub.13NO.sub.2 215.25 1-allyl-1H-indol-4-yl acetate C.sub.13H.sub.13NO.sub.2 215.25

    TABLE-US-00024 TABLE 6D Relative Amounts of Products Product Theoretical Actual Yield 3-allyl-1H-indol-4-yl 0.97 g (4.5 mmol) 0.21 g (0.98 mmol) 22% acetate 1-allyl-1H-indol-4-yl 0.97 g (4.5 mmol) 0.05 g (0.20 mmol) 5% acetate

    [0192] A solution of 1H-indol-4-yl acetate (0.79 g, 1 Eq, 4.5 mmol) dissolved in toluene (20 mL) and treated with 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (0.69 g, 0.68 mL, 1 Eq, 4.5 mmol) and copper (II) acetate (0.82 g, 1 Eq, 4.5 mmol). The sample was heated to 45 C. for 25 min, then 3-bromoprop-1-ene (0.54 g, 1 Eq, 4.5 mmol) was added dropwise over 1 hour. The reaction was left to stand for an additional 2 hours then cooled and quenched with saturated ammonium chloride solution.

    [0193] This reaction produces a mixture of products including 3-allyl-1H-indol-4-yl acetate (0.21 g, 22%) from allylation of the indole ring at a carbon on the indole ring and 1-allyl-1H-indol-4-yl acetate (0.21 g, 5%) from allylation of the indole ring at the nitrogen on the indole ring.

    Example VII

    [0194] The method shown in FIG. 16 was carried out. The reagents and products included a total volume of 183.4 mL, including 130 mL of dichloromethane, with a reaction molarity of 410 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 7A and Table 7B. Details of the products are shown in Table 7C and Table 7D.

    TABLE-US-00025 TABLE 7A Physical Properties of Reagents Reagent Formula MM (g/mol) 4-hydroxyindole C.sub.8H.sub.7NO 133.15 acetic anhydride C.sub.4H.sub.6O.sub.3 102.1 pyridine C.sub.5H.sub.5N 79.1

    TABLE-US-00026 TABLE 7B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 4-hydroxyindole 1 10 75.1 N/A dichloromethane N/A N/A N/A 130 mL acetic anhydride 4 30.67 300 Density of 1.08 Volume of 28.4 mL pyridine 4.1 24.36 307 Density of 0.98 Volume of 25 mL

    TABLE-US-00027 TABLE 7C Physical Properties of Products MM Product Formula (g/mol) 1H-indol-4-yl acetate C.sub.10H.sub.9NO.sub.2 175.19

    TABLE-US-00028 TABLE 7D Relative Amounts of Products Product Theoretical Actual Yield 1H-indol-4-yl acetate 13.16 8.6 65%

    [0195] 4-hydroxyindole (10.00 g, 1 Eq, 75.10 mmol) and dichloromethane (130 mL) were combined in a round-bottom flask. Acetic anhydride (30.67 g, 28.4 mL, 4 eq, 300.4 mmol) was added in one portion. Pyridine (24.36 g, 25 mL, 4.1 eq, 307.9 mmol) was added in one portion. The reaction mixture was stirred for 16 hours and then the reaction was concentrated in vacuo.

    [0196] The crude material was diluted with 650 ml toluene and extracted with brine (5250 ml). The organic phase was dried over anhydrous sodium sulfate and filtered through a pad of Celite diatomaceous earth.

    [0197] The resulting crude 1H-indol-4-yl acetate (8.6 g, 49.1 mmol, 65%) was recrystallized in toluene (100 mL) as a light brown solid.

    [0198] The product 1H-indol-4-yl acetate was characterized by 1H NMR (400 MHz, chloroform-D). The observed peaks on 1H NMR were 2.43 (s, 4H) 6.38-6.45 (m, 1H) 6.89 (dd, =4.44, 3.76 Hz, 1H) 7.02 (dd, =3.24, 2.56 Hz, 1H) 7.14-7.17 (m, 2H) 8.33 (br. s., 1H).

    [0199] A powder x-ray diffraction (XRD) pattern was obtained for 1H-indol-4-yl acetate crystals grown from toluene. The XRD pattern is shown in Graph 7E. [0200] Graph 7E: XRD of 1H-indol-4-yl acetate crystals grown from toluene

    Example VIII

    [0201] The method shown in FIG. 16 was carried out. The reagents and products included a total volume of 307 mL, including 200 mL of toluene, with a reaction molarity of 490 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 8A and Table 8B. Details of the products are shown in Table 8C and Table 8D.

    TABLE-US-00029 TABLE 8A Physical Properties of Reagents Reagent Formula MM (g/mol) 4-hydroxyindole C.sub.8H.sub.7NO 133.15 acetic anhydride C.sub.4H.sub.6O.sub.3 102.1 pyridine C.sub.5H.sub.5N 79.1

    TABLE-US-00030 TABLE 8B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 4-hydroxyindole 1 10 75.1 N/A Toluene N/A N/A N/A 200 mL acetic anhydride 4 61.3 601 Density of 1.08 g/mL Volume of 56.8 mL pyridine 4.1 48.8 616 Density of 0.98 Volume of 50 mL

    TABLE-US-00031 TABLE 8C Physical Properties of Products Product Formula MM (g/mol) 1H-indol-4-yl acetate C.sub.10H.sub.9NO.sub.2 175.19

    TABLE-US-00032 TABLE 8D Relative Amounts of Products Product Theoretical Actual Yield 1H-indol-4-yl acetate 26.3 19.1 72.6%

    [0202] 4-hydroxyindole (20.00 g, 1 Eq, 150.2 mmol) and toluene (200 mL) were combined in a round-bottom flask. Acetic anhydride (61.3 g, 56.8 mL, 4 eq, 600.8 mmol) was added in one portion. Pyridine (48.8 g, 50 mL, 4.1 eq, 616 mmol) was added in one portion. The reaction mixture was stirred for 1 hour and then the reaction was quenched with an aqueous solution of hydrochloric acid (0.5M, 200 mL). NOTE: The quench is slightly exothermic.

    [0203] The resultant reaction mixture was allowed to cool to room temperature.

    [0204] The aqueous solution was removed and the organic solution was washed with additional aqueous solution of hydrochloric acid (0.5M, 2200 mL), saturated solution of sodium bicarbonate (1200 mL) and brine (1200 mL). The organic layer was concentrated under reduced pressure to dryness.

    [0205] The crude material was dissolved in hot toluene (150 mL) and precipitated with n-hexanes (300 mL) to afford the product, 1H-indol-4-yl acetate (19.1 g, 109 mmol, 72.6%) as a light gray powder.

    [0206] The product was characterized by 1H NMR (400 MHz, chloroform-D). The observed peaks on 1H NMR were 2.43 (s, 4H) 6.38-6.45 (m, 1H) 6.89 (dd, =4.44, 3.76 Hz, 1H) 7.02 (dd, =3.24, 2.56 Hz, 1H) 7.14-7.17 (m, 2H) 8.33 (br. s., 1H).

    Example IX

    [0207] The method shown in FIG. 16 was carried out. The reagents and products included a total volume of 307 mL, including 200 mL of toluene, with a reaction molarity of 490 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 9A and Table 9B. Details of the products are shown in Table 9C and Table 9D.

    TABLE-US-00033 TABLE 9A Physical Properties of Reagents Reagent Formula MM (g/mol) 4-hydroxyindole C.sub.8H.sub.7NO 133.15 acetic anhydride C.sub.4H.sub.6O.sub.3 102.1 pyridine C.sub.5H.sub.5N 79.1

    TABLE-US-00034 TABLE 9B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 4-hydroxyindole 1 20 150 N/A Toluene N/A N/A N/A 200 mL acetic anhydride 4 61.3 601 Density of 1.08 g/mL Volume of 56.8 mL pyridine 4.1 48.8 616 Density of 0.98 Volume of 50 mL

    TABLE-US-00035 TABLE 9C Physical Properties of Products Product Formula MM (g/mol) 1H-indol-4-yl acetate C.sub.10H.sub.9NO.sub.2 175.19

    TABLE-US-00036 TABLE 9D Relative Amounts of Products Product Theoretical Actual Yield 1H-indol-4-yl acetate 26.3 18.09 69%

    [0208] 4-hydroxyindole (20.00 g, 1 Eq, 150.2 mmol) and toluene (200 mL) were combined in a round-bottom flask. Acetic anhydride (61.3 g, 56.8 mL, 4 eq, 600.8 mmol) was added in one portion. Pyridine (48.8 g, 50 mL, 4.1 eq, 616 mmol) was added in one portion. The reaction mixture was stirred for 1 hour and then the reaction was quenched with an aqueous solution of hydrochloric acid (0.5M, 200 mL).

    [0209] The resultant reaction mixture was allowed to cool to room temperature.

    [0210] The aqueous solution was removed and the organic solution was washed with an aqueous solution of hydrochloric acid (0.5M, 2200 mL), saturated solution of sodium bicarbonate (1200 mL) and brine (1200 mL)

    [0211] The organic solution was concentrated under reduced pressure to dryness.

    [0212] The crude material was purified by crystallization in hot toluene (60 mL at 60 C.). A second crop of crystals was obtained by concentrating the filtrate from the first crystallization. The product, 1H-indol-4-yl acetate (18.09 g, 103.2 mmol, 69%) was isolated as a light gray powder.

    [0213] The product was characterized by 1H NMR (400 MHz, chloroform-D). The observed peaks on 1H NMR were 2.43 (s, 4H) 6.38-6.45 (m, 1H) 6.89 (dd, =4.44, 3.76 Hz, 1H) 7.02 (dd, =3.24, 2.56 Hz, 1H) 7.14-7.17 (m, 2H) 8.33 (br. s., 1H).

    Example X

    [0214] The method shown in FIG. 17 was carried out. The reagents and products included a total volume of 360 mL, including 300 mL of acetonitrile, with a reaction molarity of 209 mmolar at room temperature. Details of the reagents are shown in Table 10A and Table 10B. Details of the products are shown in Table 10C and Table 10D.

    TABLE-US-00037 TABLE 10A Physical Properties of Reagents Reagent Formula MM (g/mol) 1H-indol-4-ol C.sub.8H.sub.7NO 133.15 potassium t-butoxide C.sub.4H.sub.9KO 64.06 tetrabenzyl diphosphate C.sub.28H.sub.28O.sub.7P.sub.2 538.47

    TABLE-US-00038 TABLE 10B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 1H-indol-4-ol 1.0 10.0 75.10 N/A acetonitrile N/A N/A N/A 300 mL potassium tert-butoxide 1.0 N/A 60.08 60.08 mL 1.0 M in tetrahydrofuran tetrabenzyl diphosphate 1.05 42.46 78.86 N/A

    TABLE-US-00039 TABLE 10C Physical Properties of Products Product Formula MM (g/mol) dibenzyl (1H-indol-4-yl) phosphate C.sub.22H.sub.20NO.sub.4P 393.38

    TABLE-US-00040 TABLE 10D Relative Amounts of Products Product Theoretical Actual Yield dibenzyl (1H-indol-4-yl) phosphate 29.54 g 15.44 g 52.26%

    [0215] 300 mL of acetonitrile was added to a 500 mL flask and 1H-indol-4-ol (10 g, 1 Eq, 75.00 mmol) and dibenzyl (1H-indol-4-yl) phosphate (42.46 9, 1.05 Eq, 78.86 mmol) were added to the flask. A solution of potassium tert-butoxide (1.0 M in THF, 60.08 mL, 0.8 Eq, 60.08 mmol) was added dropwise over a period of 100 min. The reaction mixture formed a crystalline solid which was filtered off and discarded. The remaining supernatant was concentrated under vacuum before being reconstituted in toluene and extracted with an aqueous solution of sodium hydroxide (1 M, 3300 mL) and brine (2300 mL). The combined organic phases were dried with anhydrous sodium sulfate, applied to a pad of silica gel and Celite diatomaceous earth, eluting with 1:1 hexanes:ethyl acetate. and then concentrated under vacuum. The solvent eluent was concentrated to dryness to yield a crude crystalline solid, which was purified by trituration using methyl tert-butyl ether. Filtration of this slurry gave dibenzyl (1H-indol-4-yl) phosphate (15.44 g, 39.25 mmol, 52.26%) as a white solid.

    [0216] The product was characterized by 1H NMR (400 MHz, chloroform-D). The observed peaks on 1H NMR were 8.85 (s, 1H), 7.36 (s, 10H), 7.21 (d, J=7.5 Hz, 1H), 7.14-7.02 (m, 3H), 6.64 (t, J=2.5 Hz, 1H), 5.21 (dt, J=8.2, 5.0 Hz, 4H).

    [0217] An XRD pattern was obtained for dibenzyl (1H-indol-4-yl) phosphate crystals grown from 3:2 toluene:heptane. The XRD pattern is shown in Graph 10E. [0218] Graph 10E: XRD of dibenzyl (1H-indol-4-yl) phosphate crystals grown from 3:2 toluene:heptane

    Example XI

    [0219] The method shown in FIG. 18 was carried out. The reagents and products included a total volume of 150 mL, including 150 mL of THF, with a reaction molarity of 30 mmolar at a temperature of 50 C. Details of the reagents are shown in Table 11A and Table 11B. Details of the products are shown in Table 11C and Table 11D.

    TABLE-US-00041 TABLE 11A Physical Properties of Reagents Reagent Formula MM (g/mol) 4-acetyl-indole C.sub.10H.sub.9NO.sub.2 175.2 allyl alcohol C.sub.3H.sub.6O 58.1 triethyl borane C.sub.6H.sub.15B 98.0 tetrakis(triphenylphosphine)palladium C.sub.27H.sub.60P.sub.4Pd 1155.6

    TABLE-US-00042 TABLE 11B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 4-acetyl-indole 1 5.26 30 N/A tetrahydrofuran N/A N/A N/A 150 mL allyl alcohol 1.5 N/A 45 Density 0.854 g/mL Volume 3.06 mL triethyl borane 0.5 15 mL 15 1.0M in THF Volume 15.0 mL tetrakis- 0.016 563 mg 0.487 N/A (triphenylphosphine)palladium

    TABLE-US-00043 TABLE 11C Physical Properties of Products Product Formula MM (g/mol) 3-allyl-1H-indol-4-yl acetate C.sub.13H.sub.13NO.sub.2 215.09

    TABLE-US-00044 TABLE 11D Relative Amounts of Products Product Theoretical Actual Yield 3-allyl-1H-indol-4-yl acetate 6.4 5.2 81%

    [0220] 150 mL of THE was added to a 250 mL round-bottom flask and sparged with argon. While sparging, 1H-indol-4-yl acetate (5.256 g, 1 Eq, 30.00 mmol) and allyl alcohol (3.06 mL, 1.5 Eq, 45.00 mmol) were added to the flask. Sparging with argon was continued for 30 minutes. After sparging, triethylborane (1.0 M in hexanes, 15.00 mL, 0.5 Eq, 15.00 mmol) and tetrakis (triphenylphosphine) palladium (563.2 mg, 0.0162 Eq, 487.4 mol) were sequentially added to the reaction.

    [0221] The reaction was heated at 50 C. and stirred for 4 hours under an argon atmosphere. Upon completion, charcoal (30 Wt %, 1.58 g) was added to the reaction mixture and the resultant mixture was filtered through a pad of Celite diatomaceous earth using hexanes (100 mL) as eluent. The crude material was purified by flash chromatography using hexanes:ethyl acetate (85:15) as eluent.

    [0222] Fractions containing the desired product were collected and concentrated in vacuo to afford 3-allyl-1H-indol-4-yl acetate (5.2 g, 24 mmol, 81%) as a light-yellow oil.

    [0223] The product was characterized by 1H NMR (300 MHz, chloroform-D). The observed peaks on 1H NMR were 3.64 (dq, J=6.40, 1.28 Hz, 2H) 4.98-5.10 (m, 2H) 5.12 (d, J=2.30 Hz, 2H) 5.15 (d, J=2.05 Hz, 2H) 6.08 (ddt, J=16.93, 10.21, 6.53, 6.53 Hz, 1H) 6.85-6.90 (m, 1H) 7.02-7.08 (m, 2H) 7.11-7.16 (m, 1H) 7.30 (s, 10H) 8.12 (br. s., 1H).

    Example XII

    [0224] The method shown in FIG. 18 was carried out. The reagents and products included a total volume of 338 mL, including 300 mL of 2-methyltetrahydrofuran, with a reaction molarity of 295 mmolar at a temperature of 60 C. Details of the reagents are shown in Table 12A and Table 12B. Details of the products are shown in Table 12C and Table 12D.

    TABLE-US-00045 TABLE 12A Physical Properties of Reagents Reagent Formula MM (g/mol) 4-acetyl-indole C.sub.10H.sub.9NO.sub.2 175.2 allyl alcohol C.sub.3H.sub.6O 58.1 triethyl borane C.sub.6H.sub.15B 98.0 tetra(triphenylphosphine)palladium C.sub.27H.sub.60P.sub.4Pd 1155.6

    TABLE-US-00046 TABLE 12B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 4-acetyl-indole 1 17.5 99.9 N/A 2-methyltetrahydrofuran N/A N/A N/A 300 mL allyl alcohol 1.5 N/A 120 Density 0.854 g/mL Volume 8.15 mL triethyl borane 0.3 N/A 30.0 1.0M in 2-MeTHF Volume 30.0 mL tetra(triphenylphosphine)- 0.03 3.46 g 3.00 N/A palladium

    TABLE-US-00047 TABLE 12C Physical Properties of Products Product Formula MM (g/mol) 3-allyl-1H-indol-4-yl acetate C.sub.13H.sub.13NO.sub.2 215.09

    TABLE-US-00048 Relative Amounts of Products Product Theoretical Actual Yield 3-allyl-1H-indol-4-yl acetate 6.4 N/A N/A

    [0225] 300 mL of tetrahydrofuran was added to a 500 mL round-bottom flask and sparged with argon. While sparging, 1H-indol-4-yl acetate (17.5 g, 1 Eq, 99.9 mmol) and allyl alcohol (8.15 mL, 1.5 Eq, 120 mmol) were added to the flask. Sparging with argon was continued for 30 minutes. After sparging, triethylborane (1.0 M in tetrahydrofuran, 30.0 mL, 0.3 Eq, 30.0 mmol) and tetrakis (triphenylphosphine)palladium (3.46 g, 0.03 Eq, 3.00 mmol) were sequentially added to the reaction.

    [0226] The reaction was heated at 60 C. and stirred for 2 hours under an argon atmosphere. Upon completion, the crude reaction mixture was quenched with water then concentrated in vacuo. The resulting crude mixture was diluted with ethyl acetate (200 mL) and the aqueous phase was removed. The organic phase was further washed with water (3200 mL), dried over anhydrous sodium sulfate (30 g), concentrated under reduced pressure and dried under vacuum for 2 h. The crude material was used in the subsequent reaction without further purification. The subsequent reaction is detailed in Example XVI.

    Example XIII

    [0227] The method shown in FIG. 19 was carried out. The reagents and products included a total volume of 21 mL, including 20 mL of THF, with a reaction molarity of 95 mmolar at a temperature of 45 C. Details of the reagents are shown in Table 13A and Table 13B. Details of the products are shown in Table 13C and Table 13D.

    TABLE-US-00049 Physical Properties of Reagents Reagent Formula MM (g/mol) dibenzyl (1H-indol-4-yl) phosphate C.sub.22H.sub.20NO.sub.4P 393.38 allyl alcohol C.sub.3H.sub.6O 58.1 triethyl borane C.sub.6H.sub.15B 98.0 tetrakis(triphenylphosphine)palladium C.sub.72H.sub.60P.sub.4Pd 1155.6

    TABLE-US-00050 TABLE 13B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes dibenzyl (1H-indol-4-yl) 1 0.787 2.0 N/A phosphate tetrahydrofuran N/A N/A N/A 20 mL allyl alcohol 1.05 N/A 6.3 Density 0.854 g/mol Volume 0.143 mL triethyl borane 0.4 N/A 0.8 1.0M in THF Volume 0.8 mL tetrakis(triphenylphosphine) 0.05 0.116 0.1 N/A palladium

    TABLE-US-00051 TABLE 13C Physical Properties of Products MM Product Formula (g/mol) 3-allyl-1H-indol-4-yl dibenzyl phosphate C.sub.25H.sub.24NO.sub.4P 433.44

    TABLE-US-00052 TABLE 13D Relative Amounts of Products Product Theoretical Actual Yield 3-allyl-1H-indol-4-yl dibenzyl phosphate 0.867 0.56 65%

    [0228] Dibenzyl (1H-indol-4-yl) phosphate (0.787 g, 1 Eq, 2.00 mmol) and tetrakis(triphenylphosphine) palladium (0.116 g, 0.05 Eq, 0.1 mmol) were added to a 100 mL flask and sparged with argon. While sparging, THF (20 mL) was added to the flask, followed by allyl alcohol (0.143 mL, 1.05 Eq, 2.10 mmol, and finally triethylborane (1.0 M in THE, 0.80 mL, 0.4 Eq, 0.80 mmol).

    [0229] The reaction was heated at 45 C. and stirred for 5 hours under an argon atmosphere. Upon completion, reaction mixture was concentrated under vacuum. Then the crude material was purified by flash chromatography using gradient hexanes:ethyl acetate (1:1) as eluent.

    [0230] Fractions containing the desired product were collected and concentrated in vacuo to afford 3-allyl-1H-indol-4-yl dibenzyl phosphate (0.56 g, 1.3 mmol, 65%) as light-yellow oil.

    [0231] The product was characterized by 1H NMR (300 MHz, chloroform-D). The observed peaks on 1H NMR were NMR (400 MHz, CDCl3) 9.12 (s, 1H), 7.36 (q, J=2.2 Hz, 10H), 7.23-7.10 (m, 2H), 7.04 (t, J=7.9 Hz, 1H), 6.89-6.78 (m, 1H), 6.28-6.06 (m, 1H), 5.24-5.17 (m, 4H), 5.17-5.07 (m, 2H), 3.73 (dq, J=6.5, 1.3 Hz, 2H).

    Example XIV

    [0232] The method shown in FIG. 20 was carried out. The reagents and products included a total volume of 140 mL, including 70 mL of tetrahydrofuran and 70 mL of water, with a reaction molarity of 50 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 14A and Table 14B. Details of the products are shown in Table 14C and Table 14D.

    TABLE-US-00053 TABLE 14A Physical Properties of Reagents Reagent Formula MM (g/mol) 3-allyl-1H-indol-4-yl acetate C.sub.13H.sub.13NO.sub.2 215.25 potassium osmate dihydrate H.sub.4K.sub.2O.sub.6Os 368.45 4-methylmorpholine 4-oxide C.sub.5H.sub.11NO.sub.2 117.15

    TABLE-US-00054 TABLE 14B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 3-allyl-1H-indol-4-yl acetate 1 1.52 g 7.06 mmol N/A tetrahydrofuran N/A N/A N/A 70 mL water N/A N/A N/A 70 mL potassium osmate dihydrate 0.05 0.13 g 0.353 mmol N/A 4-methylmorpholine 4-oxide 5 4.14 g 35.3 mmol N/A

    TABLE-US-00055 TABLE 14C Physical Properties of Products Product Formula MM (g/mol) 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate C.sub.13H.sub.15NO.sub.4 249.27

    TABLE-US-00056 TABLE 14D Relative Amounts of Products Product Theoretical Actual Yield 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate 1.76 g 1.31 g 74.4%

    [0233] 70 mL of tetrahydrofuran and 70 mL of water was added to a 250 mL round-bottom flask containing 3-allyl-1H-indol-4-yl acetate (1.52 g, 7.06 mmol). 4-Methylmorpholine 4-oxide (4.14 g, 35.5 mmol; labelled as NMO in all figures) was added in one portion. Potassium Osmate (130 mg, 0.353 mmol) was added in one portion.

    [0234] The reaction was stirred at 25 C. for 2 hours. Upon completion, the reaction was quenched with a saturated solution of sodium thiosulfate (60 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3100 mL). The combined organic extracts were concentrated in vacuo and purified by flash chromatography using hexanes:ethyl acetate (3:7) as eluent.

    [0235] Fractions containing the desired product were collected and concentrated in vacuo to afford 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate (1.31 g, 5.26 mmol, 74.4%).

    [0236] The product was characterized by .sup.1H NMR (400 MHz, acetone-D.sub.6). The observed peaks on .sup.1H NMR were 2.38 (s, 3H) 2.99 (dd, =14.35, 6.15 Hz, 1H) 3.44-3.65 (m, 4H) 3.84-3.96 (m, 1H) 6.73 (d, =7.52 Hz, 1H) 7.06 (t, =7.86 Hz, 1H) 7.18 (s, 1H) 7.28 (d, =8.20 Hz, 1H).

    Example XV

    [0237] The method shown in FIG. 20 was carried out. The reagents and products included a total volume of 200 mL, including 100 mL of tetrahydrofuran and 100 mL of water, with a reaction molarity of 100 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 15A and Table 15B. Details of the products are shown in Table 15C and Table 15D.

    TABLE-US-00057 TABLE 15A Physical Properties of Reagents Reagent Formula MM (g/mol) 3-allyl-1H-indol-4-yl acetate C.sub.13H.sub.13NO.sub.2 215.25 potassium osmate dihydrate H.sub.4K.sub.2O.sub.6Os 368.45 4-methylmorpholine 4-oxide C.sub.5H.sub.11NO.sub.2 117.15

    TABLE-US-00058 TABLE 15B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 3-allyl-1H-indol-4-yl acetate 1 8.53 g 39.6 mmol N/A tetrahydrofuran N/A N/A N/A 70 mL water N/A N/A N/A 70 mL potassium osmate dihydrate 0.05 0.73 g 1.98 mmol N/A 4-methylmorpholine 4-oxide 5 13.9 g 198.0 mmol N/A

    TABLE-US-00059 TABLE 15C Physical Properties of Products Product Formula MM (g/mol) 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate C.sub.13H.sub.15NO.sub.4 249.27

    TABLE-US-00060 TABLE 15D Relative Amounts of Products Product Theoretical Actual Yield 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate 9.87 g 4.11 g 41.6%

    [0238] 100 mL of tetrahydrofuran and 100 mL of water was added to a 300 mL round bottom flask containing 3-allyl-1H-indol-4-yl acetate (8.53 g, 39.6 mmol). Potassium Osmate (730 mg, 1.98 mmol) was added in one portion. 4-Methylmorpholine 4-oxide (13.9 g, 119 mmol) was added in one portion.

    [0239] The reaction was stirred at 25 C. for 2 hours. Upon completion, the reaction was quenched with a saturated solution of sodium thiosulfate (20 mL). Charcoal (2.6 g, 30 Wt %) was added. The resultant mixture was stirred at room temperature for 30 min then filtered through a pad of Celite diatomaceous earth. The organic phase was separated and was further washed with an aqueous solution of hydrochloric acid (0.5M, 3100 mL), saturated solution of sodium bicarbonate (100 mL) and water (3100 mL). Note: It is important to remove all the inorganic salts through excess water washes. The aqueous solution should become clear at the end of the 3rd water wash. If not, wash with more water until the aqueous solution became clear.

    [0240] The resulting organic extracts were concentrated under reduced pressure. The crude material was triturated in dichloromethane (100 mL) to afford the desired product, 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate (4.11 g, 16.5 mmol, 41.6%) as a light gray powder.

    [0241] The product was characterized by 1H NMR (400 MHz, acetone-D6). The observed peaks on 1H NMR were 2.38 (s, 3H) 2.99 (dd, =14.35, 6.15 Hz, 1H) 3.44-3.65 (m, 4H) 3.84-3.96 (m, 1H) 6.73 (d, =7.52 Hz, 1H) 7.06 (t, =7.86 Hz, 1H) 7.18 (s, 1H) 7.28 (d, =8.20 Hz, 1H).

    Example XVI

    [0242] The method shown in FIG. 20 was carried out. The reagents and products included a total volume of 220 mL, including 200 mL of 2-methyltetrahydrofuran and 20 mL of water, with a reaction molarity of 236 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 16A and Table 16B. Details of the products are shown in Table 16C and Table 16D.

    TABLE-US-00061 TABLE 16A Physical Properties of Reagents Reagent Formula MM (g/mol) 3-allyl-1H-indol-4-yl acetate C.sub.13H.sub.13NO.sub.2 215.25 potassium osmate dihydrate H.sub.4K.sub.2O.sub.6Os 368.45 4-methylmorpholine 4-oxide C.sub.5H.sub.11NO.sub.2 117.15

    TABLE-US-00062 TABLE 16B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 3-allyl-1H-indol-4-yl 1 12.0 g 55.8 mmol N/A acetate 2-methyl-tetrahydrofuran N/A N/A N/A 200 mL water N/A N/A N/A 20 mL 2,6-lutidine 2.5 14.9 g 139.4 mmol Density 0.925 g/mL Volume 16.1 mL potassium osmate 0.025 0.514 g 1.39 mmol N/A dihydrate 4-methylmorpholine 2.5 16.3 g 139.4 mmol N/A 4-oxide

    TABLE-US-00063 TABLE 16C Physical Properties of Products Product Formula MM (g/mol) 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate C.sub.13H.sub.15NO.sub.4 249.27

    TABLE-US-00064 TABLE 16D Relative Amounts of Products Product Theoretical Actual Yield 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate 13.9 g 4.42 31.8%

    [0243] 200 mL of 2-methyltetrahydrofuran and 20 mL of water was added to a 500 mL Erlenmeyer flask containing crude 3-allyl-1H-indol-4-yl acetate (12.0 g, 55.8 mmol). 2,6-lutidine (16.1 mL, 139.4 mmol) was added in one portion (lutidine not shown in FIG. 20). Potassium Osmate (519 mg, 1.39 mmol) was added in one portion. 4-Methylmorpholine 4-oxide (16.3 g, 139.4 mmol) was added in one portion.

    [0244] The reaction was stirred vigorously at 25 C. for 3 hours. Upon completion, the reaction was quenched with a saturated solution of sodium thiosulfate (60 mL). Charcoal (4 g, 33 Wt %) was added. The resultant mixture was stirred at room temperature for 30 min then filtered through a pad of Celite diatomaceous earth. The organic phase was separated and was further washed with an aqueous solution of hydrochloric acid (0.5M, 3300 mL), saturated solution of sodium bicarbonate (300 mL) and brine (200 mL)

    [0245] The resulting organic extracts were concentrated under reduced pressure. The crude material was dissolved in 1,2-dichloromethane (25 mL) and precipitated with di-isopropyl ether (100 mL) to afford the desired product, 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate (4.42 g, 17.7 mmol, 31.8%), as a light gray powder.

    [0246] The product was characterized by 1H NMR (400 MHz, acetone-D6). The observed peaks on 1H NMR were 2.38 (s, 3H) 2.99 (dd, =14.35, 6.15 Hz, 1H) 3.44-3.65 (m, 4H) 3.84-3.96 (m, 1H) 6.73 (d, =7.52 Hz, 1H) 7.06 (t, =7.86 Hz, 1H) 7.18 (s, 1H) 7.28 (d, =8.20 Hz, 1H).

    Example XVII

    [0247] The method shown in FIG. 21 was carried out. The reagents and products included a total volume of 1246 mL, including 1100 mL of 2-methyltetrahydrofuran and 60 mL of water, with a reaction molarity of 334 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 17A and Table 17B. Details of the products are shown in Table 17C and Table 17D.

    TABLE-US-00065 TABLE 17A Physical Properties of Reagents Reagent Formula MM (g/mol) 4-acetyl-indole C.sub.10H.sub.9NO.sub.2 175.2 allyl alcohol C.sub.3H.sub.6O 58.1 triethyl borane C.sub.6H.sub.15B 98.0 tetra(triphenylphosphine)palladium C.sub.27H.sub.60P.sub.4Pd 1155.6 3-allyl-1H-indol-4-yl acetate C.sub.13H.sub.13NO.sub.2 215.25 2,6-lutidine C.sub.7H.sub.9N 107.2 potassium osmate dihydrate H.sub.4K.sub.2O.sub.6Os 368.45 4-methylmorpholine 4-oxide C.sub.5H.sub.11NO.sub.2 117.15

    TABLE-US-00066 TABLE 17B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 4-acetyl-indole 1 29.3 167 N/A 2-methyl-tetrahydrofuran N/A N/A N/A 500 mL allyl alcohol 1.5 N/A 201 13.6 mL triethyl borane 0.3 N/A 50.2 1.0M in THF Volume 50.2 mL tetra(triphenylphosphine)palladium 0.03 5.80 g 5.02 N/A 2-methyl-tetrahydrofuran N/A N/A N/A 600 mL water N/A N/A N/A 60 mL 3-allyl-1H-indol-4-yl acetate N/A N/A N/A N/A 2,6-lutidine 2.5 44.8 g 418 Density mmol 0.925 g/mL Volume 48.4 mL potassium osmate dihydrate 0.025 1.54 g 4.18 N/A mmol 4-methylmorpholine 4-oxide 2.5 56.5 g 418 N/A mmol

    TABLE-US-00067 TABLE 17C Physical Properties of Products Product Formula MM (g/mol) 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate C.sub.13H.sub.15NO.sub.4 249.27

    TABLE-US-00068 TABLE 17D Relative Amounts of Products Product Theoretical Actual Yield 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate 41.7 g 9.83 g 23.6%

    [0248] 500 mL of 2-methyltetrahydrofuran was added to a 1000 mL round-bottom flask and sparged with argon. While sparging, 1H-indol-4-yl acetate (29.3 g, 1 Eq, 167.1 mmol) and allyl alcohol (13.6 mL, 1.5 Eq, 201 mmol) were added to the flask. Sparging with argon was continued for 30 minutes. After sparging, triethylborane (1.0 M in tetrahydrofuran, 50.2 mL, 0.3 Eq, 50.2 mmol) and tetrakis(triphenylphosphine) palladium (5.81 g, 0.03 Eq, 5.02 mmol) were sequentially added to the reaction.

    [0249] The reaction was heated at 60 C. and stirred for 2 hours under an argon atmosphere. Upon completion, the crude reaction mixture was washed with water (3200 mL). The organics were dried over anhydrous sodium sulfate (30 g), concentrated under reduced pressure and dried under vacuum for 2 h.

    [0250] 600 mL of 2-methyltetrahydrofuran and 60 mL of water was added to a 1000 mL Erlenmeyer flask containing crude 3-allyl-1H-indol-4-yl acetate telescoped from the allylation reaction. 2,6-lutidine (48.4 mL, 418 mmol) was added in one portion. Potassium Osmate (1.54 g, 4.18 mmol) was added in one portion. 4-Methylmorpholine 4-oxide (56.5 g, 418 mmol) was added in one portion.

    [0251] The reaction was stirred vigorously at 25 C. for 3 hours. Upon completion, the reaction was quenched with a saturated solution of sodium thiosulfate (60 mL). Charcoal (10 g, 33 Wt %) was added. The resultant mixture was stirred at room temperature for 30 min then filtered through a pad of Celite diatomaceous earth. The organic phase was separated and was further washed with an aqueous solution of hydrochloric acid (0.5M, 3300 mL), saturated solution of sodium bicarbonate (300 mL) and brine (200 mL)

    [0252] The resulting organic extracts were concentrated under reduced pressure. The crude material was dissolved in 1,2-dichloromethane (10 mL) and precipitated with di-isopropyl ether (80 mL) to afford the desired product, 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate (9.83 g, 39.4 mmol, 23.6%), as a light gray powder.

    [0253] The product was characterized by 1H NMR (400 MHz, acetone-D6). The observed peaks on 1H NMR were 2.38 (s, 3H) 2.99 (dd, =14.35, 6.15 Hz, 1H) 3.44-3.65 (m, 4H) 3.84-3.96 (m, 1H) 6.73 (d, =7.52 Hz, 1H) 7.06 (t, =7.86 Hz, 1H) 7.18 (s, 1H) 7.28 (d, =8.20 Hz, 1H).

    Example XVIII

    [0254] The method shown in FIG. 21 was carried out. The reagents and products included a total volume of 824 mL, including 750 mL of 2-methyltetrahydrofuran and 45 mL of water, with a reaction molarity of 250 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 18A and Table 18B. Details of the products are shown in Table 18C and Table 18D.

    TABLE-US-00069 TABLE 18A Physical Properties of Reagents Reagent Formula MM (g/mol) 4-acetyl-indole C.sub.10H.sub.9NO.sub.2 175.2 allyl alcohol C.sub.3H.sub.6O 58.1 triethyl borane C.sub.6H.sub.15B 98.0 tetra(triphenylphosphine)palladium C.sub.27H.sub.60P.sub.4Pd 1155.6 3-allyl-1H-indol-4-yl acetate C.sub.13H.sub.13NO.sub.2 215.25 2,6-lutidine C.sub.7H.sub.9N 107.2 potassium osmate dihydrate H.sub.4K.sub.2O.sub.6Os 368.45 4-methylmorpholine 4-oxide C.sub.5H.sub.11NO.sub.2 117.15

    TABLE-US-00070 TABLE 18B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 4-acetyl-indole 1 13.1 74.8 N/A 2-methyl-tetrahydrofuran N/A N/A N/A 300 mL allyl alcohol 1.5 N/A 89.7 6.10 mL 0.854 g/mL triethyl borane 0.3 N/A 22.4 1.0M in THF Volume 22.4 mL tetra(triphenylphosphine)palladium 0.03 2.59 g 2.24 N/A 2-methyl-tetrahydrofuran N/A N/A N/A 450 mL water N/A N/A N/A 45 mL 3-allyl-1H-indol-4-yl acetate N/A N/A N/A N/A 2,6-lutidine 2.5 20.1 g 187 Density mmol 0.925 g/mL Volume 21.7 mL potassium osmate dihydrate 0.025 689 1.87 N/A mg mmol 4-methylmorpholine 4-oxide 2.5 25.3 g 187 N/A mmol

    TABLE-US-00071 TABLE 18C Physical Properties of Products Product Formula MM (g/mol) 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate C.sub.13H.sub.15NO.sub.4 249.27

    TABLE-US-00072 TABLE 18D Relative Amounts of Products Product Theoretical Actual Yield 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate 18.6 g 2.12 g 11.4%

    [0255] 300 mL of 2-methyltetrahydrofuran was added to a 500 mL round-bottom flask and sparged with argon. While sparging, 1H-indol-4-yl acetate (13.1 g, 1 Eq, 74.8 mmol) and allyl alcohol (6.1 mL, 1.5 Eq, 89.7 mmol) were added to the flask. Sparging with argon was continued for 30 minutes. After sparging, triethylborane (1.0 M in tetrahydrofuran, 22.4 mL, 0.3 Eq, 22.4 mmol) and tetrakis(triphenylphosphine) palladium (2.59 g, 0.03 Eq, 2.24 mmol) were sequentially added to the reaction.

    [0256] The reaction was heated at 60 C. and stirred for 2 hours under an argon atmosphere. Upon completion, the crude reaction mixture was washed with water (3100 mL). The organics were dried over anhydrous sodium sulfate (20 g), concentrated under reduced pressure and dried under vacuum for 2 h.

    [0257] 450 mL of 2-methyltetrahydrofuran and 45 mL of water was added to a 1000 mL Erlenmeyer flask containing crude 3-allyl-1H-indol-4-yl acetate telescoped from the allylation reaction. 2,6-lutidine (21.7 mL, 187 mmol) was added in one portion. Potassium Osmate (689 mg, 1.87 mmol) was added in one portion. 4-Methylmorpholine 4-oxide (25.3 g, 187 mmol) was added in one portion.

    [0258] The reaction was stirred at 25 C. for 3 hours. Upon completion, the reaction was quenched with a saturated solution of sodium thiosulfate (45 mL). Charcoal (4 g, 30 Wt %) was added. The resultant mixture was stirred at room temperature for 30 min then filtered through a pad of Celite diatomaceous earth. The organic phase was separated and was further washed with an aqueous solution of hydrochloric acid (0.5M, 3300 mL), saturated solution of sodium bicarbonate (300 mL) and brine (200 mL)

    [0259] The resulting organic extracts were dried over anhydrous sodium sulfate (30 g) and concentrated under reduced pressure. The crude material was crystallized in hot toluene (770 mL) to afford the desired product, 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate (2.12 g, 8.50 mmol, 11.4%), as a light gray powder.

    [0260] The product was characterized by 1H NMR (400 MHz, acetone-D6). The observed peaks on 1H NMR were 2.38 (s, 3H) 2.99 (dd, =14.35, 6.15 Hz, 1H) 3.44-3.65 (m, 4H) 3.84-3.96 (m, 1H) 6.73 (d, =7.52 Hz, 1H) 7.06 (t, =7.86 Hz, 1H) 7.18 (s, 1H) 7.28 (d, =8.20 Hz, 1H).

    [0261] An XRD pattern was obtained for 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate crystals grown from toluene. The XRD pattern is shown in Graph 18E. [0262] Graph 18E: XRD of 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate crystals grown from toluene

    Example XIX

    [0263] The method shown in FIG. 21 was carried out. The reagents and products of the first step included a total volume of 337 mL, including 300 mL of 2-methyltetrahydrofuran, with a reaction molarity of 288 mmolar at a temperature of 25 C. The reagents and products of the second step included a total volume of 523 mL, including 450 mL of 2-methyltetrahydrofuran and 45 mL of water, with a reaction molarity of 185 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 19A and Table 19B. Details of the products are shown in Table 19C and Table 19D.

    TABLE-US-00073 TABLE 19A Physical Properties of Reagents Reagent Formula MM (g/mol) 4-acetyl-indole C.sub.10H.sub.9NO.sub.2 175.2 allyl alcohol C.sub.3H.sub.6O 58.1 triethyl borane C.sub.6H.sub.15B 98.0 tetra(triphenylphosphine)palladium C.sub.27H.sub.60P.sub.4Pd 1155.6 3-allyl-1H-indol-4-yl acetate C.sub.13H.sub.13NO.sub.2 215.25 2,6-lutidine C.sub.7H.sub.9N 107.2 potassium osmate dihydrate H.sub.4K.sub.2O.sub.6Os 368.45 4-methylmorpholine 4-oxide C.sub.5H.sub.11NO.sub.2 117.15

    TABLE-US-00074 TABLE 19B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 4-acetyl-indole 1 17.1 97.4 N/A 2-methyl-tetrahydrofuran N/A N/A N/A 300 mL allyl alcohol 1.5 N/A 117 7.95 mL 0.854 g/mL triethyl borane 0.3 N/A 29.2 1.0M in THF Volume 29.2 mL tetra(triphenylphosphine)palladium 0.03 3.38 g 2.92 N/A 2-methyl-tetrahydrofuran N/A N/A N/A 450 mL water N/A N/A N/A 45 mL 3-allyl-1H-indol-4-yl acetate N/A N/A N/A N/A 2,6-lutidine 2.5 26.1 243 Density g mmol 0.925 g/mL Volume 28.2 mL potassium osmate dihydrate 0.025 897 2.43 N/A mg mmol 4-methylmorpholine 4-oxide 2.5 32.9 243 N/A g mmol

    TABLE-US-00075 TABLE 19C Physical Properties of Products Product Formula MM (g/mol) 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate C.sub.13H.sub.15NO.sub.4 249.27

    TABLE-US-00076 TABLE 19D Relative Amounts of Products Product Theoretical Actual Yield 3-(2,3-dihydroxypropyl)-1H-indol-4-yl 24.27 g 2.41 g 10% acetate

    [0264] 300 mL of 2-methyltetrahydrofuran was added to a 500 mL round-bottom flask and sparged with argon. While sparging, 1H-indol-4-yl acetate (17.1 g, 1 Eq, 97.4 mmol) and allyl alcohol (7.95 mL, 1.5 Eq, 117 mmol) were added to the flask. Sparging with argon was continued for 30 minutes. After sparging, triethylborane (1.0 M in tetrahydrofuran, 29.2 mL, 0.3 Eq, 29.2 mmol) and tetrakis(triphenylphosphine) palladium (3.38 g, 0.03 Eq, 2.92 mmol) were sequentially added to the reaction.

    [0265] The reaction was heated at 60 C. and stirred for 2 hours under an argon atmosphere. Upon completion, the crude reaction mixture was washed with water (3100 mL). The organics were dried over anhydrous sodium sulfate (20 g), concentrated under reduced pressure and dried under vacuum for 2 h.

    [0266] 450 mL of 2-methyltetrahydrofuran and 45 mL of water was added to a 1000 mL Erlenmeyer flask containing crude 3-allyl-1H-indol-4-yl acetate telescoped from the allylation reaction. 2,6-lutidine (28.2 mL, 243 mmol) was added in one portion. Potassium Osmate (897 mg, 2.43 mmol) was added in one portion. 4-Methylmorpholine 4-oxide (32.9 g, 243 mmol) was added in one portion.

    [0267] The reaction was stirred at 25 C. for 3 hours. Upon completion, the reaction was quenched with a saturated solution of sodium thiosulfate (45 mL). Charcoal (6 g, 30 Wt %) was added. The resultant mixture was stirred at room temperature for 30 min then filtered through a pad of Celite diatomaceous earth. The organic phase was separated and was further washed with an aqueous solution of hydrochloric acid (0.5M, 3300 mL), saturated solution of sodium bicarbonate (300 mL) and brine (200 mL)

    [0268] The resulting organic extracts were dried over anhydrous sodium sulfate (30 g) and concentrated under reduced pressure. The crude material was crystallized in hot toluene (900 mL) to afford the desired product, 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate (2.41 g, 9.68 mmol, 10%), as a light gray powder.

    [0269] The filtrate from the crystallization can be treated with silica gel to afford a second crop of crystals. The filtrate was concentrated to dryness and then redissolved in 50 mL of methanol. To this solution was added 30 g of silica gel and the contents of the flask were then dried under reduced pressure. The dried contents of the flask was layered on top of 70 g of silica gel and then the silica mixture was rinsed with 400 ml of 1:1 ethyl acetate:hexanes. The product was then eluted with 700 ml of ethyl acetate. The ethyl acetate solution was concentrated to dryness and then the residue was recrystallized using 350 ml of toluene. The second crop of product, 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate (1.60 g, 6.42 mmol), was isolated as a light gray powder.

    [0270] The product was characterized by 1H NMR (400 MHz, acetone-D6). The observed peaks on 1H NMR were 2.38 (s, 3H) 2.99 (dd, =14.35, 6.15 Hz, 1H) 3.44-3.65 (m, 4H) 3.84-3.96 (m, 1H) 6.73 (d, =7.52 Hz, 1H) 7.06 (t, =7.86 Hz, 1H) 7.18 (s, 1H) 7.28 (d, =8.20 Hz, 1H).

    Example XX

    [0271] The method shown in FIG. 22 was carried out. The reagents and products included a total volume of 10 mL, including 2.5 mL of tetrahydrofuran and 2.5 mL of water for cleavage (step 1 in FIG. 22), and 5 mL of 1,2-dichloroethane for reductive amination (step 1 in FIG. 22), with a reaction molarity of 25 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 20A and Table 20B. Details of the products are shown in Table 20C and Table 20D.

    TABLE-US-00077 TABLE 20A Physical Properties of Reagents Reagent Formula MM (g/mol) 3-(2,3-dihydroxypropyl)-1H-indol-4- C.sub.13H.sub.15NO.sub.4 249.27 yl acetate sodium periodate NaIO.sub.4 213.89 pyrrolidine C.sub.4H.sub.9N 71.12 sodium triacetoxyhydroborate C.sub.6H.sub.10BNaO.sub.6 211.94

    TABLE-US-00078 TABLE 20B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 3-(2,3-dihydroxypropyl)- 1 62.3 mg 250 mol N/A 1H-indol-4-yl acetate tetrahydrofuran N/A N/A N/A 2.5 mL water N/A N/A N/A 2.5 mL sodium periodate 1.5 80.2 mg 375 mol N/A 1,2-dichloroethane N/A N/A N/A 5.0 mL pyrrolidine 1 17.8 mg 250 mol 20.5 mL sodium triacetoxyhydroborate 1.5 79.5 mg 375 mol N/A

    TABLE-US-00079 TABLE 20C Physical Properties of Products Product Formula MM (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)-1H- C.sub.16H.sub.20N.sub.2O.sub.2 272.35 indol-4-yl acetate

    TABLE-US-00080 TABLE 20D Relative Amounts of Products Product Theoretical Actual Yield 3-(2-(pyrrolidin-1-yl)ethyl)-1H- 68.1 mg N/A N/A indol-4-yl acetate

    [0272] 2.5 mL of tetrahydrofuran and 2.5 mL of water was added to a 20 mL vial containing 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate (62.3 mg, 250 mol). Sodium periodate (80.2 mg, 375 mol) was added in one portion.

    [0273] The reaction was stirred at 25 C. for 90 minutes. Upon completion, the reaction was quenched with a saturated solution of sodium thiosulfate (5 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (35 mL). The combine organic extracts were concentrated in vacuo and was used in the subsequent reaction without additional purification.

    [0274] 5 mL of 1,2-dichloroethane was added to a 20 mL vial containing crude 3-(2-oxoethyl)-1H-indol-4-yl acetate. Pyrrolidine (20.5 L, 250 mol) was added in one portion. Sodium triacetoxyhydroborate (79.5 mg, 375 mol) was added in one portion.

    [0275] The reaction was stirred at 25 C. for 2 hours. Upon completion, the reaction was quenched with an aqueous solution of sodium hydroxide (1.0N, 5 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (310 mL). The combine organic extracts were concentrated in vacuo to afford 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl acetate.

    [0276] The crude material was used in the subsequent reaction without further purification.

    Example XXI

    [0277] The method shown in FIG. 22 was carried out. The reagents and products included a total volume of 10 mL, including 5 mL of tetrahydrofuran and 5 mL of water, with a reaction molarity of 99 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 21A and Table 21B. Details of the products are shown in Table 21C and Table 21D.

    TABLE-US-00081 TABLE 21A Physical Properties of Reagents Reagent Formula MM (g/mol) 3-(2,3-dihydroxypropyl)-1H- C.sub.13H.sub.15NO.sub.4 249.27 indol-4-yl acetate sodium periodate NalO.sub.4 213.89 pyrrolidine C.sub.4H.sub.9N 71.12 sodium triacetoxyhydroborate C.sub.6H.sub.10BNaO.sub.6 211.94

    TABLE-US-00082 TABLE 21B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 3-(2,3-dihydroxypropyl)- 1 249 mg 1.00 mmol N/A 1H-indol-4-yl acetate tetrahydrofuran N/A N/A N/A 5 mL water N/A N/A N/A 5 mL sodium periodate 1.5 321 mg 1.50 mmol N/A pyrrolidine 1 71.1 mg 1.00 mmol 82.1 ml sodium 1.5 318 mg 1.50 mmol N/A triacetoxyhydroborate

    TABLE-US-00083 TABLE 21C Physical Properties of Products MM Product Formula (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)-1H- C.sub.16H.sub.20N.sub.2O.sub.2 272.35 indol-4-yl acetate

    TABLE-US-00084 TABLE 21D Relative Amounts of Products Product Theoretical Actual Yield 3-(2-(pyrrolidin-1-yl)ethyl)-1H- 272 mg N/A N/A indol-4-yl acetate

    [0278] 5 mL of THE and 5 mL of water was added to a 20 mL vial containing 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate (249 mg, 1.00 mmol). Sodium periodate (321 mg, 1.50 mmol) was added in one portion.

    [0279] The reaction was stirred at 25 C. for 1 h. Pyrrolidine (80.1 ml, 1.00 mmol) was added in one portion. Sodium triacetoxyhydroborate (318 mg, 1.5 mmol) was added in one portion.

    [0280] The reaction was stirred at 25 C. for another 2 hours. Upon completion, the reaction was quenched with an aqueous solution of sodium hydroxide (1.0N, 5 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (310 mL). The combine organic extracts were concentrated in vacuo to afford 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl acetate.

    [0281] The crude material was used in the subsequent reaction without further purification. The subsequent reaction is detailed in Example XXV.

    Example XXII

    [0282] The method shown in FIG. 22 was carried out. The reagents and products included a total volume of 31 mL, including 20 mL of 1,2-dichloroethane and 10 mL of water, with a reaction molarity of 130 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 22A and Table 22B. Details of the products are shown in Table 22C and Table 22D.

    TABLE-US-00085 TABLE 22A Physical Properties of Reagents Reagent Formula MM (g/mol) 3-(2,3-dihydroxypropyl)-1H- C.sub.13H.sub.15NO.sub.4 249.27 indol-4-yl acetate sodium periodate NalO.sub.4 213.89 pyrrolidine C.sub.4H.sub.9N 71.12 sodium triacetoxyhydroborate C.sub.6H.sub.10BNaO.sub.6 211.94

    TABLE-US-00086 TABLE 22B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 3-(2,3-dihydroxypropyl)- 1 62.3 mg 4.01 mmol N/A 1H-indol-4-yl acetate 1,2-dichloroethane N/A N/A N/A 10 mL water N/A N/A N/A 10 mL sodium periodate 1.5 1.29 mg 6.02 mmol N/A 1,2-dichloroethane N/A N/A N/A 5.0 mL pyrrolidine 3 N/A 12.0 mmol 0.988 mL Density 0.866 g/mL sodium 5 4.25 g 20.1 mmol N/A triacetoxyhydroborate

    TABLE-US-00087 TABLE 22C Physical Properties of Products Product Formula MM (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)-1H- C.sub.16H.sub.20N.sub.2O.sub.2 272.35 indol-4-yl acetate

    TABLE-US-00088 TABLE 22D Relative Amounts of Products Product Theoretical Actual Yield 3-(2-(pyrrolidin-1-yl)ethyl)-1H- 1.09 g 487 mg 44.6% indol-4-yl acetate

    [0283] 10 mL of 1,2-dichloroethane and 10 mL of water was added to a 100 mL round bottom flask containing 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate (1.00 g, 4.01 mmol). Sodium periodate (1.29 g, 6.02 mmol) was added in one portion.

    [0284] The reaction was stirred at 25 C. for 30 min and phases were separated. The organic phase was washed with water (320 mL).

    [0285] A separate 100 mL round bottom flask was charged with pyrrolidine (0.988 ml, 12.0 mmol) and sodium triacetoxyhydroborate (4.15 g, 20.1 mmol) in 1,2-dichloroethane (10 mL).

    [0286] The crude aldehyde solution in 1,2-dichloroethane (10 mL) was added dropwise over 5 minutes with vigorous stirring.

    [0287] The reaction was stirred at 25 C. for another 30 minutes. The resulting reaction mixture was filtered through a pad of silica gel (20 g). The filter cake was washed with tetrahydrofuran (100 mL). The combined organic extracts were concentrated under reduced pressure and purified by flash chromatography using dichloromethane:tetrahydrofuran (15:85) as eluent to afford the desired product, 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol (487 mg, 1.78 mmol, 44.6%) as a dark gray oil.

    [0288] The product was characterized by 12H NMR (400 MHz, dichoromethane-D.sub.2). The observed peaks on H NMR were 1.87 (m, 4H) 2.38 (s, 3H) 2.85 (9, 4H) 2.89-2.97 (m, 2H) 2.98-3.06 (m, 2H) 6.74 (dd, J=7.63, 0.61 Hz, 1H) 6.87 (s, 1H) 7.08 (t, J=7.93 Hz, 1H) 7.23 (dd, J=8.24, 0.92 Hz, 1H) 9.63 (br. s., 1H).

    Example XXIII

    [0289] The method shown in FIG. 23 was carried out. The reagents and products included a total volume of 31 mL, including 20 mL of 1,2-dichloroethane and 10 mL of water, with a reaction molarity of 130 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 23A and Table 23B. Details of the products are shown in Table 23C and Table 23D.

    TABLE-US-00089 TABLE 23A Physical Properties of Reagents Reagent Formula MM (g/mol) 3-(2,3-dihydroxypropyl)-1H- C.sub.13H.sub.15NO.sub.4 249.27 indol-4-yl acetate sodium periodate NalO.sub.4 213.89 pyrrolidine C.sub.4H.sub.9N 71.12 sodium triacetoxyhydroborate C.sub.6H.sub.10BNaO.sub.6 211.94

    TABLE-US-00090 TABLE 23B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 3-(2,3-dihydroxypropyl)- 1 1.00 g 4.01 mmol N/A 1H-indol-4-yl acetate 1,2-dichloroethane N/A N/A N/A 10 mL water N/A N/A N/A 10 mL sodium periodate 1.5 1.29 g 6.02 mmol N/A 1,2-dichloroethane N/A N/A N/A 10 mL pyrrolidine 3 N/A 12.0 mmol 0.988 mL Density 0.866 g/mL sodium 5 4.25 g 20.1 mmol N/A triacetoxyhydroborate

    TABLE-US-00091 TABLE 23C Physical Properties of Products Product Formula MM (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)-1H- C.sub.14H.sub.18N.sub.2O 230.31 indol-4-ol

    TABLE-US-00092 TABLE 23D Relative Amounts of Products Product Theoretical Actual Yield 3-(2-(pyrrolidin-1-yl)ethyl)-1H- 924 mg 573 mg 62.0% indol-4-yl acetate

    [0290] 10 mL of 1,2-dichloroethane and 10 mL of water was added to a 100 mL round bottom flask containing 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate (1.00 g, 4.01 mmol). Sodium periodate (1.29 g, 6.02 mmol) was added in one portion.

    [0291] The reaction was stirred at 25 C. for 30 min and phases were separated. The organic phase was washed with water (320 mL).

    [0292] A separate 100 mL round bottom flask was charged with pyrrolidine (0.988 ml, 12.0 mmol) and sodium triacetoxyhydroborate (4.15 g, 20.1 mmol) in 1,2-dichloroethane (10 mL).

    [0293] The crude aldehyde solution in 1,2-dichloroethane (10 mL) was added dropwise over 5 minutes with vigorous stirring.

    [0294] The reaction was stirred at 25 C. for another 30 minutes. The resulting reaction mixture was filtered through a pad of Celite diatomaceous earth. The filter cake was washed with 1,2-dichloroethane (10 mL). The combined organic extracts were heated at 45 C. while stirring to promote deacylation.

    [0295] After 2 hours, the crude mixture was concentrated under reduced pressure and deposited on silica gel (10 g). The silica gel containing the crude mixture was flushed with dichloromethane (50 mL) followed by dichloromethane:methanol (9:1, 50 mL)

    [0296] The dichloromethane eluent was discarded and the dichloromethane:methanol eluent was concentrated under reduced pressure to afford the desired product, 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol (573 mg, 2.50 mmol, 62.0%) as a dark gray oil.

    [0297] The product was characterized by 1H NMR (600 MHz, methanol-D.sub.4). The observed peaks on 1H NMR were 2.03-2.07 (m, 4H) 3.27 (t, J=7.52 Hz, 2H) 3.33 (m, 5H) 3.49 (t, J=7.52 Hz, 2H) 6.39 (d, J=8.05 Hz, 1H) 6.86 (d, J=8.07 Hz, 1H) 6.91 (dt, J=7.89, 3.76 Hz, 2H) 7.01 (s, 1H).

    Example XXIV

    [0298] The method shown in FIG. 24 was carried out. The reagents and products included a total volume of 480 mL, including 360 mL of 1,2-dichloroethane and 120 mL of water, with a reaction molarity of 100 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 24A and Table 24B. Details of the products are shown in Table 24C and Table 24D.

    TABLE-US-00093 TABLE 24A Physical Properties of Reagents Reagent Formula MM (g/mol) 3-(2,3-dihydroxypropyl)-1H- C.sub.13H.sub.15NO.sub.4 249.27 indol-4-yl acetate sodium periodate NalO.sub.4 213.89 pyrrolidine C.sub.4H.sub.9N 71.12 sodium triacetoxyhydroborate C.sub.6H.sub.10BNaO.sub.6 211.94

    TABLE-US-00094 TABLE 24B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 3-(2,3-dihydroxypropyl)- 1 6.33 g 25.4 mmol N/A 1H-indol-4-yl acetate 1,2-dichloroethane N/A N/A N/A 120 mL water N/A N/A N/A 120 mL sodium periodate 1.5 8.15 g 38.1 mmol N/A 1,2-dichloroethane N/A N/A N/A 240 mL pyrrolidine 3 N/A 76.2 mmol 6.26 mL Density 0.866 g/mL sodium 5 26.8 g 127 mmol N/A triacetoxyhydroborate

    TABLE-US-00095 TABLE 24C Physical Properties of Products Product Formula MM (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)-1H- C.sub.16H.sub.20N.sub.2O.sub.2 272.35 indol-4-yl acetate 3-(2-(pyrrolidin-1-yl)ethyl)-1H- C.sub.14H.sub.18N.sub.2O 230.31 indol-4-ol

    TABLE-US-00096 TABLE 24D Relative Amounts of Products Product Theoretical Actual Yield 3-(2-(pyrrolidin-1-yl)ethyl)- 6.92 g 2.40 g 35.0% 1H-indol-4-yl acetate 3-(2-(pyrrolidin-1-yl)ethyl)- 5.85 g 2.39 g 40.9% 1H-indol-4-ol

    [0299] 120 mL of 1,2-dichloroethane and 120 mL of water was added to a 500 mL round bottom flask containing 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate (6.33 g, 25.4 mmol). Sodium periodate (8.15 g, 38.1 mmol) was added in one portion.

    [0300] The reaction was stirred at 25 C. for 30 min and the phases were separated. The organic phase was washed with water (3100 mL).

    [0301] A separate 1 L Erlenmeyer flask was charged with pyrrolidine (6.26 ml, 76.2 mmol) and sodium triacetoxyhydroborate (26.9 g, 127 mmol) in 1,2-dichloroethane (240 mL).

    [0302] The crude aldehyde solution in 1,2-dichloroethane (120 mL) was added dropwise over 5 minutes with vigorous stirring.

    [0303] The reaction was stirred at 25 C. for another 30 minutes. The resulting reaction mixture was filtered through a pad of Celite diatomaceous earth. The filter cake was washed with 1,2-dichloroethane (100 mL). The combined organic extracts were concentrated under reduced pressure and deposited on silica gel (60 g). The silica gel containing the crude mixture was flushed with dichloromethane (500 mL) followed by dichloromethane:methanol (9:1, 1 L)

    [0304] The dichloromethane eluent was discarded and the dichloromethane:methanol eluent was concentrated under reduced pressure to afford 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl acetate (2.40 g, 8.81 mmol, 35%) and 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol (2.39 g, 10.4 mmol, 40.9%) in a mixture as a dark gray oil.

    Example XXV

    [0305] The method shown in FIG. 25 was carried out. The reagents and products included a total volume of 20 mL, including 20 mL of methanol, with a reaction molarity of 79 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 25A and Table 25B. Details of the products are shown in Table 25C and Table 25D.

    TABLE-US-00097 TABLE 25A Physical Properties of Products Reagent Formula MM (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl acetate C.sub.16H.sub.20N.sub.2O.sub.2 272.35 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol C.sub.14H.sub.18N.sub.2O 230.31 sodium borohydride NaBH.sub.4 37.8

    TABLE-US-00098 TABLE 25B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 3-(2-(pyrrolidin-1-yl)ethyl)- 1 423 mg 1.58 N/A 1H-indol-4-yl acetate 3-(2-(pyrrolidin-1-yl)ethyl)- 1 423 mg 1.85 N/A 1H-indol-4-ol sodium borohydride 1.2 144 mg 3.80 N/A methanol N/A N/A N/A 20 mL

    TABLE-US-00099 TABLE 23C Physical Properties of Products Product Formula MM (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol C.sub.14H.sub.18N.sub.2O 230.31

    TABLE-US-00100 TABLE 23D Relative Amounts of Products Product Theoretical Actual Yield 3-(2-(pyrrolidin-1-yl)ethyl)- 730 mg 487 mg 66.7% 1H-indol-4-yl acetate

    [0306] Methanol (20 mL) was added to a 100 mL round bottom flask containing a mixture of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl acetate and 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol (II). Sodium borohydride (144 mg, 1.2 Eq, 3.80 mmol) was added in one portion. CAUTION: The addition of sodium borohydride is exothermic and generates gas. The reaction mixture was allowed to stir at room temperature for 18 hours.

    [0307] The resulting reaction mixture was concentrated to dryness under reduced pressure. The resulting crude solid was dissolved in dichloromethane:methanol (9:1, 20 mL) and filtered through a pad of silica gel (50 g). The filter cake was washed with additional dichloromethane:methanol (9:1, 200 mL). The combined organic solutions were concentrated under reduced pressure to afford the desired product, 0.3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol (487 mg, 2.11 mmol, 66.7%), as a brown solid.

    [0308] The product was characterized by 1H NMR (600 MHz, methanol-D4) and The observed peaks on 1H NMR were 2.03-2.07 (m, 4H) 3.27 (t, J=7.52 Hz, 2H) 3.33 (m, 5H) 3.49 (t, J=7.52 Hz, 2H) 6.39 (d, J=8.05 Hz, 1H) 6.86 (d, J=8.07 Hz, 1H) 6.91 (dt, J=7.89, 3.76 Hz, 1H) 7.01 (s, 1H).

    Example XXVI

    [0309] The method shown in FIG. 26 was carried out. The reagents and products included a total volume of 480 mL, including 360 mL of 1,2-dichloroethane and 120 mL of water, with a reaction molarity of 100 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 26A and Table 26B. Details of the products are shown in Table 26C and Table 26D.

    TABLE-US-00101 TABLE 26A Physical Properties of Reagents Reagent Formula MM (g/mol) 3-(2,3-dihydroxypropyl)-1H-indol-4- C.sub.13H.sub.15NO.sub.4 249.27 yl acetate sodium periodate NaIO.sub.4 213.89 pyrrolidine C.sub.4H.sub.9N 71.12 sodium triacetoxyhydroborate C.sub.6H.sub.10BNaO.sub.6 211.94 sodium borohydride NaBH.sub.4 37.8

    TABLE-US-00102 TABLE 26B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 3-(2,3-dihydroxypropyl)-1H- 1 1.21 g 4.85 mmol N/A indol-4-yl acetate 1,2-dichloroethane N/A N/A N/A 20 mL water N/A N/A N/A 20 mL sodium periodate 1.5 1.56 g 7.28 mmol N/A 1,2-dichloroethane N/A N/A N/A 40 mL pyrrolidine 3 N/A 14.6 mmol 1.20 mL Density 0.866 g/mL sodium triacetoxyhydroborate 5 5.14 g 24.3 mmol N/A sodium borohydride 1.5 215 mg 3.80 N/A methanol N/A N/A N/A N/A

    TABLE-US-00103 TABLE 26C Physical Properties of Products Product Formula MM (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol C.sub.14H.sub.18N.sub.2O 230.31

    TABLE-US-00104 TABLE 26D Relative Amounts of Products Product Theoretical Actual Yield 3-(2-(pyrrolidin-1-yl)ethyl)- 1.12 g 288 mg 25.8% 1H-indol-4-yl acetate

    [0310] 20 mL of 1,2-dichloroethane and 20 mL of water was added to a 100 mL round bottom flask containing 3-(2,3-dihydroxypropyl)-1H-indol-4-yl acetate (1.21 g, 4.85 mmol). Sodium periodate (1.56 g, 7.28 mmol) was added in one portion.

    [0311] The reaction was stirred at 25 C. for 30 min and the phases were separated. The organic phase was washed with water (340 mL).

    [0312] A separate 250 mL Erlenmeyer flask was charged with pyrrolidine (1.20 ml, 14.6 mmol) and sodium triacetoxyhydroborate (5.14 g, 24.3 mmol) in 1,2-dichloroethane (40 mL).

    [0313] The crude aldehyde solution in 1,2-dichloroethane (20 mL) was added dropwise over 5 minutes with vigorous stirring.

    [0314] The reaction was stirred at 25 C. for another 30 minutes. The resulting reaction mixture was filtered through a pad of Celite diatomaceous earth. The filter cake was washed with tetrahydrofuran (50 mL). The combined organic extracts were concentrated under reduced pressure and deposited on silica gel (60 g). The silica gel containing the crude mixture was flushed with tetrahydrofuran (200 mL) and concentrated under reduced pressure.

    [0315] The crude material was then dissolved in methanol (20 mL). Sodium borohydride (144 mg, 3.80 mmol) was added in portions. CAUTION: The addition of sodium borohydride is exothermic and generates gas. The reaction mixture was allowed to stir at room temperature for 18 hours and at 50 C. for another 24 hours.

    [0316] The resulting reaction mixture was concentrated to dryness under reduced pressure. The resulting crude solid was dissolved in tetrahydrofuran (20 mL) and filtered through a pad of silica gel (50 g). The filter cake was washed with additional tetrahydrofuran (300 mL). The combined organic solutions were concentrated under reduced pressure to afford the desired product, 0.3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol (288 mg, 1.25 mmol, 25.8%), as a brown oil.

    [0317] The product was characterized by 1H NMR (600 MHz, methanol-D4). The observed peaks on 1H NMR were 2.03-2.07 (m, 4H) 3.27 (t, J=7.52 Hz, 2H) 3.33 (m, 5H) 3.49 (t, J=7.52 Hz, 2H) 6.39 (d, J=8.05 Hz, 1H) 6.86 (d, J=8.07 Hz, 1H) 6.91 (dt, J=7.89, 3.76 Hz, 1H) 7.01 (s, 1H).

    Example XXVII

    [0318] The method shown in FIG. 27 was carried out. The reagents and products included a total volume of 82.8 mL, including 25 mL of acetonitrile and 30 mL of water, with a reaction molarity of 110 mmolar at a temperature of 30 C. Details of the reagents are shown in Table 27A and Table 27B. Details of the products are shown in Table 27C and Table 27D.

    TABLE-US-00105 TABLE 27A Physical Properties of Reagents Reagent Formula MM (g/mol) 1H-indole-4-ol C.sub.8H.sub.7NO 133.15 diisopropylethylamine C.sub.8H.sub.19N 129.25 1,1,-sulfonyldiimidazole C.sub.6H.sub.6N.sub.4O.sub.2S 198.20 potassium fluoride KF 58.10 trifluoroacetic acid C.sub.2HF.sub.3O.sub.2 114.02

    TABLE-US-00106 TABLE 27B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 1H-indole-4-ol 1 1.2 9.0 N/A diisopropylethylamine 3 N/A 27.0 Density 0.742 g/mL 4.7 mL 1,1-sulfonyldiimidazole 5.1 9.06 45.7 N/A potassium fluoride 14 7.35 127 N/A trifluoroacetic acid 33 N/A 300 Density 1.49 g/mL 23.1 mL

    TABLE-US-00107 TABLE 27C Physical Properties of Products MM Product Formula (g/mol) 1H-indol-4-yl sulfurofluoridate C.sub.8H.sub.6FNO.sub.3S 215.20

    TABLE-US-00108 TABLE 27D Relative Amounts of Products Product Theoretical Actual Yield 1H-indol-4-yl sulfurofluoridate 1.9 g 1.80 g 93%

    [0319] A 40 mL capped vial (gas generation vial) was charged with 1,1,sulfonyldiimidazole (9.06 g, 44.8 mmol), potassium fluoride (7.35 g, 127 mmol), and water (30 mL) and then equipped with a magnetic stir bar. Next, 1H-indole-4-ol (1.2 g, 9.0 mmol), and diisopropylethylamine (4.7 mL, 27.3 mmol) were added to a second 40 mL capped vial (reaction vial) with acetonitrile (25 mL).

    [0320] A connecting PTFE tube was used to link the gas generation vial with the reaction vial. An empty balloon was attached to the reaction vial to balance overpressure. Trifluoroacetic acid (23.4 mL, 306 mmol) was added via syringe pump over 15 minutes.

    [0321] Upon completion (45 min) the reaction system was disassembled and evaporated to dryness. The organic residue (from reaction flask) was then reconstituted with ethyl acetate (25 mL) and extracted with an aqueous solution of hydrochloric acid (1M, 210 mL). The combined organic extracts were washed with brine (210 mL), and then concentrated under vacuum to give 1H-indol-4-yl sulfurofluoridate (1.8 g, 8.36 mmol, 93%) as an off-white powder.

    Example XXVIII

    [0322] The method shown in FIG. 28 was carried out. The reagents and products included a total volume of 10.49 ml, including 8.78 mL of acetonitrile and 1.71 mL of DIPEA with a reaction molarity of 234 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 28A and Table 28B. Details of the products are shown in Table 28C and Table 28D.

    TABLE-US-00109 TABLE 28A Physical Properties of Reagents Reagent Formula MM (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol C.sub.14H.sub.18N.sub.2O 230.31 N,N-diisopropylethylamine C.sub.8H.sub.19N 129.25 1,1-sulfonylbis(1H-imidazole) C.sub.6H.sub.6N.sub.4O.sub.2S 198.20 potassium fluoride KF 58.10 trifluoroacetic acid C.sub.2HF.sub.3O.sub.2 114.02

    TABLE-US-00110 TABLE 28B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 3-(2-(pyrrolidin-1-yl)ethyl)- 1 0.566 2.46 N/A 1H-indol-4-ol N,N-diisopropylethylamine 4 N/A 9.8302 Density 0.742 g/mL Volume 1.71 mL 1,1-sulfonylbis(1H-imidazole) 6.5 3.2 16.00 N/A potassium fluoride 15.7 2.32 40.00 N/A trifluoroacetic acid 42.3 N/A 104 Density 1.49 g/mL 8.08 mL

    TABLE-US-00111 TABLE 28C Physical Properties of Products MM Product Formula (g/mol) 1-(fluorosulfonyl)-3-(2-(pyrrolidin-1- C.sub.14H.sub.16F.sub.2N.sub.2O.sub.5S.sub.2 394.41 yl)ethyl)-1H-indol-4-yl sulfurofluoridate

    TABLE-US-00112 TABLE 28D Relative Amounts of Products Product Theoretical Actual Yield 1-(fluorosulfonyl)-3-(2-(pyrrolidin-1- 969 mg 245 mg 25.3% yl)ethyl)-1H-indol-4-yl sulfurofluoridate

    [0323] A 20 ml capped vial (gas generation vial) was charged with 1,1,sulfonyldiimidazole (3.2 g, 16.0 mmol), potassium fluoride (2.32 g, 40 mmol), and water (11 mL) and then equipped with a magnetic stir bar. Next, 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol (0.566 g, 2.46 mmol), and diisopropylethylamine (1.7 mL, 9.83 mmol) were added to a second 20 ml capped vial (reaction vial) with acetonitrile (8.78 mL).

    [0324] A connecting PTFE tube was used to link the gas generation vial with the reaction vial. An empty balloon was attached to the reaction vial to balance overpressure. Trifluoroacetic acid (8.08 mL, 104 mmol) was added via syringe pump over 10 minutes.

    [0325] Upon completion (8 hours) the reaction system was disassembled, and the contents of the reaction flask was diluted with dichloromethane (100 mL). This solution was washed with water (460 mL) and the combined organic fraction was washed with saturated brine (260 mL). The dichloromethane layer was dried with sodium sulfate and evaporated to dryness. Residue was suspended in a minimum volume of dichloromethane and purified via column chromatography (12 g silica column, eluting with ethyl acetate) to give 1-(fluorosulfonyl)-3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl sulfurofluoridate (245 mg, 0.621 mmol, 25.3%) as a clear oil.

    [0326] The product was characterized by both 1H NMR (300 MHz, CD2Cl2) 7.83 (dd, J=8.1, 1.0 Hz, 1H), 7.44-7.27 (m, 3H), 3.09-2.85 (m, 2H), 2.81-2.68 (m, 2H), 2.58-2.39 (m, 4H), 1.80-1.57 (mi, 4H) and 19F NMR (282 MHz, CD2C2) 54.25, 39.51.

    Example XXIX

    [0327] The method shown in FIG. 29 was carried out. The reagents and products included a total volume of 20 ml of DCM with a reaction molarity of 22 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 29A and Table 29B. Details of the products are shown in Table 29C and Table 29D.

    TABLE-US-00113 TABLE 29A Physical Properties of Reagents Reagent Formula MM (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)- C.sub.14H.sub.18N.sub.2O 230.31 1H-indol-4-ol 1,1-sulfonylbis(1H-imidazole) C.sub.6H.sub.6N.sub.4O.sub.2S 198.20 potassium fluoride KF 58.10 trifluoroacetic acid C.sub.2HF.sub.3O.sub.2 114.02

    TABLE-US-00114 TABLE 29B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 3-(2-(pyrrolidin-1-yl)ethyl)- 1 0.100 0.434 N/A 1H-indol-4-ol 1,1-sulfonylbis(1H-imidazole) 6.5 3.2 16.00 N/A potassium fluoride 15.7 2.32 40.00 N/A trifluoroacetic acid 42.3 N/A 104 Density 1.49 g/mL 8.08 mL

    TABLE-US-00115 TABLE 29C Physical Properties of Products MM Product Formula (g/mol) 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl C.sub.14H.sub.17FN.sub.2O.sub.3S 312.36 sulfurofluoridate

    TABLE-US-00116 TABLE 29D Relative Amounts of Products Product Theoretical Actual Yield 3-(2-(pyrrolidin-1-yl)ethyl)-1H- 136 mg 26 mg 19% indol-4-yl sulfurofluoridate

    [0328] A 20 ml capped vial (gas generation vial) was charged with 1,1,sulfonyldiimidazole (3.2 g, 16.0 mmol), potassium fluoride (2.32 g, 40 mmol), and water (11 mL) and then equipped with a magnetic stir bar. Next, 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol (0.566 g, 2.46 mmol) was added to a second 20 ml capped vial (reaction vial) with dichloromethane (20 mL).

    [0329] A connecting PTFE tube was used to link the gas generation vial with the reaction vial. An empty balloon was attached to the reaction vial to balance overpressure. Trifluoroacetic acid (8.08 mL, 104 mmol) was added via syringe pump over 10 minutes.

    [0330] Upon completion (2 hours) the reaction system was disassembled, and the heterogenous sultry was filtered. The clear supernatant was evaporated to dryness and the residue was suspended in a minimum volume of dichloromethane and purified via column chromatography (12 g silica column, eluting with a gradient of dichloromethane moving to 10% dichloromethane in methanol) to give 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-yl sulfurofluoridate (0.026 g, 0.083 mmol, 19%) as a clear oil.

    [0331] The product was characterized by both 1H NMR (400 MHz, CD2Cl2) 10.09 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.35-6.94 (m, 3H), 3.49-3.40 (m, 2H), 3.32 (q, J=5.2 Hz, 4H), 3.01-2.95 (m, 2H), 2.28-1.86 (m, 4H) and 19F NMR (282 MHz, CD2Cl2) 39.14.

    Example XXX

    [0332] The method shown in FIG. 30 was carried out. The reagents and products included a total volume of 57 mL, including 50 mL of acetone and 5 mL of water, with a reaction molarity of 98 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 30A and Table 30B. Details of the Products are shown in Table 30C and Table 30D.

    TABLE-US-00117 TABLE 30A Physical Properties of Reagents Reagent Formula MM (g/mol) 3-allyl-1H-indol-4-yl C.sub.25H.sub.24NO.sub.4P 433.44 dibenzyl phosphate 2,6-lutidine C.sub.7H.sub.9N 107.16 potassium osmate dihydrate H.sub.4K.sub.2O.sub.6Os 368.45 4-methylmorpholine 4-oxide C.sub.5H.sub.11NO.sub.2 117.15

    TABLE-US-00118 TABLE 30B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes 3-allyl-1H-indol-4-yl 1 2.40 g 5.54 mmol N/A dibenzyl phosphate acetone N/A N/A N/A 50 mL water N/A N/A N/A 5 mL 2,6-lutidine 2.5 1.48 g 13.8 mmol Density 0.925 g/mL Volume 1.60 mL potassium osmate dihydrate 0.03 61.2 mg 1.38 mmol N/A 4-methylmorpholine 4-oxide 2.5 1.87 g 13.8 mmol N/A

    TABLE-US-00119 TABLE 30C Physical Properties of Products Product Formula MM (g/mol) dibenzyl (3-(2,3-dihydroxypropyl)- C.sub.25H.sub.26NO.sub.6P 467.46 1H-indol-4-yl) phosphate

    TABLE-US-00120 TABLE 30D Physical Properties of Products Product Theoretical Actual Yield dibenzyl (3-(2,3-dihydroxypropyl)- 2.59 g 1.32 g 51.0% 1H-indol-4-yl) phosphate

    [0333] 50 mL of acetone and 5 mL of water was added to a 100 mL round bottom flask containing 3-allyl-1H-indol-4-yl dibenzyl phosphate (2.40 g, 1 Eq, 5.54 mmol). 2,6-lutidine (1.60 mL, 2.5 Eq, 13.8 mmol) was added in one portion. Potassium Osmate (61.2 mg, 3 mol %, 166 mol) was added in one portion. 4-Methylmorpholine 4-oxide (1.87 g, 2.5 Eq, 13.8 mmol) was added in one portion.

    [0334] The reaction was stirred vigorously at 25 C. for 6 hours. Upon completion, the reaction was quenched with a saturated solution of sodium thiosulfate (20 mL). Acetone was removed under reduced pressure and the resulting crude mixture was diluted with ethyl acetate (50 mL). The organic phase was separated and was further washed with an aqueous solution of hydrochloric acid (0.5M, 320 mL), saturated solution of sodium bicarbonate (20 mL) and brine (20 mL)

    [0335] The resulting organic extracts were concentrated in vacuo. The crude material was purified by flash chromatography using ethyl acetate:hexanes (9:1) as eluent to afford dibenzyl (3-(2,3-dihydroxypropyl)-1H-indol-4-yl) phosphate (1.32 g, 2.82 mmol, 51.0%) as a clear oil.

    [0336] The product was characterized by 1H NMR (300 MHz, chloroform-D). The observed peaks on 1H NMR were 2.91 (dd, J=14.62, 7.54 Hz, 1H) 3.09 (dd, J=14.28, 5.60 Hz, 1H) 3.49 (dd, J=11.19, 6.40 Hz, 1H) 3.61 (dd, J=11.19, 3.65 Hz, 1H) 3.95-4.06 (m, 1H) 6.95-7.09 (m, 3H) 7.13-7.19 (m, 1H) 7.27-7.37 (m, 10H) 8.24 (br. s., 1H).

    Example XXXI

    [0337] The method shown in FIG. 31 was carried out using a sequential, telescoped procedure. The reagents and products included a total volume of 240 mL, including 160 mL of tert-butanol and 80 mL of water with a reaction molarity of 84.6 mmolar at a temperature of 25 C. Details of the reagents are shown in Table 31A and Table 31B. Details of the Products are shown in Table 31C and Table 31D.

    TABLE-US-00121 TABLE 31A Physical Properties of Reagents Reagent Formula MM (g/mol) dibenzyl (1H-indol-4-yl) phosphate C.sub.22H.sub.20NO.sub.4P 393.38 allyl alcohol C.sub.3H.sub.6O 58.1 triethyl borane C.sub.6H.sub.15B 98.0 tetrakis(triphenylphosphine) palladium C.sub.72H.sub.60P.sub.4Pd 1155.6 3-allyl-1H-indol-4-yl dibenzyl phosphate C.sub.25H.sub.24NO.sub.4P 433.44 potassium tetrahydroxydioxidoosmium K.sub.2OsO.sub.6H.sub.4 368.45 potassium carbonate K.sub.2CO.sub.3 138.20 potassium ferricyanide K.sub.3FeC.sub.6N.sub.6 329.25

    TABLE-US-00122 TABLE 31B Relative Amounts of Reagents and Solvents Reagent Eq M (g) mmol Notes dibenzyl (1H-indol-4-yl) 1 10.0 25.4 N/A phosphate allyl alcohol 1.1 N/A 28.0 Density 0.854 g/mol Volume 1.9 mL triethyl borane 0.8 N/A 20.3 1.0 M in hexanes Volume 20.3 mL tetrakis(triphenylphosphine) 0.068 2.0 1.73 N/A palladium potassium 0.02 0.150 0.406 N/A tetrahydroxydioxidoosmium potassium carbonate 4.5 12.60 91.4 N/A potassium ferricyanide 4.5 30.10 91.4 N/A

    TABLE-US-00123 TABLE 31C Physical Properties of Products Product Formula MM (g/mol) dibenzyl (3-(2,3-dihydroxypropyl)- C.sub.25H.sub.26NO.sub.6P 467.46 1H-indol-4-yl) phosphate

    TABLE-US-00124 TABLE 31D Relative Amounts of Products Product Theoretical Actual Yield dibenzyl (3-(2,3-dihydroxypropyl)- 9.49 g 1.19 g 12.6% 1H-indol-4-yl) phosphate

    [0338] Dibenzyl (1H-indol-4-yl) phosphate (10.0 g, 1 Eq, 25.4 mmol) and tetrakis(triphenylphosphine) palladium (2.0 g, 0.068 Eq, 1.73 mmol) were added to a 500 mL flask and sparged with argon. While sparging, THE (254 mL) was added to the flask, followed by allyl alcohol (1.9 mL, 1.1 Eq, 28.0 mmol, and finally triethylborane (1.0 M in hexanes, 20.3 mL, 0.8 Eq, 20.3 mmol).

    [0339] The reaction was heated at 45 C. and stirred for 5.5 hours under an argon atmosphere. Upon completion, reaction mixture was concentrated under vacuum. Then the crude material was passed down a pad composed of a sequential layer of Celite diatomaceous earth (20 g) and silica gel (100 g) and sand eluting with 1:1 petroleum ether:ethyl acetate.

    [0340] For the second transformation, tert-butanol (160 mL) and water (80.0 mL) was charged into a 250 mL, screw cap bottle, followed by the crude 3-allyl-1H-indol-4-yl dibenzyl phosphate (8.80 g, 20.3 mmolisolated from the previous step without purification), potassium ferricyanide (30.1 g, 91.4 mmol) and potassium carbonate (12.6 g, 4.5 Eq, 91.4 mmol). Potassium tetrahydroxydioxidoosmium (150 mg, 406 mol) was then charged last and the bottle was sealed, ensuring minimal headspace remained. The mixture became heterogenous over time, forcing the stirring to be adjusted to ensure the suspension remained well mixed.

    [0341] After 4 days, the reaction was completed and now presented as a dark slurry with copious yellow precipitate. The slurry was transferred into a 1 L flask, and treated with methanol (250 mL) to force more solids to crash out of the reaction. The slurry was then filtered over C elite (20 g) and washed with methanol (50 mL). The combined supernatant was concentrated via rotary evaporation until reduced to 60 mL in volume.

    [0342] The concentrated residue was extracted with ethyl acetate (2250 mL). The combined organic phase was then washed with an aqueous solution of hydrochloric acid (1M, 3300 ml), then saturated sodium bicarbonate solution (100 mL)

    [0343] The combined organic fractions were dried with sodium sulfate, then passed down a pad composed of Celite diatomaceous earth (20 g), Silica Gel (100 g) and sand (100 g). After collection via vacuum filtration, the organic fraction was evaporated to dryness to give a crude oil. This was purified by column chromatography (20 g silica gel, eluting with petroleum ether to 4:1 petroleum ether:ethyl acetate via linear gradient) to afford dibenzyl (3-(2,3-dihydroxypropyl)-1H-indol-4-yl) phosphate (1.19 g, 2.554 mmol, 12.6%) as a clear oil.

    [0344] The product was characterized by 1H NMR (400 MHz, CDCl3) 8.52 (s, 1H), 7.26 (ddt, J=12.9, 7.0, 2.7 Hz, 13H), 7.10 (dt, J=7.7, 1.1 Hz, 1H), 7.03-6.85 (m, 3H), 5.13-5.02 (m, 4H), 3.54 (dd, J=11.3, 3.5 Hz, 1H), 3.42 (dd, J=11.3, 6.5 Hz, 1H), 3.01 (dd, J=14.5, 5.5 Hz, 1H), 2.86 (dd, J=14.5, 7.6 Hz, 1H).

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    Examples Only

    [0376] In the preceding description, for purposes of explanation, numerous details are set forth in order to provide a thorough understanding of the embodiments. However, it will be apparent to one skilled in the art that these specific details are not required.

    [0377] The above-described embodiments are intended to be examples only. Alterations, modifications and variations can be effected to the particular embodiments by those of skill in the art. The scope of the claims should not be limited by the particular embodiments set forth herein, but should be construed in a manner consistent with the specification as a whole.