Bifunctional organic catalysts

Abstract

The present invention provides a bifunctional catalyst of the formula (1): wherein: each R.sup.1 is independently selected from an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group and an optionally substituted alkaryl group; Z represents a divalent organic linking moiety optionally containing one or more stereocenters; and EWG represents an electron-withdrawing group.
(R.sup.1).sub.3PNZNH-EWG(1)

Claims

1. A catalyst having the formula (2): ##STR00110## wherein: each R.sup.1 is independently selected from the group consisting of an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group and an optionally substituted alkaryl group; EWG is an electron-withdrawing group selected from the group consisting of groups having the formulae C(X)NHR.sup.2, C(X)R.sup.2, SO.sub.2R.sup.2 and C(X)XR.sup.2, wherein X is selected from the group consisting of O and S, and wherein R.sup.2 is selected from the group consisting of an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group and an optionally substituted alkaryl group; R.sup.3, R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, an optionally substituted (C.sub.1-C.sub.10)alkyl group, an optionally substituted (C.sub.3-C.sub.10)cycloalkyl group, an optionally substituted (C.sub.6-C.sub.10)aryl group, an optionally substituted (C.sub.4-C.sub.9)heteroaryl group, an optionally substituted (C.sub.7-C.sub.14)aralkyl group, an optionally substituted (C.sub.13-C.sub.20)di-aryl-alkyl group and an optionally substituted (C.sub.7-C.sub.14)alkaryl group, or any two of R.sup.3, R.sup.4 or R.sup.5 on adjacent carbon atoms may together form a methylene chain having the formula (CH.sub.2).sub.m, wherein m is an integer of from 3 to 5, and wherein at least one of R.sup.3, R.sup.4 and R.sup.5 is not hydrogen; and n is an integer of from 0 to 3.

2. A catalyst according to claim 1, wherein each R.sup.1 is independently selected from the group consisting of an optionally substituted (C.sub.1-C.sub.10)alkyl group, an optionally substituted (C.sub.3-C.sub.10)cycloalkyl group, an optionally substituted (C.sub.6-C.sub.10)aryl group, an optionally substituted (C.sub.4-C.sub.9)heteroaryl group, an optionally substituted (C.sub.7-C.sub.14)aralkyl group and an optionally substituted (C.sub.7-C.sub.14)alkaryl group.

3. A catalyst according to claim 1, wherein EWG is selected from the group consisting of C(O)NHR.sup.2 and C(S)NHR.sup.2, wherein R.sup.2 is selected from the group consisting of an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group and an optionally substituted alkaryl group; or EWG is selected from the group consisting of C(O)NHR.sup.2 and C(S)NHR.sup.2, wherein R.sup.2 is selected from the group consisting of an optionally substituted (C.sub.1-C.sub.10)alkyl group, an optionally substituted (C.sub.3-C.sub.10)cycloalkyl group, an optionally substituted (C.sub.6-C.sub.10)aryl group, an optionally substituted (C.sub.4-C.sub.9)heteroaryl group, an optionally substituted (C.sub.7-C.sub.14)aralkyl group and an optionally substituted (C.sub.7-C.sub.14)alkaryl group.

4. A catalyst according to claim 1, wherein EWG has the formula: ##STR00111## wherein: X is selected from the group consisting of S and O; R.sup.19 is selected from the group consisting of hydrogen and C(Z)N(R.sup.21).sub.2, wherein Z is selected from the group consisting of S and O, and each R.sup.21 is independently selected from the group consisting of hydrogen, an optionally substituted (C.sub.1-C.sub.10)alkyl group, an optionally substituted (C.sub.3-C.sub.10)cycloalkyl group, an optionally substituted (C.sub.6-C.sub.10)aryl group, an optionally substituted (C.sub.4-C.sub.9)heteroaryl group, an optionally substituted (C.sub.7-C.sub.14)aralkyl group and an optionally substituted (C.sub.7-C.sub.14)alkaryl group; and each R.sup.20 is independently selected from the group consisting of hydrogen, an optionally substituted (C.sub.1-C.sub.10)alkyl group, an optionally substituted (C.sub.3-C.sub.10)cycloalkyl group, an optionally substituted (C.sub.6-C.sub.10)aryl group, an optionally substituted (C.sub.4-C.sub.9)heteroaryl group, an optionally substituted (C.sub.7-C.sub.14)aralkyl group and an optionally substituted (C.sub.7-C.sub.14)alkaryl group; or EWG is: ##STR00112##

5. A catalyst according to claim 1, having the formula (3): ##STR00113## or having the formula (4); ##STR00114## wherein X is S or O.

6. A catalyst according to claim 5, wherein at least one of R.sup.3 and R.sup.5 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, phenyl, 4-methylphenyl, 4-methoxyphenyl, 2,5-dimethyl phenyl, benzyl, 4-methoxybenzyl, diphenylmethyl, iso-propyloxymethyl and tert-butyloxymethyl, or in the case where n is 0, R.sup.3 and R.sup.5 may together form a methylene chain having the formula (CH.sub.2).sub.m, wherein m is 3 or 4.

7. A catalyst according to claim 1, wherein n is an integer from 0 to 2.

8. A catalyst according to claim 1, having the formula (5) or (6): ##STR00115## with the proviso that R.sup.3 is not hydrogen; or having the formula (7) or (8): ##STR00116## with the proviso that R.sup.5 is not hydrogen; or having the formula (9) or (10): ##STR00117## with the proviso that R.sup.3 is not hydrogen; or having the formula (11) or (12): ##STR00118## with the proviso that R.sup.5 is not hydrogen; or having the formula (13) or (14): ##STR00119## with the proviso that R.sup.3 is not hydrogen; or having formula (15) or (16): ##STR00120## with the proviso that R.sup.5 is not hydrogen; or having the formula (17), (18), (19) or (20): ##STR00121## with the provisos that R.sup.3 is not hydrogen and R.sup.5 is not hydrogen, or having the formula (21) or (22): ##STR00122## with the proviso that R.sup.3 is not hydrogen; or having the formula (23) or (24): ##STR00123## with the proviso that R.sup.5 is not hydrogen; or having the formula (25), (26), (27) or (28): ##STR00124## with the provisos that R.sup.3 is not hydrogen and R.sup.5 is not hydrogen; or having the formula (23) or (24) wherein X is S, R.sup.1 is phenyl or 4-methoxyphenyl, R.sup.2 is selected from the group consisting of 4-(trifluoromethylphenyl), 3,5-bis-(trifluoromethyl)phenyl and 4-nitrophenyl, and R.sup.5 is selected from the group consisting of iso-propyl, tert-butyl, phenyl, benzyl and diphenylmethyl.

9. A catalyst according to claim 7, wherein n is 0 or 1.

10. A catalyst according to claim 9, wherein n is 0.

Description

EXAMPLES

Example 1

Preparation of Carbamate Precursors

(1) General procedures for the preparation of carbamate precursors of the catalysts of the invention are illustrated by reference to the preparation of precursor (101).

(2) ##STR00071##

(3) A stirred solution of aminoalcohol (100) (8.98 g, 59.5 mmol) in CH.sub.2Cl.sub.2 (200 mL) was cooled to 0 C. and NEt.sub.3 (9.0 mL, 65.4 mmol) and Boc.sub.2O (12.9 g, 59.5 mmol) were added successively. The reaction mixture was left stirring at it for 16 h, then solvents were evaporated and the resulting crude product was purified by flash column chromatography to provide 12.4 g (80%) of the N-Boc-protected aminoalcohol as a colourless solid.

(4) A solution of N-Boc-protected aminoalcohol (12.4 g, 49.4 mmol) in CH.sub.2Cl.sub.2 (100 mL) was cooled to 0 C. and NEt.sub.3 (13.7 mL, 98.8 mmol) and TsCl (9.4 g, 49.4 mmol) were added successively. The reaction mixture was left stirring at it for 24 h and then 250 mL H.sub.2O were added. The phases were separated and the aqueous one was extracted with CH.sub.2Cl.sub.2. The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting crude product was purified by flash column chromatography to provide 12.0 g (60%) of the tosylate as a colourless solid.

(5) The tosylate compound (1.25 g, 3.08 mmol) was dissolved in DMF (10 mL). NaN.sub.3 (220 mg, 3.39 mmol) was added and the resulting suspension was stirred at 45 C. for 7 h. After cooling to rt, 15 mL H.sub.2O were added and it was extracted with Et.sub.2O, dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting crude product was purified by flash column chromatography to obtain 460 mg (54%) of precursor (101) as a colourless solid.

(6) Precursor (101) may be used to prepare a carbamate catalyst according to the present invention. Alternatively, the carbamate protecting group may be removed and converted to a different hydrogen bond donor group.

(7) It will be understood by the skilled person, that alternative routine procedures are available to produce azide precursors such as (101). For instance, the hydroxy group may be converted to an iodide leaving group instead of a sulfonate. Alternatively, the azide may be produced from a primary amine group by the use of a suitable diazo-transfer reagent.

Example 2

Preparation of Urea and Thiourea Precursors

(8) General procedures for the preparation of urea and thiourea precursors of the catalysts of the invention are illustrated by reference to the preparation of precursor (102) from the carbamate precursor (101).

(9) ##STR00072##

(10) A 2M solution of HCl in Et.sub.2O (15 mL, 30 mmol) was added dropwise to protected aminoazide (101) (0.386 g, 1.40 mmol) and the resulting solution was stirred at rt for 24 h. NaOH solution (2M) was added until pH 12 and the aqueous phase was extracted with Et.sub.2O (320 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude aminoazide was dissolved in 5.0 mL THF, 3,5-Bis(trifluoromethyl)phenyl isothiocyanate (0.250 mL, 1.49 mmol) was added dropwise and the solution was stirred at rt for 16 h. After evaporation of the solvents, the crude product was purified by flash column chromatography to obtain 447 mg of precursor (102) (71% yield over 2 steps) as a colourless solid.

(11) Corresponding urea precursors may be obtained by a similar procedure in which the isothiocyanate reagent is replaced by the corresponding isocyanate.

Example 3

Preparation of Amide Precursors

(12) General procedures for the preparation of amide precursors of the catalysts of the invention are illustrated by reference to the preparation of precursor (104) from the carbamate precursor (103).

(13) ##STR00073##

(14) TFA (0.50 mL) was added dropwise to protected aminoazide (103) (100 mg, 0.41 mmol) at 0 C. and the resulting solution was allowed to warm to it and stirred for 3 h. NaOH solution (2M) was added until pH 12 and the aqueous phase was extracted with Et.sub.2O, dried over Na.sub.2SO.sub.4 and concentrated. The crude aminoazide was dissolved in Et.sub.2O (1.4 mL) and Et.sub.3N (0.07 mL, 0.474 mmol). The solution was cooled to 0 C. and 3,5-bis(trifluoromethyl)benzoyl chloride (0.083 mL, 0.454 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 5 h. After evaporation of the solvents, the crude product was purified by flash column chromatography to obtain 135 mg of precursor (104) (85% yield over 2 steps) as a colourless solid.

Example 4

Preparation of Sulfonamide Precursors

(15) General procedures for the preparation of sulfonamide precursors of the catalysts of the invention are illustrated by reference to the preparation of precursor (105) from the carbamate precursor (103).

(16) ##STR00074##

(17) TFA (0.50 mL) was added dropwise to protected aminoazide (103) (100 mg, 0.41 mmol) at 0 C. and the resulting solution was allowed to warm to it and stirred for 3 h. NaOH solution (2M) was added until pH 12 and the aqueous phase was extracted with Et.sub.2O, dried over Na.sub.2SO.sub.4 and concentrated. The crude aminoazide was dissolved in Et.sub.2O (1.4 mL) and Et.sub.3N (0.07 mL, 0.474 mmol). The solution was cooled to 0 C. and 4-toluenesulfonyl chloride (87 mg, 0.454 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 5 h. After evaporation of the solvents, the crude product was purified by flash column chromatography (PE-PE/EtOAc 9:1) to obtain 30 mg of precursor (105) (25% yield over 2 steps) as a colourless solid.

Example 5

Preparation of Bifunctional Catalysts

(18) General procedures for the preparation of catalysts of the invention are illustrated by reference to the preparation of catalyst (107).

(19) ##STR00075##

(20) To azide (106) (300 mg, 0.726 mmol) in Et.sub.2O (1.8 mL) under an argon atmosphere was added triphenylphosphine (190 mg, 0.726 mmol) at rt. Stirring was maintained at room temperature for 26 h and the reaction mixture was then concentrated in vacuo to afford a colourless foam. Pentane (4 mL) was added under N.sub.2 and the mixture stirred vigorously for 2 h. The resultant suspension was filtered and dried in vacuo to afford catalyst (107) as a colourless solid (344 mg, 73% yield).

Example 6

General Procedures for the Preparation of Nitro-Mannich Addition Products

(21) ##STR00076##

(22) General procedure A: 0.02 mmol of catalyst is added to a stirred suspension of ketimine (108) (0.20 mmol) in MeNO.sub.2 (0.22 mL, 4.0 mmol) at 15 C. and the reaction mixture stirred at 15 C. in a closed vial until disappearance of starting material by TLC or for a maximum of 96 h. The reaction is quenched by addition of 0.02 mL of 1M acetic acid solution in CH.sub.2Cl.sub.2 and stirred at it for 5 min. After evaporation of the solvents, .sup.1H NMR conversion was measured and the crude reaction mixture was purified by flash column chromatography.

(23) General procedure B: 0.02 mmol of catalyst is added to a stirred suspension of ketimine (108) (0.20 mmol) in MeNO.sub.2 (0.22 mL, 4.0 mmol) at 0 C. and the reaction mixture stirred at 0 C. in a closed vial until disappearance of starting material by TLC or for a maximum of 48 h. The reaction is quenched by addition of 0.02 mL of 1M acetic acid solution in CH.sub.2Cl.sub.2 and stirred at rt for 5 min. After evaporation of the solvents, .sup.1H NMR conversion was measured and the crude reaction mixture was purified by flash column chromatography.

(24) General procedure C: 0.02 mmol of catalyst is added to a stirred suspension of ketimine (108) (0.20 mmol) in MeNO.sub.2 (0.22 mL, 4.0 mmol) at rt and the reaction mixture stirred at rt in a closed vial until disappearance of starting material by TLC or for a maximum of 24 h. The reaction is quenched by addition of 0.02 mL of 1M acetic acid solution in CH.sub.2Cl.sub.2 and stirred at rt for 5 min. After evaporation of the solvents, .sup.1H NMR conversion was measured and the crude reaction mixture was purified by flash column chromatography.

Example 7

Preparation of Racemic Nitro-Mannich Addition Products

(25) ##STR00077##

(26) Racemic catalysts having the formula (110)-(114) were used to produce racemic nitro-Mannich addition product (109) from ketimine (108) and nitromethane using general procedure C. The results are shown in Table 1.

(27) ##STR00078##

(28) TABLE-US-00001 TABLE 1 Conversion EWG (%) 110 98 111 0 97 112 98 113 92 114 99

Example 8

Stereoselective Preparation of Nitro-Mannich Addition Products

(29) Effect of Linking Moiety

(30) Catalysts having the formula (107) and (115)-(122) were used to produce nitro-Mannich addition product (109) from ketimine (108) and nitromethane using general procedure C. The results are shown in Table 2.

(31) ##STR00084## ##STR00085##

(32) TABLE-US-00002 TABLE 2 Catalyst Conversion (%) e.e. (%) 107 98 85 115 93 78 116 94 77 117 95 77* 118 93 70* 119 48 34* 120 98 20* 121 98 7 122 99 3 *products obtained with opposite stereochemistry to that shown above

Example 9

Stereoselective Preparation of Nitro-Mannich Addition Products

(33) Effect of Hydrogen Bond Donor

(34) Catalysts having the formula (107) and (123)-(133) were used to produce nitro-Mannich addition product (109) from ketimine (108) and nitromethane using general procedure C. The results are shown in Table 3.

(35) ##STR00086##

(36) TABLE-US-00003 TABLE 3 Conv. e.e. EWG (%) (%) 107 98 85 123 99 68 124 97 79 125 0 98 73 126 98 79 127 98 11 128 98 86 129 92 0 130 98 70 131 99 0 132 98 38 133 98 38

(37) The results in Table 2 demonstrate that good levels of stereoselectivity are obtained using catalysts in which the hydrogen bond donor is a thiourea or urea group. The presence of electron withdrawing groups on the thiourea or urea group increases the stereoselectivity. Lower levels of stereoselectivity are obtained with the amide catalyst (127). The sulfonamide catalyst (129) and the carbamate catalyst (131) provide negligible stereoselectivity.

(38) Almost quantitative conversions are obtained for all systems. Systems in which the hydrogen bond donor group is an amide, sulfonamide or a carbamate thus have utility for the efficient production of achiral and racemic addition products.

Example 10

Preparation of Nitro-Mannich Addition Products

(39) Effect of the Iminophosphorane

(40) The effect of the iminophosphorane substituents on the reaction rate was examined by reacting ketimine (108) with nitromethane at room temperature in the presence of catalysts (107), (134) and (135) and deuterated tetrahydrofuran. The conversion to addition product (109) was measured by .sup.1H NMR spectroscopy at 10 minute intervals and the results are shown in Figure 1. It is found that the reaction rate varies strongly with the substituents of the iminophosphorane moiety. The reaction with catalyst (135) is noticeably slower than with (107) or (134) which is believed to be due to the lower basicity of the iminophosphorane moiety.

(41) ##STR00099##

(42) The reaction of ketimine (108) with nitromethane was also examined in the presence of catalyst (136), which contains an iminophosphorane derived from a tri-alkyl phosphine.

(43) ##STR00100##

(44) The addition product (109) was obtained after 24 h in 99% conversion and 42% e.e.

Comparative Example 11

Preparation of Nitro-Mannich Addition Products with Cinchonine-Derived Organocatalyst

(45) Example 10 was repeated using the cinchonine-derived thiourea catalyst III instead of the catalysts of the present invention. After 24 h only traces (0.04%) of the addition product were observed. This clearly demonstrates that the increased reactivity of the catalyst systems of the present invention is due to the basicity of the iminophosphorane group. Furthermore, the basicity of the catalysts according to the present invention can be tuned to the acidity of a given substrate, whereas the basicity of cinchonine derivatives cannot readily be modified.

Example 12

Stereoselective Preparation of Nitro-Mannich Addition Products

(46) The catalyst of formula (107) was used to produce nitro-Mannich addition products from a range of ketimines and nitromethane using general procedures A and B. The results are shown in Table 2.

(47) ##STR00101##

(48) TABLE-US-00004 TABLE 3 Conversion R.sup.a R.sup.b T ( C.) t (h) (%) e.e. (%) C.sub.6H.sub.5 Me 15 96 89 95 4-MeC.sub.6H.sub.4 Me 0 48 96 89 4-MeOC.sub.6H.sub.4 Me 0 48 99 91 3-MeOC.sub.6H.sub.4 Me 0 48 98 91 2-MeOC.sub.6H.sub.4 Me 0 48 99 91 4-PhC.sub.6H.sub.4 Me 0 24 99 90 4-NO.sub.2C.sub.6H.sub.4 Me 15 21 98 93 2-FC.sub.6H.sub.4 Me 15 96 90 94 4-FC.sub.6H.sub.4 Me 0 48 98 85 4-ClC.sub.6H.sub.4 Me 0 20 99 90 4-BrC.sub.6H.sub.4 Me 15 96 87 86 3,4-Cl.sub.2C.sub.6H.sub.3 Me 0 20 99 84 3,5-(CF.sub.3).sub.2C.sub.6H.sub.3 Me 15 96 99 90 C.sub.6H.sub.5 Et 0 24 91 92 2-furyl Me 0 48 99 84 2-thienyl Me 15 96 17 92 2-thienyl Me 0 48 60 73 3-pyridyl Me 15 96 62 81 3-pyridyl Me 0 48 99 78 1-cyclohexyl Me 15 96 60 83 1-cyclohexyl 0 0 48 94 78

(49) Using the ketimine (137) at 15 C., 50% conversion and 92% e.e. was obtained after 96 h.

(50) ##STR00102##

Example 13

Stereoselective Preparation of Nitro-Mannich Addition Products

(51) Preparative Scale Reactions

(52) The catalyst of formula (134) was used to produce nitro-Mannich addition product (109) from ketimine (108) and nitromethane using general procedure C, except that 31 mmol of ketimine (108) and 10 equiv. of MeNO.sub.2 were used with only 1 mol % of catalyst. The nitro-Mannich addition product (109) was obtained after 21 h in 70% yield and 98% ee after recrystallisation.

(53) ##STR00103##

Example 14

Stereoselective Preparation of Michael Addition Products

(54) The Michael addition reaction of compound (138) to nitrostyrene (139) was examined in the presence of 10 mol % of catalyst (134).

(55) ##STR00104##

(56) The reaction product (140) was obtained in 95% yield after 12 h at 40 C., with an e.e. of 91% and a diastereomeric ratio (d.r.) of 8.3:1. This reaction has previously been reported in the presence of 20 mol % of cinchonine-derived catalyst Ill. At 20 C., the reaction catalysed by Ill takes 14 days to completion, and reaction products are obtained with lower e.e. (90%) and lower d.r. (2:1). Using catalyst (134) under the same conditions (20 C.), the reaction product is obtained in 15 minutes with 97% yield, 84% e.e., and a d.r. 6:1.

Example 15

Further Examples of Catalysts

(57) The following compounds were also prepared, and were shown to be effective as stereoselective catalysts:

(58) ##STR00105## ##STR00106##
where: R.sup.1=R.sup.2=H; R.sup.1=H, R.sup.2=Me; R.sup.1=Ph, R.sup.2=H, R.sup.1=Ph, R.sup.2=Me; or R.sup.1=Ph, R.sup.2=H,

(59) ##STR00107## ##STR00108## ##STR00109##