METHYL 2-ALLYL-1 -METHYL-3-OXOINDOLINE-2-CARBOXYLATE AND 9A-ALLYL-1,2,3,9A-TETRAHYDRO- 9H-PYRROLO[1,2-A]INDOL-9-ONE DERIVATIVES AND RELATED COMPOUNDS FOR USE AS FLUORESCENT MARKERS FOR LABELLING OF DRUGS, AMINO ACIDS AN PROTEINS

Abstract

Compounds of formulae (3) and (I) for use as fluorescent markers for labelling an amine containing target drug, an amino acid or a protein are disclosed. Exemplary compounds are e.g. (II) (III) (IV).

Claims

1. A compound according to formula (3): ##STR00066## wherein wherein R3 represents a 2-alkenyl or a 1-allenyl group; each Y group independently represents H, halogen, an alkoxy group, an optionally substituted alkyl group, an optionally substituted (CH.sub.2)K-carbocyclyl group, or an optionally substituted (CH.sub.2)K-aryl group, where K represents an integer from 0 to 6; R8 represents an optionally substituted hydrocarbyl group; R20 represents an alkyl group.

2. A compound of the formula (I): ##STR00067## wherein R3 represents a 2-alkenyl or a 1-allenyl group; each Y group independently represents H, halogen, an optionally substituted hydrocarbyl group, an alkoxy group, an optionally substituted (CH.sub.2)K-carbocyclyl group, or an optionally substituted (CH.sub.2)K-aryl group, where K represents an integer from 0 to 6; each Z group independently represents H, halogen, an optionally substituted hydrocarbyl group, or an alkoxy group.

3. The compound as claimed in claim 1, wherein R3 represents a 2-alkenyl group including 3 to 7 carbon atoms, or a 1-allenyl group including 3 to 5 carbon atoms.

4. The compound as claimed in claim 1, wherein R3 represents an unbranched 2-alkenyl group including 3 to 10 carbon atoms; preferably 3 or 4 carbon atoms.

5. The compound according to claim 1 having the structure of Formula (3a): ##STR00068## wherein R1, R2, R15, R16 and X independently represent H, or an optionally substituted hydrocarbyl group, where two or more of the R1, R2, R15 and R16 groups may combine to form a carbocyclyl group.

6. The compound as claimed in claim 1 having the structure of Formula (3b): ##STR00069## wherein R1, R15 and R16 independently represent H, or an optionally substituted hydrocarbyl group, where two or more of the R1, R15 and R16 groups may combine to form a carbocyclyl group.

7. The compound according to claim 2 having the structure of Formula (1a): ##STR00070## wherein R1, R2, R15, R16 and X independently represent H, an optionally substituted hydrocarbyl group (such as an alkyl group), where two or more of the R1, R2, R15 and R16 groups may combine to form a carbocyclyl group.

8. The compound according to claim 2 of the formula (Ib): ##STR00071## wherein R1, R15 and R16 independently represent H, an optionally substituted hydrocarbyl group (such as an alkyl group), where two or more of the R1, R15 and R16 groups may combine to form a carbocyclyl group.

9. The compound as claimed in claim 1 wherein each Y group independently represents H, a straight chain alkyl group including 1 to 6 carbon atoms, an alkoxy group having the structure —O—C.sub.1 to 6 alkyl group, or a substituted or unsubstituted C5 to 7 aryl group, generally having the structure —(CH.sub.2).sub.K-aryl group, where K is an integer from 0 to 6.

10. The compound as claimed in claim 1 wherein each Y group independently represents H, methyl, methoxy or a phenyl group.

11. The compound according to claim 1, wherein R8 represents an alkyl, alkylene, alkynyl, carbocycle, or aryl group.

12. The compound according to claim 1, wherein R8 represents a straight chain alkyl group having 1 to 6 carbon atoms, an aryl ring moiety having 5, 6 or 7 carbon ring atoms, in particular an optionally substituted (CH.sub.2)L aryl group or an optionally substituted (CH.sub.2)L heteroaryl group where L represents an integer from 1 to 10; a straight chain alkylene group having a carbon backbone of 3 to 6 carbon atoms, a straight chain alkynyl group having a carbon backbone of 3 to 6 carbon atoms, or a heteroaryl group.

13. The compound according to claim 2, wherein Z represents a hydrocarbyl group substituted with one or more oxygen, halogen or nitrogen group, generally a Cl to 6 hydrocarbyl group substituted with one or more oxygen, fluorine, iodine, or nitrogen group.

14. The compound as claimed in claim 1 wherein the compound is substantially uncharged.

15. The compound as claimed in claim 1 having a Stokes shift of more than 110 nm.

16. The compound as claimed in claim 1 having a number average molecular weight of 100 to 650 g/mol.

17. A method of synthesizing a compound as claimed in claim 1 according to reaction scheme A: ##STR00072## Wherein R4 represents a 2-alkenyl group, or a 2-alkynyl group, OTf represents trifluoromethane sulfonate; and TMS represents trimethylsilyl.

18. A method of synthesizing a compound as claimed in claim 2 according to reaction scheme (1): ##STR00073## Wherein R4 represents a 2-alkenyl group, or a 2-alkynyl group; OTf represents trifluoromethane sulfonate; and TMS represents trimethylsilyl.

19. A fluorescent label, comprising the compound as claimed in claim 1.

20. A method of ex-vivo or in-vitro cell imaging, comprising the step of providing the fluorescent label as claimed in claim 19.

21. A method of tagging a compound comprising an amine group comprising contacting the compound comprising an amine group with a compound as claimed in claim 1 and monitoring fluorescence emitted.

22. A method of measuring the amount of binding between a molecular target drug and a biological target wherein the molecular target drug comprises an amine group, including reacting the molecular target drug with the compound as claimed in claim 1, administering the resultant product to a sample comprising the biological target and monitoring fluorescence emitted from the sample.

Description

[0231] The present invention will now be described by way of Example only with reference to the accompanying figures.

[0232] FIG. 1 is a photo demonstrating the fluorescence of the compounds of the present invention. From left to right compounds 3ab, 3aa, 3bb, 3db, 3bc, 3eb, 3eb′ in DCM illuminated at 365 nm (structures provided below).

[0233] FIG. 2 is a photo demonstrating the fluorescence of the compounds of the present invention. From left to right compounds 3bh, 3cb, 3hb, 3ba, 3da, 3ca in DCM illuminated at 365 nm (structures provided below).

[0234] FIG. 3 is a photo demonstrating the fluorescence of the compounds of the present invention. From left to right compounds 3fa, 3fa′, 3ea, 3ea′, 3bd, 3ae in DCM illuminated at 365 nm (structures provided below).

[0235] FIG. 4 is a photo demonstrating the fluorescence of the compounds of the present invention. From left to right compounds 99a, 99c, 99d, 99b, 99e, 99f, 99g, in DCM illuminated at 365 nm (structures provided below).

EXAMPLES

General Procedure for Oxindole Synthesis

Proline Series: General Procedure 1

[0236] To a flame dried round-bottom flask, amine (5.0 eq) was added to a stirred solution of aryne precursor (1 eq) in MeCN (10 mL/mmol of aryne precursor, 100 mM) under an atmosphere of N2 at 25° C. To the mixture, tetrabutylammonium fluoride in THF (1M, 3 eq) was added over 2 h (dropwise). The mixture was run through a silica plug washing with EtOAc until all colour was removed. The filtrate was evaporated in vacuo to give the crude material which is purified by column chromatography (solutions of petrol and EtOAc as the eluent).

Malonate Series: General Procedure 2

[0237] CsF (7.5 eq) was added to a round bottom flask, and the flask was flame dried under vacuum. The flask was then filled with N2, a stirrer bar was added and the flask was briefly heated under high vacuum (the stirrer bar could melt if added at the same time as CsF) before being filled with N2. Then, the amine (1 eq) and MeCN (45 mL/mmol amine, 22 mM) were added and stirred under an atmosphere of N2 at 25° C. Then a solution of aryne precursor (1.5 eq) in MeCN (1 M) was added dropwise using a syringe pump over two hours, and the reaction mixture was left to stir 1 hour after that. The reaction mixture was then filtered through a celite plug, and the celite was washed with EtOAc (until the bright yellow colour was removed). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography.

Malonate Series: General Procedure 3

[0238] To a flame dried round-bottom flask, amine (1.5 eq) was added to a stirred solution of aryne precursor (1 eq) in MeCN (10 mL/mmol of aryne precursor, 100 mM) under an atmosphere of N2 at 25° C. To the mixture tetrabutylammonium fluoride solution (1 M, 2.9 eq) was added over 2 h (dropwise). The mixture was run through a silica plug washing with EtOAc until all colour is removed. The filtrate was evaporated in vacuo to give the crude material which is purified by column chromatography (solutions of petrol and EtOAc or Et2O as the eluent).

9a-allyl-1,2,3,9a-tetrahydro-9H-pyrrolo[1,2-a]indol-9-one 99a

[0239] ##STR00031##

[0240] To a flame dried round-bottom flask flushed with nitrogen, methyl allyl-L-prolinate (23, 280 mg, 1.65 mmol, 5 eq) was added to solution of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (80 IL, 0.33 mmol, 1 eq) in acetonitrile (10 mL) stirring at r.t. under nitrogen. Dried TBAF (1 M in THF, 1.32 mL, 1.32 mmol, 4.0 eq) was then added to the resulting solution, over 2 h (dropwise, using a syringe pump). The mixture was filtered and eluted through a silica plug washing with EtOAc first until all colour was removed (˜100 mL), and then with more EtOAc (100 mL) in order to get all the leftover methyl allyl-L-prolinate. The filtrate was evaporated in vacuo to give the crude material which was then purified by column chromatography (50 g silica, Hexane:EtOAc, 10:1) affording the title compound as a fluorescent yellow oil (31 mg, 44%).

.sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.55 (d, J7.7 Hz, 1H), 7.49-7.53 (m, 1H), 6.94 (d, J 8.2 Hz, 1H), 6.91 (t, J 7.4 Hz, 1H), 5.67-5.77 (m, 1H), 5.13 (dm, J 17.1 Hz, 1H), 5.02 (dm, J 10.2 Hz, 1H), 3.47-3.52 (m, 1H), 3.32-3.37 (m, 1H), 2.58 (dd, J 7.3 Hz, 13.9 Hz, 1H), 2.48 (dd, J 7.0 Hz, 13.9 Hz, 1H), 2.00-2.07 (m, 1H), 1.77-1.92 (m, 3H).

[0241] .sup.13C NMR (CDCl.sub.3, 100 MHz) δc 206.2 (1C); 165.2 (1C), 137.1 (1CH), 132.9 (1CH), 124.4 (1CH), 123.8 (1C), 120.5 (1CH), 118.6 (1CH.sub.2), 114.2 (1CH), 78.2 (1C), 51.2 (1CH.sub.2), 40.6 (1CH.sub.2), 31.8 (1CH.sub.2), 26.9 (1CH.sub.2).

[0242] IR υmax (thin film, cm.sup.−1) 3074, 2967, 2882, 1698, 1606, 1474.

[0243] UV-Vis (EtOH) λmax (nm), Σ(M.sup.−1 cm.sup.−1) 213 (5729), 230 (6388), 327 (1103), 388 (2462).

[0244] HRMS m/z (ESI.sup.+) calculated for C.sub.14H.sub.15NO [M+H]+214.1226, found 214.1228 (error −0.87 ppm).

9a-(2-Methylallyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indo1-9(9aH)-one 99b

[0245] ##STR00032##

[0246] According to general procedure 3, (S)-methyl 1-(2-methylallyl)pyrrolidine-2-carboxylate was reacted with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate to yield the title compound (15%) after column chromatography (9.5:0.5 v/v petrol:EtOAc) as fluorescent yellow oil. Rf=0.25 (9.5:0.5 v/v petrol:EtOAc)

.sup.1H NMR (CDCl.sub.3, 400 MHz) δH 1.68 (s, 3H), 1.72-1.77 (m, 1H), 1.84-1.90 (m, 1H), 1.92-1.97 (m, 1H), 2.05-2.12 (m, 1H), 2.42 (d, J 13.7 Hz, 1H), 2.66 (d, J 13.7 Hz, 1H), 3.34 (dd, J 6.6 Hz 17.9 Hz, 1H), 3.51 (dd, J 7.0 Hz 17.9 Hz, 1H), 4.73 (m, 2H), 6.90 (t, J 7.8 Hz, 1H), 6.91 (d, J 8.5 Hz, 1H), 7.50 (td, J 1.3 Hz, 7.0 Hz, 1H), 7.55 (d, J 7.6 Hz, 1H).
.sup.13C NMR (CDCl.sub.3, 100 MHz) δC 24.0 (1CH.sub.3), 27.0 (1CH.sub.2), 32.7 (1CH.sub.2), 43.5 (1CH.sub.2), 50.7 (1CH.sub.2), 78.6 (1C), 114.0 (1CH), 114.3 (1CH.sub.2) 120.3 (1CH), 123.6 (1C), 124.5 (1CH), 137.0 (1CH), 141.6 (1C), 165.1 (1C), 206.0 (1C).

[0247] IR υ.sub.max (thin film, cm.sup.−1): 1702 (C═O aryl), 1316 (C—N aryl).

[0248] UV-Vis (EtOH)λmax (nm), Σ(M.sup.−1cm.sup.−1) 200 (10588), 203 (9989), 236 (10856), 322 (513), 389 (999)

[0249] HRMS m/z (ESI+) calculated for C15H17NO [M+H]+; 228.1383, found 228.1386.

9a-(But-3-en-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9(9aH)-one 99c

[0250] ##STR00033##

[0251] According to general procedure 3, (S)-(E)-methyl 1-(but-2-en-1-yl)pyrrolidine-2-carboxylate was reacted with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate to yield the title compound (30%, d.r. 1:0.2) after column chromatography (9.8:0.2 v/v petrol:EtOAc) as fluorescent yellow oil. Rf=0.07 (9.8:0.2 v/v petrol:EtOAc)

[0252] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 0.93 (d, J 6.8 Hz, 2.28H, major diastereomer), 1.05 (d, J 6.9 Hz, 0.72H, minor diastereomer), 1.66-2.09 (m, 4H), 2.51-2.59 (m, 0.22H), 2.64 (dq, J 6.7 Hz 9.0 Hz, 0.78H), 3.29-3.60 (m, 2H), 5.02 (dd, J 1.9 Hz, 10.3 Hz, 0.22H), 5.04-5.09 (m, 0.22H), 5.10 (dd, J 1.8 Hz 10.2 Hz, 0.78H), 5.16 (dd, J 1.8 Hz, 17.2 Hz, 0.78H), 5.83 (ddd, J 9.2 Hz, 10.2 Hz 17.2 Hz, 0.78H), 6.04 (ddd, J 8.8 Hz, 10.2 Hz, 17.2 Hz, 0.22H), 6.54 (d, J 7.9 Hz, 0.22H), 6.71 (t, J 7.3 Hz, 0.22H), 6.88-7.00 (m, 1.56H), 7.20-7.24 (m, 0.44H), 7.48-7.54 (m, 1.56H)

[0253] .sup.13C NMR (CDCl.sub.3, 100 MHz) δC (only major diastereoisomer reported) 15.1 (1CH.sub.3), 26.2 (1CH.sub.2), 31.0 (1CH.sub.2), 45.3 (1CH), 52.7 (1CH.sub.2), 80.8 (1C), 114.7 (1CH), 116.5 (1CH.sub.2), 120.6 (1CH), 124.0 (1CH), 125.0 (1C), 137.0 (1CH), 140.0 (1CH), 166.3 (1C), 207.8 (1C).

[0254] IR υ.sub.max (thin film, cm.sup.−1): 1697 (C═O aryl), 1310 (C—N aryl).

[0255] UV-Vis (EtOH) λmax (nm), Σ(M.sup.−1cm.sup.−1) 202 (8636), 206 (8610), 235 (14460), 327 (799), 389 (1295)

[0256] HRMS m/z (ESI+) calculated for C15H17NO [M+H]+; 228.1383, found 228.1385.

9a-(2-Methylbut-3-en-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9(9aH)-one99d

[0257] ##STR00034##

[0258] According to general procedure 3, (S)-methyl 1-(3-methylbut-2-en-1-yl)pyrrolidine-2-carboxylate was reacted with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate to yield the title compound (50%) after column chromatography (9.8:0.2 v/v petrol:EtOAc) as fluorescent yellow oil. Rf=0.08 (9.8:0.2 v/v petrol:EtOAc)

[0259] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 1.05 (s, 3H), 1.14 (s, 3H), 1.74 (d, J 15.9 Hz, 2H), 1.94-1.99 (m, 2H), 3.23 (td, J 5.4 Hz 14.0 Hz, 1H), 3.42 (td, J 7.2 Hz 14.0 Hz, 1H), 5.03 (br s, 1H), 5.07 (dd, J 1.4 Hz 7.4 Hz, 1H), 6.11 (dd, J 11.1 Hz 17.2 Hz, 1H), 6.91 (t, J 7.4 Hz, 1H), 6.98 (d, J 8.4 Hz, 1H), 7.49 (t, J 7.1 Hz, 1H), 7.49 (dd, J 1.3 Hz 7.6 Hz, 1H).

[0260] .sup.13C NMR (CDCl.sub.3, 100 MHz) δC 21.1 (1CH.sub.3), 22.5 (1CH.sub.3), 25.7 (1CH.sub.2), 29.6 (1CH.sub.2), 43.6 (1C), 53.7 (1CH.sub.2), 82.5 (1C), 113.2 (1CH.sub.2), 115.0 (1CH), 120.8 (1CH), 123.6 (1CH), 126.4 (1C), 136.7 (1CH), 144.5 (1CH), 165.9 (1C), 208.5 (1C).

[0261] IR υ.sub.max (thin film, cm.sup.−1): 1699 (C═O aryl), 1311 (C—N aryl).

[0262] UV-Vis (EtOH) λmax (nm), Σ(M.sup.−1cm.sup.−1) 203 (6629), 236 (6705), 320 (496), 386 (483).

[0263] HRMS m/z (ESI+) calculated for C16H19NO [M+H]+; 242.1539, found 242.1545.

9a-(Propa-1,2-dien-1-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9(9aH)-one 99e

[0264] ##STR00035##

[0265] According to general procedure 3, (S)-methyl 1-(prop-2-yn-1-yl)pyrrolidine-2-carboxylate was reacted with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate to yield the title compound (60%) after column chromatography (9.5:0.5 v/v petrol:EtOAc) as fluorescent yellow oil.

[0266] Rf=0.22 (9.5:0.5 v/v petrol:EtOAc).

[0267] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 1.70 (dd, J 7.5 Hz 12.2 Hz, 1H), 2.04-2.17 (m, 2H), 2.19-2.28 (m, 1H), 3.24 (dt, J 7.5 Hz 10.4 Hz, 1H), 3.61 (ddd, J 4.1 Hz 7.9 Hz 10.2 Hz, 1H), 4.92 (dd, J 6.5 Hz 11.0 Hz, 1H), 4.98 (dd, J 6.6 Hz 11.0 Hz, 1H), 5.33 (t, J 6.6 Hz, 1H), 6.89 (d, J 8.2 Hz, 1H), 6.91 (t, J 7.5 Hz, 1H), 7.52 (t, J 7.7 Hz, 1H), 7.58 (d, J 7.7 Hz, 1H).

[0268] .sup.13C NMR (CDC.sub.3, 100 MHz) δC 27.7 (1CH.sub.2), 32.0 (1CH.sub.2), 50.5 (1CH.sub.2), 77.2 (1C), 78.5 (1CH.sub.2), 92.1 (1CH), 113.8 (1CH), 120.4 (1CH), 122.4 (1C), 125.0 (1CH), 137.4 (1CH), 164.6 (1C), 202.9 (1C), 207.8 (1C).

[0269] IR υ.sub.max (thin film, cm.sup.−1): 1701 (C═O aryl), 1316 (C—N aryl).

[0270] UV-Vis (EtoH) λmax (nm), Σ(M.sup.−1cm.sup.−1) 234 (13006), 335 (1068), 391 (2404).

[0271] HRMS m/z (ESI+) calculated C14H13NO [M+H]+; 212.1070, found 212.1081.

9a-(Buta-2,3-dien-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9(9aH)-one 99f

##STR00036##

[0272] According to general procedure 3, (S)-methyl 1-(but-2-yn-1-yl)pyrrolidine-2-carboxylate was reacted with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate to yield the title compound (50%) after column chromatography (9.5:0.5 v/v petrol:EtOAc) as fluorescent yellow oil which solidified on standing to a waxy fluorescent yellow solid.

[0273] Rf=0.28 (9.5:0.5 v/v petrol:EtOAc).

[0274] mp: 73-74° C.

[0275] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 1.59-1.64 (m, 1H), 1.62 (t, J 3.1 Hz, 3H), 1.99-2.06 (m, 1H), 2.11-2.18 (m, 1H), 2.28-2.34 (m, 1H), 3.26 (dt, J 7.5 Hz 10.5 Hz, 1H), 3.54 (ddd, J 4.9 Hz, 7.9 Hz, 10.6 Hz, 1H), 4.85 (dq, J 3.1 Hz 10.1 Hz, 1H), 4.95 (dq, J 3.1 Hz, 10.2 Hz, 1H), 6.90 (t, J 7.2 Hz, 1H), 6.91 (d, J 8.5 Hz, 1H), 7.52 (ddd, J 1.0 Hz, 7.2 Hz, 8.2 Hz, 1H), 7.57 (d, J 7.7 Hz, 1H).

[0276] .sup.13C NMR (CDCl.sub.3, 100 MHz) .sup.TMC 14.5 (1CH.sub.3), 27.9 (1CH.sub.2), 30.5 (1CH.sub.2), 50.1 (1CH.sub.2), 77.5 (1CH.sub.2), 79.3 (1C), 99.2 (1C), 113.7 (1CH), 120.2 (1CH), 123.0 (1C), 124.7 (1CH), 137.3 (1CH), 165.3 (1C), 204.0 (1C), 206.5 (1C).

[0277] IR υ.sub.max (thin film, cm.sup.−1): 1704 (C═O aryl), 1320 (C—N aryl).

[0278] UV-Vis (EtOH) λmax (nm), Σ(M.sup.−1cm.sup.−1) 233 (12934), 337 (1092), 392 (2350)

[0279] HRMS m/z (ESI+) calculated for C15H15NO [M+H]+; 226.1226, found 226.1225.

9a-(Penta-1,2-dien-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9(9aH)-one 99g

[0280] ##STR00037##

[0281] According to general procedure 3, (S)-methyl 1-(pent-2-yn-1-yl)pyrrolidine-2-carboxylate was reacted with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate to yield the title compound (50%) after column chromatography (9.5:0.5 v/v petrol:EtOAc) as fluorescent yellow oil.

[0282] Rf=0.35 (9.5:0.5 v/v petrol:EtOAc).

[0283] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 0.95 (t, J 7.3 Hz, 3H), 1.55-1.63 (m, 1H), 1.71-1.82 (m, 1H), 1.93-2.09 (m, 2H), 2.11-2.20 (m, 1H), 2.35 (ddd, J 3.9 Hz, 6.7 Hz, 12.5 Hz, 1H), 3.26 (dt, J 7.6 Hz 10.5 Hz, 1H), 3.54 (ddd, J 4.7 Hz 8.0 Hz, 10.6 Hz, 1H), 4.97 (dt, J 3.8 Hz 9.9 Hz, 1H), 5.08 (dt, J 3.8 Hz 9.9 Hz, 1H), 6.90 (d, J 8.2 Hz, 1H), 6.90 (t, J 7.3 Hz, 1H), 7.51 (t, J 7.6 Hz, 1H), 7.56 (d, J 7.7 Hz, 1H).

[0284] .sup.13C NMR (CDCl.sub.3, 100 MHz) δC 12.2 (1CH.sub.3), 20.1 (1CH.sub.2), 28.0 (1CH.sub.2), 30.8 (1CH.sub.2), 50.1 (1CH.sub.2), 79.4 (1C), 80.0 (1CH.sub.2), 106.3 (1C), 113.6 (1CH), 120.2 (1CH), 123.0 (1C), 124.8 (1CH), 137.2 (1CH), 165.3 (1C), 204.2 (1C), 205.8 (1C).

[0285] IR υ.sub.max (thin film, cm.sup.−1): 1705 (C═O aryl), 1319 (C—N aryl).

[0286] UV-Vis (EtOH) δmax (nm), Σ(M.sup.−1cm.sup.−1) 228 (13711), 232 (33376), 236 (33376), 337 (3189), 391 (6833).

[0287] HRMS m/z (ESI+) calculated for C16H17NO [M+H]+; 240.1383, found 240.1381.

Methyl 2-allyl-1-methyl-3-oxoindoline-2-carboxylate 3aa

[0288] ##STR00038##

[0289] According to general procedure 2, dimethyl 2-(allyl(methyl)amino)malonate (133 mg, 0.67 mmol, 1 eq) was reacted with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (297 mg, 1 mmol, 1.5 eq) to yield compound 3aa (99 mg, 61%) as a bright yellow solid after silica gel column chromatography (Toluene:EtOAc 20:1)

[0290] mp 90-93° C.

[0291] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.55 (d,J 7.7 Hz, 1H), 7.46-7.50 (m, 1H), 6.79 (d,J 8.4 Hz, 1H), 6.73 (app. t, J 7.4 Hz, 1H), 5.34-5.45 (m, 1H), 5.14 (app dm, J 16.9 Hz, 1H), 4.97 (app dm, J 10.2 Hz, 1H), 3.70 (s, 3H), 3.06 (dd, J 6.8 Hz, 14.6 Hz, 1H), 2.99 (s, 3H), 2.89 (dd, J 7.5 Hz, 14.5 Hz, 1H).

[0292] .sup.13C NMR (CDCl.sub.3, 100 MHz) δc 195.3 (1C), 167.6 (1C), 161.7 (1C), 138.0 (1CH), 131.6 (1CH), 125.1 (1CH), 119.7 (1CH.sub.2), 119.0 (1C), 117.6 (1CH), 108.3 (1CH), 76.8 (1C), 53.0 (1CH.sub.3), 36.5 (1CH.sub.2), 29.1 (1CH.sub.3).

[0293] IR υ.sub.max (thin film, cm.sup.−1): 3074, 2952, 2917, 2848, 1739, 1696, 1612, 1489.

[0294] UV-Vis (EtOH) λ.sub.max (nm), Σ(M.sup.−1 cm.sup.−1) 231 (8707), 416 (5386).

[0295] HRMS m/z (ESI.sup.+) calculated for C.sub.14H.sub.15NO.sub.3[M+H].Math.: 246.1125, found 246.1131.

Methyl 2-allyl-4-methoxy-1-methyl-3-oxoindoline-2-carboxylate 3ba

[0296] ##STR00039##

[0297] According to general procedure 2, dimethyl 2-(allyl(methyl)amino)malonate (133 mg, 0.67 mmol, 1 eq) was reacted with 3-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (327 mg, 1.0 mmol, 1.5 eq) to yield compound 3ba (116 mg, 64%) as a bright yellow solid after silica gel column chromatography (petrol:acetone, 3:1).

[0298] mp: 125-127° C.

[0299] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 7.39 (app. t, J 8.2 Hz, 1H), 6.33 (d, J 8.2 Hz, 1H), 6.14 (d, J 8.1 Hz, 1H), 5.39-5.49 (m, 1H), 5.14 (ddd, J 1.4 Hz, 3.0 Hz, 17.0 Hz, 1H), 4.98 (app. dm, J 10.1 Hz, 1H) 3.89 (s, 3H), 3.69 (s, 3H), 3.07 (app. ddt, J 1.1 Hz, 6.7 Hz, 14.6 Hz, 1H), 2.96 (s, 3H), 2.85 (app. ddt, J 1.1 Hz, 7.6 Hz, 14.6 Hz, 1H).

[0300] .sup.13C NMR (CDCl.sub.3, 100 MHz) 6.sub.c 192.4 (1C), 167.7 (1C), 163.0 (1C), 159.2 (1C), 139.6 (1CH), 130.8 (1CH), 119.6 (1CH.sub.2), 108.1 (1C), 100.5 (1CH), 98.9 (1CH), 77.0 (1C), 55.8 (1CH.sub.3), 53.0 (1CH.sub.3), 36.5 (1CH.sub.2), 29.3 (1CH.sub.3).

[0301] IR υ.sub.max (thin film, cm.sup.−1): 2920, 1738, 1688, 1603, 1583, 1501.

[0302] HRMS m/z (ESI+) calculated for C.sub.15H.sub.17NO.sub.4[M+H].sup.+; 276.123, observed 276.1226.

Methyl 2-allyl-1,4-dimethyl-3-oxoindoline-2-carboxylate 3ca

[0303] ##STR00040##

[0304] According to general procedure 2, dimethyl 2-(allyl(methyl)amino)malonate (133 mg, 0.67 mmol, 1 eq) was reacted with 3-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (311 mg, 1 mmol, 1.5 eq) to yield compound 3ca (92 mg, 54%) as a bright yellow solid after silica gel column chromatography (Petrol:Et.sub.2O 8:1).

[0305] mp 98-100° C.

[0306] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.33 (app. t, J 7.8 Hz, 1H), 6.59 (d, J 8.3 Hz, 1H), 6.49 (d, J 7.2 Hz, 1H), 5.36-5.47 (m, 1H), 5.14 (d, J 16.9 Hz, 1H), 4.97 (d, J 10.1 Hz, 1H), 3.71 (s, 3H), 3.05 (dd, J 6.7 Hz, 14.6 Hz, 1H), 2.96 (s, 3H), 2.87 (dd, J 7.6 Hz, 14.6 Hz, 1H), 2.53 (s, 3H).

[0307] .sup.13C NMR (CDCl.sub.3, 100 MHz) 6.sub.c 195.5 (1C), 167.9 (1C), 162.3 (1C), 140.6 (1C), 137.2 (1CH), 130.9 (1CH), 119.4 (1CH.sub.2), 119.2 (1CH), 117.3 (1C), 105.4 (1CH), 76.7 (1C), 53.0 (1CH.sub.3), 36.7 (1CH.sub.2), 29.2 (1CH.sub.3), 18.3 (1CH.sub.3).

[0308] IR υ.sub.max (thin film, cm.sup.−1): 2952, 2920, 1735, 1678, 1601, 1496.

[0309] HRMS m/z (ESI+) calculated for C.sub.15H.sub.17NO.sub.3[M+H].sup.+; 260.1281, observed 260.1278.

Methyl 2-allyl-3-methyl-1-oxo-2,3-dihydro-1H-benzo[e]indole-2-carboxylate 3da

[0310] ##STR00041##

[0311] According to general procedure 2, dimethyl 2-(allyl(methyl)amino)malonate (133 mg, 0.67 mmol, 1 eq) was reacted with 1-(trimethylsilyl)naphthalen-2-yl trifluoromethanesulfonate (347 mg, 1 mmol, 1.5 eq) to yield compound 3da (131 mg, 67%) as a bright yellow solid after silica gel column chromatography (Petrol : EtOAc, 8:1).

mp: 144-147° C.

[0312] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 8.70 (d, J 8.3 Hz, 1H), 7.94 (d, J 9.0 Hz, 1H), 7.71 (d, J 8.0 Hz, 1H), 7.58 (ddd, J 1.2 Hz, 7.1 Hz, 8.3 Hz, 1H), 7.31 (ddd, J 1.1 Hz, 7.1 Hz, 8.2 Hz, 1H), 7.06 (d, J 9.0 Hz, 1H), 5.39-5.49 (m, 1H), 5.17 (ddd, J 1.4 Hz, 2.9 Hz, 16.9 Hz, 1H), 4.95 (app. dm, J 10.1 Hz, 1H), 3.73 (s, 3H), 3.20 (app. ddt, J 1.2 Hz, 6.3 Hz, 14.6 Hz, 1H), 3.13 (s, 3H), 2.93 (dd, J 7.9 Hz, 16.6 Hz, 1H).

[0313] .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.c 193.1 (1C), 167.5 (1C), 164.1 (1C), 140.0 (1CH), 130.8 (1CH), 130.5 (1C), 130.1 (1CH), 128.5 (1CH), 127.1 (1C), 123.6 (1CH), 122.7 (1CH), 119.5 (1CH.sub.2), 110.0 (1CH), 109.3 (1C), 77.6 (1C), 53.1 (1CH.sub.3), 36.8 (1CH.sub.2), 29.4 (1CH.sub.3).

[0314] IR υ.sub.max (thin film, cm.sup.−1): 1737, 1657, 1625, 1588, 1567, 1532.

[0315] HRMS m/z (ESI+) calculated for C.sub.18H.sub.17NO.sub.3[M+H].sup.+; 296.1281, observed 296.1278.

Methyl 2-allyl-5-methoxy-1-methyl-3-oxoindoline-2-carboxylate 3ea

[0316] ##STR00042##

[0317] According to general procedure 2, dimethyl 2-(allyl(methyl)amino)malonate (133 mg, 0.67 mmol, 1 eq) was reacted with 4-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (327 mg, 1 mmol, 1.5 eq) to yield compounds 3ea (67 mg, 37%) as a bright yellow oil and 3ea′ (55 mg, 30%) as a bright yellow solid, after silica gel column chromatography (Petrol : EtOAc, 9:1).

[0318] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 7.18 (dd, J 2.6 Hz, 8.9 Hz, 1H), 7.01 (d, J 2.6 Hz, 1H), 6.76 (d,J 8.9 Hz, 1H), 5.36-5.44 (m, 1H), 5.14 (d, J 16.8 Hz, 1H), 4.97 (d, J 10.1 Hz, 1H), 3.75 (s, 3H), 3.71 (s, 3H), 3.04 (dd, J 6.8 Hz, 14.6 Hz, 1H), 2.97 (s, 3H), 2.88 (dd, J 7.4 Hz, 14.6 Hz, 1H).

[0319] .sup.13C NMR (CDCl.sub.3, 100 MHz) δC 195.2 (1C), 167.8 (1C), 158.1 (1C), 152.4 (1C), 130.8 (1CH), 128.7 (1CH), 119.6 (1CH.sub.2), 118.9 (1C), 109.7 (1CH), 105.0 (1CH), 77.5 (1C), 55.8 (1CH.sub.3), 53.0 (1CH.sub.3), 36.5 (1CH.sub.2), 29.4 (1CH.sub.3).

[0320] IR υ.sub.max (thin film, cm.sup.−1): 1735, 1678.

[0321] HRMS m/z (ESI+) calculated for C.sub.15H.sub.17NO.sub.4[M+H].sup.+; 276.1230, observed 276.1227.

[0322] Methyl 2-allyl-6-methoxy-1-methyl-3-oxoindoline-2-carboxylate 3ea′

##STR00043##

[0323] According to general procedure 2, dimethyl 2-(allyl(methyl)amino)malonate (133 mg, 0.67 mmol, 1 eq) was reacted with 4-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (327 mg, 1 mmol, 1.5 eq) to yield compounds 3ea (67 mg, 37%) as a bright yellow oil and 3ea′ (55 mg, 30%) as a bright yellow solid, after silica gel column chromatography (Petrol : EtOAc, 9:1).

[0324] mp 99-101° C.

[0325] .sup.1H NMR (CDCl.sub.3, 300 MHz) δ.sub.H 7.49 (d, J 8.6 Hz, 1H), 6.33 (ddd, J 0.8 Hz, 2.1 Hz, 8.6 Hz, 1H), 6.15 (d, J 1.9 Hz, 1H), 5.35-5.49 (m, 1H), 5.14 (app. dm, 17.0 Hz, 1H), 4.98 (app. dm, J 10.0 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.08 (dd, J 6.6 Hz, 14.6 Hz, 1H), 2.98 (s, 3H), 2.85 (dd, J 7.6 Hz, 14.6 Hz, 1H).

[0326] .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.c 192.5 (1C), 168.5 (1C), 167.9 (1C), 163.8 (1C), 130.8 (1CH), 126.7 (1CH), 119.5 (1CH.sub.2), 112.7 (1C), 107.2 (1CH), 91.0 (1CH), 77.5 (1C), 55.6 (1CH.sub.3), 53.0 (1CH.sub.3), 36.5 (1CH.sub.2), 29.2 (1CH.sub.3).

[0327] IR υ.sub.max (thin film, cm.sup.−1): 1734, 1670.

[0328] HRMS m/z (ESI+) calculated for C.sub.15H.sub.17NO.sub.4[M+H].sup.+; 276.1230, observed 276.1229.

Methyl 2-allyl-1,5-dimethyl-3-oxoindoline-2-carboxylate 3fa

[0329] ##STR00044##

[0330] According to general procedure 2, dimethyl 2-(allyl(methyl)amino)malonate (133 mg, 0.67 mmol, 1 eq) was reacted with 4-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (310 mg, 1 mmol, 1.5 eq) to yield compounds 3fa (54 mg, 31%) as a bright yellow solid and 3fa′ (57 mg, 33%) as a bright yellow solid, after silica gel column chromatography (Petrol:Et.sub.2O, 6:1). mp 75-77° C.

[0331] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.35 (br. s, 1H), 7.32 (d, J 8.4 Hz, 1H), 6.71 (d, J 8.4 Hz, 1H), 5.35-5.45 (m, 1H), 5.13 (app. d, J 17.0 Hz, 1H), 4.96 (d, J 10.1 Hz, 1H), 3.70 (s, 3H), 3.05 (dd, J 6.8 Hz, 14.6 Hz, 1H), 2.97 (s, 3H), 2.87 (dd, J 7.5 Hz, 14.6 Hz, 1H), 2.26 (s, 3H).

[0332] .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 195.3 (1C), 167.8 (1C), 160.4 (1C), 139.5 (1CH), 130.8 (1CH), 127.1 (1C), 124.5 (1CH), 119.6 (1CH.sub.2), 119.1 (1C), 108.2 (1CH), 77.1 (1C), 53.0 (1CH.sub.3), 36.4 (1CH.sub.2), 29.2 (1CH.sub.3), 20.3 (1CH.sub.3).

[0333] IR υ.sub.max (thin film, cm.sup.−1): 2952, 2920, 1737, 1686, 1620, 1575, 1504.

[0334] HRMS m/z (ESI+) calculated for C.sub.15H.sub.17NO.sub.3[M+H].sup.+; 260.1279, observed 260.1281.

[0335] Methyl 2-allyl-1,6-dimethyl-3-oxoindoline-2-carboxylate 3fa′

##STR00045##

[0336] According to general procedure 2, dimethyl 2-(allyl(methyl)amino)malonate (133 mg, 0.67 mmol, 1 eq) was reacted with 4-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (310 mg, 1 mmol, 1.5 eq) to yield compounds 3fa (54 mg, 31%) as a bright yellow solid and 3fa′ (57 mg, 33%) as a bright yellow solid, after silica gel column chromatography (Petrol:Et.sub.2O, 6:1).

[0337] mp 89-91° C.

[0338] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.44 (d, J 7.9 Hz, 1H), 6.58 (br. s, 1H), 6.56 (d, J 8.1 Hz, 1H), 5.34-5.44 (m, 1H), 5.13 (d, J 17.0 Hz, 1H), 4.96 (d,J 10.1 Hz, 1H), 3.69 (s, 3H), 3.05 (dd, J 6.7 Hz, 14.6 Hz, 1H), 2.97 (s, 3H), 2.86 (dd, J 7.5 Hz, 14.6 Hz, 1H), 2.37 (s, 3H).

[0339] .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.c 195.3 (1C), 167.8 (1C), 160.4 (1C), 139.5 (1CH), 130.8 (1CH), 127.1 (1C), 124.5 (1CH), 119.6 (1CH.sub.2), 119.1 (1C), 108.2 (1CH), 77.1 (1C), 53.0 (1CH.sub.3), 36.4 (1CH.sub.2), 29.2 (1CH.sub.3), 20.3 (1CH.sub.3).

[0340] IR υ.sub.max (thin film, cm.sup.−1): 2952, 2920, 1737, 1686, 1620, 1575, 1504.

[0341] HRMS m/z (ESI+) calculated for C.sub.15H.sub.17NO.sub.3[M+H].sup.+; 260.1279, observed 260.1281.

Methyl 1-methyl-3-oxo-2-(propa-1,2-dien-1-yl)indoline-2-carboxylate 3ab

[0342] ##STR00046##

[0343] According to general procedure 2, dimethyl 2-(methyl(prop-2-yn-1-yl)amino)malonate (66 mg, 0.33 mmol, 1 eq) was reacted with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (149 mg, 0.50 mmol, 1.5 eq) to yield compound 3ab (56 mg, 70%) as a bright yellow solid after silica gel column chromatography (Hexane: tOAc, 7:1).

[0344] mp 87-89° C.

[0345] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.57 (d, J 7.7 Hz, 1H), 7.48-7.52 (m, 1H), 6.79 (d, J 8.3 Hz, 1H), 6.76 (app t, J 7.5 Hz, 1H), 5.78 (t, J 6.7 Hz, 1H), 4.98 (dd, J 6.7 Hz, 11.5 Hz, 1H), 4.14 (dd, J 6.7 Hz, 11.5 Hz, 1H), 3.77 (s, 3H), 3.01 (s, 3H).

[0346] .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.c 207.4 (1C), 193.5 (1C), 166.7 (1C), 161.4 (1C), 138.1 (1CH), 125.8 (1CH), 117.9 (1CH), 117.8 (1C), 108.4 (1CH), 87.8 (1CH), 79.3 (1CH.sub.2), 76.2 (1CH), 53.3 (1CH.sub.3), 30.0 (1CH.sub.3).

[0347] IR υ.sub.max(thin film, cm.sup.−1): 3060, 3024, 2953, 2924, 2888, 2836, 1737, 1698, 1611, 1486.

[0348] HRMS m/z (ESI+) calculated for C.sub.14H.sub.13NO.sub.3[M+H].sup.+, 244.0968, observed 244.0975.

Methyl 4-methoxy-1-methyl-3-oxo-2-(propa-1,2-dien-1-yl)indoline-2-carboxylate 3bb

[0349] ##STR00047##

[0350] According to general procedure 2, dimethyl 2-(methyl(prop-2-yn-1-yl)amino)malonate (132 mg, 0.67 mmol, 1 eq) was reacted with 3-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (327 mg, 1.0 mmol, 1.5 eq) to yield compound 3bb (147 mg, 81%) as a bright yellow solid after silica gel column chromatography (Toluene : EtOAc, 10:1).

[0351] mp: 135-137° C.

[0352] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 7.40 (app. t, J 8.2 Hz, 1H), 6.34 (d, J 8.2 Hz, 1H), 6.16 (d, J 8.1 Hz, 1H), 5.79 (t, J 6.7 Hz, 1H), 4.96 (dd, J 6.7 Hz, 11.5 Hz, 1H), 4.86 (dd, J 6.7 Hz, 11.5 Hz, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 2.97 (s, 3H).

[0353] .sup.13C NMR (CDCl.sub.3, 100 MHz) δC 207.2 (1C), 190.7 (1C), 166.7 (1C), 162.7 (1C), 159.8 (1C), 139.7 (1CH), 106.7 (1CH), 100.6 (1C), 99.2 (1CH), 88.2 (1CH), 79.2 (1CH.sub.2), 76.3 (1C), 55.8 (1CH.sub.3), 53.2 (1CH.sub.3), 30.2 (1CH.sub.3).

[0354] IR υ.sub.max(thin film, cm.sup.−1): 2952, 1732, 1599, 1579, 1496.

[0355] HRMS m/z (ESI+) calculated for C.sub.15H.sub.15NO.sub.4[M+H].sup.+; 274.1074, observed 274.1082.

Methyl 1,4-dimethyl-3-oxo-2-(propa-1,2-dien-1-yl)indoline-2-carboxylate 3cb

[0356] ##STR00048##

[0357] According to general procedure 2, dimethyl 2-(methyl(prop-2-yn-1-yl)amino)malonate (106 mg, 0.53 mmol, 1 eq) was reacted with 3-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (250 mg, 0.8 mmol, 1.5 eq) to yield compound 3cb (87 mg, 64%) as a bright yellow solid after silica gel column chromatography (Petrol : Acetone 12:1).

[0358] mp: 115-117° C.

[0359] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 7.33 (dd, J 7.6 Hz, 8.0 Hz, 1H), 6.59 (d, J 8.3 Hz, 1H), 6.50 (d, J 7.3 Hz, 1H), 5.79 (t, J 6.7 Hz, 1H), 4.97 (dd, J 6.7 Hz, 11.4 Hz, 1H), 4.86 (dd, J 6.7 Hz, 11.4 Hz, 1H), 3.76 (s, 3H), 2.98 (s, 3H), 2.52 (s, 3H).

[0360] .sup.13C NMR (CDCl.sub.3, 100 MHz) δC 207.2 (1C), 193.8 (1C), 166.9 (1C), 161.9 (1C), 141.3 (1CH), 137.4 (1CH), 119.5 (1CH), 116.0 (1C), 105.5 (1C), 88.3 (1CH), 79.2 (1CH.sub.2), 76.2 (1C), 53.3 (1CH.sub.3), 30.1 (1CH.sub.3), 18.3 (1CH.sub.3).

[0361] IR υ.sub.max (thin film, cm.sup.−1): 2948, 1732, 1687, 1601, 1494.

[0362] HRMS m/z (ESI+) calculated for C.sub.15H.sub.15NO.sub.3[M+H].sup.+; 258.1125, observed 258.1122.

Methyl 3-methyl-1-oxo-2-(propa-1,2-dien-1-yl)-2,3-dihydro-1H-benzo[e]indole-2-carboxylate 3db

[0363] ##STR00049##

[0364] According to general procedure 2, dimethyl 2-(methyl(prop-2-yn-1-yl)amino)malonate (132 mg, 0.67 mmol, 1 eq) was reacted with 1-(trimethylsilyl)naphthalen-2-yl trifluoromethanesulfonate (347 mg, 1.0 mmol, 1.5 eq) to yield compound 3db (150 mg, 77%) as a bright yellow solid after silica gel column chromatography (Hexane:EtOAc 9:1).

[0365] mp: 145-147° C.

[0366] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 8.65 (d, J 8.3 Hz, 1H), 7.95 (d, J 9.0 Hz, 1H), 7.71 (d, J 8.1 Hz, 1H) 7.57 (ddd, J 1.2 Hz, 7.1 Hz, 8.3 Hz, 1H), 7.31 (ddd, J 1.1 Hz, 6.9 Hz, 8.1 Hz, 1H), 7.07 (d, J 9.1 Hz, 1H), 5.89 (t, J 6.7 Hz, 1H), 4.99 (dd, J 6.7 Hz, 11.4 Hz, 1H), 4.87 (dd,J 6.7 Hz, 11.4 Hz, 1H), 3.79 (s, 3H), 3.14 (s, 3H).

[0367] .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 207.1 (1C), 191.8 (1C), 166.5 (1C), 163.9 (1C), 140.2 (1CH), 130.9 (1CH), 130.1 (1CH), 128.6 (1CH), 127.2 (1CH), 123.7 (1CH), 122.6 (1C), 110.1 (1C), 107.9 (1C), 88.0 (1CH), 79.3 (1C), 76.8 (1CH.sub.2), 53.4 (1CH.sub.3), 30.3 (1CH.sub.3).

[0368] HRMS m/z (ESI+) calculated for C.sub.18H.sub.15NO.sub.3[M+H].sup.+; 294.1125, observed 294.1133.

Methyl 5-methoxy-1-methyl-3-oxo-2-(propa-1,2-dien-1-yl)indoline-2-carboxylate 3eb

[0369] ##STR00050##

[0370] According to general procedure 2, dimethyl 2-(methyl(prop-2-yn-1-yl)amino)malonate (132 mg, 0.67 mmol, 1 eq) was reacted with 4-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (327 mg, 1.0 mmol, 1.5 eq) to yield compounds 3eb (81 mg, 45%) as a bright yellow solid and 3eb′ (45 mg, 25%) as a bright yellow solid after silica gel column chromatography (Petrol:EtOAc 5:1).

[0371] mp98-100° C.

[0372] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 7.19, (dd, J 2.7 Hz, 8.9 Hz, 1H), 7.02 (d, J 2.7 Hz, 1H), 6.77 (d, J 8.9 Hz, 1H), 5.78 (t, J 6.7 Hz, 1H), 4.97 (dd, J 6.7 Hz, 11.5 Hz, 1H), 4.88 (dd, J 6.7 Hz, 11.5 Hz, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 2.98 (s, 3H).

[0373] .sup.13C NMR (CDCl.sub.3, 100 MHz) δC 207.4 (1C), 193.4 (1C), 166.7 (1C), 157.7 (1C), 152.5 (1C), 128.7 (1CH), 117.6 (1C), 109.8 (1CH), 105.6 (1CH), 87.8 (1CH), 79.1 (1CH.sub.2), 76.8 (1C), 55.8 (1CH.sub.3), 53.2 (1CH.sub.3), 30.2 (1CH.sub.3).

[0374] IR υ.sub.max (thin film, cm.sup.−1): 2927, 1743, 1674, 1609, 1574, 1488.

[0375] HRMS m/z (ESI+) calculated for C.sub.15H.sub.15NO.sub.4[M+H].sup.+; 274.1074, observed 274.1069.

Methyl 6-methoxy-1-methyl-3-oxo-2-(propa-1,2-dien-1-yl)indoline-2-carboxylate 3eb′

[0376] ##STR00051##

[0377] According to general procedure 2, dimethyl 2-(methyl(prop-2-yn-1-yl)amino)malonate (132 mg, 0.67 mmol, 1 eq) was reacted with 4-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (327 mg, 1.0 mmol, 1.5 eq) to yield compounds 3eb (81 mg, 45%) as a bright yellow solid and 3eb′ (45 mg, 25%) after silica gel column chromatography (Petrol:EtOAc 5:1).

[0378] mp: 105-107° C.

[0379] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.48 (d, J 8.6 Hz, 1H), 6.33 (dd, J 2.0 Hz, 8.6 Hz, 1H), 6.16 (d, J 2.0 Hz, 1H), 5.80 (t, J 6.7 Hz, 1H), 4.97 (dd, J 6.7 Hz, 11.5 Hz, 1H), 4.87 (dd, J 6.7 Hz, 11.5 Hz, 1H), 3.88 (s, 3H), 3.76 (s, 3H), 2.99 (s, 3H).

[0380] .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 207.2 (1C), 190.9 (1C), 168.6 (1C), 166.8 (1C), 163.5 (1C), 127.3 (1CH), 111.2 (1C), 107.4 (1CH), 91.2 (1CH), 88.2 (1CH), 79.2 (1CH.sub.2), 76.8 (1C), 55.6 (1CH.sub.3), 53.3 (1CH.sub.3), 30.1 (1CH.sub.3).

[0381] IR υ.sub.max (thin film, cm.sup.−1): 2950, 2835, 1734, 1677, 1602, 1580, 1500.

[0382] HRMS m/z (ESI+) calculated for C.sub.15H.sub.15NO.sub.4[M+H].sup.+; 274.1074, observed 274.1070.

Methyl 1-methyl-3-oxo-2-(propa-1,2-dien-1-yl)-2,3-dihydro-1H-benzo[f]indole-2-carboxylate 3gb

[0383] ##STR00052##

[0384] According to general procedure 2, dimethyl 2-(methyl(prop-2-yn-1-yl)amino)malonate (132 mg, 0.67 mmol, 1 eq) was reacted with 3-(trimethylsilyl)naphthalen-2-yl trifluoromethanesulfonate (347 mg, 1.0 mmol, 1.5 eq) to yield compound 3gb (70 mg, 36%) as an orange solid after silica gel column chromatography (toluene, 100%).

[0385] mp 145-147° C.

[0386] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 8.16 (s, 1H), 7.76 (d, J 8.3 Hz, 1H), 7.64 (d, J 8.3 Hz, 1H), 7.45 (ddd, J 1.0 Hz, 6.9 Hz, 8.1 Hz, 1H), 7.21 (app. t, J 7.5 Hz, 1H), 6.90 (s, 1H), 5.83 (t, J 6.7 Hz, 1H), 4.99 (dd, J 6.7 Hz, 11.5 Hz, 1H), 4.87 (dd, J 6.7 Hz, 11.5 Hz, 1H), 3.77 (s, 3H), 3.07 (s, 3H).

[0387] .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 207.6 (1C), 194.3 (1C), 167.2 (1C), 154.7 (1C), 140.2 (1C), 130.8 (1CH), 129.8 (1CH), 127.5 (1CH), 127.2 (1C), 126.4 (1CH), 122.9 (1CH), 120.7 (1C), 101.2 (1CH), 88.1 (1CH), 79.5 (1CH.sub.2), 76.3 (1C), 53.3 (1CH.sub.3), 30.3 (1CH.sub.3).

[0388] IR 80 .sub.max (thin film, cm.sup.−1): 2918, 1744, 1708, 1625, 1504.

[0389] HRMS m/z (ESI+) calculated for C.sub.18H.sub.15NO.sub.3NO.sub.3[M+H].sup.+; 294.1125, observed 294.1122.

[0390] Methyl 5,6-dimethoxy-1-methyl-3-oxo-2-(propa-1,2-dien-1-yl)indoline-2-carboxylate 3hb

##STR00053##

[0391] According to general procedure 2, dimethyl 2-(methyl(prop-2-yn-1-yl)amino)malonate (132 mg, 0.67 mmol, 1 eq) was reacted with 4,5-dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (357 mg, 1.0 mmol, 1.5 eq) to yield compound 3hb (148 mg, 74%) as a bright yellow oil after silica gel column chromatography (Petrol:Acetone 3:1).

[0392] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 6.97 (s, 1H), 6.24 (s, 1H), 5.79 (t, J 6.7 Hz, 1H), 4.96 (dd, J 6.7 Hz, 11.4 Hz, 1H), 4.87 (dd,J 12 Hz, 7 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 3.00 (s, 3H).

[0393] .sup.13C NMR (CDCl.sub.3, 100 MHz) δC 207.2 (1C), 191.1 (1C), 166.9 (1C), 159.6 (1C), 159.3 (1C), 143.3 (1C), 108.7 (1C), 105.3 (1CH), 90.7 (1CH), 88.1 (1CH), 79.0 (1CH.sub.2), 76.6 (1C), 56.24 (1CH.sub.3), 56.20 (1CH.sub.3), 53.3 (1CH.sub.3), 30.2 (1CH.sub.3).

[0394] IR υ.sub.max (thin film, cm.sup.−1): 2952, 1737, 1674, 1620, 1578, 1497.

[0395] HRMS m/z (ESI+) calculated for C.sub.16H.sub.17NO.sub.5 [M+H].sup.+; 304.1179, observed 304.1173.

Methyl 4-methoxy-1-methyl-2-(2-methylbut-3-en-2-yl)-3-oxoindoline-2-carboxylate 3bc

[0396] ##STR00054##

[0397] According to general procedure 2, dimethyl 2-(methyl(3-methylbut-2-en-1-yl)amino)malonate (0.541 mmol, 1 eq, 162 mg) was reacted with 3-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (267 mg, 0.81 mmol, 1.5 eq) to yield compounds 3bc (108 mg, 66%) as a bright yellow solid and 3bc′ (8 mg, 6%) as a bright yellow oil, after silica gel column chromatography (Toluene:EtOAc 10:1).

[0398] mp: 86-88° C.

[0399] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 7.39 (app. t, J 8.2 Hz, 1H), 6.35 (d, J 8.2 Hz, 1H), 6.30 (dd, J 10.8 Hz, 17.5 Hz, 1H), 6.19 (d, J 9 Hz, 1H), 5.08 (dd, J 1.2 Hz, 17.3 Hz, 1H), 5.04 (dd, J 1.2 Hz, 10.7 Hz, 1H), 3.91 (s, 3H), 3.65 (s, 3H), 2.98 (s, 3H), 1.40 (s, 3H), 1.18 (s, 3H).

[0400] .sup.13C NMR (CDCl.sub.3, 100 MHz) δC 193.8 (1C), 167.2 (1C), 163.8 (1C), 159.0 (1C), 143.8 (1CH), 138.9 (1CH), 113.4 (1CH.sub.2), 109.5 (1C), 101.4 (1CH), 99.6 (1CH), 80.5 (1C), 55.8 (1CH.sub.3), 52.2 (1CH.sub.3), 44.2 (1C), 34.0 (1CH.sub.3), 22.6 (1CH.sub.3), 21.5 (1CH.sub.3).

[0401] HRMS m/z (ESI+) calculated for C.sub.12H.sub.21NO.sub.4 [M+H].sup.+; 304.1543, observed 304.1549.

Methyl 4-methoxy-1-methyl-2-(3-methylbut-2-en-1-yl)-3-oxoindoline-2-carboxylate 3bc′

[0402] ##STR00055##

[0403] According to general procedure 2, dimethyl 2-(methyl(3-methylbut-2-en-1-yl)amino)malonate (0.541 mmol, 1 eq, 162 mg) was reacted with 3-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (267 mg, 0.81 mmol, 1.5 eq) to yield compounds 3bc (108 mg, 66%) as a bright yellow solid and 3bc′ (8 mg, 6%) as a bright yellow oil, after silica gel column chromatography (Toluene:EtOAc 10:1).

[0404] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 7.40 (app. t, J 8.2 Hz, 1H), 6.34 (d, J 8.3 Hz, 1H), 6.15 (d, J, 8.1 Hz, 1H), 4.72-4.76 (m, 1H), 3.90 (s, 3H), 3.70 (s, 3H), 3.01 (dd, J 7.2 Hz, 15.5 Hz, 1H), 2.94 (s, 3H), 2.80 (dd, J 7.0 Hz, 15.5 Hz, 1H), 1.64 (s, 3H), 1.56 (s, 3H).

[0405] .sup.13C NMR (CDCl.sub.3, 100 MHz) 6C 192.8 (1C), 168.1 (1C), 163.1 (1C), 159.2 (1C), 139.4 (1CH), 135.8 (1CH), 116.0 (1CH), 108.2 (1CH), 100.5 (1CH), 98.8 (1CH), 77.2 (1C), 55.80 (1CH.sub.3), 52.94 (1CH.sub.3), 30.9 (1CH.sub.2), 29.4 (1CH.sub.3), 25.8 (1CH.sub.3), 18.2 (1CH.sub.3).

[0406] IR υ.sub.max(thin film, cm.sup.−1): 2963, 1741, 1698, 1609, 1498.

[0407] HRMS m/z (ESI+) calculated for C.sub.12H.sub.21NO.sub.4[M+H].sup.+; 304.1543, observed 304.1549.

Methyl 2-(but-3-en-2-yl)-4-methoxy-1-methyl-3-oxoindoline-2-carboxylate 3bd

[0408] ##STR00056##

[0409] According to general procedure 2, (E)-2-(but-2-en-1-yl(methyl)amino)malonate (143 mg, 0.67 mmol, 1 eq) was reacted with 3-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (327 mg, 1.0 mmol, 1.5 eq) to yield compound 3bd (123 mg, 64%) as a bright yellow solid after silica gel column chromatography (Toluene:EtOAc 8:1). mp: 89-91° C.

[0410] .sup.1H NMR (CDCl.sub.3, 300 MHz) δH 7.40 (app. t, J 8.2 Hz, 1H), 6.35 (d, J 8.2 Hz, 1H), 6.15 (d, J 8.1 Hz, 1H), 5.94 (ddd, J 6.5 Hz, 10.5 Hz, 17.2 Hz, 1H), 5.22 (app. dm, J 17.2 Hz, 1H), 5.14 (app. dm, J 10.5 Hz, 1H), 3.91 (s, 3H), 3.73 (s, 3H), 3.41-3.50 (m, 1H), 3.03 (s, 3H), 0.94 (d, J 6.8 Hz, 3H).

[0411] .sup.13C NMR (CDCl.sub.3, 100 MHz) δC 191.6 (1C), 167.2 (1C), 163.4 (1C), 159.2 (1C), 139.5 (1CH), 138.6 (1CH), 117.0 (1CH.sub.2), 108.0 (1C), 100.7 (1CH), 98.9 (1CH), 80.9 (1C), 55.8 (1CH.sub.3), 52.8 (1CH.sub.3), 42.2 (1CH), 31.9 (1CH.sub.3), 12.3 (1CH.sub.3).

[0412] IR υ.sub.max (thin film, cm.sup.−1): 2976, 2953, 1735, 1688, 1601, 1586, 1498.

[0413] HRMS m/z (ESI+) calculated for C.sub.16H.sub.19NO.sub.4[M+H].sup.+; 290.1387, observed 290.1385.

Methyl 1-methyl-2-(2-methylenecyclohexyl)-3-oxoindoline-2-carboxylate 3ae

[0414] ##STR00057##

[0415] According to general procedure 2, 2-((cyclohex-1-en-1-ylmethyl)(methyl)amino)malonate (169 mg, 0.67 mmol, 1 eq) was reacted with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (297 mg, 1.0 mmol, 1.5 eq) to yield compound 3ae (105 mg, 48%) as a bright yellow oil after silica gel column chromatography (Petrol:EtOAc, 10:1).

[0416] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 7.56 (app. dm, J 7.8 Hz, 1H), 7.48 (ddd, J 1.3 Hz, 7.1 Hz, 8.4 Hz, 1H), 6.81 (d, J 8.4, 1H), 6.72 (app. t, J 7.4 Hz, 1H), 4.79 (s, 1H), 4.51 (s, 1H), 3.70 (s, 3H), 3.31-3.35 (m, 1H), 3.19 (s, 3H), 2.29-2.34 (m, 1H), 2.13 (td, J 4.6 Hz, 12.5 Hz, 1H), 1.68-1.78 (m, 2H), 1.29-1.45 (m, 4H).

[0417] .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 195.3 (1C), 167.9 (1C), 161.8 (1C), 148.1 (1C), 138.0 (1CH), 125.0 (1CH), 118.5 (1C), 117.4 (1CH), 108.4 (1CH), 107.4 (1CH.sub.2), 79.3 (1C), 53.0 (1CH.sub.3), 48.7 (1CH), 37.8 (1CH.sub.2), 30.9 (1CH.sub.3), 28.0 (2CH.sub.2), 25.7 (1CH.sub.2).

[0418] IR υ.sub.max (thin film, cm.sup.−1): 1733, 1705.

[0419] HRMS m/z (ESI+) calculated for C.sub.18H.sub.21NO.sub.3[M+H].sup.+; 300.1594, observed 300.1614.

Methyl 3-oxo-1-(prop-2-yn-1-yl)-2-(propa-1,2-dien-1-yl)indoline-2-carboxylate 3af

[0420] ##STR00058##

[0421] According to general procedure 2, dimethyl 2-(di(prop-2-yn-1-yl)amino)malonate (583 mg, 2.61 mmol, 1 eq) was reacted with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1.23 g, 4.11 mmol, 1.5 eq) to yield compound 3af (118 mg, 17%) as a bright yellow oil after silica gel column chromatography (pentane:acetone, 9:1).

[0422] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 7.62 (d, J 7.7 Hz, 1H), 7.55 (ddd, J 1.3 Hz, 7.3 Hz, 8.4 Hz, 1H), 7.02 (d, J 8.3 Hz, 1H), 6.86 (app. t, J 7.4 Hz, 1H), 5.76 (t J 6.7 Hz, 1H), 5.02 (dd, J 6.7 Hz, 11.7 Hz, 1H), 4.94 (dd, J 6.7 Hz, 11.7 Hz, 1H), 4.22 (dd, J 2.5 Hz, 18.2 Hz, 1H), 4.16 (dd, J 2.5 Hz, 18.2 Hz, 1H), 3.76 (s, 3H), 2.28 (t, J 2.5 Hz, 1H).

[0423] .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 207.6 (1C), 193.1 (1C), 166.9 (1C), 159.5 (1C), 137.9 (1CH), 125.7 (1CH), 119.0 (1CH), 118.7 (1C), 109.6 (1CH), 87.8 (1CH), 79.9 (1CH.sub.2), 78.1 (1C), 75.8 (1C), 72.5 (1CH), 53.2 (1CH.sub.3), 33.9 (1CH.sub.2).

[0424] HRMS m/z (ESI+) calculated for C.sub.16H.sub.13NO.sub.3[M+H].sup.+; 268.0974, observed 268.0972.

Methyl 2-allyl-3-oxo-1-(prop-2-yn-1-yl)indoline-2-carboxylate 3ag

[0425] ##STR00059##

[0426] According to general procedure 2, dimethyl 2-(allyl(prop-2-yn-1-yl)amino)malonate (216 mg, 0.96 mmol, 1 eq) was reacted with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (430 mg, 1.44 mmol, 1.5 eq) to yield compound 3ag (59 mg, 23%) as a bright yellow oil after silica gel column chromatography (pentane:acetone, 20:1 to 10:1).

[0427] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.60 (d, J 7.7 Hz, 1H), 7.52-7.56 (m, 1H), 6.99 (d, J 8.3 Hz, 1H), 6.84 (app t, J 7.4 Hz, 1H), 5.49-5.59 (m, 1H), 5.20 (dd, J 1.3 Hz, 17.0 Hz, 1H), 5.01 (d, J 9.9 Hz, 1H), 4.21 (dd, J 2.5 Hz, 18.4 Hz, 1H), 4.14 (dd, J 2.5 Hz, 18.4 Hz, 1H), 3.71 (s, 3H), 2.95-3.05 (m, 2H), 2.29 (t, J 2.4 Hz, 1H).

[0428] .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 194.8 (1C), 167.7 (1C), 159.9 (1C), 137.9 (1CH), 130.4 (1CH), 125.2 (1CH), 120.3 (1CH.sub.2), 119.7 (1C), 118.8 (1CH), 109.3 (1CH), 78.0 (1C), 76.7 (1C), 72.6 (1CH), 53.1 (1CH.sub.3), 37.0 (1CH.sub.2), 33.4 (1CH.sub.2).

[0429] IR υ.sub.max (thin film, cm.sup.−1): 3263, 3058, 2950, 2918, 2850, 1740, 1687,1609, 1484.

[0430] HRMS m/z (ESI.sup.+) calculated for C.sub.16H.sub.15NO.sub.3(M+H).sup.+ expected 270.1125, found 270.1124.

[0431] Methyl 2-allyl-1-benzyl-4-methoxy-3-oxoindoline-2-carboxylate 3bh

##STR00060##

[0432] According to general procedure 2, dimethyl 2-(allyl(benzyl)amino)malonate (184 mg, 0.67 mmol, 1 eq) was reacted with 3-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (327 mg, 1.0 mmol, 1.5 eq) to yield compound 3bh (17 mg, 16%) as a bright yellow oil after silica gel column chromatography (Petrol:EtOAc, 10:1).

[0433] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 7.24-7.35 (m, 6H), 6.24 (d, J 8.2 Hz, 1H), 6.21 (d, J 8.1 Hz, 1H), 5.44-5.52 (m, 1H), 5.11 (ddd, J 1.5 Hz, 3.0 Hz, 17.0 Hz, 1H), 4.98 (app. dm, J 10.1 Hz, 1H), 4.58 (d, J 16.7 Hz, 1H), 4.53 (d, J 16.7 Hz, 1H), 3.92 (s, 3H), 3.53 (s, 3H), 3.02 (app. dd, J 6.7 Hz, 14.8 Hz, 1H), 2.95 (app. dd, J 7.5 Hz, 14.8 Hz, 1H).

[0434] .sup.13C NMR (CDCl.sub.3, 100 MHz) δC 192.9 (1C), 168.1 (1C), 163.1 (1C), 159.2 (1C), 139.4 (1CH), 136.9 (1C), 130.6 (1CH), 128.6 (2CH), 127.4 (1CH), 127.1 (2CH), 120.1 (1CH.sub.2), 108.8 (1C), 101.9 (1CH), 99.7 (1CH), 77.1 (1C), 55.8 (1CH.sub.3), 52.7 (1CH.sub.3), 48.5 (1CH.sub.2), 36.8 (1CH.sub.2).

[0435] IR υ.sub.max (thin film, cm.sup.−1): 2926, 1740, 1690, 1599, 1493.

[0436] HRMS m/z (ESI+) calculated for C.sub.21H.sub.21NO.sub.4[M+H].sup.+; 352.1549, observed 352.1531.

[0437] Methyl 2-allyl-5,6-dimethoxy-1-methyl-3-oxoindoline-2-carboxylate 90f

##STR00061##

[0438] According to general procedure 3, dimethyl 2-(allyl(methyl)amino)malonate was reacted with 4,5-dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate to yield the title compound after column chromatography (6:4 v/v petrol:EtOAc) as a fluorescent yellow solid

[0439] Rf=0.17 (6:4 v/v petrol:EtOAc); mp: 100-101° C.;

[0440] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 2.86 (dd, J 7.5 Hz 14.5 Hz, 1H), 3.00 (s, 3H), 3.07 (dd, J 6.6 Hz 14.5 Hz, 1H), 3.73 (s, 3H), 3.82 (s, 3H), 3.99 (s, 3H), 4.99 (dd, J 1.5 Hz 10.0 Hz, 1H), 5.15 (dd, J 1.5 Hz 17.1 Hz, 1H), 5.42 (ddt, J 7.1 Hz 10.0 Hz 17.1 Hz, 1H), 6.23 (s, 1H), 6.99 (s, 1H).

[0441] .sup.13C NMR (CDCl.sub.3, 100 MHz) δC 29.5 (CH.sub.3), 36.5 (CH.sub.2), 53.1 (CH.sub.3), 56.2 (CH.sub.3), 56.3 (CH.sub.3), 77.2 (C), 90.6 (CH), 104.8 (CH), 110.2 (C), 119.4 (CH.sub.2), 131.0 (CH), 143.2 (C), 159.2 (C), 159.8 (C), 168.0 (C), 192.5 (C).

[0442] IR υ.sub.max (thin film, cm.sup.−1): 1732 (C═O ester), 1661 (C═O aryl), 1347 (C—N aryl), 1218 (C—O aryl);

[0443] UV-Vis (EtOH) λmax (nm), Σ(M.sup.−1cm.sup.−1) 224 (13364), 251 (15354), 283 (11763), 418 (6938);

[0444] HRMS m/z (ESI+) calculated for C.sub.16H.sub.19NO.sub.5[M+H].sup.+306.1336, found 306.1335.

Methyl 2-allyl-1-methyl-3-oxo-2,3-dihydro-1H-benzo[f]indole-2-carboxylate

[0445] ##STR00062##

[0446] According to general procedure 3, dimethyl 2-(allyl(methyl)amino)malonate was reacted with 3-(trimethylsilyl)-2-naphthyl trifluoromethanesulfonate to yield the title compound after column chromatography (9.5:0.5 v/v petrol:EtOAc) as a red solid.

[0447] Rf=0.24 (9.5:0.5 v/v petrol:EtOAc)

[0448] mp: 94-96° C.

[0449] .sup.1H NMR (CDCl.sub.3, 400 MHz) δH 2.98 (dd, J 7.3 Hz 14.7 Hz, 1H), 3.07 (s, 3H), 3.12 (dd, J 7.0 Hz 14.7 Hz, 1H), 3.73 (s, 3H), 4.98 (dd, J 1.1 Hz, 10.1 Hz, 1H), 5.18 (dd, J 1.1 Hz 17.0 Hz, 1H), 5.44 (ddt, J 7.1 Hz 10.1 Hz 17.0 Hz, 1H), 6.92 (s, 1H), 7.23 (t, J 7.5 Hz, 1H), 7.47 (t, J 7.6 Hz, 1H), 7.66 (d, J 8.4 Hz, 1H), 7.79 (d, J 8.2 Hz, 1H), 8.16 (s, 1H).

[0450] .sup.13C NMR (CDCl.sub.3, 100 MHz) δC 29.3 (CH.sub.3), 36.3 (CH.sub.2), 53.0 (CH.sub.3), 76.8 (C), 101.2 (CH), 119.9 (CH.sub.2), 121.9 (C), 122.9 (CH), 126.4 (CH), 126.7 (CH), 127.1 (C), 129.7 (CH), 130.6 (CH), 130.9 (CH), 140.2 (C), 155.1 (C), 168.2 (C), 196.6 (C).

[0451] IR υ.sub.max (thin film, cm.sup.−1): 1744 (C═O ester), 1714 (C═O aryl), 1327 (C-Naryl)

[0452] UV-Vis (EtOH) λmax (nm), Σ(M.sup.−1cm.sup.−1) 251 (58250), 258 (58250), 325 (5016), 484 (1298); m/z

[0453] HRMS m/z (ESI+) calculated for C.sub.18H.sub.17NO.sub.3[M+Na]+; 318.1101, found 318.1100.

N-(4-Trifluoromethoxy)phenyl)ethane-1,2-diamine

[0454] ##STR00063##

[0455] A solution of 4-trifluoromethoxyaniline (2.7 mL, 20.00 mmol, 2.0 equiv.) and 2-bromoethylamine hydrobromide (2.05 g, 10.00 mmol, 1.0 equiv.) in 10.0 mL toluene was stirred at reflux overnight. Once cooled the reaction mixture was diluted with 13.0 mL 30% NaOH solution and washed twice with toluene. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a crude deep orange oil. The crude oil was purified via column chromatography using 9:1 DCM:MeOH with 1.25% NH4OH to yield N-(4-trifluoromethoxy)phenyl)ethane-1,2-diamine (203, 1.43 g, 6.50 mmol, 65%) as a pale orange oil; Rf 0.42 (9:1 DCM:MeOH with 1.25% NH4OH).

[0456] IR vmax/cm-1 3317, 3040, 2938, 1614, 1514, 1252; 1H NMR (400 MHz, CDCl.sub.3) δ; 7.03 (2H, d, J=9.0 Hz, H-3′ and H-5′), 6.58 (2H, d, J=9.0 Hz, H-2′ and H-6′), 4.23 (1H, bs, NH), 3.16 (2H, t, J=6.0 Hz, H-1), 2.97 (2H, t, J=6.0 Hz, H-2), 1.70 (2H, bs, NH2); 13C NMR (100MHz, CDCl.sub.3) δ; 40.8 (C-2), 46.3 (C-1), 113.0 (C-2′ and C-6′), 122.4 (C-3′ and C-5′), 140.4 (Ar(OCF3)), 147.2 (ArC), 147.5 (ArC); MS m/z [M+H]+C9H12F3N20 requires 221.08, found 221.10.

3-(2-azidoethyl)-6-(trifluoromethoxy)benzo[d]thiazol-2(3H)-imine 15

[0457] ##STR00064##

[0458] In a dry 50-mL RBF, to a solution of N.sup.1-(4-(trifluoromethoxy)phenyl)ethane-1,2-diamine (0.83 g, 3.75 mmol, 1 eq), K.sub.2CO.sub.3 (1.21 g, 8.75 mmol, 2.3 eq) and CuSO.sub.4.5H.sub.2O (9 mg, 0.04 mmol, 0.01 eq) in MeOH (20 mL) stirred under N.sub.2, was added imidazole-1-sulfonyl azide hydrochloride (0.94 g, 4.50 mmol, 1.2 eq) in 3 portions. The reaction mixture was stirred at r.t. for 2 h and then diluted with H.sub.2O (60 mL), acidified with conc. HCl and extracted with EtOAc (2×80 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure to yield 14 as a crude orange oil (0.95 g, 100% pure by .sup.1H NMR). In a dry 50-mL RBF, to a solution of the crude product (0.95 g, based on 3.75 mmol, 1 eq) and KSCN (4.37 g, 45.0 mmol, 12 eq) in 20 mL AcOH was added bromine (0.19 mL, 3.75 mmol, 1 eq) dropwise. This mixture was stirred at r.t. for 2 h and was then diluted with H.sub.2O (60 mL), neutralised with aqueous NaOH (30% wt) and extracted with EtOAc (3×80 mL). The combined organic layers were dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography (30 g silica, EtOAc) yielding the title compound as a yellow oil (690 mg, 61%).

[0459] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.16 (d, J 1.6 Hz, 1H), 7.11 (dd, J 1.6 Hz, 8.8 Hz, 1H), 7.01 (br. s, 1H), 6.94 (d, J 8.8 Hz, 1H), 4.10 (dd, J 5.8 Hz, 5.8 Hz, 2H), 3.71 (dd, J 5.8 Hz, 5.8 Hz, 2H).

[0460] .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 161.0 (1C), 143.7 (q, J 2.0 Hz, 1C), 139.2 (1C), 123.7 (1C), 120.3 (q, J 256.9 Hz, 1C), 119.6 (1CH), 115.2 (1CH), 109.5 (1CH), 48.4 (1CH.sub.2), 42.5 (1CH.sub.2).

[0461] .sup.19F NMR (CDCl.sub.3, 376 MHz) δ.sub.r-58.4.

[0462] IR υ.sub.max 3044, 2929, 2110, 1610, 1584, 1485, 1256.

[0463] HRMS m/z (ESI.sup.+) calculated for C.sub.10H.sub.8F.sub.3NOS[M+H].sup.+: 304.05, found 304.05.

Methyl 2-allyl-1-((1-(2-(2-imino-6-(trifluoromethoxy)benzo[d]thiazol-3(2H)-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-3-oxoindoline-2-carboxylate 40

[0464] ##STR00065##

[0465] To a solution of 3-N-(azidoethyl)riluzole (45 mg, 0.15 mmol, 1.0 eq) and methyl 2-allyl-3-oxo-1-(prop-2-yn-1-yl)indoline-2-carboxylate (60 mg, 0.22 mmol, 1.5 eq) in a 1:1 mixture of THF (3 mL) and H.sub.2O (3 mL) stirring at r.t. was added dropwise an aqueous solution of CuSO.sub.4.5H.sub.2O (37 mg, 0.15 mmol, 1.0 eq) and a freshly prepared aqueous solution (0.2 mL H.sub.2O) of sodium ascorbate (59 mg, 0.30 mmol, 2.0 eq). After 1 h (total consumption of azide by TLC), aqueous NH.sub.4OH (28%, 15 mL) was added to the reaction mixture which was then extracted with DCM (3×50 mL). The combined organic layers were dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography (15 g silica, Petrol:EtOAc 1:1, to EtOAc to EtOAc:MeOH 9:1, v/v) yielding the title compound as a bright yellow solid (67 mg, 78%). methyl 2-allyl-3-oxo-1-(prop-2-yn-1-yl)indoline-2-carboxylate was also isolated (12 mg, 20%, 60% of max theoretical yield).

[0466] .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.57 (d, J 7.6 Hz, 1H), 7.31-7.35 (m, 2H), 7.10 (d, J 1.6 Hz, 1H), 7.02 (br. s, 1H), 6.89 (d, J 8.8 Hz, 1H), 6.78 (app t, J 7.4 Hz, 1H), 6.53 (d, J 8.3 Hz, 1H), 6.44 (d, J 8.8 Hz, 1H), 5.24-5.35 (m, 1H), 5.01 (dd, J 1.4 Hz, 17.0 Hz, 1H), 4.90 (d, J 10.1 Hz, 1H), 4.72 (t, J 5.8 Hz, 2H), 4.58 (d, J 16.7 Hz, 1H), 4.46 (d, J 16.7 Hz, 1H), 4.40 (t, J 5.8 Hz, 2H), 3.65 (s, 3H), 3.02 (dd, J 6.7 Hz, 14.8 Hz, 1H) 2.85 (dd, J 7.5 Hz, 14.8 Hz, 1H).

[0467] .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 194.7 (1C), 167.7 (1C), 160.71 (1C), 160.67 (1C), 144.6 (1C), 143.7 (q, J 2.0 Hz, 1C), 138.5 (1C), 137.8 (1CH), 130.5 (1CH), 125.1 (1CH), 123.6 (1CH), 123.4 (1C), 120.4 (q, J 257.5 Hz, 1C), 120.0 (1CH.sub.2), 119.7 (1CH), 119.5 (1C), 118.6 (1CH), 115.1 (1CH), 109.3 (1CH), 108.8 (1CH), 77.4 (1C), 53.1 (1CH.sub.3), 47.0 (1CH.sub.2), 43.6 (1CH.sub.2), 40.4 (1CH.sub.2), 37.2 (1CH.sub.2).

[0468] .sup.19F NMR (CDCl.sub.3, 376 MHz) δ.sub.r-58.4.

[0469] IR υ.sub.max (thin film, cm.sup.−1): 2920, 2851, 1739, 1703, 1613, 1583, 1484.

[0470] HRMS m/z (ESI.sup.+) calculated for C.sub.26H.sub.23F.sub.3N.sub.6O.sub.4S [M+H].sup.+: 573.1526, found 573.1524.

[0471] Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention which are obvious to those skilled in the relevant fields are intended to be within the scope of the following Claims.