Et2Zn-Catalyzed Intramolecular Hydroamination of Alkynyl Sulfonamides and the Related Tandem Cyclization/Addition Reaction Yan Yin, Wenying Ma, Zhuo Chai, and Gang Zhao* Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai, 200032, China
[email protected] ReceiVed April 10, 2007
Intramolecular hydroamination of alkynyl amides was effected by a catalytic amount of Et2Zn (20 mol %) to form indole derivatives, and a tandem cyclization/nucleophilic addition procedure involving reaction of the indole zinc salt intermediate with acid chlorides or halides was developed to provide an efficient approach to C3-substituted indole derivatives when an excess of Et2Zn (120 mol %) was used.
Introduction Nitrogen-containing heterocycles, especially indole derivatives, have attracted much attention because of their physiological properties as important structural units in a variety of biologically active natural products.1 Interest in the synthesis of these compounds has sparked the development of numerous methods for the construction of indole moieties and their derivatives.2 Until now, many kinds of catalysts have been reported for the synthesis of indole derivatives from 2-ethynylaniline derivatives.3 Moreover, many applications including sequential C3-functionalization of indole have also been established.4 Our research group has previously reported the intramolecular hydroamination of unsaturated sulfonamides promoted by superacid.5 Recently, Nakamura’s group has reported * Address correspondence to this author. Phone/fax: 0086-21-64166128.
(1) (a) Hibino, S.; Choshi, T. Nat. Prod. Rep. 2002, 19, 148. (b) Gupta, R. R. Heterocyclic Chemistry; Springer Publishing: New York, 1999; Vol. 2, p 193. (c) Rahman, A.; Basha, A. Indole Alkaloids; Harwood Academic Publishers: Amsterdam, The Netherlands, 1998; p 141. (d) Dewick, P. M. Medicinal Natural Products; J. Wiley & Sons: Chichester, UK, 1997; Chapter 6. (2) (a) Sundlberg, R. J. Indoles; Academic: London, UK, 1996. (b) Islam, M. S.; Brennan, C.; Wang, Q. W.; Hossain, M. M. J. Org. Chem. 2006, 71, 4675. (c) Taber, D. F.; Tian, W. W. J. Am. Chem. Soc. 2006, 128, 1058. (d) Fang, Y. Q.; Lautens, M. Org. Lett. 2005, 7, 3549. (3) (a) Sakai, N.; Annaka, K.; Konakahara, T. Tetrahedron Lett. 2006, 47, 631. (b) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126. (c) Hiroya, K.; Matsumoto, S.; Sakamoto, T. Org. Lett. 2004, 6, 2953. (d) Kamijo, S.; Sasaki, Y.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 35. (e) Koradin, C.; Dhohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P. Tetrahedron 2003, 59, 1571.
a tandem cyclization/nucleophilic addition procedure of Nbenzyl-protected alkynylanilines with electrophiles to form indole derivatives mediated by 1 equiv of n-BuLi/ZnCl2/[Pd2(dba)3] or n-BuLi/ZnCl2/CuCN‚2LiCl.6 Inspired by this work, we hypothesized that N-sulfonyl-protected alkynylanilines, owing to a higher NH acidity, when treated with a weaker base than n-BuLi that might allow a broader functionality tolerance, would generate anions with sufficient nucleophilicity to cyclize to form indoline derivatives. Herein, we report the cyclization of alkynyl sulfonamides with a catalytic amount of Et2Zn to synthesize nitrogen-containing molecules and a tandem cyclization/nucleophilic addition procedure, which was shown to be a simple and efficient method to form C3-substituted indole derivatives through an indole zinc salt intermediate. Results and Discussion With sulfonamide 1a as our initial probe substrate, a survey of different reaction conditions revealed that the intramolecular hydroamination of 1a was best performed in the presence of (4) (a) Alfonsi, M.; Arcadi, A.; Aschi, M.; Bianchi, G.; Marinelli, F. J. Org. Chem. 2005, 70, 2265. (b) Amjad, M.; Knight, D. W. Tetrahedron Lett. 2004, 45, 539. (c) Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 10546. (d) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Synthesis 2004, 1889. (5) (a) Yin, Y.; Zhao, G. Heterocycles 2006, 68, 23. (b) Yin, Y.; Zhao, G. J. Fluorine Chem. 2007, 128, 40. (6) (a) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Angew. Chem., Int. Ed. 2006, 45, 944. (b) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Org. Lett. 2006, 8, 2803.
10.1021/jo070681h CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/20/2007
J. Org. Chem. 2007, 72, 5731-5736
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Yin et al. TABLE 1. Optimization of Cyclization Reaction Conditionsa
entry
base
catalyst loading (mol %)
time (h)
yield (%)b
1 2 3 4 5 6 7 8
Et2Zn Et2Zn Et2Zn Et2Zn K2CO3 NaHCO3 pyridine Et3N
20 10 20 20 200 200 200 200
3 3 2 1 24 24 24 96
98 23 76 50 45c 20c 32c tracec
a Reaction conditions: 1a (0.3 mmol), toluene (6 mL). b Isolated yield after flash chromatography. c Recovered unconsumed 1a.
TABLE 2. Effect of the Protective Group of the Nitrogen on the Reactiona
entry
PG
substrate
yield (%)b
1 2 3 4 5 6 7 8 9 10
Mbsc Ts C6H5SO2 p-FC6H4SO2 p-NO2C6H4SO2 Ms CF3CO C6H5CO Ac H
1b 1a 1c 1d 1e 1f 1g 1h 1i 1j
98 98 96 93 95 98 0d 0d 0d 0d
a Reaction conditions: amines (0.3 mmol), Et Zn (0.06 mmol), toluene 2 (6 mL). b Isolated yield after flash chromatography. c Mbs ) p-MeOC6H4SO2. d Recovered starting materials.
Et2Zn (0.2 equiv) in refluxing toluene for 3 h (Table 1, entry 1), and the resulting product 2a was obtained in 98% yield. Decreasing either the amount of Et2Zn or the reaction time led to lower yields (entries 2-4). Further, markedly lower yields were found when K2CO3, pyridine, NaHCO3, or Et3N were utilized as bases (entries 5-8). When the Et2Zn (1.2 equiv)promoted reaction system was quenched with deuterioxide, 96.8% deuterium incorporation at the C3 position of indole was observed, which was in support of the existence of the zinc salt intermediate that might serve as a useful intermediate to synthesize polyfunctional indoles.7 Next, several N-protected 2-phenylethynylanilines were prepared to examine the effects of different protective groups on the nitrogen atom. The results are summarized in Table 2. All sulfonamides underwent the 5-endo-dig cyclization to give N-protected 2-phenylindoles in high yields after 3 h in the presence of 20 mol % of Et2Zn (entries 1-6). However, under (7) (a) Yang, C. X.; Patel, H. H.; Ku, Y. Y. Synth. Commun. 1997, 27, 2125. (b) Browder, C. C.; Mitchell, M. O.; Smith, R. L.; el-Sulayman, G. Tetrahedron Lett. 1993, 34, 6245. (c) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117 and references cited therein. (d) Bergman, J.; Venemalm, L. Tetrahedron 1990, 46, 6061. See the Supporting Information for experimental details.
5732 J. Org. Chem., Vol. 72, No. 15, 2007
the same reaction conditions, the acyl-protected compounds 1g-i failed to give any detectable amount of the desired product as determined by 1H NMR spectrum analysis (entries 7-9). Additionally, when 1g was exposed to an excess of Et2Zn, only a small amount of deacylated product 2-phenyl-1H-indole (10%) along with the unreacted starting material was obtained while no desired product was observed when the primary amine 1j was subjected to the same reaction conditions (entry 10). Therefore, sulfonyl groups are crucial to this Et2Zn-catalyzed cyclization system. A number of synthetic methods for the cleavage of the N-S bond were available,8 especially for N-detosylation of indoles.9 Thus, we turned our attention to compare a variety of 2-phenylethynyl-N-tosylaniline derivatives bearing different substituted groups at the para position on the phenyl ring, which were readily prepared by the palladium-catalyzed cross-coupling reaction of 2-iodoanilines with phenylacetylene followed by tosylation.10 Under the optimized reaction conditions, all the para substituted substrates 1k-o were converted to N-tosylindole derivatives in excellent yields and halogen, the nitro group, as well as the allyl ether structure were well tolerated. The results are shown in Table 3. The electronic nature of the aromatic amines influenced the hydroamination reaction rate: electronpoor substrates reacted faster, which was probably because electron-withdrawing substituents could make the CtC triple bond more electron-deficient to receive nucleophilic attack and could stabilize the resulting indole zinc salt intermediate more efficiently (entries 1-6). Compound 1p with substituted groups at both the meta and para positions on the phenyl ring also underwent the cyclization smoothly to gave product 2p in high yield (entry 7). Moreover, compounds with alkyl and functionalized alkyl substituents on the acetylene terminal (R1) were also tested under similar reaction conditions (entries 8-12). When substituents (n-C4H9, H, and CH2OH) were present in the substrates 1q-s, the cyclization products could be obtained in high yields (entries 8-10). However, only 82% cyclization yield was obtained when 1t was used (entry 11). When the substituent was TMS, the cyclization was inhibited completely and only the deprotection of the trimethylsilyl group in the basic condition was observed after 24 h (1u:1r 6:1) (entry 12).3a,11 To evaluate the scope of this reaction further, a series of N-tosyl-protected aliphatic aminoalkynes were also investigated in a similar procedure. The experimental results are summarized in Table 4. Of all the examples examined, only five-membered nitrogen-containing heterocyles were formed and the results were highly susceptible to the structural variations of the substrates. While δ-alkynylamine 3a and 2-propynyl N-tosyl carbamate 3e12 underwent the 5-exo-dig cyclization smoothly to give the corresponding cyclized products with an exo double bond in moderate and high yields, respectively (entries 1 and 5), only partial triple bond migrated product along with the recovered starting material were obtained for substrate 3d (entry (8) (a) Forshee, P. B.; Sibert, J. W. Synthesis 2006, 756. (b) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Chemistry, 2nd ed.; Wiley-Interscience: New York, 1991. (c) Yasuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39, 595. (d) Alonso, D. A.; Andersson, P. G. J. Org. Chem. 1998, 63, 9455. (9) Haskins, C. M.; Knight, D. W. Tetrahedron Lett. 2004, 45, 599. (10) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 17, 4467. (11) Gregory, Y. Y.; Stephenson, G. A.; Mitchell, S. Tetrahedron Lett. 2006, 47, 3811. (12) (a) Baldwin, J. E. Chem. Commun. 1976, 734. (b) Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Sillberman, L.; Thomas, R. C. Chem. Commun. 1976, 736.
Intramolecular Hydroamination of Alkynyl Sulfonamides TABLE 3. Cyclization of a Series of 2-Ethynyl-N-Sulfonylanilinesa
a Reaction conditions: amines (0.3 mmol), Et Zn (0.06 mmol), toluene (6 mL). b Isolated yield after flash chromatography. c Recovered 1u. d Ratio of 1u 2 to 1r was determined by 1H NMR spectroscopic analysis.
J. Org. Chem, Vol. 72, No. 15, 2007 5733
Yin et al. TABLE 4. Cyclization of Aliphatic Alkynylaminesa
TABLE 5. Tandem Cyclization/Nucleophilic Additiona
a Reaction conditions: amines (0.3 mmol), Et Zn (0.06 mmol), toluene 2 (6 mL). b Isolated yield after flash chromatography. c 33% 3a was recovered. d 3b was recovered. e 89% 3d was recovered.
4). Interestingly, although alkyne 3c could be transformed to 2,3-dihydropyrrole in high yields through a 5-endo-dig cyclization favored by Baldwin rules (entry 3),13 phenyl-substituted γ-alkynylamine 3b failed to react even under prolonged reaction time (entry 2). Presently, the methods14 of producing substitution at the C3position of indoles mainly consist of the Friedel-Crafts reaction catalyzed by protic or Lewis acids15 and the addition reaction of indole organometallic derivatives to electrophilic components with or without catalysts.16 We found here that the reactive indole zinc salt intermediate formed by the treatment of 1a with 1.2 equiv of Et2Zn could undergo C3 acylation smoothly through nucleophilic addition to a variety of acid chlorides to give the corresponding acylated indoles in high yields at room temperature (Table 5, entries 1-6). In addition, 3-bromo-2-phenylindole derivative 5g could also be obtained with NBS as the electrophile in moderate yield (entry 7). A control experiment demonstrated that 2a, the isolated cyclized product of 1a, did not react with benzoyl chloride to give the acylated product 5b in the absence of Et2Zn at room temperature. Thus these acylation transformations may only be explained by a tandem cyclization/nucleophilic addition process. The method thus (13) Lei, A. W.; Lu, X. Y. Org. Lett. 2000, 2, 2357. (14) (a) Wang, Y. Q.; Song, J.; Hong, R.; Li, H. M.; Deng, L. J. Am. Chem. Soc. 2006, 128, 8186. (b) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314. (c) Li, D. P.; Guo, Y. C.; Ding, Y.; Xiao, W. J. Chem. Commun. 2006, 799. (d) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett 2005, 1199 and references cited therein. (e) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 6576. (f) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed. 2005, 44, 1. (15) (a) Arcadi, A.; Bianchi, G.; Chiarini, M.; D’Anniballe, G.; Marinelli, F. Synlett 2004, 944. (b) Reddy, A. V.; Ravinder, K.; Goud, T. V.; Krishnaiah, P.; Raju, T. V.; Venkateswarlu, Y. Tetrahedron Lett. 2003, 44, 6257. (c) Yadav, J. S.; Abraham, S.; Reddy, B. V. S.; Sabitha, G. Synthesis 2001, 2165. (d) Szmuszkovicz, J. J. Am. Chem. Soc. 1957, 79, 2819. (e) Noland, W. E.; Christensen, G. M.; Sauer, G. L.; Dutton, G. G. S. J. Am. Chem. Soc. 1955, 77, 456. (16) (a) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050. (b) Nunomoto, S.; Kawakami, Y.; Yamashita, Y.; Takeuchi, H.; Eguchi, S. J. Chem. Soc., Perkin. Trans. 1 1990, 111. (c) Heacock, R. A.; Kasparek, S. AdV. Heterocycl. Chem. 1969, 10, 61. (d) Powers, J.; Meyer, W. P.; Parsons, T. G. J. Am. Chem. Soc. 1967, 89, 5812.
5734 J. Org. Chem., Vol. 72, No. 15, 2007
a All reactions were performed in refluxing toluene for 3 h with amines (0.3 mmol) and Et2Zn (0.36 mmol), then the reaction systems were cooled to room temperature and acid chlorides (0.36 mmol) were added. b Reaction time of sequent nucleophilic addition reaction. c Isolated yield after flash chromatography.
provided an easy access to 3-acylindoles, which are useful for pharmacological studies.17 The mechanism of this Et2Zn-catalyzed cyclization was probably similar to that of the intramolecular anionic cyclization of the C-Li bond to alkenes or alkynes.18 A plausible mechanism of the reaction comprised the following steps (Scheme 1): The deprotonation of aminoalkynes 1 or 3 by diethylzinc gave zinc amide A, which underwent an anionic cyclization to afford B. The intermediate B could undergo nucleophilic addition with electrophiles to provide the C3substituted indole derivatives 5. (17) (a) Yang, Z.; Liu, H. B.; Lee, C. M.; Chang, H. M.; Wang, H. N. C. J. Org. Chem. 1992, 57, 7248. (b) Allin, S. M.; Thomas, C. I.; Allard, J. E.; Doyle, K.; Elsegood, M. R. J. Tetrahedron Lett. 2004, 45, 7103. (18) (a) Fujita, H.; Tokuda, M.; Nitta, M.; Suginome, H. Tetrahedron Lett. 1992, 33, 6359. (b) Luo, F. T.; Wang, R. T. Tetrahedron Lett. 1992, 33, 6835.
Intramolecular Hydroamination of Alkynyl Sulfonamides SCHEME 1.
Proposed Reaction Mechanism
Conclusion In summary, we have developed a new and efficient method for the cyclization of alkynyl amides to form the corresponding nitrogen-containing heterocycles and a tandem cyclization/ nucleophilic addition reaction of 2-phenylethynylanilines with electrophiles to give the corresponding C3-substituted indoles in high yields mediated by Et2Zn. Further studies toward the synthetic application with our method are currently underway. Experimental Section General Information. For details, see the Supporting Information. General Procedure 1: Et2Zn-Catalyzed Cyclization of Aminoalkynes To Give 2a-f, 2k-2t, 4a, and 4c-e (Tables 3 and 4). Et2Zn (0.06 mmol) was added to a solution of aminoalkynes (0.3 mmol) in dry toluene (6 mL). The mixtures were stirred in reflux. At the end of the reaction, the mixtures were cooled to room temperature and quenched with saturated NH4Cl (2 mL) solution. The mixture was extracted with Et2O (3 × 25 mL), washed with brine, dried over Na2SO4, and concentrated. Purification of the crude products by silica gel column chromatography afforded 2a-f, 2kt, 4a, and 4c-e. N-(4-Methoxybenzenesulfonyl)-2-phenylindole (2b): white solid, mp 105-106 °C (from hexane); 1H NMR (300 MHz, CDCl3) δ 8.33-8.31 (m, 1H), 7.52-7.27 (m, 10H), 6.72-6.69 (m, 2H), 6.55 (s, 1H), 3.76 (s, 3H); IR (KBr, cm-1) 2927, 1712, 1594, 1496, 1371, 1188, 1169, 579; MS (EI) (m/z) 363, 362, 192, 171, 165, 107, 91, 77, 63; 13C NMR (75 MHz, CDCl3) δ 163.5, 142.2, 138.3, 132.5, 130.6, 130.3, 129.3, 129.0, 128.6, 127.5, 124.8, 124.3, 120.7, 116.7, 113.7, 113.6, 55.5. Anal. Calcd for C21H17NO3S: C, 69.40; H, 4.71; N, 3.85. Found: C, 69.58; H, 4.68; N, 3.63. 1-(4-Nitrobenzenesulfonyl)-2-phenyl-1H-indole (2e): yellow solid, mp 163-164 °C (from hexane); 1H NMR (300 MHz, CDCl3) δ 8.30-8.27 (m, 1H), 8.09-8.06 (m, 2H), 7.54-7.25 (m, 10H), 6.60 (s, 1H); IR (KBr, cm-1) 3030, 1607, 1528, 1382, 1347, 1185, 757, 740; MS (EI) (m/z) 378, 192, 186, 165, 91, 77; 13C NMR (75 MHz, CDCl3) δ 150.5, 142.4, 142.0, 138.2, 131.8, 130.8, 130.2, 129.1, 128.1, 127.8, 125.4, 125.2, 123.8, 121.2, 116.7, 114.7; HRMS calcd for C20H14N2O4S 378.0674, found 378.0691. 5-Bromo-2-phenyl-1-(toluene-4-sulfonyl)indole (2n): white solid, mp 155-156 °C (from hexane); 1H NMR (300 MHz, CDCl3) δ 8.20-8.18 (m, 1H), 7.58-7.45 (m, 7H), 7.26-7.24 (m, 2H), 7.08-7.05 (m, 2H), 6.48 (s, 1H), 2.31 (s, 3H); IR (KBr, cm-1) 3061, 2925, 2854, 1596, 1442, 1376, 1178, 1062, 810, 763, 582, 543; MS (EI) (m/z) 427, 425, 270, 268, 190, 155, 91, 77, 65; 13C NMR (75 MHz, CDCl3) δ 144.9, 143.4, 137.0, 134.4, 132.2, 131.8, 130.4, 129.4, 129.0, 127.6, 126.8, 126.3, 123.4, 118.1, 117.8, 112.5, 21.6. Anal. Calcd for C21H16BrNO2S: C, 59.16; H, 3.78; N, 3.29. Found: C, 59.14; H, 3.76; N, 3.04. 6-Nitro-5-chloro-2-phenyl-1-(toluene-4-sulfonyl)indole (2p): yellow solid, mp 174-175 °C (EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.92 (s, 1H), 7.60-7.44 (m, 6H), 7.26-7.09 (m, 4H), 6.54 (s, 1H), 2.33 (s, 3H); IR (KBr, cm-1) 2925, 1738, 1527, 1448, 1380, 1177, 1089, 661, 582; MS (ESI) (m/z) 427.0 [M + H+]; 13C NMR (75 MHz, CDCl3) δ 144.8, 137.5, 137.0, 135.9, 134.4, 129.7, 129.1, 127.3, 126.9, 126.4, 124.6, 123.4, 120.9, 117.4, 114.4, 111.0, 21.6. Anal. Calcd for C21H15ClN2O4S: C, 59.09; H, 3.54; N, 6.56. Found: C, 59.24; H, 3.59; N, 6.40.
2-Butyl-1-(toluene-4-sulfonyl)indole (2q): white solid, mp 7980 °C (from hexane); 1H NMR (300 MHz, CDCl3) δ 8.11-8.08 (m, 1H), 7.55-7.43 (m, 2H), 7.34-7.31 (m, 1H), 7.20-7.09 (m, 4H), 6.30 (s, 1H), 2.91 (t, J ) 7.8 Hz, 2H), 2.26 (s, 3H), 1.711.62 (m, 2H), 1.41-1.34 (m, 2H), 0.89 (t, J ) 7.5 Hz, 3H); IR (KBr, cm-1) 2970, 2870, 1738, 1452, 1366, 1217, 1174, 1091, 578, 542; MS (EI) (m/z) 327, 172, 155, 130, 91, 77, 65, 44; 13C NMR (75 MHz, CDCl3) δ 144.6, 142.6, 137.2, 136.3, 129.9, 129.8, 126.3, 123.8, 123.5, 120.1, 114.9, 108.6, 31.0, 28.8, 22.5, 21.6, 14.0; HRMS calcd for C19H21NO2S 327.1293, found 327.1298. 2-Allyloxymethyl-1-(toluene-4-sulfonyl)-1H-indole (2t): white solid, mp 56-57 °C (from hexane); 1H NMR (300 MHz, CDCl3) δ 8.12-8.09 (m, 1H), 7.82-7.80 (m, 2H), 7.49-7.46 (m, 1H), 7.32-7.17 (m, 4H), 6.67 (s, 1H), 6.02-5.89 (m, 1H), 5.35-5.22 (m, 2H), 4.90 (s, 2H), 4.10 (d, J ) 5.4 Hz, 2H), 2.33 (s, 3H); IR (KBr, cm-1) 2921, 2849, 1738, 1451, 1371, 1228, 1176, 1091, 676, 581; 13C NMR (75 MHz, CDCl3) δ 144.8, 137.5, 137.0, 135.9, 134.5, 129.7, 129.1, 126.9, 124.6, 123.5, 120.9, 117.4, 114.5, 111.1, 71.5, 65.4, 21.5; MS (EI) (m/z) 341, 300, 285, 155, 130, 91, 77, 65, 55, 41. Anal. Calcd for C19H19NO3S: C, 66.84; H, 5.61; N, 4.10. Found: C, 66.67; H, 5.68; N, 3.90. General Procedure 2: Et2Zn-Catalyzed Tandem Cyclization/ Nucleophilic Addition of 1a with Electrophiles To Give 5a-g (Table 5). Et2Zn (0.36 mmol) was added to a solution of 1a (0.3 mmol) in dry toluene (6 mL). The mixture was stirred in reflux for 3 h. At the end of the reaction, the mixture was cooled to room temperature and dry electrophiles (0.36 mmol) were added. At the end of the nucleophilic addition reaction, the mixture was quenched with saturated NH4Cl (2 mL) solution. Then the mixture was extracted with Et2O (3 × 25 mL), dried over Na2SO4, and concentrated in vacuo. Purification of the crude products by silica gel column chromatography afforded 5a-g. 1-[2-Phenyl-1-(toluene-4-sulfonyl)indol-3-yl]propenone (5a): white solid, mp 124-125 °C (from hexane); 1H NMR (300 MHz, CDCl3) δ 8.03-8.00 (m, 2H), 7.62-7.47 (m, 4H), 7.30-7.18 (m, 3H), 7.09-7.03 (m, 4H), 6.46-6.39 (m, 1H), 5.94-5.84 (m, 1H), 5.60-5.56 (m, 1H), 2.13 (s, 3H); IR (KBr, cm-1) 2924, 2853, 2220, 1698, 1365, 1169, 1087, 910, 578; MS (EI) (m/z) 401, 347, 246, 155, 55, 43; 13C NMR (75 MHz, CDCl3) δ 189.0, 145.0, 137.6, 136.6, 134.7, 131.6, 130.1, 129.8, 129.6, 129.5, 129.3, 127.5, 126.9, 126.1, 124.7, 119.9, 119.1, 116.3, 103.8, 21.6; HRMS calcd for C24H19NO3S 401.1086, found 401.1100. Phenyl[2-phenyl-1-(toluene-4-sulfonyl)indol-3-yl]methanone (5b): white solid, mp 194-195 °C (from hexane); 1H NMR (300 MHz, CDCl3) δ 7.98-7.95 (m, 2H), 7.78-7.75 (m, 1H), 7.42-7.40 (m, 3H), 7.32-7.26 (m, 6H), 7.13-7.07 (m, 6H), 2.09 (s, 3H); IR (KBr, cm-1) 3074, 2919, 1701, 1442, 1361, 1254, 1172, 1084, 751, 710, 581; MS (ESI) (m/z) 452.2 [M + H+]; 13C NMR (75 MHz, CDCl3) δ 169.7, 144.8, 138.7, 136.2, 134.3, 132.8, 132.6, 131.5, 131.3, 130.1, 129.2, 129.1, 129.0, 128.8, 128.7, 128.1, 127.6, 123.7, 122.1, 95.1, 85.4, 21.4. Anal. Calcd for C28H21NO3S: C, 74.48; H, 4.69; N, 3.10. Found: C, 74.57; H, 4.88; N, 2.95. Furan-2-yl[2-phenyl-1-(toluene-4-sulfonyl)indol-3-yl]methanone (5c): white solid, mp 155-156 °C (from hexane); 1H NMR (300 MHz, CDCl3) δ 8.02-7.99 (m, 2H), 7.72-7.70 (m, 1H), 7.55-7.49 (m, 3H), 7.32-7.18 (m, 4H), 7.08-7.04 (m, 4H), 6.226.20 (m, 1H), 6.08-6.06 (m, 1H), 2.10 (s, 3H); IR (KBr, cm-1) 2924, 2852, 1682, 1464, 1367, 1172, 1086, 757, 577; MS (ESI) (m/z) 442.3 [M + H+]; 13C NMR (75 MHz, CDCl3) δ 175.8, 157.9, 146.1, 146.0, 144.8, 137.9, 136.2, 132.6, 132.4, 131.6, 130.1,130.06 129.8, 129.0, 128.9, 128.6, 127.9, 124.2, 121.9, 118.7, 111.6, 21.4; HRMS calcd for C26H19NO4S 464.0927 [M + Na+], found 464.0931. Cyclopropyl[2-phenyl-1-(toluene-4-sulfonyl)indol-3-yl]methanone (5e): white solid, mp 125-126 °C (from hexane); 1H NMR (300 MHz, CDCl3) δ 7.80-7.97 (m, 2H), 7.65-7.61 (m, 2H), 7.52-7.44 (m, 2H), 7.30-7.18 (m, 3H), 7.06-7.00 (m, 4H), 2.12 (s, 3H), 1.34-1.28 (m, 1H), 1.18-1.12 (m, 1H), 0.99-0.91 (m, 1H), 0.72-0.68 (m, 2H); IR (KBr, cm-1) 3067, 2923, 1701, 1382, J. Org. Chem, Vol. 72, No. 15, 2007 5735
Yin et al. 1164, 1087, 666, 577; MS (ESI) (m/z) 416.2 [M + H+]; 13C NMR (75 MHz, CDCl3) δ 173.8, 144.6, 137.8, 136.5, 132.8, 132.1, 131.6, 129.9, 129.7, 129.3, 128.9, 128.7, 128.0, 124.4, 122.1, 95.4, 85.5, 21.4, 14.8, 11.1, 10.2; HRMS calcd for C25H21NO3S 438.1134 [M + Na+], found 438.1149. 2,2-Dimethyl-1-[2-phenyl-1-(toluene-4-sulfonyl)indol-3-yl]propan-1-one (5f): white solid, mp 161-162 °C (from hexane); 1H NMR (300 MHz, CDCl3) δ 7.90-7.87 (m, 2H), 7.69-7.44 (m, 4H), 7.27-7.01 (m, 7H), 2.10 (s, 3H), 1.04 (s, 9H); IR (KBr, cm-1) 2970, 2867, 1738, 1362, 1217, 1171, 1086, 758, 579; MS (ESI) (m/z) 432.2 [M + H+]; 13C NMR (75 MHz, CDCl3) δ 179.4, 144.2, 137.9, 136.9, 133.6, 132.6, 131.5, 130.0, 129.8, 128.8, 128.7, 128.6, 128.0, 125.5, 122.1, 95.4, 85.8, 43.7, 28.4, 21.4. Anal. Calcd for C26H25NO3S: C, 72.36; H, 5.84; N, 3.25. Found: C, 72.49; H, 5.83; N, 3.10. 3-Bromo-2-phenyl-1-(toluene-4-sulfonyl)indole (5g): yellow solid, mp 85-86 °C (from hexane); 1H NMR (300 MHz, CDCl3) δ 8.35-8.33 (m, 1H), 7.51-7.24 (m, 10H), 7.12-7.06 (m, 2H),
5736 J. Org. Chem., Vol. 72, No. 15, 2007
2.31 (s, 3H); IR (KBr, cm-1) 3025, 2925, 1445, 1371, 1175, 1090, 813; MS (ESI) (m/z) 426.0 [M + H+]; 13C NMR (75 MHz, CDCl3) δ 144.8, 137.1, 136.2, 132.8, 131.9, 131.6, 131.2, 129.9, 129.4, 129.0, 128.7, 128.3, 127.9, 124.3, 95.7, 85.1, 21.5; HRMS calcd for C21H16BrNO2S 426.0158 [M + H+], found 426.0140.
Acknowledgment. Generous financial support from the National Natural Science Foundation of China, QT Program, Shanghai Natural Science Council, and Excellent Young Scholars Foundation of NNSF is gratefully acknowledged. Supporting Information Available: Experimental procedures and characterization data for all substrates 1a-u, the cyclization products 2a,c,d,f,k,l,m,o,r,s and 4a,c-e, and acylated product 5d, and 1H NMR and 13C NMR for selected compounds. This material is available free of charge via the Internet at http://pubs.acs.org. JO070681H
