摘要:
Oxocarbons and related compounds. Part 24.l Chlorosquarylation of indoles Arthur H. Schmidt,* Stefan H. Thiel and Otfried Gaschler Abteilung fur Organische Chemie und Biochemie, Fachhochschule Fresenius, Kapellenstrasse 11-15, 0-65193 Wiesbaden, Germany -f Chlorosquarylated indoles 3 and 4 have been synthesized from indoles 2 and squaric dichloride 1 and have been treated with nitrogen- and oxygen-nucleophiles. A large number of indoles are distinguished by their biological activity. In particular, specifically substituted indoles serve as the starting material for the synthesis of natural products and also for pharmacologically active compounds.2 As a consequence, there is a steady demand for novel synthetically versatile indole derivatives. Of fundamental importance in the search for such building blocks is the attachment of a polyfunctional subunit to the indole nucleus, with the capacity to undergo a great many, easy chemical transformation^.^ We intended to achieve this by introducing the 2-chloro-3,4-dioxocyclobut-1-enyl group (chlorosquaryl group) to the indole nucleus.For this purpose we began an investigation into the reaction of 3,4-dichlorocyclobut-3-ene-1,2-dione (squaric dichloride) 1 with indoles. Though squaric dichloride 1 has been used extensively for the acylation of arenes there is, surprisingly, only one mention in the literature of the extension of this reaction to indoles: a solution of squaric dichloride 1 and 1,2-dimethylindole 2a (in excess) in dichloromethane was passed through a column of acidic alumina, thus affording 3,4-bis( 1,2-dimethy1-3-indolyl)-cyclobut-3-ene-1,2-dione (0.6773.’ We have found that the reaction of the indoles 2a-f with squaric dichloride 1(1 equiv.) in an appropriate solvent affords the chlorosquarylated indoles 3 and 4 (Scheme 1, Table 1).-&,R3= H R2 R’ a R’ = Me, R2 = Me b R‘ = Me, R2 = Ph O0 c R’ = CH&H2CN, R2 = PhcK’ R1 1 2 a R’ = Me, A2 = Me, R3 = H b R’=Me.R2=Ph,R3=H c R’ d R’ o R’ f R’ = CH&YCN, R2 = Ph, R3 = H R’ = H, R2 = H, R3 = Me 4 = H, R2 = H, R3 = Ph a R‘=H, R3=Me = Me, R2 = H, R3 = Me b R1=H,R3=Ph c R’ = Me, R3 = Me Scheme 1 Chlorosquarylation of indoles. For conditions see Table 1. In agreement with reports on the acylation of indoles,6 chlorosquarylation takes place at C-3 of indoles 2a-c (Table 1, t New address: Abteilung fur Organische Chemie und Biochemie, Fachhochschule Fresenius, Limburger Strasse 2, D-65510 Idstein, Germ any.entries 14) with the formation of 3a<, and at C-2 of indoles 2d-f (Table 1, entries 5-7), with the formation of 4ax. Depending on their specific substitution patterns, the chlorosquarylated indoles 3 and 4 exhibited different polarity and solubility properties. While 3a< and 4c could be recrystallized easily, this was not the case with 4a and 4b. In an attempt to recrystallize 4b from ethanol, the ethoxysquarylated indole 6 was obtained (videinfra). On heating solutions of the chlorosquarylated indole 3b in EtOH or THF with a primary amine (aniline) and a secondary amine (morpholine) for 30 min the aminosquarylated indoles 5a and 5b were obtained (Scheme 2). When 4b was heated at 5a R1 = H, R2 = Ph 5b R1, R2 = (CH,),O(CH,), 6 Scheme 2 Reagents and conditions: i, THF or EtOH, reflux, 30 min; ii, reflux, 3 min reflux in EtOH for 3 min the ethoxysquarylated indole 6, 3-ethoxy-4-(1-methyl-3 -phenyl- 1H-indol-2-yl)cyclobut-3-ene-1,Zdione, crystallized from the filtrate in analytically pure form (Scheme 2).The chlorosquaryl unit’s unique range of subsequent valuable synthetic transformations has been further demon- strated by the reaction of the chlorosquarylated indoles 3a-c with sodium azide in methanol. Accompanied by the evolution of CO and N,, the methyl indol-3-ylcyanoacetates 7a (42%),7b7 (71%) and 7c (66%) were obtained: (Scheme 3).It is FN i CH-C0,Me + NaN, -40;-N2 mR2 R’ 7 a R’ = Me. R2 = Me b R’ = Me, R2 = Ph c R’ = CH*CH2CN, R2 = Ph Scheme 3 Reagents and conditions: i, acetone-MeOH, reflux 15-30 min 1This is an extension of the reaction of 3-halogeno-4-phenylcyclobut-3-ene-1,Zdione with sodium azide. Phenylcyanoketene is generated which, in alcoholic solution, reacts further to give alkyl phenyl- cyanoacetates. J. Chem. SOC.,Perkin Trans. I 495 Table 1 Chlorosquarylation of indoles Solvent and Entry Indole conditions Time (tjmin) Product Yield (%) Mpc (T/"C) 1 2a Benzene, rt 45 3a 51 163-1 64 (decomp.) 2b Benzene, rt 45 3b 26 169-1702 2b CHCI,, rt 45 3b 21 1 68- 1 69 3 2c Benzene, reflux 120 3c 39 201-203 (decomp.)4 5 2d CH,Cl,, rt 720 4a 17 193-195 6 2e Benzene, reflux 180 4b 75 195-197 (decomp.)2f Benzene, rt 45 4c 25 141-1 42 7 a Compounds 3a-c, 4a and 4c gave satisfactory elemental analyses and were characterized by IR, 'H NMR, I3C NMR and mass spectroscopy.Yields are of purified products, if not otherwise stated. Uncorrected. 4b was purified by trituration with boiling light petroleum and did not give satisfactory elemental analyses. IR and mass spectra were taken and agreed with the structure. The structure of 4b was confirmed by the preparation of the derivative 6 which gave satisfactory elemental analysis and was characterized by a complete set of spectra.Yield of crude product. noteworthy that methyl (5-methoxyindol-3-y1)cyanoacetatehas been successfully transformed into tryptamine analogues, which have proved to be potential antihypertensive drugsg Extension of this work to the chlorosquarylation of benzofurans and benzothiophenes is under investigation. Experimenta1 3Chloro-4-(1,2dimethyl-lH-indol-3-yl)cyclobut-3-ene-1,2-dione 3a (Table 1, Entry 1) To a stirred solution of squaric dichloride 1 (1.74 g, 12.0 mmol) in benzene (30 cm3) was added a solution of 1,2-dimethylindole 2a (2.00 g, 13.3 mmol) in benzene (30 cm3) over 10 min. When the addition was completed, the mixture was stirred for a further 45 min at room temperature. The reaction mixture was then filtered and the filtrate evaporated to dryness, leaving a dark green solid.This solid was recrystallized twice from CHC1,-light petroleum (the first time with the aid of charcoal) to give 3a as greenish crystals (1.83 g, 51%), mp 163-164 "C (decomp.) (Found: C, 64.4; H, 4.0; Cl, 13.6; N, 5.4. C,,H,,- CINOz requires C, 64.75; H, 3.88; C1, 13.65; N, 5.39%); v,,,(KBr)/cm-' 3020, 2920, 1780, 1750, 1600, 1535, 1490, 1440, 1400, 1100, 840 and 745; 6,(400 MHz; CDCl,) 2.78 (3 H, s), 3.74 (3 H, s), 7.2k7.32 (3 H, m) and 8.02 (1 H, d, J 7.8 Hz); S,-(100.6 MHz; CDCl,) 13.7, 30,4, 104.0, 110.0, 122.2, 122.9, 123.6, 125.5, 138.4, 146.3, 171.7, 187.5, 190.5 and 194.7; m/z (EI) 261 (M', llx), 259 (M', 34), 205 (M+ -2C0, 34) and (M' -2C0,lOO). Acknowledgements The authors gratefully acknowledge financial support of this work from the Deutsche Forschungsgemeinschaft (DFG), Bonn-Bad Godesberg (Grant: Schm 309-6/1).They are also grateful to Dr G. Penzlin, Beilstein Institut, Frankfurt am Main, for his advice on nomenclature. References 1 Part 23, A. H. Schmidt, G. Kircher, St. Maus and H. Bach, J. Org. Chem., in the press. 2 (a) R. T. Brown, J. A. Joule and P. G. Sammes, comprehensive Organic Chemistry, eds. D. H. R. Barton and W. D. Ollis, Pergamon Press, Oxford, 1979, vol. 4; (b) L. R. Smith, Zndoles, Part 11, Wiley-Interscience, New York, 1983; (c) J. E. Saxton, Zndoles, Part IV, Wiley-Interscience, New York, 1983; (d) J. P. Kutney, The Total Synthesis of Natural Products, ed. J.Apsimon, Wiley-Interscience, New York, 1977, vol. 3. 3 S. Blechert, R. Knier, H. Schroers and T. Wirth, Synthesis, 1995, 592. 4 For selected references, see: (a) G. Maahs and P. Hegenberg, Angew. Chem., 1966,78,927;Angew. Chem., Znt. Ed. Engl., 1966,5,888; (b)B. R. Green and W. Neuse, Synthesis, 1974,46;(c)N. G. Argyropoulos, Chem. Chron., 1986, 15, 119; (d) P. M. Kazmaier, R. A. Burt and G. Baranyi, USP 4 624 904/1986, Xerox Corp., USA (Chem. Abstr., 1987, 106, 205165m); (e) Y. Akasaki, A. Tokida, K. Torigoe and A. Imai, Jap. P 62 249 952/1987, Fuiy Xerox Co., Ltd., Japan (Chem. Abstr., 1988,109, 170005s). 5 M. Matsuoka, H. Soejima and T. Kitao, Dyes Pigm., 1991, 16, 309. 6 (a) R. A. Jones, Comprehensive Heterocyclic Chemistry, eds. A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984, vol. 4, ch. 3.05, p. 201; (b) R. J. Sundberg, The Chemistry of Zndoles, Academic Press, New York, London, 1970. 7 V. S. Rozhkov, Yu. I. Smushkevich and N. N. Suvorov, fiim. Geterotsikl. Soedin, 1981, 372; Chem. Heterocycl. Compd. (Engl. Trans.), 1981,17,274; Chem. Abstr., 1981,95, 80637n. 8 (a) R. C. DeSelms, Tetrahedron Lett., 1969, 1179; (b) A. H. Schmidt and W. Ried, Tetrahedron Lett., 1969,2431. 9 L. G. Zepeda, M. Rojas-Gardida, M. S. Morales-Rios and P. Joseph- Nathan, Tetrahedron, 1989,45,6439. Paper 5/07570J Received 20th November 1995 Accepted 1lth January 1996 496 J. Chem. Soc., Perkin Trans. 1
ISSN:1472-7781
DOI:10.1039/P19960000495
出版商:RSC
年代:1996
数据来源: RSC