Abstract
The solid-state reaction between anilines and phenacyl bromides in the presence of an equimolecular amount of sodium bicarbonate gives N -phenacylanilines. Microwave irradiation of mixtures of these compounds with anilinium bromides at 540 W for 45-60 s provides a mild, general, and environmentally friendly method for the synthesis of 2-arylindoles in 50-56% overall yields. A one-pot variation of the method, involving irradiation of 2:1 mixtures of anilines and phenacyl bromides, was also developed, allowing a simplified experimental procedure and leading to improved yields (52-75%).
Key words
indole synthesis - aniline monoalkylation - solvent-free synthesis - microwave-assisted synthesis
References and Notes 1 Permanent address: Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
2 Tanaka K.
Solvent-Free Organic Synthesis
Wiley;
New York:
2003.
3a Somei M.
Yamada F.
Nat. Prod. Rep.
2003,
30:
216
3b Hibino S.
Chosi T.
Nat. Prod. Rep.
2002,
19:
148
3c Hibino S.
Chosi T.
Nat. Prod. Rep.
2001,
18:
66
3d Lounasmaa M.
Tolvanen A.
Nat. Prod. Rep.
2000,
17:
175
4 Gribble GW.
Five-membered rings with one heteroatom and fused carbocyclic derivatives, In Comprehensive Heterocyclic Chemistry
2nd ed., Vol. 2:
Bird CW.
Katrizky AR.
Rees CW.
Scriven EFV.
Pergamon Press;
Oxford:
1995.
p.207
5a Tois T.
Franzén R.
Koskinen A.
Tetrahedron
2003,
59:
5395
5b Gribble GW.
J. Chem. Soc., Perkin Trans. 1
2000,
1045
6a Brown RK.
Indoles
Part 1:
Houlighan WJ.
Wiley-Interscience;
New York:
1972.
Chap. 2.
6b Sundberg RG.
Pyrroles and their Benzo Derivatives, In Comprehensive Heterocyclic Chemistry
Vol. 4:
Bird CW.
Cheeseman GWH.
Katrizky AR.
Rees CW.
Pergamon Press;
Oxford:
1984.
p.313
6c Sundberg RJ.
Indoles
Academic Press;
New York:
1996.
7a Taylor EC.
Katz AH.
Salgado-Zamora H.
McKillop AM.
Tetrahedron Lett.
1985,
26:
5963
7b Rudisill DE.
Stille JK.
J. Org. Chem.
1989,
54:
5856
7c Ezquerra J.
Pedregal C.
Lamas C.
Barluenga J.
Pérez M.
García-Martín MA.
González JM.
J. Org. Chem.
1996,
61:
5804
7d Kondo Y.
Kojima S.
Sakamoto T.
Heterocycles
1996,
61:
5804
7e Kondo Y.
Kojima S.
Sakamoto T.
J. Org. Chem.
1997,
62:
6507
7f Dai W.-M.
Guo D.-S.
Sun L.-P.
Tetrahedron Lett.
2001,
42:
5275
8a Larock RC.
J. Organomet. Chem.
1999,
576:
111
8b Li JJ.
Gribble GW.
Palladium in Heterocyclic Chemistry. A Guide for the Synthetic Chemist
Pergamon Press;
Oxford:
2000.
8c Cacchi S.
Fabrizi G.
Parisi LM.
Heterocycles
2002,
58:
667
9a Cacchi S.
Carnicelli V.
Marinelli F.
J. Organomet. Chem.
1994,
475:
289
9b Yu MS.
Leon LL.
McGuire MA.
Botha G.
Tetrahedron Lett.
1998,
39:
9347
9c Larock RC.
Yum EK.
Refvik MD.
J. Org. Chem.
1998,
63:
7652
9d Yasuhara A.
Kanamori Y.
Kaneko M.
Numata A.
Kondo Y.
Sakamoto T.
J. Chem. Soc., Perkin Trans. 1
1999,
529 ; and references therein from the same group
9e Esseveldt BCJ.
Delft FL.
Gelder R.
Rutjes FPJT.
Org. Lett.
2003,
5:
1717
9f Kamijo S.
Yamamoto Y.
J. Org. Chem.
2003,
68:
4764
10 Hiroya K.
Itoh S.
Sakamoto T.
J. Org. Chem.
2004,
69:
1126
11 Arcadi A.
Bianchi G.
Marinelli F.
Synthesis
2004,
610
12a Kondo Y.
Kojima S.
Sakamoto T.
J. Org. Chem.
1997,
62:
6507 ; and references therein from the same group
12b Koradin C.
Dohle W.
Rodriguez AL.
Schmid B.
Knochel P.
Tetrahedron
2003,
59:
1571 ; and references therein from the same group
13a Yasuhara A.
Kanimori Y.
Kaneko M.
Numata A.
Kondo Y.
Sakamoto T.
J. Chem. Soc., Perkin Trans. 1
1999,
529
13b Botta M.
Summa V.
Corelli F.
Pietro GD.
Lombardi P.
Tetrahedron: Asymmetry
1996,
7:
1263
13c Fagnola MC.
Candidiani I.
Visentin G.
Cabri W.
Zarini F.
Mongelli N.
Bedeschi A.
Tetrahedron Lett.
1997,
38:
2307
14 Cacchi S.
Fabrizi G.
Parisi LM.
Org. Lett.
2003,
5:
2919
15a Sakamoto T.
Kondo Y.
Iwashita S.
Nagano T.
Yamanaka H.
Chem. Pharm. Bull.
1988,
36:
1305
15b Fagnola MC.
Candiani I.
Visentin G.
Cabri W.
Zarini F.
Mongelli N.
Bedeschi A.
Tetrahedron Lett.
1997,
38:
2307
15c Zhang HC.
Ye H.
Moretto AF.
Brumfield KK.
Maryanoff BE.
Org. Lett.
2000,
2:
89
15d Wu TYH.
Ding S.
Gray NS.
Schultz PG.
Org. Lett.
2001,
3:
3827
15e Barluenga J.
Tricado M.
Rubio E.
González JM.
Angew. Chem. Int. Ed.
2003,
42:
2406
15f Huang Q.
Larock RC.
J. Org. Chem.
2003,
68:
7342
15g Amjad M.
Knight DW.
Tetrahedron Lett.
2004,
45:
539
15h Hong KB.
Lee CW.
Yum EK.
Tetrahedron Lett.
2004,
45:
693
16a Gassman PG.
Van Bergen TJ.
Gilbert DP.
Cue BW.
J. Am. Chem. Soc.
1974,
96:
5495
16b Gassman PG.
Van Bergen TJ.
Org. Synth. Coll. Vol. 6
Wiley;
New York:
1988.
p.601
17 Dalpozzo R.
Bartoli G.
Curr. Org. Chem.
2005,
9:
163
18 Sundberg RJ.
The Chemistry of Indoles
Academic Press;
New York:
1970.
19a Black DSC.
Bowyer MC.
Bowyer PK.
Ivory AJ.
Kim M.
Kumar N.
McConnell DB.
Popiolek M.
Aust. J. Chem.
1994,
47:
1741
19b Bashford KE.
Cooper AL.
Kane PD.
Moody CJ.
Muthusamy S.
Swann E.
J. Chem. Soc., Perkin Trans. 1
2002,
1672
20 Pchalek K.
Jones AW.
Wekking MMT.
Black DSC.
Tetrahedron
2005,
61:
77
21a Nordlander JE.
Catalane DB.
Kotian KD.
Stevens RM.
Haky JE.
J. Org. Chem.
1981,
46:
778
21b Sundberg RJ.
Laurino JP.
J. Org. Chem.
1984,
49:
249
22 Buu-Hoi NP.
Saint-Duf G.
Deschamps R.
Bigot P.
Hieu H.-T.
J. Chem. Soc. C
1971,
2606
23a Black DSC.
Gatehouse BMKC.
Théobald F.
Wong LCH.
Aust. J. Chem.
1980,
33:
343
23b Black DSC.
Kumar N.
Wong LCH.
Aust. J. Chem.
1986,
39:
15
24a Caddick S.
Tetrahedron
1995,
38:
10403
24b de la Hoz A.
Díaz-Ortiz A.
Moreno A.
Langa F.
Eur. J. Org. Chem.
2000,
22:
3659
24c Perreux L.
Loupy A.
Tetrahedron
2001,
57:
9199
24d Lidstrom P.
Tierney J.
Wathey B.
Westman J.
Tetrahedron
2001,
57:
9225
24e Santagada V.
Perissutti E.
Caliendo G.
Curr. Med. Chem.
2002,
9:
1251
24f Microwaves in Organic Synthesis
Loupy A.
Wiley-VCH;
Weinheim:
2002.
24g Varma RS.
Advances in Green Chemistry: Chemical Synthesis Using Microwave Irradiation
AstraZeneca Research Foundation;
India:
2002.
24h Hayes BL.
Aldrichimica Acta
2004,
37:
66
24i Kappe CO.
Angew. Chem. Int. Ed.
2004,
43:
6250
24j Tierney J.
Lindstrom P.
Microwave Assisted Organic Synthesis
Blackwell;
London:
2005.
25a Pérez R.
Pérez E.
Suárez M.
González L.
Loupy A.
Jimeno ML.
Ochoa C.
Org. Prep. Proced. Int.
1997,
29:
671
25b Limousin C.
Cleophax J.
Loupy A.
Petit A.
Tetrahedron
1998,
54:
13567
25c Dandia A.
Arya K.
Khaturia S.
Yadav P.
ARKIVOC
2005,
(xii):
80
26a
General Procedure for the Two-Step Method.N-Alkylation : 2 mmol of the suitable phenacyl bromide (prepared according ref. 26b) was slowly added to a mixture of 2 mmol of the suitable arylamine and 300 mg of NaHCO3 (the order of addition of the reagents is not normally of consequence, but it is important to use the method described here in the case of the anisidine derivatives, which otherwise lead to dialkylation products). The reaction mixture was stirred at r.t. with occasional cooling in tap water, soon becoming semisolid and finally solid. This solid was kept at r.t. for 3 h, when completion of the reaction was verified by TLC. Then, H2 O was added to the mixture and the separated solid was filtered, washed with H2 O, and dried, giving materials with sufficient purity for the next step. If desired, the N -phenacylanilines can be recrystallized from EtOH.
Cyclization : a mixture of 1 mmol of the suitable N -phen-acylaniline and 1.5 mmol of the corresponding anilinium hydrobromide with 3-4 drops of DMF was irradiated in a domestic microwave oven at 540 W for the time period specified in Table
[1 2 O, dried and evaporated before chromatography. All indole derivatives were previously known, and showed the expected 1 H NMR and 13 C NMR spectra, and melting points very similar to those previously described (Table
[1
26b Cowper RM.
Davidson LH.
Org. Synth. Coll. Vol. 2
Wiley;
New York:
1962.
p.480
27a Bischler A.
Brion H.
Ber. Dtsch. Chem. Ges.
1892,
25:
2860
27b Bischler A.
Firemann P.
Ber. Dtsch. Chem. Ges.
1893,
26:
1336
28 Blades CE.
Wilds AL.
J. Org. Chem.
1956,
21:
1013
29 Smith AB.
Visnick M.
Haseltine JN.
Sprengeler PA.
Tetrahedron
1986,
42:
2957
30 Hudkins RL.
Diebold JL.
Marsh FD.
J. Org. Chem.
1995,
60:
6218
31 Junjappa H.
Synthesis
1975,
798
32 Brown F.
Mann FG.
J. Chem. Soc.
1948,
847
33 Crowther AF.
Mann FG.
Purdie D.
J. Chem. Soc.
1943,
58
34 J. Org. Chem .; 2003 , 68 : 387
35 Black DSC.
Kumar N.
McCornell DB.
Tetrahedron
2001,
57:
2203
36
General Procedure for the One-Pot Synthesis of 2-Arylindoles from Phenacyl Bromides and Anilines under Microwave Irradiation.
Phenacyl bromide (1 mmol) was stirred with aniline (2 mmol) at r.t. without any base to neutralize the liberated HBr. The mixture was kept at r.t. with occasional stirring for 3 h. To the solid mixture, containing N -phenacyl aniline and anilinium hydrobromide, was added 3-4 drops of DMF and the mixture was irradiated in a microwave oven at 600 W for 1 min. After completion of the reaction, the mixture was treated as described for the two-step method to give the pure 2-arylindoles.
