New syntheses of pyrrolo[3,4-b]indoles, benzo[b]furo[2,3-c]pyrroles, and benzo[b]thieno [2,3-c]pyrroles utilizing the reaction of münchnones (1,3-oxazolium-5-olates) with nitroheterocycles

Article abstract of DOI:10.1055/s-1998-1887

1,3-Dipolar cycloaddition of münchnones (mesoionic 1,3-oxazolium-5-olates) 3 and 4 with 2- and 3-nitroindoles, 2-nitrobenzo[b]furan, and 3-nitrobenzo[b]thiophene affords the corresponding pyrrolo[3,4-b]indoles, benzo[b]furo[2,3-c]pyrroles, and benzo[b]thi

Full text of DOI:10.1055/s-1998-1887

October 1998
SYNLETT
1061
New Syntheses of Pyrrolo[3,4-b]indoles, Benzo[b]furo[2,3-c]pyrroles, and Benzo[b]thieno
[2,3-c]pyrroles
Utilizing the Reaction of Münchnones (1,3-Oxazolium-5-olates) with Nitroheterocycles
Gordon W. Gribble,* Erin T. Pelkey, and Frank L. Switzer
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, USA
Fax: 603-646-3946; e-mail: grib@dartmouth.edu
This paper is dedicated with 35 years of friendship and admiration to Professor Victor Snieckus on the occasion of his 60th birthyear.
Received 25 August 1998
Abstract: 1,3-Dipolar cycloaddition of münchnones (mesoionic 1,3-
oxazolium-5-olates)
3 and 4 with 2- and 3-nitroindoles, 2-
nitrobenzo[b]furan, and 3-nitrobenzo[b]thiophene affords the
corresponding pyrrolo[3,4-b]indoles, benzo[b]furo[2,3-c]pyrroles, and
benzo[b]thieno[2,3-c]pyrroles, respectively, in one operation in good to
excellent yields.
3
In continuation of our interest in pyrrolo[3,4-b]indoles and other fused
Similarly, münchnones 3 and 4 reacted with 2-nitro- (9) and 3-nitro-1-
2i
heterocycles as stable synthetic analogues of indole-2,3-
(phenylsulfonyl)indole (10) to give the corresponding pyrrolo[3,4-
b]indoles 11 and 12. These results are summarized in the Table.
1
6,7
quinodimethanes, we now report an efficient one-step synthesis of this
2
important ring system. This, as summarized in Scheme 1, the 1,3-
3
dipolar cycloaddition between 1-ethoxycarbonyl-2-nitroindole (1) or 1-
1
ethoxycarbonyl-3-nitroindole (2) and the mesoionic münchnones 3 (3-
4
benzyl-2,4-diphenyl-1,3-oxazolium-5-olate) and
4
(3-benzyl-2,4-
5
dimethyl-1,3-oxazolium-5-olate)
affords 2-benzyl-1,3-diphenyl-4-
ethoxycarbonyl-2,4-dihydropyrrolo[3,4-b]indole (5) and 2-benzyl-1,3-
dimethyl-4-ethoxycarbonyl-2,4-dihydropyrrolo[3,4-b]indole (6),
respectively. The regiochemistry of the cycloaddition is displayed
arbitrarily. These new pyrrolo[3,4-b]indoles were characterized
6,7
spectroscopically including high resolution mass spectrometry.
Moreover, 12 was independently synthesized according to the method of
2g
Srinivasan, thus confirming the structure (Scheme 2).
Scheme 2
8
Likewise,
both
2-nitrobenzo[b]furan
(13)
and
3-
9
nitrobenzo[b]thiophene (14) gave rise to the novel fused heterocycles
6,7
15-18, as summarized in Scheme 3 and the Table.
The only related cycloaddition of a münchnone with a nitro-substituted
heterocycle of which we are aware is the reaction of 3-methyl-2,4-
diphenyloxazolium-5-olate with 4-nitro-3-phenylisoxazole and 3-
methyl-4-nitroisoxazole to give the corresponding 5H-pyrrolo[3,4-
Scheme 1
10
d]isoxazoles in 69% and 52%, respectively.
Münchnones 3 and 4 were generated as shown from amino acids 7 and 8
by cyclodehydration with diisopropylcarbodiimide (DIPC). Although
these relatively labile münchnones could be isolated as yellow solids, it
was more convenient to generate and trap them in situ.
In summary, we have discovered an efficient one-pot synthesis of
pyrrolo[3,4-b]indoles and related fused heterocycles. We are currently
investigating the regiochemistry of this 1,3-dipolar cycloaddition
reaction of münchnones with nitroheterocycles and this will be reported
in due course.

1062
LETTERS
SYNLETT
Spectrometry Resource, which is supported by NIH/NCRR Grant No.
P41-RR10888 (to C.E. Costello), and by Mr. Ron New and Dr. Mary K.
Young of the SOCAL Mass Spectrometry Facility, University of
California, Riverside.
References and Notes
(1) Pelkey, E.T.; Gribble, G.W. Chem. Commun. 1997, 1873, and
references cited therein.
(2) For other syntheses of pyrrolo[3,4-b]indoles, see a) Welch, W.M.
J. Org. Chem. 1976, 41, 2031. b) Sha, C.-K.; Chuang, K.-S.;
Young, J.-J. J. Chem. Soc., Chem. Commun. 1984, 1552. c) Sha,
C.-K.; Chuang, K.-S.; Wey, S.-J. J. Chem. Soc., Perkin Trans. 1
1987, 977. d) Sha, C.-K.; Yang, J.-F. Tetrahedron 1992, 48, 10645.
e) Kreher, R.P.; Dyker, G. Z. Naturforsch. Teil B: Chem. Sci. 1987,
42, 473. f) Dyker, G.; Kreher, R.P. Chem.-Ztg. 1988, 112, 235. g)
Jeevenandam, A.; Srinivasan, P.C. J. Chem. Soc., Perkin Trans. 1
1995, 2663. h) Daly, K.; Nomak, R.; Snyder, J.K. Tetrahedron
Lett. 1997, 38, 8611. i) Pelkey, E.T.; Chang, L.; Gribble, G.W. J.
Chem. Soc, Chem. Commun. 1996, 1909. j) Ref. 1.
(3) This was prepared from 2-nitroindole (Pelkey, E.T.; Gribble, G.W.
Tetrahedron Lett. 1997, 38, 5603) and sodium hydride and ethyl
chloroformate in DMF (74% yield).
(4) a) Gribble, G.W.; Switzer, F.L.; Bushweller, J.H.; Jewett, J.G.;
Brown, J.H.; Dion, J.L.; Bushweller, C.H.; Byrn, M.P.; Strouse,
C.E. J. Org. Chem. 1996, 61, 4319. b) Gribble, G.W.; Sponholtz
III, W.R.; Switzer, F.L.; D'Amato, F.J.; Byrn, M.P. Chem.
Commun. 1997, 993.
4
(5) This new münchnone was generated as described for 3.
(6) High resolution mass spectroscopy data obtained for 5, calcd for
C
H N O : 470.1994. Found: 470.1990.
32 26 2 2
For 6, calcd for C
H N O : 346.1681. Found: 346.1693.
22 22 2 2
Scheme 3
For 11, calcd for C
For 12, calcd for C
For 15, calcd for C
For 16, calcd for C
For 17, calcd for C
For 18, calcd for C
H N O S: 538.1715. Found: 538.1691.
35 26 2 2
H
N O S: 414.1402. Found: 414.1417.
2 2
25 22
H
NO: 399.1623. Found: 399.1633.
NO: 275.1310. Found: 275.1306.
NS: 415.1395. Found: 415.1405.
NS: 291.1082. Found: 291.1084.
29 21
H
19 17
Representative experimental procedure: To a stirred solution at room
temperature of 3-nitro-1-(phenylsulfonyl)indole (10) (182 mg, 0.60
mmol) and N-acetyl-N-benzylalanine (8) (398 mg, 1.80 mmol) in THF
(25 mL) was added dropwise diisopropylcarbodiimide (227 mg, 1.80
mmol). The resulting reaction mixture was heated to reflux for 9 h.
After being cooled to room temperature, the solvent was removed in
vacuo to give an amorphous solid. Purification by flash chromatography
H
29 21
H
19 17
(7) Proton NMR data (CDCl ): 5: δ 8.33-.8.35 (m, 1 H), 7.10-7.59
3
(m, 16 H), 6.58-6.64 (m, 2 H), 5.10 (s, 2 H), 3.74 (q, 2 H, J = 7.2
Hz), 0.80 (t, 3 H, J = 7.2 Hz); 6: δ 8.19-8.20 (m, 1 H), 7.61-7.64
(m, 1 H), 7.19-7.34 (m, 5 H), 6.91-6.93 (m, 2 H), 5.19 (s, 2 H),
4.50 (q, 2 H, J= 7.2 Hz), 2.56 (s, 3 H), 2.49 (s, 3 H), 1.49 (t, 3 H, J
= 7.2 Hz); 11: δ 8.20-8.23 (m, 1 H), 7.11-7.47 (m, 21 H), 6.58-
6.60 (m, 2 H), 5.11 (s, 2 H); 15: δ 7.67-7.70 (m, 1 H), 7.58-7.64
(m, 4 H), 7.27-7.50 (m, 8 H), 7.14-7.20 (m, 4 H), 6.74-6.77 (m, 2
H), 5.46 (s, 2 H); 16: δ 7.61-7.64 (m, 1 H), 7.17-7.38 (m, 6 H),
6.89-6.92 (m, 2 H), 5.16 (s, 2 H), 2.46 (s, 3 H), 2.31 (s, 3 H); 17: δ
7.66-7.69 (m, 1 H), 7.39-7.54 (m, 10 H), 7.11-7.31 (m, 6 H), 6.68-
6.71(m, 2 H), 5.37 (s, 2 H); 18: δ 7.77-7.80 (m, 1 H), 7.64-7.67
(m, 1 H), 7.17-7.34 (m, 5 H), 6.90-6.93 (m, 2 H), 5.20 (s, 2 H),
2.55 (s, 3 H), 2.31 (s, 3 H).
(1:1 CH Cl /hexanes) gave 167 mg (67%) of 2-benzyl-1,3-dimethyl-4-
2
2
(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole (12) as a light tan
solid. Recrystallization from 1:1 CH Cl /hexanes afforded yellow
crystals, mp 213-215 °C: H NMR (CDCl ) δ 8.16-8.19 (m, 1 H), 7.19-
7.54 (m, 11 H), 6.74-6.76 (m, 2 H), 5.14 (s, 2 H), 2.57 (s, 3 H), 2.32 (s, 3
H); C NMR (CDCl ) δ (one carbon unaccounted) 144.1, 138.2, 136.4,
2
2
3
3
133.2, 129.0, 128.5, 127.4, 127.3, 127.2, 125.6, 124.8, 124.2, 119.3,
177.8, 116.6, 116.1, 111.9, 47.3, 11.8, 11.1.
Acknowledgements. The authors acknowledge the Donors of the
Petroleum Research Fund (PRF), administered by the American
Chemical Society, Pfizer, and Wyeth-Ayerst for support of this project,
the PRF for a summer faculty fellowship to F.L.S., and Smithkline-
Beecham for sponsoring a Division of Organic Chemistry American
Chemical Society Graduate Fellowship to E.T.P. Mass spectral data
were provided by the Boston University School of Medicine Mass
(8) Tromelin, A.; Demerseman, P.; Royer, R. Synthesis 1985, 1074.
(9) Ono, N.; Hironaga, H.; Ono, K.; Kaneko, S.; Murashima, T.;
Ueda, T.; Tsukamura, C.; Ogawa, T. J. Chem. Soc., Perkin Trans.
1 1996, 417.
(10) Nesi, R.; Giomi, D.; Turchi, S.; Tedeschi, P.; Ponticelli, F. Gazz.
Chim. Ital. 1993, 123, 633.