Synthesis of N-substituted pyrrolo[3,4-b]indoles from 2,3-dimethylindole

Article abstract of DOI:10.1081/SCC-120004850

Pyrrolo[3,4-b]indoles 8 are conveniently synthesized from 2,3-dimethylindole (4) in four steps, the last of which is DDQ oxidation of dihydropyrrolo[3,4-b]indoles 7 (85-98% yield).

Full text of DOI:10.1081/SCC-120004850

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SYNTHESIS OF N-SUBSTITUTED PYRROLO[3,4-b]INDOLES
FROM 2,3-DIMETHYLINDOLE
Tara L. S. Kishbaugh a & Gordon W. Gribble b
a Department of Chemistry , Dartmouth College , Hanover, NH, 03755, U.S.A.
b Department of Chemistry , Dartmouth College , Hanover, NH, 03755, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Tara L. S. Kishbaugh & Gordon W. Gribble (2002) SYNTHESIS OF N-SUBSTITUTED PYRROLO[3,4-b]INDOLES
FROM 2,3-DIMETHYLINDOLE, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 32:13, 2003-2008, DOI: 10.1081/SCC-120004850
To link to this article: http://dx.doi.org/10.1081/SCC-120004850
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SYNTHETIC COMMUNICATIONS, 32(13), 2003–2008 (2002)
SYNTHESIS OF N-SUBSTITUTED
PYRROLO[3,4-b]INDOLES FROM
2,3-DIMETHYLINDOLE
*
Tara L. S. Kishbaugh and Gordon W. Gribble
Department of Chemistry, Dartmouth College,
Hanover, NH 03755, USA
ABSTRACT
Pyrrolo[3,4-b]indoles 8 are conveniently synthesized from 2,3-
dimethylindole (4) in four steps, the last of which is DDQ
oxidation of dihydropyrrolo[3,4-b]indoles 7 (85–98% yield).
Key Words: Pyrrolo[3,4-b]indoles; Indole-2,3-quinodimethane;
DDQ oxidation
In continuation of our interest in the synthesis and chemistry of
pyrrolo[3,4-b]indoles 1 as stable synthetic analogues of indole-2,3-quinodi-
methanes 2,[1] we wish to report a new synthesis of this ring system (Scheme 1).
Scheme 1.
*Corresponding author. E-mail: grib@dartmouth.edu
2003
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

2004
KISHBAUGH AND GRIBBLE
Although this ring system has a relatively long history[2] and a number
of syntheses have been described,[3,4] the direct dehydrogenation of
1,3-dihydropyrroles 3 to 1 has apparently not been reported.
Our synthetic route is summarized in the Scheme 2 and the results
are tabulated in Table 1. N-Phenylsulfonylation of commercially available
Scheme 2.
Table 1. Synthesis of 7 and 8
RNH2
% Yield, 7
% Yield, 8
(CH3)3CNH2
68 (7a)
61 (7b)
61 (7c)
74 (7d)
90 (8a)
91 (8b)
98 (8c)
85 (8d)
(CH3)2CHNH2
PhCH2NH2
p-MeOPhCH2NH2

PYRROLO[3,4-b]INDOLES
2005
2,3-dimethylindole (4) afforded 5 in excellent yield. Other methods
(NaOH, n-Bu4NHSO4, PhSO2Cl, CH2Cl2; KOH, EtOH, PhSO2Cl, ace-
tone; n-BuLi, THF, PhSO2Cl) were less efficient in our hands.[5] Bromination
of 5 with N-bromosuccinimide according to published procedure[6] gave
dibromoindole 6 as a white solid in 68% yield after flash column
chromatography. Slow addition of a dilute THF solution of one equivalent
of the amine (RNH2) to 6 in the presence of potassium carbonate afforded
dihydropyrroloindoles 7 in good yield, with little or no contamination with
bis-alkylation products. With excess amine bis-alkylation is the major
product.[7] These dihydropyrroloindoles 7 were characterized by spectral
data but were extremely susceptible to air oxidation. However, X-ray
crystal structure determinations were obtained for 7a and 7c.[8] Indeed,
oxidation of 7 to the desired pyrrolo[3,4-b]indoles 8 occurred smoothly
with DDQ in toluene at room temperature (Table 1). These compounds
have been fully characterized.
Amines with reduced nucleophilicity, for example, aniline and p-
toluenesulfonamide, failed to react with 6.
In summary, given the availability of 6 and primary amines, this alkyl-
ation–oxidation sequence is a simple and direct method for the synthesis of
1,3-unsubstituted N-alkyl pyrrolo[3,4-b]indoles 8.
EXPERIMENTAL
Melting points were determined with a Mel-Temp Laboratory Device
apparatus and are uncorrected. Elemental analyses were done by Atlantic
Microlab Inc. Infrared spectra were recorded on a BioRad FT-IR Infrared
Spectrophotometer, and 13C and 1H NMR spectra were recorded on either a
Varian XL-300 or 500 Fourier-transform NMR spectrometer. UV spectra
were recorded with a Hewlett Packard 5890 Diode Array Spectro-
photometer. Tetrahydrofuran was distilled from sodium/benzophenone,
and toluene from calcium hydride.
2-tert-Butyl-4-(phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]indole
(7a): To a refluxing solution of 2,3-dibromomethyl-1-phenylsulfonylindole
(6) (294 mg; 0.66 mmol) and K2CO3 (312 mg: 2.25 mmol) in THF (10 mL)
was added a solution of t-butylamine (90 mL; 0.8 mmol) in THF (15 mL)
slowly via addition funnel. After 10 h, the opaque solution was filtered
through a celite pad with ethyl acetate. The resulting yellow solution was
concentrated in vacuo to yield a pale yellow solid which was purified by
column chromatography (2 : 1 hexanes : ethyl acetate) to yield a white solid
(161 mg, 68%); m.p. 184–185ꢀC; H (CD2Cl2) d 7.98 (dd, 1H, 1, 7 Hz),
1
7.83–7.87 (m, 2H), 7.43–7.58 (m, 3H), 7.19–7.35 (m, 3H), 4.30 (m, 2H),

2006
KISHBAUGH AND GRIBBLE
3.96 (m, 2H), 1.18 (s, 9H); 13C (CDCl3) d 139.7, 138.5, 134.0, 129.6, 128.9,
126.9, 126.1, 123.9, 123.8, 122.9, 119.4, 114.3, 54.1, 48.8, 46.7, 26.3; IR (film)
n 3061, 2962, 1447, 1364, 1216, 1171, 1089, 995, 913, 748, 720, 682 cmÀ1; UV
(EtOH) lmax 258 nm.
2-i-Propyl-4-(phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]indole
(7b): Following the general procedure, 6 was treated with i-propylamine at
35ꢀC to form 7b in 61% yield. After column chromatography (1 :ꢀ1 ethyl
1
acetate : hexanes), 7b was isolated as a white solid; 146–147 m.p. C; H
(CD2Cl2) d 8.00 (m, 1H), 7.87 (m, 2H), 7.51–7.57 (m, 1H), 7.42–7.47
(m, 2H), 7.33–7.37 (m, 2H), 7.20–7.30 (m, 2H), 4.27–4.30 (m, 2H),
3.91–3.94 (m, 2H), 2.96 (septet, 1H, 6 Hz), 1.20 (d, 6H, 6 Hz); 13C
(CD2Cl2) d 140.5, 139.9, 138.5, 134.3, 129.8, 127.0, 126.4, 124.1, 124.0,
123.9, 119.6, 114.5, 54.5, 52.7, 50.7, 21.3; IR (film) n 2968, 2889, 2789,
1448, 1371, 1179, 996, 748, 726, 685 cmÀ1; UV (EtOH) lmax 260 nm.
2-Benzyl-4-(phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[3,4-b]indole (7c):
Following the general procedure, 6 was treated with benzylamine and was
transformed into 7c in 61% yield: m.p. 151–152ꢀC; 1H (CD2Cl2) d 8.01 (dd,
1H, 1, 8 Hz), 7.85–7.88 (m, 2H), 7.22–7.57 (m, 11H), 4.29 (m, 2H), 4.05 (s,
2H), 3.93 (m, 2H); 13C (CD2Cl2) (500 MHz) d 140.2, 139.8, 139.5, 138.4,
134.3, 129.7, 129.3, 129.0, 128.8, 128.7, 128.6, 127.5, 127.0, 126.7, 126.3,
124.03, 124.02, 123.7, 119.6, 114.5, 60.8, 55.1, 53.2; IR (film) v 3055, 2800,
1448, 1369, 1175, 1094, 997, 749, 685 cmÀ1; UV (EtOH) lmax 260 nm.
2-(p-Methoxybenzyl)-4-(phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo
[3,4-b]indole (7d): Following the general procedure, 6 was treated with
p-methoxybenzylamine and was transformed into 7d in 74% yield: m.p.
118–118.5ꢀC; H (CD2Cl2) d 8.04 (d, 1H, 8 Hz), 7.88 (m, 2H), 7.24–7.56
1
(m, 8H), 6.95 (m, 2H), 4.32 (m, 2H), 4.00 (s, 2H), 3.96 (m, 2H), 3.86
(s, 3H); 13C (CD2Cl2) d 159.2, 140.3, 139.8, 138.4, 134.3, 131.4, 130.2,
129.7, 129.3, 129.0, 128.8, 126.9, 126.7, 126.3, 124.0, 123.7, 119.6, 114.5,
114.4, 114.1, 60.1, 55.5, 54.9, 53.1; IR (film) n 3056, 2933, 2832, 1611,
1511, 1447, 1369, 1247, 1177, 996, 750, 723, 685 cmÀ1; UV (EtOH) lmax
224, 260 nm.
2-tert-Butyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole (8a): To
a r.t. stirred solution of 7a (95 mg; 0.28 mmol) in toluene (6 mL) was added
DDQ (65 mg; 0.28 mmol). After 2.5 h, the dark colored solution was filtered
through a celite pad with toluene. After evaporation of the solvent in vacuo,
the resulting oily solid was purified by column chromatography (5 : 1
hexanes : ethyl acetate) to yield the pyrroloindole 8a as a white solid
(85 mg, 90%); m.p. 190–191ꢀC; H (CD2Cl2) 8.05 (dd, 1H, 1, 8 Hz), 7.83
1
(m, 2H), 7.44–7.54 (m, 2H), 7.21–7.36 (m, 4H), 7.16 (d, 1H, 2 Hz), 7.00 (d, 1H,
2 Hz), 1.66 (s, 9H); 13C (CDCl3) d 142.2, 137.5, 133.6, 131.3, 129.3, 128.9,
128.4, 126.9, 125.6, 124.6, 124.0, 120.3, 116.5, 115.3, 105.9, 100.8, 56.5, 31.2;

PYRROLO[3,4-b]INDOLES
2007
IR (film) n 2970, 2922, 2866, 1363, 1171, 1089, 751, 726, 685 cmÀ1; UV
(EtOH) lmax 266, 298 nm. Anal. Calcd for C20H20N2O2S: C, 68.16; H,
5.71; N, 7.95; S, 9.10. Found: C, 67.95; H, 5.91; N, 7.71; S, 8.81.
2-i-Propyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole (8b): This
was prepared from 7b in 91% yield by the general method. The product
was obtained as a tan solid which was further purified by recrystallization
from EtOH to yield white crystals; m.p. 120–121ꢀC; H (CD2Cl2) d 8.03
1
(d, 1H, 8 Hz), 7.81 (m, 2H), 7.43–7.52 (m, 2H), 7.18–7.35 (m, 4H), 7.05
(s, 1H), 6.91 (s, 1H), 4.38 (septet, 1H, 6 Hz), 1.55 (d, 6H, 6Hz);
13C
CD2C12delta 142.2, 137.3, 133.9, 131.1, 129.1, 126.9, 125.7, 124.7,
124.3, 120.4, 116.6, 115.4, 113.1, 106.9, 104.6, 101.3; IR (film) n 2974,
1362, 1177, 1089, 753, 728, 685 cmÀ1; UV (EtOH) lmax 261, 304 nm.
Anal. Calcd for C19H18N2O2S: C, 67.43; H, 5.36; N, 8.28; S, 9.48.
Found: C, 67.26; H, 5.33; N, 8.24; S, 9.32.
2-Benzyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole (8c): This
was prepared from 7c in 98% yield by the general method. The product
was obtained a cream solid; m.p. 156–157ꢀC; 1H (CD2Cl2) d 8.10 (dd, 1H, 1,
8 Hz), 7.80–7.83 (m, 2H), 7.13–7.51 (m, 11H), 7.04 (d, 1H, 2 Hz), 6.85 (d, 1H,
2 Hz), 5.22 (s, 2H); 13C (CD2Cl2) d 142.3, 137.9, 137.1, 133.6, 131.6, 128.9,
128.8, 128.1, 127.0, 126.9, 125.3, 124.8, 124.1, 120.6, 117.6, 115.4, 109.6,
104.1, 54.8; IR (film) n 3061, 1447, 1415, 1361, 1175, 1089, 947, 753,
686 cmÀ1
; UV (EtOH) lmax 220, 266, 300 nm. Anal. Calcd for
C23H18N2O2S: C, 71.48; H, 4.69; N, 7.25; S, 8.30. Found: C, 71.16;
H, 4.73; N, 7.23; S, 8.10.
2-(p-Methoxybenzyl)-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole
(8d): This was prepared from 7d in 85% yield by the general method. The
reaction was complete in 5 min at 0ꢀC. After column chromatography and
attempts to purify this compound further by recrystallization, the product
1
was obtained as a blue oily solid which decomposes upon standing: H
(CD2Cl2) d 7.99–8.02 (m, 1H), 7.73–7.77 (m, 2H), 7.47–7.50 (m, 2H),
7.11–7.34 (m, 6H), 6.97 (d, 1H, 2 Hz), 6.87–6.90 (m, 2H), 6.85 (d, 1H,
2 Hz), 5.14 (s, 2H), 3.80 (s, 3H); 13C (CDCl3) d 159.7, 142.3, 137.0, 133.7,
131.5, 130.2, 129.0, 128.8, 126.9, 125.5, 124.8, 124.2, 120.5, 117.4, 115.4,
114.3, 109.5, 104.0, 55.5, 54.3; IR (film) n 3055, 2933, 2833, 1512, 1446,
1362, 1248, 1175, 1031, 944, 753, 686 cmÀ1; UV (EtOH) lmax 222, 268,
304 nm.
ACKNOWLEDGMENTS
This investigation was supported by the National Institutes of Health
(GM58601), for which support we are grateful.

2008
KISHBAUGH AND GRIBBLE
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Received in the USA July 24, 2001