Synthesis of azepino[3,4b]indoles via the Plancher rearrangement

Article abstract of DOI:10.1016/j.tetlet.2010.06.029

The reaction of benzyl 3-formylpiperidine-1-carboxylate and aryl hydrazines under standard Fisher Indole conditions followed by reductive work-up affords azepino[3,4b]indoles in moderate to good yields. The products are proposed to be derived via a Plancher rearrangement [(a) Plancher, G. Gazz. Chim. Ital. 1898, 28, II, 374; (b) Plancher, G. Atti. Accad. Lincei 1900, 9, 5, 115; (c) Boyd-Barrett, H. S. J. Chem. Soc. 1932, 321].

Full text of DOI:10.1016/j.tetlet.2010.06.029

Tetrahedron Letters 51 (2010) 4303–4305
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Tetrahedron Letters
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Synthesis of azepino[3,4b]indoles via the Plancher rearrangement
*
Shane A. Eisenbeis , James R. Phillips, Diane Rescek, Yatsandra Oyola-Cintron
Pfizer Research and Development, Eastern Point Road, Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of benzyl 3-formylpiperidine-1-carboxylate and aryl hydrazines under standard Fisher
Indole conditions followed by reductive work-up affords azepino[3,4b]indoles in moderate to good yields.
The products are proposed to be derived via a Plancher rearrangement [(a) Plancher, G. Gazz. Chim. Ital.
1898, 28, II, 374; (b) Plancher, G. Atti. Accad. Lincei 1900, 9, 5, 115; (c) Boyd-Barrett, H. S. J. Chem. Soc. 1932,
321].
Received 13 April 2010
Revised 1 June 2010
Accepted 7 June 2010
Available online 15 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Azepino[3,4b]indoles
Fisher indole
Plancher rearrangement
Indoles have an extremely diverse history in both medicinal and
natural product chemistry. Interest has been driven toward it by
the vast physiological activity this class of structures exhibits and
its broad ranging chemical reactivity.2 While investigating the
preparation of spiroindoles, we isolated an unexpected product
in good yields. Here we describe, a novel method for the synthesis
of aryl substituted azepino[3,4b]indoles (Scheme 1). A mechanism
is proposed and examples are presented to better understand the
scope, limitations and potential for its broader application.
Representative [3,4b]-indoles were generated by the treatment
of benzyl 3-formylpiperidine-1-carboxylate, aryl hydrazines and
trifluoroacetic acid in refluxing dichloromethane. The intermediate
indole was directly treated with sodium borohydride to afford the
azepino[3,4b]indoles in 35–78% isolated yields.3,4 The reaction is
flexible in aryl substitution, as well as cyclic amines. The upper
limit appeared to be azepane while the lower limit was pyrrolidine.
No products were isolated while investigating the azetidine and
azocane ring systems (Table 1).
slowly progresses at room temperature (24 h) however; in reflux-
ing DCM the rearrangement is complete after just 1 h (Scheme 3).
With the isolation and characterization of a reaction intermedi-
ate, two plausible mechanisms arose for the eventual product for-
H
Z2
Y
CHO
( )
n
Z2
X
N
H
1.) 3.4 eq. TFA
DCM, Reflux
2.) NaBH4
(
)
n
CBz
NH2
N
X
N
CBz
Y
H
N
H
Z1
Z1
Scheme 1. Synthesis of azepino[3,4b]indoles.
Table 1
Synthesis of substituted azepino[3,4b]indoles
SI no.
X
Y
Z1
Z2
n
Yielda (%)
Much of the previously reported work within this area of in-
doles has dealt with b-carbolines and the migratory aptitude of
pendant substituents.5 Typically these reactions occur under more
forcing conditions, in contrast to the extremely mild conditions
employed in this study.
To better understand a possible mechanism of product forma-
tion, the reaction was quenched prior to completion. 3,3-Spirocy-
clic indole (12) was isolated in modest yield and found to be
quite stable6 (Scheme 2).
1
2
3
4
5
6
7
8
9
H
F
Me
Me
Br
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
2
2
2
2
2
2
2
1
3
4
0
34
38
35
69
78b
21c
19c
59
65
0
10
11
H
0
The formation and eventual disappearance of intermediate spi-
roindolene could be monitored by GC/MS (Table 2). Rearrangement
a
Reported yields are isolated and unoptimized. Alternative acidic conditions
were not investigated4 while looking at the rearrangements. Compounds are
characterized by 1H and MS.
b
Crude isolated yield, single X-ray determined on derivative.
Isolated from same reaction mixture.
* Corresponding author. Tel.: +1 860 441 1866; fax: +1 860 715 8063.
E-mail address: shane.a.eisenbeis@pfizer.com (S.A. Eisenbeis).
c
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.029

4304
S. A. Eisenbeis et al. / Tetrahedron Letters 51 (2010) 4303–4305
Based on these results, the proposed mechanism is depicted in
Scheme 6.
With a clearer understanding of product formation, work is
continuing in an effort to improve yields as well as to expand upon
the scope. The preparation of a variety of chiral piperidines, furans
and thiophenes are currently the areas of active research. Future
reports will detail these findings.
CBz
N
CHO
H
N
1. TFA
DCM
NH2
N
CBz
N
H
2. NaBH4
12
Scheme 2. 3,3-Spirocyclic products.
N+
Cbz
Cbz
Cbz
N
N
Table 2
Synthesis of substituted azepino[3,4b]indoles
+
N
H
Time (h)
% Hydrazone (13)
% Spiroindole (14)
% Fused indole (15)
N
H
Plancher
Retro
Mannich
N
H+
0
1
4
6.5
8.5
22.5
24
100
42
0
0
0
0
43
49
32
29
9
0
15
57
68
71
1,2-migration
0
0
91
100
+
N
Cbz
N
0
Cbz
N
H
H
N
H
mation: a retro-Mannich pathway or a Plancher rearrangement
(Scheme 4).1
-H
-H
To distinguish the possible mechanistic pathways, the electron-
deficient N-methanesulfonyl aldehyde (16) was submitted to typ-
ical reaction conditions (Scheme 5). The electron-withdrawing nat-
ure of the mesylate would be expected to disfavor retro-Mannich
chemistry from occurring. Although the reaction did require ex-
tended reaction times, the major product isolated was once again
the ring expanded indole (17)7 which provides supportive evidence
for a Plancher rearrangement pathway.
H
[H]
[H]
N
N
N
Cbz
Cbz
Cbz
H
N
N
H
N
H
H
1
Scheme 4. Possible mechanism for product formation.
CBz
H
N
CHO
H
N
CBz
TFA
DCM
TFA
N
N
N
N
N
CBz
Ms
NH2
N
DCM, Reflux
N
N
H
N
Ms
13
14
15
16
17
Scheme 3. Synthesis of azepino[3,4b]indoles.
Scheme 5. Synthesis of electronically biased system.
CBz
N
Cbz
N
[1,3]
[3,3]
H
N
N
N
H
Cbz
NH
NH
NH
N
H
13
Cbz
N
Cbz
Cbz
N
N
-NH3
NH2
+
N
H
N
H
N
H+
1,2-migration
H
-H
+
[H]
N
N
N
Cbz
Cbz
Cbz
H
N
H
H
N
N
H
H
1
Scheme 6. Proposed mechanism of product formation.

S. A. Eisenbeis et al. / Tetrahedron Letters 51 (2010) 4303–4305
4305
4.19 (m, 1H), 4.0–3.75 (m, 2H), 3.45–3.02 (m, 3H), 2.05–1.56 (m, 5H). HRMS
calcd for C20H21FN2O2 [M+H]+ 340.1587, found 340.1649.
Supplementary data
7-Methyl-3,4,5,5a,10,10a-octahydro-1H-azepino[3,4-b]indole-2-carboxylic
acid
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.06.029.
benzyl ester (3): Yield 78% crude: mixture of rotomers: mp (hexanes) 89–
92 °C; 1H (CD3OD) 7.38–7.27 (m, 5H), 6.80 (m, 2H), 6.45 (dd, 1H) 5.20–4.99 (m,
2H), 4.22 (m, 1H), 4.02–3.02 (m, 6H), 2.27 (s, 3H), 2.05–1.56 (m, 4H). HRMS calcd
for C21H24N2O2 [M+H]+ 336.1838, found 336.1897.
7,9-Dimethyl-3,4,5,5a,10,10a-octahydro-1H-azepino[3,4-b]indole-2-carboxylic acid
benzyl ester (4): Yield 69%: mixture of rotomers: mp (hexanes) 143–145 °C; 1H
(CD3OD) 7.40 (m, 5H), 6.68 (s, 1H), 6.62 (ms 1H), 5.11 (m, 2H), 4.19–3.85 (m,
2H), 3.75 (m, 2H), 3.45–3.02 (m, 3H), 2.19 (d, 3H), 2.05 (d, 3H), 2.04–1.56 (m,
5H). HRMS calcd for C22H26N2O2 [M+H]+ 350.1994, found 336.2085.
References and notes
1. (a) Plancher, G. Gazz. Chim. Ital. 1898, 28, II, 374; (b) Plancher, G. Atti. Accad.
Lincei 1900, 9, 5, 115; (c) Boyd-Barrett, H. S. J. Chem. Soc. 1932, 321.
2. Reviews: Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209–2219; Sundberg,
R. J. The Chemisty of Indoles; Academic Press: New York, 1970; Indoles (Parts I–
III); Houlihan, W. J., Ed.; Wiley-Interscience: New York, 1979, 1972; Cordell, G.
A. Introduction to Alkaloids; Wiley-Interscience: New York, 1981; Trost, B. M.;
Brennan, M. K. Synthesis 2009, 3003.
3. Intermediate indoles could be isolated in fair to good yields prior to reduction.
4. General experimental procedure for synthesis of azepino[3,4b]indoles: A three neck
round bottomed flask equipped with an overhead stirrer, an addition funnel and
a reflux condenser was charged with DCM (1 L per 0.25 mol), phenyl hydrazine
7-Bromo-3,4,5,5a,10,10a-octahydro-1H-azepino[3,4-b]indole-2-carboxylic
acid
benzyl ester (5): Mp (hexanes) 128–133 °C; 1H (CDCl3) 7.31 (m, 4H), 7.21 (m,
2H), 7.05 (m, 1H), 6.38 (dd, 1H), 5.11 (m, 2H), 4.23 (m, 1H), 3.92–3.11 (m, 5H),
2.11–1.57 (m, 5H). HRMS calcd for C20H21BrN2O2 [M+H]+ 400.0786, found
400.0773.
(6/8)-Fluoro-3,4,5,5a,10,10a-hexahydro-1H-azepino[3,4-b]indole-2-carboxylic acid
benzyl ester (6 + 7): Yield 40%; mixture of isomers: mp (hexanes) 95–100 °C; 1
H
(CDCl3) 7.37 (m, 5H), 6.94–6.82 (m, 1H), 6.38 (m, 1H), 6.24–6.08 (m, 1H), 5.06
(m, 2H), 4.60 (dd, 1H), 4.39–4.18 (m, 1H), 3.91–3.05 (m, 5H), 2.05–1.56 (m, 5H).
HRMS calcd for C20H21FN2O2 [M+H]+ 340.1587, found 340.1611.
(1.0 equiv)
and
benzyl
3-formylpiperidine-1-carboxylate
(1.0 equiv).
Trifluoroacetic acid (3.4 equiv) was slowly added to the reaction mixture
producing a slight exotherm. After complete addition the mixture was warmed
to 40 °C overnight. The resultant darkened reaction mixture of (1) was carefully
treated with NaBH4 (1.5 equiv) followed by an additional 4 h of stirring at room
temperature. The reaction mixture became orange in color. The reaction was
checked for completion by GC/MS, and then carefully poured over a satd aq
NaHCO3 (1 L per 0.25 mol) and stirred till evolution of gas ceased. The layers are
separated followed by extraction of the aqueous layer with an additional Et2O
(2 Â 1 L per 0.25 mol). The combined organic layers were dried over MgSO4 and
concentrated to a thick dark oil which was purified by silica gel chromatography
using 25% EtOAc/Hex as eluent. The clean fractions were combined,
concentrated and crystallized from hexanes to afford the title compound (1).
Alternatively the dark oil could be dissolved in Et2O (1 L per 0.25 mol) followed
by cooling to 0 °C. HCl gas was bubbled through the ether solution resulting in a
thick slurry. The slurry was filtered to afford the title compound (1) as HCl salt.
3,4,5,5a,10,10a-Octahydro-1H-azepino[3,4-b]indole-2-carboxylic acid phenyl ester
(1): Yield 34%: mp (hexanes) 84–87 °C; 1H NMR (300 MHz, CD3OD) 7.36 (m, 4H),
6.92 (m, 2H), 6.45 (dd, 1H), 5.11 (dd, 2H), 4.16 (m, 1H), 4.00–3.75 (m, 3H), 3.42–
3.09 (m, 4H), 3.05–2.98 (m, 1H), 2.00–1.54 (m, 5H). HRMS calcd for C20H22N2O2
[M+H]+ 322.1681, found 322.1614.
2,3,4,4a,9,9a-Hexahydro-1H-b-carboline-2-carboxylic acid phenyl ester (8): Yield
59%. 1H NMR (300 MHz, CD3OD) 7.30 (m, 4H), 6.95 (m, 2H), 6.60 (m, 2H), 5.02
(bd, 2H), 3.77 (m, 1H), 3.48 (m, 1H), 3.24 (m, 3H), 1.97 (m, 2H), 1.68 (m, 1H).
HRMS calcd for C19H20N2O2 [M+H]+ 308.1525, found 308.1565.
2,3,4,5,6a,11,11a-Octahydro-1H-azepino[3,4-b]indole-2-carboxylic acid phenyl
ester (9): Mixture of rotomers: Yield 65%. 1H NMR (300 MHz, CD3OD) 7.26 (m,
5H), 7.00 (m, 2H), 6.65 (m, 2H), 5.11 (m, 2H), 4.05–3.82 (m, 2H), 3.47–2.92 (m,
4H), 1.98–1.44 (m, 4H). HRMS calcd for C21H24N2O2 [M+H]+ 336.1838, found
336.1894.
3,3-(2,3-Dihydro-1H-indol-3yl)-piperidine-1-carboxylic acid phenyl ester (12):
Mixture of rotomers: Yield 25%. 1H NMR (300 MHz, CD3OD) 7.42–6.84 (m,
9H), 5.11 (m, 2H), 3.98–3.65 (m, 3H), 3.47–2.92 (m, 3H), 2.11–1.44 (m, 7H).
HRMS calcd for C20H22N2O2 [M+H]+ 322.1681, found 322.1622.
5. (a) Jackson, A. H.; Smith, A. E. Tetrahedron 1968, 24, 403; (b) Jackson, A. H.;
Smith, p. Chem. Commun. 1967, 264; (c) Jackson, A. H.; Smith, A. E. Tetrahedron
1965, 21, 989; (d) Harmon, R. E.; Parson, J. L.; Gupta, S. K. Chem. Commun. 1969,
1365; (e) Liu, K.; Lo, J.; Comery, T.; Zhang, G. M.; Zhang, J.; Kowal, D.; Smith, D.;
Di, L.; Kerns, E.; Schechter, L.; Robichaud, A. Bioorg. Med. Chem. Lett. 2008, 18,
3929; (f) Liu, K.; Robichaud, A.; Lo, J.; Mattes, J.; Cai, Y. Org. Lett. 2006, 8, 5769.
6. Decker, M.; Faust, R.; Wedig, M. W.; Nieger, M.; Holzgrabe, U.; Lehmann, J.
Heterocycles 2001, 55, 1455.
7-Fluoro-3,4,5,5a,10,10a-octahydro-1H-azepino[3,4-b]indole-2-carboxylic
acid
benzyl ester (2): Yield 38%; mixture of rotomers: mp (hexanes) 103–105 °C; 1H
7. X-ray data provided.
(CD3OD) 7.38 (m, 5H), 6.78 (dd, 1H), 6.62 (m, 1H), 6.42 (m, 1H), 5.11 (m, 2H),