A process for the preparation of 1,2,3,4,8,9,10,10a-octahydro-7bH- cyclopenta[b][1,4]diazepino[6,7,1-hi]indole

Article abstract of DOI:10.1016/j.tetlet.2004.04.157

A synthesis of 1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4] diazepino[6,7,1-hi]indole is described exemplifying a new synthetic route to medicinally interesting compounds. The key step involves a cyclization of 2-(2,3,3a,8b-tetrahydrocyclopenta[b]indol-4(1H)-yl)-ethanamine with aqueous formaldehyde in the presence of trifluoroacetic acid.

Full text of DOI:10.1016/j.tetlet.2004.04.157

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4851–4854
A process for the preparation of 1,2,3,4,8,9,10,10a-octahydro-
bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole
7
a,
Gregory S. Welmaker and Joan E. Sabalski
b
*
a
Wyeth Research, Chemical and Screening Sciences, 500 Arcola Road, Collegeville, PA 19426 USA
b
Wyeth Research, Chemical and Screening Sciences, CN 8000, Princeton, NJ 08543 USA
Received 19 April 2004; revised 23 April 2004; accepted 27 April 2004
Available online 18 May 2004
Abstract—A synthesis of 1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole is described exemplifying a
new synthetic route to medicinally interesting compounds. The key step involves a cyclization of 2-(2,3,3a,8b-tetrahydrocyclo-
penta[b]indol-4(1H)-yl)-ethanamine with aqueous formaldehyde in the presence of trifluoroacetic acid.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
NH2
N
In collaboration with a recent medicinal chemistry
program, it became necessary to develop a practical
synthesis of diazepinoindolines 1. This new synthesis is
a,b,c,d,e
f,g,h
N
NH
N
1
O
O
O
N
H
Ac
exemplified by the preparation of one of the structures
within this series, 1,2,3,4,8,9,10,10a-octahydro-7bH-
cyclopenta[b][1,4]diazepino[6,7,1-hi]indole 2 (Fig. 1).
Scheme 1. Reagents and conditions: (a) glycine, Et
then HCl, EtOH, reflux; (b) LiAlH , THF, reflux; (c) Ac
Et O, reflux; (d) NaNO , HCl, H
O, 0 °C; (e) Zn, HOAc, <30 °C; (f)
, 5% Pd–C, TFA, EtOH; (h)
3
N, EtOH, reflux;
4
2
O, Et N,
3
2
2
2
cyclopentanone, AcOH, reflux; (g) H
NaOH, MeOH, reflux.
2
Compounds in this series were originally prepared by
1a;2
the route shown in Scheme 1. The process begins with
a condensation of glycine with isatoic anhydride to
provide the diazepinedione. The amides are then re-
duced with lithium aluminum hydride, followed by
selective acetylation of the benzylic amine. The aniline is
then converted to the hydrazine by standard methods.
The hydrazine is subjected to Fisher indole conditions
with cyclopentanone to produce the tricyclic indole.
Reduction of the indole to the indoline followed by
cleavage of the acetamide ultimately provides the
desired compound.
R3
R2
A
R4
R1
In an effort to discover alternative synthetic pathways to
these substrates, we chose to investigate a new synthesis
involving the preparation of the indoline first and then
subsequent cyclization to form the diazepino moiety
N
N
R5
R8
N
R7
N
H
R6
(Fig. 2). By developing this new synthetic procedure, the
1
2
synthesis could begin with commercially-available phe-
nyl hydrazines, eliminating the need of preparing the
hydrazine at a later stage. Additionally, this alternate
route could lead to new analogs synthetically inaccessi-
ble by the original route.
Figure 1. Structures of target compounds 1 and representative exam-
ple 2.
Keywords: Benzodiazepine; Pictet–Spengler.
*
Corresponding author. Tel.: +1-484-865-4557; fax: +1-484-865-9398;
e-mail: welmakg@wyeth.com
Ideally, the benzodiazepine could be formed directly
from an appropriately substituted substrate. In 1957,
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.157

4852
G. S. Welmaker, J. E. Sabalski / Tetrahedron Letters 45 (2004) 4851–4854
R3
aq. CH O (1 eq.)
R2
R3
2
A
R4
TFA (1-5 eq.)
N
N
R2
R1
A
R4
N
EtOH
R1
H
2
N
HN
R5
N
H
R8
N
R7
7
2
R6
Scheme 3.
1
R2
R1
NH2
a
b
N
N
N
H
N
H
H N
H N
2
2
•
HCl
•HCl
Figure 2. Retrosynthetic analysis.
4
8
7
3
Archer et al. described the unexpected preparation of 1-
ethyl-4-(3-tropanyl)-tetrahydro-1H-1,4-benzodiazepine
Scheme 4. Reagents and conditions: (a) NaOH, CH
3
CN, 30 min, rt; 2-
chloroethylamine hydrochloride, tetrabutylammonium hydrogensul-
fate, reflux, overnight; (b) H , 5% Pd–C, EtOH.
0
from the treatment of N-ethyl-N-phenyl-N -(3-tropanyl)-
ethylenediamine under Eschweiler–Clark methylation
2
4
conditions. In 1995, Zhang et al. demonstrated the
preparation of pyridoindolo-benzodiazepine utilizing
however, all attempts to prepare the benzodiazepine
skeleton from this amide either failed or provided very
limited success. Indoline 5 was then coupled with 2-
chloroacetamide to generate the primary amide 6.
Again, all attempts to cyclize amide 6 directly to the
benzodiazepine were unsuccessful. Amide 6 was then
reduced to primary amine 7 under standard conditions.
Pictet–Spengler conditions in trifluoroacetic acid. In
5
1
996, Stokker reported the preparation of 1,4-bis(tri-
fluoroacetyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
in 50% yield from the treatment of 2,2,2-trifluoro-N-
phenyl-N-2-[(trifluoroacetyl)amino]ethylacetamide with
2 4
para-formaldehyde in H SO /AcOH.
When primary amine 7 was treated with 1 equiv of
aqueous formaldehyde in the presence of trifluoroace-
tic acid in ethanol, the desired benzodiazepine 2 was
obtained in good yield (Scheme 3).
While these literature precedents illustrate the prepara-
tion of a benzodiazepine from an aliphatic, secondary
amine, from an aniline, and from an amide, none of
these examples are directly applicable to our desired
synthetic procedure.
2
3
4
Utilizing 1 equiv of formaldehyde maximizes the yield
while minimizing any undesired byproducts. Initially, we
employed only 1 equiv of trifluoroacetic acid; however,
this is not critical. Up to 5 equiv of trifluoroacetic acid
have been utilized with success.
2
. Results
Our synthetic route began with a standard Fisher indole
cyclization of phenylhydrazine (3) with cyclopentanone
to provide 1,2,3,4-tetrahydrocyclopenta[b]indole (4)
The overall synthesis can be further shortened by pre-
paring amine 7 in two steps from indole 4 (Scheme 4).
(
Scheme 2). The indole 4 was hydrogenated under acidic
6
Following the procedure of Cuadro et al., alkylation of
conditions to provide indoline 5. Initially, indoline 5 was
coupled with N-protected glycine to provide the amide;
indole 4 with 2-chloroethylamine afforded aminoethy-
lindole 8, which was isolated as the hydrochloride salt.
Hydrogenation of this salt provided aminoethylindo-
line 7.
NH2
a
N
H
N
H
In summary, we have developed a new route for the
preparation of benzodiazepines by the cyclization of
phenylethylenediamines with formaldehyde in the pres-
ence of trifluoroacetic acid. Utilizing this key cyclization
step, the synthesis of 1,2,3,4,8,9,10,10a-octahydro-7bH-
3
4
b
cyclopenta[b][1,4]diazepino[6,7,1-hi]indole
(2)
was
accomplished in four linear steps from readily-available
starting materials. To our knowledge, this is the first
example of this type of cyclization employing a primary,
aliphatic amine to prepare a benzodiazepine.
c
N
N
H
H N
2
X
6
X = O
X = H,H
5
d
7
3. Experimental
Scheme 2. Reagents and conditions: (a) cyclopentanone, concd
SO , H O; (b) H (45 psi), 5% Pd–C, concd HCl, EtOH; (c) 2-
chloroacetamide, EtN(i-Pr) THF, reflux.
, DMF, 100 °C; (d) BH
H
2
4
2
2
All reagents and solvents were obtained from commer-
cial suppliers and used without further purification.
2
3

G. S. Welmaker, J. E. Sabalski / Tetrahedron Letters 45 (2004) 4851–4854
4853
3
.1. 1,2,3,4-Tetrahydrocyclopenta[b]indole (4)
0.7 Hz, 1H), 6.18 (d, J ¼ 7:8 Hz, 1H), 4.22 (m, 1H), 3.70,
3
.58 (ABq, JAB ¼ 17:1 Hz, 2H), 3.64 (m, 1H), 1.90 (m,
Concentrated sulfuric acid (ꢀ18 M, 35 mL) was added
1H), 1.78 (m, 1H), 1.56 (m, 3H), 1.40 (m, 1H).
dropwise to a mixture of phenyl hydrazine (510 mmol,
5
(
3
0 mL) and cyclopentanone (45 mL, 510 mmol) in water
250 mL). The resulting mixture was heated to reflux for
0 min and then allowed to cool to room temperature.
3.4. 2-(2,3,3a,8b-Tetrahydrocyclopenta[b]indol-4(1H)-yl)-
ethylamine (7)
The liquid was decanted from the reaction mixture
leaving a red, gummy solid. A mixture of hexanes (500–
3.4.1. From acetamide 6. 2-(2,3,3a,8b-Tetrahydro-
cyclopenta[b]indol-4(1H)-yl)acetamide (90 mmol, 20 g)
6
00 mL) was added to the flask and the mixture was
heated to reflux. The yellow hexane solution was dec-
anted while hot from the mixture and placed in the
freezer (crystallization begins immediately). A mixture
of hexanes was again added to the flask and the proce-
dure repeated two more times using a total volume of
3
was dissolved in 1 M BH ÆTHF (200 mL) and heated to
reflux for 18 h. The reaction mixture was allowed to cool
to room temperature and then quenched slowly with
methanol. The solution was concentrated, dissolved in
methanol, and again concentrated. The resulting oil was
diluted with ether and extracted twice with 1 N HCl. The
aqueous phase was treated with 2.5 N NaOH to pH >10
and extracted with chloroform. The combined chloro-
1
was collected from the flasks and dried providing the
500 mL of hexanes. After 1 h in the freezer, the solid
7
known indole (410 mmol, 65 g, 80%). Anal. Calcd for
C H N: C, 84.04; H, 7.05; N, 8.91. Found: C, 83.92; H,
form extracts were dried over MgSO , filtered, and
4
11
11
7
.12; N, 8.85.
concentrated to provide a yellow oil.
3
.2. 1,2,3,3a,4,8b-Hexahydrocyclopenta[b]indole (5)
3.4.2. From aminoethylindole 8. A mixture of 2-(2,3-
dihydro-1H-cyclopenta[b]indol-4-yl)ethylamine hydro-
chloride (5.1 mmol, 1.2 g) and 5% Pd/C (0.5 g) in EtOH
(20 mL) was hydrogenated at 45 psi on a Parr shaker
overnight. The mixture was removed from the shaker
and filtered through Celite. The solid bed was washed
thoroughly with ethanol. The filtrate was concentrated
and the crude solid was purified by trituration from
chloroform with hexanes to afford 1.0 g (83%) of the
desired hydrochloride salt.
A
(
mixture of 1,2,3,4-tetrahydrocyclopenta[b]indole
11 mmol, 1.8 g), 5% Pd/C (0.5 g), and concentrated
hydrochloric acid (1.2 mL) in EtOH (20 mL) was
hydrogenated at 45 psi on a Parr shaker. After 3 h, the
mixture was removed from the shaker and filtered
through Celite. The solid bed was washed with metha-
nol. The filtrate was concentrated. The crude oil was
dissolved in 1 N HCl and washed with ether. The
aqueous phase was treated with 2.5 N NaOH to pH >10
and then extracted with chloroform. The combined
Anal. Calcd for C13
H, 8.04; N, 11.65. Found: C, 64.78; H, 8.21; N, 11.48.
H
18
N
2
2
ÆHClÆ0.1 mol H O: C, 64.91;
chloroform extracts were dried over MgSO , filtered and
4
þ
concentrated to give the crude indoline. The material
was purified by flash column chromatography through
silica gel (Biotage, elution with 10% ethyl acetate–hex-
MS (ESþ, m/e (%)) 203.2 (100, [MþH] ). HRESIMS
þ
m=z 203.1539 (MþH) (calcd for C13
19 2
H N , 203.1543).
IR (film ATR, cm ) 2901, 1602, 1490, 1326, 1258, 1023,
741. H NMR (DMSO-d , 400 MHz) d d 8.13 (s, 3H),
ꢁ
1
8
1
anes) to give the known indoline (7.6 mmol, 1.2 g, 69%)
13N: C, 82.97; H,
6
as a clear oil. Anal. Calcd for C11
8
H
.23; N, 8.80. Found: C, 82.61; H, 8.35; N, 8.72.
6.97–6.94 (m, 2H), 6.53 (dt, J ¼ 7:3, 0.8 Hz, 1H), 6.45(d,
J ¼ 7:8 Hz, 1H), 4.17 (m, 1H), 3.68 (dt, J ¼ 8:8, 1.5 Hz,
1
1
H), 3.41 (m, 2H), 2.95 (m, 2H), 1.96 (m, 1H), 1.72 (m,
H), 1.61 (m, 3H), 1.40 (m, 1H).
3.3. 2-(2,3,3a,8b-Tetrahydrocyclopenta[b]indol-4(1H)-yl)-
acetamide (6)
3.5.
amine (8)
2-(2,3-Dihydro-1H-cyclopenta[b]indol-4-yl)ethyl-
To a stirred solution of 1,2,3,3a,4,8b-hexahydrocyclo-
penta[b]indole (130 mmol, 21 g) in DMF (50 mL) was
added diisopropylethylamine (400 mmol, 70 mL) fol-
lowed by 2-chloroacetamide (270 mmol, 25 g). The
reaction mixture was heated to 100 °C for 18 h. The
reaction was concentrated and then diluted with ethyl
acetate and water. The phases were separated and the
organic phase was washed with brine, dried over
Sodium hydroxide (80 mmol, 3.2 g) was added to a
solution of indole 3 (22 mmol, 3.2 g) in 100 mL of
CH CN. The resulting mixture was stirred at ambient
3
temperature for 30 min and then 2-chloroethylamine
hydrochloride (24 mmol, 2.8 g) and tetrabutylammon-
ium hydrogensulfate (0.25 g, 0.74 mmol) were intro-
duced. The resulting mixture was heated to reflux
overnight. After cooling to rt, the mixture was concen-
trated. The crude product was diluted with ether and
2 N HCl. The phases were separated. The aqueous
phase was treated with 2.5 N NaOH until basic and then
extracted with chloroform. The extract was dried over
Na SO , filtered, and concentrated. The crude indole
MgSO , filtered, and concentrated. The crude material
4
was purified by flash column chromatography through
silica gel (elution with 60% ethyl acetate–hexanes) to
afford a yellow solid (90 mmol, 20 g, 69%). Anal. Calcd
for C H N O: C, 72.19; H, 7.46; N, 12.95. Found: C,
13
16
2
7
2.45; H, 7.57; N, 12.64. MS ((þ)APCI, m/e (%)) 217
þ ꢁ1
(
100, [MþH] ). IR (solid ATR, cm ) 3450, 2930, 2870,
2
4
1
1
680, 1480, 1150, 740. H NMR (DMSO-d , 400 MHz) d
was dissolved in a 1:1 ethanol–ether solution and then
treated with 4 N HCl in dioxane. The precipitate was
6
7
.20 (s, 1H), 7.05 (s, 1H), 6.90 (m, 2H), 6.48 (dt, J ¼ 7:3,

4854
G. S. Welmaker, J. E. Sabalski / Tetrahedron Letters 45 (2004) 4851–4854
collected by filtration and dried to afford the desired
indole ethylamine (3.6 g, 68%) as its hydrochloride salt.
67.02; H, 7.74; N, 10.85. MS (ESþ, m/e (%)) 215.2 (100,
þ ꢁ1
[MþH] ). IR (solid ATR, cm ) 2951, 2797, 2664, 2552,
1
1
592, 1449, 1317, 1200, 1032, 745. H NMR (DMSO-d ,
6
Anal. Calcd for C13
H
16
N
2
ÆHCl: C, 65.95; H, 7.24; N,
400 MHz) d d 9.58 (br s, 2H), 7.05 (d, J ¼ 7:2 Hz, 1H),
1
1.83. Found: C, 65.98; H, 7.14; N, 11.76. MS (ESþ,
7.00 (d, J ¼ 7:3 Hz, 1H), 6.70 (dd, J ¼ 7:5, 7.2 Hz, 1H),
þ
ꢁ1
m/e (%)) 201 (100, [MþH] ). IR (film ATR, cm ) 2897,
4.28, 3.94 (ABq, J ¼ 14:8 Hz, 2H), 3.99 (m, 1H), 3.77
AB
2
849, 1602, 1565, 1517, 1457, 1375, 1293, 1143, 942, 734.
(dt, J ¼ 8:9, 2.3 Hz, 1H), 3.50 (m, 1H), 3.40 (m, 1H),
3.10 (m, 2H), 1.95 (m, 1H), 1.80 (m, 1H), 1.70–1.52 (m,
3H), 1.42 (m, 1H).
1
H NMR (DMSO-d
d, J ¼ 8:0 Hz, 1H), 7.34 (d, J ¼ 7:4 Hz, 1H), 7.06 (dt,
J ¼ 7:4, 1.2 Hz, 1H), 7.00 (dt, J ¼ 8:0, 1.0 Hz, 1H), 4.36
t, J ¼ 7:0 Hz, 2H), 3.10 (t, J ¼ 7:0 Hz, 2H), 2.88 (t,
J ¼ 7:1 Hz, 2H), 2.75 (t, J ¼ 7:0 Hz, 2H), 2.48 (m, 2H).
6
, 400 MHz) d d 8.29 (br s, 3H), 7.49
(
(
References and notes
3.6. 1,2,3,4,8,9,10,10a-Octahydro-7bH-cyclopenta[b][1,4]-
diazepino[6,7,1-hi]indole (2)
1
. (a) Sabb, A. L.; Vogel, R. L.; Nelson, J. A.; Rosenzweig-
Lipson, S. J.; Welmaker, G. S.; Sabalski, J. E. U.S. Patent
Appl. Publ. No 2002/0107242 A1, Published August 8,
A solution of 2-(2,3,3a,8b-tetrahydrocyclopenta[b]indol-
4
2
002; (b) Welmaker, G. S.; Sabalski, J. E.; Smith, M. D.
(1H)-yl)ethylamine (1.5 mmol, 0.30 g) was dissolved in
U.S. Patent Appl. Publ. No 2002/0058689 A1, Published
May 16, 2002.
ethanol (20 mL) at room temperature and trifluoroacetic
acid (1.6 mmol, 0.12 mL) was added, followed by aque-
ous formaldehyde (1.5 mmol, 37%, 0.11 mL). The
resulting solution was stirred overnight at ambient
temperature. The solvent was then removed in vacuo.
The resulting oil was dissolved in EtOAc and washed
with satd aq NaHCO , dried over Na SO , filtered, and
2. Kim, D. H. J. Heterocycl. Chem. 1976, 13, 1187.
3. Archer, S.; Lewis, T. R.; Unser, M. J.; Hoppe, J. O.; Lape,
H. J. Am. Chem. Soc. 1957, 79, 5783.
4
. Zhang, L.; Meier, W.; Wats, E.; Costello, T. D.; Ma, P.;
Ensinger, C. L.; Rodgers, J. M.; Jacobson, I. C.; Raja-
gopalan, P. Tetrahedron Lett. 1995, 36, 8387.
. Stokker, G. E. Tetrahedron Lett. 1996, 37, 5453.
. Cuadro, A. M.; Matia, M. P.; Garcia, J. L.; Vaquero, J. J.;
Alvarez-Builla, J. Synth. Commun. 1991, 21, 535.
. Perkin, W. H., Jr.; Plant, S. G. P. J. Chem. Soc. 1923, 123,
3242.
3
2
4
5
6
concentrated in vacuo to yield a light yellow oil. The
crude product was dissolved in ether and treated
with 1 equiv of 4 N HCl in dioxane. The solid was
collected and dried to provide 0.31 g (84%) of the desired
product as its monohydrochloride salt. Anal. Calcd for
C H N ÆHCl: C, 67.05; H, 7.64; N, 11.17. Found: C,
7
8. Booth, H.; King, F. E.; Parrick, J. J. Chem. Soc. 1958, 158,
2302.
14
18
2