Efficient synthesis of bromocyclopenta[b]indoles via a bromination - Reduction sequence

Article abstract of DOI:10.1002/jhet.5570400214

Substituted cyclopenta[b]indoles are selectively brominated in good yields with excess pyridine - Br₂ charge-transfer complex (PyBr₂) in a one-pot reaction to provide 5 and/or 7-bromoindoles. The mechanism involves the formation of a

Full text of DOI:10.1002/jhet.5570400214

Mar-Apr 2003
289
Efficient Synthesis of Bromocyclopenta[b]indoles
via a Bromination – Reduction Sequence
Nicolas Lachance* and Wing Yan Chan
Merck Frosst Centre for Therapeutic Research, P.O. Box 1005,
Pointe Claire-Dorval, Québec, Canada, H9R 4P8
Received December 20, 2002
Substituted cyclopenta[b]indoles are selectively brominated in good yields with excess pyridine – Br
2
charge-transfer complex (PyBr ) in a one-pot reaction to provide 5 and/or 7-bromoindoles. The mechanism
2
involves the formation of an adduct (addition of bromine on the central double bond) which is subsequently
reduced in situ with Zn and AcOH. A variety of functional groups in the cyclopentyl and the benzenoid rings
are tolerated.
J. Heterocyclic Chem., 40, 289 (2003).
Introduction.
indole core [9]. A Nazarov cyclization was also utilized to
prepare a gem dimethyl cyclopenta[b]indole [10].
Indoles are of interest in the pharmaceutical industry as
this important core is present in many biologically active
compounds such as Indomethacin, Maxalt, Accoleit and
Ramatroban [1]. As part of our medicinal chemistry pro-
gram, we became interested in the synthesis of substituted
cyclopenta[b]indoles (Figure 1) and we envisioned that
bromoindoles could serve as versatile synthetic intermedi-
ates in their preparation [2]. Although indoles, such as
tetrahydrocarbazoles, with halogen on the benzenoid moi-
ety can be obtained via de novo indole synthesis, all our
attempts to prepare 3,5-dibromo or 3,5-disubstituted
cyclopenta[b]indoles under literature procedures failed in
our laboratory [3]. To solve this problem, we were inter-
ested in a direct bromination of the indole core. Several
groups have investigated bromination chemistry of indoles
[4], however, few examples are reported with annulated
systems [4c,5]. We wish to report herein our results in
developing a one-pot bromination – reduction sequence
resulting in good yields of halogenated indoles.
We began by investigating the reaction of indole 1 under
standard bromination conditions such as Br , NBS and pyri-
2
dinium perbromide [4c,d]. With these reagents, only decom-
position of the indole starting material 1 was observed and
this led us to examine the use of the pyridine – Br charge-
2
transfer complex (PyBr ) [11]. Thus, treatment of 1 with an
2
excess of PyBr (prepared in situ by the addition of Br to
2
2
pyridine in CH Cl at -78 °C) at -20 °C resulted in complete
2
2
consumption of the starting material within half an hour as
judged by tlc. Addition of a suspension of Zn in AcOH and
THF to the solution at -78 °C and subsequent warming of
the reaction mixture to room temperature provided
bromoindole 2 in only 5% yield along with recovered
starting material 1 (80%) (Table 1, entry 1). Increasing the
Table 1
Effect of Time, Temperature and Concentration of PyBr on the
2
Bromination of Cyclopenta[b]indole 1
Figure 1. The numbering system used in this article for cyclopenta-
[b]indoles based on IUPAC nomenclature.
Entry PyBr [a]
Time
(min)
Temp.
(°C)
Conversion [b] Yield [c]
2
(equiv)
(%)
(%)
Results and Discussion.
1
2
3
4
5
6
7
8
9
2.2
2.2
3.3
3.3
3.3
5
10
10
15
30
15
30
60
30
30
30
60
30
-20
0
20
45
25
50
60
40
– [d]
70
65
5
8
Most of the starting indoles required for our studies were
readily prepared by exposing various aryl hydrazines and
cyclopentanone to Fischer indole reaction conditions [6].
Under these conditions, α-monosubstituted cyclopen-
tanones gave low yields of the corresponding indoles. For
these substrates, an alternative preparation involving the
reaction of ortho iodoanilines and ketones was undertaken
[7]. After their condensation [8], the corresponding ena-
mine intermediate was submitted to Heck reaction
conditions as described by Chen et al. to generate the cyclic
-20
-20
-10
-20
-20
-20
-20
18
37
38
31
59
54
49
[a] PyBr was prepared in situ at -78 °C; [b] Established by the amount of
starting material recovered after the reduction with Zn/AcOH (5 to 15
equiv); [c] Isolated yield after the reduction step; [d] Not measured.
2

290
N. Lachance and W. Y. Chan
Vol. 40
number of equivalents of PyBr led to an increase in the for-
mation of the desired bromoindole 2. The optimal bromina-
tion conditions for this substrate involved the use of 10
Having established an efficient halogenation of indole 1,
we next investigated the scope of this method. In general, a
variety of indoles were successfully brominated as illus-
trated in Table 2. One exception however was indole 7
where the starting material was recovered unchanged after
the treatment with Zn. As outlined in Scheme 1, our
proposed mechanism for the indole bromination reaction
involves the formation of an indolenine 18, which has been
previously reported by Dmitrienko et al. [4c], and indolines
19 and 20 as intermediates. These indolines were observed
during the course of the bromination with the substrate 5.
2
equiv of PyBr at -20 °C to provide 59% yield of the bromi-
2
nation product (Table 1, entry 7). During the course of our
optimization studies, we observed that the reaction tempera-
ture was an important element in the success of the bromi-
nation – reduction sequence. Low temperatures, such as -20
°C for the bromination of 1 and -78 °C for the subsequent
reduction with Zn, led to less degradation material and
higher yields of product 2 (Table 1).
Scheme 1
X = Py or Br
Proposed Mechanism for the Bromination of Cyclopenta[b]indoles
1
Figure 2. Crude H nmr (500 MHz, acetone-d ) of the bromination reaction of cyclopenta[b]indole 5 followed by the reduction of the intermediates 22
6
and 23 formed: (A) cyclopenta[b]indole 5, (B) indoline 22 after the addition of 1 equiv of PyBr at -20 °C, (C) indoline 23 after the addition of excess
2
PyBr at 0 °C, (D) bromocyclopenta[b]indole 12 after the addition of Zn and AcOH.
2

Mar-Apr 2003
Efficient Synthesis of Bromocyclopenta[b]indoles
291
Scheme 2
Treatment of indole 5 with 1 equiv of PyBr led to the for-
2
mation of the bromoindoline 22 which has been isolated
and characterized (Figure 2, Spectrum B) [12,13]. Further
treatment of 22 with an excess of PyBr delivered the
2
bromoindoline 23 (Figure 2, Spectrum C) [12,14]. The fact
that indole 7 did not provide any of the expected bromina-
tion product 14 suggests that the halogenation on the
benzenoid unit requires the indoline intermediate. For
substrate 7, we propose that the formation of the indoline
19 from the intermediate 18 was not possible due to the
steric hindrance of the gem dimethyl substituents that halt
the progress of the reaction. However, indole 6, which
Reagents and conditions: (i) PyBr (2.5 equiv), CH Cl , -20 °C, 30 min;
(ii) Zn/AcOH (5 equiv), THF, -78 °C to rt. Yield estimated by H nmr.
2
2
2
1
Regioselectivity of the Bromination of Cyclopenta[b]indole 9
Table 2
Synthesis of Bromocyclopenta[b]indoles via a Bromination – Reduction Sequence
[a] Reactions were performed with PyBr (5 to 10 equiv) for 30 min followed by treatment with Zn/AcOH (5 to 10 equiv) at -78 °C; A = bromination
2
performed at -20 °C; B = 0 °C; C = rt, 30 to 60 min; [b] Isolated yield; [c] Most of the starting indole 7 was recovered.

292
N. Lachance and W. Y. Chan
Vol. 40
EXPERIMENTAL
Melting points are uncorrected. nmr spectra were recorded in
possess these substituents at the 1 position of the indole
core, gave good yield of dibromo 13 [15]. Due to the steric
hindrance of the substitution pattern present in 6, the
bromination may proceed directly through the benzenoid
ring.
acetone-d solution at room temperature, unless otherwise stated,
6
1
with solvent as the internal standard for H (500 MHz) and for
13
C (125 MHz). tlc analyses were performed on Merck Kieselgel
The regioselectivity of the indole bromination was
explored with substrate 9. Reducing the number of equiv
60 F
plates. All reactions with air-sensitive compounds were
254
carried out under a nitrogen atmosphere. 4-(Methylsulfonyl)ani-
line hydrochloride and ethyl (2-oxocyclopentyl)acetate were
obtained from Acros Chemicals. 2,2-Dimethylcyclopentanone, 3,
27 and 28 were purchased from Aldrich and 1-(phenylsulfonyl)-
1H-indole from Lancaster. Column chromatography was con-
ducted with silica gel 230-400 mesh. Elemental analyses were
performed by Oneida Research Services, Inc., Whitesboro, NY.
Hrms were performed by Biomedical Mass Spectrometry Unit,
McGill University, Montreal, Qc, Canada.
of PyBr to 2.5 resulted in the formation of mono 7-bro-
2
1
moindole 24 in 61% yield based on H nmr experiments
(Scheme 2). In this example, bromination of the benzenoid
unit occurs first at the 7 position. The substitution pattern
1
of 16 was confirmed by comparing its H nmr spectrum to
that of an authentic sample synthesized from bromocy-
clopenta[b]indole 25 under the current bromination condi-
tions.
3-Methyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]-
indole (1).
The influence of an N-substituent on the current bromi-
nation reaction was investigated by substituting the
nitrogen with a methyl or a tosyl group. Exposure of these
analogs to our standard reaction conditions only led to
recovery of starting material or decomposition.
Performing the reaction at different temperature did not
improve the reaction, underlining the importance of the
free nitrogen on the indole to the success of this reaction.
We next investigated the standard bromination condi-
To a suspension of 4-(methylsulfonyl)aniline hydrochloride
(4.97 g, 23.9 mmol) in EtOH (100 mL) was added a solution of
t-BuOK in THF (1.0 M, 26.0 mL). The slurry was stirred at rt for
15 min, and a suspension of I (6.10 g, 24.0 mmol) and Ag SO
2
2
4
(8.37 g, 26.8 mmol) in EtOH (800 mL) was added in one portion.
The resulting mixture was heated to 50 °C for 3 h. The hot
mixture was filtered through a pad of Celite, and the filtrate was
concentrated in vacuo. The residue was purified by recrystalliza-
tion from EtOH to afford 2-iodo-4-(methylsulfonyl)aniline as a
tions on tetrahydrocarbazoles 26, 27 and 28. Monitoring
1
pale yellow solid (4.96 g, 70%): mp 201-202 °C; H nmr: δ 8.08
1
by tlc the consumption of 26 with PyBr and running H
2
(1 H, d, J = 2.0 Hz), 7.63 (1 H, dd, J = 8.5, 2.0 Hz), 6.93 (1 H, d,
nmr experiments on the crude material, showed the forma-
tion of anticipated bromo intermediates. The reduction
with Zn of these intermediates only led to recovery of
starting material. The reaction was also performed with 27
and 28 without success. Surprisingly, the bromination –
reduction sequence developed in our current study, while
successful with cyclopenta[b]indoles, is completely inop-
erative with the related cyclohexyl analogs. This reactivity
difference may be a result of the corresponding strain of
the indole 3a – 8b double bond as an important factor for
the formation of the indoline intermediates 19 and 20.
13
J = 8.5 Hz), 5.78 (2 H, br s), 3.03 (3 H, s); C nmr δ 153.6,
139.3, 130.6, 129.7, 114.0, 81.0, 44.8. Hrms Calcd for
+
C H INO S: [M + H] = 297.9399. Found: 297.9400.
7
9
2
Anal. Calcd. for C H INO S: C, 28.30; H, 2.71; N, 4.71.
7
8
2
Found: C, 28.44; H, 2.86; N, 4.84.
The previous o-iodoaniline (4.01 g, 13.5 mmol) was mixed
with 2-methylcyclopentanone (1.50 mL, 14.0 mmol),
p-TsOH•H O (26 mg, 0.14 mmol), and (EtO) Si (4.00 mL, 17.9
2
4
mmol) in DMF (4 mL), and heated to 130 °C for 6 h. After cool-
ing to 120 °C, to the mixture was successively added DMF (10
mL), Pd(OAc) (120 mg, 0.54 mmol) and Hünig's base (7.00 mL,
2
40.5 mmol), and then the mixture was stirred at 125 °C for 3 h.
The mixture was diluted with EtOAc, washed with HCl (1 N) and
brine, dried (Na SO ), and filtered. The filtrate was concentrated
2
4
in vacuo to give a residue, which was purified by column chro-
matography on silica gel (toluene/EtOAc = 4/1) to afford 1 as a
1
yellow solid (1.43 g, 42%): mp 153-154 °C (hexane-EtOAc); H
nmr: δ 10.57 (1 H, br s), 7.96 (1 H, d, J = 1.4 Hz), 7.56 (1 H, dd,
J = 8.6, 1.4 Hz), 7.49 (1 H, d, J = 8.6 Hz), 3.35 (1 H, m), 3.04 (3
H, s), 2.91-2.73 (3 H, m), 2.08 (1H, m), 1.29 (3 H, d, J = 6.8 Hz);
13
C nmr δ 152.4, 144.3, 132.7, 125.0, 119.7, 119.3 (2), 112.8,
45.2, 38.7, 34.3, 24.0, 20.2. Hrms Calcd for C
[M + H] = 250.0902. Found: 250.0901.
H NO S:
13 16 2
Conclusion.
+
Anal. Calcd. for C
Found: C, 62.41; H, 5.99; N, 5.71.
H NO S: C, 62.62; H, 6.06; N, 5.62.
In summary, an efficient procedure has been outlined for
the preparation of 5 and/or 7-bromocyclopenta[b]indoles
by use of a bromination – reduction sequence. This reac-
tion has significant advantages over other reported meth-
ods to prepare these versatile synthetic intermediates and
should provide broad applicability for the synthesis of
functionalized cyclopenta[b]indoles [2].
13 15 2
[7-(Methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-
yl]acetic Acid (5).
Following the preparation of 1, the reaction of ethyl (2-oxo-
cyclopentyl)acetate (12.9 g, 76.0 mmol) and 2-iodo-4-(methyl-
sulfonyl)aniline (19.4 g, 65.4 mmol) afforded ethyl [7-(methyl-

Mar-Apr 2003
Efficient Synthesis of Bromocyclopenta[b]indoles
293
sulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetate.
After hydrolysis with THF (80 mL), MeOH (40 mL) and NaOH
(2 N, 40.0 mL) at rt for 1.5 h, the mixture was acidified with HCl
(1 N) and extracted with EtOAc. The organic layer was washed
with brine, dried (Na SO ), and filtered. The filtrate was concen-
A mixture of the previous cyclic ketone (2.38 g, 7.10 mmol)
and NaOMe (prepared from Na (1.83 g, 80.0 mmol)) in MeOH
(100 mL)) was heated to 80 °C for 15 min. The mixture was
poured into HCl (1 N) and extracted with EtOAc. The organic
layer was washed with brine, dried (Na SO ), and filtered. The
2
4
2
4
trated in vacuo to give a residue, which was triturated
(hexane/EtOAc) to afford 5 as a pale brown solid (9.13 g, 48%):
mp 222-223 °C; H nmr: δ 10.86 (1 H, br s), 10.28 (1 H, br s),
filtrate was concentrated in vacuo to give a residue, which was
purified by column chromatography on silica gel (toluene/EtOAc
= 4/1) to afford 6 [10b] as a brown solid (1.25 g, 88%): mp 163-
164 °C (hexane-EtOAc); C nmr: δ 192.6, 153.8, 144.8, 138.1,
127.2, 123.0, 122.5, 121.0, 114.5, 58.2, 36.1, 29.3.
1
13
7.98 (1 H, s), 7.58 (2 H, m), 3.63 (1 H, m), 3.04 (3 H, s), 2.91 (1
13
H, m), 2.85-2.77 (2 H, m), 2.74-2.65 (2 H, m), 2.21 (1 H, m);
C
nmr δ 174.2, 149.9, 144.2, 132.7, 124.6, 120.6, 119.6, 119.5,
Anal. Calcd. for C
H NO: C, 78.36; H, 6.58; N, 7.03. Found:
13 13
113.2, 45.2, 39.5, 36.4, 36.2, 23.7. Hrms Calcd for C
[M + H] = 294.0800. Found: 294.0801.
H NO S:
C, 78.17; H, 6.31; N, 7.12.
14 16 4
+
7-Chloro-3,3-dimethyl-1,2,3,4-tetrahydrocyclopenta[b]indole
(7).
Anal. Calcd for C
H NO S: C, 57.32; H, 5.15; N, 4.77.
14 15 4
Found: C, 57.21; H, 5.10; N, 4.78.
A mixture of 4-chlorophenylhydrazine hydrochloride (3.42 g,
19.1 mmol) and 2,2-dimethylcyclopentanone (2.40 mL, 19.1
mmol) in AcOH (40 mL) was heated to 125 °C overnight. The
mixture was poured into water and extracted with EtOAc. The
1,1-Dimethyl-1,4-dihydrocyclopenta[b]indol-3(2H)-one (6).
To a solution of 1-(phenylsulfonyl)-1H-indole (5.15 g, 20.0
mmol) in THF (200 mL) at -78 °C was added dropwise a solu-
tion of t-BuLi (1.7 M in pentane, 15.5 mL). The resulting solu-
tion was stirred at -78 °C for 1 h and a solution of freshly dis-
tilled 3-methylbut-2-enal (2.50 mL, 25.9 mmol) in THF (50 mL)
was added dropwise over 30 min. The mixture was stirred at -78
°C for 45 min. After warming to rt, the mixture was acidified
organic layer was washed with water and brine, dried (Na SO ),
2
4
and filtered. The filtrate was concentrated in vacuo to give a
residue, which was purified by column chromatography on silica
gel (hexane/EtOAc = 9/1) and by recrystallization from hexane to
1
afford 7 as a white solid (1.09 g, 26%): mp 115-116 °C; H nmr:
with aqueous NH Cl and extracted with EtOAc. The organic
δ 10.15 (1 H, br s), 7.33 (1 H, d, J = 2.0 Hz), 7.27 (1 H, d, J = 8.5
Hz), 6.97 (1 H, dd, J = 8.5, 2.0 Hz), 2.75 (2 H, m), 2.32 (2 H, m),
1.32 (6 H, s); C nmr: δ 154.4, 140.4, 126.8, 124.8, 120.5, 118.3,
4
layer was washed with brine, dried (Na SO ), and filtered. The
2
4
13
filtrate was concentrated in vacuo to give crude 3-methyl-1-[1-
(phenylsulfonyl)-1H-indol-2-yl]but-2-en-1-ol as an orange oil,
which was used for the next step without further purification. To
116.3, 113.5, 46.4, 40.1, 27.9, 23.2. Hrms Calcd for C
[M + H] = 220.0893. Found: 220.0894.
H ClN:
13 15
+
a solution of the crude alcohol in CH Cl (200 mL) at rt was
Anal. Calcd for C H ClN: C, 71.07; H, 6.42; N, 6.38. Found:
2
2
13 14
added 4-methylmorpholine N-oxide (3.51 g, 30.0 mmol) and 4 Å
molecular sieves (5.89 g). After 20 min, tetrapropylammonium
perruthenate (360 mg, 1.00 mmol) was added and the mixture
was stirred overnight at rt. The reaction mixture was purified by
C, 71.18; H, 6.17; N, 6.53.
1,2,3,4-Tetrahydrocyclopenta[b]indol-7-yl isopropylcarbamate
(8).
Following the preparation of 7, the reaction of 4-methoxy-
phenylhydrazine hydrochloride (5.04 g, 28.9 mmol) and
cyclopentanone (5.10 mL, 57.7 mmol) in EtOH (175 mL) heated
to 100 °C for 30 min afforded, after recrystallization from
hexane-CH Cl , 7-methoxy-1,2,3,4-tetrahydrocyclopenta[b]-
column chromatography on silica gel (CH Cl ). Unreacted alco-
2
2
hol recovered was resubmitted to the same reaction conditions to
afford, after recrystallization (hexane/CH Cl ) of the combined
2
2
fractions, 3-methyl-1-[1-(phenylsulfonyl)-1H-indol-2-yl]but-2-
en-1-one [16] as a white solid (2.80 g, 33%): mp 120-121 °C;
2
2
13
indole [6d] as a pale brown solid (3.98 g, 73%): mp 126-127 °C
C nmr: δ 184.2, 157.8, 142.6, 139.4, 139.0, 134.9, 129.9,
13
(hexane-CH Cl ); C nmr: δ 154.7, 145.6, 137.4, 126.0, 119.1,
129.7, 128.2, 127.8, 125.1, 124.2, 123.6, 116.5, 116.3, 27.8,
2
2
+
112.7, 110.2, 101.3, 55.8, 29.2, 26.2, 24.9.
21.0. Hrms Calcd for C
Found: 340.1009.
H
NO S: [M + H] = 340.1007.
19 18
3
To a solution of the previous methoxyindole (1.01g, 5.37
mmol) in CH Cl (25 mL) at 0 °C was added dropwise a solu-
To a solution of the previous ketone (2.50 g, 7.40 mmol) in
toluene (90 mL) at rt was added dropwise BF •OEt (2.93 mL,
2
2
tion of BBr in CH Cl (1.0 M, 6.00 mL). The resulting mixture
3
2
2
3
2
was warmed to rt for 30 min. The mixture was diluted with
23.3 mmol). The resulting mixture was heated to 120 °C
overnight. The mixture was diluted with EtOAc, washed with
brine, dried (Na SO ), and filtered through a pad of Celite. The
EtOAc, washed with aqueous NaHCO and brine, dried
3
(Na SO ), and filtered. The filtrate was concentrated in vacuo to
2
4
2
4
give crude 1,2,3,4-tetrahydrocyclopenta[b]indol-7-ol as a brown
oil, which was used for the next step without further purifica-
tion. To a solution of the crude phenol in THF (10 mL) at rt was
filtrate was concentrated in vacuo to give a residue, which was
purified by column chromatography on silica gel (toluene/EtOAc
= 4/1) to afford 1,1-dimethyl-4-(phenylsulfonyl)-1,4-dihydrocy-
clopenta[b]indol-3(2H)-one as a brown solid (2.00 g, 80%): mp
added Et N (375 µL, 2.69 mmol) and isopropyl isocyanate (3.20
3
1
mL, 32.6 mmol) and the reaction mixture was stirred overnight
at rt. The mixture was diluted with EtOAc, washed with aqueous
NaHCO and brine, dried (Na SO ), and filtered. The filtrate
199-200 °C (hexane-EtOAc); H nmr: δ 8.34 (1 H, d, J = 8.0 Hz),
8.17 (2 H, d, J = 7.6 Hz), 7.87 (1 H, d, J = 7.9 Hz), 7.70 (1 H, t,
J = 7.5 Hz), 7.61 (3 H, m), 7.41 (1 H, t, J = 7.6 Hz), 2.82 (2 H, s),
3
2
4
13
was concentrated in vacuo to give a residue, which was purified
by column chromatography on silica gel (hexane/EtOAc = 3/1)
and by recrystallization from hexane-EtOAc to afford 8 as a
1.50 (6 H, s); C nmr: δ 189.0, 161.6, 144.1, 139.5, 137.0, 135.3,
130.3, 129.8, 128.2, 125.0, 124.6, 123.2, 116.4, 58.2, 35.5, 28.3.
+
Hrms Calcd for C
378.0565.
H
KNO S: [M + K] = 378.0566. Found:
19 17
3
1
white solid (1.06 g, 76%): mp 188-189 °C; H nmr: δ 9.89 (1 H,
br s), 7.21 (1H, d, J = 8.6 Hz), 7.02 (1 H, d, J = 1.7 Hz), 6.71 (1
H, dd, J = 8.6, 1.7 Hz), 6.43 (1 H, br d, J = 6.3 Hz), 3.80 (1 H,
Anal. Calcd. for C
Found: C, 67.44; H, 4.84; N, 4.42.
H NO S: C, 67.24; H, 5.05; N, 4.13.
19 17 3

294
N. Lachance and W. Y. Chan
Vol. 40
m), 2.82 (2 H, m), 2.73 (2H, m), 2.47 (2H, m), 1.20 (6H, d, J =
6.5 Hz); C nmr: δ 155.5, 146.3, 145.6, 139.7, 125.5, 119.3,
Following the general procedure, the reaction of 4 [6a] (253
13
mg, 1.58 mmol), pyridine (640 µL, 7.91 mmol) and Br (1.0 M,
2
115.1, 112.0, 111.3, 43.8, 29.2, 26.2, 24.8, 22.9. Hrms Calcd for
7.90 mL) afforded 11 as a white solid (366 mg, 97%): mp 214-
+
1
C
H
N O : [M + H] = 259.1447. Found: 259.1447.
215 °C (hexane-CH Cl ); H nmr: δ 10.62 (1 H, br s), 8.09 (1 H,
15 19
2
2
2
2
d, J = 1.4 Hz), 7.87 (1 H, d, J = 1.4 Hz), 2.91 (2 H, m), 2.78 (2 H,
m), 2.47 (2 H, m); C nmr: δ 152.4, 147.6, 141.5, 128.1, 120.0,
Anal. Calcd. for C
Found: C, 69.75; H, 6.90; N, 10.75.
H N O : C, 69.74; H, 7.02; N, 10.84.
15 18 2 2
13
116.9, 111.6, 28.2, 26.6, 25.0. Hrms Calcd for C
[M + H] = 237.0027. Found: 237.0027.
H BrN :
10 10 2
1,2,3,4-Tetrahydrocyclopenta[b]indole (9).
+
Anal. Calcd. for C H BrN : C, 50.66; H, 3.83; N, 11.82.
Found: C, 50.86; H, 3.63; N, 11.83.
Following the preparation of 7, the reaction of phenylhy-
drazine hydrochloride (20.1 g, 139 mmol) and cyclopentanone
(12.2 mL, 138 mmol) heated to 125 °C for 1.5 h afforded 9 [6d]
as a white solid (9.64 g, 44%): C nmr: δ 144.8, 142.4, 125.7,
120.6, 119.5, 119.2, 118.8, 112.2, 29.3, 26.2, 24.9.
10
9
2
[5-Bromo-7-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]-
indol-3-yl]acetic acid (12).
13
Following the general procedure, the reaction of 5 (242 mg, 0.82
Anal. Calcd for C H N: C, 84.04; H, 7.05; N, 8.91. Found:
11 11
mmol), pyridine (400 µL, 4.95 mmol) and Br (1.0 M, 4.10 mL)
C, 84.21; H, 6.90; N, 8.96.
2
stirred at 0 °C afforded 12 as a pale brown solid (296 mg, 96%):
General Procedure for the Synthesis of Bromocyclopenta[b]-
indole (2, 10-16, 24-25).
1
mp 278-279 °C; H nmr: δ 11.05 (1 H, br s), 10.37 (1 H, br s), 8.00
(1 H, s), 7.76 (1 H, d, J = 1.2 Hz), 3.67 (1 H, m), 3.13 (3 H, s), 2.96-
13
2.80 (4 H, m), 2.62 (1 H, dd, J = 16.5, 8.2 Hz), 2.27 (1 H, m);
C
To a solution of cyclopenta[b]indole (0.41 mmol) in CH Cl
2
2
nmr (dmso-d ): δ 173.3, 150.2, 140.7, 132.5, 124.5, 120.4, 120.3,
(1.6 mL) at -78 °C was added sequentially pyridine (330 µL,
4.10 mmol) and a solution of Br in CH Cl (1.0 M, 4.10 mL).
6
117.7, 104.3, 44.3, 38.5, 35.4, 35.2, 23.1. Hrms Calcd for
2
2
2
+
C H KBrNO S: [M + K] = 409.9464. Found: 409.9466.
The mixture was stirred at -20 °C for 30 min and cooled to -78
°C. A suspension of Zn (290 mg, 4.50 mmol) and AcOH (120
µL, 2.10 mmol) in THF (2 mL) was added portionwise and the
resulting mixture was warmed to rt over 30 min and kept at rt
for another 30 min. The mixture was poured into HCl (1 N) or
10% aqueous AcOH and extracted with EtOAc. The organic
14 14
4
Anal. Calcd. for C
H BrNO S: C, 45.17; H, 3.79; N, 3.76.
14 14 4
Found: C, 45.41; H, 3.70; N, 3.82.
5,7-Dibromo-1,1-dimethyl-1,4-dihydrocyclopenta[b]indol-
3(2H)-one (13).
Following the general procedure, the reaction of 6 (201 mg,
layer was washed with brine, dried (Na SO ), and filtered. The
2
4
1.01 mmol), pyridine (810 µL, 10.0 mmol) and Br (1.0 M, 10.0
2
filtrate was concentrated in vacuo to give a residue, which was
purified by column chromatography on silica gel eluting with
the suitable toluene/EtOAc mixture to give the corresponding
bromoindole.
mL) stirred at rt for 60 min afforded 13 as a white solid (330 mg,
1
92%): mp 186-187 °C; H nmr: δ 10.97 (1 H, br s), 8.05 (1 H, s),
13
7.71 (1 H, s), 2.79 (2 H, s), 1.57 (6 H, s); C nmr: δ 192.6, 153.3,
141.8, 140.0, 131.4, 125.4, 124.2, 113.4, 107.7, 58.1, 36.4, 29.0.
5-Bromo-3-methyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrocy-
clopenta[b]indole (2).
+
Hrms Calcd for C
H Br NO: [M + H] = 355.9286. Found:
13 12 2
355.9285.
Anal. Calcd. for C H Br NO: C, 43.73; H, 3.11; N, 3.92.
Found: C, 43.70; H, 3.14; N, 4.06.
Following the general procedure, the reaction of 1 (101 mg,
13 11
2
0.41 mmol), pyridine (330 µL, 4.08 mmol) and Br (1.0 M, 4.10
2
mL) afforded 2 as a white solid (79 mg, 59%): mp 216-217 °C
(hexane-EtOAc); H nmr: δ 10.76 (1 H, br s), 7.98 (1 H, s), 7.74
5-Bromo-1,2,3,4-tetrahydrocyclopenta[b]indol-7-yl isopropyl-
carbamate (15).
1
(1 H, d, J = 1.6 Hz), 3.37 (1 H, m), 3.12 (3 H, s), 2.93-2.75 (3 H,
Following the general procedure, the reaction of 8 (102 mg,
13
m), 2.08 (1H, m), 1.33 (3 H, d, J = 6.9 Hz); C nmr: δ 153.5,
0.39 mmol), pyridine (170 µL, 2.10 mmol) and Br (1.0 M, 2.0
2
142.1, 134.2, 126.1, 121.5, 121.3, 118.8, 105.0, 45.1, 38.6, 34.3,
mL) afforded 15 as a white solid (128 mg, 96%): mp 168-169 °C;
+
24.0, 20.1. Hrms Calcd for C
365.9566. Found: 365.9567.
H
KBrNO S: [M + K]
=
13 14
2
1
H nmr: δ 10.06 (1 H, br s), 7.05 (1H, d, J = 1.6 Hz), 6.98 (1 H, d,
J = 1.6 Hz), 6.56 (1 H, br d, J = 6.7 Hz), 3.79 (1 H, m), 2.84 (2 H,
Anal. Calcd. for C
H BrNO S: C, 47.57; H, 4.30; N, 4.27.
13 14 2
13
m), 2.74 (2H, m), 2.48 (2H, m), 1.20 (6H, d, J = 6.6 Hz);
C
Found: C, 47.73; H, 4.21; N, 4.24.
nmr: δ 155.1, 147.7, 145.7, 137.7, 126.3, 120.8, 117.9, 111.0,
5-Bromo-7-chloro-1,2,3,4-tetrahydrocyclopenta[b]indole (10).
Following the general procedure, the reaction of 3 (255 mg,
103.5, 43.9, 29.1, 26.2, 24.8, 22.9. Hrms Calcd for
+
C
H
BrKN O : [M + K] = 375.0110. Found: 375.0109.
15 17
2 2
Anal. Calcd. for C
H BrN O : C, 53.43; H, 5.08; N, 8.31.
15 17 2 2
1.33 mmol), pyridine (540 µL, 6.68 mmol) and Br (1.0 M, 6.60
2
Found: C, 53.54; H, 5.16; N, 8.32.
mL) afforded 10 as a white solid (342 mg, 95%): mp 109-110 °C
1
(hexane); H nmr: δ 10.28 (1 H, br s), 7.36 (1 H, d, J = 1.7 Hz),
5,7-Dibromo-1,2,3,4-tetrahydrocyclopenta[b]indole (16).
Following the general procedure, the reaction of 9 (206 mg,
7.20 (1 H, d, J = 1.7 Hz), 2.87 (2 H, m), 2.77 (2 H, m), 2.50 (2 H,
13
m); C nmr: δ 148.5, 138.9, 127.4, 125.1, 122.5, 121.0, 118.2,
1.31 mmol), pyridine (1.06 mL, 13.1 mmol) and Br (1.0 M, 13.0
+
2
105.3, 29.1, 26.2, 24.7. Hrms Calcd for C H BrClN: [M + H]
11 10
mL) afforded 16 as a white solid (401 mg, 97%): mp 123-124 °C;
= 269.9685. Found: 269.9684.
1
H nmr: δ 10.30 (1 H, br s), 7.51 (1 H, d, J = 1.4 Hz), 7.32 (1 H,
Anal. Calcd for C H BrClN: C, 48.83; H, 3.35; N, 5.18.
11
9
13
d, J = 1.4 Hz), 2.87 (2 H, m), 2.76 (2 H, m), 2.50 (2 H, m);
C
Found: C, 49.12; H, 3.19; N, 5.32.
nmr: δ 148.3, 139.1, 128.1, 124.9, 120.8, 120.5, 112.1, 105.3,
+
3-Bromo-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyri-
dine (11).
29.1, 26.2, 24.7. Hrms Calcd for C
313.9180. Found: 313.9179.
H
Br N: [M + H]
=
11 10
2

Mar-Apr 2003
Efficient Synthesis of Bromocyclopenta[b]indoles
295
H. Stammer, F. W. Holly, L. H. Sarett, E. A. Risley, G. W. Nuss and C. A.
Winter, J. Am. Chem. Soc., 85, 488 (1963); [b] L. J. Street, R. Baker, W.
B. Davey, A. R. Guiblin, R. A. Jelley, A. J. Reeve, H. Routledge, F.
Sternfeld, A. P. Watt, M. S. Beer, D. N. Middlemiss, A. J. Noble, J. A.
Stanton, K. Scholey, R. J. Hargreaves, B. Sohal, M. I. Graham and V. G.
Matassa, J. Med. Chem., 38, 1799 (1995); [c] V. G. Matassa, T. P.
Maduskuie, H. S. Shapiro, B. Hesp, D. W. Snyder, D. Aharony, R. D.
Krell and R. A. Keith, J. Med. Chem., 33, 1781 (1990); [d] U.
Rosentreter, H. Boeshagen, F. Seuter, E. Perzborn and V. B. Fiedler,
Arzneim. Forsch., 39, 1519 (1989).
[2] M. Labelle, C. Sturino, B. Roy, C. Berthelette, M. Boyd, N.
Lachance and J. Scheigetz, US Patent 6,410,583 (2002); Chem. Abstr.,
136, 134671 (2002).
[3a] G. W. Gribble, J. Chem. Soc., Perkin Trans. I, 1045 (2000),
and references therein; [b] J. L. Rutherford, M. P. Rainka and S. L.
Buchwald, J. Am. Chem. Soc., 124, 15168 (2002).
[4] Representative examples: [a] R. J. Sundberg, Indoles,
Academic Press, London, 1996, pp 102-103, 117-118; [b] J. C. Powers, In
Indoles, W. J. Houlihan. John Wiley and Sons, New York, NY, 1972, Part
2, pp 128-137; [c] E. A. Gross, S. F. Vice and G. I. Dmitrienko, Can. J.
Chem., 59, 635 (1981), and references therein; [d] M. Tani, H. Ikegami,
M. Tashiro, T. Hiura, H. Tsukioka, C. Kaneko, T. Notoya, M. Shimizu, M.
Uchida, Y. Aida, Y. Yokoyama and Y. Murakami, Heterocycles, 34, 2349
(1992); [e] M. Hasegawa, K. Yamada, Y. Nagahama and M. Somei,
Heterocycles, 51, 2815 (1999); [f] R. P. Robinson and K. M. Donahue, J.
Org. Chem., 56, 4805 (1991); [g] A. Da Settimo and E. Nannipieri, J.
Org. Chem., 35, 2546 (1970); [h] Y. Liu and G. Gribble, W. Tetrahedron
Lett., 43, 7135 (2002).
[5a] H. Sakakibara and T. Kobayashi, Tetrahedron, 22, 2475
(1966); [b] S. G. P. Plant and M. L. Tomlinson, J. Chem. Soc., 3324
(1931).
[6] Representative examples: [a] A. H. Kelly and J. Parrick, Can.
J. Chem., 44, 2455 (1966); [b] G. Jones and G. T. Tringham, J. Chem.
Soc., Perkin Trans. I, 1280 (1975); [c] C.-A. Harrison, P. M. Jackson, C.
J. Moody and J. M. J. Williams, J. Chem. Soc., Perkin Trans. I, 1131
(1995); [d] O. Miyata, Y. Kimura and Naito, T. Synthesis, 1635 (2001),
and references therein.
Anal. Calcd for C H Br N: C, 41.94; H, 2.88; N, 4.45. Found:
C, 42.25; H, 2.78; N, 4.50.
11
9
2
7-Bromo-1,2,3,4-tetrahydrocyclopenta[b]indole (24).
Following the general procedure, the reaction of 9 (203 mg,
1.29 mmol), pyridine (260 µL, 3.21 mmol) and Br (1.0 M, 3.20
2
mL) afforded 24 [6c] as a yellow solid (141 mg, 46%; (61%)
1
estimated by H nmr of the crude material); hrms Calcd for
+
C H BrN: [M + H] = 236.0075. Found: 236.0074.
11 11
Anal. Calcd. for C
H BrN: C, 55.96; H, 4.27; N, 5.93.
11 10
Found: C, 55.96; H, 4.01; N, 5.99.
5-Bromo-1,2,3,4-tetrahydrocyclopenta[b]indole (25).
Following the preparation of 7, the reaction of 2-bromophenyl-
hydrazine hydrochloride (10.6 g, 47.6 mmol) and cyclopen-
tanone (4.20 mL, 47.5 mmol) heated to 125 °C for 20 min
afforded 25 as an off-white solid (1.53 g, 14%). Compound 25
1
was a minor product in the synthesis of 24 ((9%) estimated by H
nmr of the crude material 24; difficult to isolate from compound
1
16): mp 83-84 °C (hexane); H nmr: δ 10.05 (1 H, br s), 7.34
(1 H, d, J = 7.8 Hz), 7.18 (1 H, d, J = 7.7 Hz), 6.91 (1 H, dd, J =
13
7.8, 7.7 Hz), 2.86 (2 H, m), 2.77 (2 H, m), 2.50 (2 H, m);
C
nmr: δ 146.3, 140.2, 127.2, 123.2, 120.9, 120.6, 118.2, 104.8,
+
29.1, 26.2, 24.9. Hrms Calcd for C
236.0075. Found: 236.0074.
H
BrN: [M + H]
=
11 11
Anal. Calcd for C H BrN: C, 55.96; H, 4.27; N, 5.93. Found:
11 10
C, 56.07; H, 4.00; N, 6.03.
[6-(Methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic
Acid (26).
Following the preparation of 1 and 5, the reaction of ethyl (2-
oxocyclohexyl)acetate (3.50 g, 19.0 mmol) and 2-iodo-4-
(methylsulfonyl)aniline (4.75 g, 16.0 mmol) followed by hydrol-
ysis of the ester afforded 26 as a pale yellow solid (803 mg,
1
[7] Representative example for the preparation of ortho iodoani-
lines: W.-W. Sy, Synth. Commun., 22, 3215 (1992).
[8] B. E. Love and J. Ren, J. Org. Chem., 58, 5556 (1993).
[9] C.-y. Chen, D. R. Lieberman, R. D. Larsen, T. R. Verhoeven
and P. J. Reider, J. Org. Chem., 62, 2676 (1997).
[10a] K.-F. Cheng, K.-P. Chan, Y.-C. Kong and D.-D. Ho, J. Chem.
Soc., Perkin Trans. I, 2955 (1991); [b] J. Bergman and L. Venemalm,
Tetrahedron, 46, 6067 (1990).
[11] G. Bellucci, G. Berti, R. Bianchini and G. Ingrosso, J. Org.
Chem., 46, 2315 (1981).
16%): mp 229-230 °C H nmr: δ 10.89 (1 H, br s), 10.30 (1 H, br
s), 8.00 (1 H, d, J = 1.7 Hz), 7.58 (1 H, m), 7.54 (1H, m), 3.40 (1
H, m), 3.04 (3 H, s), 2.89 (1 H, m), 2.74 (2 H, m), 2.58 (1 H, m),
13
2.13 (1 H, m), 1.97 (1 H, m), 1.83 (1 H, m), 1.73 (1 H, m);
C
nmr (dmso-d ): δ 173.2, 139.5, 138.0, 130.6, 126.4, 118.9, 117.7,
6
111.3, 110.6, 44.7, 38.7, 30.2, 28.6, 20.7, 20.5. Hrms Calcd for
+
C
H
KNO S: [M + K] = 346.0515. Found: 346.0515.
15 17
4
Anal. Calcd for C
H NO S: C, 58.61; H, 5.57; N, 4.56.
15 17 4
Found: C, 58.64; H, 5.46; N, 4.57.
[12] Removal of traces of chlorinated solvent led to a fast
decomposition of indoline intermediates 22 and 23.
Acknowlegdments.
[13] The incorporation of two bromine atoms is supported by mass
We thank Claudio F. Sturino and Bruno Roy for their helpful
discussion and suggestions.
spectrum analysis (APCI, negative mode) giving rise to signals at 454,
-
452 and 450 corresponding to C
H
Br NO S: [M-H] .
14 14
2
4
[14] The incorporation of three bromine atoms is supported by
REFERENCES AND NOTES
mass spectrum analysis (APCI, negative mode) giving rise to signals at
-
534, 532, 530 and 528 corresponding to C
H
Br NO S: [M-H] .
14 13
3
4
*
Corresponding author. Tel: 514 428 8696; Fax: 514 428 4900;
[15] The regioselectivity of the bromination of 6 was confirmed by
NOE experiments on 13.
E-mail: nicolas_lachance@merck.com
[1a] T. Y. Shen, T. B. Windholz, A. Rosegay, B. E. Witzel, A. N.
Wilson, J. D. Willett, W. J. Holtz, R. L. Ellis, A. R. Matzuk, S. Lucas, C.
[16] E. Wenkert, E. C. Angell, V. F. Ferreira, E. L. Michelotti, S. R.
Piettre, J.-H. Sheu and C. S. Swindell, J. Org. Chem., 51, 2343 (1986).