A practical and efficient synthesis of 6-carboalkoxy-13-cycloalkyl-5H- indolo[2,1-a][2]benzazepine-10-carboxylic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.12.085

A convenient and practical synthesis of 6-carboalkoxy-13-cycloalkyl-5H- indolo[2,1-a][2]benzazepine-10-carboxylic acid derivatives (6) has been developed. The key step in the synthesis utilizes an intramolecular tandem reaction sequence of a Michael addition followed by a Horner-Wadsworth-Emmons (HWE) olefination reaction between hemi-aminal 11 and methyl 2-(dimethoxyphosphoryl)acrylate 12. The ring construction occurred efficiently and purification of the products 6 was straightforward. The C-10 methyl ester of 6a was hydrolyzed selectively to the carboxylic acid 13 while the olefin of 6d was converted to the cyclopropane 14 using trimethylsulfoxonium iodide in DMSO in the presence of NaH.

Full text of DOI:10.1016/j.tetlet.2013.12.085

Tetrahedron Letters 55 (2014) 1148–1153
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A practical and efficient synthesis
of 6-carboalkoxy-13-cycloalkyl-5H-indolo[2,1-a][2]
benzazepine-10-carboxylic acid derivatives
⇑
Piyasena Hewawasam , Yong Tu, Thomas W. Hudyma, Xiaofan Zhang, Robert G. Gentles, John F. Kadow,
Nicholas A. Meanwell
Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and practical synthesis of 6-carboalkoxy-13-cycloalkyl-5H-indolo[2,1-a][2]benzazepine-
10-carboxylic acid derivatives (6) has been developed. The key step in the synthesis utilizes an intramo-
lecular tandem reaction sequence of a Michael addition followed by a Horner–Wadsworth–Emmons
(HWE) olefination reaction between hemi-aminal 11 and methyl 2-(dimethoxyphosphoryl)acrylate 12.
The ring construction occurred efficiently and purification of the products 6 was straightforward. The
C-10 methyl ester of 6a was hydrolyzed selectively to the carboxylic acid 13 while the olefin of 6d
was converted to the cyclopropane 14 using trimethylsulfoxonium iodide in DMSO in the presence of
NaH.
Received 13 November 2013
Revised 21 December 2013
Accepted 23 December 2013
Available online 3 January 2014
Keywords:
Michael addition
Horner–Wadsworth–Emmons reaction
Indolo[2,1-a][2]benzazepine
Ring closing metathesis
Ó 2013 Elsevier Ltd. All rights reserved.
Introduction
general structure 6 were considered for examination since the ester
moiety at C-10 and the olefin at C-10-C-11 provided functionality
We have recently described the synthesis and evaluation of a
series of bridged 2-arylindole-based non-nucleoside hepatitis C
virus (HCV) non-structural protein 5B (NS5B) RNA-dependent
RNA polymerase inhibitors that bind to thumb site 1 of the
enzyme.1–4 Compound 2 (Scheme 1) is a representative prototype
that demonstrates antiviral activity in a genotype 1b HCV replicon
convenient for further elaboration.6
CO2R1
RO2C
N
with an EC50 of 0.84 l
M.1 The 3-carbon atom bridge of 2 was
R2
assembled from the acyclic precursor 1 using a ring closing
metathesis (RCM) reaction effected by the Grubbs 2nd generation
catalyst, as depicted in Scheme 1.1,5–7 Other bridge elements
(CH2)n
examined include the amide 3, EC50 = 0.07
l
M, the ether 4,
EC50 = 0.69 M, and the fused benzodiazonine 5, EC50 = 0.60
l
l
M.1
6
The potency advantage offered by the amide linker in 3 was attrib-
uted to interactions between the amide moiety and the polymerase
enzyme rather than to an effect of the linker on the dihedral angle
between the 2-phenyl substituent and the indole core, established
as a factor contributing to inhibitory potency.1
As part of the evolution of this chemotype toward compounds
with enhanced potency, we sought to explore linkers in which polar
functionality was appended to the bridge element rather than inte-
grated within it as in 3 and which would provide vectors suitable for
further probing of the interactions between inhibitor and enzyme.
To that end, 6,10-disubstituted indolo[2,1-a][2]benzazepines of
The indolo[2,1-a][2]benzazepine ring system is sparsely repre-
sented in the literature prior to the advent of the HCV NS5B thumb
site inhibitor chemotype represented by 2.6,7 The initial approach
adopted to access fused indoles 6 relied upon a ring-closing metath-
esis reaction analogous to that used to prepare 2, a procedure sum-
marized in Scheme 2. Suzuki coupling8 of 2-vinylphenylboronic
acid (8) with methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxyl-
ate (7) afforded the 2-phenyl indole 1 which was alkylated with
methyl 2-(bromomethyl)acrylate using NaH as base in DMF to give
9. A RCM approach was successful in providing 6a but this proce-
dure gave low and variable yields and purification typically re-
quired extensive chromatography.5 Moreover, due to the high
dilution requirements, extended reaction times, and the expense
associated with both the 2-vinylphenylboronic acid (8) starting
⇑
Corresponding author. Tel.: +1 203 677 7815.
E-mail address: Piyasena.Hewawasam@bms.com (P. Hewawasam).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.085

P. Hewawasam et al. / Tetrahedron Letters 55 (2014) 1148–1153
1149
1. Ring closing metathesis
MeO2C
HO2C
N
1
N
2. H2, Pd on C
3. NaOH, MeOH-THF-H2O, 90oC
2
O
NH
O
NH
HO2C
HO2C
HO2C
N
N
N
3
4
5
Scheme 1.
H
N
H
N
MeO2C
MeO2C
Br
Pd(PPh3)4, LiCl, Na2CO3
EtOH-toluene, 80 o
(HO)2B
+
C
7
8
1
CO2Me
MeO2C
MeO2C
MeO2C
N
N
Br
MeO2C
NaH, DMF
Grubb's catalyst
10-40% yield
9
6a
Scheme 2.
R3
O
O
R3
O
Nu
EWG
Nu
O
(RO)2P
EWG
R1
R2
EWG
R2
(RO)2P
Intramolecular
R1
R2
R3
R1
Nu
Michael addition
HWE olefination
Scheme 3.
material and the RCM catalyst, scale-up presented concerns of both
a practical and economical nature. As a consequence, we sought an
alternative and a more reliable synthetic approach to the prepara-
tion of 6a and its analogues.
would retard reaction at C-3, which is often favored with unsub-
stituted indole substrates.11 Vinylphosphonates containing
electron-withdrawing groups (EWGs) at the
a-position, such as
alkoxycarbonyl, carbonyl, cyano, sulfinyl, sulfonyl, or phosphoryl
groups are reactive electrophiles that have found useful applica-
tion in organic synthesis.9,10 A phosphoryl group not only facili-
tates the Michael addition but also enables a subsequent HWE
olefination of carbonyl moieties which can be presented either in-
ter- or intra-molecularly.9–11
The construction of the 5H-indolo[2,1-a][2]benzazepine ring
system using this approach required the aldehyde 11, readily pre-
pared from the 2-bromoindole 7 and 2-formylphenylboronic acid
A
tandem Michael addition-Horner–Wadsworth–Emmons
(HWE) ring closure process, captured in Scheme 3, was consid-
ered as a synthetic approach with the potential to deliver 6 from
readily available and less expensive reagents.9,10 This process
envisages the use of an activated vinylphosphonate reacting as
a Michael acceptor with the indole nitrogen as the nucleophile,
a process anticipated to be facilitated in the case at hand by
the C-6 electron withdrawing group while the cyclohexyl moiety

1150
P. Hewawasam et al. / Tetrahedron Letters 55 (2014) 1148–1153
HO
N
CHO
CHO
H
N
B(OH)2
10
H
N
MeO2C
MeO2C
MeO2C
Br
Pd(PPh3)4, LiCl, Na2CO3
EtOH-toluene, 85 oC, 3h
7
11
CO2Me
O
O
P(OMe)2
MeO2C
N
MeO
12
Cs2CO3, DMF
60 oC, 3h; 96%
6a
Scheme 4.
(10) via a Suzuki reaction (Scheme 4). 2-Formylphenylboronic acid
(10) is commercially available and over 50-fold less expensive than
2-vinylphenylboronic acid (8) which was used in the RCM ap-
proach described in Scheme 1. Interestingly, aldehyde 11 exists
primarily in the closed, hemi-aminal form also depicted in
Scheme 4. Gratifyingly, heating a mixture of 11, methyl 2-(dimeth-
oxyphosphoryl)acrylate (12), and Cs2CO3 in DMF at 60 °C under an
atmosphere of N2 for 3 h smoothly effected a tandem Michael addi-
tion-HWE ring closure to afford 6a in 96% yield after a simple filtra-
tion (Table 1, entry 1). The phosphoryl moiety of 12 was found to
Table 1
Substrate, products, and yields for the tandem Michael addition-HWE ring closure protocol to afford 6-carboalkoxy-13-cycloalkyl-5H-indolo[2,1-a][2]benzazepine-10-carboxylic
acid derivatives
Entry # Substrate
MA-HWE product
Yield
CHO
CO2Me
H
N
MeO2C
MeO2C
N
1
2
3
4
11a
11b
11c
11d
6a
96%
O
CO2Me
O
CHO
O
S
H
N
O
O
O
N
N
N
H
S
N
N
H
O
6b
6c
6d
81%
O
O
CO2Me
O
O
CHO
H
S
N
O
N
O
S
N
N
OCH3
H
N
N
O
72% over 2 steps
H
OCH3
CHO
CO2Me
H
N
MeO2C
OCH3
MeO2C
N
97% on a 2.9 g scale — gave 3.3 g
OCH3

P. Hewawasam et al. / Tetrahedron Letters 55 (2014) 1148–1153
1151
Table 1 (continued)
Entry # Substrate
MA-HWE product
Yield
O
O
CO2Me
CHO
CHO
H
N
O
O
OCH3
N
O
5
6
7
8
11e
6e
90% on a 70 g scale
OCH3
CO2Me
H
N
O
O
OBn
N
O
11f
6f
95% on a 32.5 g scale — gave 35 g product
OBn
CHO OCH3
CO2Me
H
N
MeO2C
OCH3
MeO2C
N
N
11g
6g
89%
CO2Me
O
H
N
MeO2C
MeO2C
11h
6h
80%
O
O
O
H
N
O
O
OCH3
N
O
9
11i
6i
54%
OCH3
O
CO2Me
H
MeO2C
N
MeO2C
N
10
11j
6j
0%
be essential for a successful outcome since the reaction of indole
11 with methyl acrylate provided a Michael adduct that could be
induced to undergo a Knoenvenagel reaction to afford 6a in yields
that never exceeded 27% with considerable recovery of the uncyc-
lized ester.12,13
Several additional examples of this ring closing procedure are
compiled in Table 1. The protocol is compatible with the presence
of the acidic functionality present in 11b and 11c (Table 1, entries 2
and 3) and is effective with the electron rich aldehydes 11c–g
(Table 1, entries 3–7) including the sterically encumbered alde-
hyde 11g depicted in entry 7. Ring closure onto a ketone carbonyl,
exemplified by the acetophenones 11h and 11i (Table 1, entries 8
and 9), also occurred in modest to good yield. However, the
indanone substrate 11j (Table 1, entry 10) failed to provide isolable
product, attributed to an inability of the intermediate phospho-
nate-stabilized anion to approach the ketone on a suitable trajec-
tory for reaction.14
In order to further elaborate 6a, selective hydrolysis of the C-10
ester moiety to give 13 was accomplished in 97% yield by treat-
ment with LiOH in DMF at 50 °C for 4 hours (Scheme 5). Cycloprop-
anation of the olefin of 6d was accomplished by exposure to
trimethylsulfoxonium iodide in DMSO in the presence of NaH as
the base to afford racemic 14 in 79% after chromatography.15 The
1H NMR spectral data are consistent with 14 existing as a mixture
of rapidly converting atropisomers. Selective hydrolysis of the C-10
ester of 14 using nBu4NOH in THF gave the acid 15 in 97% yield

1152
P. Hewawasam et al. / Tetrahedron Letters 55 (2014) 1148–1153
CO2R2
CO2R2
(a) LiOH/DMF
R1O2C
R1O2C
50 oC, 4 h; 97%
or
N
N
R
R
(b) TFA, DCM
rt, 2 h; 94%
13: R = R2 = H; R1 = CH3 (method a)
6a: R = H; R1 = R2 = CH3
16: R = OCH3; R1 = H; R2 = CH3 (method b)
6e: R = OCH3; R1 = tBu; R2 = CH3
6d: R = OCH3; R1 = R2 = CH3
MeO2C
HO2C
MeO2C
(CH3)3S=O+ I-
MeO2C
N
N
nBu4NOH/THF
OCH3
OCH3
6d
NaH, DMSO; 79%
RT, 3 days
40 oC, 3 h; 97%
( )-14
( )-15
Scheme 5.
after an extractive work up. The C-6 t-butyl ester moiety of 6e
could be removed selectively under acidic conditions to give 16.
These protocols for selective functionalization of 6 facilitated an
exploration of structure-activity relationship studies for this class
of HCV NS5B inhibitors.6
This process proved to be sufficiently robust and reliable that it
was employed broadly to produce fused indole core structures in a
program that ultimately led to the identification of BMS-791325
(17), a potent HCV NS5B inhibitor that is currently in clinical trials
as part of combination therapy for the treatment of HCV infec-
tion.16–18 In addition, this Michael addition-HWE protocol has been
adopted to access a series of structurally-related macrocyclic HCV
NS5B inhibitors that gave rise to TMC-647055 (18), a compound
undergoing clinical evaluation.19–21
amenable to multigram preparative scale (we have conducted
this process on scales ranging up to 1 kg) and, in principle, a
variety of functional groups could be incorporated at C-10 using
this methodological approach. The C-10 methyl ester of the 6a
can be hydrolyzed selectively in the presence of the C-6 methyl
ester.
Supplementary data
Supplementary data (experimental protocols for the prepara-
tion of compounds) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.12.
085.
O
H3C
N
CH3
N
H3C
O
N
N
O
N
S
O
O
O
S
O
O
NH
H3C
N
N
N
H
O
OMe
OMe
H3C
17 (BMS-791325)
18 (TMC-647055)
Conclusions
References and notes
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We have described the development of a practical, effective,
and economical approach to the 5H-indolo[2,1-a][2]benzazepine
ring system that does not depend on expensive catalysts or re-
agents. The process is operationally straightforward and the
product of the key Michael addition-Horner–Wadsworth–Em-
mons ring forming process is readily isolated in high purity in
the case of the prototypical compound 6a. The method is

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