The synthesis of novel heteroaryl-fused 7,8,9,10-tetrahydro-6H-azepino[1,2- a]indoles, 4-oxo-2,3-dihydro-1H-[1,4]diazepino[1,7-a]indoles and 1,2,4,5-tetrahydro-[1,4]oxazepino[4,5-a]indoles. Effective inhibitors of HCV NS5B polymerase

Article abstract of DOI:10.1039/c1ob05525a

Three synthetic approaches have been developed that allow efficient access to novel heteroaryl fused indole ring systems, including: 7,8,9,10-tetrahydro- 6H-azepino[1,2-a]indoles, 4-oxo-2,3-dihydro-1H-[1,4]diazepino[1,7-a]indoles and 1,2,4,5-tetrahydro-[1,4]oxazepino[4,5-a]indoles. Each strategy is fully exemplified and the relative merits and limitations of the approaches are discussed. The hepatitis C virus (HCV) non-structural 5B (NS5B) polymerase inhibitory activities of select examples from each molecular class are briefly presented.

Full text of DOI:10.1039/c1ob05525a

View Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 6654
www.rsc.org/obc
PAPER
The synthesis of novel heteroaryl-fused 7,8,9,10-tetrahydro-6H-azepino[1,2-
a]indoles, 4-oxo-2,3-dihydro-1H-[1,4]diazepino[1,7-a]indoles and 1,2,4,5-
tetrahydro-[1,4]oxazepino[4,5-a]indoles. Effective inhibitors of HCV NS5B
polymerase†
Min Ding,*a Feng He,a Michael A. Poss,c Karen L. Rigat,b Ying-Kai Wang,b Susan B. Roberts,b Dike Qiu,b
Robert A. Fridell,b Min Gaob and Robert G. Gentlesa
Received 4th April 2011, Accepted 16th June 2011
DOI: 10.1039/c1ob05525a
Three synthetic approaches have been developed that allow efficient access to novel heteroaryl fused
indole ring systems, including: 7,8,9,10-tetrahydro-6H-azepino[1,2-a]indoles, 4-oxo-2,3-dihydro-1H-
[1,4]diazepino[1,7-a]indoles and 1,2,4,5-tetrahydro-[1,4]oxazepino[4,5-a]indoles. Each strategy is fully
exemplified and the relative merits and limitations of the approaches are discussed. The hepatitis C
virus (HCV) non-structural 5B (NS5B) polymerase inhibitory activities of select examples from each
molecular class are briefly presented.
others6,7 evaluated more conformationally constrained tetracyclic
indole derivatives as exemplified by compound 2, and subsequently
demonstrated that these systems generally displayed improved
Introduction
Recent literature reports1–3 have disclosed a number of tricyclic
indole analogs, see Fig. 1, that display potent activity against the
potency against NS5B.
non-structural 5B (NS5B) RNA dependant RNA polymerase of
the hepatitis C virus (HCV).4 This enzyme is a key component
In our laboratories we became interested in exploring a number
of related indole ring systems in which the fused aryl moieties in 2
of the viral replicase complex, and its function is essential for
(and related structures) are replaced with a variety of heterocycles
proliferation of the pathogen. Later work by our group5 and
in an attempt to significantly extend the known structure activity
relationships (SARs) in this area.
Correspondingly, we discuss here a number of routes that
can be employed for the syntheses of five- and six-membered
heterocycles fused to the indolo systems shown in Fig. 2.
These include: 7,8,9,10-tetrahydro-6H-azepino[1,2-a]indoles
3, 4-oxo-2,3-dihydro-1H-[1,4]diazepino[1,7-a]indoles 4, and
Fig. 1 Indole and indolo-fused NS5B inhibitors.
aDiscovery Chemistry, Research and Development, Bristol-Myers Squibb
Co., 5 Research Parkway, Wallingford, CT 06492, USA. E-mail: min.ding@
bms.com
bDepartment of Virology, Research and Development, Bristol-Myers Squibb
Co., 5 Research Parkway, Wallingford, CT 06492, USA
cDiscovery Chemistry, Research and Development, Bristol-Myers Squibb
Co., Route 206 and Province Line Road, Lawrenceville, NJ 08540, USA
† Electronic supplementary information (ESI) available: 1H NMR and
13C NMR spectra for compounds 7, 9–16, 18 and 20–27. See DOI:
10.1039/c1ob05525a
Fig. 2 Novel heteroaryl fused tetracyclic indoles.
This journal is The Royal Society of Chemistry 2011
6654 | Org. Biomol. Chem., 2011, 9, 6654–6662
©

View Online
1,2,4,5-tetrahydro-[1,4]oxazepino[4,5-a]indoles 5. We comment
on the relative advantages and limitations of each of the strategies
evaluated, and briefly present the NS5B inhibitory activities of
select examples from each of these classes of heterocycles.
In reviewing approaches to these systems we primarily consid-
ered the routes depicted by the disconnections shown in Scheme 1.
Each retrosynthetic analysis is to some extent complementary.
Route 1 is most appropriate for the synthesis of a number of fused
1,3-azoles. These can be assembled in the penultimate step from
suitably functionalized bromo-ketones using standard alkylation-
condensation chemistries. In Route 2, the fused-heterocycle and
bridging moiety are introduced in a more convergent manner,
with the key step involving an intramolecular coupling reaction.
Lastly, in Route 3, what will ultimately be the fused heterocycle
is introduced at an early stage, and the bridging moiety is
constructed towards the end of the synthesis using a variety
of chemistries dictated by the functionality required in the
bridge.
Starting from the suitably functionalized indole 6,3 treatment
with methyl 5-bromovalerate afforded the N-alkylated methyl
ester, hydrolysis of which resulted in the formation of the related
di-acid 8. This on treatment with a mixture of TFAA and TFA8
efficiently underwent an intramolecular Friedel–Crafts reaction
to give the tricyclic azepinone intermediate 9. Bromination with
copper(II) bromide9 gave the key a-bromoketo compound 10. The
desired fused heterocyclic products 11 and 12 could then be gener-
ated by reacting 10 with either formamide or thioacetamide. A key
advantage of this methodology is that a diversity of functionalized
heterocyclic systems can be accessed from a common intermediate,
and this methodology can be applied efficiently to array synthesis
due to the heterocycle being constructed toward the conclusion of
the syntheses.
Route 2
A potentially more convergent approach to these polycyclic indole
systems employs the methodology depicted in Scheme 3 that
describes the synthesis of the pyrido[2¢,3¢:6,7][1,4]oxazepino[4,5-
a]indole derivative 16. The key step in this reaction sequence
involves an intramolecular coupling reaction, a step that we envi-
sioned could be best accomplished using Heck-type conditions.10
Starting from methyl 3-cyclohexylindole-6-carboxylate 6,3 alky-
lation with benzyl 2-bromoethyl ether using sodium hydride
as base gave an N-alkylated intermediate 13 which on hydro-
genation provided the indoylethanol 14. Mitsunobu reaction of
this intermediate with 2-bromo-3-pyridinol afforded the pyridyl
ether 15. The subsequent intramolecular Heck reaction followed
Results and discussion
Route 1
As outlined above, the most obvious route to access a diversity
of five-membered heterocycles fused to the indolo-systems of the
current discussion involves the syntheses of intermediate bromo-
ketones of the type shown in Route 1 of Scheme 1. This strategy
is exemplified in Scheme 2 by the syntheses of the oxazole and
thiazole derivatives 11 and 12.
Scheme 1 Considered disconnections in the retrosynthetic analysis of targeted heterocycles.
The Royal Society of Chemistry 2011 Org. Biomol. Chem., 2011, 9, 6654–6662 | 6655
This journal is
©

View Online
and the Mitsunobu reaction product subjected to the same Heck
conditions no cyclization product was formed, and attempts to
use more forcing conditions only resulted in dehalogenation of the
starting material. Therefore, although it may be envisioned that
this approach offers the possibility of the introduction of a variety
of fused heterocycles and bridging elements, the compatibility of
the relevant intermediates with the Heck coupling conditions is key
to the successful deployment of this methodology. The efficiency
of the key annulation can be expected to be strongly influenced by
the product ring size, the tether flexibility in analogs of type 15,
and the exact electronic character of the halogenated heterocycle.
Route 3
Within the scope of the work presented here, the most general
approach for accessing the tetracyclic indoles discussed above
employs the strategy depicted in Route 3 of Scheme 1. This ap-
proach is characterized by the early introduction of the heterocycle
that will ultimately be fused to the polycyclic indole ring system.
In order to maximize the generality of this methodology, we
desired to use the 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
1H-indole 18 as a partner in a key Suzuki type coupling step. We
anticipated that this reagent would be suitably reactive with a wide
array of halo-substituted heteroaryls and would obviate the need
to employ potentially difficult to access heteroaryl boronic acids
or related stannyl compounds. In addition, reagent 18 exploits the
intrinsic electron rich nature of the indole ring system that should
facilitate its coupling to a range of electron deficient heterocycles.
Given the importance of this intermediate, efforts were directed at
optimizing its synthesis, as shown in Scheme 4 and Table 1.
Scheme 2 Reagents and conditions: (a) methyl 5-bromovalerate, NaH,
DMF, 57%; (b) NaOH, THF–MeOH–H2O; (c) TFAA–TFA, 85% (two
steps b and c); (d) CuBr2, EtOAc–CHCl3, 64%; (e) formamide, DMF,
150 ◦C, 21%; (f) thioacetamide, ethanol, reflux, 56%.
Scheme 4 Synthesis of 18. Reagents and conditions: (a) PdCl2(dppf),
NaOAc, CH3CN, 150 ◦C; (b) Pd(dba)2, PCy3, KOAc, dioxane, 80 ◦C; (c)
[(Ir(OMe)(cod)]2, 4,4¢-di-tert-butyl-2,2¢-bipyridine (dtbpy), THF, 30 ◦C,
41%. cod = 1,5-cyclooctadiene.
To access 18, we examined a palladium catalyzed reaction be-
tween the bromo indole 173 and bis(pinacolato)diboron (pin2B2).
In our hands under a variety of conditions, we could only obtain 18
as a mixture with the dehalogenated by-product 6 and unreacted
starting material 17, as reported in Table 1. These mixtures proved
difficult to fractionate and required that a mixture be used in the
subsequent coupling reaction, where the desired products were
typically easier to isolate.
In an attempt to address this issue we looked for alter-
native boronylation conditions that might obviate the use of
the 2-bromo indole 17, and therefore facilitate the isolation of
the boronate ester 18. In this regard, the recently reported12
Scheme 3 Reagents and conditions: (a) NaH, benzyl 2-bromoethyl
ether, DMF, 76%; (b) H2, Pd/C, 98%; (c) 2-bromo-3-pyridinol, PPh3,
DBAD, THF, 58%; (d) Pd(PPh3)4, KOAc, DMA, 160 ◦C; (e) NaOH,
THF–MeOH–H2O, 42%(two steps d and e).
by base-catalyzed hydrolysis using sodium hydroxide gave the
targeted pyrido[2¢,3¢:6,7][1,4]oxazepino[4,5-a]indole 16 in good
overall yield. However, in our hands, the intramolecular Heck
reaction11 was sensitive to the position of the halogen on the
pyridyl moiety: When 3-bromo-2-pyridinol was reacted with 14
6656 | Org. Biomol. Chem., 2011, 9, 6654–6662
This journal is
The Royal Society of Chemistry 2011
©

View Online
Table 1 Product ratios for boronylation of indole 6
Relative ratios of products
Coupling conditions
17
6
18
HPLC per cent yield of 18
PdCl2(dppf), NaOAc, CH3CN, 150 ◦
Pd(dba)2, PCy3, KOAc, dioxane, 80 ◦
C
C
1.8
0.28
3.4
1
1
2.1
16
62
iridium-catalyzed direct boronylation of aromatic C–H moi-
eties was of particular interest. Iridium complexes of the type,
iridium(I)-2,2¢-bipyridine prepared from [{Ir(OMe)(cod)}2] and
4,4¢-di-tert-butyl-2,2¢-bipyridine (dtbpy), have been shown to be
highly active catalysts for the boronylation of a range of aromatic
substrates using stoichiometric amounts of pin2B2 at room temper-
ature in non-polar, inert solvents (typically hexanes or octanes).12
In our studies, attempts to convert 6 to 18 proved unsuccessful due
to the limited solubility of 6 in non-polar solvents. However, the use
of 1,3,5-trimethylbenzene, in which 6 is significantly more soluble
resulted in approximately 40% conversion of 6 to 18, as estimated
by LCMS analysis. Even more encouraging was the observation
that in THF at 30 ◦C for three hours and using one equivalent
of pin2B2, the conversion improved to 70–80%. Importantly, the
crude reaction mixture could simply be concentrated, whereupon
18 could be isolated as a crystalline material by trituration with
a mixture of 1 : 4 ethyl acetate–hexanes. (The filtrand from these
processes could be recycled to obtain further quantities of 18.)
This methodology was then applied to the synthesis of multi-gram
quantities of 18.
With an efficient route to the boronate in hand, we sought to
evaluate the strategy depicted in Route 3 of Scheme 1 to access
a range of tetracyclic indole systems using a variety of D-ring
heterocycles in combination with a range of bridging functionality.
This is exemplified in the synthesis of the fused pyridyl systems
shown in Schemes 5 and 6, in which both hydrocarbon and lactam
bridges are constructed in the syntheses of the two heterocyclic
ring systems: 7H-pyrido[3¢,2¢:3,4]azepino[1,2-a]indole and 5H-
pyrido[3¢,2¢:5,6][1,4]diazepino[1,7-a]indol-6(7H)-one.
The synthesis of the indoloazepine 23 proceeded as shown in
Scheme 5. A Stille coupling13 of 2, 3-dibromopyridine 19 with
tributylvinyltin was found to give exclusively the 3-bromo-2-
vinylpyridine 20. Suzuki coupling of 20 with 18 provided the (2-
vinylpyridin-3-yl)-1H-indole 21 in good yield. Subsequent alkyla-
tion with allyl bromide gave the N-alkylated derivative, which was
then subjected to a ring-closing metathesis reaction using Grubbs’
second generation catalyst14 to provide the unsaturated tetracyclic
indole derivative 22. Sequential hydrogenation and hydrolysis
then afforded the targeted indole, 13-cyclohexyl-6,7-dihydro-5H-
pyrido[3¢,2¢:3,4]azepino[1,2-a] indole-10-carboxylic acid 23. A
further example of this methodology involving the synthesis
of a more highly functionalized bridging element is shown in
Scheme 6.
Scheme 5 Reagents and conditions: (a) tributylvinyltin, PdCl2(PPh3)2,
LiCl, DMF, 100 ◦C, 53%; (b) Pd(PPh3)4, LiCl, Na2CO3, EtOH–toluene,
80 ◦C, 65%;(c) NaH, allyl bromide, DMF; (d) Grubbs catalyst 2nd
generation, CH2Cl2, reflux, 58% (two steps c and d); (e) H2/Pd–C; (f)
NaOH, THF–MeOH–H2O, 99% (two steps e and f).
In this synthesis, 2,3-dibromopyridine 19 was coupled with
18 to provide exclusively, methyl 2-(3-bromopyridin-2-yl)-3-
cyclohexyl-1H-indole-6-carboxylate 24 in good yield. Alkylation
with 2-bromoacetamide gave the N-alkylated intermediate 25.
This compound was subjected to a palladium catalyzed in-
tramolecular N-arylation reaction15 that efficiently provided the
lactam 26. Hydrolysis of this intermediate gave the targeted
acid, 13-cyclohexyl-6-oxo-6,7-dihydro-5H-pyrido[3¢,2¢:5,6][1,4]-
Scheme 6 Reagents and conditions: (a) Pd(PPh3)4, LiCl, Na2CO3,
EtOH–toluene, 80 ◦C, 70%; (b) KH, DMF, bromoacetamide, 76%; (c)
Pd2(dba)3, Xantphos, Cs2CO3, 1,4-dioxane, 100 ◦C, 57%; (d) LiI, pyridine,
180 ◦C, 98%.
diazepino[1,7-a]indole-10-carboxylic acid 27. This reaction re-
quired the use of LiI in pyridine16 in order to obviate the hydrolysis
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6654–6662 | 6657
©

View Online
Table 2 Enzymatic and replicon inhibition data
Compound
HCV NS5B Genotype 1b IC50 (mM)
Replicon Genotype 1b EC50 (mM)
Replicon Mutant P495L EC50 (mM)
11
12
16
23
27
1
>12.5
>10
>10
0.98
0.52 0.15
1.8
>10
>10
>10
>10
>10
8.3 3.2
0.39 0.23
0.45 0.04
0.28 0.04
0.43
Note: The reported IC50 and EC50values (mM) equal the concentration of each compound that inhibits HCV NS5B enzyme activity (genotype 1b derived
from Con 1) by 50%. The IC50 values were determined in assays described previously using poly A and/or poly C templates.17 Reported values are the
mean from at least 2 independent test occasions. The EC50 values were determined in the Luciferase assay.18
of the lactam moiety which proved to be sensitive to a range of
base-catalyzed hydrolysis conditions.
Experimental section
General
As can be seen from the preceding two schemes, the strategy
outlined in Route 3 of Scheme 1 is highly flexible, both in
regard to the range of heterocycles that can be incorporated,
as well as the type of functionality that can be introduced into
the bridging element that constitutes Ring C. An important
aspect in the successful execution of this chemistry was de-
veloping an efficient preparation of the boronate intermediate,
methyl 3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-1H-indole-6-carboxylate 18, and our use of an iridium cat-
alyzed procedure was key to the successful synthesis and isolation
of this compound.
Solvents and reagents unless otherwise noted, were obtained from
commercial suppliers and were used without further purification.
Melting point was recorded on an EZ-Melt Automated Melt-
ing Point Apparatus and was not calibrated. Infrared spectra
data were recorded on a Perkin Elmer Spectrum One FT-IR
Spectrometer as solid neat sample or film in CHCl3. NMR
spectra were recorded on Bruker spectrometers (300, 400 or
1
500 MHz for H NMR and 100 or 125 MHz for 13C NMR).
Chemical shifts for observed signals are reported in parts per
million downfield from tetramethylsilane and are measured using
the residual resonance from the deuterated solvent as reference.
Compound 6 was synthesized according to the procedure reported
in reference 3 [{Ir(OMe)(cod)}2] was prepared by a published
protocol.19 Reverse Phase Preparative HPLC was performed on
a Shimadzu instrument with a Sunfire column C18 19 mm
X 150 mm using acetonitrile–water–0.1% TFA as the mobile
solvent system. Low resolution mass spectra were measured on
a Shimadzu LC-MS with Waters Micromass ZQ in positive ESI
mode. High resolution mass spectrometry (HRMS) analyses were
performed on a hybrid linear ion trap LTQ XL Fourier transform
Orbitrap mass spectrometer (Thermo Fisher Scientific) in positive
ionization electrospray mode operating at 30,000 resolution (full
width at half height maximum, FWHM).
Determination of NS5B Inhibitory Activities
All of the final targets of the above syntheses were assayed for their
inhibitory activities against the HCV NS5B genotype 1b enzyme.17
In addition, the compounds activities were also assessed in a cell-
based HCV genotype 1b replicon system18 as well as a mutant
replicon containing a P495L mutation in the NS5B gene.18 The
results from these experiments are shown in Table 2.
It is apparent that the 5-membered heterocycles examined
here are significantly less active than the fused pyridino analogs
explored, all of which displayed similar levels of enzyme activity
to the acyclic analog 1, discussed in the introduction. In addition,
these activities are mostly reproduced in the replicon assay,
suggesting that the incorporation of the heterocycle does not
prevent or significantly impair cellular penetration. In addition,
the reduced activities observed in the mutant replicon system
suggest that all of the analogs examined bind in the “thumb”
domain of the NS5B polymerase, proximal to the P495L mutation,
as has been described with related analogs.1–3,5
Methyl 3-cyclohexyl-1-(5-methoxy-5-oxopentyl)-1H-indole-6-
carboxylate 7
To a suspension of NaH (85.5 mg of 60% dispersion in mineral oil,
2.14 mmol) in DMF (5 mL), 6 (500 mg, 1.94 mmol) was added and
the reaction mixture was stirred at room temperature for 15 min.
Methyl 5-bromovalerate (0.305 mL, 2.14 mmol) was then added.
The reaction mixture was stirred at room temperature overnight.
It was then quenched with ice, extracted with ethyl acetate (2 ¥ 50
mL) and the organic layers were combined. It was then washed
with 1 N HCl solution, dried (MgSO4) and concentrated. The
residue was purified by flash column chromatography (silica gel,
hexanes to 25% ethyl acetate in hexanes) to give a colorless thick
oil as the desired product. (0.41 g, 57% yield) IR (film, nmax/cm-1):
2924, 2851, 1736, 1709, 1615, 1472, 1434, 1274, 1239, 1200, 1089.
1H NMR (300 MHz, CDCl3) d 1.17–1.95 (m, 12 H), 1.99–2.18 (m,
2 H), 2.34 (t, J = 7.32 Hz, 2 H), 2.73–2.92 (m, 1 H), 3.67 (s, 3 H),
3.94 (s, 3 H), 4.15 (t, J = 6.95 Hz, 2 H), 7.01 (s, 1 H), 7.64 (d, J =
8.42 Hz, 1 H), 7.76 (dd, J = 8.42, 1.10 Hz, 1 H), 8.05 (s, 1 H).
Conclusion
We have presented three general routes for the syntheses of
series of novel tetracyclic indole ring systems. The advantages
and limitations of each of the strategies have been outlined,
and taken collectively these procedures provide a comprehensive
set of methodologies that can be used to access a number
of functionalized derivatives of these heterocyclic ring systems.
Additionally, we have briefly presented the activity of compounds
of this type against the NS5B polymerase of the hepatitis C virus,
and the further characterization and optimization of this property
will be the subject of future manuscripts.
6658 | Org. Biomol. Chem., 2011, 9, 6654–6662
This journal is
The Royal Society of Chemistry 2011
©

View Online
13C NMR (125 MHz, CDCl3) d 22.35, 26.41, 26.84, 29.79, 33.47,
34.14, 35.26, 46.00, 51.57, 51.88, 111.63, 118.99, 119.42, 122.34,
122.82, 126.66, 130.72, 135.59, 168.31, 173.56. LRMS m/z 372.3
(M + H). HRMS calcd for C22H30O4N (M + H): 372.2169, found:
372.2156.
dried (MgSO4) and concentrated. The residue was then purified by
Reverse Phase Preparative HPLC column to afford an orange solid
as the desired product. (15 mg, 21% yield) IR (film, nmax/cm-1):
3325 (br), 2943, 2834, 1650, 1449, 1434, 1413, 1110, 1019. 1H NMR
(500 MHz, DMSO-d6) d 1.27–1.46 (m, 3 H), 1.67–1.87 (m, 5 H),
1.91–2.05 (m, 2 H), 2.10–2.18 (m, 2 H), 3.12 (t, J = 6.71 Hz, 2 H),
3.88–4.04 (m, 1 H), 4.29–4.40 (m, 2 H), 7.57 (dd, J = 8.54, 1.53 Hz,
1 H), 7.83 (d, J = 8.54 Hz, 1 H), 8.10 (s, 1 H), 8.47 (s, 1 H), 12.57 (s,
br, 1 H). 13C NMR (125 MHz, DMSO-d6) d 24.27, 25.71, 25.77,
26.89, 32.28, 34.95, 43.20, 111.42, 119.18, 119.48, 120.20, 123.04,
127.72, 129.01, 129.50, 135.67, 148.84, 151.04, 168.28. LRMS m/z
351.3 (M + H). HRMS calcd for C21H23O3N2 (M + H): 351.1703,
found: 351.1696.
1-(4-Carboxybutyl)-3-cyclohexyl-1H-indole-6-carboxylic acid 8
To a solution of 7 (410 mg, 1.1 mmol) in THF–methanol mixture
(5.0 mL/5.0 mL), 2 N NaOH solution (5.0 mL) was added. The
reaction mixture was heated at 100 ◦C under microwave conditions
for 15 min. It was then concentrated and acidified with 1 N HCl
solution. The diacid product precipitated and was collected by fil-
tration. This crude material was used as is, in the preparation of 9.
12-Cyclohexyl-5,6-dihydro-2-methyl-4H-thiazolo[4¢,5¢:3,4]-
azepino[1,2-a]indole-9-carboxylic acid 12
11-Cyclohexyl-10-oxo-7,8,9,10-tetrahydro-6H-azepino[1,2-
a]indole-3-carboxylic acid 9
A mixture of TFA (1.0 mL) and TFAA (469 mg, 2.232 mmol)
was added dropwise to the above acid 8 at 0 ◦C. The reaction
mixture was then warmed to room temperature and stirred for 4 h.
Water was added slowly to quench the reaction and a light yellow
solid was collected as the desired product. (305 mg, 85% yield) IR
(neat, nmax/cm-1): 2922, 1670, 1610, 1557, 1421, 1332, 1302, 1263,
1240, 1210. 1H NMR (500 MHz, CD3OD) d 1.32–1.55 (m, 3 H),
1.71–1.83 (3 H, m, 3 H), 1.82–2.05 (m, 6 H), 2.05–2.17 (m, 2 H),
2.78–2.92 (m, 2 H), 3.38–3.49 (m, 1 H), 4.32–4.60 (m, 2 H), 7.71
(dd, J = 8.70, 1.37 Hz, 1 H), 7.96 (d, J = 8.55 Hz, 1 H), 8.18 (s,
1 H). 13C NMR (125 MHz, CDCl3) d 21.28, 26.28, 26.95, 27.02,
33.01, 35.78, 41.94, 43.48, 113.22, 120.21, 122.96, 124.91, 128.38,
129.64, 136.82, 137.34, 172.17, 197.67. LRMS m/z 326.2 (M + H).
HRMS calcd for C20H24O3N (M + H): 326.1751, found: 326.1750.
To a solution of 10 (20 mg, 0.049 mmol) in ethanol (5.0 mL),
thioacetamide (5.6 mg, 0.074 mmol) was added. The reaction
mixture was heated under reflux overnight. The ethanol was
evaporated and the residue was then purified by Reverse Phase
Preparative HPLC column to afford a light yellow solid as product.
(10.5 mg, 56% yield) IR (film, nmax/cm-1): 3393 (br), 2927, 2850,
1676, 1610, 1449, 1434, 1206, 1012. 1H NMR (500 MHz, DMSO-
d6) d 1.23–1.50 (m, 3 H), 1.65–1.88 (m, 5 H), 1.88–2.04 (m, 2 H),
2.18–2.32 (m, 2 H), 2.69 (s, 3 H), 2.98 (t, J = 7.17 Hz, 2 H), 3.41–
3.58 (m, 1 H), 4.13–4.30 (m, 2 H), 7.60 (dd, J = 8.55, 1.22 Hz, 1
H), 7.83 (d, J = 8.54 Hz, 1 H), 8.12 (s, 1 H), 12.54 (s, 1 H). 13C
NMR (125 MHz, DMSO-d6) d 19.01, 22.92, 25.74, 26.85, 28.98,
32.38, 35.64, 42.03, 111.55, 119.29, 119.49, 120.15, 123.07, 129.39,
133.60, 133.73, 135.66, 143.24, 162.01, 168.27. LRMS m/z 381.3
(M + H). HRMS calcd for C22H25O2N2S(M + H): 381.1631, found:
381.1624.
9-Bromo-11-cyclohexyl-10-oxo-7,8,9,10-tetrahydro-6H-
azepino[1,2-a]indole-3-carboxylic acid 10
Methyl 1-(2-(benzyloxy)ethyl)-3-cyclohexyl-1H-indole-6-
carboxylate 13
To a refluxing suspension of CuBr2 (80 mg, 0.36 mmol) in ethyl
acetate (3.0 mL), a solution of 9 (78 mg, 0.24 mmol) in chloroform
(3.0 mL) was added. The reaction mixture was heated under reflux
for 4 h. It was then cooled down and filtered to remove the solids.
The filtrate was then concentrated and the residue was purified
by Reverse Phase Preparative HPLC to give a light yellow solid as
the desired product. (62 mg, 64% yield) IR (neat, nmax/cm-1): 2934,
2854, 1673, 1344, 1253, 1056, 1033. 1H NMR (500 MHz, CD3OD)
d 1.32–1.54 (m, 3 H), 1.66–2.07 (m, 7 H), 2.14–2.27 (m, 1 H),
2.27–2.52 (m, 3 H), 3.04–3.22 (m, 1 H), 4.08 (ddd, J = 14.65, 9.31,
2.59 Hz, 1 H), 4.59–4.71 (m, 1 H), 5.01 (dd, J = 5.95, 2.90 Hz, 1 H),
7.73 (dd, J = 8.54, 1.53 Hz, 1 H), 7.94 (d, J = 8.54 Hz, 1 H), 8.18
(s, 1 H). 13C NMR (125 MHz, CDCl3) d 24.87, 26.22, 26.91, 26.94,
31.67, 32.65, 33.02, 36.13, 44.98, 55.40, 113.37, 120.48, 122.80,
125.33, 129.64, 131.09, 135.27, 137.31, 171.34, 191.11. LRMS m/z
404.2 (M + H), 406.2 (M + 2 + H). HRMS calcd for C20H23O3NBr
(M + H): 404.0856, found: 404.0851.
To a suspension of NaH (192 mg of 60% dispersion in mineral oil,
4.8 mmol) in DMF (8 mL), 6 (1.029 g, 4.0 mmol) was added, and
the reaction mixture was stirred at room temperature for 15 min.
Benzyl 2-bromoethyl ether (0.7 mL, 4.4 mmol) was then added.
The reaction mixture was stirred at room temperature for 2 h. It
was then quenched with water, extracted with ethyl acetate (2 ¥ 50
mL) and the organic layers were combined. It was then washed
with 1 N HCl solution, dried (MgSO4) and concentrated. The
residue was purified by flash column chromatography (silica gel,
3 : 1 hexanes : ethyl acetate) to give a colorless thick oil as the
desired product. (1.19 g, 76% yield) IR (film, nmax/cm-1): 2924,
1
2851, 1709, 1615, 1470, 1277, 1240, 1090. H NMR (500 MHz,
CDCl3) d 1.26–1.38 (m, 1 H), 1.42–1.56 (m, 4 H), 1.77–1.93 (m, 3
H), 2.06–2.16 (m, 2 H), 2.81–2.90 (m, 1 H), 3.81 (t, J = 5.49 Hz,
2 H), 3.95 (s, 3 H), 4.35 (t, J = 5.49 Hz, 2 H), 4.47 (s, 2 H),
7.14 (s, 1 H), 7.19–7.24 (m, 2 H), 7.25–7.32 (m, 3 H), 7.68 (d,
J = 8.55 Hz, 1 H), 7.80 (d, J = 8.55 Hz, 1 H), 8.10 (s, 1 H).
13C NMR (125 MHz, CDCl3) d 26.42, 26.84, 34.11, 35.22, 46.27,
51.83, 69.08, 73.15, 111.68, 118.91, 119.50, 122.27, 122.76, 127.42,
127.60, 127.69, 128.30, 130.83, 135.71, 137.77, 168.30. LRMS m/z
392.3 (M + H). HRMS calcd for C25H30O3N (M + H): 392.2220,
found: 392.2204.
12-Cyclohexyl-5,6-dihydro-4H-oxazolo[4¢,5¢:3,4]azepino[1,2-
a]indole-9-carboxylic acid 11
To a solution of 10 (80 mg, 0.198 mmol) in DMF (3.0 mL),
formamide (1.5 mL) was added. The reaction mixture was heated
at 150 ◦C for 2 h. The reaction was added to water and extracted
with ethyl acetate (2 ¥ 20 mL). The organic layers were combined,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6654–6662 | 6659
©

View Online
Methyl 3-cyclohexyl-1-(2-hydroxyethyl)-1H-indole-6-carboxylate
14
to 4–5 with 1 N HCl solution. The light yellow solid was collected
as product. (58 mg, 42% yield) IR (neat, nmax/cm-1): 2500–3500
(br), 2933, 2853, 1685, 1611, 1467, 1426, 1245, 1181, 1122, 1107,
1033. 1H NMR (500 MHz, CD3OD) d 1.32–1.47 (m, 3 H), 1.74–
1.81 (m, 1 H), 1.82–1.94 (m, 4 H), 1.96–2.12 (m, 2 H), 3.33–3.40
(m, 1 H), 4.47 (t, J = 5.49 Hz, 2 H), 4.56 (t, J = 5.49 Hz, 2 H), 7.50
(dd, J = 8.24, 4.88 Hz, 1 H), 7.72 (dd, J = 8.09, 1.37 Hz, 1 H), 7.75
(dd, J = 8.55, 1.53 Hz, 1 H), 7.95 (d, J = 8.55 Hz, 1 H), 8.22 (s, 1 H),
8.55 (dd, J = 4.73, 1.37 Hz, 1 H).13C NMR (125 MHz, CD3OD) d
27.57, 28.46, 34.25, 37.43, 42.43, 75.85, 112.76, 121.13, 122.41,
123.85, 125.62, 126.09, 131.68, 133.11, 135.94, 137.02, 145.66,
146.57, 152.98, 171.15. LRMS m/z 363.3 (M + H). HRMS calcd
for C22H23O3N2 (M + H): 363.1703, found: 363.1699.
To a solution of 13 (1.19 g, 3.04 mmol) in ethyl acetate (50 mL),
10% Pd on carbon (0.12 g) was added. Next, about five drops of 1 N
HCl solution were added to the reaction mixture which was stirred
at room temperature under a hydrogen balloon for three days. It
was then filtered through celite and washed with ethyl acetate. The
filtrate was concentrated to give a light yellow solid as the desired
product. (0.9 g, 98% yield) IR (neat, nmax/cm-1): 3386 (br), 2922,
2849, 1698, 1614, 1544, 1439, 1335, 1289, 1274, 1240, 1128, 1087.
1H NMR (500 MHz, CDCl3) d 1.22–1.37 (m, 1 H), 1.38–1.54 (m,
4 H), 1.73–1.93 (m, 4 H), 2.03–2.14 (m, 2 H), 2.78–2.88 (m, 1 H),
3.94 (s, 3 H), 3.97 (t, J = 5.19 Hz, 2H), 4.29 (t, J = 5.19 Hz, 2 H),
7.09 (s, 1 H), 7.66 (d, J = 8.39 Hz, 1 H), 7.77 (dd, J = 8.39, 1.37 Hz,
1 H), 8.08 (s, 1H). 13C NMR (125 MHz, CDCl3) d 26.39, 26.83,
34.07, 35.24, 48.62, 51.92, 62.00, 111.67, 119.10, 119.69, 122.67,
123.02, 127.33, 130.93, 135.80, 168.28. LRMS m/z 302.3 (M + H).
HRMS calcd for C18H24O3N (M + H): 302.1751, found: 302.1748.
Methyl 3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-1H-indole-6-carboxylate 18
In a flame-dried flask equipped with magnetic stirrer was added
[Ir(OMe(cod)]2 (150 mg, 0.225 mmol), 4,4¢-di-tert-butyl-2,2¢-
bipyridine (120 mg, 0.45 mmol), and bis(pinacolato)diboron
(7.62 g, 30 mmol). The flask was flushed with N2 and sealed with
a septum. Anhydrous THF (45 mL) was added and the solution
was stirred at room temperature for 10 min. The solution turned
dark purple. 6 (7.71 g, 30 mmol) was then added in one portion
under nitrogen. The reaction mixture was stirred at 30 ◦C for 3 h.
The solution turned red–brown. The solvents were then removed
under reduced pressure, and the residue was treated with hexane
(10 mL). The crystalline product was collected and washed with
ethyl acetate–hexanes (1 : 3) and air dried to give a white solid as
the desired product. (4.7 g, 41% yield) The mother liquor was also
concentrated. Hexanes were added and the crystalline solid was
collected to give 3.3 g of material as a mixture of 18 and 6, which
was recycled. mp: 195–197 ◦C (decomp.). IR (neat, nmax/cm-1):
3384, 2977, 2922, 2850, 1695, 1439, 1333, 1292, 1247, 1138, 1087.
1H NMR (500 MHz, CDCl3) d 1.37 (s, 12H), 1.39–1.51 (m, 3H),
1.75–1.92 (m, 5 H), 1.92–2.07 (m, 2 H), 3.20–3.40 (m, 1 H), 3.96
(s, 3 H), 7.71 (dd, J = 8.54, 1.53 Hz, 1 H), 7.85 (d, J = 8.55 Hz,
1H), 8.08 (1 H, s), 8.51 (s, br, 1H). 13C NMR (125 MHz, CDCl3)
d 24.86, 26.34, 27.33, 33.70, 36.87, 51.92, 83.99, 113.74, 119.37,
120.96, 124.65, 130.34, 134.77, 137.52, 168.11. HRMS calcd for
C22H31O4N10B (M + H): 383.2377, found: 383.2378.
Methyl 1-(2-(2-bromopyridin-3-yloxy)ethyl)-3-cyclohexyl-1H-
indole-6-carboxylate 15
To a solution of 2-bromo-3-pyridinol (173 mg, 0.995 mmol) in
THF (10 mL), PPh3 (261 mg, 0.995 mmol) and di-tert-butyl
azodicarboxylate (229 mg, 0.995 mmol) were added. The reaction
mixture was stirred at room temperature for 0.5 h. Next, a solution
of 14 (200 mg, 0.66 mmol) in THF (3 mL) was added. The reaction
mixture was stirred at room temperature overnight. The solvent
was then evaporated to give a brownish oil as crude product. The
brownish oil solidified upon standing. It was then triturated with
methanol to give a grayish solid as product. (175 mg, 58% yield)
IR (neat, nmax/cm-1): 2923, 2852, 1699, 1612, 1564, 1470, 1446,
1
1417, 1294, 1276, 1246, 1205, 1128, 1076, 1052, 987. H NMR
(300 MHz, CDCl3) d 1.17–1.56 (m, 5 H), 1.67–1.93 (m, 3 H),
1.98–2.15 (m, 2 H), 2.75–2.90 (m, 1 H), 3.95 (s, 3 H), 4.31 (t, J =
4.94 Hz, 2 H), 4.64 (t, J = 4.94 Hz, 2 H), 6.96 (dd, J = 8.05, 1.46 Hz,
1 H), 7.13 (dd, J = 8.23, 4.57 Hz, 1 H), 7.32 (s, 1 H), 7.65 (d, J =
8.42 Hz, 1 H), 7.78 (dd, J = 8.42, 1.46 Hz, 1 H), 7.98 (dd, J = 4.76,
1.46 Hz, 1 H), 8.12 (s, 1 H). 13C NMR (125 MHz, CDCl3) d 26.40,
26.83, 34.04, 35.20, 45.37, 51.94, 68.01, 111.26, 119.17, 119.27,
119.83, 122.82, 123.07, 123.25, 128.24, 131.12, 132.91, 135.42,
141.74, 151.73, 168.28. LRMS m/z 457.2 (M + H), 459.2 (M
+ 2 + H). HRMS calcd for C23H26O3N2Br (M + H): 457.1121,
found: 457.1102.
3-Bromo-2-vinylpyridine 20
To a solution of 2,3-dibromopyridine (2.0 g, 8.44 mmol) in DMF
(10 mL), tributyl(vinyl)tin (2.94 g, 9.29 mmol), LiCl (1.07 g, 25.32
mmol) and PdCl2(PPh3)2 (0.296 g, 0.422 mmol) were added. The
reaction mixture was heated at 100 ◦C overnight. It was then
added to a saturated solution of KF and stirred for 4 h. Next, it
was extracted with hexanes (3 ¥ 50 mL) and the organic layers
were combined. It was then washed with 1 N HCl solution. The
aqueous layer was separated, neutralized with 1 N NaOH solution,
and extracted with hexanes. The organic layer was separated, dried
(MgSO4) and concentrated to give a yellowish oil as product.
(0.83 g, 53% yield) IR (film, nmax/cm-1): 2946, 2832, 1442, 790,
13-Cyclohexyl-6,7-dihydropyrido[2¢,3¢:6,7][1,4]oxazepino[4,5-
a]indole-10-carboxylic acid 16
To a mixture of 15 (174 mg, 0.38 mmol), KOAc (75 mg, 0.76
mmol) and Pd(PPh3)4 (22 mg, 0.019 mmol) in a sealed tube,
dimethylacetamide (3 mL) was added. The reaction mixture was
heated at 160 ◦C for 5 h. It was then filtered to remove the
Pd precipitate and washed with ethyl acetate. The filtrate was
concentrated and the residue was purified by Reverse Phase
Preparative HPLC to afford a light yellow solid as the cyclized
product. The solid was then dissolved in a THF–methanol mixture
(1.5 mL/1.5 mL), and 2 N NaOH solution (1.0 mL) was added.
The reaction mixture was heated at 100 ◦C under microwave
conditions for 15 min. It was then concentrated and adjusted pH
1
735, 702. H NMR (400 MHz, CD3OD) d 5.57 (dd, J = 10.88,
1.83 Hz, 1 H), 6.38 (dd, J = 17.12, 1.96 Hz, 1 H), 7.19 (dd, J =
8.07, 4.65 Hz, 1H), 7.25 (dd, J = 16.87, 10.76 Hz, 1H), 8.00 (dd,
J = 8.07, 1.47 Hz, 1 H), 8.48 (dd, J = 4.65, 1.47 Hz, 1 H).13C
6660 | Org. Biomol. Chem., 2011, 9, 6654–6662
This journal is
The Royal Society of Chemistry 2011
©

View Online
NMR (100 MHz, CD3OD) d (ppm) 121.77, 122.19, 125.52, 134.77,
142.63, 149.34, 154.32. LRMS m/z 184.0 (M + H), 186.0 (M +
2 + H). HRMS calcd for C7H7NBr (M + H): 183.9756, found:
183.9752.
13-Cyclohexyl-6,7-dihydro-5H-pyrido[3¢,2¢:3,4]azepino[1,2-
a]indole-10-carboxylic acid 23
To a solution of 22 (1.0 g, 2.68 mmol) in ethyl acetate (500 mL),
10% Pd on carbon (100 mg) was added. The reaction mixture
was stirred under a hydrogen balloon at room temperature for
4 h. It was then filtered through celite, washed with ethyl acetate,
and the filtrate was concentrated. The residue was then dissolved
in THF–MeOH (10 mL/10 mL), and 2 N NaOH solution (15
mL) was added. Next, the reaction mixture was heated at 100 ◦C
under microwave conditions for 15 min. The reaction was then
concentrated and the pH was adjusted 4–5 with 1 N HCl solution.
An off-white solid was collected as product. (0.96 g, 99% yield)
IR(neat, nmax/cm-1): 2500–3500 (br), 2925, 2850, 1685, 1612, 1418,
1379, 1253, 1185. 1H NMR (500 MHz, CD3OD) d 1.22–1.54 (m,
3 H), 1.60–1.71 (m, 1 H), 1.75–2.30 (m, 7 H), 2.42–2.56 (m, 1 H),
2.65–2.79 (m, 1 H), 2.85 (tt, J = 12.25, 3.62 Hz, 1 H), 2.89–2.98 (m,
1 H), 3.60–3.75 (m, 1 H), 4.53–4.67 (m, 1 H), 7.50 (dd, J = 7.63,
5.19 Hz, 1 H), 7.72 (dd, J = 8.54, 1.22 Hz, 1 H), 7.82–7.90 (m, 2 H),
8.14 (s, 1 H), 8.51 (dd, J = 5.04, 1.68 Hz, 1 H). 13C NMR (125 MHz,
CD3OD) d 27.44, 28.34, 31.05, 34.31, 34.71, 38.12, 41.48, 112.34,
120.79, 121.00, 121.62, 123.73, 126.97, 130.00, 130.79, 137.15,
137.20, 139.02, 149.44, 160.29, 172.65. LRMS m/z 361.1 (M + H).
HRMS calcd for C23H25O2N2(M + H): 361.1911, found: 361.1906.
Methyl 3-cyclohexyl-2-(2-vinylpyridin-3-yl)-1H-indole-6-
carboxylate 21
To a mixture of 18 (2.5 g, 6.52 mmol), 20 (1.56 g, 8.48 mmol) and
LiCl (553 mg, 13.04 mmol), ethanol (20 mL) and toluene (20 mL)
were added. 2 M Na2CO3 (8.15 mL, 16.3 mmol) aqueous solution
was then added, and the mixture was degassed with N2. Pd(PPh3)4
(377 mg, 0.326 mmol) was added and the reaction mixture was
heated at 80 ◦C for 3 h. The reaction mixture was filtered and
concentrated. It was then extracted with ethyl acetate (2 ¥ 50 mL).
The organic layers were combined, washed with brine and dried
(MgSO4). Evaporation of solvent gave a brownish oil which was
purified by flash column chromatography (silica gel, hexanes to
ethyl acetate) to afford a light yellow solid as product (1.52 g, 65%
yield). IR (neat, nmax/cm-1): 2923, 2850, 1712, 1433, 1288, 1217,
1
1105, 985. H NMR (500 MHz, CD3OD) d 1.17–1.39 (m, 3 H),
1.60–1.95 (m, 7 H), 2.45–2.58 (m, 1 H), 3.91 (s, 3 H), 5.41 (dd,
J = 10.99, 1.83 Hz,1 H), 6.30 (dd, J = 17.09, 1.83 Hz, 1 H), 6.65
(dd, J = 17.24, 10.83 Hz, 1 H), 7.42 (dd, J = 7.63, 4.88 Hz, 1 H),
7.71 (dd, J = 8.39, 1.37 Hz, 1 H), 7.76–7.84 (m, 2 H), 8.07 (s,
1 H), 8.62 (dd, J = 4.88, 1.53 Hz, 1 H). 13C NMR (125 MHz,
CD3OD) d 27.42, 28.34, 34.49, 38.15, 52.52, 114.68, 120.53,
120.78, 120.99, 121.82, 123.70, 124.15, 129.70, 131.91, 135.05,
135.36, 137.56, 141.13, 150.55, 155.34, 170.12. LRMS m/z 361.3
(M + H). HRMS calcd for C23H25O2N2 (M + H): 361.1911, found:
361.1904.
Methyl 2-(3-bromopyridin-2-yl)-3-cyclohexyl-1H-indole-6-
carboxylate 24
To a mixture of 18 (1000 mg, 2.61 mmol), 2,3-dibromopyridine
(742 mg, 3.13 mmol) and LiCl (221 mg, 5.22 mmol), ethanol (15
mL) and toluene (15 mL) were added. 2 M Na2CO3 (3.26 mL,
6.52 mmol) aqueous solution was then added and the mixture was
degassed with N2. Pd(PPh3)4 (151 mg, 0.13 mmol) was added and
the reaction mixture was heated at 80 ◦C overnight. The reaction
mixture was then filtered and concentrated. Next, it was extracted
with ethyl acetate (2 ¥ 80 mL). The organic layers were combined,
washed with brine and dried (MgSO4). Evaporation of solvent gave
a brownish oil which was purified by flash column chromatography
(silica gel, hexanes to 50% ethyl acetate in hexanes) to afford a light
yellow solid as the desired product. (750 mg, 70% yield) IR(neat,
Methyl 13-cyclohexyl-7H-pyrido[3¢,2¢:3,4]azepino[1,2-a]indole-10-
carboxylate 22
To a suspension of NaH (230 mg of 60% dispersion oil, 5.77
mmol) in DMF (10 mL), 21 (1.6 g, 4.44 mmol) was added and
the reaction mixture was stirred at room temperature for 15 min.
Allyl bromide (0.46 mL, 5.33 mmol) was then added. The reaction
mixture was stirred at room temperature for 2 h. It was then
quenched with water, and extracted with ethyl acetate (100 mL).
The organic layer was separated, washed with 1 N HCl solution,
dried (MgSO4) and concentrated to give an orange oil. It was then
dissolved in dichloromethane (500 mL) and Grubbs Catalyst 2nd
generation (377 mg, 0.444 mmol) was added. The reaction mixture
was heated under reflux overnight. The solvent was evaporated
and the residue was purified by flash column chromatography
(silica gel, 1 : 1 hexanes : ethyl acetate) to give an off-white solid
as product. (0.95 g, 58% yield) IR (neat, nmax/cm-1): 1702, 1427,
1380, 1323, 1279, 1248, 1104. 1H NMR (500 MHz, DMSO-d6) d
1.12–2.14 (m, 10 H), 2.60–2.75 (m, 1 H), 3.89 (s, 3 H), 4.26 (s, br,
1 H), 5.23 (s, br, 1 H), 6.64 (dt, J = 10.45, 6.68 Hz, 1 H), 6.91 (d,
J = 10.68 Hz, 1 H), 7.53 (dd, J = 7.63, 4.58 Hz, 1 H), 7.63 (d,
J = 8.24 Hz, 1 H), 7.85–7.98 (m, 2 H), 8.30 (s, 1 H), 8.69 (d, J =
3.66 Hz, 1 H). 13C NMR (125 MHz, DMSO-d6) d 25.45, 26.59,
32.55, 36.29, 51.83, 111.69, 118.98, 119.51, 120.69, 121.92, 122.28,
126.53, 129.34, 133.54, 134.47, 134.94, 135.26, 138.14, 148.81,
153.22, 167.06. LRMS m/z 373.2 (M + H). HRMS calcd for
C24H25O2N2 (M + H): 373.1911, found: 373.1903.
n
max/cm-1): 3305, 2924, 2849, 1693(br), 1619, 1505, 1434, 1407,
1319, 1282, 1216, 1095. 1H NMR (500 MHz, CDCl3) d 1.26–1.38
(m, 3 H), 1.70–1.98 (m, 7 H), 2.71–2.82 (m, 1 H), 3.95 (s, 3 H),
7.25 (dd, J = 8.24, 4.58 Hz, 1 H), 7.79 (dd, J = 8.54, 1.53 Hz, 1 H),
7.88 (d, J = 8.54 Hz, 1 H), 8.04 (dd, J = 8.24, 1.53 Hz, 1 H), 8.11 (s,
1 H), 8.42 (s, br, 1 H), 8.68 (dd, J = 4.58, 1.53 Hz, 1 H). 13C NMR
(125 MHz, CDCl3) d 26.26, 27.09, 32.72, 36.96, 51.94, 113.59,
120.04, 120.80, 121.89, 121.94, 123.98, 124.24, 130.37, 133.87,
135.56, 141.05, 148.10, 151.88, 168.04. LRMS m/z 413.0 (M +
H), 415.0 (M + 2 + H). HRMS calcd for C21H22O2N2Br: 413.0859,
found: 413.0850.
Methyl 1-(2-amino-2-oxoethyl)-2-(3-bromopyridin-2-yl)-3-
cyclohexyl-1H-indole-6-carboxylate 25
To a suspension of NaH (25.5 mg of 60% dispersion oil, 0.64
mmol) in DMF (3 mL), 24 (220 mg, 0.53 mmol) was added and the
reaction mixture was stirred at room temperature for 15 min. Next,
2-bromoacetamide (80 mg, 0.583 mmol) was added. The reaction
mixture was stirred at room temperature for 2 h. It was then
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6654–6662 | 6661
©

View Online
quenched with water, extracted with ethyl acetate (2 ¥ 50 mL), and
the organic layers were combined. Next, the organic layers were
washed with 1 N HCl solution, dried (MgSO4) and concentrated.
The residue was purified by flash column chromatography (silica
gel, ethyl acetate) to give a colorless thick oil as the desired
product.(190 mg, 76% yield) IR (film, nmax/cm-1): 3362 (br), 2928,
d6) d 25.67, 26.79, 32.34, 35.38, 47.03, 111.64, 119.92, 120.86,
120.94, 123.70, 124.12, 129.19, 130.08, 133.87, 134.44, 141.84,
145.70, 168.04. LRMS m/z 376.3 (M + H). HRMS calcd for
C22H22O3N3 (M + H): 376.1656, found: 376.1652.
Notes and references
1
2852, 1696 (br), 1435, 1382, 1282, 1255, 1242, 1020. H NMR
(500 MHz, CDCl3) d 1.18–1.36 (m, 3 H), 1.67–1.89 (m, 6 H),
2.03–2.11 (m, 1 H), 2.45–2.59 (m, 1 H), 3.96 (s, 3 H), 4.41 (d,
J = 17.70 Hz, 1 H), 4.70 (d, J = 17.70 Hz, 1 H), 5.37 (s, br, 1
H), 6.19 (s, br, 1 H), 7.35 (dd, J = 8.24, 4.58 Hz, 1 H), 7.85–7.91
(m, 2 H), 8.08–8.14 (m, 2 H), 8.70 (dd, J = 4.73, 1.37 Hz, 1 H).
13C NMR (125 MHz, CDCl3) d 26.14, 26.91, 27.02, 32.31, 33.10,
37.22, 47.78, 52.08, 111.91, 121.00, 121.10, 122.25, 124.00, 124.72,
125.17, 130.15, 135.58, 136.36, 141.11, 148.40, 150.72, 167.66,
170.39. LRMS m/z 470.2 (M + H), 472.2 (M+2+H). HRMS calcd
for C23H25O3N3Br (M + H): 470.1074, found: 470.1069.
1 S. Harper, B. Pacini, S. Avolio, M. Di Filippo, G. Migliaccio, R. Laufer,
R. De Francesco, M. Rowley and F. Narjes, J. Med. Chem., 2005, 48,
1314–1317.
2 S. Harper, S. Avolio, B. Pacini, M. Di Filippo, S. Altamura, L. Tomei,
G. Paonessa, S. Di Marco, A. Carfi, C. Giuliano, J. Padron, F. Bonelli,
G. Migliaccio, R. De Francesco, R. Laufer, M. Rowley and F. Narjes,
J. Med. Chem., 2005, 48, 4547–4557.
3 P. L. Beaulieu, J. Gillard, D. Bykowski, C. Brochu, N. Dansereau, J.-S.
Duceppe, B. Hache, A. Jakalian, L. Lagace, S. LaPlante, G. McKercher,
E. Moreau, S. Perreault, T. Stammers, L. Thauvette, J. Warrington and
G. Kukolj, Bioorg. Med. Chem. Lett., 2006, 16, 4987–4993.
4 For recent reviews on HCV NS5B polymerase inhibitors, see: (a) M. H.
Powdrill, J. A. Bernatchez and M. Gotte, Viruses, 2010, 2, 2169–2195;
(b) P. L. Beaulieu, Expert Opin. Ther. Pat., 2009, 19, 145–164; (c) E.
Tramontano, Mini-Rev. Med. Chem., 2008, 8, 1298–1310.
Methyl 13-cyclohexyl-6-oxo-6,7-dihydro-5H-pyrido[3¢,2¢:5,6][1,4]-
diazepino[1,7-a]indole-10-carboxylate 26
5 T. W. Hudyma, X. Zheng, F. He, M. Ding, C. P. Bergstrom, P.
Hewawasam, S. W. Martin and R. G. Gentles, US Pat., 7 348 425,
2008.
In a microwave reactor tube, 25 (500 mg, 1.063 mmol), Xantphos
(92 mg, 0.159 mmol), Pd2(dba)3 (97 mg, 0.1063 mmol) and Cs2CO3
(518 mg, 1.59 mmol) were added. The reaction was then flushed
with nitrogen and sealed. 1,4-dioxane (10 mL) was added and
the mixture was heated at 100 ◦C under microwave conditions
for 5 h. Next, water was added and the reaction was extracted
with ethyl acetate (2 ¥ 75 mL). The organic layers were combined,
dried (MgSO4) and concentrated. The residue was purified by flash
column chromatography (silica gel, 20% ethyl acetate in hexanes
to 60% ethyl acetate in hexanes) to give a yellowish solid as the
desired product. (235 mg, 57% yield) IR (neat, nmax/cm-1): 2924,
6 K. Ikegashira, T. Oka, S. Hirashima, S. Noji, H. Yamanaka, Y. Hara, T.
Adachi, J.-I. Tsuruha, S. Doi, Y. Hase, T. Noguchi, I. Ando, N. Ogura,
S. Ikeda and H. Hashimoto, J. Med. Chem., 2006, 49, 6950–6953.
7 (a) I. Stansfield, C. Ercolani, A. Mackay, I. Conte, M. Pompei, U.
Koch, N. Gennari, C. Giuliano, M. Rowley and F. Narjes, Bioorg. Med.
Chem. Lett., 2009, 19, 627–632; (b) F. Narjes, B. Crescenzi, M. Ferrara,
J. Habermann, S. Colarusso, M. Ferreira, I. Stansfield, A. Mackay,
I. Conte, C. Ercolani, S. Zaramella, M-C. Palumbi, P. Meuleman, G.
Leroux-Roels, C. Giuliano, F. Fiore, S. Di Marco, P. Baiocco, U. Koch,
G. Migliaccio, S. Altamura, R. Laufer, R. De Francesco and M. Rowley,
J. Med. Chem., 2011, 54, 289–301.
8 D. Hellwinkel and T. Kosack, Liebigs Ann. Chem., 1985, 2, 226–38.
9 D. Bai, R. Xu, G. Chu and X. Zhu, J. Org. Chem., 1996, 61, 4600–4606.
10 For the synthesis of tetracyclic indole derivatives using the Heck
reaction, see: (a) S. H. Lee, S. H. Kim, T. H. Kim and J. N.
Kim, Tetrahedron Lett., 2008, 49, 1773–1776; (b) C. Blaszykowski, E.
Aktoudianakis, D. Alberico, C. Bressy, D. G. Hulcoop, F. Jafarpour, A.
Joushaghani, B. Laleu and M. Lautens, J. Org. Chem., 2008, 73, 1888–
1897; (c) C. Bressy, D. Alberico and M. Lautens, J. Am. Chem. Soc.,
2005, 127, 13148–13149; (d) R. Faust, P. J. Garratt, R. Jones, L.-K. Yeh,
A. Tsotinis, M. Panoussopoulou, T. Calogeropoulou, M.-T. Teh and
D. Sugden, J. Med. Chem., 2000, 43, 1050–1061; (e) A. P. Kozikowski
and D. Ma, Tetrahedron Lett., 1991, 32, 3317–3320.
1
1708, 1686, 1613, 1443, 1389, 1255, 1044. H NMR (500 MHz,
DMSO-d6) d 1.20–1.47 (m, 3H), 1.66–1.86 (m, 5 H), 1.89–2.05
(m, 2 H), 3.33–3.42 (m, 1 H), 3.90 (s, 3 H), 4.91 (s, br, 2 H), 7.52
(dd, J = 8.09, 4.43 Hz, 1 H), 7.64 (dd, J = 8.09, 1.37 Hz, 1 H), 7.69
(dd, J = 8.54, 1.22 Hz, 1 H), 7.99 (d, J = 8.55 Hz, 1 H), 8.30 (s,
1 H), 8.61 (dd, J = 4.42, 1.37 Hz, 1 H), 10.44 (s, 1 H). 13C NMR
(125 MHz, DMSO-d6) d 25.64, 26.75, 32.31, 35.35, 47.02, 51.92,
111.59, 119.60, 120.99, 121.03, 122.93, 123.74, 129.40, 130.08,
133.90, 134.36, 134.75, 141.72, 145.70, 166.94, 167.98. LRMS m/z
390.3 (M + H). HRMS calcd for C23H24O3N3 (M + H): 390.1812,
found: 390.1811.
11 For selected reviews on intramolecular Heck reactions, see: (a) P. J.
Guiry and D. Kiely, Curr. Org. Chem., 2004, 8, 781–794; (b) A. B.
Dounay and L. E. Overman, Chem. Rev., 2003, 103, 2945–2963; (c) J. T.
Link, Organic Reactions, 2002, 60, 157–534.
12 (a) T. Ishiyama, J. Takagi, J. F. Hartwig and N. Miyaura, Angew. Chem.,
Int. Ed., 2002, 41, 3056–3058; (b) T. Ishiyama, Y. Nobuta, J. F. Hartwig
and N. Miyaura, Chem. Commun., 2003, 2924–2925.
13-Cyclohexyl-6-oxo-6,7-dihydro-5H-pyrido[3¢,2¢:5,6][1,4]diazepi-
no[1,7-a]indole-10-carboxylic acid 27
13 (a) J. K. Stille, Pure Appl. Chem., 1985, 57, 1771–1780; (b) J. K. Stille,
Angew. Chem., Int. Ed. Engl., 1986, 25, 508–524.
To a solution of 26 (180 mg, 0.462 mmol) in pyridine (7 mL), LiI
(186 mg, 1.387 mmol) was added. The reaction mixture was heated
at 180 ◦C under microwave conditions for 2.5 h. Water was added
and the reaction mixture was adjusted to pH 4–5 with 1 N HCl
solution. A light brownish solid was collected as product. (170 mg,
98% yield) IR (neat, nmax/cm-1): 2500–3500 (br), 2923, 2847, 1685,
1671, 1438, 1401, 1252, 1202, 1136. 1H NMR (500 MHz, DMSO-
d6) d 1.17–1.49 (m, 3 H), 1.64–1.86 (m, 5 H), 1.89–2.04 (m, 2 H),
4.89 (s, br, 2 H), 7.51 (dd, J = 8.09, 4.42 Hz, 1 H), 7.64 (dd, J = 8.24,
1.53 Hz, 1 H), 7.68 (dd, J = 8.54, 1.53 Hz, 1 H), 7.96 (d, J = 8.55 Hz,
1 H), 8.26 (d, J = 1.22 Hz, 1 H), 8.61 (dd, J = 4.58, 1.53 Hz, 1 H),
10.44 (s, 1 H), 12.76 (s, br, 1 H). 13C NMR (125 MHz, DMSO-
14 (a) T. M. Trnka and R. H. Grubbs, Acc. Chem. Res., 2001, 34, 18–29;
(b) L. Yet, Chem. Rev., 2000, 100, 2963–3007; (c) M. Scholl, S. Ding,
C. W. Lee and R. H. Grubbs, Org. Lett., 1999, 1, 953–956.
15 J. Yin and S. L. Buchwald, Org. Lett., 2000, 2, 1101–1104.
16 U. Luning, C. Wangnick, K. Peters and H. G. Von Schnering, Chem.
Ber., 1991, 124, 397–402.
17 (a) Y.-K. Wang, K. L. Rigat, S. B. Roberts and M. Gao, Anal. Biochem.,
2006, 359, 106–111; (b) Y-K. Wang, Y. Wang, K. L. Rigat, J-H. Sun,
M. Gao and S. B. Roberts, Arch. Biochem. Biophys., 2008, 470, 146–52.
18 (a) R. A. Fridell, D. Qiu, C. Wang, L. Valera and M. Gao, Antimicrob.
Agents Chemother., 2010, 54, 3641–3650; (b) D. R. O’Boyle, II, P. T.
Nower, J. A. Lemm, L. Valera, J.-H. Sun, K. Rigat, R. Colonno and
M. Gao., Antimicrob. Agents Chemother., 2005, 49, 1346–1353.
19 M. Marigo, N. Marsich and E. J. Farnetti, J. Mol. Catal. A: Chem.,
2002, 187, 169.
6662 | Org. Biomol. Chem., 2011, 9, 6654–6662
This journal is
The Royal Society of Chemistry 2011
©