One-step assembly of carbamoyl-substituted heteroannelated [1,4]thiazepines

Article abstract of DOI:10.1021/jo052640w

We present a convenient synthesis of novel heteroaryl-fused 3-oxo-1,4-thiazepine-5-carboxamides and 5-oxo-1,4-thiazepine-3-carboxamides using a modification of four-component Ugi condensation. We demonstrate the usefulness and versatility of the developed approach for the synthesis of variously substituted compounds and discuss the scope and limitations of the chemistry involved.

Full text of DOI:10.1021/jo052640w

One-Step Assembly of Carbamoyl-Substituted Heteroannelated
[1,4]Thiazepines
Alexey P. Ilyn,† Marina V. Loseva,† Vladimir Y. Vvedensky,‡ Elena B. Putsykina,†
Sergey E. Tkachenko,‡ Dmitri V. Kravchenko,† Alexandr V. Khvat,‡
Mikhail Y. Krasavin,‡ and Alexandre V. Ivachtchenko*,†
Department of Organic Chemistry, Chemical DiVersity Research Institute, 114401 Khimki,
Moscow Reg., Russia, and ChemDiV, Inc., 11558 Sorrento Valley Road, Suite 5,
San Diego, California 92121
aV@chemdiV.com
ReceiVed December 23, 2005
We present a convenient synthesis of novel heteroaryl-fused 3-oxo-1,4-thiazepine-5-carboxamides and
5-oxo-1,4-thiazepine-3-carboxamides using a modification of four-component Ugi condensation. We
demonstrate the usefulness and versatility of the developed approach for the synthesis of variously
substituted compounds and discuss the scope and limitations of the chemistry involved.
Introduction
integrase2b and reverse transcriptase2c inhibitors, and antitumor
agents.2d Several heteroannelated bioisosteric analogues of this
core fragment were described as potent inhibitors of Herpes
simplex virus type 1 (HSV-1) replication (structure II),3a
compounds possessing H1 antihistamine activity (structure
III),3b selective antagonists of 5-HT1A and dopamine D2
receptors (structure IV),3c and vasoconstrictor agents (structure
V).3d According to these examples, aryl-fused 1,4-thiazepines
The 1,4-thiazepine fragment is present in a wide number of
natural and synthetic biologically active agents.1 Among them,
aryl- and heteroaryl-fused derivatives of this heterocycle
represent an important group of compounds with interesting
pharmaceutical properties.2,3 In particular, different alkyl deriva-
tives of 3,4-dihydro-5-oxo-1,4-benzothiazepine I (Figure 1) were
described as calcium channel antagonists,2a HIV-1 enzyme
(2) (a) Malli, R.; Frieden, M.; Trenker, M.; Graier, W. F. J. Biol. Chem.
2005, 280, 12114-12122. (b) Neamati, N.; Turpin, J. A.; Winslow, H. E.;
Christensen, J. L.; Williamson, K.; Orr, A.; Rice, W. G.; Pommier, Y.;
Garofalo, A.; Brizzi, A.; Campiani, G. J. Med. Chem. 1999, 42, 3334-
3341. (c) Maruenda, H.; Johnson F. J. Med. Chem. 1995, 38, 2145-2151.
(d) Garofalo, A.; Campiani, G.; Fiorini, I.; Nacci, V. Farmaco 1993, 48,
275-283.
(3) (a) Boulware, S. L.; Bronstein, J. C.; Nordby, E. C.; Weber, P. C.
AntiVir. Res. 2001, 51, 111-125. (b) Cale, A. D.; Gero, T. W.; Walker, K.
R.; Lo, Y. S.; Welstead, W. J.; Jaques, L. W.; Johnson, A. F.; Leonard, C.
A.; Nolan, J. C.; Johnson, D. N. J. Med. Chem. 1989, 32, 2178-2199. (c)
Nakao, T.; Tanaka, H.; Yamato, H.; Akagi, T.; Takehara, S. US 5141930;
Chem. Abstr. 1992, 116, 194290b. (d) Schlosser, K. M.; Krasutsky, A. P.;
Hamilton, H. W.; Reed, J. E.; Sexton, K. Org. Lett. 2004, 6, 819-821.
* To whom correspondence should be addressed. Phone: (858) 794-4860.
Fax: (858) 794-4931.
† Chemical Diversity Research Institute.
‡ ChemDiv, Inc.
(1) (a) Skiles, J. W.; Suh, J. T.; Williams, B. E.; Menard, P. R.; Barton,
J. N.; Love, B.; Jones, H.; Neiss, E. S.; Schwab, A.; Mann, W. S. J. Med.
Chem. 1986, 29, 784-796. (b) Crescenza, A.; Botta, M.; Corelli, F.; Santini,
A.; Tafi, A. J. Org. Chem. 1999, 64, 3019-3025. (c) Umemiya, H.;
Fukasawa, H.; Ebisawa, M.; Eyrolles, L.; Kawachi, E.; Eisenmann, G.;
Gronemeyer, H.; Hashimoto, Y.; Shudo, K.; Kagechika, H. J. Med. Chem.
1997, 40, 4222-4234. (d) Venkatesan, A. M.; Gu, Y.; Dos Santos, O.;
Abe, T.; Agarwal, A.; Yang, Y.; Petersen, P. J.; Weiss, W. J.; Mansour, T.
S.; Nukaga, M.; Hujer, A. M.; Bonomo, R. A.; Knox, J. R. J. Med. Chem.
2004, 47, 6556-6568.
10.1021/jo052640w CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/07/2006
J. Org. Chem. 2006, 71, 2811-2819
2811

Ilyn et al.
Using 1,8-naphthalaldehydic acid, 2-formylphenoxyacetic acid,
and 2′-formylphenoxy-2-benzoic acid as the BFRs in Ugi
coupling, a series of rare 6-, 7- and 8-membered heterocyclic
rings was obtained.6a Reaction of ω-ketoacids6b or aldehyde
acids6c with the corresponding isonitriles and amines led to
â-lactams. Several model 1,4-benzothiazepin-5-ones were syn-
thesized starting from the corresponding thiacarboxylic keto
acids, amines, and isocyanides.7 Recently, we developed a
modified variant of the classical Ugi reaction, in which
heterocyclic keto acids were used as the bifunctional coupling
components for the synthesis of rare heterocyclic structures.8
Using this method, we efficiently synthesized several series of
novel pyrrolo[1,2-a][1,4]diazepines,8a 3,4-dihydropyrazino[1,2-
a]indol-1(2H)-ones, and 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-
ones.8b In this work, we have focused on broadening the scope
of this useful synthetic methodology. Specifically, we describe
an efficient route to novel heteroaryl-fused carboxamide deriva-
tives of 3-oxo-1,4-thiazepine VI and 5-oxo-1,4-thiazepine VII
(Figure 1) heterocycles, which were not previously reported in
the literature.
FIGURE 1. Biologically active molecules containing the aryl- and
heteroaryl-fused 5-oxo-1,4-thiazepine moiety (structures I-V), and
compounds synthesized in this work (structures VI and VII).
Results and Discussion
In the first part of our work, we synthesized four series of
novel heteroaryl-fused 3-oxo-1,4-thiazepine-5-carboxamides of
general structure VI (Figure 1). The bifunctional reagents for
Ugi condensation 3a-d were obtained using a modified
approach by Cagniant et al.9 (Scheme 1).
and their heterocyclic analogues represent promising synthetic
targets. Development of efficient synthetic approaches to the
related scaffolds may provide a valuable source of novel
physiologically active agents.
The initial formyl chlorides 1a-d, obtained following known
approaches,10-13 were converted to the corresponding BFRs
3a-d using two synthetic methods. According to method A,
the methyl carboxylates 2a,b were initially synthesized in
moderate yields (38% and 56%, respectively) from 1a,b by using
the reaction with methyl mercaptoacetate in the presence of K2-
CO3 in DMF. Esters 2a,b were then smoothly hydrolyzed by
aqueous alkali to furnish the desired aldehyde acids 3a and 3b
(yields 86 and 85%, respectively). The relatively low overall
yields of the desired BFRs achieved in these reaction sequences
prompted us to explore an alternative synthetic route. We have
found that reaction of 1a-d with disodium mercaptoacetate in
methanol (method B) led to the desired heterocycles 3a-d in
45-70% yield. Due to better overall yields and a shortened
synthetic procedure, route B can be recommended as method
of choice for the synthesis of 3a-d.
In the reported synthetic approaches to the aryl- and het-
eroaryl-fused derivatives of 3(5)-oxo-1,4-thiazepine, a key
reaction is the intramolecular cyclization of the appropriate aryl/
heteroaryl derivatives leading to the desired molecules.2d,4 For
example, 5-oxo-1,4-thiazepino[6,7-b]indole was synthesized
using intramolecular amide bond formation in 3-[(2-aminoethyl)-
thio]-1H-indole-2-carboxylate in the presence of sodium ethylate.4a
Similar scheme was used for assembly of benzothieno[2,3-f]-
1,4-thiazepin-5(2H)-one II.4d However, the described synthetic
strategies have found limitations mainly due to lack of versatility
and a limited number of the appropriate initial reactants. In
addition, these approaches have not provided a robust method
suitable for the production of combinatorial libraries.
Multiple component condensations (MCCs) are of great value
for the contemporary organic and medicinal chemistry because
large arrays of compounds with diverse substitution patterns
can be prepared in one step under mild reaction conditions. A
classical example of MCC is the four-component Ugi reaction
between aldehyde, amine, isonitrile, and carboxylic acid, which
has emerged as a powerful tool for rapid identification and
optimization of lead compounds in drug discovery.5 One
important modification of this reaction is the use of bifunctional
reagents (BFRs).6-8 For example, a series of 2,3-dihydro-1H-
isoindol-3-ones was prepared from 2-formylbenzoic acid.6a
(6) (a) Ley, S. V.; Taylor, S. J. Bioorg. Med. Chem. Lett. 2002, 12, 1813-
1816. (b) Short, K. M.; Mjalli, A. M. M. Tetrahedron Lett. 1997, 38, 359-
362. (c) Zhang, J.; Jacobson, A.; Rusche, J. R.; Herlihy, W. J. Org. Chem.
1999, 64, 1074-1076. (d) Marcaccini, S.; Pepino, R.; Torroba, T.; Miguel,
D.; Garcia-Valverde, M. Tetrahedron Lett. 2002, 43, 8591-8593.
(7) Marcaccini, S.; Miguel, D.; Torroba, T.; Garcia-Valverde, M. J. Org.
Chem. 2003, 68, 3315-3318.
(8) (a) Ilyn, A. P.; Trifilenkov, A. S.; Kuzovkova, J. A.; Kutepov, S. A.;
Nikitin, A. V.; Ivachtchenko, A. V. J. Org. Chem. 2005, 70, 1478-1481.
(b) Ilyn, A. P.; Kuzovkova, J. A.; Potapov, V. V.; Shkirando, A. M.;
Kovrigin, D. I.; Tkachenko, S. E.; Ivachtchenko, A. V. Tetrahedron Lett.
2005, 46, 881-884.
(9) Cagniant P.; Briola M.-M.; Kirsch G. C. R. Acad. Sci. 1977, C285,
21-24.
(4) (a) Nagarajan, K.; Arya, V. P.; Parthasarathy, T. N.; Shenoy, S. J.;
Sahah, R. K.; Kulkarni, Y. S. Indian J. Chem. 1981, 20, 672-679. (b)
Nefzi, A.; Ong, N. A.; Giulianotti, M. A.; Ostresh, J. M.; Houghten, R. A.
Tetrahedron Lett. 1999, 40, 4939-4942. (c) Hirai, K.; Iwano, Y.; Mikoshiba,
I.; Homma, H. Annu. Rept. Sankyo Res. Lab. 1992, 44, 141-150. (d)
Czollner, L.; Szilagyi, G.; Lango, J. Magy. Kem. Folyoir. 1998, 94, 332-
335. (e) Khatana, S. S.; Boschelli, D. H.; Kramer, J. B.; Connor, D. T.;
Barth, H.; Stoss, P. J. Org. Chem. 1996, 61, 6060-6062.
(5) (a) Ugi, I.; Lohberger, S.; Karl, R. The Passerini and Ugi Reactions.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Heathcock,
C., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 1083-1109. (b)
Domling, A.; Ugi, I. Angew. Chem. 2000, 39, 3168-3210.
(10) Deng, H.; Konopelski, J. P. Org. Lett., 2001, 3, 301-304.
(11) Lavergne, O.; Lesueur-Ginot, L.; Pla Rodas, F.; Kasprzyk, P. G.;
Pommier, J.; Demarquay, D.; Pre’vost, G.; Ulibarri, G.; Rolland, A.;
Schiano-Liberatore, A.-M.; Harnett, J.; Pons, D.; Camara, J.; Bigg, D. C.
H. J. Med. Chem. 1998, 41, 5410-5419.
(12) Barreiro, E. J.; Camara, C. A.; Verli, H.; Brazil-Ma’s, L.; Castro,
N. G.; Cintra, W. M.; Aracava, Y.; Rodrigues, C. R.; Fraga, C. A. M. J.
Med. Chem. 2003, 46, 1144-1152.
(13) Majo, V. J.; Perumal, P. T. J. Org. Chem. 1996, 61, 6523-6525.
2812 J. Org. Chem., Vol. 71, No. 7, 2006

Carbamoyl-Substituted Heteroannelated [1,4]Thiazepines
SCHEME 1. Synthesis of Bifunctional Reagents 3a-d
SCHEME 2. Synthesis of Heteroaryl-Fused 3-Oxo-1,4-thiazepine-5-carboxamides
SCHEME 3. Mechanism of Formation of the Desired
Thiazepines and the Side Products
We have found that reaction of aldehyde acids 3a-d with
various amines 4{1-33} and isocyanides 5{1-9} in methanol
led to novel heteroaryl-fused derivatives of 3-oxo-1,4-thiazepine-
5-carboxamides 6{1-45}, 7, 8a,b, and 9a-d in moderate to
good yield (Scheme 2). The reaction yields were found to be
sensitive to the order in which the amine and isonitrile
components were added to the initial aldehyde acids. In an
optimized experimental protocol, the equimolar amounts of
aldehyde acid and primary amine were dissolved in an ap-
propriate solvent (or solvent mixture), and the mixture was kept
at room temperature for 10-60 min until the complete conver-
sion of the BFR. Then the equimolar amount of isocyanide was
added, and the resulting mixture was heated for 1-24 h,
depending on the nature of reactants.
The described reactions presumably follow the same initial
mechanism as the classical Ugi condensation (Scheme 3). The
initial step is the formation of a Schiff base as a result of reaction
of the aldehyde VIII with the primary amine. The resulting
imine IX is then attacked by the isonitrile to give an iminovinyl
intermediate X. The latter then reacts intramolecularly with the
carboxylic group, and the acylation product undergoes recy-
clization leading to the final thiazepine XI. When unreacted
aldehyde acid is present in the reaction mixture, there is the
possibility of an intermolecular interaction between the inter-
mediate X and the second molecule of acid VIII leading to a
standard Ugi 4CC product XII. The process is controlled
kinetically, and the overall yield of the desired thiazepines
depends on the relative rate constants at each step.
unwanted side product corresponding to structure XII in Scheme
3. According to LC/MS analysis of the reaction mixture, its
relative amount exceeded 35% of the desired compound. As a
result, the yield of the purified diazepine 7 was significantly
decreased (up to 20-30%). To prevent the possibility of this
side reaction, we used a modified protocol for this condensation.
At the first step, aldehyde acid 3b was reacted with primary
amine at room temperature for 1 h. After the complete
conversion of 3b, isonitrile was added, and the resulting mixture
was stirred at 60 °C for 24 h. Due to this modification, the
yield of the desired compound was increased up to 68%.
Similar modification allowed us to optimize the reaction
conditions and improve the yields of all other cyclization
products depicted in Scheme 2. Although LC/MS analysis of
For example, in the case of [(3-formyl-8-methylquinolin-2-
yl)thio]acetic acid 3b, simultaneous addition of isonitrile and
amine to the initial BFR led to a significant amount of the
J. Org. Chem, Vol. 71, No. 7, 2006 2813

Ilyn et al.
FIGURE 2. Amines 4{1-33} and isonitriles 5{1-9} used in this work.
the reaction mixtures still shows the presence of such side
products corresponding to structure XII in Scheme 3, their
relative amount did not exceed 3-5% of the desired product
for most of the studied reactions.
presence of Na2CO3 in water led to ketoacid 11 in a good yield
(80%). The desired thiazepino[6,7-b]indoles 12a-e were then
synthesized by the reaction with benzylamines 4{27, 30-33}
and cyclopentylisocyanide 5{9} in methanol at room temper-
ature (yield 64-75%). Of note, the reaction yields in this case
were found to be independent of the order in which the amine
and isonitrile components were added to the initial keto acid.
Structures and yields of the synthesized compounds from this
series are shown in Table 2.
Typically, the full conversion of initial aldehyde acids was
achieved within 1-24 h, depending primarily on both the nature
of the heterocyclic BFR and the amine component. With respect
to amine reagent, various cycloaliphatic and aromatic primary
amines, such as substituted anilines, benzyl and phenylamines,
and linear and branched aliphatic amines, were well tolerated
(Figure 2). Somewhat surprisingly, even aromatic anilines with
electron-withdrawing groups, such as 3-CF3-C6H4NH2, readily
reacted in this condensation, though after more prolonged
heating as compared to more nucleophilic amines. A restriction
is the limited number of commercially or synthetically available
isonitriles. In this work, we used nine different isonitriles 5{1-
9} available from commercial sources (Figure 2).
In both condensation variants, the desired products usually
precipitated from the reaction mixtures after the reaction was
cooled to room temperature. All compounds were obtained as
racemic mixtures. The assignment of these structures was made
1
on the basis of H NMR, 13C NMR, and high-resolution mass
spectroscopy data. In many cases, pure crystalline substances
could be obtained, thus allowing analysis of the individual
compounds through X-ray crystallography.
Structures and yields of the representative condensation
products are shown in Table 1.
In summary, we have shown that carboxamide derivatives
of heteroaryl-fused 5(3)-oxo-1,4-thiazepine can be efficiently
prepared by a novel modification of four-component Ugi
reaction of bifunctional aldehyde/keto acids, isonitriles, and
amines. Considering the ease of the preparation of initial
reactants, convenient synthesis and isolation of products, and
the overall good chemical yields of the described transforma-
tions, this route provides a new valuable entry to novel
heterocycle-fused analogues of biologically active thiazepines.
As a synthetic tool for creating diverse compound libraries, the
four-component condensation used in this work offers a large
number of potential input reactants and resulting products. The
For assembly of the aryl-fused 5-oxo-1,4-thiazepine-3-car-
boxamide heterocyclic system (structure VII, Figure 1), we
explored the possibility of use of ketoacid 11 as an alternative
BFR in the reaction with isonitriles and primary amines (Scheme
4). A similar scheme was reported by Marcaccini et al. for the
synthesis of a series of 1,4-benzothiazepin-5-ones.7
Compound 10 was prepared as reported by Blank et al.14 The
reaction of mercapto acid 10 with 1-bromoacetone in the
(14) Blank, B.; DiTullio, N. W.; Owings, F. F.; Deviney, L.; Miao, C.
K.; Saunders: H. L. J. Med. Chem. 1977, 20, 572-576.
2814 J. Org. Chem., Vol. 71, No. 7, 2006

Carbamoyl-Substituted Heteroannelated [1,4]Thiazepines
TABLE 1. Structures and Yields of Representative Compounds 6{1-45}, 7, 8a,b, and 9a-d
SCHEME 4. Synthesis of Heteroaryl-Fused 5-Oxo-1,4-thiazepine-3-carboxamides 12a-e
TABLE 2. Structures and Yields of Compounds 12a-e
obtained compounds represent valuable starting points for the
development of compounds of biological interest. The use of
compounds from series 6-9 and 12 in the search for novel
bioactive agents is under investigation by the ChemDiv Co. and
will be reported in due course.
Experimental Section
(3-Formyl-1-methyl-1H-indol-2-ylsulfanyl)acetic Acid 3a. K2-
CO3 (8.8 g, 0.064 mol) was added to a solution of 2 chloro-1-
methyl-1H-indolcarbaldehyde (8.8 g, 0.064 mol) in DMF (50 mL)
followed by a dropwise addition of methyl mercaptoacetate (6.4 g,
0.060 mol). The mixture was stirred at 35 °C for 3 h, and then
water (100 mL) was added. The mixture was extracted with
benzene, the combined extracts were dried over CaCl2, and the
solvent was removed in vacuo. The crude residue was triturated in
hexane, and the resulting precipitate was filtered off and dried to
afford 5.4 g (38%) of 2a (mp 74-76 °C), which was used at the
J. Org. Chem, Vol. 71, No. 7, 2006 2815

Ilyn et al.
next step without further purification. KOH (0.042 mol) was added
dropwise to a solution of 2a (0.021 mol) in ethanol (50 mL). The
reaction mixture was stirred at 30 °C for 1.5 h and then treated
with water (50 mL) and acidified with concd HCl until pH 2 was
reached. The formed precipitate was filtered off and dried in vacuo.
Recrystallization from benzene/acetonitrile mixture gave 4.1 g
(82%) of 3a. Mp: 182-184 °C. 1H NMR (DMSO-d6): δ 3.75 (s,
2 H), 3.92 (s, 3 H), 7.29 (t, Ja ) 7.55 Hz, Jb ) 8.0 Hz, 1 H), 7.36
(t, Ja ) 8.35 Hz, Jb ) 7.55 Hz, 1 H), 7.64 (d, J ) 8.35 Hz, 1 H),
8.15 (d, J ) 8.0 Hz, 1 H), 10.18 (s, 1 H), 12.85 (br s, 1 H). 13C
NMR (DMSO-d6): δ 178.0, 172.7, 164.9, 133.3, 124.3, 122.3,
120.6, 116.9, 110.8, 107.0, 35.3, 31.4. Anal. Calcd for C12H11-
NO3S: C, 57.82; H, 4.45; N, 5.62. Found: C, 57.65; H, 4.37; N,
5.79.
(3-Formyl-8-methylquinolin-2-ylsulfanyl)acetic Acid 3b. This
compound was obtained in 48% overall yield from 1b by the same
procedure described for 3a. Mp: 185-187 °C. 1H NMR (DMSO-
d6): δ 10.25 (s, 1 H), 8.78 (s, 1 H), 7.84 (d, J ) 8.0 Hz, 1 H), 7.67
(d, J ) 7.2 Hz, 1 H), 7.43 (t, J ) 7.5 Hz, 1 H), 4.00 (s, 2 H), 2.60
(s, 3 H). 13C NMR (DMSO-d6): δ 192.3, 170.9, 156.3, 147.7, 146.7,
136.2, 134.0, 127.9, 127.1, 126.8, 124.8, 32.9, 18.0.
(4-Formyl-2-methyl-2H-pyrazol-3-ylsulfanyl)acetic Acid 3c.
NaOH (10.9 g, 0.37 mol) was added to a solution of thioglycolic
acid (11.4 g, 0.12 mol) in absolute ethanol (45 mL). The reaction
mixture was stirred at 40-50 °C for 2 h and then cooled to rt. The
formed precipitate was filtered off, washed with absolute ethanol,
and dried to yield 12.4 g (74%) of disodium mercaptoacetate. This
compound was added to a solution of chloride 1c (16 g, 0.08 mol)
in MeOH (160 µL). The reaction mixture was heated at reflux for
4 h and then cooled to rt. Water (100 mL) was added, and the
resulting mixture was acidified with aqueous HCl until pH 2 was
reached and then stirred at rt overnight. The formed precipitate was
filtered off, washed thoroughly with water, and dried to afford 3c
as colorless crystals. Mp: 63-65 °C. Yield: 70%. 1H NMR
(DMSO-d6): δ 2.43 (s, 3 H), 3.54 (s, 2 H), 7.47-7.64 (m, 5 H),
10.03 (s, 1 H), 12.83 (br.s, 1 H). 13C NMR (DMSO-d6): δ 180.1,
171.4, 150.3,146.9, 142.3, 131.5, 128.0, 124.4, 121,0 38.4, 13.0.
Anal. Calcd for C13H12N2O3S: C, 56.51; H, 4.38; N, 10.14.
Found: C, 56.54; H, 4.25; N, 10.49.
(2-Formyl-1-methyl-1H-indol-3-ylsulfanyl)acetic Acid 3d. This
compound was obtained in 45% yield by the same procedure
described for 3c. Mp: 156-158 °C. 1H NMR (DMSO-d6): δ 3.75
(s, 2 H), 3.92 (s, 3 H), 7.29 (t, Ja ) 7.55 Hz, Jb ) 8.0 Hz, 1 H),
7.36 (t, Ja ) 8.35 Hz, Jb ) 7.55 Hz, 1 H), 7.64 (d, J ) 8.35 Hz,
1 H), 8.15 (d, J ) 8.0 Hz, 1 H), 10.18 (s, 1 H), 12.85 (br s, 1 H).
13C NMR (DMSO-d6): δ 181.6, 170.3, 138.6, 134.0, 125.1, 122.4,
121.8, 118.7, 115.3, 111.0, 38.8, 31.1. Anal. Calcd for C12H11-
NO3S: C, 57.82; H, 4.45; N, 5.6. Found: C, 57.68; H, 4.39; N,
5.72.
H), 7.07 (t, J ) 7.5 Hz, 1 H), 5.31 (s, 1 H), 4.76 (sept, J ) 6.6 Hz,
1 H), 4.21 (d, J ) 13.9 Hz,. 1 H), 3.62 (s, 3 H), 3.50 (d, J ) 13.9
Hz, 1 H), 3.31 - 3.03 (m, 6 H), 1.59-1.45 (m, 2 H), 1.23 (d, J )
7.0 Hz, 3 H), 0.94 (t, J ) 7.0 Hz, 3 H), 0.81 (d, J ) 6.6 Hz, 3 H).
13C NMR (DMSO-d6): δ 170.2, 167.8, 136.3, 131.5, 127.2, 120.8,
119.6, 116.4, 108.9, 105.2, 67.7, 65.2, 51.6, 45.4, 37.3, 32.0, 29.8,
28.8, 19.9, 19.3, 14.8. HRMS: m/z 404.2002 (M+). Anal. Calcd
for C21H29N3O3S: C, 62.50; H, 7.24; N, 10.41. Found: C, 62.58;
H, 7.29; N, 10.67.
N-(3-Isopropoxypropyl)-10-methyl-3-oxo-4-(3-piperidin-1-yl-
propyl)-3,4,5,10-tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-
carboxamide 6{2}. Yield: 71%. 1H NMR (DMSO-d6): δ 7.65 (t,
J ) 5.7 Hz, 1 H), 7.62 (d, J ) 7.9 Hz, 1 H), 7.41 (d, J ) 7.9 Hz,
1 H), 7.13 (t, J ) 7.9 Hz, 1 H), 7.06 (t, J ) 7.9 Hz, 1 H), 5.49 (s,
1 H), 4.38 (d, J ) 13.8 Hz, 1 H), 3.87-3.73 (m, 1 H), 3.62 (s, 3
H), 3.47 (d, J ) 13.8 Hz, 1 H), 3.43-3.21 (m, 4 H), 3.19-3.09
(m, 2 H), 2.31-1.93 (br m, 6 H), 1.66-1.43 (m, 4 H), 1.43-1.20
(br m, 6 H), 0.96 (d, J ) 5.8 Hz, 3 H), 0.96 (d, J ) 5.8 Hz, 3 H),
0.94 (d, J ) 5.8 Hz, 3 H). 13C NMR (DMSO-d6): δ 169.9, 168.6,
136.3, 131.7, 127.5, 120.9, 119.5, 116.5, 108.8, 104.6, 70.5 (2C),
65.0, 58.4, 55.2, 53.5 (2C), 47.4, 37.0, 31.9, 29.8, 29.3, 25.0, 24.7,
23.7, 21.8 (2C). HRMS: m/z 501.2903 (M+). Anal. Calcd for
C27H40N4O3S: C, 64.77; H, 8.05; N, 11.19. Found: C, 64.85; H,
8.18; N, 11.02. Crystallographic data: monoclinic single crystal
(0.40 × 0.15 × 0.05 mm3), space group P21/n, unit cell constants
a ) 12.252(4) Å, b ) 13.211(4) Å, c, 17.676(5) Å, R ) 90°, â )
102.16(2)°, γ ) 90°, V ) 2796.9(15) Å3, Z ) 4, Dx ) 1.189 Mg/
m3. The final R indices are R1 ) 0.0467, wR2 ) 0.0835.
N-Benzyl-4-(2-cyclohex-1-en-1-ylethyl)-10-methyl-3-oxo-3,4,5,-
10-tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-carboxamide 6-
1
{4}. Yield: 69%. H NMR (DMSO-d6): δ 8.35 (t, J ) 5.8 Hz, 1
H), 7.65 (d, J ) 7.5 Hz, 1 H), 7.42 (d, J ) 7.5 Hz, 1 H), 7.34-
7.17 (m, 5 H), 7.12 (t, J ) 7.5 Hz, 1 H), 7.06 (t, J ) 7.5 Hz, 1 H),
5.53 (s, 1 H), 4.78 (br s, 1 H), 4.43 (d, J ) 13.8 Hz, 1 H), 4.34
(dd, J ) 14.9, 5.8 Hz 1 H), 4.24 (dd, J ) 14.9, 5.8 Hz, 1 H),
4.08-3.89 (m, 1 H), 3.61 (s, 3 H), 3.39 (d, J ) 13.8 Hz, 1 H),
3.24-3.14 (m, 1 H), 2.09-1.05 (m, 10 H). 13C NMR (DMSO-d6):
δ 170.3, 168.5, 139.1, 136.2, 133.8, 132.1, 128.2 (2C), 127.7, 127.2
(2C), 126.8, 122.3, 120.8, 119.4, 116.6, 108.6, 104.7, 58.4, 47.7,
42.8, 35.7, 32.0, 29.8, 27.4, 24.5, 22.2, 21.6. HRMS: m/z 474.2218
(M+). Anal. Calcd for C28H31N3O2S: C, 71.01; H, 6.60; N, 8.87.
Found: C, 71.54; H, 6.49; N, 8.67.
4-Cyclopropyl-N-(3-ethoxypropyl)-10-methyl-3-oxo-3,4,5,10-
tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-carboxamide 6{5}.
1
Yield: 59%. H NMR (DMSO-d6): δ 7.62 (d, J ) 7.5 Hz, 1 H),
7.42 (d, J ) 7.5 Hz, 1 H), 7.44 (t, J ) 5.5 Hz, 1 H), 7.14 (t, J )
7.5 Hz, 1 H), 7.07 (t, J ) 7.5 Hz, 1 H), 5.40 (s, 1 H), 4.13 (d, J )
13.9 Hz, 1 H), 3.62 (s, 3 H), 3.48 (d, J ) 13.9 Hz, 1 H), 3.31-
3.18 (m, 4 H), 3.14 (q, J ) 6.2 Hz, 1 H), 2.88-2.79 (m, 1 H), 1.59
(q, J ) 6.2 Hz, 2 H), 0.95 (t, J ) 7.0 Hz, 3 H), 0.86-0.66
(m, 2 H), 0.66-0.54 (m, 1 H), 0.45-0.32 (m, 1 H). 13C NMR
(DMSO-d6): δ 170.3, 170.0 136.3, 131.6, 127.3, 121.0, 119.7,
116.2, 109.0, 104.5, 67.6, 65.2, 59.9, 37.2, 33.2, 32.6, 29.8, 28.9,
14.8, 8.8, 7.2. HRMS: m/z 402.1850 (M+). Anal. Calcd for
C21H27N3O3S: C, 62.82; H, 6.78; N, 10.46. Found: C, 62.66; H,
6.57; N, 10.74.
The same synthetic procedure described for 3c,d can be used
for the synthesis of 3a,b (yields 56% and 65%, respectively).
General Procedure for Preparation of 10-Methyl-3-oxo-3,4,5,-
10-tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-carboxam-
ides 6{1-45}. The aldehyde acid 3a (0.5 mmol) and the corre-
sponding primary amine (0.5 mmol) were dissolved in methanol
(3 mL). The solution was kept for 10 min at rt, the isonitrile 5{1-
6} (0.5 mmol) was added, and the resulting mixture was stirred at
50 °C for 2-3 h. The reaction was followed by TLC (5% MeOH
in CH2Cl2). On completion, the reaction mixture was cooled to rt,
and the formed precipitate was filtered off, washed with methanol,
and purified by recrystallization from diethyl ether of by chroma-
tography on silica gel, eluting with CH2Cl2. The title compounds
were obtained as colorless solids in moderate to good yields (61-
89%).
4-Cyclopentyl-N-(4-fluorobenzyl)-10-methyl-3-oxo-3,4,5,10-
tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-carboxamide 6{6}.
1
Yield: 68%. H NMR (DMSO-d6): δ 8.05 (t, J ) 6.0 Hz, 1 H),
7.73 (d, J ) 8.1 Hz, 1 H), 7.43 (d, J ) 8.1 Hz, 1 H), 7.30-7.20
(m, 2 H), 7.18-7.01 (m, 4 H), 5.28 (s, 1 H), 4.89 (d, J ) 8.3 Hz,
1 H), 4.22 (d, J ) 6.0 Hz, 2 H), 3.97 (d, J ) 13.9 Hz, 1 H), 3.62
(s, 3 H), 3.43 (J ) 13.9 Hz, 1 H), 3.62 (s, 3 H), 3.43 (J ) 13.9 Hz,
1 H), 1.97-1.28 (m, 7 H), 1.18-0.95 (m, 1 H). 13C NMR (DMSO-
d6): δ 170.4, 167.8, 161.1, 135.9 (2C), 131.7, 129.3, 129.2, 127.4,
120.8, 119.7, 116.2, 115.0, 114.7, 108.9, 104.9, 55.4, 52.7, 42.4,
31.6, 29.9, 28.8, 28.2, 23.8, 23.6. HRMS: m/z 452.1808 (M+). Anal.
Calcd for C23H22FN3O2S: C, 65.23; H, 5.24; N, 9.92. Found: C,
65.39; H, 5.09; N, 10.12.
Representative spectral data for compounds 6{1-45}:
N-(3-Ethoxypropyl)-4-isopropyl-10-methyl-3-oxo-3,4,5,10-tet-
rahydro-2H-[1,4]thiazepino[7,6-b]indole-5-carboxamide 6{1}.
1
Yield: 66%. H NMR (DMSO-d6): δ 7.78 (d, J ) 7.5 Hz, 1 H),
7.41 (d, J ) 7.5 Hz, 1 H), 7.40 (br s, 1 H), 7.13 (t, J ) 7.5 Hz, 1
2816 J. Org. Chem., Vol. 71, No. 7, 2006

Carbamoyl-Substituted Heteroannelated [1,4]Thiazepines
4-Cyclohexyl-N-(4-fluorobenzyl)-10-methyl-3-oxo-3,4,5,10-tet-
rahydro-2H-[1,4]thiazepino[7,6-b]indole-5-carboxamide 6{7}.
Yield: 79%. H NMR (DMSO-d6): δ 8.04 (t, J ) 6.9 Hz, 1 H),
4-(3-Acetylphenyl)-N-(3-ethoxypropyl)-10-methyl-3-oxo-3,4,5,-
10-tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-carboxamide 6-
{17}. Yield: 56%. H NMR (DMSO-d6): δ 7.88 (d, J ) 7.3 Hz,
1
1
7.81 (d, J ) 8.1 Hz, 1 H), 7.41 (d, J ) 8.1 Hz, 1 H), 7.31-7.18
(m, 2 H), 7.17-6.98 (m, 4 H), 5.42 (s, 1 H), 4.44-4.29 (br m, 1
H), 4.31-4.13-4.03 (m, 2 H), 4.08 (d, J ) 13.9 Hz, 1 H), 3.61 (s,
3 H), 3.44 (d, J ) 13.9 Hz, 1 H), 1.86-1.42 (m, 5 H), 1.42-0.96
(m, 5 H). 13C NMR (DMSO-d6): δ 170.5, 167.8, 161.1, 135.8 (2C),
131.6, 129.3, 129.2, 127.4, 120.7, 119.6, 116.5, 115.0, 114.7, 108.9,
105.2, 53.8, 52.4, 42.3, 31.9, 30.1, 29.8, 29.3, 25.2, 25.3, 24.7.
HRMS: m/z 466.1956 (M+). Anal. Calcd for C26H28FN3O2S: C,
67.07; H, 6.06; N, 9.03. Found: C, 67.21% H, 6.16; N, 9.15.
4-(1-Benzylpiperidin-4-yl)-N-(3-ethoxypropyl)-10-methyl-3-
oxo-3,4,5,10-tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-car-
1 H), 7.75 (s, 1 H), 7.63-7.49 (m, 3 H), 7.46-7.33 (m, 2 H), 7.14
(t, J ) 7.3 Hz, 1 H), 7.02 (t, J ) 7.3 Hz, 1 H), 5.74 (s, 1 H), 4.49
(d, J ) 13.9 Hz, 1 H), 3.72 (d, J ) 13.9 Hz, 1 H), 3.70 (s, 3 H),
3.30-3.11 (m, 4 H), 2.53 (s, 3 H), 1.62-1.55 (m, 2 H), 0.94 (t, J
) 7.0 Hz, 3 H). 13C NMR (DMSO-d6): δ 197.2, 169.6, 168.9,
144.6, 137.6, 136.4, 131.9, 131.3, 129.4, 127.4, 126.8, 125.9, 121.2,
119.7, 116.5, 109.1, 103.7, 67.6, 65.2, 61.6, 37.4, 32.4, 30.0, 28.9,
26.7, 14.8. HRMS: m/z 480.1951 (M+). Anal. Calcd for C26H29-
N3O4S: C, 65.11; H, 6.09; N, 8.76. Found: C, 64.98; H, 6.27; N,
8.92.
Ethyl 4-(5-{[(4-Fluorobenzyl)amino]carbonyl}-10-methyl-3-
oxo-2,3,5,10-tetrahydro-4H-[1,4]thiazepino[7,6-b]indol-4-yl)ben-
1
boxamide 6{10}. Yield: 62%. H NMR (DMSO-d6): δ 7.81 (d,
1
J ) 7.3 Hz, 1 H), 7.46-7.37 (m, 2 H), 7.36-7.18 (m, 5 H), 7.17-
7.04 (m, 2 H), 5.35 (s, 1 H), 4.37-4.23 (m, 1 H), 4.27 (d, J )
13.9 Hz, 1 H), 3.60 (s, 3 H), 3.52 (d, J ) 13.9 Hz, 1 H), 3.43 (s,
2 H), 3.30-3.16 (m, 4 H), 3.12-2.91 (m, 2 H), 2.95-2.85 (m, 1
H), 2.75-2.64 (m, 1 H), 2.07-1.83 (m, 3 H), 1.76-1.29 (m, 4 H),
1.20-1.05 (m, 1 H), 0.94 (t, J ) 7.2 Hz, 3 H). 13C NMR (DMSO-
d6): δ 170.1, 168.4, 138.2, 136.2, 131.7, 128.7 (2C), 128.0 (2C),
127.2, 126.8, 120.9, 119.7, 116.5, 108.9, 105.0, 67.6, 65.1, 61.8,
52.7, 52.5, 52.4, 37.3, 32.1 (2C), 29.8, 29.3, 28.8, 28.6, 14.8.
HRMS: m/z 535.2742 (M+). Anal. Calcd for C30H38N4O3S: C,
67.39; H, 7.16; N, 10.48. Found: C, 67.53; H, 7.29; N, 10.44.
N-(3-Ethoxypropyl)-4-(2-furylmethyl)-10-methyl-3-oxo-3,4,5,-
10-tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-carboxamide 6-
zoate 6{18}. Yield: 71%. H NMR (DMSO-d6): δ 8.19 (t, J )
6.0 Hz, 1 H), 7.95 (d, J ) 8.5 Hz, 2 H), 7.62 (d, J ) 7.9 Hz, 1 H),
7.46 (d, J ) 7.9 Hz, 1 H), 7.37 (d, J ) 8.5 Hz, 2 H), 7.28-7.16
(m, 2 H), 7.19-6.97 (m, 4 H), 5.88 (s, 1 H), 4,34 (d, J ) 13.8 Hz,
1 H), 4.40-4.17 (m, 4 H), 3.69 (s, 3 H), 3.66 (d, J ) 13.8 Hz, 1
H), 1.30 (t, J ) 7.0 Hz, 3 H). 13C NMR (DMSO-d6): δ 169.8,
168.4, 165.1, 161.1, 148.2, 135,9 (2C), 135.2, 129.9 (2C), 129.3,
129.2, 127.9, 127.5, 126.7 (2C), 121.1, 119.8, 116.5, 115.0, 114.7,
109.1, 103.6, 61.3, 60.7, 42.4, 32.2, 30.0, 14.1. HRMS: m/z
532.1702 (M+). Anal. Calcd for C29H26FN3O4S: C, 65.52; H, 4.93;
N, 7.90. Found: C, 65.72; H, 4.68; N, 7.81.
N-(3-Ethoxypropyl)-4-(3-methoxybenzyl)-10-methyl-3-oxo-
3,4,5,10-tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-carboxa-
1
1
{11}. Yield: 68%. H NMR (DMSO-d6): δ 7.72 (t, J ) 5.5 Hz,
mide 6{19}. Yield: 64%. H NMR (DMSO-d6): δ 7.79 (t, J )
1 H), 7.47 (d, J ) 7.9 Hz, 1 H), 7.39-7.25 (m, 2 H), 7.11 (t, J )
7.9 Hz, 1 H), 7.03 (t, J ) 7.9 Hz, 1 H), 6.19 (dd, J ) 3.2, 2.0, Hz,
1 H), 6.13 (d, J ) 3.2 Hz, 1 H), 5.55 (s, 1 H), 5.09 (d, J ) 15.6
Hz, 1 H), 4.53 (d, J ) 13.8 Hz, 1 H), 4.40 (d, J ) 15.6 Hz, 1 H),
3.62 (s, 3 H), 3.57 (d, J ) 13.8 Hz, 1 H), 3.28-3.15 (m, 4 H),
3.13 (q, J ) 6.4 Hz, 2 H), 1.60 (q, J ) 6.4 Hz, 2 H), 0.99 (t, J )
6.8 Hz, 3 H). 13C NMR (DMSO-d6): δ 169.7, 169.1, 150.6, 142.4,
136.2, 131.6, 127.3, 120.9, 119.4, 116.5, 110.3, 108.9, 107.8, 104.4,
67.5, 65.2, 58.1, 45.5, 37.0, 32.1, 29.9, 28.9, 14.9. HRMS: m/z
442.1799 (M+). Anal. Calcd for C23H27N3O4S: C, 62.56; H, 6.16;
N, 9.52. Found: C, 62.46; H, 5.84; N, 9.71.
5.5 Hz, 1 H), 7.39-7.24 (m, 2 H), 7.17-7.04 (m, 2 H), 6.99 (t, J
) 7.3 Hz, 1 H), 6.92 (d, J ) 7.3 Hz, 1 H), 6.85 (d, J ) 8.1 Hz, 1
H), 6.65 (t, J ) 7.3 Hz, 1 H), 5.48 (s, 1 H), 5.05 (d, J ) 16.2 Hz,
1 H), 4.66 (d, J ) 13.8 Hz, 1 H), 4.38 (d, J ) 16.2 Hz, 1 H), 3.68
(s, 3 H), 3.66 (s, 3 H), 3.56 (d, J ) 13.8 Hz, 1 H), 3.29-3.13 (m,
4 H), 3.14 (q, J ) 6 Hz, 2 H), 1.60-1.48 (m, 2 H), 1.00 (t, J ) 7
Hz, 3 H). 13C NMR (DMSO-d6): δ 169.8, 169.6, 156.6, 136.3,
131.9, 128.0, 127.3, 127.0, 125.0, 121.0, 120.0, 119.4, 116.5, 110.2,
108.9, 104.6, 67.4, 65.2, 59.2, 55.1, 48.9, 36.9, 32.5, 29.9, 28.9,
14.9. HRMS: m/z 482.2106 (M+). Anal. Calcd for C25H29N3O4S:
C, 64.22; H, 6.25; N, 8.99. Found: C, 64.46; H, 6.12; N, 8.68.
4-[2-(2,4-Dimethoxyphenyl)ethyl]-N-(4-fluorobenzyl)-10-methyl-
3-oxo-3,4,5,10-tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-car-
boxamide 6{21}. Yield: 61%. 1H NMR (DMSO-d6): δ 8.30 (t, J
) 6.2 Hz, 1 H), 7.56 (d, J ) 7.9 Hz, 1 H), 7.41 (d, J ) 7.9 Hz, 1
H), 7.26-7.17 (m, 2 H), 7.17-6.99 (m, 4 H), 6.72 (d, J ) 8,1 Hz,
1 H), 6.28 (d, J ) 2.1 Hz, 1 H), 6.19 (dd, J ) 8.1, 2.1 Hz, 1 H),
5.50(s, 1 H), 4.35 - 4.13 (m, 2 H), 4.20 (d, J ) 13.9 Hz, 1 H),
4.13-3.97-3.86 (m, 1 H), 3.66 (s, 3 H), 3.62 (s, 3 H), 3.61 (s, 3
H), 3.39 (d, J ) 13.8 Hz,1 H), 3.39-3.25 (m, 1 H), 2.57-2.41 (m,
2 H). 13C NMR (DMSO-d6): δ 170.2, 168.1, 161.1, 158.9, 157.8,
135.6 (2C), 131.8, 130.0, 129.3, 129.2, 127.7, 120.8, 119.4, 118.3,
116.4, 115.0, 114.7, 108.8, 104.5, 104.0, 97.9, 58.7, 55.2, 54.9,
49.8, 42.2. 31.7, 29.8, 27.4, HRMS: m/z 548.2020 (M+), Anal.
Calcd for C30H30FN3O4S: C, 65.80; H, 5.52; N, 7.67. Found: C,
65.92; H, 5.64; N, 7.46.
N-(3-Ethoxypropyl)-10-methyl-3-oxo-4-(2-thien-3-ylethyl)-
3,4,5,10-tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-carboxa-
1
mide 6{13}. Yield: 62%. H NMR (DMSO-d6): δ 7.69 (t, J )
5.5 Hz, 1 H), 7.65 (d, J ) 7.7 Hz, 1 H), 7.42 (d, J ) 7.7 Hz, 1 H),
7.31-7.25 (m, 1 H), 7.13 (t, J ) 7.7 Hz, 1 H), 7.07 (t, J ) 7.7 Hz,
1 H), 6.97-6.77 (m, 1 H), 6.88 (d, J ) 4.9 Hz, 1 H), 5.60 (s, 1 H),
4.40 (d, J ) 13.6 Hz, 1 H), 4.06-3.91 (m, 1 H), 3.62 (s, 3 H),
3.60-3.46 (m, 1 H), 3.48 (d, J ) 13.6 Hz, 1 H), 3.33-3.20 (m, 4
H), 3.20-3.09 (m, 2 H), 2.67-2.55 (m, 2 H), 1.61-1.51 (m, 2 H),
0.97 (t, J ) 7.0 Hz, 3 H). 13C NMR (DMSO-d6): δ 170.0, 168.5,
138.8, 136.2, 131.8, 128.2, 127.5, 125.5, 121.0, 120.9, 119.5, 116.5,
198.8, 104.6, 67.5, 65.2, 58.4, 49.8, 37.0, 31.9, 29.8, 28.9, 28.0,
14.8. HRMS: m/z 472.1722 (M+). Anal. Calcd for C24H29N3O3S2:
C, 61.12; H, 6.20; N, 8.91. Found: C, 61.07; H, 6.03; N, 8.72.
N-(3-Ethoxypropyl)-10-methyl-3-oxo-4-(pyridin-3-ylmethyl)-
3,4,5,10-tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-carboxa-
4-(1,3-Benzodioxol-5-yl)-N-(3-ethoxypropyl)-10-methyl-3-oxo-
3,4,5,10-tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-carboxa-
1
mide 6{14}. Yield: 69%. H NMR (DMSO-d6): δ 8.39 (d, J )
1
Hz 1.5, 1 H), 8.28 (dd, J ) 4.7, 1.5 Hz, 1 H), 7.76 (t, J ) 5.5 Hz,
1 H), 7.55 (dt, J ) 7.9, 1.9 Hz, 1 H), 7.48 (d, J ) 7.9 Hz, 1 H),
7.38 (d, J ) 7.9 Hz, 1 H), 7.15 (dd, J ) 7.9, 4.9, 1 H), 7.10 (t, J
) 7.9 Hz, J ) 4.9 Hz, 1 H), 7.00 (t, J ) 7.9 Hz, 1 H), 5.59 (s, 1
H), 5.13 (d, J ) 15.6 Hz, 1 H), 4.58 (d, J ) 13.8 Hz, 1 H), 4.46
(d, J ) 15.6 Hz, 1 H), 3.63 (s, 3 H), 3.61 (d, 13.8 Hz,1 H), 3.26
(q, J ) 7.0 Hz, 4 H),3.14 (q, J ) 6.4 Hz, 2 H), 1.59 (q, J ) 6.4
Hz, 2 H). 13C NMR (DMSO-d6): δ 169.7, 169.6, 148.5, 148.0,
136.2, 134.8, 133.2, 131.8, 127.2, 123.1, 121.0, 119.4, 116.5, 198.9,
104.3, 67.4, 65.2, 59.1, 50.6, 37.0, 32.2, 30.0, 28.9, 14.9. HRMS:
m/z 453.1953 (M+). Anal. Calcd for C24H28N4O3S: C, 63.69; H,
6.24; N, 12.38. Found: C, 63.76; H, 6.34; N, 12.46.
mide 6{22}. Yield: 64%. H NMR (DMSO-d6): δ 7.57 (t, J )
5.5 Hz, 1 H), 7.54 (d, J ) 8.1 Hz, 1 H), 7.45 (d, J ) 8.1 Hz, 1 H),
7.13 (t, J ) 8.1 Hz, 1 H), 7.02 (t, J ) 8.1 Hz, 1 H), 6.86 (d, J )
8.3 Hz, 1 H), 6.77 (d, J ) 1.8 Hz, 1 H), 6.59 (dd, J ) 8.3, 1.8 Hz,
1 H), 6.02 (s, 2 H), 5.59 (s, 1 H), 4.50 (d, J ) 13.9 Hz, 1 H), 3.68
(s, 3 H), 3.64 (d, J ) 13.9 Hz, 1 H), 3.32-3.11 (m, 6 H), 1.61-
1.52 (m, 2 H), 0.95 (t, J ) 6.8 Hz, 3 H). 13C NMR (DMSO-d6):
δ 169.6, 168.9, 147.2, 145.8, 138.6, 136.4, 131.9, 127.4, 121.1 (2C),
119.7, 116.4, 109.0, 108.0, 107.9, 103.8, 101.4, 67.6, 65.2, 62.3,
37.3, 32.4, 29.9, 28.9, 14.8. HRMS: m/z 482.1752 (M+). Anal.
Calcd for C25H27N3O5S: C, 62.35; H, 5.65; N, 8.73. Found: C,
62.06; H, 5.71; N, 8.84.
J. Org. Chem, Vol. 71, No. 7, 2006 2817

Ilyn et al.
4-(2,3-Dihydro-1,4-benzodioxin-6-yl)-10-methyl-N-(3-methyl-
butyl)-3-oxo-3,4,5,10-tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-
5-carboxamide 6{23}. Yield: 68%. 1H NMR (DMSO-d6): δ 7.69
(t, J ) 5.7 Hz, 1H), 7.52 (d, J ) 7.9 Hz, 1H), 7.44 (d, J ) 7.9 Hz,
1H), 7.13 (t, J ) 7.9 Hz, 1H), 7.01 (t, J ) 7.9 Hz, 1H), 6.81 (d, J
) 8.5 Hz, 1H), 6.70 (d, J ) 2.4 Hz, 1H), 6.58 (dd, J ) 2.4, 8.5
Hz, 1H), 5.55 (s,1H), 4.61 (d, J ) 13.8 Hz, 1H), 4.22 (s, 4H), 3.68
(s, 3H), 3.62 (d, J ) 13.8 Hz, 1H), 3.11 (q, J ) 6,4 Hz, 2H), 1.49
(sept, J ) 6.4 Hz, 1H), 1.28 (q, J ) 7.2 Hz, 2H), 0.83 (t, J ) 6.4
Hz, 6H). 13C NMR (DMSO-d6): δ 169.4, 168.9, 143.0, 142.2,
138.0, 136.3, 131.9, 127.3, 121.0, 119.6, 119.3, 116.9, 116.5, 115.4,
109.0, 104.0, 64.1, 64.0, 62.3, 37.8 (2C), 32.5, 29.9, 25.2, 22.3
(2C). HRMS: m/z 480.1943 (M+). Anal. Calcd for C26H29N3O4S:
C, 65.11; H, 6.09; N, 8.76. Found: C, 65.29; H, 6.27; N, 8.53.
Crystallographic data: monoclinic single crystal (0.35 × 0.20 ×
0.12 mm3, space group P21/n, unit cell constants a ) 12.1930(14)
Å, b ) 12.6276(16) Å, c ) 15.837(2) Å, R ) 90°, â ) 99.091-
(3)°, γ ) 90°, V ) 2407.8(5) Å3, Z ) 4, Dx ) 1.323 Mg/m3). The
final R indices are R1 ) 0.0912, wR2 ) 0.1108.
N-Benzyl-10-methyl-4-(4-methyl-2-oxo-2H-chromen-7-yl)-3-
oxo-3,4,5,10-tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-car-
boxamide 6{24}. Yield: 73%. 1H NMR (DMSO-d6): δ 8.20 (t, J
) 6.0 Hz, 1 H), 7.74 (d, J ) 8.5 Hz, 1 H), 7.66 (d, J ) 7.9 Hz, 1
H), 7.46 (d, J ) 7.9 Hz 1 H), 7.37-7.08 (m, 8 H), 7.03 (t, J ) 7.9
Hz, 1 H), 6.38 (s, 1 H), 5.97 (s, 1 H), 4.47-4.18 (m, 2 H), 4.40 (d,
J ) 13.9 Hz, 1 H), 3.70 (d, J ) 13.9 Hz, 1 H), 3.68 (s, 3 H), 2.41
(s, 3 H). 13C NMR (DMSO-d6): δ 169.8, 168.6, 159.6, 153.0, 152.8,
146.8, 139.0, 136.5, 131.8, 128.2 (2C), 127.6, 127.1 (2C), 126.8,
125.6, 122.7, 121.1, 119.7, 118.0, 116.6, 114.2, 114.0, 109.1, 103.6,
61.4, 43.1, 32.2, 30.0, 18.0. HRMS: m/z 524.1644 (M+). Anal.
Calcd for C30H25N3O4S: C, 68.82; H, 4.81; N, 8.02. Found: C,
68.62; H, 4.58; N, 8.29.
45}. Compounds 8a,b were purified by chromatography on silica
gel, eluting with CH2Cl2.
N-Cycloheptyl-5-cyclohexyl-3-methyl-6-oxo-1-phenyl-4,5,6,7-
tetrahydro-1H-pyrazolo[4,3-f][1,4]thiazepine-4-carboxamide 8a.
1
Yield: 62%. H NMR (DMSO-d6): δ 7.65 (d, J ) 8.5 Hz, 1 H),
7.56-7.36 (m, 5 H), 4.88 (s, 1 H), 4.37 (t, J ) 10.0 Hz, 1 H), 4.10
(d, J ) 13.8 Hz, 1 H), 3.77-3.61 (m, 1 H), 3.42 (d, J ) 13.8 Hz,
1 H), 2.28 (s, 3 H), 1.86-1.02 (m, 22 H). 13C NMR (DMSO-d6):
δ 168.0 (2C), 148.6, 138.6, 133.5, 129.3 (2C), 127.8, 123.6 (2C),
113.2, 54.2, 52.4, 50.9, 33.9, 33.8, 32.9, 30.2, 29.1, 27.4, 27.4 (2C),
25.4, 24.7, 24.0 (2C), 12.3. HRMS: m/z 481.2637 (M+). Anal.
Calcd for C27H36N4O2S: C, 67.47; H, 7.55; N, 11.66. Found: C,
67.19; H, 7.38; N, 11.51. Crystallographic data: monoclinic single
crystal (0.40 × 0.15 × 0.05 mm3), space group P21/n, unit cell
constants a ) 12.252(4) Å, b ) 13.211(4) Å, c 17.676(5) Å, R )
90°, â ) 102.16(2)°, γ ) 90°, V ) 2796.9(15) Å3, Z ) 4, Dx )
1.189 Mg/m3. The final R indices are R1 ) 0.0467, wR2 ) 0.0835.
5-Benzyl-N-cycloheptyl-3-methyl-6-oxo-1-phenyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-f][1,4]thiazepine-4-carboxamide 8b.
1
Yield: 65%. H NMR (DMSO-d6): δ 7.91 (d, J ) 8.1 Hz, 1 H),
7.58-7.38 (m, 5 H), 7.32-7.15 (m, 5 H), 5.14 (d, J ) 15.1 Hz, 1
H), 5.02 (s, 1 H), 4.52 (d, J ) 13.8 Hz, 1 H), 4.38 (d, J ) 15.1 Hz,
1 H), 3.75-3.68 (m, 1 H), 3.47 (d, J ) 13.8 Hz, 1 H), 1.98 (s, 3
H), 1.81-1.24 (m, 12 H). 13C NMR (DMSO-d6): δ 168.8, 167.4,
136.3, 129.0, 124.7, 122.3, 119.2, 117.6, 110.2, 103.1, 54.2, 52.8,
51.1, 33.8 (2C), 33.8 (2C), 32.9, 30.5 (2C), 30.4, 29.0, 27.3 (2C),
25.3, 24.5, 24.0 (2C). HRMS: m/z 489.2317 (M+). Anal. Calcd
for C28H32N4O2S: C, 68.82; H, 6.60; N, 11.47. Found: C, 69.07;
H, 6.88; N, 11.71.
General Procedure for Preparation of 6-Methyl-3-oxo-3,4,5,6-
tetrahydro-2H-[1,4]thiazepino[6,7-b]indole-5-carboxamides 9a-
d. The title compounds were prepared by condensation of 3d with
the corresponding amine and isocyanide using the same procedure,
which was described for compounds 6{1-45}, except the reaction
mixture after addition of isocyanide was heated at reflux for 18 h.
Compounds 9a-d were purified by chromatography on silica gel,
eluting with CH2Cl2. The title compounds were obtained as colorless
solids in 56-70% yield.
N-Cycloheptyl-6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-
3,4,5,6-tetrahydro-2H-[1,4]thiazepino[6,7-b]indole-5-carboxam-
ide 9a. Yield: 70%. 1H NMR (DMSO-d6): δ 7.97 (d, J ) 7.9 Hz,
1 H), 7.77-7.57 (m, 3 H), 7.576-7.34 (m, 3 H), 7.26 (t, J ) 7.9
Hz, 1 H), 7.11 (t, J ) 7.9 Hz, 1 H), 5.76 (s, 1 H), 4.31 (d, J ) 13.8
Hz, 1 H), 3.88-3.76 (m, 1 H), 3.66 (s, 3 H), 3.59 (d, J ) 13.8 Hz,
1 H), 1.94-1.17 (m, 12 H). 13C NMR (DMSO-d6): δ 170.0, 166.6,
144.7, 136.6, 130.9, 130.4, 129.5, 127.6, 127.5, 125.0, 124.1, 123.7,
122.6, 122.0, 119.4, 117.9, 110.4, 104.3, 61.5, 51.3, 33.9, 33.8,
30.2, 27.3 (2C), 24.0 (2C). HRMS: m/z 516.2527 (M+). Anal. Calcd
for C27H28F3N3O2S: C, 62.90; H, 5.47; N, 8.15. Found: C, 63.03;
H, 5.69; N, 8.37.
N-Cycloheptyl-4-cyclohexyl-6-methyl-3-oxo-3,4,5,6-tetrahydro-
2H-[1,4]thiazepino[6,7-b]indole-5-carboxamide 9b. Yield: 76%.
1H NMR (DMSO-d6): δ 7.58 (d, J ) 8.3 Hz, 1 H), 7.49 (d, J )
7.9 Hz, 1 H), 7.29 (d, J ) 7.9 Hz, 1 H), 7.21 (t, J ) 7.9 Hz, 1 H),
7.05 (t, J ) 7.9 Hz, 1 H), 5.21 (s, 1 H), 4.41 (t, J ) 11.1 Hz, 1 H),
3.86 (d, J ) 13.8 Hz, 1 H), 3.80 (s, 3 H), 3.60-3.51 (m, 1 H),
3.40 (d, 13.8 Hz, 1 H), 2.00-0.90 (m, 22 H). 13C NMR (DMSO-
d6): δ 168.8, 167.4, 136.3, 129.0, 124.7, 122.3, 119.2, 117.6, 110.2,
103.1, 54.2, 52.8, 51.1, 33.8 (2C), 32.9, 30.5 (2C), 30.4, 29.0, 27.3
(2C), 25.3, 24.5, 24.0 (2C). HRMS: m/z 454.2516 (M+). Anal.
Calcd for C26H35N3O2S: C, 68.84; H, 7.78; N, 9.26. Found: C,
69.04; H, 8.02; N, 9.04.
N-Benzyl-4-(4-chloro-2-methoxy-5-methylphenyl)-10-methyl-
3-oxo-3,4,5,10-tetrahydro-2H-[1,4]thiazepino[7,6-b]indole-5-car-
1
boxamide 6{25}. Yield: 69%. H NMR (DMSO-d6): δ 8.81-
8.15 (br s, 1 H), 7.56 (d, J ) 7.9 Hz, 1 H), 7.42 (d, J ) 7.9 Hz, 1
H), 7.36-7.18 (m, 5 H), 7.12 (t, J ) 7.9 Hz, 1 H), 7.00 (t, J ) 7.9
Hz, 1 H), 6.84 (br s, 1 H), 5.55 (s, 1 H), 5.45-4.62 (br m, 1 H),
4.47-4.09 (br m, 2 H), 3.69 (s, 3 H), 3.58 (d, J ) 13.8 Hz, 1 H),
2.19 (br s, 3 H). 13C NMR (DMSO-d6): δ 170.0, 169.4, 153.2,
138.8, 136.2, 132.0, 131.9, 131.0, 128.2 (2C), 127.4 (3C), 126.9
(2C); 121.0, 119.3, 117.0, 116.9, 113.4, 108.8, 104.7, 61.5, 56.1,
43.0, 32.7, 29.9, 18.5. HRMS: m/z 520.1450 (M+). Anal. Calcd
for C28H26ClN3O3S: C, 64.67; H, 5.04; N, 8.08. Found: C, 64.41;
H, 5.26; N, 8.31.
Ethyl N-{[4-(4-Methoxybenzyl)-10-methyl-3-oxo-2,3,4,5-tetra-
hydro[1,4]thiazepino[7,6-b]quinolin-5-yl]carbonyl}glycinate 7.
A solution of aldehyde acid 3b (104 mg, 0.4 mmol) and 4-meth-
oxybenzylamine (55 mg, 0.4 mmol) in 3 mL of MeOH/DMSO/
THF mixture (1:1:1) was kept for 1 h at rt. The reaction mixture
was cooled to 0 °C, ethyl isocyanoacetate was added, and the
solution was heated at 60 °C for 24 h. The solvent was evaporated
in vacuo, and the resulting residue was purified by chromatography
on silica gel, eluting with a gradient of 0-10% MeOH in CH2Cl2.
Yield: 68%.1H NMR (DMSO-d6): δ 8.22 (t, J ) 5.9 Hz, 1 H),
7.89 (s, 1 H), 7.53-7.56 (m, 2 H), 7.36 (t, J ) 7.3 Hz, 1 H), 7.12-
7.14 (m, 2 H), 6.60-6.62 (m, 2 H), 5.57 (s, 1 H), 5.13 (d, J )
14.6 Hz, 1 H), 4.52 (d, J ) 15.0, 1 H), 4.26 (d, J ) 14.6 Hz, 1 H),
4.10 (q, J ) 6.9 Hz, 2 H), 3.88 (dd, J ) 17.2, 5.9 Hz, 1 H), 3.75
(dd, J ) 17.2, 5.9 Hz, 1 H), 3.50 (s, 3 H), 3.33 (d, J ) 15.0 Hz,
1 H), 2.58 (s, 3 H), 1.18 (t, J ) 6.9 Hz, 3 H). 13C NMR (DMSO-
d6): δ 169.8, 169.7, 169.3, 158.5, 157.0, 145.6, 140.6, 134.4, 130.7,
129.5 (2C), 129.4, 125.9, 125.8, 125.5, 125.2, 113.6 (2C), 65.4,
60.9, 55.0, 51.7, 41.8, 31.8, 17.5, 14.2. HRMS: m/z 494.1744 (M+).
General Procedure for Preparation of 1-Phenyl-3-methyl-6-
oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-f][1,4]thiazepine-4-car-
boxamides 8a,b. The title compounds were prepared by conden-
sation of 3c with the corresponding amine and isocyanide using
the same procedure, which was described for compounds 6{1-
N-Benzyl-4-(4-methoxyphenyl)-6-methyl-3-oxo-3,4,5,6-tet-
rahydro-2H-[1,4]thiazepino[6,7-b]indole-5-carboxamide 9c. Yield:
1
64%. H NMR (DMSO-d6): δ 8.54 (t, J ) 6,0 Hz, 1 H), 7.50 (d,
J ) 8.1 Hz, 1 H),k 7.39 (d, J ) 8.1 Hz, 1 H), 7.36-7.04 (m, 7 H),
7.17 (d, J ) 9.0 Hz, 2 H), 6.92 (d, J ) 9.0 Hz, 2 H), 5.68 (s, 1 H),
4.45 - 4.28 (m, 2 H), 4.03 (d, J ) 13.8 Hz, 1 H), 3.74 (s, 3 H),
3.65 (s, 3 H), 3.46 (d, J ) 13.8 Hz, 1 H). 13C NMR (DMSO-d6):
2818 J. Org. Chem., Vol. 71, No. 7, 2006

Carbamoyl-Substituted Heteroannelated [1,4]Thiazepines
δ 169.3, 168.4, 157.8, 139.2, 137.4, 136.6, 128.2 (2C), 127.8 (2C),
127.3 (2C), 126.8, 124.9 (2C), 122.6, 119.4, 117.8, 114.1 (2C),
110.5, 103.7, 62.0, 55.3, 43.3, 33.0, 30.1. HRMS: m/z 472.1688
(M+). Anal. Calcd for C27H25N3O3S: C, 68.77; H, 5.34; N, 8.91.
Found: C, 68.64; H, 5.15; N, 8.69.
(m, 7 H),7.22 (t, J ) 7.7 Hz, 1 H), 7.05 (t, J ) 7.7 Hz, 1 H), 5.02
(d, J ) 16.8 Hz, 1 H), 4.49 (d, J ) 16.8 Hz, 1 H), 3.91 (d, J )
13.8 Hz, 1 H), 3.68-3.58 (m, 1 H), 3.39 (d, J ) 13.8 Hz, 1 H),
1.69-1.09 Hz, 7 H), 1.51 (s, 3 H), 0.97-0.78 (m, 1 H). 13C NMR
(DMSO-d6): δ 170.2, 164.2, 138.7, 135.8, 130.8, 130.3, 128.4 (2C),
127.9 (2C), 126.0, 124.4, 119.5, 119.4, 112.3 (2C), 109.4, 68.3,
51.0, 48.4, 42.4, 31.5, 31.4, 25.4, 23.5, 23.4. HRMS: m/z 478.1507
(M+).
N-Benzyl-6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4,5,6-
tetrahydro-2H-[1,4]thiazepino[6,7-b]indole-5-carboxamide 9d.
1
Yield: 56%. H NMR (DMSO-d6): δ 8.59 (t, J ) 5.7 Hz, 1 H),
7.75 (s, 1 H), 7.71-7.57 (m, 2 H), 7.57-7.18 (m, 9 H), 7.11 (t, J
) 7.5 Hz, 1 H), 5.95 (s, 1 H), 4.47-4.29 (m, 2 H), 4.02 (d, J )
14.0 Hz, 1 H), 3.70 (s, 3zH), 3.55 (d, J ) 14.0 Hz, 1 H). HRMS:
m/z 510.1460 (M+). Anal. Calcd for C27H22F3N3O2S: C, 63.64; H,
4.35; N, 8.25. Found: C, 63.91; H, 4.63; N, 8.51.
N-Cyclopentyl-3-methyl-4-(4-methylbenzyl)-5-oxo-3,4,5,6-tet-
rahydro-2H-[1,4]thiazepino[6,7-b]indole-3-carboxamide 12c.
1
Yield: 75%. H NMR (DMSO-d6): δ 11.47 (s, 1 H), 7.56-7.30
(m, 5 H), 7.22 (t, J ) 7.2 Hz, 1 H), 7.17-7.00 (m, 3 H), 5.05 (d,
J ) 16.0 Hz, 1 H), 4.47 (d, J ) 16.0 Hz, 1ZH), 3.90 (d, J ) 13.8
Hz, 1 H), 3.69-3.59 (m, J ) (1 H), 3.35 (d, J ) 13.8 Hz, 1 H),
2.26 (s, 3 H), 1.67-1.13 (m, 7 H), 1.51 (s, 3 H), 0.92-0.75 (m, 1
H); 13C NMR (DMSO-d6): δ 170.3, 164.2, 136.5, 135.8, 135.3,
130.6, 128.6 (2C), 126.5, 126.1, 124.3, 119.5, 119.4, 112.2 (2C),
109.1, 68.2, 51.0, 48.4, 42.6, 31.5, 31.4, 25.5, 23.5, 23.4, 20.6.
HRMS: m/z 448.2056 (M+).
3-(2-Oxopropylsulfanyl)-1H-indole-2-carboxylic Acid 11. A
solution of 3-mercapto-1H-indole-2-carboxylic acid 10 (19.3 g, 0.1
mol) in 200 mL of 10% aqueous Na2CO3 was treated with
bromoacetone (16.4 g, 0.12 mol) at rt under stirring. The mixture
was stirred at rt for 1 h and then acidified with diluted aqueous
HCl until pH 3 was reached. The formed precipitate was filtered
off, washed thoroughly with water, and dried to yield 11 (20 g,
80% yield), which was used at the next step without any further
purification. 1H NMR (DMSO-d6): δ 11.49 (s, 1 H), 10.22 (br s 1
H), 7.45-7.26 (m, 4 H), 3.45 (s, 2 H), 1.8 (s, 3 H). HRMS: m/z
249.2932 (M+). Anal. Calcd for C26H27N3O5S: C, 63.27; H, 5.51;
N, 8.51. Found: C, 62.99; H, 5.22; N, 8.28.
General Procedure for Preparation of N-Cyclopentyl-3-
methyl-5-oxo-3,4,5,6-tetrahydro-2H-[1,4]thiazepino[6,7-b]indole-
3-carboxamides 12a-e. Equimolar amounts (0.5 mmol) of com-
pound 11, cyclopentyl isocyanide, and the corresponding benzylamine
were dissolved in methanol (3 mL). The reaction mixture was stirred
at rt for 2-3 h. The reaction was followed by TLC (5% MeOH in
CH2Cl2). On completion, the reaction mixture was cooled to rt,
the formed precipitate was filtered off, and purified by chroma-
tography on silica gel, eluting with a gradient of 0-10% MeOH in
CH2Cl2.
N-Cyclopentyl-4-(4-fluorobenzyl)-3-methyl-5-oxo-3,4,5,6-tet-
rahydro-2H-[1,4]thiazepino[6,7-b]indole-3-carboxamide 12d.
1
Yield: 58%. H NMR (DMSO-d6): δ 11.47 (s, 1 H), 7.50-7.3
(m, 5 H), 7.22 (t, J ) 7.2 Hz, 1 H), 7.17-6.95 (m, 5 H), 5.07 (d,
J ) 16.0 Hz,1 H), 4.49 (d, J ) 16.0 Hz, 1 H), 3.90 (d, J ) 13.8
Hz, 1 H), 3.69 (q, J ) 6.0 Hz, 1 H), 3.34 (d, J - 13.8 Hz, 1 H),
1.72-1.14 (m, 7 H), 1.53 (s, 3 H), 1.02-0.83 (m, 1 H). 13C NMR
(DMSO-d6): δ 170.3, 164.3, 160.8, 135.8 (2C), 130.5, 128.5, 128.4,
126.0, 124.3, 119.5, 119.4, 114.8, 114.5, 112.3 (2C), 109.2, 68.2,
51.0, 48.2, 42.4, 31.5, 31.4, 25.5, 23.5, 12.4. HRMS: m/z 452.1800
(M+).
4-Benzyl-N-cyclopentyl-3-methyl-5-oxo-3,4,5,6-tetrahydro-
2H-[1,4]thiazepino[6,7-b]indole-3-carboxamide 12e. Yield: 63%.
1H NMR (DMSO-d6): δ 11.54 (s, 1 H), 7.5-7.0 (m, 10), 5.13 (d,
J ) 16.8 Hz, 1 H), 4.46 (d, J ) 16.8 Hz, 1 H), 3.90 (d, J ) 13.8
Hz, 1 H), 3.70 (q, J ) 6.2 Hz, 1 H), 3.33 (d, J ) 13.8 Hz, 1 H),
1.52 (s, 3 H), 1.67-0.8 (m, 8 H). 13C NMR (DMSO-d6): δ 170.3,
164.2, 139.6, 135.8, 130.5, 128.0 (2C), 126.5 (2C), 125.3, 126.1,
124.3, 119.5, 119.4, 112.3, 109.2, 68.3, 51.0, 48.8, 42.6, 31.5, 31.4,
25.5, 23.5, 23.4. HRMS: m/z 434.1904 (M+).
4-(1,3-Benzodioxol-5-ylmethyl)-N-cyclopentyl-3-methyl-5-oxo-
3,4,5,6-tetrahydro-2H-[1,4]thiazepino[6,7-b]indole-3-carboxam-
1
ide 12a. Yield: 68%. H NMR (DMSO-d6): δ 11.57 (s, 1 H),
7.53-7.30 (m, 3 H), 7.21 (t, J ) 7.9 Hz, 1 H), 7.10-6.98 (m, 2
H), 6.91-6.77 (m, 2 H), 5.97 (d, J ) 3.4 Hz, 2 H), 5.00 (d, J )
16.2 Hz, 1 H), 4.44 (d, J ) 16.2 Hz, 1 H), 3.92 (d, J ) 13.8 Hz,
1 H), 3.63-3.55 (m, 1 H), 3.33 (d, J ) 13.8 Hz, 1 H), 1.65-1.08
(m, 7 H), 1,51 (s, 3 H), 0.92-0.73 (m, 1 H). 13C NMR (DMSO-
d6): δ 170.3, 164.5, 147.1, 145.6, 135.9, 133.5, 130.7, 126.1, 124.2,
119.5, 119.4, 112.2 (2C), 108.7, 107.8, 107.5, 100.7, 68.0, 51.0,
48.1, 42.5, 31.5, 31.4, 25.6, 23.5, 23.4. HRMS: m/z 478.1793 (M+).
4-(4-Chlorobenzyl)-N-cyclopentyl-3-methyl-5-oxo-3,4,5,6-tet-
rahydro-2H-[1,4]thiazepino[6,7-b]indole-3-carboxamide 12b.
Acknowledgment. We thank Dr. Konstantin V. Balakin and
Dr. Yan A. Ivanenkov (ChemDiv, Inc.) for help in preparation
of the manuscript.
Supporting Information Available: Structures and yields of
compounds 6{26-45} and spectral and crystallographic data for
the synthesized compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
Yield: 64%. H NMR (DMSO-d6): δ 11.56 (s, 1 H), 7.56-7.28
JO052640W
J. Org. Chem, Vol. 71, No. 7, 2006 2819