Synthesis of 7-sulfamoyl-substituted 2-oxo-2,3,4,5-tetrahydro-1H-benzo[b] azepines

Article abstract of DOI:10.1080/00397910600943493

Sulfochlorination of 2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine led to regioselective formation of the corresponding 7-chlorosulfonyl derivative. Starting from this reagent, a large number of substituted 2-oxo-7-sulfamoyl-2,3, 4,5-tetrahydro-1H-benzo[b]a

Full text of DOI:10.1080/00397910600943493

This article was downloaded by: [Stony Brook University]
On: 26 October 2014, At: 02:41
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of 7‐Sulfamoyl‐substituted
2‐Oxo‐2,3,4,5‐tetrahydro‐1H‐benzo[b]azepines
Mikhail V. Dorogov a , Sergey A. Ivanovsky a , Maria Y. Khakhina a , Dmitry V.
Kravchenko b , Sergey E. Tkachenko c & Alexandre V. Ivachtchenko c
a Ushinsky Yaroslavl State Pedagogical University , Yaroslavl, Russia
b Chemical Diversity Research Institute , Khimki, Moscow, Russia
c ChemDiv, Inc. , San Diego, California, USA
Published online: 24 Nov 2006.
To cite this article: Mikhail V. Dorogov , Sergey A. Ivanovsky , Maria Y. Khakhina , Dmitry V. Kravchenko ,
Sergey E. Tkachenko & Alexandre V. Ivachtchenko (2006) Synthesis of 7‐Sulfamoyl‐substituted
2‐Oxo‐2,3,4,5‐tetrahydro‐1H‐benzo[b]azepines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:23, 3525-3535, DOI: 10.1080/00397910600943493
To link to this article: http://dx.doi.org/10.1080/00397910600943493
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 36: 3525–3535, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600943493
Synthesis of 7-Sulfamoyl-substituted
2-Oxo-2,3,4,5-tetrahydro-1H-
benzo[b]azepines
Mikhail V. Dorogov, Sergey A. Ivanovsky, and
Maria Y. Khakhina
Ushinsky Yaroslavl State Pedagogical University, Yaroslavl, Russia
Dmitry V. Kravchenko
Chemical Diversity Research Institute, Khimki, Moscow, Russia
Sergey E. Tkachenko and Alexandre V. Ivachtchenko
ChemDiv, Inc., San Diego, California, USA
Abstract: Sulfochlorination of 2-pxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine led to
regioselective formation of the corresponding 7-chlorosulfonyl derivative. Starting
from this reagent, a large number of substituted 2-oxo-7-sulfamoyl-2,3,4,5-tetra-
hydro-1H-benzo[b]azepines were obtained. This approach is amenable to combinatorial
production of the title compounds, which possess promising therapeutic potential.
Keywords: Benzoazepines, combinatorial synthesis, regioselective reaction,
sulfonamides
The 2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine heterocycle is a core
scaffold of many physiologically active compounds, including protease inhibi-
tors,[1,2] calcium-channel blockers,[3] N-methyl-D-aspartate (NMDA)
glycine-site antagonists,[4] integrin antagonists,[5] and growth hormone secre-
tagogues,[6] to name just a few. Beilstein database[7] cites more than 2,600
compounds, including 650 physiologically active ones, which contain this
fragment. According to these numerous examples, the 2-oxo-2,3,4,5-
Received in the USA April 20, 2006
Address correspondence to Alexandre V. Ivachtchenko, ChemDiv, Inc., 11558
Sorrento Valley Road, Suite 5, San Diego, CA 92121, USA. E-mail: av@chemdiv.com
3525

3526
M. V. Dorogov et al.
tetrahydro-1H-benzo[b]azepine heterocycle can be considered as a privileged
one. The term privileged structure describes structural chemotypes (orig-
inally, benzodiazepine-2-ones[8]) that bind to multiple unrelated classes of
protein receptors as high affinity ligands.[9,10] Privileged substructures are
typically rigid, polycyclic, or heterocyclic systems capable of orienting
various substituents in a well-defined three-dimensional space.
To the best of our knowledge, there have been no 7-sulfonyl derivatives of
2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine heterocycle reported to date.
This situation prompted us to explore synthetic routes to 2-oxo-7-
sulfamoyl-2,3,4,5-tetrahydro-1H-benzo[b]azepines, which can serve as a
promising source of bioactive molecules.
Synthetic routes to 2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine 1,
which was used in this work as an initial reagent, are well documented in
literature. For example, compound 1 can be prepared by self-condensation
of ethyl 4-(2-aminophenyl)butanoate I[11] or by interaction of 1-tetralone
(3,4-dihydro-1(2H)-naphtalenone) II with sodium azide.[12,13] In our
opinion, the reaction of 1-tetralone II with hydroxylamine followed by the
Beckman rearrangement of the resulting oxime III is the most suitable
method for the preparation of 1 (Scheme 1).[14] This method, which was
used in this work, provides optimal yield and is experimentally convenient.
2-Oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-sulfonyl chloride 2 was
prepared in 80% yield by treatment of 1 (1 equiv.) with a mixture containing
5 equiv. of chlorosulfonic acid and the same volume of CCl4. The reaction was
regioselective and led to one major 7-substituted product, as was evidenced
1
from O-1O nuclear Overhauser effect spectroscopy (NOESY) 2-D corre-
lation spectra.
A combinatorial library of 265 substituted 2-pxo-2,3,4,5-tetrahydro-1H-
benzo[b]azepine-7-sulfonamides 5f1–288g was further synthesized by
treatment of chloride 2 with various amines 3 and 4 in the presence of
Scheme 1. Synthesis of 2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine.

Synthesis of Substituted Benzo[b]azepines
3527
Scheme 2. Synthesis of sulfonamide derivatives of 2-pxo-2,3,4,5-tetrahydro-1H-ben-
zo[b]azepine: (a) 708C, 3 h, 80%; (b) dioxane, TEA, 608C, 3 h, 40–85%; (c) NaOH,
H2O, 508C, 1 h, 50–85%; (d) 1,4-dioxane, TEA, 608C, 3 h, 40–85%; and
(e) NaOH, H2O, 1008C, 15 min, 60–85%.
triethylamine (TEA) (1:1.1:1.5) in 1,4-dioxane (Scheme 2). In these parallel
reactions, we used 190 primary amines 3f1–165g and 98 secondary amines
4f1–98g, including alkylamines, cycloalkylamines, substituted anilines,
benzyl- and phenethylamines, pyrrolidines, piperidines, piperazines, morpho-
lines, and heteroarylamines. Structures of some representative amines are
given in Fig. 1.
The structural diversity of the sulfonyl amide derivatives of 1 can be
increased through application of various amino acids or their ester derivatives
as amine components. Reaction of chloride 2 with amino acids 6a–g in an
aqueous solution of NaOH at 508C afforded the corresponding carboxylic
acids 7a–g in 40–70% yield. Alternatively, acids 7 can be obtained via the cor-
responding alkyl carboxylate intermediates in those cases when the correspond-
ing amino esters are more commercially accessible than the free acids. For
example, the reaction of chloride 2 with ethyl nipecotate 8a or ethyl isonipeco-
tate 8b followed by alkali hydrolysis of the obtained esters 9a,b led to acids 7h,i.

3528
M. V. Dorogov et al.
Figure 1. Representative primary 3f1–165g and secondary 4f1–98g amines.
The resulting acids 7a–i were used as building blocks for parallel synthesis
of a small series of carboxamides 11a–i. The latters were synthesized using
1,10-carbonyldiimidazole (CDI)-promoted coupling of acids 7a–i with several
arbitrary amines from the corresponding sets 3f1–165g and 4f1–98g
(Scheme 3). Reaction of acids 7a–i with CDI (0.9 equiv.) readily proceeded
in dry DMF at 608C. The resulting imidazolide intermediates 10a–i were
then treated with the corresponding amines to obtain the final products 11a–i
in 30–70% yield (from 7a–i). In most cases, the desired products precipitated
from the reaction mixtures upon addition of water. Purity of the synthesized
compounds collected as precipitates was 95% or higher. Given the simple
synthesis and purification procedures, the developed approach to carboxamides
11a–i can be readily applied in a high-throughput combinatorial format. The
analytical samples were obtained by recrystallization from ethanol. Structures
and yields of the synthesized compounds 11a–i are given in Table 1.
All the synthesized compounds within the combinatorial series 5f1–
1
288g, 7a–i, and 11a–i were characterized by H NMR, liquid chromato-
graphy mass-spectrometry; CDI, 1,10-carbonyldiimidazole (LCMS), and
elemental analysis. The analytical data were in agreement with the
suggested structures.
The regioselective character of sulfochlorination of compound 1 has been
proven by 1H NMR studies. Thus, 1H NMR spectra of all the synthesized sul-
fonamides contain three signals corresponding to abx-system: two doublets
with Jo ¼ 8.3 Hz and Jm ¼ 1.8 Hz and a doublet of doublets with similar
spin–spin coupling constants. This picture corresponds to location of the
1
sulfonyl group in positions 7 or 8. In H-1H NOESY spectra of a sample
Scheme 3. Synthesis of carboxamides 11a–i.

Synthesis of Substituted Benzo[b]azepines
3529
Table 1. Structures and yields of compounds 11a–i
Compound
Y
NR1R2
Yield (%)
75
5f1g
—
5f2g
5f3g
11a
—
—
80
67
52
11b
45
11c
11d
60
67
11e
11f
53
65
11g
54
11h
11i
50
70
compound 5f2g (Fig. 2), we observed a cross-pick, which characterizes an
interaction of the H1 proton of NH group with the H9 proton of benzene
ring. The 1-D NMR signal of this proton is a doublet (Jo ¼ 8.3 Hz) of the
abx-system. Such a picture would be impossible if the sulfonyl group was
in position 8. In this case, the signal would be a singlet or a doublet with a

3530
M. V. Dorogov et al.
Figure 2. 7-(4-Methyl-piperidine-1-sulfonyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-
1
one 5f2g H-1H NOESY spectra.
small coupling constant corresponding to meta-interaction H9-H7. At the
same time, we observed a cross-pick characterizing the ortho-interaction
H9-H8. The actual spectrum also contains a couple of doublet signals
(Jm ¼ 1.8 Hz), which correspond to meta-interacting protons H6-H8. One of
them gives a cross-pick with a signal of the H5-proton (2.8 ppm). The
observed signals unambiguously prove the location of the sulfonyl group in
position 7 of the 2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine heterocycle.
In summary, an efficient way to combinatorial libraries of novel
7-sulfamoyl derivatives of 2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine
was developed. The desired compounds were obtained in good to excellent
yields with a high level of purity using simple purification procedures. The
synthesized compounds have great potential bioactivity and are valuable
objects for biological screening.
Structures and 1H NMR spectra of synthesized compounds are available
from the authors.
EXPERIMENTAL
General Information
Melting points (8C) were measured with Koeffler melting-point apparatus and
are uncorrected. Thin-layer chromatography (TLC) was performed on

Synthesis of Substituted Benzo[b]azepines
3531
1
aluminum sheets precoated with silica gel (Merck, Kieselgel 60 F-254). H
NMR spectra were recorded on Bruker AMX-400 using TMS as an internal
standard (chemical shifts in parts per million, ppm). LCMS spectra were
recorded with PE SCIEX API 150EX liquid chromatograph equipped with a
UV detector (lmax 215 and 254 nm) and using a C18 column (100 ꢀ 4 mm).
Elution started with water, ended with acetonitrile/water (95:5, v/v), and
used a linear gradient at a flow rate of 0.15 mL/min and an analysis cycle
time of 25 min. All solvents and reagents were obtained from commercial
sources and used without purification. The parallel solution-phase syntheses
of compounds 5f1–288g were accomplished using a laboratory synthesizer
CombiSyn-012-3000 on the 50- to 100-mg scale.
2-Oxo-2,3,4,5-tetrahydro-1 H-benzo[b]azepine-7-sulfonyl chloride (2):
1,3,4,5-Tetrahydro-benzo[b]azepin-2-one 1 (0.5 mol) was slowly added to a
mixture of chlorosulfonic acid (165 mL, 2.5 mol) and tetrachloromethane
(165 mL) at 08C. The mixture was stirred at 708C for 3 h, then cooled
down, and poured onto crushed ice. The formed precipitate of 2-oxo-
2,3,4,5-tetrahydro-1 H-benzo[b]azepine-7-sulfonyl chloride 2 was collected
by filtration, washed with cold water, and purified by crystallization from
toluene to give pure 2 in 80% yield, mp 200–2028C (toluene).
General Procedure for Synthesis of 2-Oxo-2,3,4,5-tetrahydro-1H-
benzo[b]azepine-7-sulfonic Acid Amides (5f1–288g)
Sulfonyl chloride 2 (1.0 mmol) was added to a solution of amine 3 or 4
(1.1 mmol) and TEA (1.5 mmol) in dioxane (3 mL) at room temperature.
The mixture was stirred for 3 h at 608C, then cooled down to room tempera-
ture, and mixed with water (15 mL). The formed precipitate was collected by
filtration, washed with water, and recrystallized from 2-propanol to give pure
5 in 40–85% yields.
Analytical Data for Representative Compounds
2-Oxo-2,3,4,5-tetrahydro-1 H-benzo[b]azepine-7-sulfonic acid cyclopenty-
1
lamide 5f1g: yield 75%, mp 211–2148C; LCMS m/z 0309 (M þ 1); H NMR
0
0
0
(500 MHz): d 1.4 (m, 4H, 3 ,4 CH2), 1.6 (m, 4H, 2 ,5 CH2), 2.20 (m, 4H,
0
3,4CH2), 2.75 (t, 2H, CH2), 3.35 (m, 1H, 1 CH), 7.05 (d, 1H, J9–8 ¼ 8.3 Hz,
5
9CH), 7.3 (d, 1H, SO2NH), 7.55 (d, 1H, J6–8 ¼ 1.8 Hz, CH), 7.60 (dd, 1H,
6
8
J8–9 ¼ 8.3 Hz, J8–6 ¼ 1.8 Hz, CH), 9.75 [s, 1H, C(O)NH]. Anal. calcd. for
C27H28F3N3O2S: C (58.42%), H (6.54%), N (9.08%). Found: C (58.38%), H
(6.58%), N (8.89%).
7-(4-Methyl-piperidine-1-sulfonyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-
1
one 5f2g: yield 80%, mp 229–2328C; LCMS m/z 323 (M þ 1); H NMR

3532
M. V. Dorogov et al.
0
0
(500 MHz): d 0.830 (d, 2H, CCH3), 1.14 (m, 2Hax, 3 ,5 CH2), 1.3 (m, 1H, 4CH),
0
1.64 (m, 2Heq, 3 ,5 CH2), 2.15 (m, 2Hax, 2NCH2), 2.20 (m, 4H, 3,4CH2), 2.79
(t, 2H, 5CH2), 3.6 (m, 2Heq, 2NCH2), 7.15 (d, 1H, J9–8 ¼ 8.3 Hz, 9CH), 7.52
8
(dd, 1H, J8–9 ¼ 8.3 Hz, J8–6 ¼ 1.8 Hz, CH), 7.62 (d, 1H, J6–8 ¼ 1.8 Hz,
6CH), 9.93 [s, 1H, C(O)NH]. Anal. calcd. for C16H22N2O3S: C (59.60%), H
(6.88%), N (8.69%). Found: C (59.11%), H (6.96%), N (8.61%).
General Procedure for Synthesis of 4-(2-Oxo-2,3,4,5-tetrahydro-
1H-benzo[b]azepine-7-sulfonylamino)-carboxylic Acids (7a–g)
2-Oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-sulfonyl chloride 2 (0.1 mol)
was added to a solution of NaOH (0.22 mol) and amino acid 6a–g (0.11 mol) in
water (150 mL) at 308C. The mixture was stirred at 608C for 1 h, then cooled
down to room temperature, and neutralized with a 10% solution of hydro-
chloric acid to maintain pH 2–3. The formed precipitate was collected by
filtration, washed with water, and recrystallized from MeCN to give pure
7a–g in 40–70% yield.
Analytical Data for Representative Compounds
2-Methyl-[(2-oxo-2,3,4,5-tetrahydro-1H-1-benzo[b]azepine-7-yl)-sulfonyl]-
aminoacetic acid (7a): yield 55%, mp 237–2408C; LCMS m/z 313 (M þ 1);
1H NMR (500 MHz): d 2.23 (m, 4H, 4,3CH2), 2.8 (m, 5H, 5CH2, NCH3), 3.82
(s, 2H, NCH2), 7.11 (d, 1H, J9–8 ¼ 8.3 Hz, 9CH), 7.56 (dd, 1H, J8–
8
6
¼ 8.3 Hz, J8–6 ¼ 1.8 Hz, CH), 7.59 (d, 1H, J6–8 ¼ 1.8 Hz, CH), 9.75 [s,
9
1H, C(O)NH], (s, 1H, COOH). Anal. calcd. for C13H16N2O5S: C (49.99%),
H (5.16%), N (8.97%). Found: C (50.06%), H (5.18%), N (8.91%).
3-Methyl-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-sulfonylamino)-
1
butyric acid (7b): yield 67%, mp 221–2228C; LCMS m/z 341 (M þ 1); H
NMR (500 MHz): d 0.85 (d, 3H, CH3), 0.9 (d, 3H, CH3), 2.0 (m, 1H,
5
CCHC), 2.2 (m, 4H, 4,3CH2), 2.8 (m, 2H, CH2), 3.5 [m, 1H, NCHC(O)],
7.05 (d, 1H, J9–8 ¼ 8.3 Hz, 9CH), 7.16 [d, 1H, JS(O)NH-NCH2 ¼ 6.6 Hz,
S(O)NH], 7.58 (m, 2H, 6,8CH), 9.7 [s, 1H, C(O)NH], 12.1 (s, 1H, COOH).
Anal. calcd. for C15H20N2O5S: C (52.93%), H (5.92%), N (8.23%). Found:
C (52.99%), H (5.86%), N (8.28%).
General Procedure for Synthesis of Ethyl 4-(2-Oxo-2,3,4,5-
tetrahydro-1H-benzo[b]azepine-7-sulfonylamino)-carboxylates
(9a,b)
2-Oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-sulfonyl chloride 2 (0.2 mol)
was slowly added to a solution of ethyl carboxylate 8a,b (0.22 mol) and

Synthesis of Substituted Benzo[b]azepines
3533
TEA (0.22 mol) in dry DMF (50 mL). The mixture was stirred for 15 h at
room temperature and then mixed with 5% solution of hydrochloric acid
(200 mL). The formed precipitate was collected by filtration, washed with
water, and recrystallized from ethanol to give pure 9a,b in 70–80% yield.
Analytical Data
1-(2-Oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-sulfonyl)-piperidine-4-
carboxylic acid ethyl ester (8a): yield 80%, mp 165–1678C, LCMS m/z 381
(M þ 1); 1H NMR (500 MHz): d 1.15 (t, 3H, CH3), 1.7 (m, 2Hax, CCH2), 1.9
(m, 2Heq, CCH2), 2.25 [m, 5H, C(O)CH, 4,3CH2], 2.4 (m, 2Hax, NCH2), 2.9
5
(m, 2H, CH2), 3.55 (m, 2Heq, NCH2), 4.05 (m, 2H, OCH2), 7.1 (d, 1H, J9–
9
¼ 8.3 Hz, CH), 7.50 (dd, 1H, J8–9 ¼ 8.3 Hz, J8–6 ¼ 1.8 Hz, 28CH), 7.55
8
(d, 1H, J6–8 ¼ 1.8 Hz, 6CH), 9.8 [s, 1H, C(O)NH]. Anal. calcd. for
C18H24N2O5 S: C (56.82%), H (6.36%), N (7.36%). Found: C (56.94%), H
(6.38%), N (7.34%).
General Procedure for Synthesis of 4-(2-Oxo-2,3,4,5-tetrahydro-
1H-benzo[b]azepine-7-sulfonylamino)-carboxylic Acids (7 h,i).
A suspension of ester 9a,b (0.1 mol) in a mixture of ethanol (30 mL) and 5%
solution of NaOH (100 mL) was stirred at 808C for 1 h. The unsolved precipi-
tate was filtered off; the clear solution was cooled down to room temperature
and acidified with 10% solution of hydrochloric acid to maintain pH 2–3. The
formed precipitate was collected by filtration, washed with water, and recrys-
tallized from MeCN to give pure 7h,i in 55–70% yields.
Analytical Data
1-[(2-Oxo-2,3,4,5-tetrahydro-1H-1-benzo[b]azepine-7-yl)sulfonyl]-4-
piperidinecarboxylic acid (7 h): yield 55%, mp 270–2738C, LCMS m/z 353
(M þ 1); 1H NMR (500 MHz): d 1.65 (m, 2Hax, CCH2), 1.9 (m, 2Heq, CCH2),
2.18 [m, 1H, C(O)CH], 2.22 (m, 4H, 4,3CH2), 2.5 (m, 2Hax, NCH2),
5
9
2.8 (m, 2H, CH2), 3.5 (m, 2Heq, NCH2), 7.1 (d, 1H, J9–8 ¼ 8.3 Hz, CH),
7.50 (dd, 1H, J8–9 ¼ 8.3 Hz, J8–6 ¼ 1.8 Hz, 8CH), 7.55 (d, 1H,
J6–8 ¼ 1.8 Hz, 6CH), 9.8 [s, 1H, C(O)NH], 12.0 (s, 1H, COOH).
Anal. calcd. for C16H20N2O5S: C (54.53%), H (5.72%), N (7.95%). Found:
C (54.58%), H (5.65%), N (7.88%).
General Procedure for Synthesis of 4-(2-Oxo-2,3,4,5-tetrahydro-1H-
benzo[b]azepine-7-sulfonylamino)-carboxylic Acid Amides 11a–i
A suspension of carboxylic acid 7a–i (0.9 mmol) and CDI (0.8 mmol) in
4 mL of dry DMF was stirred at 50–608C until full dissolution of the initial

3534
M. V. Dorogov et al.
material. Then amine 3 or 4 (0.9 mmol) was added to the resulting solution,
and the mixture was stirred at 1008C for 2 h. Then the mixture was
cooled down to room temperature and mixed with water (20–30 mL). The
formed precipitate was collected by filtration, washed with cold water
(50 mL), and recrystallized from ethanol to give pure 7a–i in 30–70% yield.
Analytical Data for Representative Compounds
2-[Methyl-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-sulfonyl)-
amino]-N-quinolin-4-yl-acetamide (11a): yield 52%, mp 254–2578C,
1
4
LCMS m/z 439 (M þ 1); H NMR (500 MHz): d 2.15 (m, 2H, CH2), 2.25
3
(m, 2H, CH2), 2.6 (s, 3H, NCH3), 2.7 (m, 2H, CH2), 2.85 (s, 3H, ArCH3),
5
9
4.2 (s, 2H, NCH2), 7.12 (d, 1H, J9–8 ¼ 8.3 Hz, CH), 7.45 (m, 1H, CHAr),
7.65 (m, 3H 6,8CH, CHAr), 7.85 (d, 1H, CHAr), 7.9 (s, 1H, CHAr), 8.2
(d, 1H, CHAr), 9.6 [s, 1H, C(O)NH], 10.0 [s, 1H, C(O)NH]. Anal. calcd.
for C22H22N4O4S: C (60.26%), H (5.06%), N (12.78%). Found: C
(60.21%), H (4.98%), N (12.82%).
2-Oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-sulfonic acid [1-(2,3-
dihydro-indole-1-carbonyl)-2-methyl-propyl]-amide (11b): yield 45%,
mp 231–2348C, LCMS m/z 442 (M þ 1); 1H NMR (500 MHz): d 1.0
(m, 6H, 2CH3), 1.85 (m, 1H, CCHC) 2.0 (m, 2H, CCH2), 2.5 (m, 4H,
5
4,3CH2), 3.05 (m, 2H, CH2), 3.85 [m, 1H, NCHC(O)], 4.0 (m, 2H, NCH2),
6.95 (m, 2H, CHAr, 9CH), 7.00 (t, 1H, CHAr), 7.05 [d, 1H, JS(O)NH-
¼ 6.6 Hz, S(O)NH], 7.5 (d, 1H, J6–8 ¼ 1.8 Hz, 6CH), 7.6 (m, 2H,
NCH2
8CH, CHAr), 7.85 (d, 1H, CHAr), 9.5 [s, 1H, C(O)NH]. Anal. calcd. for
C23H27N3O4S: C (62.56%), H (6.16%), N (9.52%). Found: C (62.59%), H
(6.10%), N (9.48%).
ACKNOWLEDGMENTS
The authors thank Konstantin V. Balakin (ChemDiv, Inc.) for discussion and
help in preparation of the manuscript.
REFERENCES
1. Tabrizchi, R. SLV-306. Solvay. Curr. Opin. Investig. Drugs 2003, 4, 329–332.
2. Robl, J. A.; Simpkins, L. M.; Stevenson, J.; Sun, C. Q.; Murugesan, N.;
Barrish, J. C.; Asaad, M. M.; Bird, J. E.; Schaeffer, T. R.; Trippodo, N. R.;
Petrillo, E. W.; Karanewsky, D. S. Dual metalloprotease inhibitors, I: Constrained
peptodomimetics of mercaptoacyl dipeptides. Bioorg. Med. Chem. Lett. 1994, 4,
1789–1794.

Synthesis of Substituted Benzo[b]azepines
3535
3. Floyd, D. M.; Kimball, S. D.; Krapcho, J.; Das, J.; Turk, C. F.; Moquin, R. V.;
Lago, M. W.; Duff, K. J.; Lee, V. G.; White, R. E. Benzazepinone calcium
channel blockers, 2: Structure–activity and drug metabolism studies leading to
potent antihypertensive agents: Comparison with benzothiazepinones. J. Med.
Chem. 1992, 35, 756–772.
4. Donati, D.; Fabio, R. D. Embolizing mobile thrombus associated with prolapse and
mixoid degeneration of the mitral valve. Pharm. Acta Helv. 2000, 74, 239–246.
5. Kling, A.; Backfisch, G.; Delzer, J.; Geneste, H.; Graef, C.; Hornberger, W.;
Lange, U. E. W.; Lauterbach, A.; Seitz, W.; Subkowski, T. Bioorganic design
and synthesis of 1,5- and 2,5-substituted tetrahydrobenzazepinones as novel
potent and selective integrin alphaVbeta3 antagonists. Med. Chem. 2003, 11,
1319–1341.
6. Schoen, W. R.; Pisano, J. M.; Prendergast, K.; Wyvratt Jr. M. J.; Fisher, M. H.;
Cheng, K.; Chan, W. W.; Butler, B.; Smith, R. G.; Ball, R. G. A novel 3-substituted
benzazepinone growth hormone secretagogue (L-692,429). J. Med. Chem. 1994,
37, 897–906.
7. http:// www.mdl.com/products/knowledge/crossfire_beilstein/index.jsp
8. Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.;
Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S.;
Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.;
Springer, J. P.; Hirshfield, J. Methods for drug discovery: Development of
potent, selective, orally effective cholecystokinin antagonists. J. Med. Chem.
198831, 2235–2246.
9. Horton, D. A.; Bourne, G. T.; Smythe, M. L. The combinatorial synthesis of
bicyclic privileged structures or privileged substructures. Chem. Rev. 2003103,
893–930.
10. Mason, J.; Morize, I.; Menard, P.; Cheney, D.; Hulme, C.; Labaudiniere, R. New
4-point pharmacophore method for molecular similarity and diversity applications:
Overview of the method and applications, including a novel approach to the design
of combinatorial libraries containing privileged substructures. J. Med. Chem.
199942, 3251–3264.
11. Ito, Y.; Kobayashi, K.; Maeno, M.; Saegusa, T. A new synthetic method for prep-
aration of 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one derivatives. Chem. Lett.
19805, 487–490.
12. Chen, W.-Y.; ;Gilman, N. W. Synthesis of 7-phenylpyrimido[5,4-d][1]benzaze-
pin-2-ones. J. Heterocycl. Chem. 198320, 663–666.
13. Asaad, M. M.; Robl, J. A.; Simpkins, L. M. N-Formylhydroxylaminecontainingdi-
peptides:Generationofanewclassofvasopeptidaseinhibitors. Bioorg. Med. Chem.
Lett 200010, 257–260.
14. Tamura, S. Y.; Goldman, E. A.; Semple, J. E.; Bergum, P. W. Novel benzo-fused
lactam scaffolds as factor Xa inhibitors. Bioorg. Med. Chem. Lett. 19999,
2573–2578.