New four-component ugi-type reaction. Synthesis of heterocyclic structures containing a pyrrolo[1,2-a][1,4]diazepine fragment

Article abstract of DOI:10.1021/jo048204b

(Chemical Equation Presented) We present a convenient synthesis of novel heterocyclic structures containing pyrrolo[1,2-α][l,4]diazepine fragment using a novel modification of four-component Ugi condensation. We demonstrate the usefulness and versatility

Full text of DOI:10.1021/jo048204b

approaches to the related scaffolds will provide a valuable
source of novel physiologically active agents.
New Four-Component Ugi-Type Reaction.
Synthesis of Heterocyclic Structures
Containing a Pyrrolo[1,2-a][1,4]diazepine
Fragment
Depending on the substitution pattern of pyrrolo[1,2-
a][1,4]diazepines, several synthetic approaches are possi-
ble. For instance, synthetic approaches to pyrrolo[1,2-a]-
[1,4]benzodiazepines based on Mannich reaction between
1-(2-aminomethylphenyl)-1H-pyrrole and aldehydes or
ketones were developed.2d,5 Syntheses of pyrrolothieno-
[1,4]diazepines utilizing 3-(2-formyl-1H-pyrrol-1-yl)-2-thio-
phenecarboxamide6 or 2-(2-formyl-1H-pyrrol-l-yl)-3-thio-
phenecarbonitrile7 as starting materials were reported.
The synthetic pathway leading to 5,6-dihydro-4H-furo-
[3,2-f]pyrrolo[1,2-a][1,4]diazepines was described starting
from R-bromophenones via 2-amino-3-furonitriles.8 How-
ever, the described synthetic strategies still have limita-
tions in terms of the possible substituents around the core
scaffold.
Alexey P. Ilyn,† Andrey S. Trifilenkov,‡
Julia A. Kuzovkova,‡ Sergey A. Kutepov,‡
Alexandre V. Nikitin,‡ and Alexandre V. Ivachtchenko*,†
ChemDiv, Inc., 11558 Sorrento Valley Rd., Suite 5,
San Diego, California, 92121, and Department of Organic
Chemistry, Chemical Diversity Research Institute,
114401 Khimki, Moscow Reg., Russia
av@chemdiv.com
Received October 12, 2004
In this work, we describe an efficient synthetic route
to aryl- and heteroaryl-fused carboxamide derivatives of
the pyrrolo[1,2-a][1,4]diazepine heterocycle, which were
not previously reported in the literature. Our synthetic
method is based on the four-component Ugi reaction
between aldehyde, amine, isonitrile, and carboxylic acid,
which has emerged as a powerful tool for rapid identifi-
cation and optimization of lead compounds in drug
discovery.9 One important modification of this reaction
is the use of bifunctional reagents. In particular, modified
syntheses using bifunctional keto acids (or aldehyde
acids), amine, and isonitrile as starting materials have
been reported. For example, reaction of ω-ketoacids10 or
aldehydes11 with the corresponding isonitriles and amines
led to â-lactams. A series of 2,3-dihydro-1H-isoindole-3-
ones was prepared from 2-formylbenzoic acid.12 Using 1,8-
naphthalaldehydic acid, 2-formylphenoxyacetic acid, and
2′-formylphenoxy-2-benzoic acid as the bifunctional re-
agents in Ugi coupling, a series of rare six-, seven-, and
eight-membered heterocyclic rings was obtained.12 Re-
cently, Marcaccini et al. reported a synthetic approach
to novel S,N-heterocycles, starting from the correspond-
ing thiacarboxylic keto acids.13 In this context, the syn-
thetic approach to the title structures developed in this
work can be referred to as an evolutionary modification
We present a convenient synthesis of novel heterocyclic
structures containing pyrrolo[1,2-a][1,4]diazepine fragment
using a novel modification of four-component Ugi condensa-
tion. 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.
Among a variety of physiologically active diazepines,
the derivatives of pyrrolo[1,2-a][1,4]benzodiazepines and
their bioisosteric analogues represent a relatively little-
explored group with interesting pharmaceutical proper-
ties. In particular, they were described as antitumor a-
gents acting against various types of leukemia cell lines1
and CNS active agents.2 A series of structurally related
imidazo[1,5-a][1,4]benzodiazepines entered preclinical
and clinical trials as agonists or antagonists of benzodi-
azepine receptors;3 one of them, Flumazenil,4 was launched
into market as neurologic drug. According to these exam-
ples, differently substituted pyrrolo[1,2-a][1,4]benzodia-
zepines and their modified analogues with bioisosterically
transformed benzene and pyrrole rings represent promis-
ing synthetic targets. Development of efficient synthetic
(3) (a) Atack, J. R. Curr. Drug Targets CNS Neurol. Disord. 2003,
2, 213-232. (b) Martin, J. R.; Jenck, F.; Moreau, J. L. J. Pharmacol.
Exp. Ther. 1995, 275, 405-411.
(4) Codding, P. W.; Muir, A. K. Mol. Pharmacol. 1985, 28, 178-
184.
(5) Raines, S.; Chai, S. Y.; Palopoli, F. P. J. Heterocycl. Chem. 1976,
13, 711-716.
* To whom correspondence should be addressed. Phone: (858) 794-
4860. Fax: (858) 794-4931.
(6) Boulouard, M.; Dallemagne, P.; Alsaiedi, A.; Rault, S. J. Het-
erocycl. Chem. 1996, 33, 1743-1749.
† ChemDiv, Inc.
‡ Chemical Diversity Research Institute.
(7) Boulouard, M.; Rault, S.; Alsaidi, A.; Dallemagne, P.; Robba, M.
J. Heterocycl. Chem. 1995, 32, 1719-1724.
(1) (a) Kaneko, T.; Wong, H.; Doyle, T. W.; Rose, W. C.; Bradner,
W. T. J. Med. Chem. 1985, 28, 388-392. (b) Lisowski, V.; Fabis, F.;
Pierre, A.; Caignard, D. H.; Renard, P.; Rault, S. J. Enzyme Inhib.
Med. Chem. 2002, 17, 403-407.
(8) Feng, X.; Lancelot, J.-C.; Gillard, A.-C.; Landelle, H.; Rault, S.
J. Heterocycl. Chem. 1998, 35, 1313-1316.
(9) (a) Ugi, I.; Lohberger, S.; Karl, R. The Passerini and Ugi
Reactions. In Comprehensive Organic Synthesis; Trost, B. M., Flem-
ming, I., Heathcock, C. Eds.; Pergamon Press: Oxford, 1991; Vol. 2,
pp 1083-1109. (b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000,
39, 3168-3210.
(2) (a) Hara, T.; Kayama, Y.; Mori, T.; Itoh, K.; Fujimori, H.; Sunami,
T.; Hashimoto, Y.; Ishimoto, S. J. Med. Chem. 1978, 21, 263-268. (b)
Vega, S.; Gil, M. S.; Darias, V.; Sanchez Mateo, C. C.; Exposito, M. A.;
Tello, M. L.; Albertos, L. M. Arch. Pharm. (Weinheim, Ger.) 1994, 327,
721-728. (c) Vega, S.; Gil, M. S.; Darias, V.; Sanchez Mateo, C. C.;
Exposito, M. A. Pharmazie 1995, 50, 27-33. (d) Massa, S.; Corelli, F.;
Artico, M.; Mai, A.; Silvestri, R.; Pantaleoni, G. C.; Palumbo, G.; Fanini,
D.; Giorgi, R. Farmacol. 1989, 44, 109-123. (e) Massa, S.; Artico, M.;
Mai, A.; Corelli, F.; Pantaleoni, G. C.; Giorgi, R.; Ottaviani, D.;
Cagnotto, A. Farmacologia 1990, 45, 1265-1281.
(10) Short, K. M.; Mjalli, A. M. M. Tetrahedron Lett. 1997, 38, 359-
362.
(11) Zhang, J.; Jacobson, A.; Rusche, J. R.; Herlihy, W. J. Org. Chem.
1999, 64, 1074-1076.
(12) Ley, S. V.; Taylor, S. J. Bioorg. Med. Chem. Lett. 2002, 12,
1813-1816.
10.1021/jo048204b CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/19/2005
1478
J. Org. Chem. 2005, 70, 1478-1481

SCHEME 1. Synthesis of Bifunctional Reagents
for Ugi Condensation
SCHEME 2. Four-Component Ugi Condensation
of the classical Ugi four-component reaction with the use
of bifunctional reagents.
In the first part of our work, syntheses of novel bi-
functional reagents for Ugi condensation 4a-c were ac-
complished (Scheme 1). The commercially available ami-
nocarboxylates 1a-c were easily converted to the corre-
sponding 1H-pyrrol-1-yl derivatives 2a-c using reaction
with 2,5-dimethoxytetrahydrofuran in acetic acid (yields
78-97%). Treatment of 2a-c with POCl3 at 50-60 °C
in the presence of DMF led to 2-formyl-1H-pyrroles 3a-c
in good yields (64-77%). Esters 3a-c were hydrolyzed
by aqueous alkali to furnish the desired aldehyde acids
4a-c in good yields (62-84%).
At the next step, we used a novel approach to the pyr-
rolo[1,2-a][1,4]diazepine heterocycles based on a novel
modification of the Ugi four-component reaction. The Ugi
condensation can be readily applied in combinatorial
chemistry approaches and is an effective synthetic method
to the assembly of differently substituted derivatives of
benzodiazepine.14 In this work we have found that the
reaction of aldehyde acids 4a-c with the corresponding
isonitriles and amines in methanol at 40 °C led to novel
pyrrolo[1,2-a][1,4]diazepine heterocyclic structures 5a-l
(yield 67-85%), 6a-h (yield 60-78%), and 7a,b (yield
75-85%) (Scheme 2), which were not previously de-
scribed in scientific literature.
The reaction presumably follows the same initial
course as the classical Ugi condensation with an inter-
mediate imine being attacked by the isonitrile to give a
nitrilium intermediate, which then undergoes intramo-
lecular cyclization.9 As a synthetic tool for creating di-
verse compound libraries, the developed Ugi-type con-
densation offers a large number of various amines and
isonitriles. We have observed that the nature of the initial
heterocyclic core moieties (e.g., types a-c) does not sub-
stantially affect the reaction yield and time, and various
aldehyde acids 4a-c could be used. With respect to amine
component, various aliphatic and aromatic primary am-
ines, such as substituted anilines, linear and branched
aliphatic amines, and nitrogen-containing compounds,
were tolerated without any limitations. A restriction is
the limited number of commercially or synthetically
available isonitriles. In this work, we used carbocyclic
isonitriles available from commercial sources. Structures
and yields of the synthesized compounds are shown in
Table 1.
In summary, we have shown that pyrrolo[1,2-a][1,4]-
diazepine heterocycles can be efficiently prepared by a
novel modification of four-component Ugi reaction of bi-
functional aldehyde-acids, isonitriles, and amines. Con-
sidering 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 pyrrolo-
[1,2-a][1,4]diazepines and their bioisosteric analogues. 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 obtained compounds represent valuable
starting points for the development of compounds of
biological interest. The use of compounds from series 5-7
in the search for novel bioactive agents is under inves-
tigation at Chemical Diversity, Inc. and will be reported
in due course.
Experimental Section
General Procedure for Preparation of Aryl-Fused 3-Oxo-
2,3-dihydro-1H-pyrrolo[1,2-a][1,4]diazepine-1-carboxylic
Acid Amides 5-7. Equimolar amounts of compounds 4a-c, the
isonitrile, and the corresponding amine were dissolved in meth-
anol to an approximate concentration of 1 M in each component.
The reaction mixture was stirred at 40 °C for 4-18 h. The re-
action was followed by TLC (5% MeOH in CH2Cl2). On comple-
tion, the reaction mixture was cooled to room temperature, and
the formed precipitate was filtered out and purified (if desired)
by recrystallization from diethyl ether or by chromatography on
silica gel, eluting with a gradient of 0-10% MeOH in CH2Cl2.
N-Cyclohexyl-5-(3-methoxybenzyl)-4-oxo-1-phenyl-1,4,5,6-
tetrahydropyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepine-6-
carboxamide 5a: mp 186-189 °C; IR (KBr, cm-1) ν 1630 (CO),
1670 (CO), 3330 (NH); 1H NMR (400 MHz, DMSO-d6 + CCl4) δ
0.75-1.7 (m, 10 H), 3.26-3.3 (m, 1 H), 3.73 (s, 3 H), 4.67 (d, J
) 2.3 Hz, 1 H), 4.8 (d, J ) 2.3 Hz, 1 H), 5.35 (s, 1 H), 6.0-6.1 (d,
J ) 4.9 Hz, 2 H), 6.15-6.22 (s, 1 H), 6.8 (d, J ) 4.0 Hz, 1 H),
7.0-7.1 (d+d, J ) 7.3 Hz, 2 H), 7.2-7.29 (t, J ) 7.3 Hz, 1 H),
7.38-7.51 (m, 5 H), 7.82 (s, 1 H); HRMS m/z 510.2493 (M+).
5-(2-Chlorobenzyl)-N-cyclohexyl-4-oxo-1-phenyl-1,4,5,6-
tetrahydropyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepine-6-
(13) (a) Marcaccini, S.; Pepino, R.; Torroba, T.; Miguel, D.; Garcia-
Valverde, M. Tetrahedron Lett. 2002, 43, 8591-8593. (b) Marcaccini,
S.; Miguel, D.; Torroba, T.; Garcia-Valverde, M. J. Org. Chem. 2003,
68, 3315-3318.
(14) (a) Kennedy, A. L.; Fryer, A. M.; Josey, J. A. Org. Lett. 2002, 4,
1167-1170. (b) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1996,
61, 8935-8939.
J. Org. Chem, Vol. 70, No. 4, 2005 1479

TABLE 1. Structures and Yields of Compounds 5a-l, 6a-h, and 7a,ba
a
All compounds were obtained as racemic mixtures of enantiomers. The assignment of these structures was made on the basis of 1H NMR and high-
resolution mass-spectroscopy. The 1H NMR spectra of compounds 5-7 contain the single aliphatic proton of the diazepine ring, which can be seen as a
characteristic singlet in the range of δ 5.11-5.48. The characteristic aromatic protons of the pyrrole ring can be seen as doublets at δ 6.2-6.9 Hz (H-2) and
δ 5.8-6.3 Hz (H-4).
carboxamide 5b: mp 138-141 °C; IR (KBr, cm-1) ν 1625 (CO),
1675 (CO), 3325 (NH); 1H NMR (400 MHz, DMSO-d6 + CCl4) δ
1.0-1.75 (m, 10 H), 3.3-3.48 (m, 1 H), 4.5-4.6 (d, J ) 2.0 Hz,
1 H), 5.16 (s, 1 H), 5.3-5.44 (d, J ) 2.0 Hz, 1 H), 5.75-5.8 (t, J
) 8.4 Hz, 1 H), 6.0 (d, J ) 7.9, 1 H), 6.22 (d, J ) 7.9 Hz, 1 H),
7.0-7.5 (m, 10 H), 7.86 (s, 1 H); HRMS m/z 514.2005 (M+).
N-Cycloheptyl-4-oxo-1-phenyl-5-(2-phenylethyl)-1,4,5,6-
tetrahydropyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepine-6-
carboxamide 5c: mp 164-167 °C; IR (KBr, cm-1) ν 1620 (CO),
1680 (CO), 3310 (NH); 1H NMR (400 MHz, DMSO-d6 + CCl4) δ
1.1-1.63 (m, 12 H), 2.7-2.84 (m, 1 H), 2.9-3.08 (m, 1 H), 3.5-
3.69 (m, 2 H), 4.0-4.2 (m, 1 H), 5.5 (s, 1 H), 6.07-6.1 (t, J ) 8.2
Hz, 1 H), 6.21 (d, J ) 7.7 Hz, 1 H), 6.27 (d, J ) 7.7 Hz, 1 H),
7.0-7.08 (d, J ) 4.2 Hz, 1 H), 7.1-7.22 (m, 5 H), 7.37-7.5 (m,
5 H), 7.8 (s, 1 H); HRMS m/z 508.2703 (M+).
N-Cycloheptyl-5-(2-furylmethyl)-4-oxo-1-phenyl-1,4,5,6-
tetrahydropyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepine-6-
carboxamide 5d: mp 157-161 °C; IR (KBr, cm-1) ν 1630 (CO),
1670 (CO), 3340 (NH); 1H NMR (400 MHz, DMSO-d6 + CCl4) δ
1.09-1.64 (m, 12 H), 3.46-3.6 (m, 1 H), 4.7 (d, J ) 2.6 Hz, 1 H),
4.84 (d, J ) 2.6 Hz, 1 H), 5.25 (s, 1 H), 6.0-6.1 (m, 2 H), 6.11-
6.17 (t, J ) 8.5 Hz, 1 H), 6.35-6.4 (d, J ) 7.8 Hz, 1 H), 6.46 (d,
J ) 7.8 Hz, 1 H), 6.6 (d, J ) 5.2 Hz, 1 H), 7.31-7.57 (m, 6 H),
7.81 (s, 1 H); HRMS m/z 484.2341 (M+).
N-Cycloheptyl-5-(3-isopropoxypropyl)-4-oxo-1-phenyl-
1,4,5,6-tetrahydropyrazolo[4,3-f]pyrrolo[1,2-a][1,4]-
diazepine-6-carboxamide 5e: mp 143-145 °C; IR (KBr, cm-1
)
ν 1630 (CO), 1660 (CO), 3330 (NH); 1H NMR (400 MHz, DMSO-
d6 + CCl4) δ 1.1-1.2 (s, 6 H), 1.23-1.7 (m, 12 H), 1.66-1.7 (m,
1 H), 1.7-1.87 (m, 1 H), 3.3-3.55 (m, 4 H), 3.59-3.7 (m, 1 H),
1480 J. Org. Chem., Vol. 70, No. 4, 2005

3.85-4.1 (m, 1 H), 5.3 (s, 1 H), 6.05-6.1 (t, J ) 8.2 Hz, 1 H), 6.2
(d, J ) 7.7 Hz, 1 H), 6.28 (d, J ) 7.7 Hz, 1 H), 7.05-7.12 (br s,
1 H), 7.35-7.57 (m, 5 H), 7.8 (s, 1 H); HRMS m/z 504.2963 (M+).
5.2 (s, 1 H), 6.19 (s, 2 H), 6.8 (s, 1 H), 7.1-7.2 (br s, 1 H); HRMS
m/z 497.2576 (M+).
N-Cyclohexyl-5-(2-methoxyethyl)-6-oxo-5,6,7,8,9,10-
hexahydro-4H-[1]benzothieno[3,2-f]pyrrolo[1,2-a][1,4]-
N-Cycloheptyl-5-(4-methylbenzyl)-4-oxo-1-phenyl-1,4,5,6-
tetrahydropyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepine-6-
carboxamide 5f: mp 210-212 °C; IR (KBr, cm-1) ν 1635 (CO),
1680 (CO), 3380 (NH); 1H NMR (400 MHz, DMSO-d6 + CCl4) δ
0.8-1.55 (m, 12 H), 2.21 (s, 3 H), 3.35-3.46 (m, 1 H), 4.54 (d, J
) 2.7 Hz, 1 H), 4.9 (d, J ) 2.7 Hz, 1 H), 5.3 (s, 1 H), 6.05 (t, J )
8.2 Hz, 1 H), 6.1 (d, J ) 7.7 Hz, 1 H), 6.18 (d, J ) 7.7 Hz, 1 H),
7.15 (d, J ) 7.3 Hz, 2 H), 7.3-7.5 (m, 7 H), 7.82 (s, 1 H), HRMS
m/z 508.2702 (M+).
N-Cycloheptyl-5-cyclohexyl-4-oxo-1-phenyl-1,4,5,6-tet-
rahydropyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepine-6-car-
boxamide 5g: mp 227-234 °C; IR (KBr, cm-1) ν 1630 (CO), 1655
(CO), 3400 (NH); 1H NMR (400 MHz, DMSO-d6 + CCl4) δ 1.09-
2.1 (m, 22 H), 3.5-3.67 (m, 1 H), 4.41-4.6 (m, 1 H), 5.4 (s, 1 H),
6.07 (t, J ) 8.6 Hz, 1 H), 6.15 (d, J ) 7.9 Hz, 1 H), 6.24 (d, J )
7.9 Hz, 1 H), 6.6-6.8 (d, J ) 4.4 Hz, 1 H), 7.3-7.5 (m, 5 H), 7.8
(s, 1 Hz H); HRMS m/z 482.2474 (M+).
N-Cycloheptyl-5-(3-methoxybenzyl)-4-oxo-1-phenyl-
1,4,5,6-tetrahydropyrazolo[4,3-f]pyrrolo[1,2-a][1,4]-
diazepine-6-carboxamide 5h: mp 179-182 °C; 1H NMR (400
MHz, DMSO-d6 + CCl4) δ 0.8-1.53 (m, 12 H), 3.38-3.5 (m, 1
H), 3.75 (s, 3 H), 4.51 (d, J ) 2.8 Hz, 1 H), 4.88 (d, J ) 2.8 Hz,
1 H), 5.32 (s, 1 H), 6.0 (s, 1 H), 6.01 (t, J ) 8.4 Hz, 1 H), 6.07 (d,
J ) 7.8 Hz, 1 H), 6.14 (d, J ) 7.8 Hz, 1 H), 6.8 (d, J ) 5.2 Hz,
1 H), 7.0-7.1 (m, 2 H), 7.19-7.3 (m, 1 H), 7.36-7.5 (m, 5 H),
7.84 (s, 1 H); HRMS m/z 524.2651 (M+).
diazepine-4-carboxamide 6c: mp 157-159 °C; IR (KBr, cm-1
)
ν 1630 (CO), 1670 (CO), 3300 (NH); 1H NMR (400 MHz, DMSO-
d6 + CCl4) δ 0.76-3.73 (m, 22 H), 3.33 (s, 3 H), 4.13 (s, 1 H),
5.17 (s, 1 H), 6.18 (s, 2 H), 6.84 (s, 1 H), 6.5-6.69 (br s, 1 H);
HRMS m/z 442.2152 (M+).
5-(4-Chlorophenyl)-N-cyclohexyl-6-oxo-5,6,7,8,9,10-
hexahydro-4H-[1]benzothieno[3,2-f]pyrrolo[1,2-a][1,4]-
diazepine-4-carboxamide 6d: mp 216-218 °C; IR (KBr, cm-1
)
ν 1630 (CO), 1685 (CO), 3400 (NH); 1H NMR (400 MHz, DMSO-
d6 + CCl4) δ 0.8-3.0 (m, 18 H), 3.31-3.49 (s, 1 H), 5.35 (s, 1 H),
6.8-6.0 (br s, 1 H), 6.23 (s, 2 H), 6.91 (s, 1 H), 7.2-7.4 (m, 4 H);
HRMS m/z 494.1661 (M+).
N-Cyclohexyl-6-oxo-5-(tetrahydrofuran-2-ylmethyl)-
5,6,7,8,9,10-hexahydro-4H-[1]benzothieno[3,2-f]pyrrolo-
[1,2-a][1,4]diazepine-4-carboxamide 6e: mp 168-170 °C; 1H
NMR (400 MHz, DMSO-d6 + CCl4) δ 1.0-3.2 (m, 24 H), 3.5-
3.6 (m, 1 H), 3.7-4.0 (m, 2 H), 4.2-4.5 (q, J ) 1.8 Hz, 1 H), 5.26
(s, 1 H), 6.15 (s, 2 H), 6.87 (d, J ) 7.7 Hz, 1 H), 7.3 (br s, 1 H);
HRMS m/z 482.2474 (M+).
N-Cyclohexyl-5-(3-methylbutyl)-6-oxo-5,6,7,8,9,10-hexahy-
dro-4H-[1]benzothieno[3,2-f]pyrrolo[1,2-a][1,4]diazepine-
4-carboxamide 6f: mp 152-154 °C; IR (KBr, cm-1) ν 1625 (CO),
1690 (CO), 3420 (NH); 1H NMR (400 MHz, DMSO-d6 + CCl4) δ
0.6-2.0 (m, 18 H), 1.5 (s, 6 H), 2.3-3.0 (m, 4 H), 3.3-3.47 (m, 1
H), 5.07 (s, 1 H), 5.9-6.0 (m, 1 H), 6.23 (d, J ) 7.8 Hz, 2 H),
6.88 (s, 1 H); HRMS m/z 458.2521 (M+).
N-Cyclohexyl-5-cyclopentyl-6-oxo-5,6,7,8,9,10-hexahydro-
4H-[1]benzothieno[3,2-f]pyrrolo[1,2-a][1,4]diazepine-4-car-
boxamide 6g: mp 192-194 °C; IR (KBr, cm-1) ν 1620 (CO), 1680
(CO), 3410 (NH); 1H NMR (400 MHz, DMSO-d6 + CCl4): δ 1.1-
2.0 (m, 26 H), 2.8-3.0 (m, 1 H), 3.47-3.59 (m, 1 H), 5.1 (s, 1 H),
5.7-5.9 (br s, 1 H), 6.16-6.3 (d, J ) 7.6 Hz, 2 H), 6.9 (s, 1 H);
HRMS m/z 466.2513 (M+).
N-Cycloheptyl-5-(3-methoxypropyl)-4-oxo-1-phenyl-
1,4,5,6-tetrahydropyrazolo[4,3-f]pyrrolo[1,2-a][1,4]-
1
diazepine-6-carboxamide 5i: mp 150-152 °C; H NMR (400
MHz, DMSO-d6 + CCl4) δ 1.1-1.64 (m, 12 H), 1.66-2.0 (2m, 2
H), 3.25 (s, 3 H), 3.3-3.38 (m, 2 H), 3.5-3.65 (m, 2 H), 3.72-3.9
(m, 1 H), 5.27 (s, 1 H), 6.05 (t, J ) 8.3 Hz, 1 H), 6.16 (d, J ) 7.7
Hz, 1 H), 6.2 (d, J ) 7.7 Hz, 1 H), 7.2 (d, J ) 3.8 Hz, 1 H), 7.35-
7.5 (m, 5 H), 7.79 (s, 1 H); HRMS m/z 476.2652 (M+).
N-Cyclohexyl-5-(3-isopropoxypropyl)-6-oxo-5,6,7,8,9,10-
5-(2-Chlorobenzyl)-N-cycloheptyl-4-oxo-1-phenyl-1,4,5,6-
tetrahydropyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepine-6-
carboxamide 5j: mp 121-123 °C; 1H NMR (400 MHz, DMSO-
d6 + CCl4) δ 1.2-1.6 (m, 12 H), 3.55-3.67 (m, 1 H), 4.5-4.59
(d, J ) 2.0 Hz, 1 H), 5.15 (s, 1 H), 5.26-5.4 (d, J ) 2.0 Hz, 1 H),
5.75-5.84 (t, J ) 8.4 Hz, 1 H), 5.94-6.07 (d, J ) 7.8 Hz, 1 H),
6.13-6.24 (d, J ) 7.8 Hz, 1 H), 6.95-7.0 (m, 1 H), 7.15-7.8 (m,
4 H), 7.82-7.51 (m, 5 H), 7.8 (s, 1 H); HRMS m/z 528.2154 (M+).
N-Cycloheptyl-5-(3-fluorobenzyl)-4-oxo-1-phenyl-1,4,5,6-
tetrahydropyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepine-6-
carboxamide 5k: mp 123-126 °C; 1H NMR (400 MHz, DMSO-
d6 + CCl4) δ 1.0-1.63 (m, 12 H), 3.50-3.62 (m, 1 H), 4.68-4.76
(d, J ) 2.2 Hz, 1 H), 4.82-4.9 (d, J ) 2.2 Hz, 1 H), 5.4 (s, 1 H),
6.0-6.15 (m, 2 H), 6.17 (d, J ) 8.2 Hz, 1 H), 6.27-6.45 (m, 1 H),
6.97-7.05 (t(F), J ) 9.0 Hz, 1 H), 7.2-7.4 (t(F), J ) 9.1 Hz, 2
H), 7.41-7.5 (m, 6 H), 7.8 (s, 1 H); HRMS m/z 512.2452 (M+).
hexahydro-4H-[1]benzothieno[3,2-f]pyrrolo[1,2-a][1,4]-
diazepine-4-carboxamide 6h: mp 117-119 °C; IR (KBr, cm-1
)
ν 1635 (CO), 1660 (CO), 3320 (NH); 1H NMR (400 MHz, DMSO-
d6 + CCl4): δ 1.1 (2s, 3 H), 1.04-2.1 (m, 24 H), 2.65-2.7 (m, 2
H), 3.25-3.32 (m, 2 H), 3.39-3.58 (m, 2 H), 3.5-3.61 (m, 1 H),
3.62-3.73 (m, 1 H), 5.12 (s, 1 H), 5.9-6.05 (br s, 1 H), 6.21-6.3
(d, J ) 7.9 Hz, 2 H), 6.8 (s, 1 H, ArH); HRMS m/z 498.2763 (M+).
8-Chloro-N-cycloheptyl-5-(4-methylbenzyl)-6-oxo-5,6-di-
hydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine-4-carboxam-
ide 7a: mp 165-168 °C; IR (KBr, cm-1) ν 1635 (CO), 1665 (CO),
1
3350 (NH); H NMR (400 MHz, DMSO-d6 + CCl4): δ 0.75-1.6
(m, 12 H), 2.3 (s, 3 H), 3.3-3.48 (m, 1 H), 4.6-4.7 (q, J ) 5.6
Hz, 2 H), 5.15 (s, 1 H), 5.9 (d, J ) 2.2 Hz, 1 H), 6.0-6.08 (s, 1
H), 6.18-6.2 (s, 1 H), 7.0-7.4 (m, 7 H), 7.78 (d, J ) 7.7 Hz, 1
H); HRMS m/z 476.2091 (M+).
8-Chloro-N-cycloheptyl-5-benzyl-6-oxo-5,6-dihydro-4H-
pyrrolo[1,2-a][1,4]benzodiazepine-4-carboxamide 7b: mp
124-127 °C; IR (KBr, cm-1) ν 1630 (CO), 1670 (CO), 3330 (NH)
cm-1; 1H NMR (400 MHz, DMSO-d6 + CCl4) δ 0.73-1.58 (m, 12
H), 3.28-3.47 (m, 1 H), 4.61-4.72 (d, J ) 5.9 Hz, 2 H), 4.8-
4.96 (d, J ) 5.9 Hz, 2 H), 5.12 (s, 1 H), 5.9-6.0 (m, 2 H, ArH),
6.18 (s, 1 H), 7.0-7.4 (m, 8 H), 7.77 (d, J ) 7.8 Hz, 1 H); HRMS
m/z 462.1935 (M+).
Acknowledgment. The authors would like thank
Dr. Konstantin V. Balakin (Chemical Diversity, Inc.) for
help in preparation of the manuscript. The authors also
thank the Scripps Center for Mass Spectrometry (La
Jolla, CA) for HRMS spectral data.
N-Cycloheptyl-4-oxo-1-phenyl-5-(tetrahydrofuran-2-yl-
methyl)-1,4,5,6-tetrahydropyrazolo[4,3-f]pyrrolo[1,2-a][1,4]-
1
diazepine-6-carboxamide 5l: mp 162-165 °C; H NMR (400
MHz, DMSO-d6 + CCl4) δ 1.0-2.17 (m, 16 H), 3.0-3.12 (m, 1
H), 3.55-4.17 (m, 4 H), 4.3-4.4 (m, 1 H), 4.5-4.6 (t, J ) 2.6
Hz, 1 H), 5.3 (s, 1 H), 5.5 (s, 1 H), 6.05 (t, J ) 8.5 Hz, 1 H), 6.15
(d, J ) 7.9 Hz, 1 H), 6.16 (d, J ) 7.9 Hz, 1 H), 7.3-7.5 (m, 5 H),
7.78 (s, 1 H), 7.9 (d, J ) 6.3 Hz, 1 H); HRMS m/z 488.265 (M+).
N-Cyclohexyl-6-oxo-5-(2-pyrrolidin-2-ylethyl)-5,6,7,8,9,-
10-hexahydro-4H-[1]benzothieno[3,2-f]pyrrolo[1,2-a][1,4]-
diazepine-4-carboxamide 6a: mp 189-192 °C; IR (KBr, cm-1
)
ν 1635 (CO), 1675 (CO), 3200 (NH); 1H NMR (400 MHz, DMSO-
d6 + CCl4) δ 0.75-3.45 (m, 30 H), 4.37-4.52 (t, J ) 3.1 Hz, 1
H), 5.15 (s, 1 H), 6.17 (s, 2 H), 6.8 (s, 1 H), 8.15-8.3 (br s, 1 H);
HRMS m/z 481.2633 (M+).
Supporting Information Available: Experimental pro-
cedures and characterization of 2a-c, 3a-c, and 4a-c and1H
and 13C NMR spectral data for all final products 5-7. This
material is available free of charge via the Internet at
http://pubs.acs.org.
N-Cyclohexyl-5-(2-morpholin-4-ylethyl)-6-oxo-5,6,7,8,9,-
10-hexahydro-4H-[1]benzothieno[3,2-f]pyrrolo[1,2-a][1,4]-
diazepine-4-carboxamide 6b: mp 180-182 °C; IR (KBr, cm-1
)
ν 1640 (CO), 1675 (CO), 3250 (NH); 1H NMR (400 MHz, DMSO-
d6 + CCl4) δ 0.85-3.77 (m, 30 H), 4.2-4.4 (t, J ) 3.4 Hz, 1 H),
JO048204B
J. Org. Chem, Vol. 70, No. 4, 2005 1481