A tandem one-pot, microwave-assisted synthesis of regiochemically differentiated 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones

Article abstract of DOI:10.1021/ol801841m

(Chemical Equation Presented) A one-pot, two-step synthesis of the title compounds employs a multicomponent Ugl condensation reaction, microwave irradiation, and Fe(0) as a reductant. Two pathways are accessible; both routes utilize bifunctional, o-nitro-substituted arenes leading to either C2, N4, C5 substitution (A) or C2, N4 substitution (B).

Full text of DOI:10.1021/ol801841m

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4541-4544
A Tandem One-Pot, Microwave-Assisted
Synthesis of Regiochemically Differentiated
1,2,4,5-Tetrahydro-1,4-benzodiazepin-3-ones
Ravindra A. De Silva, Soumava Santra, and Peter R. Andreana*
Department of Chemistry, Wayne State UniVersity, 5101 Cass AVenue,
Detroit, Michigan 48202
pra@chem.wayne.edu
Received August 7, 2008
ABSTRACT
A one-pot, two-step synthesis of the title compounds employs a multicomponent Ugi condensation reaction, microwave irradiation, and Fe(0)
as a reductant. Two pathways are accessible; both routes utilize bifunctional, o-nitro-substituted arenes leading to either C2, N4, C5 substitution
(A) or C2, N4 substitution (B).
Tandem reactions allow for the generation of complex
molecular scaffolds from simple precursors with, in most
cases, the concominant formation of stereogenic centers.1
Bifunctional substrates allow for progressional reactivity in
tandem reactions leading to advantages such as intramolecu-
lar bond-forming processes,2 with a high degree of atom
economy3 and the alleviation of workup and isolation of
transient intermediates. One-pot tandem processes that gener-
ate biologically validated structural motifs will facilitate the
development of new therapeutic agents.
For a number of years, scientists have been exploring the
biological activities of benzodiazepine (BDZ) derivatives.4-6
A number of synthetic approaches to 1,4-benzodiazepin-3-
ones have been reported including a CuI-catalyzed Ullmann-
type aryl amination,7 addition/elimination nucleophilic aro-
matic substitution of primary or secondary amines,4a,5b,8
a
retro-Michael/amidation,9 and an intramolecular 1,3-dipolar
cycloaddition.10 Of the aforementioned reaction types, none
have been developed to access 1,4-benzodiazepin-3-ones in
a single pot. Although substrate diversity can readily be
accessible in all processes described, regiochemical substitu-
tion remains a challenge.
(1) (a) Tandem Organic Reactions; Tse-Lok, H., Ed.; Wiley-VCH: New
York, 1992. (b) Tietze, L. F. Chem. ReV. 1996, 96, 115–136. (c) Domino
Reactions in Organic Synthesis; Tietze, L. F., Brasche, G., Gericke, K.,
Eds.; Wiley-VCH: New York, 2006.
Our approach to synthesizing 1,4-benzodiazepin-3-ones
involves the Ugi four-component coupling reaction (U-
4CCR) in conjunction with microwave (µwave) irradiation
to rapidly access differentially substituted motifs in a one-
pot protocol utilizing environmentally benign reagents.11 The
(2) (a) Vilotijevic, I.; Jamison, T. F. Science 2007, 317, 1189–1192.
(b) Trost, B. M.; Shi, Y. J. Am. Chem. Soc. 1991, 113, 701–703. (c) Oble,
J.; El Kaim, L.; Gizzi, M.; Grimaud, L. Heterocycles 2007, 73, 503–517.
(3) (a) Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, 259–281. (b) Trost,
B. M. Science 1991, 254, 1471–1477.
10.1021/ol801841m CCC: $40.75
Published on Web 09/24/2008
2008 American Chemical Society

Ugi reaction is the condensation of an aldehyde or ketone
(1), an amine (2), an isocyanide (3), and a carboxylic acid
(4) yielding an R-acylaminoamide (Scheme 1). All steps are
regioselective bond forming reactions in a one-pot protocol.
Furthermore, µwave-based organic synthesis has underex-
plored potential for controlling pathway selectivity as we
have recently illustrated.14 In this paper, we describe use of
microwaves to facilitate a 7-exo aza-Michael cyclization
event which sets substitution patterns on BDZ arising from
the bifunctional substrates o-nitrobenzaldehyde (1a) and
o-nitrobenzylamine (2a).
Scheme 1
.
Mechanism of the Ugi Reaction Leading to an
R-Acylaminoamide
reversible except for the proposed rate determining Mumm
rearrangement.12 Ultimately the reaction proceeds in the
forward direction due to a more stable +4 oxidation state of
carbon from its +2 state in the starting isonitrile.13
As a synthetic tool for creating diversity in compound
libraries, the Ugi reaction readily accommodates a large
number of potential inputs although a limited number of
isocyanides are commercially available. However, by incor-
porating bifunctional substrates into the condensation reac-
tion, one can readily achieve structural diversification through
We envisioned formation of a seven-membered diazepine
through a post Ugi reductive aza-Michael reaction onto a
doubly conjugated olefin obtained from (E)-fumaric acid
monoethyl ester (4a) (eqs 1 and 2). Use of o-nitrobenzal-
dehyde (1a) gave a C2, N4, C5 substitution pattern ((A)
while o-nitrobenzylamine (2a) provided a C2, N4 derivatized
benzodiazepine product ((B). For the reduction, we elected
to use the two electron reducing conditions of Fe(0)15 and
NH4Cl in an aqueous media due to its mild nature and the
fact that iron has a high functional group tolerance.16 Benzyl-
based substrates did not fair well under hydrogenolysis
conditions with palladium or platinum and although tin(II)
chloride worked reasonably well for the aryl nitro reduction,
the combination of Fe(0) and NH4Cl was most efficient and
effective.
While optimizing the 7-exo aza-Michael cyclization some-
thing of particular interest was observed with substrates
derived from o-nitrobenzaldehyde (1a). After the synthesis
and purification of acyclic Ugi compound 5, using Pirrung’s
method,17 we assumed that a spontaneous cyclization would
occur under Fe/NH4Cl reduction conditions yielding benzo-
diazepine 6. However, as noted in Table 1, entry 4, this
cyclization event proceeded with µwave irradiation (300 W,
150 °C and 10 bar, 45 min). It is important to note that only
C2, N4, C5 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (mix
of diastereomers) and acyclic aniline compound 7 could be
isolated, inferring that substrate degradation did not occur.
When the reaction was run in a sealed tube at temperatures
exceeding 200 °C, less than 10% of 6 was observed after
45 min. In fact, reactions run at temperatures exceeding 200
°C for longer than 1 h (microwave and sealed tube) led to
extensive decomposition.
(4) Fibrinogen receptor antagonist: (a) Miller, W. H.; Ku, T. W.; Ali,
F. E.; Bondinell, W. E.; Calvo, R. R.; Davis, L. D.; Erhard, K. F.; Hall,
L. B.; Huffman, W. F.; Keenan, R. M.; Kwon, C.; Newlander, K. A.; Ross,
S. T.; Samanen, J. M.; Takata, D. T.; Yuan, C.-K. Tetrahedron Lett. 1995,
36, 9433–9436. (b) Samanen, J. M.; Ali, F. E.; Barton, L. S.; Bondinell,
W. E.; Burgess, J. L.; Callahan, J. F.; Calvo, R. R.; Chen, W.; Chen, L.;
Erhard, K.; Feuerstein, G.; Heys, R.; Hwang, S. M.; Jakas, D. R.; Keenan,
R. M.; Ku, T. W.; Kwon, C.; Lee, C. P.; Miller, W. H.; Newlander, K. A.;
Nichols, A.; Parker, M.; Peishoff, C. E.; Rhodes, G.; Ross, S.; Shu, A.;
Simpson, R.; Takata, D.; Yellin, T. O.; Uzsinskas, I.; Venslavsky, J. W.;
Yuan, C. K.; Huffman, W. F. J. Med. Chem. 1996, 39, 4867–4840. (c)
Keenan, R. M.; Callahan, J. F.; Samanen, J. M.; Bondinell, W. E.; Calvo,
R. R.; Chen, L.; DeBrosse, C.; Eggleston, D. S.; Haltiwanger, R. C.; Hwang,
S. M.; Jakas, D. R.; Ku, T. W.; Miller, W. H.; Newlander, K. A.; Nichols,
A.; Parker, M. F.; Southhall, L. S.; Uzinskas, I.; Vasko-Moser, J. A.;
Venslavsky, J. W.; Wong, A. S.; Huffman, W. F. J. Med. Chem. 1999, 42,
545–559.
(5) Angiotensin analogues: (a) Rosenstroem, U.; Skold, C.; Lindeberg,
G.; Botros, M.; Nyberg, F.; Karlen, A.; Hallberg, A. J. Med. Chem. 2004,
47, 859–870. (b) Rosenstroem, U.; Skold, C.; Lindeberg, G.; Botros, M.;
Nyberg, F.; Karlen, A.; Hallberg, A. J. Med. Chem. 2006, 49, 6133–6137.
(6) Protein kinase C activators: Ma, D.; Wang, G.; Wang, S.; Kozikows-
ki, A. P.; Lewin, N. E.; Blumberg, P. M Bioorg. Med. Chem. Lett. 1999, 9,
1371–1374.
(7) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583–2586.
(8) (a) Clement, E. C.; Carlier, P. R. Tetrahedron Lett. 2005, 46, 3633–
3635. (b) Rosenstroem, U.; Skoeld, C.; Plouffe, B.; Beaudry, H.; Lindeberg,
G.; Botros, M.; Nyberg, F.; Wolf, G.; Karlen, A.; Gallo-Payet, N.; Hallberg,
A. J. Med. Chem. 2005, 48, 4009–4024.
(9) Andrews, I. P.; Atkins, R. J.; Badham, N. F.; Bellingham, R. K.;
Breen, G. F.; Carey, J. S.; Etridge, S. K.; Hayes, J. F.; Hussain, N.; Morgan,
D. O.; Share, A. C.; Smith, S. A. C.; Walsgrove, T. C.; Wells, A. S.
Tetrahedron Lett. 2001, 42, 4915–4917.
(10) (a) Akritopoulou-Zanze, I.; Gracias, V.; Djuric, S. W. Tetrahedron
Lett. 2004, 45, 8439–8441. (b) Molteni, G.; Del Buttero, P. Tetrahedron:
Asymmetry 2007, 18, 1197–1201.
(14) Santra, S.; Andreana, P. R. Org. Lett. 2007, 9, 5035–5038.
(15) For the mechanism, see: Agrawal, A.; Tratnyek, P. G. EnViron.
Sci. Technol. 1996, 30, 153–160.
(11) For a recent one-pot synthesis of tetrahydro-1H-1,5-benzodiazepine-
2-carboximides using the Ugi reaction, see: Shaabani, A.; Maleki, A.;
Mofakham, H. J. Comb. Chem. 2008, 10, 595–598.
(16) (a) Di Santo, R.; Costi, R.; Artico, M.; Ragno, R.; Lavecchia, A.;
Novellino, E.; Gavuzzo, E.; La Torre, F.; Cirilli, R.; Cancio, R.; Maga, G.
ChemMedChem 2006, 1, 82–95. (b) Fox, B. A.; Threlfall, T. L. Org. Synth.
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(13) (a) Nef, J. U. Justus Liebigs Ann. Chem. 1892, 270, 267. (b) Nef,
J. U. Justus Liebigs Ann. Chem. 1899, 309, 126.
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4542
Org. Lett., Vol. 10, No. 20, 2008

additions described in Tables 1 and 2. We elected to use
isobutyraldehyde (1d), 2-nitrobenzylamine (2a), benzyl iso-
cyanide (3d), and fumaric acid monoethyl ester (4a) as our
initial set of starting substrates leading to BDZ of type B
(Table 3). Protic solvents such as aqueous methanol or
Table 1. Aza-Michael Cyclization Yielding C2, N4, C5
Substitution of 1,2,4,5-Tetrahydro-1,4-benzodiazepin-3-ones
Table 3. One-Pot Protocol for BDZ Synthesis
entry
conditions
% yield of 6 % yield of 7
1
2
3
4
140 °Ca, 5 h
<1b
<1b
<1b,c
75e
>98b
>98b
>98b
25e
140 °Ca, 24 h
sealed tube, 140 °Ca, 24 h
µwave for 45 mind
a Denotes oil bath temperature. b Determined by 1H NMR. c At
temperatures exceeding 200 °C, <10% was observed after 45 min. Extended
reaction times led to extensive decomposition. d Microwave equilibrated
to 300 W, 150 °C, and 10 bar. e Isolated.
time
(min) (°C)
T
% yield of % yield of
entry
solvent
EtOH
11a
12b
1
2
3
4
5
6
7
30
30
30
15
75
150
150
150
180
140
120
110
77
73
85
71
82
80
81
10
5
3
7
3
H2O
EtOH/H2O, 3:1
EtOH/H2O, 3:1
EtOH/H2O, 3:1
EtOH/H2O, 3:1
EtOH/H2O, 3:1
b
A similar study was conducted to optimize a 7-exo aza-
Michael cyclization for C2, N4 substituted 1,2,4,5-tetrahydro-
1,4-benzodiazepin-3-ones. A purified acyclic Ugi product 8,
arising from isobutyraldehyde (1d), o-nitrobenzylamine (2a),
tert-butyl isocyanide (3a), and fumaric acid monoethyl ester
(4a), was used as the starting substrate. Traditional heating
methods worked well in the cyclization process giving BDZ
of type B (Table 2, entries 2-4) in 55-80% yield, however,
100
180
1
3
3
a Isolated. Determined by H NMR.
ethanol gave the desired Ugi product in high yields (>98%;
denoted by 1H NMR) after being subjected to µwave
irradiation for 1 h at 60 °C. Fe(0) and NH4Cl were then added
to the reaction flask, and the mixture was further subjected
to µwave irradiation until all starting materials were con-
verted to 11 (X-ray) and 12.
Table 2. Aza-Michael Cyclization Yielding C2, N4 Substitution
of 1,2,4,5-Tetrahydro-1,4-benzodiazepin-3-ones
The reduction reaction worked best in the µwave at 150
°C for 30 min in a 3:1 ratio of EtOH/water. Important to
note is that in the absence of µwave irradiation or other heat
sources in the one-pot protocol, only the acyclic Ugi product
could be isolated (approximately 80% yield in 18 h, refer to
Table 2 for cyclization conditions) suggesting a high energy
of activation for nitro reduction with Fe(0).
We next turned our attention to examining the scope of
the one-pot protocol. As noted in Table 4, entries 1-5, BDZs
of type A were formed in 70-80% yield with high
diastereomeric ratios. In fact, compounds 15 and 16 (Table
4, entries 4 and 5) were obtained as single diastereomers
determined by 1H NMR. NOe data assisted in elucidating a
2,5-cis relationship between the acid and aldehyde compo-
nents of the coupling product.
entry
conditions
rt for 48 h
% yield of 9 % yield of 10
1
2
3
4
5
NR
55b
73b
80b
90d
NR
40b
22b
17b
7d
140 °Cafor 5 h
140 °Ca, 24 h
sealed tube, 140 °Ca, 24 h
µwave for 45 minc
b
a Denotes oil bath temperature. Obtained via H NMR. c Microwave
1
equilibrated to 300 W, 150 °C, and 10 bar. d Isolated.
These data correspond nicely with literature precedent in
which similar types of 1,2,4,5-tetrahydro-1,4-benzodiazepin-
3-ones were synthesized.8b Diastereomers were rationalized
to arise from the E olefin geometry of the fumaric acid
component (4a/4b).
Using 2-nitrobenzylamine (2a) as a substrate in the
U-4CCR gave benzodiazepines of type B following the one-
pot protocol (Table 4, entries 6-7). Although we observed
higher yields of C2, N4 substituted 1,2,4,5-tetrahydro-1,4-
benzodiazepin-3-ones, diastereomeric ratios were determined
µwave irradiation (Table 2, entry 5) provided compound 9
in 90% yield with the greatest efficiency. It is important to
note that the o-nitro group in compounds 5 and 8 was not
reduced by Fe(0) and NH4Cl at room temperature and 7
would not undergo an aza-Michael cyclization unless µwave
irradiation was applied.
We were encouraged to attempt a one-pot two step
protocol for the formation of 1,2,4,5-tetrahydro-1,4-benzo-
diazepin-3-ones based on our results with the 7-exo Michael
Org. Lett., Vol. 10, No. 20, 2008
4543

Table 4. Scope of the One-Pot Microwave-Assisted Synthesis of Regiochemically Differentiated
1,2,4,5-Tetrahydro-1,4-benzodiazepin-3-one
compd. typea/
% yieldb
entry
R1
R2
R3
R4
drc
5:1
20:1
20:1
single
single
1.5:1
1.5:1
1
2
3
4
5
6
7
8
2-nitro-4-(trifluoromethyl)phenyl (1b) 4-bromobenzyl (2c)
tert-butyl (3a) ethoxycarbonyl (4a) A (6)/75
tert-butyl (3a) ethoxycarbonyl (4a) A (13)/75
2-nitrophenyl (1a)
4,5-dimethoxy-2-nitrophenyl (1c)
2-nitrophenyl (1a)
2-nitrophenyl (1a)
isopropyl (1d)
benzyl (2b)
allyl (2d)
cyclohexyl (3b) benzoyl (4b)
A (14)/70
piperonyl (2e)
tert-butyl (3a) ethoxycarbonyl (4a) A (15)/73
4-aminoacetophenone (2f) cyclopentyl (3c) 4-methylbenzoyl (4c) A (16)/78
2-nitrobenzyl (2a)
2-nitrobenzyl (2a)
2-nitrobenzyl (2a)
tert-butyl (3a) ethoxycarbonyl (4a) B (9)/90
benzyl (3d)
ethoxycarbonyl (4a) B (11d,e)/85
tert-butyl (3a) H (4d)
acyclic (17f)/100d
isopropyl (1d)
isopropyl (1d)
a Compound number denoted in parentheses. b Isolated. c Determined by using an unpurified sample with 1H NMR. d See the Supporting Information for
the X-ray structure. e At temperatures >180 °C the major product was 2,5-diketopiperazine. f Isolated the acyclic aniline Ugi product.
to be, at best, 1.5:1 (1H NMR). The diastereomeric mixture
proved difficult to separate and required a silica gel column
of considerable length.
reduction. Our results suggest that compound 19 resulted
from the direct reduction of 18 and not from prior -NO2 f
-NH2 reduction.
Interestingly, when acrylic acid (4d) was used as a
coupling component and subjected to our one-pot cyclization
conditions, an eight-membered ring was not observed and
only the acyclic aniline U-4CC product 17 (X-ray) was
isolated (Table 4, entry 8).
At high µwave intensity, a one-pot 6-exo aza-Michael
cyclization occurred to form 2,5-diketopiperazines 18 and
19 as illustrated in Scheme 2.13 This potentially competing
In summary, we have developed a one-pot, two-step
reaction protocol for the synthesis of regiochemically dif-
ferentiated 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones. Us-
ing protic solvents, controlled µwave irradiation and the two
electron reducing agent Fe(0)/NH4Cl, these biologically
relevent small molecules can be prepared efficiently and are
highly amenable to derivatization. We have shown that
o-nitrobenzaldehyde (1a) and o-nitrobenyzlamine (2a) not
only act as bifunctional substrates in the reaction protocol
but establish a C2, N4, C5 substitution pattern for BDZ of
type A and a C2, N4 substitution pattern for BDZ of type
B. Our laboratory continues to explore the chemistry
described herein and biological evaluation of the resulting
products.
Scheme 2. Microwave Intensity Controls Pathway Selectivity
Acknowledgment. R.D., S.S., and P.R.A. thank Dr. Mary
Jane Heeg (Wayne State University) for X-ray data. P.R.A.
acknowledges WSU for start-up funds and a WSU Research
Grant (145767).
Supporting Information Available: Experimental pro-
tocols and NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
reaction pathway could readily be suppressed by reduction
of µwave intensity to exclusively form BDZ 11. This
transformation indicates that a 6-exo aza-Michael cyclization,
from an amide, occurs faster than the zerovalent iron metal
OL801841M
4544
Org. Lett., Vol. 10, No. 20, 2008