Two-step syntheses of fused quinoxaline-benzodiazepines and bis-benzodiazepines

Article abstract of DOI:10.1016/j.tetlet.2010.06.116

A two-step solution phase synthesis employing a double UDC (Ugi/Deprotect/Cyclize) strategy has been utilized to obtain fused 6,7,6,6-quinoxalinone-benzodiazepines and 6,7,7,6-bis-benzodiazepines. Optimization of the methodology to produce these tetracyclic scaffolds was enabled by microwave irradiation, incorporation of trifluoroethanol as solvent, and the use of the convertible isocyanide, 4-tert-butyl cyclohexen-1-yl isocyanide.

Full text of DOI:10.1016/j.tetlet.2010.06.116

Tetrahedron Letters 51 (2010) 4566–4569
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Two-step syntheses of fused quinoxaline-benzodiazepines and
bis-benzodiazepines
*
Zhigang Xu, Justin Dietrich, Arthur Y. Shaw, Christopher Hulme
College of Pharmacy, Department of Pharmacology and Toxicology, Division of Medicinal Chemistry, BIO5 Institute,
Southwest Comprehensive Center for Drug Discovery and Development, University of Arizona, AZ 85721, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A two-step solution phase synthesis employing a double UDC (Ugi/Deprotect/Cyclize) strategy has been
utilized to obtain fused 6,7,6,6-quinoxalinone-benzodiazepines and 6,7,7,6-bis-benzodiazepines. Optimi-
zation of the methodology to produce these tetracyclic scaffolds was enabled by microwave irradiation,
incorporation of trifluoroethanol as solvent, and the use of the convertible isocyanide, 4-tert-butyl
cyclohexen-1-yl isocyanide.
Received 5 June 2010
Revised 22 June 2010
Accepted 23 June 2010
Available online 30 June 2010
Published by Elsevier Ltd.
Application of the multi-component reaction (MCR) is a well-
known synthetic strategy in which three or more starting materials
react in a convergent manner to obtain a single highly functionalized
product.1 In drug discovery, MCRs are of interest as an enabling tech-
nology to efficiently probe new dimensions of chemical space in the
production of small molecule libraries that contain high iterative
efficiency potential.2 Of particular note is the Ugi reaction, an isoni-
trile-based MCR in which an amine, carbonyl compound, carboxylic
acid, and isonitrile undergo a condensation reaction to afford the
incorporated to pre-form the Schiff base 5 by reacting N-Boc-1,2-
phenylenediamine 3 with ethyl glyoxylate 4 in DCM at 130 °C for
15 min. Lower temperatures required longer times for the com-
plete disappearance of the starting material and conversion to
Schiff base and they were not compatible with succinct, short
microwave reaction times. The solvent was then evaporated and
the Schiff base, n-butyl isonitrile 6, and Boc-2-aminobenzoic acid
7 were reacted in methanol at room temperature. The Ugi product
8 was successfully obtained albeit in low yield (21%) with the
majority of mass balance accounted for by the highly conjugated
Schiff base starting material (tlc). The Ugi product 8 was further re-
acted in the presence of 10% TFA in DCE under microwave irradia-
tion at 180 °C for 20 min to give the target product 1 in low yield
(37%). The major side product observed was tetracyclic triazadi-
benzoazulenone 9 (27% yield).
This finding suggested that two electrophilic carbonyls (one de-
rived from the carboxylic acid input, the other emanating from the
isonitrile) were competing for the same internal amine. As shown
in Scheme 2, upon removal of the N-Boc-protecting group on the
1,2-phenylenediamine buried in the Ugi scaffold, this amino group
can follow one of two ring-closing routes—nucleophilic displace-
ment of the n-butyl group which was derived from the n-butyl iso-
nitrile (path A) or alternatively, a cyclodehydration reaction with
corresponding functionalized a
-acylamino amide.2b,3 UDC (Ugi/de-
protect/cyclize) methodologies employ the Ugi MCR as the initial
diversity generating event and subsequently, strategically posi-
tioned internal masked nucleophiles are deprotected, promoting a
series of ring-closing events.4 This methodology has been utilized
in the production of a plethora of pharmacologically relevant tem-
plates some of which have ultimately led to clinical evaluation.4f,5
In thisLetter, wedescribe a two-stepUDC-based methodologyto ob-
tain fused 6,7,6,6-quinoxalinone-benzodiazepines 1 and 6,7,7,6-bis-
benzodiazepines 2 Figure 1 that relies on the incorporation of two
masked amine nucleophiles, ethyl glyoxalate as the carbonyl com-
ponent, and the convertible isocyanide, 4-tert-butyl cyclohexen-1-
yl isocyanide. One example of scaffold 1 (R1 = R2 = H) prepared
conventionally in five steps has been previously reported in 1980
by Massa et al. whereas scaffold 2 is completely unreported.6
As indicated in Scheme 1, compound 1 was initially prepared by
a four-component Ugi reaction involving N-Boc-1,2-phenylenedi-
amine 3, ethyl glyoxylate 4, n-butylisonitrile 6, and Boc-2-amino-
benzoic acid 7. However, attempts to form the desired Ugi
product by mixing the four components all at once were unsuc-
cessful and resulted in a significant amount of Passerini product
and un-reacted amine.7 Accordingly, a microwave procedure was
R1
R2
O
O
R1
R2
N
N
NH
HN
NH
HN
O
O
O
2
1
O
* Corresponding author. Tel.: +1 520 626 5322.
E-mail address: hulme@pharmacy.arizona.edu (C. Hulme).
Figure 1. Targeted fused tetracyclic quinoxalinone-benzodiazepines 1 and bis-
benzodiazepines 2.
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.06.116

Z. Xu et al. / Tetrahedron Letters 51 (2010) 4566–4569
4567
H
N
O
O
N
6
NH2
N
µw, 130 ºC, 15 min
O
O
N
BocHN
DCM
O
O
NHBoc
COOH
NHBoc
O
8 21%
7
3
5
O
NHBoc
H
NHBoc
O
4
MeOH, rt
N
O
N
10% TFA/DCE
N
NH
O
+
NH
µw, 180 ºC, 20 min
HN
HN
9 27%
O
O
O
1 37%
Scheme 1. Initial synthetic route to scaffold 1.
potential route to a new generic library in just two steps. Thus,
subsequently the yield of the Ugi reaction was optimized by the use
of co-solvents trifluoroethanol and dichloroethane. As before, the
Schiff base was formed in DCM via microwave irradiation and then
trifluoroethanol was added (1:1, v/v, trifluoroethanol/DCM) along
with the acid and isonitrile components. When using this alterna-
tive procedure, the Ugi yield increased from 21% to 46%, Scheme 3.
Addition of trifluoroethanol has been shown to produce a similar
increase in the yields for other Ugi reactions.8
With the Ugi product 12 in-hand, cyclization under microwave
irradiation at 180 °C for 20 min afforded compound 1 in good yield
(67%, 31% overall, two steps).9 With satisfactory conditions in
place, a small array of fused 6,7,6,6-quinoxalinone-benzodiazepine
derivatives was thus synthesized with diversity being generated
through the utilization of various benzoic acids and N-Boc dia-
mines to afford the Ugi and final cyclization products with yields
of 45–71% and 67–78%, respectively (Fig. 2). In synthesizing the
small array of molecules, we observed a slight increase in the yield
of the Ugi product when using mono-N-Boc-3,4-dimethylphenyl-
enediamine. This may be attributed to the increased basicity of
the highly conjugated Schiff base derived from this input. Conse-
quently, a methylene linker was inserted to break conjugation of
the Schiff base intermediate by the use of tert-butyl 2-(amino-
methyl)phenylcarbamate 21 as the amine source, Scheme 4. Schiff
base formation was accomplished in just 15 min at room temper-
ature, and addition of acid and isonitrile gave the Ugi product 22
in high yield (82%).
CN
11
A
H
N
NH2
O
B
A
O
O
1
N
O
B
NH2
9
10
Scheme 2. Proposed mechanism of synthesizing benzodiazepines.
the amide group derived from the acid input in the Ugi reaction
(path B). The other amine derived from the protected anthranilic
acid input, however, exclusively reacts with the electrophilic car-
bonyl from the ester group, which is expected to be rapid.4c In
order to redirect the reaction to proceed solely through path A,
we incorporated the convertible isonitrile, 4-tert-butyl cyclohexen-
1-yl isocyanide 11, in the initial Ugi reaction to increase the electro-
philic nature of the corresponding amide (this occurs via formation
of an activated N-acyliminium species under acidic conditions).
Alternatively, we also hypothesized that introduction of a bulkier
isonitrile such as tert-butyl isonitrile would favor the formation
of the corresponding novel triazadibenzoazulenone 9, another
N
O
O
NH
10% TFA/DCE
DCM, CF3CH2OH
O
1
5
67%
7
+
+
N
rt
µw, 180 ºC, 20 min
NHBoc
O
11
12
46%
NHBoc
Scheme 3. New process of synthesizing compound 1.

4568
Z. Xu et al. / Tetrahedron Letters 51 (2010) 4566–4569
O
O
O
O
MeO
Cl
N
O
N
O
N
O
N
NH
NH
NH
NH
Cl
HN
HN
HN
HN
O
O
O
O
O
13, 52%, 71%
14, 45%, 72%
15, 52%, 73%
16, 63%, 70%
O
O
O
N
O
Cl
N
N
O
N
NH
O
NH
NH
N
NH
HN
19, 48%, 74%
HN
HN
N
H
O
O
O
O
20, 71%, 78%
O
O
18, 50%, 73%
17, 65%, 72%
Figure 2. Structures of bicyclic quinoxalinone-benzodiazepines (Ugi % yield, cyclization % yield).
O
O
4
H
N
O
BocHN
+
10% TFA/DCE
DCM, CF3CH2OH
r.t
NH2
+
N
2
62%
7
+
O
NHBoc
µw, 180 ºC, 20 min
11
82%
22
21
BocHN
Scheme 4. Route to fused bis-benzodiazepine 2.
O
O
MeO
O
N
Cl
N
O
N
NH
NH
NH
HN
HN
HN
O
O
O
O
O
24, 67%, 50%
25, 71%, 56%
23, 73%, 55%
Figure 3. Structures of fused bis-benzodiazepines (Ugi % yield, cyclization % yield).
However, the increased flexibility associated with an additional
methylene linker and increased free energy associated with form-
ing a seven-member ring in lieu of a six-member ring had a nega-
tive effect on the second cyclization to form 2 in lower observed
yields (62%).10 Three additional tetracyclic bis-benzodiazepines
23, 24, and 25 were also synthesized and the yields are shown,
Figure 3.
In summary, two series of tetracyclic quinoxalinone-benzodi-
azepines and novel fused bis-benzodiazepine scaffolds were syn-
thesized in two steps employing a UDC strategy. Ugi reactions
were optimized by addition of trifluoroethanol, and control over
cyclization modes was attained by employing 4-tert-butyl cycloh-
exen-1-yl isocyanide, respectively. Based on the uniqueness of
these scaffolds, the desirable drug-like properties of the molecules
(compound 1, MW = 293, c Log P = 1.19, tPSA = 78.51), and the ease
of synthesis, these scaffolds have the potential to be of interest in
future library enrichment strategies.
Abbott Laboratories are also thanked for a New Faculty Award
to C.H.
References and notes
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We would like to thank the Office of the Director, NIH, and the
National Institute of Mental Health for funding (1RC2MH090878-01).

Z. Xu et al. / Tetrahedron Letters 51 (2010) 4566–4569
4569
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10. For the preparation of 22 and general library protocol: A solution of tert-butyl
2-(aminomethyl)phenylcarbamate (0.22 g, 1.00 mmol) and ethyl glyoxalate
(50%, 0.20 ml, 1.00 mmol) in DCM (1.00 ml) was reacted at room temperature
for 15 min. Then, appropriate benzoic acid (1.00 mmol), trifluoroethanol
(1.0 ml), and 4-tert-butyl cyclohexen-1-yl isocyanide were added with
stirring and followed by TLC (reactions completed between 20 and 60 min).
When there was no SM left, the solvent was removed in vacuo. The product
was purified by column chromatography (hexane/ethyl acetate, 1:4) to afford a
white solid (580 mg, 0.82 mmol). For the preparation of 1, 2 and general library
protocol: The appropriate Ugi product (0.20 mmol) in 10% TFA/DCE (5.0 ml)
was reacted in microwave at 180 °C for 20 min. The solvent was removed
under reduced pressure and the residue was purified by column
chromatography (hexanes/ethyl acetate, 2:3) to afford the pure solid.
Compound 1: 1H NMR (300 MHz, DMSO) 11.08 (s, 1H), 10.92 (s, 1H), 8.06 (d,
J = 8.2 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.32 (t, J = 7.6 Hz,
1H), 7.20 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 7.1 Hz, 1H), 7.04–6.95 (m, 2H), 5.12 (s,
1H); 13C NMR (75 MHz, DMSO) 166.73, 165.84, 161.10, 136.89, 133.21, 131.81,
128.37, 126.55, 125.38, 124.62, 122.85, 122.60, 121.78, 120.90, 116.39, 57.74.
Compound 2: 1H NMR (300 MHz, DMSO) 10.52 (s, 2H), 7.78 (d, J = 7.8 Hz, 1H),
7.52 (t, J = 7.7 Hz, 1H), 7.37–7.16 (m, 3H), 7.08 (t, J = 7.4 Hz, 3H), 5.38 (d,
J = 13.8 Hz, 1H), 4.88 (s, 1H), 4.35 (s, 1H); 13C NMR (75 MHz, DMSO) 168.27,
166.12, 137.26, 133.58, 132.30, 130.14, 127.34, 125.15, 121.71, 121.62, 100.67,
79.37, 45.81.
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9. For the preparation of 12 and general library protocol: A solution of N-BOC-1,2-
phenylenediamine (0.21 g, 1.00 mmol) and ethyl glyoxalate (50%, 0.20 ml,
1.00 mmol) in DCM (1.00 ml) was reacted in microwave at 130 °C for 15 min.
After the reaction mixture was cooled down to room temperature, appropriate
benzoic acid(1.00 mmol), trifluoroethanol (1.0 ml), and 4-tert-butyl cyclohexen-
1-yl isocyanide (0.16 g, 1.00 mmol) were added. The resulting solution was
stirred overnight, and the solvent was removed in vacuo. The product was
purified by column chromatography (hexanes/ethyl acetate, 1:4) to afford a
white solid 12 (320 mg, 0.46 mmol).