One-step assembly of carbamoyl substituted annulated 1,4-oxazepines

Article abstract of DOI:10.1016/j.tetlet.2006.01.158

We present a convenient synthesis of heterocyclic scaffolds using a novel modification of four-component Ugi condensation. Two complementary variants of this useful synthetic strategy provide an efficient one-step assembly of four novel pharmaceutically r

Full text of DOI:10.1016/j.tetlet.2006.01.158

Tetrahedron Letters 47 (2006) 2649–2653
One-step assembly of carbamoyl substituted annulated
1,4-oxazepines
Alexey P. Ilyin,a Vladislav Z. Parchinski,a Julia N. Peregudova,a Andrey S. Trifilenkov,a
Elena B. Poutsykina,a Sergey E. Tkachenko,b Dmitri V. Kravchenkoa
and Alexandre V. Ivachtchenkob,*
aDepartment of Organic Chemistry, Chemical Diversity Research Institute, 114401 Khimki, Moscow Reg, Russia
bChemDiv, Inc., 11558 Sorrento Valley Road, Suite 5, San Diego, CA 92121, USA
Received 30 August 2005; revised 30 January 2006; accepted 31 January 2006
Available online 24 February 2006
Abstract—We present a convenient synthesis of heterocyclic scaffolds using a novel modification of four-component Ugi condensa-
tion. Two complementary variants of this useful synthetic strategy provide an efficient one-step assembly of four novel pharmaceu-
tically relevant (hetero)aryl-fused 1,4-oxazepines with different substituents’ profile.
Ó 2006 Elsevier Ltd. All rights reserved.
Among a variety of physiologically active 5(3)-oxo-1,4-
oxazepines the derivatives of their aryl-fused analogs
represent a relatively little-explored group with interest-
ing pharmaceutical properties. They were described as
effective protease inhibitors,1 non-peptidergic GPCR
inhibitors,2 integrin antagonists,3 squalene synthase,4
and reverse transcriptase inhibitors.5 For example,
3-alkylamino-substituted 2,3-dihydro-5H-benzo[b][1,4]-
oxazepin-4-one I is a strong inhibitor of angiotensin-
converting enzyme (ACE),1a which plays a key role in
the modern approaches to hypertension and diabetic
nephropathy therapy, end-organ protection, and heart
failure treatment.6 3,4-Dihydropyrido[3,4-f][1,4]oxa-
zepin-5(2H)-one II and 3,4-dihydropyrido[3,2-f][1,4]-
According to these examples, aryl- and heteroaryl-fused
derivatives of 5(3)-oxo-1,4-oxazepine represent promis-
ing synthetic targets. Development of efficient synthetic
approaches to these scaffolds may provide a valuable
source of novel physiologically active agents. In this
paper, we communicate our success in developing a novel
four-component Ugi-type reaction for the synthesis of
novel aryl- and heteroaryl-fused derivatives of 5-carb-
oxamide-3-oxo-1,4-oxazepine V and 3-carboxamide-3-
methyl-5-oxo-1,4-oxazepine VI–VIII (Fig. 1), which can
be applied in combinatorial chemistry approaches.
In the reported synthetic approaches to the aryl-fused
derivatives of oxo-1,4-oxazepines, the key reaction is
the intermolecular cyclization of the appropriate aryl
derivatives leading to the desired molecules.10 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, the de-
scribed approaches have not provided a robust method
suitable for the production of combinatorial libraries.
The Ugi reaction11 was shown to be an effective
approach to the assembly of diverse compound libraries,
which can be readily applied in combinatorial chemistry
format. One of the important modifications of the clas-
sical four-component Ugi reaction includes the use of
bifunctional reagents.12 One example of the use of the
Ugi reaction to prepare annulated 1,4-oxazepines has
been reported by Zhang et al.12a
oxazepine-5(2H)-thione III represent
a
promising
structural class of compounds possessing H1 antihista-
minic activity,7 which can be used for the efficient
therapy of some allergic reactions and dermatological
affections.8 Dibenz[b,f][1,4]oxazepin-11(10H)-one IV
was found to selectively inhibit human immunodefi-
ciency virus type 1 (HIV-1) reverse transcriptase.9
Keywords: Ugi condensation; 5-Oxo-1,4-oxazepine-3-carboxamide;
3-Oxo-1,4-oxazepine-5-carboxamide; Parallel synthesis; Compound
library.
*
Corresponding author. Tel.: +1 858 794 4860; fax: +1 858 794
4931; e-mail addresses: dk@chemdiv.com; av@chemdiv.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.158

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A. P. Ilyin et al. / Tetrahedron Letters 47 (2006) 2649–2653
F
O
OH
H3C
F
O
N
N
CH3
F
N
H
O
NH
O
N
O
N
CH3
O
II
OH
I
CH3
N
CH3
O
O
N
N
N
CH3
O
S
H3C
IV
III
2
2
O
R
O
R
O
O
O
X
N
H
N
H
O
N
S
N
CH3
O
N
CH3
1
1
R
1
R
R
O
O
O
NH
VII: X=C
VIII: X=N
2
V
VI
R
Figure 1. Examples of physiologically active aryl-fused 1,4-oxazepinones (structures I–IV) and compounds synthesized in this work (structures
V–VIII).
Recently, we have described a convenient synthetic
approach to novel aryl(heteroaryl)-fused pyrazines using
a modification of four-component Ugi condensation
with 2-oxoethylamino-acetic acid fragment as a bifunc-
tional component.13 As a further modification of this
prospective methodology, we developed an efficient
synthetic route to novel aryl and heteroaryl-fused deriv-
atives of 3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a][1,4]diaze-
pine heterocyclic structures based on Ugi-type reaction
of bifunctional reagents bearing N-(carboxyaryl)-2-for-
myl fragment of corresponding pyrroles with isonitriles
and amines.14 In the mentioned works, we demonstrated
the efficacy and versatility of this efficient coupling
strategy for the production of combinatorial libraries
of heterocyclic structures representing promising phar-
maceutically relevant synthetic targets.
In this work, we have focused on broadening the scope
of the developed method and synthesized four novel
heterocyclic templates V–VIII, which were not described
before in the literature. Key bifunctional keto acids 3a–c
for the synthesis of heteroaryl-fused 5-oxo-1,4-oxaze-
pines 6–8 (Scheme 1) were obtained from the corre-
sponding hydroxy-substituted heteroaryl carboxylates
O
CH3COCH2Cl
CH3
R
R2
O
4a-r R1-NH2
5a-e R2-NC
K2CO3/18-crown-6/MeCN
OH
O
O
O
N
or NaH/DMF
H
W
W
W
O
MeOH, 50 0C
3-8 h
O
N
2-10 h
R
CH3
R1
O
O
1a-c, R=CH3
2a-c, R=CH3, 60-70%
6a-r, 13-66%;
7a,b, 89-94%
8a,b, 52-55%
5% NaOH,
EtOH-H2O
3a-c, R=H, 60-65%
*
*
*
N
W:
*
Ph
Ph
*
*
O
S
S
1a
1b
1c
Scheme 1. Synthesis of novel aryl and heteroaryl-fused derivatives of 3-methyl-5-oxo-1,4-oxazepine-3-carboxamides 6a–r, 7a,b, and 8a,b (Table 2).

A. P. Ilyin et al. / Tetrahedron Letters 47 (2006) 2649–2653
2651
Table 1. Synthesis of ketoesters 2a–c
Initial reagent
1a15a
1b15b
1c15c
Reaction conditions
1.2 mol equiv of K2CO3,
0.01 mol equiv of 18-crown-6,
MeCN, 10 h at reflux
Extraction with EtOAc,
recrystallization from EtOH
2 mol equiv of K2CO3,
0.01 mol equiv of 18-crown-6,
MeCN, 2 h at reflux
Crystallization from the
reaction mixture, recrystallization
from MeOH
1.1 mol equiv of NaH,
DMF, 8 h at 50 °C
Purification
Extraction with CHCl3,
recrystallization from EtOH–water (2:1)
Yield of 2a–c
70%
60%
60%
Table 2. Structures and yields of the synthesized compounds 6a–r,
7a,b, and 8a,b
1a–c, which are readily available from commercial
sources or synthetically.15 At the first step, ketoesters
2a–c were obtained by using the reaction of 1a–c with
chloroacetone. The optimal reaction and purification
conditions significantly varied according to the nature
of the initial bifunctional reactant (Table 1). The reac-
tion led to the desired ketoesters 2a–c in 60–70% yield.
The latter were hydrolyzed by 5% alkali in a mixture
of ethanol and water (3:1, v/v), and the resulting keto
acids 3a–c were isolated in 60–65% yield.
R2
R2
O
O
O
O
X
S
N
N
H
H
Ph
N
O
N
CH3
R1
CH3
R1
O
O
7a,b: X = CH
8a,b: X = N
6a-r
No. R1
R2
Yield, %
25
We have found that reaction of keto acids 3a–c with
various amines 4a–r and isocyanides 5a–e in methanol
at 50 °C led to novel heteroaryl-fused derivatives of
3-methyl-5-oxo-1,4-oxazepine-3-carboxamides 6a–r, 7a,b,
and 8a,b (Table 2). Typically, the full conversion of
initial keto acids was achieved within 3–8 h, depending
on the structure of the keto acid. The process presum-
ably follows the same initial course as the classical Ugi
condensation with an intermediate imine being attacked
by the isonitrile to give a nitrilium intermediate, which
then undergoes intramolecular cyclization. With respect
to the amine component, various cycloaliphatic and
aromatic primary amines, such as substituted anilines,
benzyl and phenyl amines, linear and branched aliphatic
amines, were tolerated without any limitations. As iso-
nitrile reagents, we used five different isonitriles 5a–e
available from commercial sources.
6a
6b
6c
6d
6e
6f
3-Cl–C6H4–CH2
C6H5–(CH2)3
MeO–(CH2)2
C6H5–CH2
2-MeO–C6H4–CH2 34
2-MeO–C6H4–CH2 29
2-Cyclohex-1-en-1-ylethyl 2-MeO–C6H4–CH2 45
2-F–C6H4–CH2
2-Me–C6H4–(CH2)2
3-Br–C6H4–CH2
2-Me–C6H4–(CH2)2
4-Me–C6H4–CH2
Bn
2-MeO–C6H4–CH2 64
2-MeO–C6H4–CH2 22
c-C5H9
c-C5H9
c-C5H9
c-C5H9
C6H5–CH2
2-MeO–C6H4–CH2 52
c-C5H9
c-C5H9
c-C5H9
c-C5H9
c-C5H9
c-C5H9
c-C7H13
c-C8H15
c-C6H11
c-C6H11
6g
6h
6i
29
18
66
55
44
6j
6k
6l
n-Bu
n-Pr
6m Bn
61
34
38
64
21
48
89
94
52
55
6n
6o
6p
6q
6r
2-F–C6H4–CH2
4-EtO–C6H4–CH2
2-Me–C6H4–CH2
4-i-Pr–C6H4–CH2
3-F–C6H4–CH2
4-Me–C6H4–CH2
4-Me–C6H4–CH2
Bn
7a
7b
8a
8b
For assembly of the aryl-fused 3-oxo[1,4]oxazepine-
5-carboxamide heterocyclic system, we explored the
possibility of the use of formyl carboxylate 9 as an alter-
native bifunctional reagent in a similar condensation
(Scheme 2). Compound 9 was prepared as reported by
Hullar and Failla.16 The reaction of 9 with amines 4a–w
and cyclopentylisocyanide 5a in methanol at 50 °C
led to a medium-sized library of novel N-substituted
3-oxo-naphtho[1,2-f][1,4]oxazepine-5-cyclopentylcarbox-
amides 10a–w in 14–74% yield. This condensation
C6H5–(CH2)2
proceeded more slowly than reaction of 3a–c with
isocyanides and amines; typically, the complete conver-
sion of initial reactants was achieved within 16–18 h.
O
OH
O
4a-w R1-NH2
5a NC
O
O
O
N
H
R1
MeOH, 50 0C, 18 h
O
N
H
10a-w (14-74%)
9
Scheme 2. Synthesis of novel N-substituted derivatives of 3-oxo-naphtho[1,2-f][1,4]oxazepine-5-cyclopentylcarboxamide 10a–w (Table 3).

2652
A. P. Ilyin et al. / Tetrahedron Letters 47 (2006) 2649–2653
Table 3. Structures and yields of the synthesized compounds 10a–w
References and notes
No.
R1
Yield, %
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3-F–C6H4–CH2
4-Me–C6H4–CH2
4-Et–C6H4–CH2
4-F–C6H4–CH2
1,3-Benzodioxol-5-ylmethyl
c-C5H9
c-C6H11
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3-Cl–4-MeO–C6H3
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was made on the basis of H NMR, 13C NMR, and
1
high-resolution mass-spectroscopy data. Thus, two
non-equivalent methylene protons of the oxazepine ring
of compounds 6–8 can be seen as two doublets in the
range of d 4.0–4.5 and d 4.7–5.0 ppm with the geminal
spin–spin coupling constants in the range of 13.6–
14.1 Hz. The characteristic signals from methylene pro-
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In summary, we have developed a convenient synthetic
strategy to the assembly of the aryl(heteroaryl)-fused
derivatives of 5(3)-oxo-1,4-oxazepine heterocyclic
structures based on a novel modification of the Ugi
four-component reaction. As a synthetic tool for creat-
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condensation used in this work offers a large number
of potential input reactants and resulting products and
can be used in a combinatorial format.
Supplementary data
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2006.01.158.

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