Rapid access to multi-substituted pyrimido[4,5-b][1,4]diazepine-2,4,6- trione and pyrimido[4,5-b][1,4]diazepine-2,4-dione as novel and versatile scaffolds for drug discovery

Article abstract of DOI:10.1016/j.tetlet.2012.06.143

A novel pyrimido[4,5-b][1,4]diazepine-2,4,6-trione was synthesized with an efficient strategy. Especially, the key intermediate 2,4-dimethoxypyrimido[4,5- b][1,4]diazepin-6-one was promoted by one pot tandem reduction-cyclization with Na₂S₂O₄. Subsequently, reduction of lactams 6 with LiAlH₄ afforded a more flexible scaffold of pyrimidodiazepines. The synthetic strategy was versatile since it facilitated the sequential functionalization on the pyrimidodiazepine at three positions. Thus a convenient and effective method for the rapid preparing of multi-substituted pyrimido[4,5-b][1,4]diazepines was developed.

Full text of DOI:10.1016/j.tetlet.2012.06.143

Tetrahedron Letters 53 (2012) 5193–5196
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid access to multi-substituted pyrimido[4,5-b][1,4]diazepine-2,4,6-trione
and pyrimido[4,5-b][1,4]diazepine-2,4-dione as novel and versatile scaffolds
for drug discovery
⇑
⇑
Gong Li, Xiaowei Wang , Chao Tian, Tongbo Zhang, Zhili Zhang, Junyi Liu
The State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel pyrimido[4,5-b][1,4]diazepine-2,4,6-trione was synthesized with an efficient strategy. Especially,
the key intermediate 2,4-dimethoxypyrimido[4,5-b][1,4]diazepin-6-one was promoted by one pot tan-
dem reduction–cyclization with Na2S2O4. Subsequently, reduction of lactams 6 with LiAlH4 afforded a
more flexible scaffold of pyrimidodiazepines. The synthetic strategy was versatile since it facilitated
the sequential functionalization on the pyrimidodiazepine at three positions. Thus a convenient and
effective method for the rapid preparing of multi-substituted pyrimido[4,5-b][1,4]diazepines was
developed.
Received 18 May 2012
Revised 26 June 2012
Accepted 29 June 2012
Available online 5 July 2012
Keywords:
Pyrimidodiazepine
Pyrimido[4,5-b][1,4]diazepine-2,4,6-trione
Pyrimido[4,5-b][1,4]diazepine-2,4-dione
Ó 2012 Elsevier Ltd. All rights reserved.
At present, an effective approach for identification of new lead
compounds in drug discovery involves screening of chemical li-
braries based upon privileged structure.1,2 These frameworks could
address multiple biological targets by varying the nature of periph-
eral substituents. Benzodiazepines are the prototypical privileged
due to its important potential biological properties.8 Moreover, as
a special interest in developing flexible scaffold of HIV-1 RT inhib-
itors,7 we performed the reduction of lactam 6 which provided the
pyrimido[4,5-b][1,4]diazepine-2,4-dione scaffold (Fig. 1).
From the structural perspective, pyrimido[4,5-b][1,4]diazepine
represents a versatile intermediate for bearing three orthogonal
groups with R1, R2 and R3. Therefore, a library of pyrimidodiazepine
compounds could provide the structure–activity relationship (SAR)
study based on privileged structure. However, there is no example
for synthesizing skeleton of target compounds with a combination
of privileged structure and I.
The reported synthetic strategies, in which 5,6-diaminouracils
were usually adopted to undergo an intermolecular condensation
with ether chalcones or b-dicarbonyl compounds to afford the
pyrimido[4,5-b][1,4]diazepine skeleton,9 were not efficient for the
preparation of highly substituted pyrimido[4,5-b][1,4]diazepine-
2,4,6-triones (Fig. 1). The first reason is that diaminopyrimidines
are usually expensive and difficult for preservation. Another one
is that though the presence of non-equivalent amino groups, the de-
sired cyclization manner could not be exclusive. The cyclization
products, formed as a mixture of two regioisomers, are difficult
for isolation and identification from each other due to their similar
physico-chemical properties. Concerning the above disadvantages,
we make efforts to develop a novel strategy that permits the rapid
and efficient synthesis of multi-substituted pyrimido[4,5-b][1,4]
diazepine-2,4,6-triones.
structures, among them, 1,5-benzodiazepine-2-ones exhibit
a
range of biological activities.3–5 Since pyrimidines are often incor-
porated into drugs designed for cancer and anti-viral treatment
due to their wide range of biological activities, best known as the
heterocyclic core of the nucleic acid bases.6 We suppose that if
the bioisosteric replacement of archetypal benzene ring by pyrim-
idine on the 1,5-benzodiazepine-2-one could give us an unique
handle toward developing druggable molecules against cancer
and virus. And it is also believed that the corresponding pyrimi-
do[4,5-b][1,4]diazepine scaffolds comprising part of the privileged
structure should share the good physico-chemical and pharmaco-
kinetic properties of benzodiazepine.
Intrigued by this idea, we would like to hybridize the 1,5-ben-
zodiazepine-2-one skeleton with compound I (Fig. 1) which was
previously reported as a potent HIV-1 RT inhibitor7 to achieve
the pyrimido[4,5-b][1,4]diazepine-2,4,6-trione scaffold (Fig. 1). As
far as we know the pyrimidodiazepine scaffolds had never been
studied as the inhibitors of HIV-1 RT, though a number of unique
approaches in regard to pyrimidodiazepine have been explored
⇑
In our synthetic strategy, the fused bicyclic core was obtained in
two steps as illustrated in Scheme 1 from the easily prepared
Corresponding authors.
E-mail addresses: xiaoweiwang@bjmu.edu.cn (X. Wang), jyliu@bjmu.edu.cn
(J. Liu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.143

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G. Li et al. / Tetrahedron Letters 53 (2012) 5193–5196
O
N
R2
R2
O
O
R3
N
O
N
5
N
5
O
HN
HN
HN
3
1
N
3
1
N
9
N
9
N
O
R2
O
O
N
R3
R3
O
R1
R1
R1
pyrimido[4,5-b][1,4]
diazepine-2,4diones
pyrimido[4,5-b][1,4]
diazepine-2,4,6-triones
privileged structure
1,5-benzodiazepin-2-ones
I
target compounds
Figure 1. Structures of privileged skeleton, I and target compounds.
OMe
COOMe
OMe
R1HN
NO2
R1=phenyl, 3a (78%)
NO2
Cl
N
O
1
N
R1=cyclohexyl, 3b (89%)
t-BuOH
MeO
N
N
OMe
MeO
N
2
R1
3
H2, Pd/C
or SnCl2
Na2S2O4, 50%EtOH
OMe
NH2
N
O
OMe
O
H
N
MeO
N
N
OMe
N
R1=phenyl, 5a (86%)
R1=cyclohexyl, 5b (84%)
MeO
N
N
R1
5
4 (20% for H2, Pd/C)
Scheme 1. Synthesis of pyrimido[4,5-b][1,4]diazepines from 2,4-dimethoxyl-6-chloro-5-nitro-pyrimidine and b-aminopropanoates.
intermediate 2.10 First, nucleophilic substitution of 2,4-dimeth-
oxyl-6-chloro-5-nitropyrimidine 2 with b-aminopropanoates 1
afforded intermediates 3 in good yields. Obviously, a free amino
group was necessary for the coming intramolecular cyclization.
Therefore, three reagents were examined for the reduction of 3a.
First, 3a was treated with hydrogen in the presence of a catalytic
amount of 10% palladium on carbon to give the aminopyrimidine
we did not reach an acceptable yield when introducing the isopro-
pyl group by using NaH as base. Alternatively, the phase-transfer
catalysis method in which the two substrates were refluxing with
KOH/TBAB for 5 h in CH3CN facilitated the isopropylated products
6b and 6e in high yields (Table 1).
Deblocking of the 2,4-dimethoxypyrimidine ring of 6 to uracil 7
was achieved under a relatively mild condition with TMSCl and NaI
as deprotection agents to give compound 7a and 7b, while 7c was
achieved by an alternative HCl/THF hydrolysis method (Scheme 3).
The results indicated that the lactam was tolerated to HCl/THF
condition. Treatment of 7 with N,O-bis(trimethylsilyl)acetamide
(BSA) and alkyl chloromethyl ether in CHCl3 at room temperature
gave the N1 substituted uracils 8 in good yields (Scheme 3).7 More-
over, the N3 substituted compounds 9a and 9b were also isolated
and identified as byproducts in 40% and 33% yields respectively
(Scheme 3).
The reduction of lactams 6 with LiAlH4 afforded a more flexible
scaffold of pyrimidodiazepine 10 (Scheme 3), which was character-
ized by 1H NMR, and MS. However, the N1 and N3 regioisomers
showed very similar physical and chemical properties. Therefore,
it would be difficult to distinguish between the N1 and N3 alkyl-
ation products with 1H NMR only. To facilitate more exact struc-
tural information of the N113 and N3 regioisomers, the X-ray
structural analyses of 11a and 12a were shown in Figure 2.
In conclusion, we have developed an effective synthesis strat-
egy that permits the rapid access to the pyrimido[4,5-b][1,4]diaze-
pine-2,4,6-triones and pyrimido[4,5-b][1,4]diazepine-2,4-diones
11
4 in an unacceptable yield. Second, SnCl2 was used as reduction
agent which could afford the cyclization product 5a, but in rather
low yield. Finally, we found that the reduction of nitro compounds
3 took place along with an intramolecular cyclization when
10 equiv of Na2S2O412 was used in the circumstance of 50% alcohol
at refluxing for 6 h to give lactam 5 in excellent yields (84–86%).
The analytical data showed that no amino compounds 4 were iso-
lated, which meant that treatment of nitro compounds 3 with ex-
cess Na2S2O4 gave the amino compounds, and then immediately
carried out an intramolecular nucleophilic attack by amino on es-
ter to give the seven-membered ring compounds 5. It had to be
noted here that Na2S2O4 also showed purification advantage that
crude cyclization product collected from the extraction of reaction
mixture could be used directly for the next step without further
purification. It was evident that the present methodology short-
ened the synthesis steps and increased the reaction yields.
Subsequent N5-alkylation of lactams 5 occurred smoothly on
treatment with different alkyl halides (CH3I, BnBr) in the presence
of NaH to give 6a, 6c, and 6d in good yields (Scheme 2). However,
R2
OMe
OMe
Table 1
N5-alkylation on lactams 5
H
N
O
O
N
R2X
N
N
Entry
6
R1
R2X
Base
Yield (%)
MeO
N
MeO
N
N
R1
N
1
2
3
4
5
6a
6b
6c
6d
6e
Ph
Ph
Ph
CH3I
CH(CH3)2Br
BnBr
CH3I
CH(CH3)2Br
NaH
KOH
NaH
NaH
KOH
92
96
99
88
98
R1
6
5
Cyclohexyl
Cyclohexyl
Scheme 2. Reaction conditions: NaH (60% dispersion in mineral oil) THF, rt; KOH/
TBAB, acetonitrile, refluxing.

G. Li et al. / Tetrahedron Letters 53 (2012) 5193–5196
5195
R2
N
R2
N
R2
N
R2
N
OMe
N
O
O
N
O
O
O
O
O
N
HN
HN
R3O
N
a
b
+
MeO
O
N
H
O
O
N
H
N
N
N
N
R3O
6
7
8
9
R2 = CH3:
R3=Et, 8a (77%)
R3=Bn, 8b (70%)
R2 = CH3, 7a (69%)
R
2 = CH(CH3)2, 7b (79%)
2 = Bn, 7c (63%)
R2 = CH(CH3)2: R3=Et, 8c (64%)
R
R3=Bn, 8d (49%)
R3=Et, 8e (50%), 9a (40%)
R3=Bn, 8f (55%), 9b (33%)
R2=Bn:
LiAlH4
Et2O
R2
N
R2
R2
O
OMe
O
N
N
N
HN
R3O
N
a,b
+
MeO
N
O
N
O
N
H
N
N
N
R3O
10
2 = CH3, 10a (76%)
2 = CH(CH3)2, 10b (65%)
2 = Bn, 10c (66%)
11
R2 = CH3:
12
R3 = Et, 11a (69%), 12a (16%)
R3 = Bn, 11b (58%), 12b (35%)
R
R
R
R2=CH(CH3)2: R3 = Et, 11c (45%)
3 = Bn,11d (51%)
R3 = Et, 11e (61%)
3 = Bn, 11f (42%)
R
R2=Bn:
R
Scheme 3. Reagents and conditions: (a) TMSCl/NaI or HCl/THF; (b) BSA, R3OCH2Cl.
Figure 2. X-ray crystal structure of 11a and 12a.
from the readily available 2,4-dimethoxyl-6-chloro-5-nitropyrimi-
dine and b-aminopropanoates. The overall yield is acceptable and
the purification of intermediates is trouble-free. The synthetic
strategy is versatile for the sequential functionalization on the pyr-
imidodiazepine which are of great interest in drug discovery based
on privileged structure. More detailed SAR studies are underway
with a focus on exploring the important role of this unique struc-
tural feature.
Supplementary data
Crystallographic data (excluding structure factors) for the struc-
tures in this paper have been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publication 782159
CCDC.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
06.143.
Acknowledgment
References and notes
We thank the National Science Foundation of China(21042009,
2009ZX09301-010, 20972011, 21172014) for financial support.
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