Synthesis of novel 8,9-dihydro-5 h -pyrimido[4,5- e ][1,4]diazepin-7(6 h)-ones

Article abstract of DOI:10.1021/cc100039w

Practical and efficient methods have been developed for the synthesis of 4,6,8,9-tetrasubstituted 8,9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones from 4,6-dicholoropyrimidine aldehyde, N-substituted amino acid esters, and amines in five steps. This synthetic strategy is based on suitably substituted pyrimidines as bis-electrophilic species reacting with various amines to construct the pyrimido[4,5-e][1,4]diazepine core with a strategically anchored functional group for further derivatization. The utility of this methodology was demonstrated through the preparation of a 33-membered library of representative 8,9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones in good to excellent yields.

Full text of DOI:10.1021/cc100039w

J. Comb. Chem. 2010, 12, 503–509
503
Synthesis of Novel
8,9-Dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones
Jinbao Xiang, Dongsheng Wen, Hongxiang Xie, Qun Dang, and Xu Bai*
The Center for Combinatorial Chemistry and Drug DiscoVery, The School of Pharmaceutical Sciences
and The College of Chemistry, Jilin UniVersity, 1266 Fujin Road, Changchun, Jilin 130021, P. R. China
ReceiVed March 9, 2010
Practical and efficient methods have been developed for the synthesis of 4,6,8,9-tetrasubstituted 8,9-dihydro-
5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones from 4,6-dicholoropyrimidine aldehyde, N-substituted amino
acid esters, and amines in five steps. This synthetic strategy is based on suitably substituted pyrimidines as
bis-electrophilic species reacting with various amines to construct the pyrimido[4,5-e][1,4]diazepine core
with a strategically anchored functional group for further derivatization. The utility of this methodology
was demonstrated through the preparation of a 33-membered library of representative 8,9-dihydro-5H-
pyrimido[4,5-e][1,4]diazepin-7(6H)-ones in good to excellent yields.
Introduction
tage of the reactive chloro functionality as shown in
Scheme 1. Herein, the details of these studies are
presented.
The search for novel compound libraries with potential
biological activities is a major focus for chemical biology
and medicinal chemistry. Libraries based on small mol-
ecules of privileged structures are of special interest.1 The
pyrimidine moiety was widely incorporated in the design
of privileged structures in medicinal chemistry.1b Bicyclic
pyrimido[4,5-e][1,4]diazepines have been reported to
exhibit a variety of biological activities. For example, their
analogs are known as tachykinin receptor antagonists,2
anticonvulsant agents,3 raf kinase inhibitors,4 and cysteine
protease inhibitors.5 Despite interesting biological activi-
ties and a few reported syntheses of pyrimido[4,5-
e][1,4]diazepines,6 we were only able to find one method
for the synthesis of pyrimido[4,5-e][1,4]diazepin-7(6H)-
one derivatives which were prepared by condensation of
2-cyano-5-((4-methoxyphenylamino)methyl)-4-(neopenty-
lamino) pyrimidine with chloroacetyl chloride.5 An ef-
ficientsyntheticmethodtoaccesspyrimido[4,5-e][1,4]diazepin-
7(6H)-ones with diverse structural features should be
useful for the exploration of biological activities of this
class of compounds.
Results and Discussion
The key precursors 2 were synthesized in a three-step
sequence as depicted in Scheme 2. The treatment of 4,6-
dichloro-5-formylpyrimidine9 1 with racemic amino acid
esters in CHCl3 in the presence of Et3N gave corresponding
substituted 5-formylpyrimidines 5 in good yields. Reduction
of the formyl group in 5 with NaBH3CN in the presence of
AcOH in EtOH furnished the corresponding alcohol deriva-
tives 6. Intermediates 6 were treated with SOCl2 to afford
the desired chloromethylpyrimidine precursors 2 in high
overall yields from 5.
Initially, precursor 2a was selected to test the reaction
conditions required to generate pyrimidodiazepine 3a.
When 2a and 1.2 equiv of n-BuNH2 were treated with
Et3N in CH3CN for 25 h at room temperature, cyclization
product 3.1a was successfully obtained in 87% yield (entry
1, Table 1). However, under the above conditions,
treatment of precursor 2a with aniline did not give the
desired product 3.14a (entry 2, Table 1). When the reaction
temperature was increased to refluxing CH3CN, intermedi-
ate 7a was isolated as the sole product in 91% yield after
7.5 h (entry 3, Table 1). Changing the solvent to toluene
led to the desired product 3.14a in 40% yield (entry 4,
Table 1), while the use of AcOH-toluene conditions only
produced 38% yield of the desired product 3.14a after
72 h (entry 5, Table 1). Inspired by the publication of
Prasad and co-workers,10 the conditions of Et3N/CH3CN
under reflux for 11 h and then reflux in 10% acetic acid
in toluene for 1 h were investigated, which produced the
desired product in 86% yield (entry 6, Table 1). To test
whether acetic acid is required or not, the conditions of
Et3N/DMF/120 °C were tested (entry 7, Table 1). Although
the desired product was isolated in 49% yield, the
As part of our ongoing efforts to prepare libraries of
novel heterocycles,7 we reported a series of methodologies
to rapidly access various tricyclic or tetracyclic hetero-
cyclic scaffolds with pyrimidodiazepine as the core.8 As
a continuing endeavor, we envisioned that 8,9-dihydro-
5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones 3 could be
readily prepared by the reaction of key precursors 2,
prepared from simple pyrimidine 1 and derivatives of
amino acids, with different amines (Scheme 1). Moreover,
compounds 3 could be further modified by taking advan-
* Corresponding author. E-mail: xbai@jlu.edu.cn. Tel: +86-431-
85188955. Fax: +86-431-85188900.
10.1021/cc100039w  2010 American Chemical Society
Published on Web 05/27/2010

504 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Xiang et al.
Scheme 1. Strategy for Preparation of Pyrimido[4,5-e][1,4]diazepin-7(6H)-ones
Scheme 2. Synthesis of the Key Precursors 2
Table 1. Optimization of the Cyclization Conditions
entry
R3NH2
conditions
time (h)
product
yield (%)a
yield 7a (%)a
1
2
3
4
5
6
7
n-BuNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
Et3N/CH3CN, rt
Et3N/CH3CN, rt
Et3N/CH3CN, reflux
Et3N/toluene, reflux
AcOH/toluene, reflux
1) Et3N/CH3CN, reflux, 2) AcOH/toluene, reflux
Et3N/DMF, 120 °C
25
24
7.5
72
72
3.1a
87
3.14a
3.14a
3.14a
3.14a
3.14a
3.14a
NRb
91
40
38
86
49
11 + 1
12
37
a Isolated yield. b NR denotes no reaction.
precyclized product 7a was also isolated, suggesting that
acetic acid is required for the efficient cyclization of the
current reaction. Therefore, the conditions of Et3N/CH3CN
were used in the current cyclization reactions with
aliphatic amines, while Et3N/CH3CN and follow-up treat-
ment with AcOH-toluene was used in the case of
aromatic amines. The results are summarized in Table 2.
As disclosed in Table 2, various amines ranging from
ammonia, aliphatic amines, and aromatic amines to amino
acid esters and amino alcohol are compatible for the
current reactions to produce the expected pyrimido[4,5-
e][1,4]diazepin-7(6H)-ones 3 in good to excellent yields.
The reaction rate appeared to be sensitive to both steric
and electronic effects. For aliphatic amines, the reaction
temperature was increased with increasing size of the
aliphatic group (entries 1, 2, and 4 vs entries 5-9, Table
2). For aromatic amines, the reaction proceeded faster for
aromatic amines with an electron-donating group com-
pared to those with an electron-withdrawing group (entries
10-14 vs entries 15-17, Table 2). When an ortho
substituent is present in the aromatic amine, the reaction
was slower than the corresponding meta and para
substituted analogs (entry 13 vs entries 12 and 11, Table
2). For amino acid esters, the cyclization reactions
involving phenylalanine ethyl ester required higher tem-
perature for completion compared to phenylglycine ethyl
ester and glycine ethyl ester (entry 19 vs entries 18 and
17, Table 2). Similarly, reactions with larger R1 and R2
groups also required higher temperature for completion
(entry 25 vs entry 24 vs entry 23, Table 2).
Two compounds (3.1a and 3.14a) were selected as
representative examples to examine the reactivity of the 4-Cl
group toward various nucleophiles and coupling reagents.
As depicted in Table 3, compounds 3.1a or 3.14a reacted
readily with an amine under either basic conditions of Et3N
(for n-BuNH2, piperazine, pyrrolidine) or acidic conditions
of concentrated aqueous HCl (for aniline) to give the desired
N-substituted products in good to excellent yields (entries
1-4, 8, Table 3). Other nucleophiles with heteroatoms, such
as alcohols and thiols, were also tested. Compounds 3.1a
reacted with thiophenol under Et3N/EtOH conditions to give
the corresponding substituted product 4.1.5a in 91% yield
(entry 5, Table 3), while compounds 3.1a reacted with
n-butanol smoothly under NaH/THF conditions to give the
n-butyloxy-substituted product 4.1.6a in 94% yields (entry
6, Table 3). Under Suzuki-Miyaura cross-coupling condi-
tions, compound 3.1a reacted with phenylboronic acid to
yield aryl-substituted product 4.1.7a in 99% yields (entry 7,
Table 3). These results clearly indicate that the chloro group

8,9-Dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 505
Table 2. Preparation of Pyrimido[4,5-e][1,4]diazepin-7(6H)-ones
entry
R1
R2
R3
conditions
time (h)
25
35
9
45
3.5
17
23
product
yield (%)a
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
n-Bu
Me
H
Et3N/CH3CN, rt
Et3N/CH3CN, rt
Et3N/CH3CN, 85 °C
Et3N/CH3CN, rt
Et3N/CH3CN, reflux
Et3N/CH3CN, reflux
Et3N/CH3CN, reflux
Et3N/CH3CN, reflux
Et3N/CH3CN, reflux
3.1a
3.2a
3.3a
3.4a
3.5a
3.6a
3.7a
3.8a
86
74b
70c
99
86
86
70
79
98
87
86
78
81
83
84
88
60
90
73
57
84
67
73
50
86
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
i-Pr
Ph
Bn
cyclobutyl
cyclopentyl
cyclohexyl
i-Pr
1-phenylethyl
p-MeOPh
p-MePh
8
36
9
3.9a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
(1) Et3N/CH3CN, reflux, (2) AcOH/toluene, reflux
(1) Et3N/CH3CN, reflux, (2) AcOH/toluene, reflux
(1) Et3N/CH3CN, reflux, (2) AcOH/toluene, reflux
(1) Et3N/CH3CN, reflux, (2) AcOH/toluene, reflux
(1) Et3N/CH3CN, reflux, (2) AcOH/toluene, reflux
(1) Et3N/CH3CN, reflux, (2) AcOH/toluene, reflux
(1) Et3N/CH3CN, reflux, (2) AcOH/toluene, reflux
(1) Et3N/CH3CN, reflux, (2) AcOH/toluene, reflux
Et3N/CH3CN, reflux
3 + 0.5
3.5 + 0.7
4.5 + 1
6 + 4
11 + 1
24 + 4.5
20 + 4
42 + 4.5
7
28
11 + 2
12
1.5 + 6
4 + 3
20
3.10a
3.11a
3.12a
3.13a
3.14a
3.15a
3.16a
3.17a
3.18a
3.19a
3.20a
3.21a
3.1b
m-MePh
o-MePh
Ph
p-ClPh
p-CH3COPh
p-NO2Ph
CH2CO2C2H5
CH(Ph)CO2C2H5
CH(Bn)CO2C2H5
CH2CH2OH
n-Bu
Et3N/CH3CN, reflux
(1) Et3N/CH3CN, reflux, (2) AcOH/toluene, reflux
Et3N/CH3CN, rt
(1) K2CO3/CH3CN, reflux, (2) AcOH/toluene, reflux
(1) Et3N/CH3CN, reflux, (2) AcOH/toluene, reflux
Et3N/CH3CN, reflux
Me
Me
-(CH2)3-
n-Bu
n-Bu
n-Bu
3.1c
3.1d
3.1e
Et3N/CH3CN, rt
17
a Isolated yield. b Methylamine alcohol solution (27-32%) was utilized. c Ammonia saturated methanol was utilized, and the reaction was conducted
in a sealed tube.
Table 3. Results of 4-Cl Replacements in Compounds 3
.
entry
R1
R2
R3
R4
conditions
Et3N/n-BuOH, reflux
Et3N/n-BuOH, reflux
Et3N/n-BuOH, reflux
conc. HCl/n-BuOH, reflux
Et3N/EtOH, reflux
NaH/THF, rt
Pd(OAc)2, K2CO3, Ph3P/DME-H2O, reflux
conc. HCl/n-BuOH, reflux
time (h)
product
yield (%)a
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Ph
n-BuNH
piperazin-1-yl
pyrrolidin-1-yl
PhNH
72
24
25
12
5
72
2
18
4.1.1a
4.1.2a
4.1.3a
4.1.4a
4.1.5a
4.1.6a
4.1.7a
4.14.4a
78
91
99
83
91
94
99
64
PhS
n-BuO
Phb
PhNH
a Isolated yield. b PhB(OH)2 was used.
in compounds 3 is highly reactive toward further modifica-
tions to increase the molecular diversity.
or transition-metal-catalyzed cross coupling reactions. These
novel heterocycles based on privileged structures could be
of interest in studies of chemical biology and drug discovery.
Conclusion
Experimental Section
In summary, a representative library of pyrimido[4,5-
e][1,4]diazepin-7(6H)-ones was readily prepared by the
reaction of suitably substituted pyrimidines 2 with different
amines. The synthetic strategy combines three structural
motifs, namely a pyrimidine, an amino acid ester, and an
amine, to form a pyrimido[4,5-e][1,4]diazepin-7(6H)-one
scaffold. The resulting heterocycles possess a reactive chloro
group on the pyrimidine moiety which allows further
introduction of a new element via nucleophilic substitution
General Consideration. Acetonitrile (CH3CN) was dried
with CaH2 and distilled. Dichloromethane (CH2Cl2) was dried
with P2O5 and distilled. Ethanol (EtOH) was dried with Na
and distilled. All other commercial reagents were used as
received without additional purification. The melting point
was uncorrected. Mass spectra and HPLC data were recorded
on a LC/MS system with an evaporative light scattering
detector (ELSD). The 1H and 13C NMR data were obtained

506 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Xiang et al.
on a 300 MHz NMR spectrometer with tetramethylsilane
(TMS) as the internal standard and CDCl3 as solvent unless
otherwise stated. Multiplicities are indicated as the following:
s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd,
doubled doublet; br, broad. Coupling constants (J values)
where noted are quoted in hertz.
further purification. The crude 6 was dissolved in CH2Cl2
(4 mL) and cooled to 0 °C before SOCl2 (4.8 mmol) was
added. The mixture was allowed to warm to room temper-
ature. After complete consumption of compound 6, as
indicated by TLC, cold water (5 mL) was added. The water
layer was treated with saturated aqueous NaHCO3 (1 mL)
and extracted with CH2Cl2 (3 × 10 mL). The combined
CH2Cl2 layer was washed with brine (20 mL), dried over
anhydrous Na2SO4, concentrated in vacuo, and purified by
flash chromatography (petroleum ether/EtOAc, 4:1, v/v) to
afford the desired product 2.
Ethyl 2-((6-Chloro-5-(chloromethyl)pyrimidin-4-yl)
(methyl)amino)acetate 2a. 86%. mp: 78-80 °C. 1H NMR
δ 8.31 (s, 1H), 4.72 (s, 2H), 4.28-4.21 (m, 4H), 3.42 (s,
3H), 1.30 (t, 3H, J ) 7.5). 13C NMR δ 169.5, 164.0, 163.2,
155.9, 61.2, 54.2, 40.7, 40.3, 14.1. MS (ESI): m/z 278.0 [M
+ H+].
General Procedure for the Synthesis of Amino Acid
Ester Substituted 6-Chloro-5-formylpyrimidine 5. Et3N
(7 mmol) in CH2Cl2 (3 mL) was added dropwise to a stirred
solution of 4,6-dichloro-5-formylpyrimidine 1 (2.8 mmol)
and amino acid ester hydrochloride (3.08 mmol) in CHCl3
(3 mL) at 0 °C. After an additional 10 min, the reaction
mixture was allowed to warm to room temperature. After
complete consumption of the starting material 1, as indicated
by thin-layer chromatography (TLC), the solvent was
removed in vacuo and water (50 mL) was added, it was then
extracted with CH2Cl2 (3 × 50 mL). The combined organic
layers were washed with water (30 mL) and brine (50 mL),
dried over Na2SO4, concentrated in vacuo, and purified by
flash chromatography (petroleum ether/EtOAc, 4:1, v/v) to
afford the desired product 5.
Ethyl
2-(6-Chloro-5-(chloromethyl)pyrimidin-4-
ylamino)acetate 2b. 89%. mp: 86-88 °C. 1H NMR δ 8.37
(s, 1H), 5.86 (s, 1H), 4.73 (s, 2H), 4.31-4.24 (m, 4H), 1.30
(t, 3H, J ) 7.2). MS (ESI): m/z 263.9 [M + H+].
Ethyl 2-((6-Chloro-5-formylpyrimidin-4-yl)(methyl)
amino)acetate 5a. 81%. mp: 75-77 °C. 1H NMR δ 10.43
(s, 1H), 8.35 (s, 1H), 4.33 (s, 2H), 4.25 (q, 2H, J ) 7.2),
3.01 (s, 3H), 1.29 (t, 3H, J ) 7.5). MS (ESI): m/z 258.0 [M
+ H+].
Ethyl 2-((6-Chloro-5-(chloromethyl)pyrimidin-4-yl)
(methyl)amino)-3-methylbutanoate 2c. 92%. oil. 1H NMR
δ 8.35 (s, 1H), 4.77 (s, 2H), 4.58 (d, 1H, J ) 11.1), 4.24 (q,
2H, J ) 7.5), 3.30, (s, 3H), 2.42-2.33 (m, 1H), 1.29 (t, 3H,
J ) 7.2), 1.06 (d, 3H, J ) 6.6). 0.92 (d, 3H, J ) 7.2). MS
(ESI): m/z 320.0 [M + H+].
Ethyl 2-(6-Chloro-5-formylpyrimidin-4-ylamino)acetate
1
5b. 52%. mp: 120-122 °C. H NMR δ 10.41 (s, 1H), 9.50
Ethyl 2-((6-Chloro-5-(chloromethyl)pyrimidin-4-yl)
(methyl)amino)-2-phenylacetate 2d. 90%. oil. 1H NMR δ
8.39 (s, 1H), 7.41-7.39 (m, 3H), 7.34-7.26 (m, 2H), 6.04
(s, 1H), 4.69 (q, 2H, J ) 12.4), 4.29-4.23 (m, 2H), 3.08 (s,
3H), 1.27 (t, 3H, J ) 7.2). MS (ESI): m/z 354.0 [M + H+].
Ethyl 1-(6-Chloro-5-(chloromethyl)pyrimidin-4-yl)pyr-
(br, 1H), 8.44 (s, 1H), 4.34 (d, 2H, J ) 5.4), 4.26 (q, 2H, J
) 7.2), 1.31 (t, 3H, J ) 7.2). MS (ESI): m/z 244.2 [M +
H+].
Ethyl 2-((6-Chloro-5-formylpyrimidin-4-yl)(methyl)
1
amino)-3-methylbutanoate 5c. 57%. oil H NMR δ 10.40
1
(s, 1H), 8.37 (s, 1H), 4.99 (d, 1H, J ) 10.2), 4.21 (q, 2H, J
) 7.2), 2.91 (s, 3H), 2.41-2.33 (m, 1H), 1.28 (t, 3H, J )
7.5), 1.09 (d, 3H, J ) 6.3), 0.99 (d, 3H, J ) 6.6). MS (ESI):
m/z 300.1 [M + H+].
rolidine-2-carboxylate 2e. 71%. oil. H NMR δ 8.24 (s,
1H), 4.85 (d, 2H, J ) 4.6), 4.72 (dd, 1H, J ) 7.7, 5.7),
4.29-3.99 (m, 4H), 2.41-2.14 (m, 2H), 2.14-1.93 (m, 2H),
1.26 (t, 3H, J ) 7.1). MS (ESI): m/z 304.0 [M + H+].
Synthesisof8,9-Dihydro-5H-pyrimido[4,5-e][1,4]diazepin-
7(6H)-ones 3 (for Aliphatic Amines). To a stirred solution
of compound 2 (1 mmol) in CH3CN (4 mL) was added amine
(1.2 mmol) followed by Et3N (1.5 mmol). The resulting
solution was stirred for the corresponding time at room
temperature or reflux. After complete consumption of the
starting material 2, as indicated by TLC, the volatiles were
removed in vacuo before water (5 mL) was added. The
reaction mixture was extracted with CH2Cl2 (3 × 10 mL).
The combined organic layers were washed with brine (20
mL) followed by drying (Na2SO4) and concentrated in vacuo.
Purification by flash column chromatography (petroleum
ether/DCM 2:1-1:2 or DCM/MeOH 40:1-10:1, v/v) af-
forded the desired products 3.
Aternative Procedure (For Aromatic Amines). To a
stirred solution of compound 2 (1 mmol) in CH3CN (4 mL)
was added amine (1.2 mmol) followed by Et3N or K2CO3
(1.5 mmol). The resulting solution was stirred for the
corresponding time at reflux. The volatiles were removed in
vacuo to dryness. The crude residue was dissolved in toluene
(4 mL) and AcOH (0.4 mL). The mixture was stirred for
the corresponding time at reflux. The volatiles were removed
Ethyl
2-((6-Chloro-5-formylpyrimidin-4-yl)
(methyl)amino)-2-phenylacetate 5d. 85%. oil. 1H NMR δ
10.42 (s, 1H), 8.43 (s, 1H), 7.44-7.37 (m, 3H), 7.29-7.26
(m, 2H), 6.38 (s, 1H), 4.39-4.28 (m, 2H), 2.67 (s, 3H), 1.32
(t, 3H, J ) 7.5). MS (ESI): m/z 334.0 [M + H+].
Ethyl 1-(6-Chloro-5-formylpyrimidin-4-yl)pyrrolidine-
2-carboxylate 5e. 73%. oil. 1H NMR δ 10.43 (s, 1H), 8.34
(s, 1H), 4.75 (t, 1H, J ) 4.2), 4.19 (q, 2H, J ) 6.9), 3.33
(m, 1H), 3.16 (m,1H), 2.34 (m, 1H), 2.15-2.00 (m, 3H),
1.26 (t, 3H, J ) 7.2). MS (ESI): m/z 284.0 [M + H+].
General Procedure for the Synthesis of Amino Acid
Ester Substituted 6-Chloro-5-chloromethylpyrimidine 2.
To a stirred solution of compound 5 (1.2 mmol) in EtOH (4
mL) was added NaBH3CN (3.1 mmol) followed by AcOH
(12.5 mmol). After complete consumption of the starting
material 5, as indicated by TLC, water (0.2 mL) was added
to quench the reaction. The volatiles were removed in vacuo,
and water (10 mL) was added; it was then extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were
washed with saturated aqueous NaHCO3 (5 mL) and water
(5 mL), dried (MgSO4), and concentrated in vacuo to afford
product 6. Compound 6 was used at the next step without

8,9-Dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 507
in vacuo before water (10 mL) was added. The reaction
mixture was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were washed with brine (20 mL),
dried (Na2SO4), and concentrated in vacuo. Purification by
flash column chromatography (petroleum ether/DCM 2:1-1:
2, v/v) afforded the desired products 3.
4-Chloro-6-(4-methoxyphenyl)-9-methyl-8,9-dihydro-
5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-one 3.10a. 87%.
mp: 192-193 °C. 1H NMR δ 8.32 (s, 1H), 7.14 (d, 2H, J )
8.7), 6.90 (d, 2H, J ) 9.0), 5.13 (s, 2H), 4.51 (s, 2H), 3.81
(s, 3H), 3.39 (s, 3H). 13C NMR δ 166.9, 161.9, 158.5, 157.6,
156.8, 134.6, 126.9, 114.6, 110.3, 56.2, 55.6, 50.5, 40.5. MS
(ESI): m/z 319.1 [M + H+].
4-Chloro-9-methyl-6-p-tolyl-8,9-dihydro-5H-pyrimi-
do[4,5-e][1,4]diazepin-7(6H)-one 3.11a. 86%. mp: 232-234
°C. 1H NMR δ 8.32 (s, 1H), 7.19 (d, 2H, J ) 7.8), 7.11 (d,
2H, J ) 8.4), 5.14 (s, 2H), 4.5 (s, 2H), 3.39 (s, 3H), 2.35
(m, 3H). MS (ESI): m/z 303.1 [M + H+].
4-Chloro-9-methyl-6-m-tolyl-8,9-dihydro-5H-pyrimi-
do[4,5-e][1,4]diazepin-7(6H)-one 3.12a. 78%. mp: 229-
230 °C. 1H NMR δ 8.33 (s, 1H), 7.30-7.25(m, 1H),
7.11-7.02 (m, 3H), 5.15 (s, 2H), 4.51 (s, 2H), 3.39(s, 3H),
2.35 (s, 3H). MS (ESI): m/z 303.1 [M + H+].
6-Butyl-4-chloro-9-methyl-8,9-dihydro-5H-pyrimido[4,5-
1
e][1,4]diazepin-7(6H)-one 3.1a. 86%. mp: 81-83 °C. H
NMR δ 8.27 (s, 1H), 4.73 (s, 2H), 4.34 (s, 2H), 3.49 (t, 2H,
J ) 7.2), 3.33 (s, 3H), 1.55-1.48 (m, 2H), 1.32-1.24 (m,
2H), 0.90 (t, 3H, J ) 7.2). MS (ESI): m/z 269.2 [M + H+].
4-Chloro-6,9-dimethyl-8,9-dihydro-5H-pyrimido[4,5-
e][1,4]diazepin-7(6H)-one 3.2a. 74%. mp: 116-118 °C. 1H
NMR δ 8.27 (s, 1H), 4.74 (s, 2H), 4.35 (s, 2H), 3.33 (s,
3H), 3.10 (s, 3H). MS (ESI): m/z 227.1 [M + H+].
4-Chloro-9-methyl-8,9-dihydro-5H-pyrimido[4,5-
e][1,4]diazepin-7(6H)-one 3.3a. 70%. mp: 220-222 °C. 1H
NMR δ 8.29 (s, 1H), 6.47 (br, 1H), 4.63 (d, 2H, J ) 6.0),
4.27 (s, 2H), 3.34 (s, 3H). MS (ESI): m/z 213.0 [M + H+].
6-Benzyl-4-chloro-9-methyl-8,9-dihydro-5H-pyrimido[4,5-
e][1,4]diazepin-7(6H)-one 3.4a. 99%. mp: 155-156 °C. 1H
NMR δ 8.22 (s, 1H), 7.31-7.23 (m, 5H), 4.65 (s, 2H), 4.62
(s, 2H), 4.39 (s, 2H), 3.35 (s, 3H). MS (ESI): m/z 303.1 [M
+ H+].
4-Chloro-9-methyl-6-o-tolyl-8,9-dihydro-5H-pyrimi-
do[4,5-e][1,4]diazepin-7(6H)-one 3.13a. 81%. mp: 200-
1
201 °C. H NMR δ 8.33 (s, 1H), 7.26-7.22 (m, 3H),
7.07-7.04 (m, 1H), 5.04 (s, 2H), 4.54 (d, 1H, J ) 14.4),
4.47 (d, 1H, J ) 15), 3.42 (s, 3H), 2.13 (s, 3H). MS (ESI):
m/z 303.1 [M + H+].
4-Chloro-9-methyl-6-phenyl-8,9-dihydro-5H-pyrimi-
do[4,5-e][1,4]diazepin-7(6H)-one 3.14a. 83%. mp: 263-
4-Chloro-6-cyclobutyl-9-methyl-8,9-dihydro-5H-pyrim-
ido[4,5-e][1,4]diazepin-7(6H)-one 3.5a. 86%. mp: 161-163
1
265 °C. H NMR δ 8.33 (s, 1H), 7.42-7.38 (m, 2H),
7.31-7.24 (m, 3H), 5.12 (s,2H), 4.52 (s, 2H), 3.40 (s, 3H).
1
°C. H NMR δ 8.26 (s, 1H), 4.98-4.89 (m, 1H), 4.79 (s,
MS (ESI): m/z 289.0 [M + H+].
2H), 4.33 (s, 2H), 3.32 (s, 3H), 2.23-2.03 (m, 4H),
1.78-1.59 (m, 2H). 13C NMR δ 167.1, 161.8, 157.1, 156.5,
156.4, 110.4, 90.4, 56.1, 48.3, 41.5, 40.3, 28.7, 28.5, 28.4,
14.8. MS (ESI): m/z 267.0 [M + H+].
4-Chloro-6-(4-chlorophenyl)-9-methyl-8,9-dihydro-5H-
pyrimido[4,5-e][1,4]diazepin-7(6H)-one 3.15a. 84%. mp:
1
221-222 °C. H NMR δ 8.33 (s, 1H), 7.36 (d, 2H, J )
9.0), 7.2 (d, 2H, J ) 8.4), 5.16 (s, 2H), 4.51 (s, 2H), 3.39 (s,
3H). MS (ESI): m/z 323.0 [M + H+].
4-Chloro-6-cyclopentyl-9-methyl-8,9-dihydro-5H-py-
rimido[4,5-e][1,4]diazepin-7(6H)-one 3.6a. 86%. mp:
6-(4-Acetylphenyl)-4-chloro-9-methyl-8,9-dihydro-5H-
pyrimido[4,5-e][1,4]diazepin-7(6H)-one 3.16a. 88%. mp:
1
143-144 °C. H NMR δ 8.26 (s, 1H), 4.93 (m, 1H), 4.67
(s, 2H), 4.33 (s, 2H), 3.33 (s, 3H), 1.91-1.89 (m, 2H),
1.83-1.77 (m, 2H), 1.63-1.59 (m, 2H), 1.49-1.40 (m, 2H).
13C NMR δ 167.8, 161.9, 157.1, 156.5, 110.7, 55.9, 54.4,
41.6, 40.3, 29.6, 24.4. MS (ESI): m/z 281.1 [M + H+].
1
196-197 °C. H NMR δ 8.34 (s, 1H), 7.99 (d, 2H, J )
9.0), 7.40 (d, 2H, J ) 9.0), 5.23 (s, 2H), 4.53 (s, 2H), 3.40
(s, 3H), 2.59 (s, 3H). MS (ESI): m/z 331.0 [M + H+].
4-Chloro-9-methyl-6-(4-nitrophenyl)-8,9-dihydro-5H-
pyrimido[4,5-e][1,4]diazepin-7(6H)-one 3.17a. 60%. mp:
4-Chloro-6-cyclohexyl-9-methyl-8,9-dihydro-5H-pyrim-
ido[4,5-e][1,4]diazepin-7(6H)-one 3.7a. 70%. mp: 193-195
1
232-233 °C. H NMR δ 8.35 (s, 1H), 8.26 (d, 2H, J )
1
°C. H NMR δ 8.25 (s, 1H), 4.68 (s, 2H), 4.39-4.38 (m,
9.6), 7.5 (d, 2H, J ) 9.0), 5.27 (s, 2H), 4.55 (s, 2H), 3.40 (s,
3H). 13C NMR δ 166.6, 161.9, 157.7, 157.2, 147.0, 145.6,
125.7, 124.8, 109.5, 56.2, 49.8, 40.6. MS (ESI): m/z 334.0
[M + H+].
1H), 4.35 (s, 2H), 3.33 (s, 3H), 1.80-1.79 (m, 2H),
1.65-1.62 (m, 4H), 1.46-1.35 (m, 4H). 13C NMR δ 167.1,
161.8, 156.9, 156.4, 110.8, 55.9, 53.0, 41.0, 40.2, 30.6, 25.4,
25.2. MS (ESI): m/z 295.2 [M + H+].
4-Chloro-6-(2-ethoxy-2-oxoethyl)-9-methyl-8,9-dihydro-
4-Chloro-6-isopropyl-9-methyl-8,9-dihydro-5H-pyrim-
ido[4,5-e][1,4]diazepin-7(6H)-one 3.8a. 79%. mp: 131-
5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-one 3.18a. 90%.
mp: 120-121 °C. H NMR δ 8.29 (s, 1H), 4.81 (s, 2H),
1
1
134 °C. H NMR δ 8.25 (s, 1H), 4.84-4.77 (m, 1H), 4.66
4.38 (s, 2H), 4.25 (s, 2H), 4.16 (q, 2H, J ) 6.9), 3.34 (s,
3H), 1.23 (t, 3H, J ) 7.2). MS (ESI): m/z 299.1 [M + H+].
4-Chloro-6-(2-ethoxy-2-oxo-1-phenylethyl)-9-methyl-
8,9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-one
(s, 2H), 4.33 (s, 2H), 3.33 (s, 3H), 1.17 (s, 3H), 1.44 (s,
3H). MS (ESI): m/z 255.0 [M + H+].
4-Chloro-9-methyl-6-(1-phenylethyl)-8,9-dihydro-5H-
pyrimido[4,5-e][1,4]diazepin-7(6H)-one 3.9a. 98%. mp:
1
3.19a. 73%. mp: 98-100 °C. H NMR δ 8.18 (s, 1H),
1
135-136 °C. H NMR δ 8.21 (s, 1H), 7.33-7.26 (m, 5H),
7.34-7.33(m, 3H), 7.20-7.19 (m, 2H), 6.38 (s, 1H), 4.80
(d, 1H, J ) 18.0), 4.63-4.53 (m, 2H), 4.27 (q, 2H, J )
6.9), 4.15 (d, 1H, J ) 15.0), 3.35 (s, 3H), 1.25 (t, 3H, J )
6.9). 13C NMR δ 170.0, 168.8, 161.9, 157.8, 156.1, 133.7,
129.2, 129.1, 128.8, 110.5, 61.9, 60.4, 55.2, 43.6, 40.2, 14.1.
MS (ESI): m/z 375.1 [M + H+].
5.6 (q, 1H, J ) 6.9), 4.52(d, 1H, J ) 15.0), 4.54-4.45 (m,
2H), 4.22 (d, 1H, J ) 15.0), 3.37 (s, 3H), 1.52 (d, 3H, J )
7.2). 13C NMR δ 167.7, 162.0, 157.4, 156.4, 139.5, 128.7,
128.1, 127.4, 110.8, 55.8, 51.3, 41.7, 40.4, 16.5. MS (ESI):
m/z 316.8 [M + H+].

508 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Xiang et al.
4-Chloro-6-(1-ethoxy-1-oxo-3-phenylpropan-2-yl)-9-
methyl-8,9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-
one 3.20a. 57%. mp: 108-109 °C. 1H NMR δ 8.13 (s, 1H),
7.10-7.08 (m, 3H), 6.96-6.94 (m, 2H), 5.50 (dd, 1H, J )
12.6, 5.1), 4.76-4.49 (m, 2H), 4.47 (d, 1H, J ) 14.7), 4.22
(q, 2H, J ) 7.2), 3.85 (d, 1H, J ) 14.7), 3.48 (dd, 1H, J )
15.3, 5.1), 3.07 (s, 3H), 3.01-2.95 (m, 1H). 1.27 (t, 3H, J
) 7.2).13C NMR δ 170.8, 168.9, 162.0, 157.8, 156.4, 136.2,
128.6, 128.4, 127.2, 110.4, 62.2, 58.1, 55.1, 45.2, 40.2, 35.8,
14.5. MS (ESI): m/z 389.1 [M + H+].
4-Chloro-6-(2-hydroxyethyl)-9-methyl-8,9-dihydro-5H-
pyrimido[4,5-e][1,4]diazepin-7(6H)-one 3.21a. 84%. mp:
136-138 °C. 1H NMR δ 8.27 (s, 1H), 4.85 (s, 2H), 4.38 (s,
2H), 3.81 (t, 2H, J ) 5.1), 3.68 (t, 2H, J ) 5.4), 3.36 (s,
3H). 13C NMR δ 168.4, 161.9, 157.5, 156.5, 110.2, 60.9,
55.8, 50.2, 48.0, 40.4. MS (ESI): m/z 256.8 [M + H+].
6-Butyl-4-chloro-8,9-dihydro-5H-pyrimido[4,5-
e][1,4]diazepin-7(6H)-one 3.1b. 67%. mp: 195-197 °C 1H
NMR δ 8.20 (s, 1H), 5.95 (br, 1H), 4.72 (s, 2H), 4.25 (d,
2H, J ) 5.1), 3.52 (t, 2H, J ) 7.2), 1.60-1.52(m, 2H),
1.35-1.23 (m, 2H), 0.90 (t, 3H, J ) 7.2). MS (ESI): m/z
255.1 [M + H+].
6-Butyl-4-chloro-8-isopropyl-9-methyl-8,9-dihydro-5H-
pyrimido[4,5-e][1,4]diazepin-7(6H)-one 3.1c. 73%. oil. 1H
NMR δ 8.33 (s, 1H), 4.72 (d, 1H, J ) 17.7), 4.60 (d, 1H, J
) 17.4), 3.85 (d, 1H, J ) 5.1), 3.59-3.49 (m, 1H),
3.42-3.20 (m, 4H), 2.39-2.31 (m, 1H), 1.53-1.37 (m, 2H),
1.32-1.20 (m, 2H), 1.05-0.81 (m, 9H). MS (ESI): m/z 310.8
[M + H+].
6-Butyl-4-chloro-9-methyl-8-phenyl-8,9-dihydro-5H-py-
rimido[4,5-e][1,4]diazepin-7(6H)-one 3.1d. 50%. mp: 90-
92 °C. 1H NMR δ 8.39 (s, 1H), 7.46-7.34 (m, 3H),
7.27-7.23 (m, 2H), 5.52 (s, 1H), 4.20 (d, 1H, J ) 16.2),
4.08 (d, 1H, J ) 16.8), 3.52-3.41 (m, 5H).1.55-1.45
(m,2H),1.28-1.21 (m,2H), 0.89 (t, 3H, J ) 7.2). MS (ESI):
m/z 345.1 [M + H+].
6-Butyl-4-chloro-7a,8,9,10-tetrahydro-5H-pyrimido[5,4-
f]pyrrolo[1,2-a][1,4]diazepin-7(6H)-one 3.1e. 86%. oil. 1H
NMR δ 8.24 (s, 1H), 5.07-4.97 (m, 2H), 4.51 (d, 1H, J )
17.4), 3.76-3.65 (m, 2H), 3.64-3.43 (m, 2H), 2.75-2.64
(m, 1H), 2.13-1.87 (m, 3H), 1.58-1.49 (m, 2H), 1.35-0.93
(m, 2H), 0.90 (t, 3H, J ) 7.5). MS (ESI): m/z 295.2 [M +
H+].
Ethyl 2-((6-Chloro-5-((phenylamino)methyl)pyrimidin-
4-yl)(methyl)amino)acetate 7a. 91%. mp: 107-109 °C. 1H
NMR δ 8.34 (s, 1H), 7.28-7.23 (m, 2H), 6.84 (t, 1H, J )
7.2), 6.73 (d, 2H, J ) 7.8), 4.31 (s, 2H), 4.22-4.15 (m, 4H),
3.33 (s, 3H), 1.23 (t, 3H, J ) 7.2). MS (ESI): m/z 335.0 [M
+ H+].
General Procedure for Displacement of the Chloro
Group in 3.1a with n-BuNH2, Piperazine, and Pyrroli-
dine, Preparation of Compounds 4.1.1a, 4.1.2a, and
4.1.3a. To a solution of compound 3.1a (0.5 mmol) in
n-BuOH (4.0 mL) was added amine (1.5 mmol) followed
by Et3N (2 mmol). The resulting solution was stirred for the
corresponding time at reflux. The volatiles were removed in
vacuo, before water (10 mL) was added. The reaction mixture
was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were washed with brine (20 mL), dried
(Na2SO4), and concentrated in vacuo. Purification by flash
column chromatography (petroleum ether/DCM 2:1-1:2,
v/v) afforded the desired products.
6-Butyl-4-(butylamino)-9-methyl-8,9-dihydro-5H-py-
rimido[4,5-e][1,4]diazepin-7(6H)-one 4.1.1a. 78%. mp:
1
46-47 °C. H NMR δ 8.17 (s, 1H), 4.26 (s, 2H), 4.13 (s,
2H), 4.06 (t, 1H, J ) 5.1), 3.49-3.42 (m, 4H), 3.25 (s, 3H),
1.65-1.56 (m, 2H), 1.51-1.40 (m, 4H), 1.38-1.22 (m, 2H),
0.96 (t, 3H, J ) 7.2), 0.88 (t, 3H, J ) 7.2). 13C NMR δ
168.9, 160.7, 159.4, 156.0, 92.4, 55.3, 47.5, 44.7, 41.7, 39.0,
32.1, 30.3, 20.2, 20.0, 13.9, 13.8. MS (ESI): m/z 306.0 [M
+ H+].
6-Butyl-9-methyl-4-(piperazin-1-yl)-8,9-dihydro-5H-py-
rimido[4,5-e][1,4]diazepin-7(6H)-one 4.1.2a. 91%. mp:
1
67-68 °C. H NMR δ 8.28 (s, 1H), 4.44 (s, 2H), 4.21 (s,
2H), 3.42 (t, 2H, J ) 7.2), 3.30 (s, 3H), 3.17-3.14 (m, 4H),
3.04-3.01 (m, 4H), 2.46 (br, 1H), 1.44-1.39 (m, 2H),
1.23-1.16 (m, 2H), 0.84 (t, 3H, J ) 7.2). 13C NMR δ 168.5,
165.9, 162.0, 155.9, 100.1, 55.0, 51.1, 47.0, 46.7, 45.9, 45.7,
39.2, 30.3, 19.8, 13.8. MS (ESI): m/z 319.4 [M + H+].
6-Butyl-9-methyl-4-(pyrrolidin-1-yl)-8,9-dihydro-5H-
pyrimido[4,5-e][1,4]diazepin-7(6H)-one 4.1.3a. 99%. mp:
1
76-77 °C. H NMR δ 8.16 (s, 1H), 4.34 (s, 2H), 4.12 (s,
2H), 3.45-3.36 (m, 6H), 3.28 (s, 3H), 1.93 (s, 4H),
1.42-1.35 (m, 2H), 1.27-1.72 (m, 2H), 0.85 (t, 3H, J )
7.2). 13C NMR δ 168.9, 163.5, 161.6, 154.7, 94.7, 54.7, 50.6,
48.3, 47.1, 38.5, 30.3, 25.6, 19.8, 13.7. MS (ESI): m/z 304.0
[M + H+].
General Procedure for Displacement of the Chloro
Group in 3.1a or 3.14a with Aniline, Preparation of
Compounds 4.1.4a and 4.14.4a. To a solution of compound
3.1a or 3.14a (0.5 mmol) in n-BuOH (4.0 mL) was added
aniline (5 mmol) followed by concentrated aqueous HCl (3
to 4 drops). The resulting solution was stirred for the
corresponding time at reflux. The volatiles were removed in
vacuo before water (10 mL) was added. The reaction mixture
was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were washed with brine (20 mL), dried
(Na2SO4), and concentrated in vacuo. Purification by flash
column chromatography (petroleum ether/DCM 2:1-1:2,
v/v) afforded the desired products.
6-Butyl-9-methyl-4-(phenylamino)-8,9-dihydro-5H-py-
rimido[4,5-e][1,4]diazepin-7(6H)-one 4.1.4a. 83%. mp:
1
131-133 °C. H NMR δ 8.25 (s, 1H), 7.36-7.30 (m, 2H),
7.16-7.06 (m, 3H), 6.34 (br, 1H), 4.24 (s, 2H), 4.19 (m, 2H),
3.75 (t, 2H, J ) 7.2), 3.32 (s, 3H), 1.44-1.34 (m, 2H),
1.25-1.13 (m, 2H), 0.83 (t, 3H, J ) 7.2). 13C NMR δ 168.3,
161.6, 157.6, 156.2, 140.7, 129.1, 123.3, 120.5, 96.5, 54.9, 47.0,
46.0, 39.1, 30.1, 19.7, 13.6. MS (ESI): m/z 326.0 [M + H+].
9-Methyl-6-phenyl-4-(phenylamino)-8,9-dihydro-5H-
pyrimido[4,5-e][1,4]diazepin-7(6H)-one 4.14.4a. 64%. mp:
173-174 °C. 1H NMR δ 8.29 (s, 1H), 7.37-7.05 (m, 10H),
6.22 (br, 1H), 4.70 (s, 2H), 4.38 (s, 2H), 3.37 (s, 3H). 13C
NMR δ 167.7, 161.8, 157.7, 156.6, 142.3, 140.6, 129.2,
126.9, 125.5, 123.5, 120.8, 96.3, 55.8, 49.5, 39.2. MS (ESI):
m/z 346.0 [M + H+].
Preparation of 6-Butyl-9-methyl-4-(phenylthio)-8,9-dihydro-
5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-one 4.1.5a. To a solu-
tion of compound 3.1a (0.5 mmol) in EtOH (3 mL) was

8,9-Dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 509
added PhSH (5 mmol) followed by Et3N (5 mmol). The
resulting solution was stirred for 5 h at room temperature.
Saturated aqueous NH4Cl was added to quench the reaction.
The reaction mixture was extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were washed with brine
(20 mL), dried (Na2SO4), and concentrated in vacuo.
Purification by flash column chromatography (DCM/MeOH
30:1, v/v) afforded 161 mg (94%) of 4.1.5a as a white solid.
mp: 86-87 °C. 1H NMR δ 8.24 (s, 1H), 7.51-7.46 (m, 2H),
7.44-7.40 (m, 3H), 4.70 (s, 2H), 4.32 (s, 2H), 3.53 (t, 2H,
J ) 7.5), 3.30 (s, 3H), 1.61-1.54 (m, 2H), 1.34-1.27 (m,
2H), 0.92 (t, 3H, J ) 7.5). 13C NMR δ 167.6, 163.7, 160.0,
156.2, 134.4, 129.4, 129.1, 128.9, 109.6, 55.6, 46.9, 46.0,
39.8, 30.2, 19.8, 13.7. MS (ESI): m/z 342.7 [M + H+].
129.1, 128.7, 128.5, 110.5, 55.6, 47.2, 46.2, 39.9, 29.9, 19.6,
13.5. MS (ESI): m/z 311.2 [M + H+]
Acknowledgment. This work was supported by National
Natural Science Foundation of China (No. 90713008),
National Science & Technology Major Project “Key New
Drug Creation and Manufacturing Program” of China (No.
2009ZX09501-010), and Changchun Discovery Sciences,
Ltd.
Supporting Information Available. Copies of LC-MS-
ELSD and NMR spectra for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
References and Notes
(1) (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.;
Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.;
Hirshfield, J. J. Med. Chem. 1988, 31, 2235–2246. (b) Horton,
D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893–930.
(2) (a) Seto, S.; Tanioka, A.; Ikeda, M.; Izawa, S. Bioorg. Med.
Chem. 2005, 13, 5717–5732. (b) Seto, S.; Tanioka, A.; Ikeda,
M.; Izawa, S. Patent EP1496059, 2005.
(3) Kim, D. H.; Santilli, A. A. Patent US3535310, 1970.
(4) Cossrow, J.; Guan, B.; Ishchenko, A.; Jones, J. H.; Kumaravel,
G.; Lugovskoy, A.; Peng, H.; Powell, N.; Raimundo, B. C.;
Tanaka,H.;Vessels,J.;Wynn,T.;Xin,Z.PatentUS20090005359,
2009.
(5) Ohmoto, K.; Hisaichi, K.; Okuma, M.; Tanaka, M.; Kawada,
N. Patent US20070197510, 2007.
Preparation of 4-Butoxy-6-butyl-9-methyl-8,9-dihydro-
5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-one 4.1.6a. To a
solution of compound 3.1a (0.5 mmol) in THF (2 mL) was
added EtOH (5 mmol) followed by NaH (2 mmol). The
resulting solution was stirred for 72 h at room temperature.
Saturated aqueous NH4Cl was added to quench the reaction
and water (10 mL). The reaction mixture was extracted with
EtOAc (3 × 10 mL). The combined organic layers were
washed with brine (20 mL), dried (Na2SO4), and concentrated
in vacuo. Purification by flash column chromatography
(DCM/MeOH 10:1, v/v) afforded 139 mg (91%) of 4.1.6a
1
as a white solid. mp: 55-57 °C. H NMR δ 8.21 (s, 1H),
4.54 (s, 2H), 4.32 (t, 2H, J ) 6.3), 4.26 (s, 3H), 3.45 (t, 2H,
J ) 7.5), 3.29 (s, 3H), 1.79-1.69 (m, 2H), 1.49-1.42 (m,
4H), 1.30-1.22 (m, 2H), 0.98 (t, 3H, J ) 7.5), 0.88 (t, 3H,
J ) 6.9). 13C NMR δ 167.8, 165.2, 161.6, 155.7, 96.1, 66.2,
55.4, 46.6, 42.1, 39.2, 30.8, 29.9, 19.7, 19.0, 13.5, 13.4. MS
(ESI): m/z 307.0 [M + H+].
(6) (a) Heaney, F.; Burke, C.; Cunningham, D.; McArdle, P.
J. Chem. Soc., Perkin Trans. 1 2001, 622–632. (b) Huddleston,
N. E.; Harris, J. L.; Nguyen, H. L.; Ray, P. S. Heterocycl.
Commun. 2004, 10, 405–406.
(7) (a) Yang, J.; Dang, Q.; Liu, J.; Wei, Z.; Wu, J.; Bai, X.
J. Comb. Chem. 2005, 7, 474–482. (b) Zheng, L.; Xiang, J.;
Dang, Q.; Guo, S.; Bai, X. J. Comb. Chem. 2005, 7, 813–
815. (c) Fu, R.; Xu, X.; Dang, Q.; Bai, X. J. Org. Chem. 2005,
70, 10810–10816. (d) Liu, J.; Dang, Q.; Wei, Z.; Shi, F.; Bai,
X. J. Comb. Chem. 2006, 8, 410–416. (e) Fu, R.; Xu, X.;
Dang, Q.; Bai, X. Org. Lett. 2007, 9, 571–574. (f) Xu, X.;
Guo, S.; Dang, Q.; Chen, J.; Bai, X. J. Comb. Chem. 2007,
9, 773–782. (g) Shi, F.; Xu, X.; Zheng, L.; Dang, Q.; Bai, X.
J. Comb. Chem. 2008, 10, 158–161. (h) Che, X.; Zheng, L.;
Dang, Q.; Bai, X. J. Org. Chem. 2008, 73, 1147–1149.
(8) (a) Yang, J.; Che, X.; Dang, Q.; Wei, Z.; Gao, S.; Bai, X.
Org. Lett. 2005, 7, 1541–1543. (b) Che, X.; Zheng, L.; Dang,
Q.; Bai, X. Tetrahedron 2006, 62, 2563–2568. (c) Zheng, L.;
Xiang, J.; Dang, Q.; Guo, S.; Bai, X. J. Comb. Chem. 2006,
8, 381–387.
Preparation of 6-Butyl-9-methyl-4-phenyl-8,9-dihydro-
5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-one 4.1.7a. Com-
pound 3.1a (0.5 mmol) and phenylboronic acid (0.6 mmol)
were dissolved in DME (ethylene glycol dimethyl ether) (2
mL) under a nitrogen atmosphere. K2CO3 (138 mg, 1.0
mmol) in water (2 mL) was added, followed by palladium(II)
acetate (0.005 mmol) and triphenylphosphine (0.02 mmol).
The resulting mixture was refluxed with stirring for 2 h
before water (10 mL) was added. The reaction mixture was
extracted with EtOAc (3 × 10 mL). The combined organic
layers were washed with saturated aqueous NaHCO3 (20
mL), water (20 mL), and brine (20 mL) in sequence, dried
with Na2SO4, and concentrated in vacuo. Purification by flash
column chromatography (DCM/MeOH 30:1, v/v) afforded
154 mg (99%) of 4.1.7a as a white solid. mp: 100-102 °C.
1H NMR δ 8.56 (s, 1H), 7.49-7.45 (m, 3H), 7.41-7.38 (m,
2H), 4.51 (s, 2H), 4.37 (s, 2H), 3.38 (s, 3H), 3.25 (t, 2H, J
) 7.2), 1.20-1.17 (m, 2H), 1.11-1.06 (m, 2H), 0.74 (t, 3H,
J ) 7.2). 13C NMR δ 167.7, 163.2, 161.3, 156.5, 138.1,
(9) Gomtsyan, A.; Didomenico, S.; Lee, C. H.; Matulenko, M. A.;
Kim, K.; Kowaluk, E. A.; Wismer, C. T.; Mikusa, J.; Yu, H.;
Kohlhaas, K.; Jarvis, M. F.; Bhagwat, S. S. J. Med. Chem.
2002, 45, 3639–3648.
(10) Prasad, C. V. C.; Mercer, S. E.; Dubowchik, G. M.; Macor,
J. E. Tetrahedron Lett. 2007, 48, 2661–2665.
CC100039W