Concise access to pyrimidine-annulated azepine and azocine derivatives by ruthenium-catalyzed ring-closing metathesis

Article abstract of DOI:10.1055/s-0029-1219228

Synthetic approaches to five- and six-membered-ring systems are commonly undertaken through cyclization and cycloaddition reactions, but the formation of seven- and eight-membered-ring systems are not as abundant. An efficient and high-yielding method for

Full text of DOI:10.1055/s-0029-1219228

1176
PAPER
Concise Access to Pyrimidine-Annulated Azepine and Azocine Derivatives by
Ruthenium-Catalyzed Ring-Closing Metathesis
P
yrimidine-Annula
.
ted
A
zepine
C
a
nd Azocine
D
e
.
rivatives Majumdar,* Shovan Mondal, Debankan Ghosh
Department of Chemistry, University of Kalyani, Kalyani 741235, WB, India
E-mail: kcm_ku@yahoo.co.in
Received 24 November 2009; revised 8 December 2009
drawbacks. The first is that palladium-catalyzed cycliza-
Abstract: Synthetic approaches to five- and six-membered-ring
systems are commonly undertaken through cyclization and cycload-
dition reactions, but the formation of seven- and eight-membered-
ring systems are not as abundant. An efficient and high-yielding
tion by the application of intramolecular Heck reactions
require harsh reaction conditions where a nitrogen-con-
taining compound is used as the starting material.10 The
method for the synthesis of seven- and eight-membered-ring nitro- second problem is that the two available modes of cycliza-
gen-containing heterocycles by ring-closing metathesis is reported.
tion, endo-trig and exo-trig, often compete with each oth-
er. Consequently, there is always a tendency for a mixture
of products to be obtained. For example, Hii et al.
reported11 the competitive formation of 7-exo-trig cy-
clized product benzazepine and 8-endo-trig cyclized prod-
uct benzazocine, as an inseparable mixture of products in
the pallladium-catalyzed intramolecular Heck reaction;
however, they did demonstrate the importance of temper-
ature and ligand effects on the regioselectivity of the reac-
tion. These findings prompted us to undertake a study on
the synthesis of biologically interesting azepine and azo-
cine derivatives in which the major drawbacks can be
overcome. In a continuation of our work on ring-closing
metathesis12 and the synthesis of bio-active heterocy-
cles,13 we have utilized the ring-closing metathesis proto-
col for the synthesis of pyrimidine-annulated azepine and
azocine derivatives. Here we report our results.
Keywords: uracil, azepine, azocine, ring-closing metathesis
Due to the rich chemistry and biology of nitrogen-contain-
ing compounds, the synthesis of N-heterocycles has been
a central and important theme in organic chemistry.1 Me-
dium-sized N-containing fused-ring systems, in particular
seven-membered rings (azepines) and eight-membered
rings (azocines), are key structures occurring in many nat-
ural products (Figure 1).2–7 Despite their bioactivity,8
azepine- and azocine-fused ring systems have not been
much investigated. One barrier to their study is the unsat-
isfactory synthetic procedures available.9
Me
HN
N
N
N
Me
O
For the synthesis of pyrimido-azepine and azocine deriv-
atives, compounds 4a–c, which are common starting ma-
terials, were prepared according to our recently published
procedure.14,15 5-Bromouracil derivatives 1a–c were sub-
jected to allylamine in ethanol to give the 5-allylaminou-
racil derivatives 2a–c followed by BF3·Et2O catalyzed
Claisen rearrangement to give the 5-amino-6-allyluracil
derivatives 3a–c in excellent yields. Treatment of com-
pounds 3a–c with p-TsCl in pyridine gave the correspond-
ing tosyl derivatives 4a–c, which were used as the starting
materials for the present study. The route for the prepara-
tion of these starting materials 4a–c are shown in
Scheme 1.
H
O
O
O
Br
O
N
H
N
H
H
OMe
Br
ceratamine A
(–)-stenine
H
(–)-securinine
Me
O
OMe
O
O
N
N
O
O
Me
OH
MeO
N
The required precursors 5a–c for the synthesis of pyrimi-
do-azepine derivatives, and 5d–f for the synthesis of py-
rimido-azocine derivatives, were prepared in 90–94%
yields by the reaction of 4a–c with either allyl bromide or
homoallyl bromide, in the presence of anhydrous potassi-
um carbonate in refluxing acetone for 4–5 hours
(Scheme 2).
MeO
Me
(–)-lycoramine
buflavine
stemonamine
Figure 1 Azepine- and azocine-containing alkaloids
Recently, however, palladium-catalyzed intramolecular
Heck coupling has been explored for the synthesis of
azepine and azocine derivatives. There are two main
Finally, for the synthesis of the target pyrimidine-fused
azepine and azocine derivatives from the substrates 5a–f,
the ring-closing metathesis strategy was adopted. Among
the available metathesis catalysts (Figure 2), we used cat-
alyst A (Grubbs 1st generation) for the present work.
SYNTHESIS 2010, No. 7, pp 1176–1180
Advanced online publication: 20.01.2010
DOI: 10.1055/s-0029-1219228; Art ID: Z25309SS
x
x
.
x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

PAPER
Pyrimidine-Annulated Azepine and Azocine Derivatives
1177
Ts
N
O
O
N
O
N
Ts
N
O
N
H
R2
N
Br
R2
O
N
Me
O
Me
O
(i)
(i)
N
N
N
90%
O
N
R1
R1
Me
Me
5a
6a
1a–c
2a–c
a, R1 = R2 = Me
a, R1 = R2 = Me; 84%
b, R1 = R2 = Et; 82%
c, R1 = Et, R2 = Me; 85%
Scheme 3 Synthesis of azepine derivative 6a. Reagents and condi-
tions: (i) anhydrous CH2Cl2, Grubbs catalyst A, r.t., 10 h.
(ii)
b, R1 = R2 = Et
c, R1 = Et, R2 = Me
O
O
Ts
Encouraged by this result, further substrates 5b–f were
similarly treated with the catalyst A in dichloromethane to
afford the corresponding azepine derivatives 6b and 6c,
and azocine derivatives 6d–f in 85–89% yields. The re-
sults are summarized in Table 1.
R2
O
NH2
R2
O
NH
N
N
(iii)
N
R1
N
R1
3a–c
4a–c
a, R1 = R2 = Me; 95%
b, R1 = R2 = Et; 90%
c, R1 = Et, R2 = Me; 93%
a, R1 = R2 = Me; 90%
b, R1 = R2 = Et; 97%
Table 1 Synthesis of Pyrimidine-Containing Azepine and Azocine
Derivatives 6a–f
c, R1 = Et, R2 = Me; 95%
Entry Starting material 5
Product 6
Yield
(%)
Scheme 1 Synthesis of starting materials 4a–c. Reagents and con-
ditions: (i) allyl amine, EtOH, reflux, 5–6 h; (ii) BF3·OEt2, xylene,
120 °C, 4–5 h; (iii) TsCl, Py, 80 °C, 1–2 h.
Ts
N
O
Ts
O
Me
O
N
Me
N
N
O
Ts
1
2
3
4
5a
5b
5c
5d
6a
6b
6c
6d
90
88
87
89
O
Ts
N
R2
O
NH
R2
O
N
O
N
N
N
(i)
Me
Me
N
N
Ts
O
Ts
N
O
R1
R1
N
Et
O
Et
5a–c
4a–c
N
N
a, n = 1, R1 = R2 = Me, 93%
b, n = 1, R1 = R2 = Et, 91%
c, n = 1, R1 = Et, R2 = Me, 90%
(ii)
N
O
N
Et
Et
O
Ts
N
Ts
O
Ts
O
R2
N
N
Me
O
N
Me
O
N
N
N
O
N
R1
d, n = 1, R1 = R2 = Me, 91%
e, n = 1, R1 = R2 = Et, 94%
f, n = 1, R1 = Et, R2 = Me, 92%
N
N
Et
Et
5d–f
Ts
N
O
Ts
N
O
Scheme 2 Synthesis of precursors 5a–f. Reagents and conditions:
(i) allyl bromide, K2CO3, acetone, reflux, 4–5 h; (ii) homoallyl bro-
mide, K2CO3, acetone, reflux, 4–5 h.
Me
O
Me
O
N
N
N
When a dichloromethane solution of the substrate 5a and
ruthenium carbene complex A (5 mol%) was stirred at
room temperature for ten hours under a nitrogen atmo-
sphere, ring-closing metathesis proceeded smoothly to af-
ford the azepine derivative 6a in 90% yield (Scheme 3).
Me
Me
Ts
N
O
Ts
O
Et
O
N
Et
O
N
N
5
6
5e
5f
6e
6f
87
85
N
N
Et
Et
CF3
F3C
Ph
Ts
N
O
Ts
O
Me
O
N
Me
O
O
N
N
PCy3
Ru
PCy3
Ru
Ph
Ph
Mo
Cl
Cl
Cl
Cl
N
N
Ph
N
O
Et
Et
F3C
CF3
PCy3
PCy3
A
B
C
In conclusion, based on combined aza-Claisen rearrange-
ment and ring-closing metathesis, we have developed a
general and straightforward methodology for the synthe-
sis of pyrimido-azepine and azocine derivatives in excel-
lent yields. It is important to note that pyrimidine
Grubbs' catalysts
Schrock's catalyst
Figure 2
Synthesis 2010, No. 7, 1176–1180 © Thieme Stuttgart · New York

1178
K. C. Majumdar et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 12.6, 14.3, 21.6, 33.2, 36.8, 41.2,
51.9, 111.9, 118.8, 119.8, 128.2, 129.3, 132.6, 133.1, 136.0, 143.7,
150.6, 156.5, 159.3.
derivatives and its fused heterocycles such as purines,
pyrrolopyrimidines, pyrazolopyrimidine, etc., constitute
the backbone of several biologically active compounds.
For example, 4H-pyrido[1,2-a]pyrimidin-4-ones have
been used as anticancer agents16 and HIV-integrase inhib-
itors,17 and pteridines are potent antitumor agents.18 For
this reason, novel methodologies for the synthesis of pyri-
midine scaffolds are of particular interest in medicinal
chemistry. This sequence affords a very short synthesis of
those derivatives and provides easy access to libraries for
medicinal and pharmaceutical applications.
MS: m/z = 417 [M+].
Anal. Calcd for C21H27N3O4S: C, 60.41; H, 6.52; N, 10.06. Found:
C, 60.34; H, 6.59; N, 10.16.
N-Allyl-N-(6-allyl-1-ethyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahy-
dropyrimidin-5-yl)-4-methylbenzenesulfonamide (5c)
Yield: 90%; white solid; mp 110–112 °C.
IR (KBr): 1707, 1660, 1344 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.28 (t, J = 7.2 Hz, 3 H), 2.42 (s,
3 H), 3.22 (s, 3 H), 3.50 (dd, J = 16.6, 5.3 Hz, 1 H), 3.85 (q, J = 7.6
Hz, 2 H), 4.07 (dd, J = 16.6, 5.2 Hz, 2 H), 4.22 (dd, J = 13.9, 5.1 Hz,
1 H), 5.04 (d, J = 10.0 Hz, 2 H), 5.17 (d, J = 17.3 Hz, 1 H), 5.27 (d,
J = 10.3 Hz, 1 H), 5.73–5.75 (m, 1 H), 5.90–5.92 (m, 1 H), 7.28 (d,
J = 8.0 Hz, 2 H), 7.72 (d, J = 7.6 Hz, 2 H).
Melting points were determined in open capillaries and are uncor-
rected. IR spectra were recorded with KBr discs with a Perkin–
1
Elmer 120–000A apparatus. H NMR spectra were determined as
solutions in CDCl3 with TMS as internal standard on a Bruker DPX-
400 instrument. 13C NMR spectra were determined as solutions in
CDCl3 on a Bruker DPX-400 instrument. MS were recorded with a
Qtof Micro YA263 instrument. CHN analyses were recorded on a
2400 series II CHN analyzer (Perkin–Elmer) in the Chemistry De-
partment of Kalyani University. Silica gel (60–120 mesh) was used
for chromatographic separation. Silica gel-G [E-Mark (India)] was
used for TLC. Petroleum ether (PE) refers to the fraction boiling be-
tween 60 and 80 °C.
MS: m/z = 403 [M+].
Anal. Calcd for C20H25N3O4S: C, 59.53; H, 6.25; N, 10.41. Found:
C, 59.69; H, 6.29; N, 10.32.
N-(6-Allyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimi-
din-5-yl)-N-(but-3-enyl)-4-methylbenzenesulfonamide (5d)
Reaction performed according to the typical procedure described
above using homoallyl bromide in place of allyl bromide.
N-Allyl-N-(6-allyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-
pyrimidin-5-yl)-4-methylbenzenesulfonamide (5a); Typical
Procedure
Yield: 91%; white solid; mp 102–104 °C.
IR (KBr): 1700, 1654, 1345 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.01 (m, 1 H), 2.13–2.22 (m, 1 H),
2.42 (s, 3 H), 3.22 (s, 3 H), 3.42 (s, 3 H), 3.44–3.46 (m, 1 H), 3.60
(m, 1 H), 4.04 (m, 1 H), 4.92 (m, 1 H), 5.04 (d, J = 10.6 Hz, 2 H),
5.19 (d, J = 17.5 Hz, 1 H), 5.32 (d, J = 10.4 Hz, 1 H), 5.57–5.64 (m,
1 H), 5.85–5.90 (m, 1 H), 7.27 (d, J = 8.2 Hz, 2 H), 7.71 (d, J = 8.2
Hz, 2 H).
A mixture of compound 4a (0.50 g, 1.43 mmol), allyl bromide (0.35
g, 2.86 mmol) and anhydrous K2CO3 (1.0 g) was stirred for 4 h in
refluxing acetone (50 mL). The reaction mixture was cooled, fil-
tered and the solvent was removed. The residual mass was extracted
with chloroform (3 × 20 mL), washed with H2O (2 × 10 mL) and
brine (5 mL) and dried (Na2SO4). Removal of the chloroform gave
the crude product, which was purified by chromatography over sil-
ica gel (60–120 mesh; PE–EtOAc, 9:1) to give compound 5a.
MS: m/z = 403 [M+].
Anal. Calcd for C20H25N3O4S: C, 59.53; H, 6.25; N, 10.41. Found:
C, 59.61; H, 6.30; N, 10.32.
Yield: 93%; white solid; mp 94–96 °C.
IR (KBr): 1701, 1654, 1343 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.42 (s, 3 H), 3.22 (s, 3 H), 3.45
(s, 3 H), 3.50 (dd, J = 16.6, 5.3 Hz, 1 H), 3.85 (q, J = 9.0 Hz, 1 H),
3.92 (dd, J = 16.6, 5.2 Hz, 1 H), 4.24 (dd, J = 13.9, 5.1 Hz, 1 H),
5.04 (d, J = 10.6 Hz, 2 H), 5.17 (d, J = 17.4 Hz, 1 H), 5.30 (d,
J = 10.3 Hz, 1 H), 5.70–5.84 (m, 1 H), 5.85–5.90 (m, 1 H), 7.28 (d,
J = 8.0 Hz, 2 H), 7.71 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 21.3, 28.4, 32.5, 34.2, 45.4,
111.8, 119.2, 119.9, 128.2, 129.2, 132.6, 133.1, 135.9, 143.8, 151.5,
156.8, 159.7.
N-(6-Allyl-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-
5-yl)-N-(but-3-enyl)-4-methylbenzenesulfonamide (5e)
Yield: 94%; white solid; mp 106–108 °C.
IR (KBr): 1703, 1651, 1340 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.13 (t, J = 6.9 Hz, 3 H), 1.30 (t,
J = 7.0 Hz, 3 H), 2.34–2.38 (m, 2 H), 2.42 (s, 3 H), 3.68–3.72 (m,
1 H), 3.83–3.92 (m, 1 H), 3.93–4.07 (m, 4 H), 4.08–4.15 (m, 2 H),
4.97–5.06 (m, 2 H), 5.19 (d, J = 17.6 Hz, 1 H), 5.31 (d, J = 10.4 Hz,
1 H), 5.66–5.70 (m, 1 H), 5.79–5.86 (m, 1 H), 7.28 (d, J = 8.4 Hz,
2 H), 7.72 (d, J = 8.4 Hz, 2 H).
MS: m/z = 389 [M+].
MS: m/z = 431 [M+].
Anal. Calcd for C19H23N3O4S: C, 58.59; H, 5.95; N, 10.79. Found:
C, 58.71; H, 5.92; N, 10.87.
Anal. Calcd for C22H29N3O4S: C, 61.23; H, 6.77; N, 9.74. Found: C,
61.33; H, 6.86; N, 9.82.
N-Allyl-N-(6-allyl-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyri-
midin-5-yl)-4-methylbenzenesulfonamide (5b)
Yield: 91%; white solid; mp 116–118 °C.
IR (KBr): 1705, 1651, 1340 cm–1.
N-(6-Allyl-1-ethyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyri-
midin-5-yl)-N-(but-3-enyl)-4-methylbenzenesulfonamide (5f)
Yield: 92%; white solid; mp 126–128 °C.
IR (KBr): 1699, 1652, 1346 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.07 (t, J = 7.0 Hz, 3 H), 1.27 (t,
J = 7.0 Hz, 3 H), 2.40 (s, 3 H), 3.49 (dd, J = 16.6, 5.3 Hz, 1 H), 3.85
(q, J = 6.9 Hz, 4 H), 3.90 (dd, J = 16.6, 5.2 Hz, 1 H), 4.25 (dd,
J = 13.9, 5.1 Hz, 2 H), 5.04 (d, J = 10.6 Hz, 2 H), 5.17 (d, J = 17.4
Hz, 1 H), 5.27 (d, J = 10.3 Hz, 1 H), 5.73–5.87 (m, 1 H), 5.88–5.93
(m, 1 H), 7.26 (d, J = 8.0 Hz, 2 H), 7.67 (d, J = 8.0 Hz, 2 H).
1H NMR (400 MHz, CDCl3): d = 1.30 (t, J = 7.2 Hz, 3 H), 2.08–
2.17 (m, 1 H), 2.23–2.31 (m, 1 H), 2.42 (s, 3 H), 3.24 (s, 3 H), 3.28–
3.31 (m, 1 H), 3.58–3.66 (m, 2 H), 3.89–3.99 (m, 2 H), 4.07–4.14
(m, 1 H), 4.99–5.03 (m, 2 H), 5.19 (d, J = 17.6 Hz, 1 H), 5.31 (d,
J = 10.4 Hz, 1 H), 5.60–5.71 (m, 1 H), 5.93–6.01 (m, 1 H), 7.28 (d,
J = 8.4 Hz, 2 H), 7.72 (d, J = 8.4 Hz, 2 H).
Synthesis 2010, No. 7, 1176–1180 © Thieme Stuttgart · New York

PAPER
Pyrimidine-Annulated Azepine and Azocine Derivatives
1179
13C NMR (100 MHz, CDCl3): d = 14.3, 21.6, 28.3, 33.1, 33.2, 41.4,
48.5, 112.2, 116.9, 118.7, 128.3, 129.2, 132.6, 134.6, 135.9, 143.7,
150.9, 156.2, 159.9.
Anal. Calcd for C18H21N3O4S: C, 57.58; H, 5.64; N, 11.19. Found:
C, 57.69; H, 5.71; N, 11.11.
(Z)-1,3-Dimethyl-5-tosyl-5,6,7,10-tetrahydropyrimido[5,4-
b]azocine-2,4(1H,3H)-dione (6d)
Yield: 89%; white solid; mp 178–180 °C.
IR (KBr): 1712, 1651, 1340 cm–1.
MS: m/z = 417 [M+].
Anal. Calcd for C21H27N3O4S: C, 60.41; H, 6.52; N, 10.06. Found:
C, 60.48; H, 6.56; N, 10.01.
(Z)-1,3-Dimethyl-5-tosyl-5,6-dihydro-1H-pyrimido[5,4-
b]azepine-2,4(3H,9H)-dione (6a); Typical Procedure
1H NMR (400 MHz, CDCl3): d = 2.26 (q, J = 7.6 Hz, 1 H), 2.42 (s,
3 H), 2.64 (t, J = 11.4 Hz, 1 H), 2.96–3.08 (m, 2 H), 3.29 (s, 3 H),
3.56 (s, 3 H), 3.81 (dd, J = 14.8, 3.0 Hz, 1 H), 4.10 (q, J = 8.2 Hz,
1 H), 5.87–5.93 (m, 2 H), 7.31 (d, J = 7.8 Hz, 2 H), 8.06 (d, J = 7.9
Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 21.6, 28.6, 29.1, 29.5, 33.1, 48.7,
112.8, 127.6, 128.8, 129.3, 133.6, 136.2, 143.8, 151.4, 160.2.
5a (100 mg, 0.26 mmol) was taken in anhydrous CH2Cl2 (7 mL) in
a small flask and degassed for 10 min with anhydrous N2 gas.
Grubbs’ catalyst A (11 mg, 5 mol%) was dissolved in anhydrous
CH2Cl2 and also degassed for 10 min. The catalyst solution was in-
jected into the solution of compound 5a and the solution was stirred
at 25 °C for 10 h. The solvent was removed under reduced pressure
to give a dark mass, which was purified by column chromatography
over silica gel (PE–EtOAc, 8:2) to give the product 6a.
MS: m/z = 375 [M+].
Anal. Calcd for C18H21N3O4S: C, 57.58; H, 5.64; N, 11.19. Found:
C, 57.68; H, 5.59; N, 11.23.
Yield: 90%; white solid; mp 182–184 °C.
IR (KBr): 1710, 1654, 1328 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.42 (s, 3 H), 3.13 (q, J = 8.7 Hz,
1 H), 3.35 (s, 3 H), 3.52 (s, 3 H), 3.62 (d, J = 18.4 Hz, 1 H), 4.25 (t,
J = 18.3 Hz, 2 H), 5.55–5.58 (m, 1 H), 5.73–5.77 (m, 1 H), 7.32 (d,
J = 8.0 Hz, 2 H), 8.06 (d, J = 8.1 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 21.6, 26.6, 29.0, 33.2, 46.6,
112.7, 119.7, 128.4, 129.1, 129.3, 136.8, 143.8, 151.5, 157.9, 160.4.
MS: m/z = 361 [M+].
(Z)-1,3-Diethyl-5-tosyl-5,6,7,10-tetrahydropyrimido[5,4-b]azo-
cine-2,4(1H,3H)-dione (6e)
Yield: 87%; white solid; mp 132–134 °C.
IR (KBr): 1703, 1655, 1331 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.14 (t, J = 6.9 Hz, 3 H), 1.35 (t,
J = 7.0 Hz, 3 H), 2.26 (q, J = 7.4 Hz, 1 H), 2.41 (s, 3 H), 2.66 (t,
J = 11.1 Hz, 1 H), 2.96–3.00 (m, 2 H), 3.69 (q, J = 6.9 Hz, 2 H),
3.90 (q, J = 6.9 Hz, 2 H), 4.08–4.12 (m, 1 H), 4.26–4.29 (m, 1 H),
5.87–5.93 (m, 2 H), 7.29 (d, J = 6.8 Hz, 2 H), 7.91 (d, J = 7.4 Hz,
2 H).
13C NMR (100 MHz, CDCl3): d = 12.8, 14.5, 21.6, 28.9, 29.1, 37.1,
42.0, 48.8, 112.8, 128.2, 128.7, 129.2, 133.1, 136.3, 143.7, 150.5,
159.9, 160.2.
Anal. Calcd for C17H19N3O4S: C, 56.50; H, 5.30; N, 11.63. Found:
C, 56.64; H, 5.37; N, 11.68.
(Z)-1,3-Diethyl-5-tosyl-5,6-dihydro-1H-pyrimido[5,4-
b]azepine-2,4(3H,9H)-dione (6b)
Yield: 88%; white solid; mp 136–138 °C.
IR (KBr): 1705, 1656, 1332 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.21 (t, J = 6.9 Hz, 3 H), 1.28 (t,
J = 7.0 Hz, 3 H), 2.42 (s, 3 H), 3.03 (q, J = 8.9 Hz, 1 H), 3.61 (d,
J = 18.6 Hz, 1 H), 3.94–4.10 (m, 4 H), 4.26 (t, J = 16.0 Hz, 2 H),
5.56–5.59 (m, 1 H), 5.75–5.79 (m, 1 H), 7.32 (d, J = 7.9 Hz, 2 H),
8.05 (d, J = 8.0 Hz, 2 H).
MS: m/z = 403 [M+].
Anal. Calcd for C20H25N3O4S: C, 59.53; H, 6.25; N, 10.41. Found:
C, 59.41; H, 6.19; N, 10.48.
(Z)-1-Ethyl-3-methyl-5-tosyl-5,6,7,10-tetrahydropyrimido[5,4-
b]azocine-2,4(1H,3H)-dione (6f)
Yield: 85%; white solid; mp 188–190 °C.
13C NMR (100 MHz, CDCl3): d = 12.7, 14.6, 21.5, 26.2, 37.2, 40.9,
46.5, 112.8, 120.1, 128.3, 129.2, 129.3, 136.8, 143.7, 150.7, 157.6,
159.9.
IR (KBr): 1709, 1651, 1325 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.14 (t, J = 7.2 Hz, 3 H), 2.26–
2.32 (m, 1 H), 2.46 (s, 3 H), 2.67–2.72 (m, 1 H), 2.96–3.07 (m,
2 H), 3.32 (s, 3 H), 3.71–3.80 (m, 1 H), 3.82–3.88 (m, 1 H), 4.12–
4.17 (m, 1 H), 4.32–4.37 (m, 1 H), 5.87–5.97 (m, 2 H), 7.34 (d,
J = 8.4 Hz, 2 H), 7.99 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 14.6, 21.6, 28.5, 28.9, 29.0, 42.1,
48.8, 112.9, 128.2, 128.8, 129.3, 133.2, 136.2, 143.8, 150.9, 159.8,
160.7.
MS: m/z = 389 [M+].
Anal. Calcd for C19H23N3O4S: C, 58.59; H, 5.95; N, 10.79. Found:
C, 58.70; H, 6.02; N, 10.86.
(Z)-1-Ethyl-3-methyl-5-tosyl-5,6-dihydro-1H-pyrimido[5,4-
b]azepine-2,4(3H,9H)-dione (6c)
Yield: 87%; white solid; mp 160–162 °C.
IR (KBr): 1703, 1654, 1330 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.21 (t, J = 6.9 Hz, 3 H), 2.42 (s,
3 H), 3.06 (q, J = 8.8 Hz, 1 H), 3.34 (s, 3 H), 3.60 (d, J = 18.5 Hz,
1 H), 3.98–4.11 (m, 2 H), 4.26 (t, J = 18.0 Hz, 2 H), 5.56–5.59 (m,
1 H), 5.75–5.79 (m, 1 H), 7.32 (d, J = 7.6 Hz, 2 H), 8.06 (d, J = 7.6
Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 14.7, 21.6, 26.3, 28.6, 41.1, 46.6,
112.8, 120.1, 128.4, 129.3, 129.5, 136.8, 143.8, 151.2, 157.7, 160.5.
MS: m/z = 375 [M+].
MS: m/z = 389 [M+].
Anal. Calcd for C19H23N3O4S: C, 58.59; H, 5.95; N, 10.79. Found:
C, 58.68; H, 5.99; N, 10.73.
Acknowledgment
We thank the DST (New Delhi) and the CSIR (New Delhi) for fi-
nancial assistance. Two of us (S.M. and D.G.) are thankful to the
CSIR (New Delhi) for Senior and Junior research fellowships, re-
spectively.
Synthesis 2010, No. 7, 1176–1180 © Thieme Stuttgart · New York

1180
K. C. Majumdar et al.
PAPER
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