Concise synthesis of pyrimido-azocine derivatives via aza-claisen rearrangement and intramolecular heck reaction

Article abstract of DOI:10.1055/s-0029-1219276

An expedient approach involving BF₃OEt₂-catalyzed aza-Claisen rearrangement and palladium-catalyzed intramolecular Heck reaction for the synthesis of pyrimidine-fused azocine derivatives is described. The mechanistic interpretation o

Full text of DOI:10.1055/s-0029-1219276

PAPER
1315
Concise Synthesis of Pyrimido-azocine Derivatives via Aza-Claisen
Rearrangement and Intramolecular Heck Reaction
C
oncise Synthesis
.
of Pyrimido-
C
azocine Derivati
.ves Majumdar,* Shovan Mondal, Debankan Ghosh, Buddhadeb Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741235, WB, India
E-mail: kcm_ku@yahoo.co.in
Received 14 December 2009; revised 23 December 2009
din-4-ones have been used as anticancer agents,7 and
HIV-integrase inhibitors.8 Pteridines are potent antitumor
agents.9 Therefore, novel methodologies for the synthesis
of pyrimidine-fused azocine derivatives are of particular
interest in medicinal chemistry. Despite their bioactivity,
azocine-fused ring systems have not been sufficiently in-
vestigated. One barrier to this, generally, may be due to
unsatisfactory synthetic procedures.10 Cyclization strate-
gies to azocine rings are often inhibited due to entropic
factors and transannular interactions.11
Abstract: An expedient approach involving BF3·OEt2-catalyzed
aza-Claisen rearrangement and palladium-catalyzed intramolecular
Heck reaction for the synthesis of pyrimidine-fused azocine deriva-
tives is described. The mechanistic interpretation of the plausible
mode of cyclization is also described.
Key words: uracil, aza-Claisen rearrangement, azocine, Heck reac-
tion
As a result of rich chemistry and biology of nitrogen-con-
taining compounds, N-heterocycles, in particular eight-
membered azocines, are key structures in many natural
products. For example, the alkaloid manzamine A (1), iso-
lated from the sea sponges Haliclona sp.,1 Xestopongia
sp.,2 and Pellina sp.,3 found in the waters of the Okinawa
Sea, exhibits significant antileukemic and antimicrobial
activity.4 The okaramine A (2) and okaramine N (3) are
biologically active alkaloids5 isolated from the fungus
Penicillium simplicissum6 (ATCC 90288) (Figure 1).
We recently reported pyrimidine-fused azocine deriva-
tives by a thiophenol-mediated radical cyclization strate-
gy.12 In continuation of our work in palladium
chemistry,13 we undertook an initiative to synthesize
pyrimido-azocine derivatives by palladium-catalyzed in-
tramolecular Heck reaction. Here we disclose our results.
For the synthesis of pyrimidine-fused azocine derivatives,
the starting materials 4a–c were prepared according to our
recently published procedure.12,14 5-Bromouracil deriva-
tives 1a–c were subjected to allylamine in ethanol to give
5-(allylamino)uracil derivatives 2a–c, this was followed
by boron trifluoride–diethyl ether complex catalyzed
Claisen rearrangement to give the 6-allyl-5-aminouracil
derivatives 3a–c in excellent yields. Treatment of com-
pounds 3a–c with tosyl chloride in pyridine gave the cor-
responding tosyl derivatives 4a–c, which are the starting
Moreover pyrimidine derivatives and pyrimidine-fused
heterocycles, such as purines, pyrrolopyrimidines, pyra-
zolopyrimidines etc., constitute the backbone of several
biologically active compounds. 4H-Pyrido[1,2-a]pyrimi-
O
N
H
N
HO
H
H
N
N
OH
NH
O
O
N
H
N
H
R2
O
Br
R2
O
N
O
N
N
(i)
N
N
N
R1
R1
1a–c
2a–c
okaramine A (2)
manzamine A (1)
a, R1 = R2 = Me
a, R1 = R2 = Me, 84%
b, R1 = R2 = Et, 82%
c, R1 = Et, R2 = Me 85%
O
O
b, R1 = R2 = Et
(ii)
H
c, R1 = Et, R2 = Me
HO
N
O
N
O
Ts
NH
R2
O
NH2
R2
O
NH
H
N
H
N
N
(iii)
N
N
R1
R1
3a–c
4a–c
okaramine N (3)
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%
Figure 1 Examples of azocine-containing alkaloids
c, R1 = Et, R2 = Me, 95%
SYNTHESIS 2010, No. 8, pp 1315–1320
Advanced online publication: 25.01.2010
DOI: 10.1055/s-0029-1219276; Art ID: Z27009SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
0
Scheme 1 Synthesis of starting materials 4a–c. Reagents and con-
ditions: (i) allylamine, EtOH, reflux, 5–6 h; (ii) BF3·OEt2, xylene, 120
°C, 4–5 h; (iii) TsCl, Py, 80 °C, 1–2 h.

1316
K. C. Majumdar et al.
PAPER
materials for the present study. The schematic route for tion may give the thermodynamically stable products 7.
the preparation of these starting materials 4a–c is shown The other possibility is that a double bond isomerization
in Scheme 1.
(path b) prior to the Heck reaction may occur followed by
8-endo Heck cyclization to give the products 7
(Scheme 4).
The required Heck precursors 6a–f for our present study
were synthesized in 80–95% yields by refluxing 6-allyl-5-
(tosylamino)uracil derivatives 4a–c with benzyl bromides
5a–c in anhydrous acetone in the presence of anhydrous
potassium carbonate for four to five hours (Scheme 2).
Ts
O
N
Me
N
For the synthesis of our target azocine derivatives by the
implementation of the Heck reaction, we initiated our in-
vestigation with substrate 6a. When the compound 6a was
heated at 90 °C in anhydrous N,N-dimethylformamide us-
ing potassium acetate (2.75 equiv) as a base, tetrabutyl-
ammonium bromide (1.2 equiv) as a promoter, and
palladium(II) acetate (10 mol%) as the catalyst under a ni-
trogen atmosphere, the reaction proceeded smoothly and
was complete within one hour affording the pyrimido-
azocine derivative 7a in 85% yield. Among the different
possibilities only one product was obtained showing com-
plete regioselectivity (Scheme 3).
O
N
Me
9
not observed
Ts
O
O
Ts
N
N
Me
N
Me
O
(i)
N
O
N
Br
N
Me
H
Me
7a (85%)
Me
6a
observed
Ts
N
O
Then we performed Heck reactions of other substrates
6b–e under the same condition to give the azocine deriv-
atives 7b–e in 80–85% yields. However, substrate 6f con-
taining the 5-nitro-2-iodobenzyl moiety afforded an
intractable complex mixture. Subsequently we changed
the catalyst [Pd(PPh3)4, Pd2(dba)3], base (Et3N, Ag2CO3),
and solvent (DMA, MeCN) and we also tried different
ligands [Ph3P, (o-Tol)3P], but in all cases only complex
mixtures of products were obtained. The results are sum-
marized in Table 1.
Me
N
O
N
Me
8
not observed
Scheme 3 Synthesis of pyrimido-azocine derivative 7a. Reagents
and conditions: (i) Pd(OAc)2 (10 mol%), KOAc (2.75 equiv), TBAB
(1.2 equiv), DMF, 90 °C, 1 h.
R3
The formation of the endocyclic products 7a–e may be ra-
tionalized via two possible pathways, i.e. either through
an 8-exo mode (path a) of cyclization to give the kinetical-
ly controlled products 8, which by double bond isomeriza-
Ts
N
O
R2
O
N
N
R1
Br
O
Ts
9
R2
O
NH
X
N
+
9-endo-trig
O
N
R1
4a–c
R3
R3
Br
5a–c
Ts
N
O
a, R3 = H, X = Br
b, R3 = OMe, X = Br
c, R3 = NO2, X = I
Ts
a, R1 = R2 = Me
R2
O
R3
R2
N
b, R1 = R2 = Et
N
8-exo-trig
path a
N
c, R1 = Et, R2 = Me
N
R1
R3
O
N
H
R1
6
(i)
8
O
Ts
double bond
isomerization
R2
N
N
kinetically controlled product
path b
R3
X
O
N
R1
Ts
O
O
Ts
6a–f
R2
O
R3
N
R2
N
a, R1 = R2 = Me, R3 = H, X = Br, 91%
b, R1 = R2 = Me, R3 = OMe, X = Br, 94%
c, R1 = R2 = Et, R3 = H, X = Br, 90%
N
N
8-endo-trig
Br
N
O
N
R1
d, R1 = R2 = Et, R3 = OMe, X = Br, 93%
e, R1 = Et, R2 = Me, R3 = OMe, X = Br, 95%
f, R1 = Et, R2 = Me, R3 = NO2, X = I, 80%
R1
7
Me
10
thermodynamically controlled product
Scheme 2 Synthesis of Heck precursors 6a–f. Reagents and condi-
tions: (i) K2CO3, acetone, reflux, 4–5 h.
Scheme 4 Possible mechanistic pathway of Heck cyclization
Synthesis 2010, No. 8, 1315–1320 © Thieme Stuttgart · New York

PAPER
Concise Synthesis of Pyrimido-azocine Derivatives
1317
Table 1 Synthesis of Pyrimido-azocine Derivatives via Heck Reactions
Entry
1
Heck precursors
Azocine derivatives
Time (h)
Yielda (%)
Ts
O
O
Ts
N
N
Me
Me
O
N
N
1
85
Br
O
N
N
Me
Me
6a
7a
OMe
Ts
N
O
O
Ts
N
Me
O
OMe
N
Me
O
2
3
4
1
83
80
81
N
N
Br
N
Me
Me
7b
6b
Ts
O
Ts
N
O
N
Et
O
Et
O
N
N
1.5
1.5
Br
N
N
Et
Et
6c
7c
OMe
Ts
N
O
O
Ts
N
Et
O
OMe
N
Et
O
N
N
Br
N
Et
Et
7d
6d
OMe
Ts
O
O
Ts
N
N
Me
O
OMe
N
Me
O
5
1
85
N
N
Br
N
Et
Et
7e
6e
NO2
O
Ts
N
Me
O
b
6
–
1.5
–
N
I
N
Et
6f
a Isolated yield.
b Complex mixture.
In conclusion, we have developed an efficient method for endo-trig cyclized products; they have studied the temper-
the construction of pyrimido-azocine derivatives by palla- ature and ligand effect on the regioselectivity. Our method
dium-catalyzed, ligand-free Heck coupling reaction. Here is relatively simple, straightforward, and regioselective
it is important to note that recently Hii et al. reported15 the and the reaction was complete within 1–1.5 hours.
synthesis of benzazocine derivatives by a palladium-cata-
lyzed Heck cyclization strategy using a phosphine ligand
Melting points were determined in open capillaries and are uncor-
and harsh reaction conditions (140 °C) with a long reac-
tion time required for completion (22 h). Additionally,
they obtained an inseparable mixture of 7-exo-trig and 8-
rected. IR spectra (KBr discs) were determined on a Perkin Elmer
120-000A spectrophotometer. 1H NMR (CDCl3 soln, TMS as inter-
nal standard) were determined on a Bruker DPX-400. 13C NMR
(CDCl3 soln) were determined on a Bruker DPX-400. MS were re-
Synthesis 2010, No. 8, 1315–1320 © Thieme Stuttgart · New York

1318
K. C. Majumdar et al.
PAPER
corded on a Qtof Micro YA263 instrument. CHN was recorded on
a Perkin Elmer 2400 series II CHN analyzer. Silica gel (60–120
mesh) was used for chromatographic separation. Silica gel G [E.
Merck (India)] was used for TLC. Petroleum ether (PE) refers to the
fraction with bp 60–80 °C.
N-(6-Allyl-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-
5-yl)-N-(2-bromo-5-methoxybenzyl)-4-methylbenzenesulfon-
amide (6d)
White solid; yield: 93%; mp 110–112 °C.
IR (KBr): 1699, 1652, 1342 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.11 (t, J = 7.2 Hz, 3 H), 1.16 (t,
J = 7.2 Hz, 3 H), 2.45 (s, 3 H), 3.83 (s, 3 H), 3.85–3.91 (m, 6 H),
4.68 (d, J = 13.6 Hz, 1 H), 4.82 (d, J = 17.2 Hz, 1 H), 4.90–4.95 (m,
2 H), 5.15–5.19 (m, 1 H), 6.69 (dd, J = 8.8, 3.2 Hz, 1 H), 7.04 (d,
J = 3.2 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 3 H), 7.75 (d, J = 8.0 Hz, 2 H).
N-(6-Allyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimi-
din-5-yl)-N-(2-bromobenzyl)-4-methylbenzenesulfonamide
(6a); Typical Procedure
A mixture of 4a (0.50 g, 1.43 mmol), 2-bromobenzyl bromide (5a,
0.43 g, 1.71 mmol), and dry K2CO3 (1.0 g) in acetone (50 mL) was
stirred and refluxed for 4 h. The mixture was cooled and filtered and
the solvent was removed. The residual mass was extracted with
CHCl3 (3 × 20 mL), washed with H2O (2 × 10 mL) and brine (5 mL)
and dried (Na2SO4). Removal of CHCl3 gave a crude product that
was chromatographed (silica gel, 60–120 mesh, PE–EtOAc, 9:1) to
give 6a as a white solid; yield: 91%; mp 184–186 °C.
MS: m/z = 575 [M+], 577 [M + 2]+.
Anal. Calcd for C26H30BrN3O5S: C, 54.17; H, 5.25; N, 7.29. Found:
C, 54.05; H, 5.13; N, 7.35.
N-(6-Allyl-1-ethyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyri-
midin-5-yl)-N-(2-bromo-5-methoxybenzyl)-4-methylbenzene-
sulfonamide (6e)
IR (KBr): 1708, 1656, 1342 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.43 (s, 3 H), 3.15 (dd, J = 16.7,
5.1 Hz, 1 H), 3.22 (s, 3 H), 3.30 (s, 3 H), 3.55 (dd, J = 16.6, 4.8 Hz,
1 H), 4.68 (d, J = 17.4 Hz, 1 H), 4.73 (d, J = 13.4 Hz, 1 H), 4.87 (d,
J = 10.2 Hz, 1 H), 4.96 (d, J = 13.3 Hz, 1 H), 5.00–5.03 (m, 1 H),
7.10 (t, J = 7.4 Hz, 1 H), 7.20–7.25 (m, 1 H), 7.29 (d, J = 7.8 Hz, 2
H), 7.44 (t, J = 7.8 Hz, 2 H), 7.72 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 21.9, 28.5, 33.3, 33.6, 51.5,
111.2, 118.5, 125.5, 128.1, 128.4, 129.6, 130.0, 131.4, 132.8, 132.9,
133.0, 133.3, 135.4, 136.4, 144.1, 151.7, 157.5, 159.9.
White solid; yield: 95%; mp 130–132 °C.
IR (KBr): 1700, 1652, 1343 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.13 (t, J = 6.9 Hz, 3 H), 2.43 (s,
3 H), 3.19–3.40 (m, 5 H), 3.71 (s, 3 H), 3.78–3.93 (m, 2 H), 4.63 (d,
J = 13.6 Hz, 1 H), 4.71–4.96 (m, 3 H), 5.19–5.25 (m, 1 H), 6.67 (dd,
J = 8.8, 3.0 Hz, 1 H), 7.01 (d, J = 3.0 Hz, 1 H), 7.26–7.31 (m, 3 H),
7.01 (d, J = 8.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 14.2, 21.7, 28.2, 32.7, 41.0, 51.7,
55.5, 111.4, 115.5, 116.6, 117.0, 118.0, 128.1, 128.3, 129.4, 132.1,
133.2, 133.5, 136.0, 136.3, 143.9, 151.0, 156.8, 159.2, 159.9.
MS: m/z = 517 [M+], 519 [M + 2]+.
MS: m/z = 561 [M+], 563 [M + 2]+.
Anal. Calcd for C23H24BrN3O4S: C, 53.29; H, 4.67; N, 8.11. Found:
C, 53.38; H, 4.71; N, 8.01.
Anal. Calcd for C25H28BrN3O5S: C, 53.38; H, 5.02; N, 7.47. Found:
C, 53.45; H, 5.09; N, 7.42.
N-(6-Allyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimi-
din-5-yl)-N-(2-bromo-5-methoxybenzyl)-4-methylbenzene-
sulfonamide (6b)
White solid; yield: 94%; mp 142–144 °C.
IR (KBr): 1699, 1651, 1341 cm–1.
N-(6-Allyl-1-ethyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyri-
midin-5-yl)-N-(2-iodo-5-nitrobenzyl)-4-methylbenzenesulfon-
amide (6f)
White solid; yield: 80%; mp 208–210 °C.
1H NMR (400 MHz, CDCl3): d = 2.42 (s, 3 H), 3.20 (dd, J = 16.7,
5.1 Hz, 2 H), 3.30 (s, 6 H), 3.70 (s, 3 H), 4.52 (d, J = 13.8 Hz, 1 H),
4.73 (d, J = 12.4 Hz, 2 H), 4.89 (d, J = 11.8 Hz, 1 H), 5.62–5.75 (m,
1 H), 6.65 (d, J = 6.4 Hz, 1 H), 7.02–7.09 (m, 1 H), 7.24–7.28 (m, 3
H), 7.71 (d, J = 6.9 Hz, 1 H), 7.79 (d, J = 6.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.6, 28.3, 33.1, 33.4, 51.5, 55.4,
111.0, 118.3, 120.0, 128.1, 128.3, 129.4, 131.2, 132.9, 133.2, 133.5,
135.8, 135.9, 136.1, 136.6, 143.9, 151.5, 157.3, 159.7.
IR (KBr): 1680, 1622, 1520, 1349 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.19 (t, J = 7.1 Hz, 3 H), 2.44 (s,
3 H), 3.13 (dd, J = 17.2, 5.3 Hz, 1 H), 3.22 (s, 3 H), 3.52 (dd,
J = 17.3, 5.0 Hz, 1 H), 3.72 (q, J = 7.2 Hz, 1 H), 3.97 (q, J = 7.0 Hz,
1 H), 4.65 (d, J = 17.4 Hz, 1 H), 4.75 (d, J = 14.4 Hz, 1 H), 4.82 (d,
J = 10.4 Hz, 1 H), 5.00 (d, J = 14.6 Hz, 1 H), 5.27–5.31 (m, 1 H),
7.31 (d, J = 8.0 Hz, 2 H), 7.71 (d, J = 8.1 Hz, 2 H), 7.82 (d, J = 8.4
Hz, 1 H), 8.13 (dd, J = 8.6, 1.6 Hz, 1 H), 8.54 (d, J = 1.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.4, 21.7, 28.4, 32.5, 41.4, 55.7,
99.5, 111.3, 117.7, 123.4, 128.3, 129.5, 131.5, 132.0, 134.3, 135.6,
144.4, 146.1, 147.5, 150.8, 156.7, 159.7.
MS: m/z = 547 [M+], 549 [M + 2]+.
Anal. Calcd for C24H26BrN3O5S: C, 52.56; H, 4.78; N, 7.66. Found:
C, 52.67; H, 4.72; N, 7.71.
MS: m/z = 624 [M+].
N-(6-Allyl-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-
5-yl)-N-(2-bromobenzyl)-4-methylbenzenesulfonamide (6c)
White solid; yield: 90%; mp 154–156 °C.
Anal. Calcd for C24H25IN4O6S: C, 46.16; H, 4.04; N, 8.97. Found:
C, 46.27; H, 3.98; N, 9.08.
IR (KBr): 1704, 1658, 1339 cm–1.
(Z)-1,3,11-Trimethyl-5-tosyl-5,6-dihydrobenzo[f]pyrimido[5,4-
b]azocine-2,4(1H,3H)-dione (7a) by Heck reaction; Typical Pro-
cedure
1H NMR (400 MHz, CDCl3): d = 1.11 (t, J = 7.2 Hz, 6 H), 2.43 (s,
3 H), 3.16 (dd, J = 16.2, 4.8 Hz, 1 H), 3.26 (dd, J = 16.1, 4.3 Hz, 1
H), 3.77–3.88 (m, 4 H), 4.71 (d, J = 13.6 Hz, 1 H), 4.77 (d, J = 17.4
Hz, 1 H), 4.90 (d, J = 10.1 Hz, 1 H), 4.96 (d, J = 13.6 Hz, 1 H),
5.15–5.22 (m, 1 H), 7.10 (t, J = 7.3 Hz, 1 H), 7.23 (t, J = 7.5 Hz, 1
H), 7.29 (d, J = 7.7 Hz, 2 H), 7.43 (d, J = 7.8 Hz, 1 H), 7.48 (d,
J = 7.5 Hz, 1 H), 7.74 (d, J = 7.8 Hz, 2 H).
A mixture of 6a (150 mg, 0.29 mmol), TBAB (112 mg, 0.35 mmol),
and fused KOAc (78 mg, 0.80 mmol) was taken up in anhyd DMF
(10 mL) and N2 was bubbled through the mixture. Pd(OAc)2 (6.5
mg, 10 mol%) was added and the mixture was stirred at 90 °C for 1
h. The mixture was cooled, H2O (20 mL) was added, and it was ex-
tracted with EtOAc (3 × 20 mL). The combined EtOAc extracts
were washed with H2O (4 × 10 mL) and brine (10 mL), and dried
(Na2SO4). The solvent was distilled off to furnish a viscous mass
that was purified by column chromatography (silica gel, 30%
MS: m/z = 545 [M+], 547 [M + 2]+.
Anal. Calcd for C25H28BrN3O4S: C, 54.95; H, 5.16; N, 7.69. Found:
C, 55.07; H, 5.22; N, 7.58.
Synthesis 2010, No. 8, 1315–1320 © Thieme Stuttgart · New York

PAPER
Concise Synthesis of Pyrimido-azocine Derivatives
1319
EtOAc–hexane) to give 7a as a white solid; yield: 85%; mp 250–
252 °C.
Anal. Calcd for C26H29N3O5S: C, 63.01; H, 5.90; N, 8.48. Found: C,
63.12; H, 5.97; N, 8.42.
IR (KBr): 1704, 1658, 1345 cm–1.
(Z)-1-Ethyl-8-methoxy-3,11-dimethyl-5-tosyl-5,6-dihydroben-
zo[f]pyrimido[5,4-b]azocine-2,4(1H,3H)-dione (7e)
White solid; yield: 85%; mp 206–208 °C.
IR (KBr): 1703, 1659, 1338 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.18 (s, 3 H), 2.44 (s, 3 H), 3.22
(s, 6 H), 3.29 (d, J = 13.0 Hz, 1 H), 4.85 (d, J = 12.9 Hz, 1 H), 5.90
(s, 1 H), 7.05 (d, J = 7.4 Hz, 2 H), 7.16 (t, J = 7.3 Hz, 1 H), 7.23 (t,
J = 7.8 Hz, 1 H), 7.33 (d, J = 7.7 Hz, 2 H), 7.90 (d, J = 7.7 Hz, 2 H).
1H NMR (400 MHz, CDCl3): d = 1.11 (t, J = 6.9 Hz, 3 H), 2.15 (s,
3 H), 2.43 (s, 3 H), 3.22 (s, 3 H), 3.67 (q, J = 6.9 Hz, 1 H), 3.71 (s,
3 H), 3.85 (q, J = 6.9 Hz, 1 H), 4.24 (d, J = 13.2 Hz, 1 H), 4.85 (d,
J = 13.3 Hz, 1 H), 5.91 (s, 1 H), 6.57 (s, 1 H), 6.75 (d, J = 8.4 Hz, 1
H), 6.97 (d, J = 8.4 Hz, 1 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.88 (d,
J = 7.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 13.8, 21.6, 26.1, 28.3, 41.7, 52.8,
55.2, 111.2, 113.5, 114.3, 116.7, 128.1, 129.2, 129.4, 131.9, 133.0,
136.9, 143.5, 146.1, 150.6, 154.1, 158.9, 161.0.
13C NMR (100 MHz, CDCl3): d = 21.6, 25.7, 28.4, 33.2, 52.6,
111.2, 117.6, 127.7, 127.9, 128.1, 128.2, 129.5, 129.6, 131.3, 136.7,
140.1, 143.6, 146.1, 151.1, 154.2, 161.0.
MS: m/z = 437 [M+].
Anal. Calcd for C23H23N3O4S: C, 63.14; H, 5.30; N, 9.60. Found: C,
63.02; H, 5.24; N, 9.65.
(Z)-8-Methoxy-1,3,11-trimethyl-5-tosyl-5,6-dihydrobenzo[f]py-
rimido[5,4-b]azocine-2,4(1H,3H)-dione (7b)
White solid; yield: 83%; mp 230–232 °C.
MS: m/z = 481 [M+].
Anal. Calcd for C25H27N3O5S: C, 62.35; H, 5.65; N, 8.73. Found: C,
62.22; H, 5.59; N, 8.78.
IR (KBr): 1706, 1668, 1335 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.18 (s, 3 H), 2.44 (s, 3 H), 3.24
(s, 6 H), 3.71 (s, 3 H), 4.24 (d, J = 13.4 Hz, 1 H), 4.86 (d, J = 13.2
Hz, 1 H), 5.92 (s, 1 H), 6.57 (s, 1 H), 6.76 (d, J = 8.4 Hz, 1 H), 6.98
(d, J = 8.2 Hz, 1 H), 7.33 (d, J = 7.6 Hz, 2 H), 7.90 (d, J = 7.7 Hz, 2
H).
13C NMR (100 MHz, CDCl3): d = 21.6, 26.0, 28.4, 33.2, 52.8, 55.2,
111.3, 113.6, 114.3, 117.3, 128.1, 129.2, 129.4, 129.5, 132.0, 132.9,
136.9, 143.5, 146.0, 151.2, 154.5, 159.0, 161.0.
Acknowledgment
We thank the DST (New Delhi) and the CSIR (New Delhi) for fi-
nancial assistance. Three of us (S.M., D.G. and B.C.) are thankful
to the CSIR (New Delhi) for their research fellowships.
MS: m/z = 467 [M+].
References
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Anal. Calcd for C24H25N3O5S: C, 61.65; H, 5.39; N, 8.99. Found: C,
61.56; H, 5.42; N, 9.04.
(Z)-1,3-Diethyl-11-methyl-5-tosyl-5,6-dihydrobenzo[f]pyrimi-
do[5,4-b]azocine-2,4(1H,3H)-dione (7c)
White solid; yield: 80%; mp 192–194 °C.
(2) Ichiba, T.; Sakai, R.; Kohmoto, S.; Saucy, G.; Higa, T.
Tetrahedron Lett. 1988, 29, 3083.
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IR (KBr): 1704, 1659, 1339 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.10 (t, J = 6.9 Hz, 6 H), 2.22 (s,
3 H), 2.44 (s, 3 H), 3.68 (q, J = 6.9 Hz, 1 H), 3.79–3.88 (m, 3 H),
4.28 (d, J = 13.3 Hz, 1 H), 4.90 (d, J = 13.2 Hz, 1 H), 5.99 (s, 1 H),
7.05 (dd, J = 6.9, 3.0 Hz, 2 H), 7.16 (t, J = 7.1 Hz, 1 H), 7.22 (d,
J = 7.5 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 2 H), 7.89 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 12.7, 13.9, 21.6, 25.9, 37.0, 41.7,
52.6, 111.3, 117.0, 127.8, 127.9, 128.1, 128.2, 129.5, 131.6, 136.9,
140.0, 143.5, 146.2, 150.3, 154.1, 160.6.
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1999, 62, 315. (d) Shiono, Y.; Akiyama, K.; Hayashi, H.
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MS: m/z = 465 [M+].
Anal. Calcd for C25H27N3O4S: C, 64.50; H, 5.85; N, 9.03. Found: C,
64.63; H, 5.91; N, 8.98.
(Z)-1,3-Diethyl-8-methoxy-11-methyl-5-tosyl-5,6-dihydroben-
zo[f]pyrimido[5,4-b]azocine-2,4(1H,3H)-dione (7d)
White solid; yield: 81%; mp 222–224 °C.
IR (KBr): 1706, 1659, 1336 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.10 (t, J = 6.9 Hz, 6 H), 2.07 (s,
3 H), 2.43 (s, 3 H), 3.71 (s, 3 H), 3.84 (q, J = 6.9 Hz, 4 H), 4.24 (d,
J = 13.5 Hz, 1 H), 4.91 (d, J = 13.5 Hz, 1 H), 5.97 (s, 1 H), 6.57 (s,
1 H), 6.75 (d, J = 6.6 Hz, 1 H), 6.99 (d, J = 8.4 Hz, 1 H), 7.32 (d,
J = 7.8 Hz, 2 H), 7.87 (d, J = 7.9 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 12.7, 13.9, 21.6, 26.3, 37.0, 41.7,
52.8, 55.2, 111.3, 113.5, 114.1, 116.6, 128.1, 129.3, 129.4, 131.9,
133.1, 137.0, 143.5, 146.0, 150.2, 154.4, 158.9, 160.6.
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MS: m/z = 495 [M+].
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