Chemoselective multicomponent condensation of 1,3-cyclohexanedione, urea or thiourea with aldehydes: One-pot synthesis of two families of fused heterobicyclic and spiro-fused heterobicyclic aliphatic rings

Article abstract of DOI:10.3987/com-04-10112

One-pot chemoselective condensation of 1,3-cyclohexanedione, urea or thiourea with aldehydes has been performed by using TMSCI as a Lewis acid in DMF/MeCN. This extended Biginelli-type reaction afforded two families of fused heterobicyclic and spiro-fused

Full text of DOI:10.3987/com-04-10112

HETEROCYCLES, Vol. 65, No. 1, 2005
133
HETEROCYCLES, Vol. 65, No. 1, 2005, pp. 133 - 142
Received, 6th May, 2004, Accepted, 2nd November, 2004, Published online, 9th November, 2004
CHEMOSELECTIVE MULTICOMPONENT CONDENSATION OF
1,3-CYCLOHEXANEDIONE,
UREA
OR
THIOUREA
WITH
ALDEHYDES: ONE-POT SYNTHESIS OF TWO FAMILIES OF FUSED
HETEROBICYCLIC
ALIPHATIC RINGS
AND
SPIRO-FUSED
HETEROBICYCLIC
Yulin Zhu, Yuanjiang Pan*, and Shenlin Huang
Chemistry Department of Zhejiang University, Hangzhou, 310027, P. R. China
E-mail: panyuanjiang@zju.edu.cn
Abstract- One-pot chemoselective condensation of 1,3-cyclohexanedione, urea
or thiourea with aldehydes has been performed by using TMSCl as a Lewis acid
in DMF/MeCN. This extended Biginelli-type reaction afforded two families of
fused heterobicyclic and spiro-fused heterobicyclic compounds in excellent yields.
para-Substituted benzaldehydes exhibited different chemical behaviors to ortho-
or meta-substituted benzaldehydes and aliphatic aldehydes. The possible
mechanism was discussed to account for experimental results.
INTRODUCTION
Biginelli reaction is one of the most powerful synthetic methodologies for the heterocyclic six-membered
rings. 3,4-Dihydropyrimidin-2(1H)-ones (DHPMs) and their derivatives have attracted considerable
interest due to their wide range of therapeutic and pharmacological properties, such as antiviral, antitumor,
1
antibacterial and antiinflammatory properties. The first synthesis of 3,4-dihydropyrimidin-2-(1H)-ones
2
was described by Biginelli in 1893. Large number of improving methods and new Biginelli-like
3
scaffolds have been reported over the past decade.
Recently, Biginelli-type reaction which used cyclic β-diketones instead of open-chain dicarbonyl
compounds has attracted a synthetical interest. Spiro-fused heterocycles were synthesized by a
4
multicomponent reaction between an aldehyde, urea or thiourea and a cyclic β-diester. The scope of the
extended Biginelli reaction was extended by a variety of cyclic β-diester shown in Figure 1.
We investigated 1,3-cyclohexanedione reacted with aromatic aldehydes and aliphatic aldehydes in the

134
HETEROCYCLES, Vol. 65, No. 1, 2005
Y
O
O
X
X
X
O
O
X = O, Y = CMe2
X = NH, Y = CO
X = NMe, Y = CO
X = O
X = CH2
X = CH , Y = CMe2
2
X = Y = CH2
Figure 1.
reaction system TMSCl–DMF–MeCN in room temperature and found interestingly that two families of
fused heterobicyclic and spiro-fused heterobicyclic compounds were formed; para-substituted
benzaldehydes exhibited different chemical behaviors to ortho-, meta-substituted benzaldehydes and
aliphatic aldehydes.
RESULTS AND DISCUSSION
We first tried to proceed the transformation by a simple mixture of 1,3-cyclohexanedione (1, 10 mmol),
thiourea (2a, 12 mmol), and benzaldehyde (3a, 10 mmol) in the system TMSCl–DMF–MeCN (10
mmol–4 mL–8 mL, respectively). The reaction was performed in room temperature for 2-3 h. The
corresponding product 1, 5-diphenyl-3-thioxo-2, 4-diazaspiro[5, 5]undecane-7, 11-dione (Figure 2, 4a)
was isolated and identified by NMR and HRMS. But under the same experimental conditions, the
reaction between 1,3-cyclohexanedione (1), urea (2b), and benzaldehyde (3a) afforded the unexpected
fused heterobicyclic compound phenyl-4,6,7,8-tetrahydro-1H,3H-quinazoline-2,5-dione (Figure 2, 5i) in
4
-c
8
6% isolated yield; no spiro-fused heterobicyclic products were observed.
S
HN
NH
O
O
O
NH
N
O
H
4
a
5
i
Figure 2.
For the experiment results above, series of reactions were investigated in details. Aromatic aldehydes
3b-3i) instead of benzaldehyde (3a) reacted with 1,3-cyclohexanedione (1) and thiourea (2a) or urea (2b).
(
These reactions were carried out in DMF/MeCN at room temperature for 2-3 h in molar ratio/1 : 2 : 3 :
TMSCl = 1.0 : 1.2 : 1.0 : 1.0. A similar result was obtained with two families of fused heterobicyclic and
spiro-fused heterobicyclic compounds (4, 5) in excellent yields with high purities. The results were
summarized in Table 1.

HETEROCYCLES, Vol. 65, No. 1, 2005
135
Table 1. Multicomponent Rections between 1,3-Cyclohexanedione, Thiourea or Urea and
Aldehydes.[a]
X
O
R
HN
NH
X
O
O
TMSCl
R
O
R
O
NH
RCHO
H N
NH2
2
DMF/MeCN
N
H
X
1
2
3
4
5
Run
X
3 : R
3a: C
3b: 4-Cl-C
3c: 4- Me-C
3c: 4-Me-C
3d: 4-F-C
3e: 4-NO
3d: 4-F-C
T( ) t (h) DMF/MeCN 4[b]
5[b]
1
2
3
4
5
6
7
8
9
S
S
S
O
O
O
S
S
O
S
O
S
O
S
S
O
S
S
S
O
O
O
O
6
H
5
3
2
2
2
2
2
3
3
2
2
2
2
2
2
3
2
3
3
3
3
3
3
3
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
4a: 77 5a: 21
4b: 80 5b: 13
4c: 79 5c: 11
4d: 78 5d: 15
4e: 70 5e: 23
4f: 69 5f: 25
5g: 76
6
H
4
6
H
4
6
H
4
6
H
4
2
-C
6
H
4
6
H
4
3e: 4-NO
3a: C
2
-C
6
H
4
5h: 74
5i: 86
5j: 82
5k: 90
5l: 92
5m: 93
5n: 85
5o: 80
5p: 90
5q: 77
5r: 80
5s: 85
5t: 93
5u: 82
5v: 86
5w: 83
6
H
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3f: 2-F-C
3f: 2-F-C
3g: 2-Br-C
3g: 2-Br-C
6
H
H
4
6
4
6
H
H
4
6
4
3h: 2-MeO-C
6
H
4
4
3i: 3-NO
3i: 3-NO
3j: n-Pr
3l: n-Bu
3m: i-Bu
3j: n-Pr
3k: i-Pr
3m: i-Bu
2
-C
-C
6
H
H
2
6
4
80
80
80
80
80
80
80
3n: n-C
6
H
13
1
13
[
a]All compounds were characterized by H-NMR, C NMR, and MS spectroscopies. [b]Isolated yields
The yields of 4 and 5 were based on 1,3-cyclohexandione).
(
In the mentioned syntheses from Runs (1) to (6), para-substituted aromatic aldehydes afforded mainly
spiro-fused heterobicyclic products. The stereochemistry of the aryl rings (products 4a–f) was assigned
4
c
cis based on the work of Byk. We also found these reactions were accompanied by small amounts of
fused heterobicyclic compounds (5a-f) in yields from 11% to 25%.
For the reactions of urea (2b) shown in Table 1 (runs 7-8), para-substituted aromatic aldehydes carrying
2
either electron-donating (-Me) or electron-withdrawing (-F, -NO ) substituents yielded spiro-fused
heterobicyclic aliphatic compounds (4d, 4e, 4f). But thiourea (2a) exhibited different behaviors to that of
urea under similar conditions. para-Substituted aromatic aldehydes carrying electron-withdrawing (-F,
-
NO ) substituents proceeded smoothly to fused heterobicyclic products (5g–h).
2

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HETEROCYCLES, Vol. 65, No. 1, 2005
Interestingly, the reaction between 1,3-cyclohexanedione (1), benzaldehyde (3a), and urea (2b) proceeded
smoothly to give fused heterocyclic scaffold product (5i) in yield 86%, and no other product was detected.
Aromatic aldehydes carrying either electron-donating or electron-withdrawing substituents in the ortho or
meta positions (3f-i) proceeded smoothly to give a family of fused bicyclical rings (products: 5j-p) in
good yields; no spiro-fused heterobicyclic products were detected. Thiourea (2a) exhibited analogue
behavior to urea under similar conditions. All reactions were spontaneous under TMSCl in DMF/ MeCN
at room temperature with yields ranging from 74 to 93%. This result was in agreement with the classical
Biginelli reaction.
Our interest lead us attempt to extend the methodology to aliphatic aldehydes. Aliphatic aldehydes were
used with similar success to ortho-, meta-substituted benzaldehydes. n-Butyraldehyde (3j),
iso-butyraldehyde (3k), n-valeraldehyde (3l), iso-valeraldehyde (3m), and n-heptaldehyde (3n) afforded
fused bicyclic compounds 4-alkyl-2-thioxo-2,3,4,6,7,8-hexahydro-1H-quinazolin-5-one (5q-s) and
4
2
-alkyl-4,6,7,8- tetrahydro-1H,3H-quinazoline-2,5-dione (5t-w) with yields from 77 to 93% at 80 ℃ for
-3 h (Table 1). But aliphatic aldehydes exhibited lower activity, the reactions required higher
temperatures to convert into target compounds.
5
TMSCl shows remarkable reactivity as a Lewis acid in Biginelli reaction. We assume that steric
hindrances from the substituent in the ortho or meta positions have influenced on the formation of
products. The nucleophilic additions are more facilitated to form key intermediate (9) from
6
N-acyliminium ion intermediate (7). Subsequently, two trends are presented in Scheme 1. One is
X
X
X
TMSCl
-HCl
RCHO
TMSHN
N
R
H N
NH2
TMSHN
NHTMS
2
TMS
7
2
6
O
OTMS
8
X
O
R
O
R
O
HN
NH
NH
O
RCHO
R
R
NH
X
O
O
X
NTMS
NHTMS
R
X = O, R = 3b-e;
X = S, R = 3a-e
4
X = O, R = 3b-e;
X = S, R = 3a-e
9
X = O; S
1
0
O
R
O
R
-
TMSOH
NH
NH
N
H
X
N
H
X
TMSO
X = O, R = 3a, 3f-n;
X = S, R = 3d-n
X = O, R = 3a, 3f-n;
X = S, R = 3d-n
11
5
Scheme 1.

HETEROCYCLES, Vol. 65, No. 1, 2005
137
involving condensation of aldehyde with intermediate (10) and then nucleophilic addition to spiro-fused
heterobicyclic compounds (4). The other is cyclization to hexahydropyrimidine (11) and acid-catalyzed
elimination to fused heterobicyclic compounds (5). The steric hindrance from the substituent in the ortho
or meta position hampered nucleophilic addition to furnish spiro-fused heterobicyclic compounds (4). For
aliphatic aldehydes, ion intermediate (10) shows lower stability when R = alkyl, and is inclined to furnish
the cyclization products (5).
In summary, we have studied the reactivity of 1,3-cyclohexanedione (1) toward the Biginelli reaction in a
systematic manner. In the reaction, para-substituted benzaldehydes exhibited different chemical
behaviors to ortho-, or meta-substituted benzaldehydes and aliphatic aldehydes by using TMSCl as a
Lewis acid in DMF/MeCN. The successful reactions have expanded the synthetic scope of the
multicomponent Biginelli reaction.
EXPERIMENTAL
1. General
Reagents and all solvents were analytically pure grade and were used without further purification.
Anhydrous conditions were not required for the reaction. Melting points were measured on a XT-4 and
1
13
were uncorrected, IR spectra were recorded as KBr pellets on a NEXUS 470 FT-IR. H and C-NMR
spectra were recorded on Bruker AVANCE DMX-500 spectrometer at 500 and 125 MHz in DMSO,
respectively, chemical shifts were given in ppm (δ), TMS as internal standard and coupling constants (J)
were given in Hz, HRMS spectra were recorded with a Bruker APEX 3 system.
2
. General procedures for synthesis of fused heterobicyclic (5a-f) and spiro-fused heterocyclic
compounds (4a-f)
,3-Cyclohexanedione (1, 1.120 g, 10 mmol), thiourea (2a, 0.912 g, 12 mmol) or urea (2b, 0.720 g, 12
1
mmol), aromatic aldehydes (3a–e, 10 mmol), and DMF/MeCN (4 mL/8 mL) were mixed in a flask and
TMSCl (1.086 g, 10 mmol) was added dropwise at rt. The reaction mixture was stirred at rt for 2-3 h. The
products (4) precipitated from the reaction medium, and then isolated by a filtration from the reaction
mixture. The solution was poured into crashed ice with stirring. The precipitation (5) was filtered and
2
washed by ethanol. The products (4) and (5) were purified by recrystallization (DMSO/H O).
1
Spiro-fused heterocyclic product (4a) mp 209-211 ℃; H NMR (DMSO-d
6
) δ (ppm) 8.67 (s, 2H),
7
.33-7.32 (m, 6H), 7.00-6.99 (m, 4H), 4.98 (s, 2H), 1.82 (t, J = 6.1 Hz, 2H), 1.52 (t, J = 6.0 Hz, 2H), 0.51
1
3
(
t, J = 6.1 Hz, 2H); C NMR (DMSO- d ) δ (ppm) 210.9, 206.1, 177.9, 135.9, 129.8, 129.5, 128.6, 65.9,
6
-1
6
2.8, 43.2, 41.9; IR (KBr) 3359, 3170, 2950, 1689, 1556, 1456, 1198 cm ; HRMS: Calcd for
+
C
21
H
20
N
2
O
2
S: 365.1318 [M+H] found: 365.1310; Anal. Calcd for C21
H
20
N
2
O
2
S: C, 69.20; H, 5.53; N,
7
.69. Found: C, 69.32; H, 5.55; N, 7.72.

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HETEROCYCLES, Vol. 65, No. 1, 2005
1
Spiro-fused heterocyclic product (4b) mp 219-222 ℃; H NMR (DMSO-d
6
) δ (ppm) 8.79 (s, 2H), 7.40 (t,
J = 8.3 Hz, 4H), 6.95 (d, J = 8.2 Hz, 4H), 4.99 (s, 2H), 1.91 (m, 2H), 1.64 (m, 2H), 0.61 (t, J = 5.6 Hz,
1
3
2
H); C NMR (DMSO-d ) δ (ppm) 210.7, 206.2, 194.9, 177.9, 175.4, 151.9, 143.1, 134.8, 133.0, 130.5,
6
1
29.6, 129.2, 109.6, 65.6, 52.3, 43.3, 41.9, 37.2, 26.2, 21.4, 15.0; IR (KBr) 3422, 3240, 2924, 1630, 1565,
-1
+
1
490, 1181 cm ; HRMS Calcd for C H N O Cl S: 455.0358 [M+Na] ; found: 455.0367; Anal. Calcd
21 18 2 2 2
for C21
H
18
N
2
O
2
Cl
2
S: C, 58.20; H, 4.19; N, 6.46. Found: C, 58.32; H, 4.25; N, 6.38.
1
Spiro-fused heterocyclic product (4c) mp 242-245 ℃; H NMR (DMSO-d
6
) δ (ppm) 8.56 (s, 2H),
1
3
7
.12-7.10 (m, 8H), 4.92 (s, 2H), 2.51 (s, 6H), 1.92-1.83 (m, 2H), 1.54 (m, 2H), 0.55 (m, 2H); C NMR
(
DMSO-d ) δ (ppm) 211.0, 194.8, 175.3, 151.5, 141.3, 139.0, 137.6, 132.9, 130.0, 129.9, 128.4, 127.2,
6
1
1
C
10.1, 65.9, 62.9, 62.6, 52.5, 37.3, 26.2, 31.6, 21.5, 14.8; IR (KBr) 3431, 3246, 2921, 1629, 1567, 1460,
-1
+
374 cm ; HRMS Calcd for C H N O S: 393.1631 [M+H] ; found: 393.1627; Anal. Calcd for
2
3
24
2
2
23
H
24
N
2
O
2
S: C, 70.38; H, 6.16; N, 7.14. Found: C, 70.57; H, 6.13; N, 7.20.
1
Spiro-fused heterocyclic product (4d) mp 190-192 ℃; H NMR (DMSO-d
6
) δ (ppm) 7.15-7.14 (d, J= 7.8
Hz, 4H), 6.90 (d, J = 7.8 Hz, 4H), 5.01 (s, 2H), 2.25 (s, 6H), 1.82 (t, J = 6.1 Hz, 2H), 1.57 (t, J = 6.1 Hz,
1
3
2
1
6
H), 0.56 (t, J = 6.2 Hz, 2H); C NMR (DMSO-d ) δ (ppm) 210.8, 206.5, 157.3, 139.2, 133.4, 130.7,
-1
29.6, 128.3, 126.6, 66.9, 62.1, 43.3, 42.0, 21.6, 14.9; IR (KBr) 3428, 2922, 1686, 1650, 1511, 1206 cm ;
+
HRMS Calcd for C23
H
24
N
2
O
3
: 377.1860 [M+H] ; found: 377.1865; Anal. Calcd for C23
H
24
N
2
O
3
: C,
7
3.38; H, 6.43; N, 7.44. Found: C, 73.49; H, 6.38; N, 7.35.
1
Spiro-fused heterocyclic product (4e) mp 268-270 ℃; H NMR (DMSO-d
.02 (s, 2H), 1.85 (t, J=6.3 Hz, 2H), 1.63 (t, J = 6.2 Hz, 2H), 0.60 (t, J = 6.3 Hz, 2H); C NMR
DMSO-d ) δ (ppm) 211.2, 206.2, 164.0 and 162.0 (split), 156.4, 133.4, 130.6, 130.5, 116.5, 116.4, 67.7,
6
) δ (ppm) 7.19-7.04 (m, 8H),
1
3
5
(
6
-1
6
2.1, 43.4, 42.0, 15.1; IR (KBr) 3421, 3265, 2921, 1672, 1621, 1376, 1240 cm ; HRMS Calcd for C21H
18
+
N
2
O
3
F
2
: 385.1106 [M+H] ; found:385.1113; Anal. Calcd for C21
H
18
N
2
O
3
F
2
: C, 65.62; H, 4.72; N, 7.29.
Found: C, 65.37; H, 4.79; N, 7.17.
Spiro-fused heterocyclic product (4f) mp 218-221 ℃; H NMR (DMSO-d
.32-7.29 (m, 6H), 5.22 (s, 2H), 1.92 (t, J = 6.0 Hz, 2H), 1.65 (t, J = 5.5 Hz, 2H), 0.56 (t, J = 6.0 Hz, 2H);
1
6
) δ (ppm) 8.22-8.18 (m, 4H),
7
1
3
C NMR (DMSO-d ) δ (ppm) 210.7, 205.6, 156.1, 148.5, 144.5, 130.0, 128.6, 124.7, 57.3, 52.5, 43.2,
6
-1
4
18 4 7
1.9, 15.2; IR (KBr) 3244, 2921, 1686, 1523, 1350 cm ; HRMS Calcd for C21H N O : 439.1248
+
[
M+H] ; found: 439.1255; Anal. Calcd for C21
H
18
N
4
O
7
: C, 57.53; H, 4.14; N, 12.78. Found: C, 57.72; H,
4
3
1
.07; N, 12.90.
. General procedures for synthesis of fused heterobicyclic compounds (5g-w)
,3-cyclohexanedione (1, 1.120 g, 10 mmol), thiourea (2a, 0.912 g, 12 mmol) or urea (2b, 0.720 g, 12
mmol), aldehydes (3e–n, 10 mmol), and DMF/MeCN (4 mL/8 mL) were mixed in a flask and TMSCl
1.086 g, 10 mmol) was added dropwise at rt. The resulting reaction mixture was stirred at 80 ℃for 3 h,
(

HETEROCYCLES, Vol. 65, No. 1, 2005
139
cooled into rt, and then poured into crashed ice with stirring. The precipitation was isolated by filtered
through a Buechner funnel and washed with ethanol, and then dried to give the crystalline powder.
Purification by recrystallization (DMSO/H
2
O) gave the products (5g-w)
1
Fused heterocyclic product (5g) mp 278-280 ℃; H NMR (DMSO-d
6
) δ (ppm) 10.63 (s, 1H), 9.68 (s, 1H),
7
.24 (t, J = 7.9 Hz, 2H), 7.17-7.14 (m, 2H), 5.18 (s, 1H), 2.55-2.50 (m, 2H), 2.31-2.20 (m, 2H), 1.94-1.81
1
3
(
6
m, 2H); C NMR (DMSO-d ) δ (ppm) 195.0, 175.4, 163.4 and 161.5 (split), 151.8, 140.5, 133.4, 129.5,
-
1
1
17.5, 116.4, 109.9, 52.3, 37.3, 26.3, 21.5; IR (KBr) 3432, 3248, 2921, 1625, 1454, 1180 cm ; HRMS
+
13 2 13 2
Calcd for C14H N OFS: 299.0625 [M+Na] ; found: 299.0635; Anal. Calcd for C14H N OFS: C, 60.85;
H, 4.74; N, 10.14. Found: C, 61.02; H, 4.81; N, 10.05.
1
Fused heterocyclic product (5h) mp 261-263℃; H NMR (DMSO-d
6
) δ (ppm) 10.76 (s, 1H), 9.78 (s, 1H),
8
2
1
.21 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 5.33 (d, J = 2.5 Hz, 1H), 2.52 (m, 2H), 2.32-2.20 (m,
1
3
H), 1.95-1.92 (m, 1H), 1.82-1.80 (m, 1H); C NMR (DMSO-d ) δ (ppm) 194.9, 175.7, 152.3, 151.2,
6
47.8, 128.7, 124.8, 109.1, 52.6, 37.2, 26.3, 21.4; IR (KBr) 3429, 3180, 2953, 1635, 1566, 1348, 1176
-1
+
13 3 3 13 3 3
cm ; HRMS Calcd for C14H N O S: 304.0750 [M+H] ; found: 304.0746; Anal. Calcd for C14H N O S:
C, 55.43; H, 4.32; N, 13.85. Found: C, 55.60; H, 4.38; N, 13.78.
1
Fused heterocyclic product (5i) mp 282-285 ℃; H NMR (DMSO-d
6
) δ (ppm) 9.49 (s, 1H), 7.77 (s, 1H),
7
1
5
.31-7.17 (m, 5H), 5.17 (d, J = 2.6 Hz, 1H), 2.49-2.43 (m, 2H), 2.27-2.19 (m, 2H), 1.92-1.90 (m, 1H),
1
3
.81-1.79 (m, 1H); C NMR (DMSO-d ) δ (ppm) 194.2, 155.4, 152.8, 145.6, 129.3, 128.9, 127.2, 109.5,
6
-1
2.7, 37.4, 26.8, 21.8; IR (KBr) 3431, 3232, 2953, 1697, 1607, 1379, 1243, 1190 cm ; HRMS Calcd for
+
C
14
H
14
N
2
O
2
: 265.0947 [M+Na] ; found: 265.0943; Anal. Calcd for C14
H
14
N
2
O
2
: C, 69.41; H, 5.82; N,
11.56. Found: C, 69.53; H, 5.79; N, 11.48.
1
Fused heterocyclic product (5j) mp 286-288 ℃; H NMR (DMSO-d
6
) δ (ppm) 10.60 (s, 1H), 9.60 (s, 1H),
7
1
1
.38-7.12 (m, 4H), 5.39 (s, 1H), 2.57-2.49 (m, 2H), 2.26-2.14 (m, 2H), 1.95-1.91 (m, 1H), 1.82-1.80 (m,
1
3
H); C NMR (DMSO-d ) δ (ppm) 194.6, 175.1, 161.6 and 159.6 (split), 151.9, 131.0, 130.7, 130.4,
6
-1
25.4, 116.6, 108.5, 48.4, 37.2, 26.2, 21.5; IR (KBr) 3429, 3273, 2921, 1621, 1566, 1460, 1178 cm ;
+
HRMS Calcd for C14
H
13
N
2
OFS: 277.0805 [M+H] ; found: 277.0805; Anal. Calcd for C14
H
13
2
N OFS: C,
6
0.85; H, 4.74; N, 10.14. Found: C, 61.01; H, 4.80; N, 10.21.
1
Fused heterocyclic product (5k) mp 278-281℃; H NMR (DMSO-d
.29-7.10 (m, 4H), 5.39 (s, 1H), 2.48-2.46 (m, 2H), 2.25-2.12 (m, 2H), 2.07-1.82 (m, 2H); C NMR
DMSO-d ) δ (ppm) 193.9, 161.7 and 159.7 (split), 155.9, 152.2, 132.1, 130.2, 130.1 125.3, 116.5, 107.5,
6
) δ (ppm) 9.54 (s, 1H), 7.70 (s, 1H),
1
3
7
(
6
-
1
4
8.3, 37.7, 26.8, 21.8; IR (KBr) 3431, 3229, 2923, 1695, 1604, 1378, 1193 cm ; HRMS Calcd for
+
C
14
H
13
N
2
O
2
F: 283.0852 [M+Na] ; found: 283.0847; Anal. Calcd for C14
H
13
N
2
O
2
F: C, 64.61; H, 5.03; N,
10.76. Found: C, 64.32; H, 5.01; N, 10.73.

140
HETEROCYCLES, Vol. 65, No. 1, 2005
1
Fused heterocyclic product (5l) mp 289-292 ℃; H NMR (DMSO-d
6
) δ (ppm) 10.63 (s, 1H), 9.56 (s, 1H),
7
2
1
.56 (d, J = 8.0 Hz, 1H), 7.36-7.17 (m, 3H), 5.55 (d, J = 2.2 Hz, 1H), 2.59-2.49 (m, 2H), 2.24-2.16 (m,
1
3
H), 2.07-1.84 (m, 2H); C NMR (DMSO-d
6
) δ (ppm) 194.5, 174.9, 152.1, 142.7, 133.7, 130.8, 130.5,
29.2, 123.4, 109.3, 53.8, 37.3, 26.2, 21.5; IR (KBr) 3422, 3156, 2995, 1617, 1559, 1458, 1374, 1174
-1
+
13 2
cm ; HRMS Calcd for C14H N OBrS: 337.0005 [M+H] ; found: 337.0001; Anal. Calcd for
C
14
H
13
N
2
OBrS: C, 49.86; H, 3.89; N, 8.31. Found: C, 48.98; H, 3.79; N, 8.28.
1
Fused heterocyclic product (5m) mp 240-243 ℃; H NMR (DMSO-d
6
) δ (ppm) 9.58 (s, 1H), 7.63 (s, 1H),
7
1
1
2
.55 (t, J = 9.2 Hz, 1H), 7.33-7.30 (m, 1H), 7.26-7.24 (m, 1H), 7.19-7.07 (m, 1H), 5.54 (d, J = 1.6 Hz,
1
3
H), 2.51-2.48 (m, 2H), 2.21-2.13 (m, 2H), 1.93-1.86 (m, 2H); C NMR (DMSO-d
6
) δ (ppm) 193.9,
62.6, 156.2, 151.9, 143.7, 133.7, 130.2, 129.2, 123.4, 108.3, 53.6, 36.8, 31.8, 21.8; IR (KBr) 3411, 3297,
-1
+
13 2 2
945, 1658, 1619, 1358, 1176 cm ; HRMS Calcd for C14H N O Br: 320.9339 [M+H] ; found: 320.9345;
Anal. Calcd for C14
H
13
N
2
O
2
Br: C, 52.36; H, 4.08; N, 8.72. Found: C, 52.44; H, 4.09; N, 8.78.
1
Fused heterocyclic product (5n) mp 278-280 ℃; H NMR (DMSO-d
6
) δ(ppm) 10.49 (s, 1H), 9.18 (s, 1H),
7
2
1
2
3
.24 (t, J = 7.45 Hz, 1H), 7.00 (t, J = 8.7 Hz, 2H), 6.86 (t, J = 7.3 Hz, 1H), 5.43 (s, 1H), 3.79 (s, 3H),
1
3
.59-2.46 (m, 2H), 2.47-2.17 (m, 2H), 1.94-1.87 (m, 2H); C NMR (DMSO-d
6
) δ (ppm) 194.6, 175.2,
57.9, 152.3, 131.0, 130.4, 128.9, 121.1, 112.4, 108.3, 56.5, 49.0, 37.3, 26.2, 21.6; IR (KBr) 3366, 3169,
-1
+
16 2 2
924, 1606, 1555, 1461, 1375, 1175 cm ; HRMS Calcd for C15H N O S: 311.0825 [M+Na] ; found:
11.0825; Anal. Calcd for C15
H
16
N O
2 2
S: C, 52.36; H, 4.08; N, 8.72. Found: C, 52.44; H, 4.15; N, 8.87.
1
Fused heterocyclic product (5o) mp 255-257 ℃; H NMR (DMSO-d
6
) δ (ppm) 9.65 (s, 1H), 8.10(t, J =8.0
Hz, 2H), 7.92 (s, 1H), 7.70-7.61 (m, 2H), 5.33 (d, J = 2.0 Hz, 1H), 2.52-2.18 (m, 4H), 1.94-1.80 (m, 2H);
1
3
6
C NMR(DMSO-d ) δ (ppm) 194.4, 156.2, 152.4, 148.7, 147.6, 134.0, 131.1, 123.2, 121.9, 108.4, 52.4,
-
1
3
7.1, 26.8, 21.6; IR (KBr) 3431, 3254, 2925, 1705, 1618, 1530, 1349, 1191 cm ; HRMS Calcd for
+
C
14
H
13
N
3
O
3
S: 304.0750 [M+H] ; found: 304.0759; Anal. Calcd for C14
H
13
N
3
O
3
S: C, 55.43; H, 4.32; N,
1
3.85. Found: C, 55.60; H, 4.46; N, 13.75.
Fused heterocyclic product (5p) mp 289-292 ℃; H NMR (DMSO-d
.44-8.06(m, 4H), 5.35 (s, 1H), 2.54-2.51 (m, 2H), 2.32-2.24 (m, 2H), 1.96-1.82 (m, 2H); C NMR
DMSO-d ) δ (ppm) 197.4, 166.5,151.3, 147.5, 135.6, 130.6, 123.7, 122.4, 115.4, 37.2, 32.4, 27.4, 20.8;
IR (KBr) 3425, 2922, 1671, 1532, 1351 cm ; HRMS Calcd for C14
1
6
) δ (ppm) 10.78 (s, 1H), 9.82 (s, 1H),
1
3
8
(
6
-1
+
13 3 4
H N O : 310.0798 [M+Na] ; found:
3
10.0791; Anal. Calcd for C14
H
13
N O
3 4
: C, 58.53; H, 4.56; N, 14.63. Found: C, 58.39; H, 4.68; N, 14.77.
1
Fused heterocyclic product (5q) mp: 223-226 ℃; H NMR (DMSO-d
6
) δ (ppm) 10.31 (s, 1H), 9.25 (s,
1
0
2
H), 4.15 (s, 1H), 2.40 (t, J = 4.8 Hz, 2H), 2.24 (t, J = 5.6 Hz, 2H), 1.91-1.80 (m, 2H), 1.39-1.17 (m, 4H),
1
3
.82 (t, J = 7.2 Hz, 3H); C NMR (DMSO-d
6
) δ (ppm) 195.1, 176.0, 152.0, 109.6, 49.6, 39.3, 37.4, 26.2,
-1
1.7, 17.5, 14.8; IR (KBr) 3255, 3131, 2924, 1657, 1621, 1400, 1184 cm ; HRMS Calcd for C11
16 2
H N OS:

HETEROCYCLES, Vol. 65, No. 1, 2005
141
+
2
16 2
25.1056 [M+H] ; found: 225.1059; Anal. Calcd for C11H N OS: C, 58.90; H, 7.19; N, 12.49. Found: C,
5
8.67; H, 7.02; N, 12.73.
1
Fused heterocyclic product (5r) mp 227-229 ℃; H NMR (DMSO-d
6
) δ (ppm) 10.32 (s, 1H), 9.26 (s, 1H),
1
3
4
.15 (d, J = 2.9Hz, 1H), 2.52-2.23 (m, 4H), 1.90-1.89 (m, 2H), 1.40-1.14 (m, 6H), 0.84-0.77 (m, 3H); C
NMR (DMSO-d ) δ (ppm) 195.1, 175.9, 152.0, 109.5, 49.7, 37,3, 36.6, 26.3, 23.0, 21.3, 21.0, 14.9; IR
6
-1
+
(
18 2
KBr) 3252, 3180, 2924, 1646, 1625, 1401, 1181 cm ; HRMS Calcd for C12H N OS: 239.1213 [M+H] ;
found: 239.1220; Anal. Calcd for C12
1.66.
H
18
N
2
OS: C, 60.47; H, 7.61; N, 11.75. Found: C, 60.64; H, 7.75; N,
1
1
Fused heterocyclic product (5s) mp 220-223 ℃; H NMR (DMSO-d
6
) δ (ppm) 10.36 (s, 1H), 9.34 (s, 1H),
4
1
4
.15 (t, J = 3.8 Hz, 1H), 2.42 (m, 2H), 2.24-2.22 (m, 2H), 1.91-1.63 (m, 3H), 1.32-1.28 (m, 1H),
1
3
.10-1.06 (m, 1H), 0.87-0.83 (m, 6H); C NMR (DMSO-d ) δ (ppm) 196.7, 177.7, 153.6, 112.5, 49.5,
6
-1
8.2, 39.1, 28.0, 26.3, 25.5, 24.8, 23.4; IR (KBr) 3243, 2951, 1624, 1575, 1462, 1179 cm ; HRMS Calcd
+
for C12
H
18
N
2
OS: 239.1213 [M+H] ; found: 239.1218; Anal. Calcd for C12
H
18
N
2
OS: C, 60.47; H, 7.61; N,
11.75. Found: C, 60.32; H, 7.74; N, 11.59.
1
Fused heterocyclic product (5t) mp 250-253 ℃; H NMR (DMSO-d
6
) δ (ppm) 10.31 (s, 1H), 9.25 (s, 1H),
4
7
.15 (s, 1H), 2.39-2.35 (m, 2H) , 2.23-2.20 (m, 2H), 1.91-1.80 (m, 2H), 1.39-1.17 (m, 4H), 0.83 (t, J =
1
3
.2Hz, 3H); C NMR (DMSO-d ) δ (ppm) 195.1, 155.5, 153.3, 109.1, 49.2, 37.3, 26.8, 21.6, 17.5, 14.8;
6
-
1
16 2 2
IR (KBr) 3427, 3244, 2929, 1715, 1634, 1380, 1184 cm ; HRMS Calcd for C11H N O : 231.1104
+
[
M+Na] ; found: 231.1105; Anal. Calcd for C11
H
16
N
2
O
2
: C, 63.44; H, 7.74; N, 13.45. Found: C, 63.52; H,
7
.82; N, 13.56.
1
Fused heterocyclic product (5u) mp 246-249 ℃; H NMR (DMSO-d
6
) δ (ppm) 9.18 (s, 1H), 7.27 (s, 1H),
1
3
3
.98 (s, 1H), 2.36-2.22 (m, 4H), 1.91-1.66 (m, 3H), 0.80 (d, J = 6.6 Hz, 3H), 0.69 (d, J = 6.5 Hz, 3H); C
NMR (DMSO-d ) δ (ppm) 194.5, 156.0, 153.7, 108.2, 54.5, 37.4, 34.5, 26.8, 21.8, 19.5, 16.6; IR (KBr)
6
-1
+
3
436, 3247, 2961, 1703, 1612, 1386, 1250, 1192 cm ; HRMS Calcd for C H N O : 231.1104 [M+Na] ;
11 16 2 2
found: 231.1100; Anal. Calcd for C11
3.61.
H
16
N
2
O
2
: C, 63.44; H, 7.74; N, 13.45. Found: C, 63.32; H, 7.68; N,
1
1
Fused heterocyclic product (5v) mp 264-267 ℃; H NMR (DMSO-d
6
) δ (ppm) 10.37 (s, 1H), 9.34 (s, 1H),
4
1
.15 (t, J = 3.8 Hz, 1H), 2.42 (s, 2H), 2.23 (t, J = 6.0 Hz, 2H), 1.91-1.80 (m, 1H), 1.79 (d, J = 6.2 Hz, 1H),
1
3
6
.66-1.63 (m, 1H), 1.32-1.28 (m, 1H), 1.10-1.06 (m, 1H), 0.85 (q, J = 6.4 Hz, 6H); C NMR (DMSO-d )
δ (ppm) 196.7, 177.7, 153.6, 112.5, 49.5, 18.3, 39.1, 28.0, 26.3, 25.5, 24.8, 23.5; IR (KBr) 3211, 2802,
-1
+
1
18 2 2
706, 1631, 1405, 1243, 1190 cm ; HRMS Calcd for C12H N O : 223.1441 [M+H] ; found: 223.1447;
Anal. Calcd for C12
H
18
N
2
O
2
: C, 64.84; H, 8.16; N, 12.60. Found: C, 64.96; H, 8.19; N, 12.73.
1
Fused heterocyclic product (5w) mp 189-191 ℃; H NMR (DMSO-d
6
) δ (ppm) 9.18 (s, 1H), 7.29 (s, 1H),
1
3
4
.10 (s, 1H), 2.49-2.19 (m, 4H), 1.90-1.79 (m, 2H), 1.34-1.29 (m, 10H), 0.84 (t, J = 12.6 Hz, 3H); C

142
HETEROCYCLES, Vol. 65, No. 1, 2005
NMR (DMSO-d
6
) δ (ppm) 194.3, 155.4, 153.2, 109.1, 49.3, 37.4, 37.3, 32.2, 29.6, 26.7, 24.3, 23.0, 21.9,
-1
1
4.9; IR (KBr) 3432, 3250, 2923, 1715, 1639, 1384, 1191 cm ; HRMS Calcd for C H N O : 251.1754
14 22 2 2
+
[
M+H] ; found: 251.1751; Anal. Calcd for C14
22 2 2
H N O : C, 67.17; H, 8.86; N, 11.19. Found: C, 67.33; H,
8
.80; N, 11.08.
ACKNOWLEDGEMENTS
This research was funded by NSFC of China (20375036) and NSF of Zhejiang Province (Rc0042)
REFERENCES AND NOTES
1
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3
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4
559.
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(a) S. I. Zavyalov and L. B. Kulikova, Khim.-Farm. Zh., 1992, 26; (b) G. Sabitha, G. S. Kiran Kumar
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5
C. O. Kappe, J. Org. Chem., 1997, 62, 7201.