10126
I.A. Khan et al. / Tetrahedron 68 (2012) 10122e10129
afford the pure product 7 as a white powder (0.31 g, 40%). The fil-
trate was evaporated in vacuo and washed the with 10 ml water
and extracted with EtOAc (2ꢀ20 ml). The organic layer was dried
over sodium sulfate (anhyd) and concentrated under pressure to
obtain crude substance, which was subjected to flash chromatog-
raphy (EtOAc/hexane 60:40) to obtain compound 10, 8, and 9 at 24,
(d, J¼8.0 Hz, 1H, ArH), 7.47e7.36 (m, 1H, ArH), 7.28e7.14 (m, 2H,
13
ArH), 2.47 (s, 3H, SMe); C NMR (40 MHz, DMSO-d
6
þCDCl
3
, ppm)
d
164.15, 162.11, 159.21, 156.48, 138.55, 135.73, 121.53, 121.30,
115.44, 106.68, 106.52, 83.88, 13.01; ESI-MS 287.4 (Mþ1), 271
(Mꢂ18); HRMS calculated for C13
10
H N
4
O
2
S: 286.0524, found:
286.0521.
4
0 min, 84 min in 1e2%, 8% and 14% whereas the mixture of com-
0
0
0
0
0
pound 11 and 12 was found to be contained in the fractions be-
tween 5 and 18 min. The fractions of 5e18 min was collected,
concentrated, and subjected to flash chromatography (EtOAc/hex-
ane 40:60) to obtain 11 and 12 in 19% and 11% at 20 and 32 min.
4.2.6. 6 -(Methylthio)-5 ,7a -dihydro-1 H-spiro[indoline-3,3 -iso-
0
0
xazolo[3,4-d]pyrimidine]-2,4 (3a H)-dione (11a). A solution of bo-
rane dimethylsulfide complex (10 M, 0.4 ml) was added dropwise
to a stirred solution of 11 (0.454 g, 2.0 mmol) in trifluoroacetic acid
ꢁ
(
6 ml) at 0 C in an atmosphere of nitrogen for 10 min. The reaction
0
0
ꢁ
4
.2.1. 2,2 -Bis(methylthio)-3H-spiro[pyrimido[4,5-b]quinoline-5,5 -
mixture was stirred at 30 C for another 3 h, and was then diluted
with water (0.4 ml), concentrated and basified with ammonia so-
lution. The aqueous solution was extracted with ethyl acetate
0
0
0
0
ꢁ
pyrrolo[2,3-d]pyrimidine]-4,4 ,6 (3 H,7 H,10H)-trione (7). Mp >240 C;
max, cm ): 3393, 3152, 1681, 1658, and 1637. 1H NMR
ꢂ1
IR (KBr,
300 MHz, DMSO-d
J¼5.5 Hz, 2.8, 1H, ArH), 7.20e7.02 (q, J¼5.2, 3.5 Hz, 2H, ArH),
n
(
6
, ppm): 8.29e8.06 (s, 1H, NH), 7.38e7.20 (dd,
d
(2ꢀ30 ml) dried over anhyd Na
2 4
SO on evaporating the organic
under vacuo the crude yellowish liquid was purified from flash
13
6
(
1
1
.95e6.73 (m, 1H, ArH), 2.57e2.32 (d, J¼5.6 Hz, 6H, 2SMe); C NMR
40 MHz, DMSO-d , ppm) 174.63, 173.40, 172.14, 167.56, 161.05,
57.95, 156.58, 137.59, 128.81, 126.91, 126.87, 126.15, 126.14, 126.10,
25.01, 115.07, 104.60, 101.02, 60.49, 13.26, 13.11. ESMS m/z (%): 427.1
chromatography. Yield 48%; R
neat, cm ): 3451.2, 3321.4, 2905.2, 1677.5, 1654.2, 1602.1, 1341.2,
1265.7,1097.9, 954.2; H NMR (300 MHz, DMSO-d , ppm) d 10.23 (s,
6
3H, NH), 7.41 (d, J¼7.4 Hz, 1H, ArH), 7.24 (t, J¼7.5 Hz, 1H, ArH), 6.98
(t, J¼7.3 Hz, 1H, ArH), 6.79 (d, J¼7.1 Hz, 1H, ArH), 6.17e5.98 (m, 1H,
NCHN), 5.88 (s, 1H, NH), 3.50e3.33 (m, 0.4H, cis CH), 3.24 (d,
f
0.28 (60:40, EtOAc/hexane); IR (
n
max
,
ꢂ1
6
d
1
(
4
Mþ1); HRMS calculated for
18 14 6 3 2
C H N O S :
426.0569. Found:
26.0549.
13
J¼11.9 Hz, 0.5H, trans CH), 2.55 (s, 3H, SMe); C NMR (40 MHz,
DMSO-d , ppm) 171.23e170.73, 162.38e161.88, 156.95e156.45,
144.01e143.51, 130.17e129.63, 127.66e127.16, 126.05e125.49,
123.40e122.90, 109.60e109.03, 82.28e81.62, 62.64e62.10,
14.04e13.54.; ESI-MS (Mþ1) 305.2; HRMS calculated for
S: 304.0474, found: 304.0480.
0
0
0
0
0
0
0
4.2.2. 2 ,8 -Bis(methylthio)-7 ,9a ,10 ,10a -tetrahydro-3 H-spiro[indo-
6
d
0
0
0
0
0
0
line-3,5 -pyrido[2,3-d:6,5-d ]dipyrimidine]-2,4 ,6 (4a H,5a H)-trione
ꢁ
(8). R
f
¼0.25 (EtOAc/methanol¼99:1); Mp¼190 C. IR (KBr,
n
max
1
,
ꢂ1
cm ): 3429.3, 3250.2, 1684, 1668, 1647.1, 1357.2, 1101.1, 946.1. H
NMR (300 MHz, DMSO-d
H, ArH), 7.28e7.00 (m, 2H, 2ArH), 6.70e6.40 (m, 1H, ArH), 5.74
dd, J¼8.6, 3.9 Hz, 2H, 2NCHN), 3.35 (d, J¼8.7 Hz, 2H, 2NCCH), 2.49
s, 6H, 2SMe). 13C NMR (40 MHz, DMSO-d
, ppm) 170.82, 165.32,
55.03, 139.21, 128.24, 127.67, 125.88, 120.87, 108.01, 64.03, 60.75,
6
, ppm)
d
9.71 (s, 1H, NH), 8.31e7.96 (m,
13 12 4 3
C H N O
1
(
(
0
0
4.2.7. 3-(Methylthio)-4a,5,7,11c-tetrahydropyrimido [4 ,5 :3,4] [1,2]
oxazino[6,5-b]indol-1(2H)-one (12a). Similar procedure of 11a for-
mation was carried out using 12. Yield 36%; yellow liquid; IR (
neat, cm ); isolation with flash chromatography (EtOAc/
6
d
1
4
C
n
max
,
ꢂ1
0.66, 13.68. ESMS: 431.2 (Mþ1); HRMS calculated for
18
H
18
N
6
O
3
S
2
: 430.5039; found 430.5045 along with the molecular
hexane¼90:10); R
f
¼0.25 (EtOAc/methanol¼99:1); IR (KBr,
n
max
1
,
þ
ꢂ1
ion peak MþNa was also obtained; HRMS calculated for
cm ): 3429.3, 3240.2, 1674, 1643, 1611.1, 1347.2, 1191.1, 936.1. H
C
18
H
18
N
6
O
3
S
2
Na: 453.4937; found 453.4954.
NMR (300 MHz, DMSO-d
6
, ppm) d 7.69e7.45 (m, 1H, ArH),
7
.34e7.16 (m, 1H, ArH), 7.13e6.92 (m, 2H, 2ArH), 6.07e5.83 (dd,
0
0
0
0
0
0
4
.2.3. 2 ,8 -Bis(methylthio)-10 ,10a -dihydro-3 H-spiro[indoline-3,5 -
J¼7.5, 4.5 Hz, 1H, CH), 4.69e4.47 (br s, 1H, NH), 4.29e4.16 (d,
0
0
0
0
0
pyrido[2,3-d:6,5-d ]dipyrimidine]-2,4 ,6 (4a H,7 H)-trione
9). Yellow solid; R
J¼7.8 Hz, 0.6H, CH), 4.14e4.03 (d, J¼7.8 Hz, 0.4H, CH), 2.53e2.34 (s,
ꢁ
13
13
(
f
¼0.30 (EtOAc/methanol¼99:1); Mp¼190 C. IR
3H, SCH
3 6
); C NMR (75 MHz, DMSO-d , ppm). C NMR (40 MHz,
ꢂ1
(
KBr,
n
max, cm ): 3439.3, 3250.2, 1674, 1660, 1644.1, 1337.2, 1101.1,
DMSO-d ) d 170.87, 160.80, 151.41, 146.86, 133.18, 124.24, 120.52,
6
1
9
(
46.1. H NMR (300 MHz, DMSO-d
d, J¼7.8 Hz, 1H, ArH), 7.19 (t, J¼7.5 Hz, 1H, ArH), 7.13e6.98 (m, 2H,
ArH), 5.40 (dd, J¼8.7, 3.7 Hz, 1H, NCHN), 3.10 (d, J¼8.7 Hz, 1H,
6
, ppm)
d
10.48 (s, 1H, NH), 7.28
114.67, 108.20, 102.87, 66.79, 66.75, 34.62, 13.83; ESI-MS (Mþ1)
289.5; HRMS calculated for
288.0688.
13 12 4 2
C H N O S: 288.0681, found:
13
NCCH), 2.52 (s, 3H, SMe), 2.45 (s, 3H, SMe). C NMR (40 MHz,
DMSO-d , ppm) 180.36, 167.31, 160.96, 157.61, 157.31, 157.03,
0
6
d
4.2.8. Reduction of 2,2 -bis(methylthio)-3H-spiro[pyrimido[4,5-b]
0
0
0
0
0
1
6
56.73, 150.18, 138.81, 131.78, 128.00, 123.85, 122.33, 107.75, 83.55,
quinoline-5,5 -pyrrolo[2,3-d]pyrimidine]-4,4 ,6 (3 H,7 H,10H)-trione
(7). The compound 7 (1.0 mmol) was added to a mixture of dry
aluminium chloride (2.0 mmol) and LAH (0.5 mmol) in 25 ml of dry
dioxane, which had been refluxed for 8e9 h, 0.25 ml of tert-butanol
was added and refluxed for 1.5 h then the mixture was stirred
overnight. A conventional workup was performed, yielding
a product mixture, which immediately was taken for flash
chromatography.
0.72, 49.32, 44.04, 13.24, 12.81; ESI-MS 429.1 (Mþ1); HRMS cal-
culated for C18
H
16
N
6
O
S
3 2
: 428.0725, found: 428.0731.
0
0
0
4
.2.4. 6 -(Methylthio)-1 H-spiro-[indoline-3,3 -isoxazolo[3,4-d]-py-
0
0
rimidine]-2,4 (5 H)-dione (11). Liquid;
R
f
¼0.40 (EtOAc/meth-
ꢂ1
anol¼99:1); IR (neat,
n
max, cm ): 3429.3, 3250.2, 1684, 1668,
1
1
647.1, 1357.2, 1101.1, 946.1; H NMR (300 MHz, DMSO-d
6
, ppm)
d
7.14 (d, J¼7.4 Hz, 2H, ArH), 7.04 (d, J¼7.5 Hz, 1H, ArH), 6.93 (t,
13
0 0 0
4.2.8.1. 2,2 -Bis(methylthio)-7 ,7a ,10,10a-tetrahydro-3H-spiro-
J¼7.3 Hz, 1H, ArH), 2.36 (s, 3H, SMe); C NMR (40 MHz, DMSO-
þCDCl , ppm) 172.17, 162.45, 159.44, 155.86, 144.09, 127.73,
27.44, 125.58, 122.93, 110.80, 88.88, 86.85, 12.54; ESI-MS 289.4
0 0
[pyrimido[4,5-b]quinoline-5,5 -pyrrolo[2,3-d]pyrimidine]-4,4 ,
d
1
6
3
d
0
0
0
1
6 (3 H,4aH,4a H)-trione (7a). Yield¼32%;
H NMR (300 MHz,
(
Mþ1), 271 (Mꢂ18); HRMS calculated for C13
H
12
N
4
O
2
S: 288.0681,
DMSO-d , ppm)
6
d
¼8.14e7.86 (d, J¼6.7 Hz, 1H, ArH), 7.86e7.58 (d,
found: 288.0675.
J¼7.5 Hz, 1H, ArH), 7.25e7.10 (t, J¼6.8 Hz, 2H, ArH), 7.08e6.92 (t,
J¼7.7 Hz, 1H, ArH), 6.52e6.36 (br s, 1H, NH), 6.25e6.07 (m, 1H, CH),
5.88e5.59 (d, J¼3.3 Hz, 1H, CH), 4.06e3.83 (s, 1H, ArH), 3.41e3.23
0
0
4
.2.5. 3-(Methylthio)-5,7-dihydropyrimido[4 ,5 :-3,4][1,2]oxazine
13
[6,5-b]indol-1(2H)-one (12). Yellow liquid; R
f
¼0.45 (EtOAc/meth-
(s, 6H, 2SMe), 2.56e2.31 (s, 6H, 2SMe); C NMR (40 MHz, DMSO-
ꢂ1
anol¼99:1); IR (KBr,
n
max, cm ): 3429.3, 3250.1, 1674, 1668, 1645.1,
d
6
, ppm)
d 173.87, 165.60, 165.34, 163.01, 155.34, 130.41, 126.55,
1
1
6
355.2, 1100.1, 947.1. H NMR (300 MHz, DMSO-d , ppm) d 7.50
124.85, 117.87, 114.92, 76.47, 58.87, 53.28, 40.68, 13.56, 13.05; ESMS: