2-(Benzylsulfanyl)-6-chloro-9-isopropylpurine, a Precursor of 2,6-Diaminopurine CDK Inhibitors
FULL PAPER
resulting solution was cooled to –50 °C. DIAD (0.33 mL,
1.6 mmol) was added dropwise under nitrogen at the same tem-
perature with stirring continued for 15 minutes then 2-propanol
(0.12 mL, 1.6 mmol) was added dropwise to the yellow mixture at –
50 °C. The resulting solution was gradually warmed to room tem-
perature and stirred for 3 days under nitrogen. Following evapora-
tion to full dryness the oily residue was purified by flash column
chromatography on silica gel using petroleum ether (40–60 °C),
then EtOAc/Petroleum ether (1:1) to afford the 9-isopropylpurine
12a as a pale yellow solid (320 mg, 69%); m.p. 76–78 °C; Rf
3292 m, 3066 m, 3034 m, 2964s, 2921s, 2874 m, 2811 m, 1871 w,
1623 vs, 1586 vs, 1460 m, 1409s, 1370 m, 1314 vs, 1284 vs, 1253 s,
1200 m, 1174 m, 1152 m, 1112 s, 1074 m, 965 m, 870 m, 802 w,
791 w, 777 w, 752 m, 716 w, 697 s, 671 m, 697 s, 631 m, 589 w, 577
w, 559 w, 512 s. C20H27N5O3S: calcd. C 57.53, H 6.52, N 16.77, S
7.68; found C 57.60, H 6.41, N 16.98, S 7.37.
2-(Benzylsulfanyl)-6-(3-chlorophenylamino)-9-isopropylpurine (14):
To a mixture of 6-chloropurine 12a (250 mg, 0.79 mmol) in n-buta-
nol (10 mL) was added m-chloroaniline (0.12 mL, 1.18 mmol) then
concentrated hydrochloric acid (2 drops) and the solution was
stirred at 120 °C for 24 hours. Following cooling of the resulting
mixture and evaporation to full dryness into a dark oil, flash col-
umn chromatography on silica gel using petroleum ether (40–60 °C)
then EtOAc/petroleum ether (1:1) afforded the 6-anilinopurine 14
as a pale yellow foam (316 mg, 98%); Rf [EtOAc/petroleum ether
1
[EtOAc/hexane, 2:1] = 0.38. H NMR (300 MHz, MeOD, 25 °C):
3
δ= 1.47 [d, J(H,H) = 6.7 Hz, 6 H, methyls C(CH3)2], 4.28 (s, 2 H,
3
PhCH2S–), 4.73 (septet, JH,H = 6.7 Hz, 1 H, purine CHMe2),
7.00–7.13 (m, 3 H, aromatics PhCH2S–), 7.29–7.31 (m, 2 H, aro-
matics PhCH2S–), 8.30 (s, 1 H, purine 8-H) ppm. 13C NMR
(75.4 MHz, MeOD, 25 °C): δ = 22.8 (s, methyl CHMe2), 37.1 (s,
PhCH2S–), 50.2 (s, tertiary NCHMe2), 128.6 (s, Ph C-4Ј), 129.8 (s,
Ph C-2Ј), 129.9 (s, purine C-5), 130.4 (s, Ph C-2Ј), 139.2 (s, Ph C-
1Ј), 145.4 (s, purine C-8), 151.3 (s, purine C-6), 153.9 (s, purine C-
4), 166.5 (s, purine C-2) ppm. MS (ESI+): m/z = 341.0602 [M +
1
(40Ϫ60 °C), 1:1] = 0.19. H NMR (300 MHz, [D6]DMSO, 25 °C):
3
δ = 1.52 (d, JH,H = 6.7 Hz, 6 H, methyl NCHMe2), 4.42 (s, 2 H,
3
PhCH2S–), 4.76 (s, JH,H = 6.7 Hz, 1 H, tertiary NCHMe2), 7.04
3
3
3
(ddd, JH,H = 3.1, JH,H = 2.0, JH,H = 1.0 Hz, 1 H, aniline Hb),
7.15–7.34 (m, 4 H, aromatics PhCH2S– and aniline Hd), 7.38–7.45
Na]+, C H N SClNa requires 341.0604. IR (KBr disc, cm–1): ν
˜
3
3
15 15
4
(m, 2 H, aromatics PhCH2S–), 7.81 (dd, JH,H = 7.7 Hz and JH,H
= 3106 m, 3083 m, 3050 m, 3026 m, 3022 m, 2975 m, 2925 m, 2864
m, 1780 w, 1733 w, 1693 w, 1588 vs, 1546 vs, 1495 vs, 1495 s, 1457
s, 1410 s, 1359 vs, 1240 s, 1211 s, 1186 s, 1156 s, 1132 s, 1104 s,
1081 m, 1025 m, 958 s, 895 wm, 868 s, 772 s, 703 m, 648 s, 622 s,
570 m, 565 m. C15H15ClN4S: calcd. C 56.51, H 4.74, N 17.57, S
10.06; found C 56.97, H 4.78, N 17.53, S 10.40. Crystals suitable
for X-ray crystallography were obtained by recrystallisation from
hexane.
3
3
= 3.1 Hz, 1 H, aniline He), 8.16 (dd, JH,H = 4.1 Hz and JH,H
=
2.0 Hz, 1 H, aniline Hc), 8.32 (s, 1 H, purine H8), 10.18 (s, 1 H,
aniline NH). 13C NMR (75.4 MHz, [D6]DMSO, 25 °C): δ = 22.4
(s, valinol methyl Me2CH–), 35.0 (s, valinol tertiary –CHMe2), 47.2
(s, PhCH2S–), 118.4 (s, aniline Cb), 118.7 (s, purine C-5), 120.5 (s,
aniline Cf), 123.6 (s, aniline Cd), 127.4 (s, Ph C-2Ј), 128.8 (s, Ph C-
3Ј), 129.4 (s, Ph C-4Ј), 130.2 (s, aniline Cc), 134.9 (s, aniline Ce),
137.9 (s, purine C-8), 138.3 (s, Ph C-1Ј), 141.4 (s, aniline Ca), 150.7
(s, purine C-4), 151.5 (s, purine C-6), 164.9 (s, purine C-2) ppm.
MS (ESI+): m/z = 410.1221 [M + H]+, C21H21N5SCl requires
(2R)-[2-(Benzylsulfonyl)-9H-purin-6-ylamino]-3-methylbutan-1-ol
(13): A mixture of m-chloroperbenzoic acid (284 mg, 1.15 mmol)
and magnesium sulphate (400 mg, 3.33 mmol) in DCM (5 mL) was
stirred overnight under nitrogen. Purine 12a (122 mg, 0.38 mmol)
was added and the mixture was stirred under nitrogen overnight.
Following filtration of the precipitate and washing with DCM
(50 mL), the filtrate was evaporated to full dryness into a pale yel-
low solid (MS (ESI–): m/z = 349.0534 [M – H]; C15H14ClN4O2S
requires 349.0526). The crude 2-(benzylsulfonyl)purine was dis-
solved in anhydrous THF (10 mL) then d-valinol (223 mg, 2.16
mml) was added and the resulting solution was refluxed overnight
at 90 °C under nitrogen and monitored by TLC. Evaporation to
full dryness afforded a yellow solid that was purified by flash col-
umn chromatography on silica gel using 2–10% MeOH in DCM
to afford the 6-aminopurine 13 as a colourless solid (80 mg, 44%);
410.1206. IR (KBr disc, cm–1): ν = 3321 m, 3213 m, 3112 m, 3062
˜
m, 3029 m, 2978 s, 2933 m, 1709 s, 1616 vs, 1575 vs, 1532 s, 1456
vs, 1372 s, 1325 s, 1286 s, 1268 s, 1223 m, 1197 m, 1164 m, 1132
m, 1098 m, 1077 m, 1029 s, 996 m, 948 m, 917 m, 898 w, 812 m,
788 s, 698 s, 661 m, 638 m, 610 m, 580, 564 w, 542 w, 513 w.
C21H20ClN5S: calcd. C 61.53, H 4.92, N 17.08, S 7.82; found C
61.87, H 4.74, N 17.42, S 7.52.
2-(Benzylsulfonyl)-6-(3-chlorophenylamino)-9-isopropylpurine (15):
To a stirred mixture of magnesium sulphate (1.136 g, 9.47 mmol)
and m-chloroperbenzoic acid (760 mg, 3.08 mmol) in anhydrous
DCM was added a solution of the 2-(benzylsulfanyl)purine 14
(420 mg, 1.03 mmol) in DCM (10 mL) dropwise. Overnight stirring
was continued overnight, then the precipitate was filtered off,
washed thoroughly with DCM. The combined organics were evap-
orated to full dryness into a colourless solid that was purified by
1
m.p. 176 °C; Rf [DCM/MeOH, 95:5] = 0.36. H NMR (300 MHz,
3
MeOD, 25 °C): δ = 0.95 (2d, JH,H = 6.9 Hz, 2 × 3 H, valinol
methyl Me2CH–), 1.44 (d, 3JH,H = 6.7 Hz, 6 H, methyl NCHMe2), flash column chromatography on silica gel using EtOAc/petroleum
3
2.00 [o, JH,H = 6.7 Hz, 1 H, valinol tertiary (CH3)2CH–], 3.21 (q, ether (40Ϫ60 °C9 (1:1) at first to elute the m-chlorobenzoic acid,
3JH,H = 1.5 Hz, 1 H, valinol tertiary HOCH2CHNH–), 3.70 (m, 2 then with EtOAc/petroleum ether (3:1) to afford the 2-(benzylsul-
3
H, valinol secondary HOCH2CH–), 4.28 (dd, JH,H = 11.0 Hz and
fonyl)purine 15 as a colourless foam (450 mg, 99%); m.p. 234 °C.
3
3
3JH,H = 6.1 Hz, 1 H, valinol OH), 4.70 (d, JH,H = 4.9 Hz, 1 H,
1H NMR (300 MHz, [D6]DMSO, 25 °C): δ = 1.53 (d, JH,H
=
3
valinol NH), 4.78 [septet, JH,H = 6.7 Hz, 1 H, tertiary CH(CH3)2], 6.7 Hz, 6 H, methyl NCHMe2), 4.74 (s, 2 H, PhCH2SO2–), 4.89 [s,
3
4.83 (s,
2
H, PhCH2SO2–), 7.10–7.13 (m,
3
H, aromatics 3JH,H = 6.7 Hz, 1 H, tertiary NCH(CH3)2], 7.05 (ddd, JH,H = 7.9,
3
PhCH2SO2–), 7.19–7.22 (m, 2 H, aromatics PhCH2SO2–), 8.11 (s,
1 H, purine 8-H) ppm. 13C NMR (75.4 MHz, MeOD, 25 °C): δ =
19.2 (s, valinol methyl MeCH), 20.5 (s, valinol methyl MeCH), 22.4
(s, methyl NCHMe2), 30.9 (s, valinol tertiary –CHMe2), 50.5 (s,
tertiary NCHMe2), 59.1 (s, PhCH2SO2–), 59.6 (s, valinol HNCH–),
63.7 (s, valinol HOCH2–), 129.5 (s, purine C-5), 130.1 (s, Ph C-4Ј),
131.5 (s, Ph C-2Ј), 132.7 (s, Ph C-3Ј), 135.9 (s, Ph C-1Ј), 146.7 (s,
purine C-8), 154.3 (s, purine C-6), 156.9 (s, purine C-4), 159.8 (s,
purine C-2) ppm. MS (ESI+): m/z = 418.1918 [M + H]+,
3JH,H = 1.8, JH,H = 0.8 Hz, 1 H, aniline Hb), 7.19Ϫ7.23 (m, 4 H,
aromatics PhCH2SO2– and aniline Hd), 7.27–7.33 (m, 2 H, aro-
matics PhCH2SO2–), 7.61 (ddd, 3JH,H = 8.2 Hz and 3JH,H = 2.0 Hz
3
3
and JH,H = 0.8 Hz, 1 H, aniline He), 7.87 (t, JH,H = 2.0 Hz, 1 H,
aniline He), 7.98 (s, 1 H, purine H-8), 8.14 (s, 1 H, aniline NH)
ppm. 13C NMR (75.4 MHz, [D6]DMSO, 25 °C): δ = 23.3 (s, methyl
NCHMe2), 48.2 (s, tertiary –NCHMe2), 58.2 (s, PhCH2SO2–),
118.8 (s, aniline Cb), 120.8 (s, aniline Cf), 121.8 (s, aniline Cd), 121.9
(s, purine C-5), 124.6 (s, Ph Cc), 127.6 (s, Ph C-1Ј), 129.1 (s, Ph C-
3Ј), 130.6 (s, Ph C-2Ј), 131.7 (s, Ph C-4Ј), 135.1 (s, aniline Ce), 139.4
C H N O S requires 418.1913. IR (KBr disc, cm–1): ν = 3504 m,
˜
20 28
5
3
Eur. J. Org. Chem. 2005, 939–947
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
945