A novel synthesis of tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1 H,3 H)-diones

Article abstract of DOI:10.1055/s-0033-1339977

A novel simple five-step synthesis of 1,6-disubstituted tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones has been developed. The synthetic protocol starts with 'ring switching' transformation of commercially available 5,6-dihydro-2H-pyran-2-one into

Full text of DOI:10.1055/s-0033-1339977

3404▌
PAPER
paper
A Novel Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones
Novel Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidines
Jona Mirnik,a Uroš Grošelj,*a Ana Novak,a Georg Dahmann,b Amalija Golobič,a Marta Kasunič,a Branko Stanovnik,a
Jurij Svete*a
a
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
Fax +386(1)2419360; E-mail: Jurij.svete@fkkt.uni-lj.si
b
Boehringer Ingelheim Pharma GmbH & Co. KG, Medicinal Chemistry, 88397 Biberach, Germany
Received: 19.07.2013; Accepted after revision: 18.09.2013
tor type I (Alk 4).8 Pyrazolo[1,5-c]pyrimidinones are used
Abstract: A novel simple five-step synthesis of 1,6-disubstituted
as photographic materials,9 while related 2,5-diarylpyr-
tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones has been
azolo[1,5-c]pyrimidine-7(6H)-thiones inhibit corrosion
developed. The synthetic protocol starts with ‘ring switching’ trans-
formation of commercially available 5,6-dihydro-2H-pyran-2-one
of ferrous alloys.10 In contrast to hundreds of known de-
into the 5-(2-hydroxyethyl)pyrazolidin-3-one, followed by addition rivatives of 1, the fully saturated analogues 2 are practical-
of the latter to isocyanates, Appel bromination, cyclization, and
N(1)-alkylation with alkyl halides to give the title compounds. In
comparison to a 12-step synthesis reported recently, the present
method is clearly superior with respect to the number of synthetic
steps and versatility of substituents at position 6.
ly unknown (Scheme 1).
H
N2H4•H2O
N 2
O
O
1
HN
EtOH, r.t.
O
3
5
4
2'
Key words: pyrazolo[1,5-c]pyrimidines, ring-switching, cycliza-
tion, saturated heterocycles, 3-pyrazolidinones
5
1'
HO
6
R1NCO (7a–d)
DMF, r.t.
O
H
N
O
N
R1HN
Since a plethora of different heterocyclic systems are key
constituents of naturally occurring compounds, a wide-
spread use of heterocyclic scaffolds in medicinal chemis-
try, catalysis, and material science is not surprising.1 In
this context, pyrazolo[1,5-c]pyrimidine (1) belongs to a
group of less explored systems, where most of the known
derivatives of 1 have been synthesized for application in
biological studies.2 Biologically active pyrazolo[1,5-
c]pyrimidine derivatives exhibit kinase inhibition,3 antivi-
ral,4 anticancer,5 GPR119 modulatory,6 and antibacterial
activity.7 They also possess high affinity for transforming
growth factor β type I receptor (Alk 5) and activin recep-
HO
8a–d
O
H
N
CBr4, Ph3P
CH2Cl2, r.t.
O
N
R1HN
Br
9a–d
O
H
N1
8
N
7
2
O
KOt-Bu, DMF, r.t.
R1
N
6
3
3a
4
R1
transformation
5
7a O2 10a
7b O2 10b
7c O2 10c
7d O2 10d
Ph
10a–d
R2
4-MeOC6H4
Et
7
1
8
R1
N
6 N
N
N
CH2CO2Et
N
O
N
2
R2
5
3a
O
3
4
N
2
R2X 11, DMF, K2CO3, r.t.
1
O
N
R1
R2
N
R1
CO2Me
O
alkyl halides R2X:
N
12 steps
ref. 11
R1, R2 = alkyl
N
N
4a–j
O
MeI (11a), EtI (11b), BnBr (11c),
BrCH2CO2Et (11d), ClCH2CH2NMe2•HCl (11e)
3
4
O
R2
R1
5 steps
transformation
this work
10a + 11aO2 4a
10a + 11bO2 4b
10a + 11cO2 4c
10a + 11dO2 4d
10b + 11bO2 4e
10b + 11cO2 4f
10b + 11eO2 4g
10c + 11cO2 4h
10d + 11aO2 4i
10d + 11dO2 4j
Ph
Me
Et
1 = alkyl, aryl, R2 = alkyl
Ph
R
5
Ph
Ph
Bn
CH2CO2Et
Me
Bn
CH2CH2NMe2
Bn
Me
CH2CO2Et
Scheme 1 Pyrazolo[1,5-c]pyrimidine (1), 1,6-disubstituted octahy-
dropyrazolo[1,5-c]pyrimidine (2), and 1,6-dialkyltetrahydropyrazo-
lo[1,5-c]pyrimidine-2,7(1H,3H)-diones 4 available in 12 steps from
311 or in five steps from 5
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Et
CH2CO2Et
CH2CO2Et
SYNTHESIS 2013, 45, 3404–3412
Advanced online publication: 18.10.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
Scheme 2
DOI: 10.1055/s-0033-1339977; Art ID: SS-2013-T0509-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidines
3405
In continuation of our previous work on the chemistry of room temperature to give the urea derivatives 8a–d in 73–
3-pyrazolidinones12 and the pyrazole analogues of hista- 100% yields. Next, Appel-type bromination of the alcohols
mine,13 we recently reported a 12-step transformation of 8a–d with PPh3/CBr4 in anhydrous CH2Cl2, followed by
methyl acrylate (3) into tetrahydropyrazolo[1,5-c]pyrimi- evaporation gave the crude bromoethyl intermediates 9a–
dine-2,7(1H,3H)-diones 4 as the first representatives of d. Removal of Ph3P=O form the crude bromides 9a–d by
this saturated heterocyclic system.11 Though reliable and column chromatography was successful only in the case
reproducible, this synthesis sequence is quite tedious and of 9a. On the other hand, compounds 9b–d were still con-
hardly applicable in combinatorial synthesis of title com- taminated with substantial amounts of Ph3P=O and were
pounds. Consequently, we decided to develop a concise used in subsequent step without further purification. It is
and more efficient synthesis of 4. Herein, we report an im- noteworthy, that bromides 9 were quite unstable and had
proved and substantially shortened five-step synthesis of to be transformed into 10 as soon as possible. Cyclization
title compounds 4 from commercially available 5,6-di- of 9a–d with t-BuOK in anhydrous DMF, followed by
hydro-2H-pyran-2-one (5) (Scheme 1).
column chromatography gave the 6-substituted tetrahy-
dropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones 10a–d
in 40–62% yields over two steps. Finally, SN2-type N-al-
kylation of 10a–d with alkyl halides 11a–e, followed by
isolation by flash column chromatography and purifica-
tion by medium pressure liquid chromatography fur-
nished title compounds 4a–j in 22–93% yields (Scheme 2,
Table 1).
‘Ring switching’ transformation of commercially avail-
able 5,6-dihydro-2H-pyran-2-one (5) with hydrazine hy-
drate in ethanol at room temperature gave 5-(2-
hydroxyethyl)pyrazolidin-3-one (6) in quantitative yield.
Subsequent reaction of 6 with phenyl (7a), 4-methoxy-
phenyl (7b), and ethyl isocyanate (7c) and with ethyl iso-
cyanatoacetate (7d) was performed in anhydrous DMF at
Table 1 Experimental Data for Compounds 4, 6, and 8–10
Compound R1
R2
Reaction Time (h) CC/FC/MPLC
–
Yield
Appearance
colorless oil
Mp (°C)
6
–
–
quant.a
–
8a
Ph
–
24
24
24
24
2
EtOAc
3698 mg (97%) white solid
quant.a
yellowish oil
151–152
8b
4-MeOC6H4
–
–
–
–
–
8c
Et
–
EtOAc–MeOH, 10:1
EtOAc–MeOH, 10:1
EtOAc–hexanes, 3:2
EtOAc–hexanes, 1:2
EtOAc
2247 mg (73%) colorless oil
3767 mg (95%) brown oil
8d
CH2CO2Et
–
9a
Ph
–
164 mg (75%)
yellowish solid 166–167
9ba,b
9ca,b
9da,b
10a
10b
10c
10da,b
4a
4-MeOC6H4
–
1
–
colorless oil
colorless oil
yellowish oil
–
a,b
a,b
Et
–
2
–
–
a,b
CH2CO2Et
–
1
EtOAc
–
–
Ph
–
2
EtOAc–MeOH, 5:1
EtOAc–MeOH, 5:1
EtOAc–MeOH, 5:1
EtOAc–MeOH, 5:1
EtOAc
1634 mg (62%) white solid
236–238
233–236
4-MeOC6H4
–
1
1191 mg (40%) brown solid
a,b
a,b
Et
–
1
–
–
brown solid
orange solid
white solid
white solid
white solid
–
a,b
a,b
CH2CO2Et
–
1
–
Ph
Ph
Ph
Ph
Me
48
24
24
24
48
72
228 mg (93%)
122 mg (47%)
71 mg (22%)
282 mg (89%)
242 mg (88%)
281 mg (80%)
136–137
100–101
147–148
4b
Et
EtOAc
4c
Bn
EtOAc
4d
CH2CO2Et
EtOAc
yellowish solid 120–121
yellowish solid 110–112
yellowish solid 139–140
4e
4-MeOC6H4 Me
4-MeOC6H4 Bn
EtOAc–MeOH, 10:1
EtOAc
4f
4g
4-MeOC6H4 CH2CH2NMe2 144
EtOAc–MeOH–Et3N, 50:50:1 283 mg (61%)
brown oil
orange oil
yellow oil
brown oil
–
–
–
–
4h
Et
Bn
24
24
24
EtOAc–MeOH, 10:1
EtOAc
82 mg (30%)
102 mg (40%)
288 mg (88%)
4i
CH2CO2Et
CH2CO2Et
Me
4j
CH2CO2Et
EtOAc
a Crude unpurified intermediate.
b Contaminated with residual Ph3PO.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3404–3412

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J. Mirnik et al.
PAPER
1
The structures of all novel compounds 4a–j, 6, 8a–d, 9a– pure form. Their identities were confirmed by H NMR,
d, and 10a–d were determined by spectroscopic methods 13C NMR, and HRMS analyses. The identities of the inter-
(1H and 13C NMR, MS, HRMS, IR) and elemental analy- mediates 6, 8c,d, 9a, 10a,b,d, and final products 4b,g–j
1
ses for C, H, and N. Compounds 8a, 4a, and 4c–f were ob- were established by H NMR, 13C NMR, and HRMS,
tained in analytically pure form. Compounds 6, 8b–d, 9a– whereas the crude intermediates 9b–d, and 10c were char-
d, 10a–d, and 4b,g–j were not obtained in analytically acterized only by 1H NMR spectroscopy (Tables 1–3).
Table 2 Analytical, MS, and IR Data for Compounds 4, 6, and 8–10
Compound Molecular formula, elemental analysis ESI-MS (m/z) ESI-HRMS (m/z)
IR (cm–1)
6
C5H10N2O2
130 [M+]
249 [M+]
calcd: 130.0742
found: 130.0742
3201, 2937, 2884, 1657, 1514, 1410, 1355, 1047,
961, 852, 675, 653
8a
C12H15N3O3
Calcd: C, 57.82; H, 6.07; N, 16.86
Found: C, 57.75; H, 6.11; N, 16.70
calcd: 249.1113
found: 249.1117
3282, 3164, 3116, 2840, 1714, 1649, 1596, 1540,
1498, 1446, 1320, 1292, 1257, 1222, 1201, 1030,
970, 912, 870, 735, 692, 646
8ba
8c
C13H17N3O4
C8H15N3O3
–
–
–
201 [M+]
calcd: 201.1113
found: 201.1117
3325, 3100, 2973, 2935, 2877, 1644, 1528, 1441,
1421, 1376, 1357, 1310, 1258, 1232, 1146, 1044,
947, 904, 849, 767, 683
8d
9a
C10H17N3O5
259 [M+]
calcd: 259.1168
found: 259.1167
3385, 2931, 2858, 1707, 1655, 1521, 1461, 1409,
1388, 1358, 1252, 1191, 1088, 1047, 1026, 941,
907, 889, 843, 810, 781, 694, 662
C12H15BrN3O2
312 [M + H]+ calcd: 312.0342
found: 312.0342
3283, 3175, 3121, 2854, 1709, 1649, 1596, 1543,
1494, 1484, 1440, 1370, 1333, 1306, 1234, 1207,
1067, 912, 868, 751, 693, 639, 612
9ba
9ca
C13H16BrN3O3
C8H14BrN3O2
–
–
–
–
–
3074, 3051, 2975, 2935, 1711, 1664, 1590, 1538,
1483, 1437, 1308, 1263, 1241, 1187, 1163, 1117,
1093, 1072, 1027, 996, 939, 861, 748, 718, 693
9d
C10H16BrN3O4
321 [M+]
231 [M+]
calcd: 321.0324
found: 321.0324
3056, 2984, 2931, 1719, 1676, 1660, 1590, 1522,
1484, 1437, 1408, 1376, 1351, 1301, 1183, 1118,
1093, 1070, 1046, 1025, 996, 924, 861, 852, 749,
720, 693, 644
10a
10b
C12H13N3O2
C13H15N3O3
calcd: 231.0080
found: 231.0060
3055, 3009, 2929, 2878, 1690, 1650, 1592, 1487,
1411, 1328, 1302, 1287, 1218, 1155, 1109, 1071,
990, 968, 941, 913, 837, 767, 730, 695, 674, 626
262 [M + H]+ calcd: 262.1186
found: 262.1186
2936, 1690, 1658, 1511, 1468, 1442, 1414, 1334,
1293, 1245, 1219, 1180, 1107, 1027, 948, 833,
789, 742, 725, 698, 677, 637
10c
10d
C8H13N3O2
C10H15N3O4
–
–
–
241 [M+]
calcd: 241.0630
found: 241.0610
3117, 2945, 1736, 1710, 1633, 1486, 1436, 1402,
1371, 1286, 1201, 1118, 1070, 1041, 1021, 1004,
974, 940, 915, 887, 749, 721, 694, 642
4a
4b
C13H15N3O2·¼H2O
Calcd: C, 62.51; H, 6.25; N, 16.82
Found: C, 62.86; H, 6.21; N, 16.89
245 [M+]
259 [M+]
calcd: 245.1164
found: 245.1166
3074, 3056, 2985, 2941, 2921, 2879, 1703, 1657,
1594, 1493, 1467, 1434, 1406, 1371, 1339, 1304,
1283, 1216, 1187, 1139, 1119, 1108, 1069, 1028,
966, 940, 904, 836, 757, 721, 698, 668, 637, 610
C14H17N3O2
calcd: 259.1321
found: 259.1322
3056, 3036, 2990, 2972, 2944, 2896, 2874, 1702,
1672, 1625, 1597, 1497, 1468, 1436, 1397, 1376,
1348, 1308, 1276, 1223, 1184, 1119, 1071, 1025,
995, 971, 954, 899, 861, 829, 800, 753, 721, 694,
640
Synthesis 2013, 45, 3404–3412
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidines
3407
Table 2 Analytical, MS, and IR Data for Compounds 4, 6, and 8–10 (continued)
Compound Molecular formula, elemental analysis ESI-MS (m/z) ESI-HRMS (m/z)
IR (cm–1)
4c
C19H19N3O2
Calcd: C, 71.01; H, 5.96; N, 13.08
Found: C, 70.94; H, 5.91; N, 13.03
321 [M+]
calcd: 321.1477
found: 321.1476
3054, 3038, 2969, 2942, 1702, 1664, 1595, 1496,
1469, 1454, 1432, 1413, 1396, 1377, 1348, 1306,
1284, 1265, 1221, 1196, 1181, 1155, 1120, 1082,
1066, 1029, 1011, 961, 931, 874, 855, 758, 736,
695, 678, 626
4d
4e
4f
C16H19N3O4
Calcd: C, 60.56; H, 6.03; N, 13.24
Found: C, 60.50; H, 6.28; N, 13.10
317 [M+]
calcd: 317.1376
found: 317.1374
3066, 3010, 2982, 2929, 2881, 1748, 1705, 1657,
1593, 1494, 1474, 1433, 1416, 1390, 1376, 1343,
1296, 1193, 1095, 1074, 1055, 1024, 969, 938,
919, 870, 768, 735, 701, 670, 651, 624
C14H17N3O3
Calcd: C, 61.08; H, 6.22; N, 15.26
Found: C, 60.84; H, 6.06; N, 15.15
276 [M + H]+ calcd: 276.1343
found: 276.1345
2963, 2938, 2901, 2876, 2839, 1702, 1665, 1608,
1511, 1465, 1433, 1408, 1394, 1374, 1345, 1325,
1316, 1296, 1283, 1243, 1172, 1139, 1102, 1068,
963, 917, 809, 750, 716, 686, 664, 628
C20H21N3O2·¼H2O
Calcd: C, 67.49; H, 6.09; N, 11.81
Found: C, 67.14; H, 5.99; N, 11.79
352 [M + H]+ calcd: 352.1656
found: 352.1657
2962, 1699, 1667, 1607, 1584, 1512, 1497, 1469,
1433, 1398, 1376, 1348, 1335, 1294, 1246, 1221,
1196, 1174, 1122, 1108, 1027, 961, 926, 892, 829,
751, 731, 694, 638
4g
4h
C17H24N4O3
C15H19N3O2
333 [M + H]+ calcd: 333.1921
found: 333.1922
2939, 2857, 2821, 2770, 1665, 1607, 1510, 1467,
1441, 1399, 1343, 1294, 1245, 1227, 1174, 1100,
1029, 968, 958, 832, 810, 773, 748, 686, 653, 639
273 [M+]
calcd: 273.1477
found: 273.1475
3339, 3030, 2970, 2931, 2872, 1696, 1664,
1526.8, 1480.6, 1421.4, 1402.2, 1375.4, 1344.3,
1289.7, 1220.2, 1186.0, 1110.5, 1078.7, 1027.6,
994.7, 962.3, 925.5, 860.8, 821.8, 753, 723, 701,
671, 637.4, 613.5
4i
4j
C11H17N3O4
C14H21N3O6
255 [M+]
327 [M+]
calcd: 255.1219
found: 255.1221
2980, 2936, 1742, 1698, 1668, 1479, 1435, 1412,
1373, 1342, 1294, 1196, 1137, 1026, 997, 967,
914, 886, 859, 754, 722, 696, 669, 637
calcd: 327.1430
found: 327.1429
2982, 2940, 2909, 2875, 1741, 1716, 1667, 1483,
1438, 1409, 1372, 1343, 1293, 1185, 1118, 1095,
1023, 985, 961, 912, 862, 750, 721, 675
a Crude unpurified intermediates were characterized only by 1H NMR and IR spectra.
Table 3 Spectral Data for Compounds 4, 6, and 8–10
Compound Solvent
1H NMR (500 MHz, δ) and 13C NMR (126 MHz, δ)
6
DMSO-d6
DMSO-d6
δH: 1.52 and 1.63 (2 H, 2 br sext, 1:1, J = 6.6 Hz, 1′-CH2), 1.97 (1 H, dd, J = 15.8, 7.5 Hz, 4-Ha), 2.33 (1 H, br dd, J =
15.8, 7.3 Hz, 4-Hb), 3.40–3.47 (2 H, m, 5-H, 2′-Ha), 3.49 (1 H, quint, J = 7.7 Hz, 2′-Hb), 4.47 (1 H, br t, J = 6.7 Hz,
OH), 5.17 (1 H, s, 1-H), 8.93 (1 H, s, 2-H)
δC: 36.0, 37.9, 55.0, 58.0, 175.9
8a
δH: 1.65 (1 H, br sext, J = 6.7 Hz, 1′-Ha), 1.69–1.77 (1 H, m, 1′-Hb), 2.07 (1 H, br d, J = 16.6 Hz, 4-Ha), 2.97 (1 H,
dd, J = 16.6, 8.8 Hz, 4-Hb), 3.56 (2 H, br q, J = 5.4 Hz, 2′-CH2), 4.61 (1 H, br q, J = 7.6 Hz, 5-H), 4.89 (1 H, br t, J =
4.8 Hz, OH), 7.00 (1 H, t, J = 7.3 Hz, p-Ph), 7.28 (2 H, dd, J = 8.5, 7.3 Hz, m-Ph), 7.51 (2 H, dd, J = 8.5, 1.1 Hz, o-
Ph), 8.86 (1 H, s, 2-H), 9.99 (1 H, br s, NHPh)
δC: 35.9, 36.7, 56.2, 57.3, 119.1, 122.5, 128.6, 139.2, 157.1, 174.2
8b
8c
DMSO-d6
DMSO-d6
δH: 1.63 (1 H, br sext, J = 6.7 Hz, 1′-Ha), 1.68–1.77 (1 H, m, 1′-Hb), 2.05 (1 H, br d, J = 16.7 Hz, 4-Ha), 2.94 (1 H,
dd, J = 16.7, 8.8 Hz, 4-Hb), 3.55 (2 H, br q, J = 5.4 Hz, 2′-CH2), 3.71 (3 H, s, OCH3), 4.60 (1 H, br q, J = 7.6 Hz, 5-
H), 4.81 (1 H, br t, J = 4.9 Hz, OH), 6.86 and 7.40 (4 H, 2 dt, 1:1, J = 9.0, 2.8 Hz, C6H4), 8.72 (1 H, br s, NH), 9.91
(1 H, br s, NH)
δC: 35.9, 36.9, 55.2, 56.3, 57.4, 113.8, 121.1, 132.2, 154.9, 157.5, 174.5
δH: 1.02 (3 H, t, J = 7.2 Hz, CH3CH2), 1.55 (1 H, br sext, J = 6.7 Hz, 1′-Ha), 1.60–1.69 (1 H, m, 1′-Hb), 1.97 (1 H, br
d, J = 16.7 Hz, 4-Ha), 2.79 (1 H, dd, J = 16.7, 8.7 Hz, 4-Hb), 3.00–3.14 (2 H, m, CH2CH3), 3.42–3.53 (2 H, m, 2′-
CH2), 4.49 (1 H, br q, J = 7.6 Hz, 5-H), 4.58 (1 H, t, J = 5.2 Hz, OH), 6.79 (1 H, br s, NH), 9.72 (1 H, s, NH)
δC: 15.2, 34.7, 35.6, 37.2, 56.2, 57.5, 160.1, 174.9
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3404–3412

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J. Mirnik et al.
PAPER
Table 3 Spectral Data for Compounds 4, 6, and 8–10 (continued)
1H NMR (500 MHz, δ) and 13C NMR (126 MHz, δ)
Compound Solvent
8d
DMSO-d6
δH: 1.19 (3 H, t, J = 7.1 Hz, CH3CH2), 1.57 (1 H, sext, J = 6.7 Hz, 1′-Ha), 1.68 (1 H, br sext, J = 6.7 Hz, 1′-Hb), 2.01
(1 H, br d, J = 16.7 Hz, 4-Ha), 2.78 (1 H, dd, J = 16.7, 8.6 Hz, 4-Hb), 3.49 (2 H, nonet, J = 5.6 Hz, 2′-CH2), 3.78 (2
H, d, J = 5.9 Hz, CH2NH), 4.09 (2 H, q, J = 7.1 Hz, CH2CH3), 4.53 (1 H, br q, J = 7.2 Hz, 5-H), 4.56 (1 H, t, J = 5.1
Hz, OH), 7.21 (1 H, s, NH), 9.91 (1 H, br s, NH)
δC: 14.1, 35.7, 37.0, 41.9, 56.6, 57.4, 60.3, 160.5, 170.2, 175.4
9a
DMSO-d6
δH: 2.02 (1 H, br sext, J = 6.8 Hz, 1′-Ha), 2.08–2.18 (2 H, m, 1′-Hb and 4-Ha), 2.99 (1 H, dd, J = 16.9, 8.7 Hz, 4-Hb),
3.58 (2 H, br t, J = 6.8 Hz, CH2Br), 4.69 (1 H, br q, J = 7.4 Hz, 5-H), 7.01 (1 H, t, J = 7.3 Hz, p-Ph), 7.27 (2 H, br dd,
J = 8.6, 7.2 Hz, m-Ph), 7.55 (2 H, br dd, J = 7.4, 1.3 Hz, o-Ph), 8.80 (1 H, s, 2-H), 9.86 (1 H, s, NHPh)
δC: 30.5, 35.3, 37.3, 57.5, 119.6, 122.7, 128.5, 139.0, 157.2, 175.2
9ba
9ca
9da
10a
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
δH: 2.00 (1 H, br sext, J = 6.7 Hz, 1′-Ha), 2.06–2.17 (2H, m, 1′-Hb and 4-Ha), 2.97 (1 H, dd, J = 16.8, 8.6 Hz, 4-Hb),
3.56 (2 H, t, J = 7.0 Hz, CH2Br), 3.71 (3 H, s, OCH3), 4.67 (1 H, br q, J = 7.4 Hz, 5-H), 6.86 and 7.40 (4 H, 2 dt, 1:1,
J = 9.0, 2.8 Hz, C6H4), 8.71 (1 H, br s, NH), 9.82 (1 H, br s, NH)
δH: 1.02 (3 H, t, J = 7.2 Hz, CH3CH2), 1.89–1.98 (1 H, m, 1′-Ha), 1.98–2.09 (2 H, m, 1′-Hb and 4-Ha), 2.82 (1 H, dd,
J = 16.8, 8.7 Hz, 4-Hb), 3.00–3.14 (2 H, m, CH2CH3), 3.52 (2 H, t, J = 6.9 Hz, CH2Br), 4.56 (1 H, br q, J = 7.4 Hz,
5-H), 6.89 (1 H, s, NH), 9.69 (1 H, s, NH)
δH: 1.19 (3 H, t, J = 7.2 Hz, CH3CH2), 1.92–1.98 (1 H, m, 1′-Ha), 2.00–2.10 (2 H, m, 1′-Ha and 4-Ha), 2.80 (1 H, dd,
J = 16.8, 8.5 Hz, 4-Hb), 3.51 (2 H, t, J = 6.9 Hz, CH2Br), 3.78 (2 H, d, J = 5.9 Hz, CH2NH), 4.09 (2 H, q, J = 7.1,
CH2CH3), 4.55–4.62 (1 H, m, 5-H), 7.30 (1 H, t, J = 5.9 Hz, NH), 9.90 (1 H, s, NH)
δH: 1.94 (1 H, dddd, J = 13.4, 12.3, 10.6, 3.5 Hz, 4-Ha), 2.38 (1 H, dddd, J = 13.4, 5.8, 3.5, 2.2 Hz, 4-Hb), 2.52 (1 H,
q, J = 8.1 Hz, 3-Hb), 2.58 (1 H, dd, J = 16.2, 11.5, Hz, 3-Ha), 3.64 (1 H, dt, J = 12.3, 3.5 Hz, 5-Ha), 3.73 (1 H, td, J =
12.3, 2.2 Hz, 5-Hb), 4.35 (1 H, dddd, J = 11.5, 10.6, 8.1, 5.8, 3a-H), 7.16 (1 H, tt, J = 6.8, 1.9 Hz, p-Ph), 7.31–7.37 (4
H, m, o,m-Ph), 10.53 (1 H, s, NH)
δC: 28.7, 38.3, 39.5, 46.8, 57.8, 125.0, 128.5, 143.2, 154.0, 171.3
10b
DMSO-d6
δH: 1. 93 (1 H, dddd, J = 13.5, 12.3, 10.7, 3.5 Hz, 4-Ha), 2.35 (1 H, dddd, J = 13.5, 6.1, 3.5, 2.3 Hz, 4-Hb), 2.51 (1 H,
q, J = 8.1 Hz, 3-Hb), 2.57 (1 H, dd, J = 16.2, 11.4 Hz, 3-Ha), 3.53 (1 H, dt, J = 12.3, 3.5 Hz, 5-Ha), 3.69 (1 H, td, J =
12.3, 2.3 Hz, 5-Hb), 3.74 (3 H, s, OCH3), 4.33 (1 H, dddd, J = 11.4, 10.7, 8.1, 6.1 Hz, 3a-H), 6.90 and 7.21 (4 H, 2 dt,
1:1, J = 8.9, 2.8 Hz, C6H4), 10.50 (1 H, s, NH)
δC: 28.8, 38.3, 47.2, 55.3, 57.7, 113.8, 126.7, 136.1, 154.3, 156.7, 171.3
10c
10d
DMSO-d6
DMSO-d6
δH: 1.01 (3 H, t, J = 7.2 Hz, CH3CH2), 1.64 (1 H, dtd, J = 13.0, 12.4, 10.6, 4.9 Hz, 4-Ha), 2.26 (1 H, ddt, J = 13.0, 6.0,
3.1, 2.8 Hz, 4-Hb), 2.47–2.54 (2 H, overlapped by the signals of DMSO, 3-CH2), 3.12–3.29 (3 H, m, CH2CH3 and 5-
Ha), 3.35–3.42 (1 H, m, overlapped by the signal of H2O, 5-Hb), 4.19 (1 H, tdd, J = 11.4, 10.6, 8.7, 6.0 Hz, 3a-H),
10.33 (1 H, s, NH)
δH: 1.20 (3 H, t, J = 7.1 Hz, CH3CH2), 1.76 (1 H, tdd, J = 12.4, 10.7, 3.6 Hz, 4-Ha), 2.27 (1 H, dddd, J = 13.2, 6.0, 3.6,
2.4 Hz, 4-Hb), 2.48 (1 H, dd, J = 11.3, 9.0 Hz, 3-Ha), 2.49–2.53 (1 H, m, overlapped by the signals of DMSO, 3-Hb),
3.26 (1 H, dt, J = 12.4, 3.6 Hz, 5-Ha), 3.39 (1 H, dd, J = 12.4, 2.4 Hz, 5-Hb), 3.96 and 4.17 (2 H, 2 d, 1:1, J = 17.6
Hz, CH2NH), 4.10 (2 H, qd, J = 7.1, 1.1 Hz, CH2CH3), 4.26 (1 H, dddd, J = 11.3, 10.7, 8.2, 6.0 Hz, 3a-H), 10.45 (1
H, s, NH)
δC: 28.5, 30.8, 35.8, 38.3, 44.9, 49.0, 57.6, 155.1, 162.3, 169.9
4a
4b
4c
CDCl3
CDCl3
CDCl3
δH: 1.96 (1 H, dddd, J = 12.9, 12.4, 10.8, 3.7 Hz, 4-Ha), 2.51 (1 H, dddd, J = 12.9, 6.7, 3.5, 2.1 Hz, 4-Hb), 2.59 (1 H,
dd, J = 15.9, 12.4 Hz, 3-Ha), 2.68 (1 H, dd, J = 15.9, 7.1 Hz, 3-Hb), 3.35 (3 H, s, CH3), 3.70 (1 H, ddd, J = 12.4, 3.7,
3.5 Hz, 5-Ha), 3.85 (1 H, td, J = 12.4, 2.1 Hz, 5-Hb), 4.36 (1 H, dddd, J = 12.4, 10.8, 7.1, 6.7 Hz, 3a-H), 7.21 (1 H,
br t, J = 7.3 Hz, p-Ph), 7.31 (2 H, br d, J = 7.5 Hz, m-Ph), 7.37 (2 H, br t, J = 7.8 Hz, o-Ph)
δC: 30.1, 33.8, 39.4, 46.9, 58.5, 125.1, 126.2, 129.1, 142.4, 156.1, 170.7
δH: 1.20 (3 H, t, J = 7.1 Hz, CH3CH2), 1.99 (1 H, dddd, J = 14.2, 12.4, 10.5, 3.4 Hz, 4-Ha), 2.51 (1 H, dddd, J = 13.5,
7.0, 3.4, 2.1 Hz, 4-Hb), 2.60 (1 H, dd, J = 15.8, 12.4 Hz, 3-Ha), 2.68 (1 H, dd, J = 15.8, 7.0 Hz, 3-Hb), 3.70 and 4.06
(2 H, 2 sext, J = 7.3 Hz, CH2CH3), 3.71 (1 H, dt, J = 12.4, 3.4 Hz, 5-Ha), 3.88 (1 H, td, J = 12.4, 2.1 Hz, 5-Hb), 4.29
(1 H, ddt, J = 12.4, 10.5, 7.0 Hz, 3a-H), 7.17–7.24 (1 H, m, p-Ph), 7.30–7.41 (4 H, m, o,m-Ph)
δC: 12.1, 30.1, 39.6, 40.8, 46.8, 59.0, 124.9, 125.9, 129.0, 142.3, 155.6, 170.6
δH: 1.95 (1 H, dddd, J = 13.5, 12.3, 10.5, 3.7 Hz, 4-Ha), 2.42 (1 H, dddd, J = 13.5, 6.9, 3.7, 2.1 Hz, 4-Hb), 2.62 (1 H,
dd, J = 15.9, 12.4 Hz, 3-Ha), 2.71 (1 H, dd, J = 15.9, 6.9 Hz, 3-Hb), 3.63 (1 H, dt, J = 12.5, 3.7 Hz, 5-Ha), 3.69 (1 H,
td, J = 12.3, 2.1 Hz, 5-Hb), 4.05 (1 H, ddt, J = 12.4, 10.5, 6.9 Hz, 3a-H), 4.73 and 5.37 (2 H, 2 d, 1:1, J = 14.9 Hz,
CH2Ph), 7.21 (1 H, t, J = 7.4 Hz, p-PhN), 7.26–7.33 (7 H, m, o-PhN and C6H5), 7.37 (2 H, dd, J = 8.4, 7.3 Hz, m-PhN)
δC: 29.9, 39.4, 46.6, 48.8, 58.7, 125.0, 126.0, 127.7, 128.5, 128.6, 129.0, 136.4, 142.3, 155.5, 170.9
Synthesis 2013, 45, 3404–3412
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidines
3409
Table 3 Spectral Data for Compounds 4, 6, and 8–10 (continued)
Compound Solvent
1H NMR (500 MHz, δ) and 13C NMR (126 MHz, δ)
4d
DMSO-d6
δH: 1.28 (3 H, t, J = 7.2, CH3CH2), 2.00 (1 H, dddd, J = 13.0, 12.4, 10.8, 3.5 Hz, 4-Ha), 2.51 (1 H, dddd, J = 13.0, 7.0,
3.5, 2.1 Hz, 4-Hb), 2.67 (1 H, dd, J = 16.0, 12.4 Hz, 3-Ha), 2.80 (1 H, dd, J = 16.0, 7.0 Hz, 3-Hb), 3.68 (1 H, dt, J =
12.5, 3.5 Hz, 5-Ha), 3.86 (1 H, td, J = 12.4, 2.1 Hz, 5-Hb), 4.19 and 4.22 (2 H, 2 dq, J = 7.2, 10.7 Hz, CH2CH3), 4.43
and 4.77 (2 H, 2 d, 1:1, J = 18.1 Hz, CH2CO2Et), 4.61 (1 H, ddt, J = 12.4, 10.8, 7.0 Hz, 3a-H), 7.21 (1 H, td, J = 7.3,
1.4 Hz, p-Ph), 7.31 (2 H, dd, J = 8.5, 1.4 Hz, o-Ph), 7.37 (2 H, dd, J = 8.5, 7.3 Hz, m-Ph)
δC: 14.1, 29.8, 38.9, 46.7, 47.9, 58.4, 61.6, 124.9, 126.0, 128.9, 142.2, 155.3, 168.5, 173.1
4e
4f
CDCl3
CDCl3
CDCl3
δH: 1.95 (1 H, dddd, J = 14.0, 12.6, 10.6, 3.5 Hz, 4-Ha), 2.49 (1 H, dddd, J = 13.5, 7.0, 3.5, 2.1 Hz, 4-Hb), 2.59 (1 H,
dd, J = 15.9, 12.3 Hz, 3-Ha), 2.68 (1 H, dd, J = 15.9, 7.0 Hz, 3-Hb), 3.34 (3 H, s, NCH3), 3.61 (1 H, dt, J = 12.6, 3.5
Hz, 5-Ha), 3.80 (3 H, s, OCH3), 3.83 (1 H, td, J = 12.6, 2.1 Hz, 5-Hb), 4.36 (1 H, ddt, J = 12.3, 10.6, 7.0 Hz, 3a-H),
6.90 and 7.21 (4 H, 2 dt, 1:1, J = 8.9, 2.8 Hz, C6H4)
δC: 30.2, 33.8, 39.4, 47.3, 55.7, 58.5, 114.4, 126.7, 135.4, 156.4, 157.9, 170.7
δH: 1.93 (1 H, dddd, J = 14.0, 12.5, 10.5, 3.5 Hz, 4-Ha), 2.40 (1 H, dddd, J = 13.6, 7.0, 3.5, 2.1 Hz, 4-Hb), 2.61 (1 H,
dd, J = 15.9, 12.3 Hz, 3-Ha), 2.70 (1 H, dd, J = 15.9, 7.0 Hz, 3-Hb), 3.54 (1 H, dt, J = 12.6, 3.5 Hz, 5-Ha), 3.65 (1 H,
td, J = 12.5, 2.1 Hz, 5-Hb), 3.80 (3 H, s, OCH3), 4.04 (1 H, ddt, J = 12.3, 10.5, 7.0 Hz, 3a-H), 4.73 and 5.35 (2 H, 2d,
1:1, J = 14.8 Hz, CH2Ph), 6.89 and 7.18 (4 H, 2 d, 1:1, J = 8.9, 2.8 Hz, C6H4), 7.27–7.35 (5 H, m, C6H5)
δC: 30.1, 39.5, 47.2, 49.0, 55.7, 58.8, 114.4, 126.7, 127.9, 128.6, 128.7, 135.4, 136.6, 156.0, 157.9, 171.1
4g
δH: 1.97 (1 H, dddd, J = 13.7, 12.4, 10.8, 3.6 Hz, 4-Ha), 2.32 [6 H, s, N(CH3)2], 2.39 (1 H, ddd, J = 12.7, 5.9, 3.6 Hz,
1 H of CH2NMe2), 2.47 (1 H, dddd, J = 12.5, 7.0, 3.6, 2.1 Hz, 4-Hb), 2.59 (1 H, dd, J = 15.9, 12.3 Hz, 3-Ha), 2.70 (1
H, dd, J = 15.9, 7.0 Hz, 3-Hb), 2.85 (1 H, ddd, J = 12.7, 9.8, 5.9 Hz, 1 H of CH2NMe2), 3.62 (1 H, dt, J = 12.5, 3.6
Hz, 5-Ha), 3.75 (1 H, br ddd, J = 14.2, 5.9, 3.6 Hz, 1 H of 1-NCH2), 3.80 (3 H, s, OCH3), 3.82 (1 H, td, J = 12.4, 2.1
Hz, 5-Hb), 4.20 (1 H, ddd, J = 14.2, 9.8, 5.9 Hz, 1 H of 1-NCH2), 4.34 (1 H, ddt, J = 12.3, 10.8, 7.0 Hz, 3a-H), 6.89
and 7.21 (4 H, 2 br d, 1:1, J = 8.9 Hz, C6H4)
δC: 30.1, 39.8, 43.7, 45.5, 47.3, 55.3, 55.7, 58.6, 114.4, 126.6, 135.5, 155.9, 157.8, 172.0
4h
4i
CDCl3
CDCl3
CDCl3
δH: 1.12 (3 H, t, J = 7.1 Hz, CH3CH2), 1.68 (1 H, dddd, J = 13.0, 12.5, 10.4, 3.7 Hz, 4-Ha), 2.30 (1 H, dddd, J = 13.0,
7.0, 3.7, 2.3 Hz, 4-Hb), 2.50 (1 H, dd, J = 15.9, 12.5 Hz, 3-Ha), 2.62 (1 H, dd, J = 15.9, 7.0 Hz, 3-Hb), 3.14 (1 H, dt,
J = 12.5, 3.7 Hz, 5-Ha), 3.25 (1 H, td, J = 12.5, 2.3 Hz, 5-Hb), 3.33 and 3.50 (2 H, 2 sext, 1:1, J = 7.1 Hz, CH2CH3),
3.92 (1 H, ddt, J = 12.5, 10.4, 7.0 Hz, 3a-H), 4.71 and 5.32 (2 H, 2 d, 1:1, J = 14.7 Hz, CH2Ph), 7.24–7.35 (5 H, m,
C6H5)
δC: 13.1, 29.8, 39.3, 42.6, 42.9, 48.9, 58.4, 127.6, 128.4, 128.5, 136.5, 156.4, 171.1
δH: 1.28 (3 H, t, J = 7.1 Hz, CH3CH2), 1.99 (1 H, dddd, J = 13.2, 12.4, 10.8, 3.7 Hz, 4-Ha), 2.379 (1 H, dddd, J = 13.2,
6.7, 3.7, 2.2 Hz, 4-Hb), 2.55 (1 H, dd, J = 15.8, 12.4 Hz,, 3-Ha), 2.63 (1 H, dd, J = 15.8, 7.2 Hz, 3-Hb), 3.22 (1 H, dt,
J = 12.4, 3.7 Hz, 5-Ha), 3.31 (3 H, s, 1-CH3), 3.58 (1 H, td, J = 12.4, 2.2 Hz, 5-Hb), 4.08 and 4.20 (2 H, 2 d, 1:1, J =
17.8 Hz, CH2CO2Et), 4.20 and 4.21 (2 H, 2 quint, J = 7.1 Hz, CH2CH3), 4.29 (1 H, br dddd, J = 12.4, 10.8, 7.2, 6.7
Hz, 3a-H)
δC: 14.3, 29.6, 33.7, 39.4, 45.3, 49.5, 58.6, 61.6, 157.1, 169.8, 170.6
4j
δH: 1.27 and 1.29 (6 H, 2 t, 1:1, J = 7.1 Hz, 2 × CH3CH2), 2.01 (1 H, br dtd, J = 12.9, 12.0, 5.1 Hz, 4-Ha), 2.38 (1 H,
dtd, J = 12.9, 3.7, 2.0 Hz, 4-Hb), 2.88 (1 H, dd, J = 16.6, 11.0 Hz, 3-Ha), 3.04 (1 H, dd, J = 16.6, 10.1 Hz, 3-Hb), 3.26
(1 H, ddd, J = 12.0, 5.1, 2.0 Hz, 5-Ha), 3.51 (1 H, td, J = 12.0, 3.7 Hz, 5-Hb), 4.04 (1 H, d, J = 17.8 Hz, 1 H of
CH2CO2Et), 4.13–4.29 (5 H, m, 1 H of CH2CO2Et and 2 × CH2CH3), 4.38 and 4.73 (2 H, 2d, 1:1, J = 18.1 Hz,
CH2CO2Et), 4.52 (1 H, dddd, J = 12.0, 11.0, 10.1, 3.7 Hz, 3a-H)
δC: 14.2, 14.2, 29.4, 38.9, 45.1, 48.0, 49.3, 58.6, 61.4, 61.6, 156.4, 168.4, 169.7, 173.2
a Crude unpurified intermediates contaminated with residual Ph3PO.
A detailed 3D structure of tetrahydropyrazolo[1,5-c]py- The structures of compounds 8a, 8b, 10a, 10d, 4b, and 4f
rimidine-2,7(1H,3H)-diones 4 and 10 was also estab- were determined by X-ray diffraction (Figures 2–4, see
lished on the basis of characteristic vicinal coupling also Supporting Information).
3
3
constants, JH-H. Large coupling constants, J3Ha-3aH
=
In conclusion, a novel five-step synthesis of 1,6-dialkyl-
tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones
4 from commercially available 5,6-dihydro-2H-pyran-2-
one (6) was developed. The lower number of synthetic
steps and higher versatility of substituents make this
method superior to the previously reported 12-step syn-
thesis. Thus, alkyl or aryl substituents at position N(6) are
introduced by addition of isocyanates 7 to the pyrazolidi-
none 6 in the second step, whereas the N(1)-substituent is
introduced in the last step by SN-type alkylation. This syn-
3J4Ha-5Hb = 12.5 Hz and J4Ha-3aH = 10.5 Hz are in agree-
ment with antiperiplanar trans-orientation of these nuclei.
Accordingly, both the pyrimidine and the pyrazole part of
tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-dione
system must adopt a half-chair conformation where C-3
and C-4 are pointing out of the plane of the system and
where 3-Ha, 3aH, 4-Ha, and 5-Hb are axial. These charac-
teristic NMR data were also in good agreement with the
data of closely related known compounds (Figure 1, Table
3).11
3
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3404–3412

3410
J. Mirnik et al.
PAPER
thetic method offers an easy access to this almost un-
known group of saturated heterocyclic compounds which
may be useful in various applications.
R2
7O
R1
6N
Ha
1
8H
a N 2
N
Ha
4
3Hb
O
5
Hb
3a
H
Hb
4, 10
3J3Ha-3aH = 12.5 Hz (trans, a-a, θ ~ 150°)
3J4Ha-5Hb = 12.5 Hz (trans, a-a, θ ~ 180°)
3J4Ha-3aH = 10.5 Hz (trans, a-a, θ ~ 160°)
3J4Hb-5Ha = 3.5 Hz (θ ~ 60°)
Melting points were determined on a Kofler micro hot stage. The
NMR spectra were obtained on a Bruker Avance III UltraShield 500
plus at 500 MHz for 1H and 126 MHz for 13C nucleus in acetone-d6,
acetonitrile-d3, CDCl3, and DMSO-d6 with TMS as the internal
standard. Mass spectra were recorded on an Agilent 6224 Accurate
Mass TOF LC/MS spectrometer and IR spectra on a PerkinElmer
Spectrum BX FTIR spectrophotometer. Microanalyses were per-
formed on a PerkinElmer CHN Analyzer 2400 II. Flash column
chromatography (FC) and column chromatography (CC) were per-
formed on silica gel (Fluka, Silica gel 60, particle size 0.035–0.070
mm). Medium pressure liquid chromatography (MPLC) was per-
formed on a Büchi Sepacore® Preparative Chromatography System
(Büchi Fraction Collector C-660, Büchi Pump Module C-605, Bü-
chi Control Unit C-620) on silica gel using Sepacore® Flash Car-
tridges HP (Silica HP, 15–40 μm, pore size 60 Å, column
dimensions: 12 g, 21 × 77 mm), backpressure: 3 bar, detection: UV
(254 nm). MPLC purification of sparingly soluble compounds 4
was performed by adsorption of the crude 4 on silica gel (Fluka, sil-
ica gel 60, particle size 0.035–0.070 mm), followed by application
of Büchi Prep Elut Adapter (d = 12 mm, V = 17 mL) connected be-
tween the pump and the separation column.
3J3Hb-3aH = 7 Hz (cis, e-a, θ ~ 30°)
3J4Hb-3aH = 7 Hz (cis, e-a, θ ~ 40°)
3J4Ha-5Ha = 3.5 Hz (cis, a-e, θ ~ 60°)
3J4Hb-5Hb = 2 Hz (θ ~ 60°)
Figure 1 Structure determination of tetrahydropyrazolo[1,5-c]py-
rimidine-2,7(1H,3H)-diones 4 and 10 by 1H NMR spectroscopy
Experimental and characterization data for compounds 4, 6, and 8–
10 are given in Tables 1 and 2.
5-(2-Hydroxyethyl)pyrazolidin-3-one (6)
NH2NH2·H2O (759 μL, 15.6 mmol) was added to a solution of 5,6-
dihydro-2H-pyran-2-one (5; 90%, 1.668 g, 15.3 mmol) in EtOH (30
mL) and the mixture was stirred at r.t. for 24 h. Volatile components
were evaporated in vacuo to give the crude 6, which was used in the
following step without further purification.
Figure 2 ORTEP14 view of compound 8a
N-Substituted 5-(2-Hydroxyethyl)-3-oxopyrazolidine-1-carbox-
amides 8a–d, General Procedure
Isocyanate 7a–d (15.3 mmol) was added to a solution of the crude
6 (ca. 15.3 mmol) in anhydrous DMF (30 mL) and the mixture was
stirred at r.t. for 24 h. Volatile components were evaporated in vac-
uo and the residue was purified by CC [first EtOAc to elute the less
polar impurities, then EtOAc–MeOH (10:1) to elute the product 8].
Fractions containing the product were combined and volatile com-
ponents evaporated in vacuo to give the corresponding 8a–d (Ta-
bles 1–3).
N-Substituted 5-(2-Bromoethyl)-3-oxopyrazolidine-1-carbox-
amides 9a–d; General Procedure
PPh3 (284 mg, 1.083 mmol) was added under argon to a solution of
8a–d (0.7 mmol) in anhydrous CH2Cl2 (10 mL) at 0 °C followed by
the addition of CBr4 (359 mg, 1.083 mmol) in one portion. The re-
sulting mixture was stirred at 0 °C for 1 h and at r.t. for 1–2 h. Vol-
atile components were evaporated in vacuo to give the crude 9a–d,
which were used in subsequent transformations. Compounds 9a–d
were purified by CC (EtOAc–hexanes). Fractions containing the
product were combined and volatile components evaporated in vac-
uo to give the pure compound 9a and partially purified compounds
9b–d. It is noteworthy, that the bromides 9a–d were quite unstable,
therefore CC purification had to be performed immediately and
quickly (Tables 1–3).
Figure 3 ORTEP14 view of compound 10a
6-Substituted Tetrahydropyrazolo[1,5-c]pyrimidine-
2,7(1H,3H)-diones 10a–d; General Procedure
t-BuOK (2.56 g, 22.8 mmol) was added under argon to a solution of
9a–d (3.07 g, 11.4 mmol) in anhydrous DMF (100 mL) at 0 °C and
the mixture was stirred at 0 °C for 1 h and at r.t. for 1–2 h. Concd
HCl (37%, 2 mL, 24 mmol) was added slowly, the mixture was
stirred at r.t. for 10 min and then a solution of NaHCO3 (924 mg, 11
mmol) in H2O (5 mL) was added. Volatile components were evap-
Figure 4 ORTEP14 view of compound 4b
Synthesis 2013, 45, 3404–3412
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Novel Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidines
3411
orated in vacuo and the residue was purified by CC [first EtOAc–
hexanes (2:1) to elute the less polar impurities, then EtOAc–MeOH
(5:1) to elute the product 10]. Fractions containing the product were
combined and volatile components evaporated in vacuo to give re-
spective 10a–d (Tables 1–3).
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X-ray Structure Analysis15
8a
C12H15N3O3, Mr = 249.27, Dx = 1.396 Mg m−3, monoclinic, C2/c, a
= 22.8369(4), b = 11.2233(2), c = 9.3211(2) Å, β = 96.720(2)°, V =
2372.64(8) Å3, Z = 8, colorless needle, 0.3 × 0.15 × 0.15 mm, T =
150 K, MoKα radiation, λ = 0.7107 Å, SuperNova-Atlas single-
crystal diffractometer, 14114 measured, 2728 independent and
2412 observed reflections, Rint = 0.0250, ω scans, refinement on F2,
R[F2 > 2σ(F2)] = 0.0367, wR(F2) = 0.0878, 2728 contributing reflec-
tions, 171 parameters, Δρmax = 0.255 e Å−3, Δρmin = −0.211 e Å−3.
10a
C12H13N3O2, Mr = 231.25, Dx = 1.368 Mg m−3, orthorhombic, Pcab,
a = 7.3620(3), b = 7.7090(3), c = 39.5720(16) Å, V = 2245.86(16)
Å3, Z = 8, colorless plate, 0.40 × 16 × 0.08 mm, T = 293 K, MoKα
radiation, λ = 0.7107 Å, Nonius-Kappa-CCD single-crystal diffrac-
tometer, 12272 measured, 2273 independent and 1600 observed re-
flections, Rint = 0.033,  and ω scans, refinement on F2, R[F2 >
2σ(F2)] = 0.044, wR(F2) = 0.121, 2273 contributing reflections, 158
parameters, Δρmax = 0.151 e Å−3, Δρmin = −0.147 e Å−3.
4b
C14H17N3O2, Mr = 259.31, Dx = 1.312 Mg m−3, monoclinic, P21, a =
6.0044(3), b = 10.6528(4), c = 10.2959(4) Å, β = 94.784(4)°, V =
656.27(5) Å3, Z = 2, colorless plate, 0.1 × 0.1 × 0.02 mm, T = 293
K, CuKα radiation, λ = 1.54184 Å, SuperNova-Atlas single-crystal
diffractometer, 2423 measured, 1765 independent and 1561 ob-
served reflections, Rint = 0.0227, ω scans, refinement on F2, R[F2 >
2σ(F2)] = 0.0455, wR(F2) = 0.1194, 1765 contributing reflections,
173 parameters, Δρmax = 0.324 e Å−3, Δρmin = −0.183 e Å−3.
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Acknowledgment
The financial support from Boehringer-Ingelheim Pharma (Biberach,
Germany) and from the Slovenian Research Agency through grant
P1-0179 is gratefully acknowledged. We also thank EN-FIST Cen-
tre of Excellence (Ljubljana, Slovenia) for using the SuperNova dif-
fractometer.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are 1H and 13C NMR spectra of compounds 4, 6, and 8–10, as well
as ORTEP views and diffraction data for compounds 8b, 10d, and
4f.SnuIpgforim
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3404–3412

3412
J. Mirnik et al.
PAPER
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(15) Structural and other crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication numbers CCDC 941194–
941199 for compounds 4b, 4f, 8a, 8b, 10a, and 10d,
respectively. A copy of the data can be obtained, free of
charge, by applying to CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK [fax: +44(1223)336033 or e-mail:
deposit@ccdc.cam.ac.uk].
Synthesis 2013, 45, 3404–3412
© Georg Thieme Verlag Stuttgart · New York