Synthesis of 6-alkyl-7-oxo-4,5,6,7-tetrahydropyrazolo[1,5-c]pyri-midine-3-carboxamides

Article abstract of DOI:10.1055/s-0034-1379547

Two variants of the synthesis of 6-alkyl-7-oxo-4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidine-3-carboxamides have been developed. The first pathway comprises nine steps starting with the introduction of the 6-alkyl group (R¹) via addition of a primary alkylamine to methyl acrylate followed by a seven-step transformation into the 6-benzyl-7-oxo-4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidine-3-carboxylic acid, which is then amidated into title compounds. The other variation is based on an analogous four-step transformation of Boc-β-alanine into a 6-unsubstituted benzyl ester as the key intermediate. The 6-alkyl group (R¹) is then introduced by N-alkylation with alkyl halides, followed by O-debenzylation to give the carboxylic acids, and amidation. A library of 18 title carboxamides was prepared in very good yields.

Full text of DOI:10.1055/s-0034-1379547

SYNTHESIS
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1
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7
-
2
1
0
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 497–506
paper
497
K. Lombar et al.
Paper
Synthesis
Synthesis of 6-Alkyl-7-oxo-4,5,6,7-tetrahydropyrazolo[1,5-c]pyri-
midine-3-carboxamides
Klara Lombara
Uroš Grošelja
Georg Dahmannb
Branko Stanovnika
Jurij Svete*a
COOH
O
O
R1
R1
N
N
N
N
N
N
R1
N
R2
Boc
COOBn
N
R3
O
R1–3 = H, alkyl, arylalkyl
a Faculty of Chemistry and Chemical Technology, University of
Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
?
jurij.svete@fkkt.uni-lj.si
b Boehringer Ingelheim Pharma GmbH & Co. KG, Medicinal
Chemistry, 88397 Biberach, Germany
O
R2
Received: 26.09.2014
Accepted after revision: 29.10.2014
Published online: 24.11.2014
7
4
1
N
8
N
R1
6N
N
N
N
2
O
DOI: 10.1055/s-0034-1379547; Art ID: ss-2014-t0590-op
5
3a
3
O
2
1
Abstract Two variants of the synthesis of 6-alkyl-7-oxo-4,5,6,7-tetra-
hydropyrazolo[1,5-c]pyrimidine-3-carboxamides have been developed.
The first pathway comprises nine steps starting with the introduction of
the 6-alkyl group (R1) via addition of a primary alkylamine to methyl ac-
rylate followed by a seven-step transformation into the 6-benzyl-7-oxo-
4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidine-3-carboxylic acid, which is
then amidated into title compounds. The other variation is based on an
analogous four-step transformation of Boc-β-alanine into a 6-unsubsti-
tuted benzyl ester as the key intermediate. The 6-alkyl group (R1) is
then introduced by N-alkylation with alkyl halides, followed by O-de-
benzylation to give the carboxylic acids, and amidation. A library of 18
title carboxamides was prepared in very good yields.
refs. 11, 12
R1
N
N
N
R2
N
O
R3
3
Figure 1 Pyrazolo[1,5-c]pyrimidine (1), tetrahydropyrazolo[1,5-c]py-
rimidine-2,7(1H,3H)-diones 2, and 6-alkyl-7-oxo-4,5,6,7-tetrahydropyr-
azolo[1,5-c]pyrimidine-3-carboxamides 3
Recently, we reported the synthesis of tetrahydropyra-
zolo[1,5-c]pyrimidine-2,7(1H,3H)-diones 2 as the first rep-
resentatives of this saturated heterocyclic system.11,12 Two
synthetic methods were developed: a 12-step from methyl
acrylate11 and a five-step synthesis from commercially
available 5,6-dihydro-2H-pyran-2-one.12 In continuation of
our previous work on the synthesis of the pyrazole ana-
logues of histamine,13 we came to study the synthesis of
Key words histamine analogues, pyrazolo[1,5-c]pyrimidines, parallel
synthesis, cyclization, amidation
Heterocyclic systems are common building blocks for
the synthesis of various biologically important and natural-
ly occurring compounds. Consequently, heterocycles are
commonly used building blocks for applications in medici-
nal chemistry, catalysis, and material science.1 In this con-
text, 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
studies2 and exhibit kinase inhibition,3 antiviral,4 antican-
cer,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 receptor type I (Alk 4).8
Their applications in material science comprise the use as
photographic materials9 and inhibition of corrosion of fer-
rous alloys.10 In contrast to hundreds of known derivatives
of 1, the fully saturated analogues 2 are practically un-
known (Figure 1).
tetrahydropyrazolo[1,5-c]pyrimidine-3-carboxamides
3
(Figure 1) as novel heterocyclic and conformationally con-
strained histamine analogues. To our pleasant surprise, the
literature search revealed that 6-alkyl-7-oxo-4,5,6,7-tetra-
hydropyrazolo[1,5-c]pyrimidine-3-carboxamides
3 were
unknown, which prompted us to focus our attention on
their synthesis. The results of this study are reported here-
in.
According to our initial synthetic plan, the β-keto ester
5a, available in four steps from methyl acrylate via N-ben-
zyl-N-Boc-β-alanine (4a),13c was treated with N,N-dimeth-
ylformamide dimethylacetal (DMFDMA). The so-formed
enaminone intermediate13c,14 was cyclized with hydrazine
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498
K. Lombar et al.
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Synthesis
COOH
Boc
COOR
O
hydrochloride to give the pyrazole methyl ester 6a in 40%
yield over two steps. Acidolytic removal of the Boc group
gave the free amine dihydrochloride 7a in 84% yield. Cy-
clization of 7a with 1,1′-carbonyldiimidazole (CDI) in MeCN
then afforded tetrahydropyrazolo[1,5-c]pyrimidine ester 8a
in 79% yield. Unfortunately, it was not possible to prepare
the carboxylic acid 9a by the hydrolysis of 8a with aqueous
NaOH or LiOH as the reaction took place preferentially at
position 7 and not at the methyl ester group to give a mix-
ture of products with the free base 7a as the major compo-
nent. To avoid this limitation, the CO2Me group was re-
placed by the CO2Bn group, which was expected to be re-
movable under mild hydrogenolytic conditions. Thus,
condensation of the β-alanine derivative 4a with potassium
monobenzyl malonate15 gave the corresponding β-keto es-
ter 5b in quantitative yield. Following a slight modification
of the above procedure for the synthesis of 8a, the benzyl
ester analogue 8b was prepared in similar overall yield. Cat-
alytic hydrogenation in the presence of Pd/C under mild
conditions was chemoselective to furnish the desired car-
boxylic acid 9a in 98% yield (Scheme 1, Table 1).
1. DMFDMA
2. N2H4•HCl
Masamune–
Claisen
ref. 13c
ref. 14
Bn
N
4a
Bn
N
3 steps from
methyl acrylate (ref. 13c)
Boc
5a,b
Boc
N
Bn
•2HCl
BnHN
H
H
N
N
HCl–EtOAc
N
N
ROOC
ROOC
7a,b
6a,b
Bn
Bn
6 N
N
7
O
O
N
R = Me
5
CDI, Et3N
MeCN
H2O, LiOH
N 8
N
N 1
4
pyrimidone
ring-
opening
2
3
ROOC
HOOC
9a
8a,b
H2, Pd/C, MeOH
R = Bn
transformation:
5a→6a→7a→8a: R = Me
5b→6b→7b→8b→9a: R = Bn
Scheme 1 An eight-step synthesis of 9a from methyl acrylate (method
A) with diversification at N(6) in the first step (ref. 13c). Masamune–
Claisen reaction conditions: CDI, THF, r.t., 2 h; then KO2C-CH2-CO2R (R =
Me or Bn), MgCl2, r.t.
Table 1 Experimental Data for Compounds 5b,c, 6a–c, 7a–c, 8a–d, 9a,b, and 3a–r
Compound
R1
Amine R2R3NH
CC or DVFC
Yield (%)
Appearance
Mp (°C)
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
8d
9a
9b
3a
3b
3c
–
–
–
quant.
quant.
40
yellow-brown oil
orange oil
–
–
–
–
–
–
–
EtOAc–hexanes (1:2)
brown-yellow oil
yellow oil
–
–
–
EtOAc–hexanes (2:3)
43
–
–
–
EtOAc–hexanes (1:2)
91a
brown solid
white solid
115–120
175–180
129–132
151–156
151–155
112–113
170–173
131–136
255–260
232–237
131–136
149–154
128–133
–
–
–
84a
–
–
–
83a
white solid
–
–
–
89
white solid
Bn
Bn
–
–
–
79a,b
74a,b, 62a,c
44c
white solid
–
EtOAc–hexanes (1:1)c
white solid
–
EtOAc
–
white solid
Me
Bn
Me
Bn
Me
Bn
–
83c
yellow solid
white solid
–
–
98a
–
–
83
yellowish solid
brownish solid
brownish solid
brownish solid
benzylamine (11a)
benzylamine (11a)
propylamine (11b)
EtOAc
EtOAc
EtOAc
quant.
94
quant.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 497–506

499
K. Lombar et al.
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Synthesis
Table 1 (continued)
Compound
R1
Me
Amine R2R3NH
CC or DVFC
Yield (%)
Appearance
Mp (°C)
3d
3e
3f
propylamine (11b)
MeO(CH2)2NH2 (11c)
MeO(CH2)2NH2 (11c)
2-picolylamine (11d)
Me2N(CH2)3NH2 (11e)
HO(CH2)3NH2 (11f)
pyrrolidine (11g)
piperidine (11h)
EtOAc
82
brown resin
–
Bn
Me
Bn
Bn
Bn
Bn
Bn
Me
Bn
Me
Bn
Bn
Bn
Me
EtOAc
quant.
79
brownish solid
brownish solid
brown oil
96–101
164–169
–
EtOAc–EtOH (5:1)
EtOAc–EtOH (5:1)
3g
3h
3i
86
d
–
quant.
99
yellow-brown oil
yellowish solid
yellow-brown solid
brown solid
–
EtOAc–EtOH (5:1)
EtOAc
120–125
184–189
115–120
–
3j
50
3k
3l
EtOAc
quant.
95
piperidine (11h)
EtOAc–EtOH (5:1)
EtOAc
yellow-brown oil
brownish solid
yellow-brown solid
brown oil
3m
3n
3o
3p
3q
3r
morpholine (11i)
morpholine (11i)
4-methylpiperazine (11j)
Et2NH (11k)
quant.a
92
138–141
136–141
–
EtOAc–EtOH (5:1)
EtOAc–EtOH (1:1)
EtOAc
77
79
brownish solid
yellow solid
74–79
82–86
–
BnNHMe (11l)
EtOAc
quant.a
40
BnNHMe (11l)
EtOAc–EtOH (1:1)
yellow-brown oil
a Analytical purity confirmed by CHN analysis; the found values for C, H, and N were within ± 0.4% deviation from the theoretical values.
b Method A.
c Method B.
d This highly polar compound could not be purified by DVFC.
COOH
Boc
COOBn
O
1. DMFDMA
2. N2H4•HCl
Next, a variation of the synthetic method was studied
with both diversification steps late in the synthesis. For this
purpose, commercially available Boc-β-alanine (4b) was
transformed into benzyl tetrahydropyrazolo[1,5-c]pyrimi-
dine-3-carboxylate 8c following essentially the same proce-
dure as described above for 8a. Alkylation of 8c with benzyl
bromide (10a) and methyl iodide (10b) was performed in
DMF in the presence of K2CO3 to afford the benzylated 8b
and the methylated analogue 8d in 62% and 83% yield, re-
spectively. Finally, hydrogenolytic O-debenzylation fur-
nished the key intermediates 9a and 9b in high yields
(Scheme 2, Table 1).
It is noteworthy that the yield of cyclization of 7c with
CDI was substantially lower (44%) than in the cyclization of
7b (74%). Possibly, a base-catalyzed equilibration between
the bicyclic 8c and the open-chain (isocyanate) form 8′c
and subsequent reaction of 8′c with traces of water in the
solvent and/or with water during workup gives the starting
diamine 7c. Consequently, the yield of 8c is diminished. On
the other hand, the 6-alkylated analogues 8a,b,d cannot
undergo such ring-opening and, hence, the yield is much
higher even upon extraction workup (Scheme 3).
Masamune–
Claisen
ref. 14
ref. 14
HN
4b
HN
commercially
available
Boc
5c
Boc
HN
•2HCl
H2N
H
H
N
N
HCl–EtOAc
N
N
BnOOC
BnOOC
7c
6c
H
O
N
N
R1X (10a,b)
K2CO3, DMF
CDI, Et3N, MeCN
N
BnOOC
8c
R1
N
R1
O
N
O
N
H2, Pd/C, MeOH
N
N
N
Parallel amidation of the carboxylic acids 9a and 9b was
performed with 12 primary and secondary amines 11a–l
using bis(pentafluorophenyl) carbonate (BPC)16 as the acti-
vating reagent. Quite expectedly,13,14,16 none of these ami-
dations was problematic and the corresponding carboxam-
ides 3a–r were obtained in quantitative yields upon evapo-
rative workup. Subsequent purification of the crude
HOOC
BnOOC
transformation:
8b,d
9a,b
8c+10a→8b→9a: R1 = Bn
8c+10b→8d→9b: R1 = Me
Scheme 2 Method B: A six-step synthesis of 9a,b from Boc-β-alanine
(4b); diversification at N(6) in the fifth step. Masamune–Claisen reac-
tion conditions are given in Scheme 1.
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Synthesis
R1
N
R1
N
O
H
C
1. BPC, Et3N, MeCN
2. R2R3NH (11a–l), Et3N
O
N
O
N
O
N
N
CDI
H
N
N
7c
N
N
N
N
R2
N
HOOC
BnOOC
BnOOC
R3
8c
O
8'c
9a R1 = Bn
9b R1 = Me
H2O
3a–r R1 = Bn, Me
– CO2
amines R2R3NH:
Scheme 3 Probable mechanism for the formation of 7c from 8c
N
NH2
Ph
NH2
MeO
NH2
NH2
compounds with dry-vacuum flash chromatography
(DVFC)17 on silica gel gave a library of title carboxamides
3a–r in 40% to quantitative yields (Scheme 4, Table 1).
The structures of all novel compounds 5b,c, 6a–c, 7a–c,
8a–d, 9a,b, and 3a–r were determined by spectroscopic (1H
and 13C NMR, IR, MS, HRMS) methods and by elemental
analyses for C, H, and N (Table 2 and Table 3). Compounds
5b,c, 6a,b, 7c, 8c,d, 9b, and 3a–l,n–p,r were not obtained in
analytically pure form. Their identities were confirmed by
13C NMR and HRMS. The crude intermediates 5 were used
for further transformation without purification.
11a
Me2N
11b
11c
11d
NH2
HO
NH2
11e
11f
NH
NH
O
NH Me
N
NH
11g
11h
11i
Me
11j
N
Ph
N
H
H
11k
11l
Scheme 4 Synthesis of title compounds 3a–r
Table 2 Analytical, MS, and IR Data for compounds 5b,c, 6a–c, 7a–c, 8a–d, 9a,b, and 3a–r
Compound Molecular formula
Elemental analysis
ESI-MS m/z
ESI-HRMS m/z
IR (ATR, cm–1
)
5b
5c
6a
6b
6c
C24H29NO5
312 [MH2 – Boc]+
222 [MH2 – Boc]+
360 [M + H]+
Calcd: 312.1594
Found: 312.1596
2976, 1739, 1687, 1413, 1366, 1244, 1157, 735, 697
3367, 2977, 1706, 1501, 1248, 1160, 744, 697
C
C
C
C
17H23NO5
Calcd: 222.1125
Found: 222.1122
19H25N3O4
Calcd: 360.1918
Found: 360.1913
3221, 2976, 1711, 1694, 1418, 1366, 1250, 1163, 1098
3215, 2975, 1689, 1664, 1243, 1155, 1076, 732, 696
3205, 2975, 1688, 1546, 1288, 1166, 1090, 749, 701
25H29N3O4
336 [MH2–Boc]+
246 [MH2 – Boc]+
Calcd: 336.1707
Found: 336.1704
18H23N3O4·1⁄5H2O
Calcd: 246.1237
Found: 246.1236
Calcd: C, 61.95; H, 6.76; N, 12.04
Found: C, 61.96; H, 6.82; N, 12.30
7a
7b
C14H17N3O2·1⅓HCl
Calcd: C, 54.61; H, 6.00; N, 13.65
Found: C, 54.64; H, 6.22; N, 13.45
260 [M + H]+
336 [M + H]+
Calcd: 260.1394
Found: 260.1393
3413, 2947, 2788, 1734, 1717, 1434, 1100, 748, 698
3419, 1712, 1572, 1293, 1248, 1093, 774, 732, 694
C20H21N3O2·2HCl
Calcd: C, 58.83; H, 5.68; N, 10.29
Found: C, 58.60; H, 5.89; N, 10.28
Calcd: 336.1707
Found: 336.1704
7c
8a
C13H15N3O2·2HCl
246 [M + H]+
286 [M + H]+
Calcd: 246.1237
Found: 246.1237
3010, 1721, 1296, 1255, 1206, 1081, 866, 748, 695
3417, 1712, 1638, 1618, 1593, 1271, 1026, 700, 618
C
15H15N3O3
Calcd: 286.1186
Found: 286.1187
Calcd: C, 63.15; H, 5.30; N, 14.73
Found: C, 62.87; H, 5.38; N, 14.74
8b
C21H19N3O3
Calcd: C, 69.79; H, 5.30; N, 11.63
Found: C, 70.02; H, 5.20; N, 11.62
362 [M + H]+
Calcd: 362.1499
Found: 362.1514
3028, 1705, 1586, 1245, 1160, 1012, 725, 693
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Table 2 (continued)
Compound Molecular formula
Elemental analysis
ESI-MS m/z
ESI-HRMS m/z
IR (ATR, cm–1
)
8c
8d
9a
C14H13N3O3
272 [M + H]+
286 [M + H]+
272 [M + H]+
Calcd: 272.1030
Found: 272.1031
3233, 3122, 1720, 1711, 1587, 1267, 1177, 740, 698
2934, 1716, 1588, 1243, 1171, 1023, 726, 691
2858, 1714, 1667, 1593, 1416, 1256, 744, 697
C
C
15H15N3O3
14H13N3O3
Calcd: 286.1186
Found: 286.1188
Calcd: 272.1030
Found: 272.1032
Calcd: C, 61.99; H, 4.83; N, 15.49
Found: C, 62.02; H, 4.75; N, 15.34
9b
3a
3b
3c
3d
3e
3f
C8H9N3O3
196 [M + H]+
361 [M + H]+
285 [M + H]+
313 [M + H]+
275 [M + K]+
329 [M + H]+
275 [M + Na]+
362 [M + H]+
356 [M + H]+
329 [M + H]+
325 [M + H]+
339 [M + H]+
285 [M + Na]+
341 [M + H]+
Calcd: 196.0717
Found: 196.0720
2928, 1730, 1694, 1571, 1415, 1242, 886, 740
3309, 1713, 1633, 1592, 1513, 1270, 976, 698
3323, 1710, 1633, 1589, 1514, 1327, 1269, 978
C
C
C
21H20N4O2
15H16N4O2
17H20N4O2
Calcd: 361.1659
Found: 361.1654
Calcd: 285.1346
Found: 285.1349
Calcd: 313.1659
Found: 313.1654
3466, 3363, 3238, 2969, 1713, 1591, 1272, 979, 745,
697
C11H16N4O2
17H20N4O3
C11H16N4O3
Calcd: 275.0905
Found: 275.0903
3470, 3372, 3247, 2934, 1713, 1591, 1266, 747
C
Calcd: 329.1608
Found: 329.1607
3460, 3370, 3243, 2937, 1715, 1594, 1323, 1271,
1125, 697
Calcd: 275.1115
Found: 275.1115
3328, 2930, 1719, 1647, 1587, 1516, 1326, 1269, 978
3327, 1714, 1643, 1590, 1513, 1268, 979, 745, 699
3307, 1715, 1644, 1594, 1494, 1270, 1180, 980
3g
3h
3i
C
C
C
20H19N5O2
19H25N5O2
17H20N4O3
Calcd: 362.1612
Found: 362.1609
Calcd: 356.2081
Found: 356.2081
Calcd: 329.1608
Found: 329.1609
3400, 3289, 2924, 1704, 1598, 1511, 1476, 1276, 973,
698
3j
C18H20N4O2
Calcd: 325.1659
Found: 325.1661
2973, 2877, 1712, 1595, 1564, 1417, 1329, 1275, 745,
699
3k
3l
C
C
C
19H22N4O2
13H18N4O2
18H20N4O3
Calcd: 339.1816
Found: 339.1815
2937, 1718, 1615, 1440, 1421, 1256, 985, 700
2936, 1720, 1602, 1513, 1437, 1325, 1256, 981
2859, 1718, 1618, 1514, 1421, 1246, 1112, 993, 978
Calcd: 285.1322
Found: 285.1318
3m
Calcd: 341.1608
Found: 341.1607
Calcd: C, 63.52; H, 5.92; N, 16.46
Found: C, 63.80; H, 5.66; N, 16.27
3n
3o
3p
3q
C12H16N4O3
265 [M + H]+
354 [M + H]+
327 [M + H]+
375 [M + H]+
Calcd: 265.1295
Found: 265.1298
2864, 1716, 1612, 1426, 1245, 990
C
C
C
19H23N5O2
18H22N4O2
22H22N4O2
Calcd: 354.1925
Found: 354.1924
2940, 1716, 1618, 1495, 1421, 1258, 998, 978
2974, 1717, 1612, 1420, 1264, 1151, 699
3029, 2924, 1716, 1617, 1580, 1249, 743, 697
Calcd: 327.1816
Found: 327.1820
Calcd: 375.1816
Found: 375.1816
Calcd: C, 70.57; H, 5.92; N, 14.96
Found: C, 70.31; H, 5.66; N, 14.69
3r
C16H18N4O2
299 [M + H]+
Calcd: 299.1503
Found: 299.1508
2925, 1717, 1615, 1579, 1400, 1324, 1249, 1015, 745,
699
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Paper
Synthesis
Table 3 NMR Data for Compounds 5b,c, 6a–c, 7a–c, 8a–d, 9a,b, and 3a–r
Compound Solvent
1H NMR (500 MHz, δ) and 13C NMR (126 MHz, δ)
5b
CDCl3
δH = 1.39–1.52 (9 H, m, t-C4H9), 2.70 and 2.77 (2 H, 2 br s, 1:1, CH2CH2CO), 3.41 (2 H, s, CH2CO2Bn), 3.44 (2 H, br s, NCH2CH2), 4.40 (2
H, s, NCH2Ph), 5.13 (2 H, s, OCH2Ph), 7.17–7.40 (10 H, m, 2 × C6H5)
δC = 28.4, 41.5/41.8, 42.0, 49.1/49.3, 50.5/51.5, 67.1, 80.1, 127.2/127.3, 127.3/127.6, 128.3, 128.3/128.4, 128.5, 128.6,
135.1/135.2, 138.1/138.3, 155.5/155.7, 166.7/166.8, 201.2/201.5
5c
6a
6b
6c
7a
7b
CDCl3
δH = 1.42 (9 H, s, t-C4H9), 2.76 (2 H, br t, J = 5.6 Hz, CH2CH2CO), 3.37 (2 H, br q, J = 5.8 Hz, NHCH2CH2), 3.50 (2 H, s, CH2CO2Bn), 4.96
(1 H, br s, NH), 5.18 (2 H, s, OCH2Ph), 7.32–7.40 (5 H, m, C6H5)
δC: 28.5, 35.1, 43.2, 49.4, 67.4, 79.5, 128.5, 128.7, 128.8, 135.3, 156.0, 166.9, 202.3
CDCl3
δH = 1.44 (9 H, s, t-C4H9), 3.26 (2 H, br s, CH2CH2Het), 3.64 (2 H, br s, NCH2CH2), 3.81 (3 H, s, OCH3), 4.42 (2 H, s, NCH2Ph), 7.20 (2
Harom, br s, o-Ph), 7.24–7.28 (1 Harom, m, p-Ph), 7.31 (2 Harom, br t, J = 7.2 Hz, m-Ph), 7.94 (1 H, s, 3-H), 11.91 (1 H, br s, 1-H)
δC = 24.7/25.1, 28.3/28.4, 44.7/45.3, 49.5/50.5, 51.1, 80.0/81.0, 110.9, 127.3, 127.5, 128.5, 137.9, 140.9, 145.9, 156.0/156.4, 164.2
CDCl3
δH = 1.44 (9 H, s, t-C4H9), 3.22 (2 H, br s, CH2CH2Het), 3.63 (2 H, br s, NCH2CH2), 4.37 (2 H, s, NCH2Ph), 5.26 (2 H, s, OCH2Ph), 7.12–
7.19 and 7.26–7.42 (10 H, 2 m, 1:4, 2 × C6H5), 7.96 (1 H, s, 3-H), 1-H exchanged
δC = 24.8, 28.4, 44.4, 50.5, 65.7, 81.1, 110.8, 127.3, 127.3, 128.1, 128.2, 128.5, 128.6, 136.3, 137.8, 141.4, 146.0, 156.6, 163.6
CDCl3
δH = 1.40 (9 H, s, t-C4H9), 3.16–3.21 (2 H, m, CH2CH2Het), 3.45–3.51 (2 H, m, NHCH2CH2), 5.04 (1 H, br s, NHBoc), 5.28 (2 H, s,
OCH2Ph), 7.32–7.44 (5 H, m, C6H5), 7.99 (1 H, s, 3-H), 1-H exchanged
δC = 26.9, 28.4, 39.4, 65.8, 79.8, 111.1, 128.1, 128.2, 128.6, 136.2, 139.5, 147.6, 156.6, 163.7
DMSO-d6
DMSO-d6
δH = 3.14–3.24 (2 H, m, CH2CH2Het), 3.29–3.33 (2 H, m, NHCH2CH2), 3.72 (3 H, s, OCH3), 4.18 (2 H, br t, J = 5.7 Hz, NHCH2Ph), 7.36–
+
7.44 (3 Harom, m, m,p-Ph), 7.61 (2 Harom, br dd, J = 7.6, 1.6 Hz, o-Ph), 8.15 (1 H, s, 3-H), 9.33 and 9.77 (4 H, 2 br s, 1:1, 2 × NH2
δC = 23.7, 45.1, 50.2, 51.5, 110.7, 129.0, 129.3, 130.6, 132.4, 135.9, 147.8, 163.9
)
δH = 3.18–3.25 (2 H, m, CH2CH2Het), 3.30–3.35 (2 H, m, NHCH2CH2), 4.16 (2 H, br t, J = 5.7 Hz, NHCH2Ph), 5.27 (2 H, s, OCH2Ph), 7.33
(1 Harom, br tt, J = 7.2, 1.6 Hz, p-Ph), 7.37–7.46 (7 H, m, 7 H of 2 × C6H5), 7.59 (2 Harom, br dd, J = 7.5, 1.8 Hz, o-Ph), 8.23 (1 H, s, 3-H),
9.65 (2 H, br s, NH2+), 1-H exchanged
δC = 23.3, 44.6, 49.7, 64.9, 110.1, 127.8, 127.9, 128.5, 128.6, 128.8, 130.0, 131.9, 135.5, 136.5, 147.6, 162.8
7c
8a
8b
8c
8d
9a
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
CDCl3
δH = 3.09–3.16 (2 H, m, CH2CH2Het), 3.18–3.23 (2 H, m, NH2CH2CH2), 5.28 (2 H, s, OCH2Ph), 7.34 (1 Harom, br t, J = 7.2 Hz, p-Ph), 7.39
+
(2 Harom, br t, J = 7.4 Hz, m-Ph), 7.45 (2 Harom, br d, J = 7.2 Hz, o-Ph), 8.22 (1 H, s, 3-H), 8.28 (5 H, br s, NH2+ and NH3
)
δC = 24.7, 37.3, 64.9, 110.1, 127.8, 127.9, 128.4, 135.7, 136.5, 147.7, 162.8
δH = 3.30 (2 H, t, J = 6.8 Hz, 4-CH2), 3.59 (2 H, t, J = 6.8 Hz, 5-CH2), 3.78 (3 H, s, OCH3), 4.69 (2 H, s, NCH2Ph), 7.28–7.34 (1 Harom, m, p-
Ph), 7.38 (4 Harom, br d, J = 4.4 Hz, o,m-Ph), 8.06 (1 H, s, 2-H)
δC = 21.5, 43.6, 51.4, 51.6, 112.3, 128.2, 128.3, 128.9, 135.7, 143.5, 144.7, 148.2, 162.9
δH = 3.29 (2 H, t, J = 6.8 Hz, 4-CH2), 3.58 (2 H, t, J = 6.8 Hz, 5-CH2), 4.68 (2 H, s, NCH2Ph), 5.29 (2 H, s, OCH2Ph), 7.28–7.45 (10 H, m, 2
× C6H5), 8.09 (1 H, s, 2-H)
δC = 21.0, 43.7, 50.7, 65.5, 111.2, 127.5, 127.7, 127.9, 128.1, 128.5, 128.6, 136.0, 136.5, 142.7, 146.1, 147.5, 161.8
δH = 3.24 (2 H, t, J = 6.7 Hz, 4-CH2), 3.45 (2 H, br td, J = 6.7, 2.6 Hz, 5-CH2), 5.30 (2 H, s, OCH2Ph), 7.35 (1 Harom, br t, J = 7.2 Hz, p-Ph),
7.40 (2 Harom, br t, J = 7.3 Hz, m-Ph), 7.45 (2 Harom, br d, J = 7.0 Hz, o-Ph), 8.07 (1 H, s, 2-H), 8.37 (1 H, br s, NH)
δC = 21.5, 37.4, 65.5, 111.2, 127.9, 128.1, 128.5, 136.1, 142.3, 146.5, 147.2, 161.9
δH = 3.20 (3 H, s, NCH3), 3.39 (2 H, t, J = 6.8 Hz, 4-CH2), 3.62 (2 H, t, J = 6.8 Hz, 5-CH2), 5.31 (2 H, s, OCH2Ph), 7.35–7.44 (5 H, m, C6H5),
8.05 (1 H, s, 2-H)
δC = 21.4, 35.9, 46.4, 66.3, 112.3, 128.3, 128.4, 128.7, 135.7, 143.4, 144.8, 148.1, 162.4
DMSO-d6
δH = 3.29 (2 H, t, J = 6.8 Hz, 4-CH2), 3.58 (2 H, t, J = 6.8 Hz, 5-CH2), 4.69 (2 H, s, NCH2Ph), 7.29–7.34 (1 Harom, m, p-Ph), 7.38 (4 Harom, br
d, J = 4.4 Hz, o,m-Ph), 8.00 (1 H, s, 2-H), OH exchanged
δC = 20.9, 43.8, 50.7, 112.5, 127.5, 127.7, 128.6, 136.6, 143.0, 145.5, 147.7, 163.6.
9b
3a
DMSO-d6
δH = 3.04 (3 H, s, NCH3), 3.29 (2 H, t, J = 6.8 Hz, 4-CH2), 3.61 (2 H, t, J = 6.8 Hz, 5-CH2), 7.95 (1 H, s, 2-H), OH exchanged
δC = 20.8, 35.1, 45.6, 112.5, 142.7, 145.3, 147.7, 163.7
CDCl3
δH = 3.36 (2 H, br t, J = 6.6 Hz, 4-CH2), 3.47 (2 H, br t, J = 6.7 Hz, 5-CH2), 4.56 (2 H, d, J = 5.7 Hz, NHCH2Ph), 4.71 (2 H, s, NCH2Ph), 6.72
(1 H, br s, NH), 7.23–7.38 (10 H, m, 2 × C6H5), 7.93 (1 H, s, 2-H)
δC = 21.4, 43.5, 43.8, 51.5, 114.9, 127.6/127.6, 127.8, 128.2, 128.3, 128.7/128.7, 129.0, 135.6, 137.8/137.8, 140.4/140.4, 144.0,
148.4, 162.2/162.3
3b
3c
3d
3e
CDCl3
CDCl3
CDCl3
CDCl3
δH = 3.17 (3 H, s, NCH3), 3.47 (2 H, t, J = 6.8 Hz, 4-CH2), 3.61 (2 H, t, J = 6.8 Hz, 5-CH2), 4.57 (2 H, d, J = 5.7 Hz, NHCH2Ph), 6.40 (1 H, br
s, NH), 7.29–7.36 (5 H, m, C6H5), 7.84 (1 H, s, 2-H)
δC = 21.2, 35.7, 43.5, 46.6, 115.0, 127.6, 127.8, 128.7, 137.8, 140.3, 143.9, 148.4, 162.2
δH = 0.95 (3 H, t, J = 7.4 Hz, CH2CH3), 1.61 (2 H, sext, J = 7.4 Hz, CH2CH2CH3), 3.35 (2 H, br q, J = 6.8 Hz, NHCH2CH2), 3.38 (2 H, t, J = 6.9
Hz, 4-CH2), 3.50 (2 H, t, J = 6.8 Hz, 5-CH2), 4.76 (2 H, s, NCH2Ph), 6.32 (1 H, br s, NH), 7.30–7.38 (5 H, m, C6H5), 7.92 (1 H, s, 2-H)
δC = 11.4, 21.4, 22.9, 41.3, 43.9, 51.5, 115.2, 128.1, 128.2, 129.0, 135.7, 140.3, 143.7, 148.4, 162.3
δH = 0.96 (3 H, t, J = 7.4 Hz, CH2CH3), 1.61 (2 H, sext, J = 7.3 Hz, CH2CH2CH3), 3.18 (3 H, s, NCH3), 3.35 (2 H, br q, J = 6.8 Hz,
NHCH2CH2), 3.45 (2 H, t, J = 6.9 Hz, 4-CH2), 3.60 (2 H, t, J = 6.6 Hz, 5-CH2), 6.52 (1 H, br t, J = 4.9 Hz, NH), 7.92 (1 H, s, 2-H)
δC = 11.5, 21.3, 22.9, 35.8, 41.2, 46.7, 115.3, 140.3, 143.5, 148.5, 162.4
δH = 3.37 (2 H, t, J = 6.8 Hz, 4-CH2), 3.38 (3 H, s, OCH3), 3.50 (2 H, t, J = 6.8 Hz, 5-CH2), 3.53 (2 H, br t, J = 4.8 Hz, CH2CH2OMe), 3.59 (2
H, br q, J = 5.2 Hz, NHCH2CH2), 4.76 (2 H, s, NCH2Ph), 6.46 (1 H, br s, NH), 7.30–7.38 (5 H, m, C6H5), 7.90 (1 H, s, 2-H)
δC = 21.4, 39.1, 43.8, 51.5, 58.9, 71.0, 115.0, 128.1, 128.2, 128.9, 135.7, 140.3, 143.7, 148.4, 162.2
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Synthesis
Table 3 (continued)
Compound Solvent
1H NMR (500 MHz, δ) and 13C NMR (126 MHz, δ)
3f
CDCl3
δH = 3.19 (3 H, s, NCH3), 3.39 (3 H, s, OCH3), 3.46 (2 H, t, J = 6.8 Hz, 4-CH2), 3.55 (2 H, br t, J = 4.8 Hz, CH2CH2OMe), 3.58–3.64 (4 H, m,
NHCH2CH2 and 5-CH2), 6.59 (1 H, br s, NH), 7.90 (1 H, s, 2-H)
δC = 21.3, 35.8, 39.1, 46.6, 58.8, 71.0, 115.0, 140.2, 143.7, 148.4, 162.4
3g
CDCl3
δH = 3.37 (2 H, t, J = 6.2 Hz, 4-CH2), 3.49 (2 H, t, J = 6.3 Hz, 5-CH2), 4.68 (2 H, d, J = 5.3 Hz, NHCH2Py), 4.74 (2 H, s, NCH2Ph), 7.24 (1 H,
br ddd, J = 7.6, 5.0, 1.2 Hz, 5′-H), 7.30–7.37 (6 H, m, C6H5 and 3′-H), 7.69 (1 H, br s, NH), 7.70 (1 H, td, J = 7.7, 1.8 Hz, 4′-H), 8.01 (1 H,
s, 2-H), 8.53 (1 H, br ddd, J = 4.9, 1.6, 0.8 Hz, 6′-H)
δC = 21.8, 44.2, 44.4, 51.8, 115.4, 122.9, 123.1, 128.5, 128.6, 129.3, 136.1, 137.8, 141.1, 144.0, 148.8, 149.0, 156.6, 162.7
3h
3i
CDCl3
CDCl3
δH = 1.92–1.99 (2 H, m, CH2CH2CH2), 2.57 [6 H, s, N(CH3)2], 2.83 (2 H, t, J = 6.6 Hz, CH2CH2NMe2), 3.34–3.40 (2 H, m, 4-CH2), 3.46–
3.53 (4 H, m, NHCH2CH2 and 5-CH2), 4.76 (2 H, s, NCH2Ph), 7.31–7.38 (5 H, m, C6H5), 8.00 (1 H, s, 2-H), 8.18 (1 H, br s, NH)
δC = 21.8, 25.2, 41.1, 44.0, 44.3, 51.8, 56.6, 115.7, 128.5, 128.5, 129.3, 136.1, 141.5, 143.9, 148.9, 163.1
δH = 1.78 (2 H, br quint, J = 5.6 Hz, CH2CH2CH2), 3.37 (2 H, t, J = 6.8 Hz, 4-CH2), 3.50 (2 H, t, J = 6.8 Hz, 5-CH2), 3.55 (2 H, br q, J = 5.8
Hz, NHCH2CH2), 3.74 (2 H, br t, J = 5.5 Hz, CH2CH2OH), 3.98 (1 H, br s, OH), 4.74 (2 H, s, NCH2Ph), 7.30–7.38 (6 H, m, C6H5 and NH),
8.01 (1 H, s, 2-H)
δC = 21.3, 31.5, 37.0, 43.9, 51.5, 60.1, 115.2, 128.1, 128.3, 129.0, 135.5, 140.8, 143.7, 148.7, 163.0
3j
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
δH = 1.88–2.05 (4 H, m, Hpyrrolidine), 3.34 (2 H, t, J = 6.4 Hz, 4-CH2), 3.49 (2 H, t, J = 6.4 Hz, 5-CH2), 3.60 (2 H, br t, J = 6.6 Hz, Hpyrrolidine),
3.69 (2 H, br t, J = 6.4 Hz, Hpyrrolidine), 4.77 (2 H, s, NCH2Ph), 7.31–7.38 (5 H, m, C6H5), 7.88 (1 H, s, 2-H)
δC = 22.2, 24.4, 26.9, 44.3, 46.9, 48.8, 51.8, 116.1, 128.5, 128.6, 129.3, 136.2, 141.6, 144.7, 148.9, 162.4
3k
3l
δH = 1.62 (4 H, br s, Hpiperidine), 1.68–1.73 (2 H, m, Hpiperidine), 3.18 (2 H, t, J = 6.7 Hz, 4-CH2), 3.50 (2 H, t, J = 6.7 Hz, 5-CH2), 3.60 (4 H, br
s, Hpiperidine), 4.77 (2 H, s, NCH2Ph), 7.30–7.38 (5 H, m, C6H5), 7.71 (1 H, s, 2-H)
δC = 21.3, 24.5, 25.6, 26.6, 43.3, 43.8, 48.6, 51.4, 115.0, 128.1, 128.2, 128.9, 135.8, 141.3, 142.8, 148.4, 162.6
δH = 1.64 (4 H, br s, Hpiperidine), 1.70–1.75 (2 H, m, Hpiperidine), 3.20 (3 H, s, NCH3), 3.28 (2 H, t, J = 6.8 Hz, 4-CH2), 3.62 (2 H, t, J = 6.8 Hz,
5-CH2), 3.62 (4 H, br s, Hpiperidine), 7.69 (1 H, s, 2-H)
δC = 21.1, 24.5, 25.6, 26.7, 35.8, 43.4, 46.6, 48.6, 114.9, 141.0, 142.8, 148.4, 162.7
3m
3n
3o
3p
3q
δH = 3.20 (2 H, t, J = 6.7 Hz, 4-CH2), 3.52 (2 H, t, J = 6.7 Hz, 5-CH2), 3.70 (4 H, br s, 4 Hmorpholine), 3.72 (4 H, br s, Hmorpholine), 4.77 (2 H, s,
NCH2Ph), 7.30–7.38 (5 H, m, C6H5), 7.72 (1 H, s, 2-H)
δC = 21.3, 42.6, 43.8, 47.7, 51.5, 66.8, 114.1, 128.2, 128.3, 129.0, 135.7, 141.1, 143.5, 148.3, 162.8
δH = 3.20 (3 H, s, NCH3), 3.29 (2 H, t, J = 6.8 Hz, 4-CH2), 3.63 (2 H, t, J = 6.8 Hz, 5-CH2), 3.71 (4 H, br s, Hmorpholine), 3.73 (4 H, br s,
Hmorpholine), 7.69 (1 H, s, 2-H)
δC = 21.2, 35.8, 42.5, 46.6, 47.6, 66.8, 114.1, 140.9, 143.4, 148.2, 162.8
δH = 2.34 (3 H, s, NCH3), 2.43–2.49 (4 H, m, Hpiperazine), 3.18 (2 H, t, J = 6.7 Hz, 4-CH2), 3.50 (2 H, t, J = 6.7 Hz, 5-CH2), 3.69 (4 H, br s,
Hpiperazine), 4.75 (2 H, s, NCH2Ph), 7.30–7.39 (5 H, m, C6H5), 7.70 (1 H, s, 2-H)
δC = 21.6, 41.1, 44.2, 46.2, 51.8, 55.2, 115.0, 128.6, 128.6, 129.3, 136.1, 141.7, 143.5, 148.8, 162.9
δH = 1.23 (6 H, br t, J = 7.0 Hz, 2 × NCH2CH3), 3.21 (2 H, t, J = 6.7 Hz, 4-CH2), 3.44–3.53 (6 H, m, 2 × NCH2CH3 and 5-CH2), 4.77 (2 H, s,
NCH2Ph), 7.31–7.38 (5 H, m, C6H5), 7.74 (1 H, s, 2-H)
δC = 12.9, 14.7, 21.4, 40.0, 43.1, 43.9, 51.4, 115.4, 128.1, 128.2, 128.9, 135.8, 140.6, 143.3, 148.5, 163.1
δH = 3.07 (3 H, br s, NCH3), 3.25 (2 H, br t, J = 6.7 Hz, 4-CH2), 3.50 (2 H, br t, J = 6.7 Hz, 5-CH2), 4.69 (2 H, s, NMeCH2Ph), 4.77 (2 H, s,
NCH2Ph), 7.29–7.40 (10 H, m, 2 × C6H5), 7.60 and 7.79 (1 H, 2 br s, 1:1, 2-H)
δC = 21.5, 33.9/36.6, 43.8, 51.1/54.7, 51.4, 114.9, 126.2, 127.6, 128.1, 128.2, 128.8/129.1, 128.9, 135.8, 136.3/136.7, 140.8/141.4,
143.7, 148.4, 163.8/164.6
3r
CDCl3
δH = 3.09 [3 H, br s, N(CH3)CH2Ph], 3.20 (3 H, s, NCH3), 3.32–3.38 (2 H, m, 4-CH2), 3.61 (2 H, br t, J = 6.6 Hz, 5-CH2), 4.71 (2 H, s,
NMeCH2Ph), 7.19–7.40 (5 H, m, C6H5), 7.54 and 7.80 (1 H, 2 br s, 1:1, 2-H)
δC = 21.5, 32.7, 35.9, 46.8, 53.4, 106.5, 128.9, 129.0, 129.8, 132.9, 141.7, 143.9, 148.5, 162.5
In the 1H NMR spectra of the ‘open-chain’ intermediates
6 and 7, the signals for the methylene protons of the amino-
ethyl residue Het–CH2CH2–NRR′ generally appear as broad
signals. Like in analogous compounds,11–14 such broadening
is explainable by two effects, first by a somewhat hindered
(or slow) rotation around the C–C and C–N single bonds in
the aminoethyl residue in CDCl3 or DMSO-d6 solution and
second, by fast tautomerization of the pyrazole residue be-
tween the 1H- and the 2H-form.18 On the other hand, the
signals for the methylene protons in the nontautomerizable
bicyclic analogues 3, 8, and 9 appear as sharp triplets with a
very characteristic vicinal coupling constant 3J4H,5H = 6.8 Hz.
This indicates that broad signals for C–H protons in the
NMR spectra of the open-chain derivatives 6 and 7 are pre-
dominantly due to their fast tautomerization in solution
(Scheme 5).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 497–506

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Synthesis
R1
N
R1
N
Experimental and characterization data for compounds 5b,c, 6a–c,
7a–c, 8a–d, 9a,b, and 3a–r are given in Tables 1–3.
H
N
R
R
N
fast
Potassium Monobenzyl Malonate
N
NH
A solution of 85% KOH (16.5 g, 0.25 mol) in anhydrous EtOH (500 mL)
was slowly added to a vigorously stirred solution of malonic acid
monobenzyl ester19 (50 g, 0.258 mol) in anhydrous EtOH (250 mL) at
~20 °C (water bath). The so formed suspension was diluted with Et2O
(500 mL), the precipitate was collected by filtration, and washed with
Et2O (2 × 100 mL) to give potassium monobenzyl malonate as a white
solid in quantitative yield.
ROOC
1H-tautomer
ROOC
2H-tautomer
compounds 6 and 7
O
R1
N
N
N
N-Substituted Benzyl 5-(tert-Butoxycarbonylamino)-3-oxopent-
anoates 5b,c
X = OH, OR, NR2R3
H2C
C
H2
Under argon, 1,1′-carbonyldiimidazole (CDI, 20.3 g, 125 mmol) was
added to a solution of respective 4a,b (100 mmol) in anhydrous THF
(200 mL) and the mixture was stirred at r.t. for 2 h. Then a solid mix-
ture of anhydrous MgCl2 (9.2 g, 97 mmol) and potassium monobenzyl
malonate (34.8 g, 150 mmol) was added under argon in one portion
via a powder funnel, which was rinsed with anhydrous THF (50 mL),
and the mixture was stirred under argon at r.t. for 24 h. Volatile com-
ponents were evaporated in vacuo, EtOAc (300 mL) was added to the
residue, and the resulting suspension was washed with 1 M aq
NaHSO4 (2 × 100 mL) and brine (2 × 100 mL). The organic phase was
dried (Na2SO4), filtered, and the filtrate was evaporated in vacuo to
give respective 5b,c, which were used for further transformations
without purification.
X
O
3J4H,5H = 6.8 Hz (triplet)
compounds 3, 8, and 9
Scheme 5 Fast tautomerization of 6 and 7 in solution
In conclusion, two variants of a synthetic method that
enable the preparation of tetrahydropyrazolo[1,5-c]pyrimi-
dine-3-carboxamides 3 as novel histamine analogues were
developed. To the best of our knowledge, title compounds 3
are also the first representatives of the so far unknown par-
tially saturated heterocyclic system. Novel compounds 3
may be useful in various applications.
N-Substituted Alkyl/Benzyl 5-[2-(tert-Butoxycarbonylamino)eth-
yl]-1H-pyrazole-4-carboxylates 6a–c
A mixture of 5 (10 mmol), anhydrous CH2Cl2 (20 mL), and DMFDMA
(1.33 mL, 10 mmol) was stirred at r.t. for 20 h and volatile compo-
nents were evaporated in vacuo. The residue (the crude enaminone
intermediate14) was dissolved in MeOH (20 mL), N2H4·HCl (685 mg, 10
mmol) was added, and the mixture was stirred at r.t. for 24 h. Volatile
components were evaporated in vacuo, the residue was triturated
with H2O (30 mL) and the product was extracted with EtOAc (2 × 40
mL). The combined organic phases were washed with brine (3 × 20
mL), dried (Na2SO4), filtered, and the filtrate was evaporated in vacuo.
The residue was purified by CC (EtOAc–hexanes). Fractions containing
the product were combined and evaporated in vacuo to give 6a–c.
Melting points were determined on a Stanford Research Systems
MPA100 OptiMelt automated melting point system. NMR spectra
were obtained on a Bruker Avance III UltraShield 500 spectrometer
plus at 500 MHz for 1H and 126 MHz for 13C nucleus, using CDCl3 and
DMSO-d6 as solvents with TMS as the internal standard. Mass spectra
were recorded on an Agilent 6224 Accurate Mass TOF LC/MS spec-
trometer and IR spectra on a Bruker FTIR Alpha Platinum ATR spec-
trophotometer. Microanalyses were performed on a PerkinElmer CHN
Analyzer 2400 II. Column chromatography (CC) and dry-vacuum flash
chromatography (DVFC)17 were performed on silica gel (Fluka, Silica
gel 60, particle size 0.035–0.070 mm). Catalytic hydrogenation was
carried out on a Parr 3916EF Hydrogenation Apparatus (500 mL).
Methyl/Benzyl 5-[2-(Substituted amino)ethyl]-1H-pyrazole-4-car-
boxylate Dihydrochlorides 7a–c
A 2 M solution of HCl–EtOAc (50 mL, 100 mmol) was added to a
stirred solution of 6 (10 mmol) in EtOAc (50 mL) and the mixture was
stirred at r.t. for 5 h. The precipitate was collected by filtration
through a sintered glass funnel and washed with EtOAc (2 × 15 mL) to
give 7a–c.
Parallel stirring and filtration was carried out on Mettler-Toledo
Bohdan MiniBlock™ Compact Shaking and Washing Station and Vac-
uum Collection Base (2 × 12 positions, Vortex stirring, 400 r.p.m. in all
cases). Parallel evaporations were carried out on Büchi Syncore® Poly-
vap parallel reactor (24 positions, Vortex stirring, 400 r.p.m. in all cas-
es). Parallel drying of the products was carried out on Hettlab IR-
Dancer Infra-Red Vortex-Evaporator (42 positions, Vortex stirring,
400 r.p.m. in all cases).
Benzyl 7-Oxo-4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidine-3-car-
boxylate (8c)
Boc-β-alanine (4a), hydrazine hydrochloride, CDI, DMFDMA, alkyl ha-
lides 10a,b, amines 11a–l, Et3N, anhydrous MgCl2, anhydrous K2CO3,
10% Pd/C (Sigma-Aldrich), dibenzyl malonate (TCI Europe), and BPC
(ABCR) are commercially available. Malonic acid monobenzyl ester19
and β-keto ester 5a13c were prepared following the literature proce-
dures.
Et3N (3.93 mL, 28.2 mmol) and CDI (2.08 g, 12.8 mmol) were added to
a stirred suspension of 7c (4.07 g, 12.8 mmol) in MeCN (70 mL) and
the mixture was stirred at r.t. for 4 days. Then, silica gel (15 g) was
added to the reaction mixture and the so formed suspension was
carefully evaporated in vacuo. The solid sandy residue was poured
onto a stabilized column (7.5 × 15 cm, silica gel, EtOAc) and the prod-
uct was eluted with EtOAc. Fractions containing the product were
combined and evaporated in vacuo to give 8c.
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505
K. Lombar et al.
Paper
Synthesis
6-Substituted Alkyl/Benzyl 7-Oxo-4,5,6,7-tetrahydropyrazolo[1,5-
c]pyrimidine-3-carboxylates 8a,b,d
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379547. Included are 1H and 13C
Method A, Cyclization of 7a,b with CDI: Et3N (1.04 mL, 7.48 mmol) and
CDI (551 mg, 3.40 mmol) were added to a stirred suspension of re-
spective 7a,b (3.40 mmol) in MeCN (45 mL) and the mixture was
stirred at r.t. for 5 h. Volatile components were evaporated in vacuo,
the residue was dissolved in EtOAc (100 mL) and the solution was
washed with brine (50 mL), 1 M aq HCl (50 mL), and brine (50 mL).
The organic phase was dried (Na2SO4), filtered, and the filtrate was
evaporated in vacuo to give respective 8a,b.
NMR spectra of compounds 3 and 5–9.
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References
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Method B, Alkylation of 8c with Alkyl Halides 10a,b: Under argon, BnBr
(10a; 1.07 mL, 9 mmol) or MeI (10b; 1.12 mL, 18 mmol) was added to
a stirred mixture of 8c (271 mg, 1 mmol), K2CO3 (553 mg, 4 mmol),
and anhydrous DMF (5 mL) and the mixture was stirred under argon
for 5 days. Volatile components were evaporated in vacuo, H2O (25
mL) was added to the residue, and the product was extracted with
EtOAc (50 mL). The organic phase was washed with H2O (2 × 25 mL),
brine (2 × 25 mL), dried (Na2SO4), filtered, and the filtrate was evapo-
rated in vacuo to give respective 8b,d. Compound 8b was additionally
purified by CC (EtOAc–hexanes). Fractions containing the product
were combined and evaporated in vacuo to give the purified com-
pound 8b.
6-Alkyl-7-oxo-4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidine-3-car-
boxylic Acids 9a,b
A mixture of the benzyl ester 8b,d (1 mmol), 10% Pd/C (~30 mg), and
MeOH (15 mL) was hydrogenated (1 bar of H2) at r.t. for 4 h (8b → 9a)
or 31 h (8d → 9b). The catalyst was removed by filtration, washed
with MeOH (2 × 10 mL), and the combined filtrate was evaporated in
vacuo to give the respective acids 9a,b.
Parallel Synthesis of 6-Alkyl-7-oxo-4,5,6,7-tetrahydropyrazo-
lo[1,5-c]pyrimidine-3-carboxamides 3a–r
MiniBlock™ parallel reactors with 12 positions were equipped with
fritted-bottom reaction vessels and charged with carboxylic acids 9a
(12 × 136 mg, 12 × 0.5 mmol) and 9b (6 × 98 mg, 6 × 0.5 mmol), MeCN
(18 × 5 mL), and Et3N (18 × 0.07 mL, 18 × 0.5 mmol), and the reaction
mixtures were stirred at r.t. for 5 min. Then, BPC (18 × 197 mg, 18 ×
0.5 mmol) was added and the reaction mixtures were stirred at r.t. for
45 min (activation of carboxylic acids 9). Next, primary amines 11a–f
(9 × 0.5 mmol) or secondary amines 11g–l (9 × 5.0 mmol) and Et3N
(18 × 0.07 mL, 18 × 0.5 mmol) were added and stirring at r.t. was con-
tinued for 18 h. The reaction mixtures were filtered, washed with
MeCN (18 × 2 mL) and the combined filtrates were evaporated in vac-
uo on Syncore® Polyvap (80 °C/2 mbar) to give the crude semi-solid
carboxamides 3a–r. The strongly basic carboxamide 3h was purified
by drying at 60 °C/0.01 mbar for 3 h. The other carboxamides 3a–g,i–r
were purified by DVFC on silica gel (d = 1.5 cm, h = 5 cm, EtOAc or
EtOAc–EtOH, 70 mL). The combined eluates were evaporated in vacuo
and the residues were dried at 60 °C/0.01 mbar for 3 h to give the pu-
rified carboxamides 3a–g,i–r.
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Financial support from Boehringer-Ingelheim Pharma (Biberach, Ger-
many) and from the Slovenian Research Agency through grant P1-
0179 is gratefully acknowledged.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 497–506