Regioselective synthesis of 1- and 4-substituted 7-oxopyrazolo[1,5-a]pyrimidine-3-carboxamides

Article abstract of DOI:10.1016/j.tet.2014.09.020

The synthesis of 7-substituted pyrazolo[1,5-a]pyrimidine-3-carboxamides was studied. First, methyl 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (5) was prepared in three steps from methyl 5-amino-1H-pyrazole-4-carboxylate (3). Treatment of 5 with POCl₃ gave the highly reactive 7-chloro derivative 10, which was reacted with amines, benzyl alcohol, and phenylboronic acid in the presence of Pd-catalyst to give the corresponding 7-substituted derivatives 11. Hydrolysis of the esters 5 and 11 followed by amidation gave the corresponding carboxamides 16a-h and 15. Regioselectivity of N-alkylation of 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid derivatives 5 and 16 was tunable by the carboxy function. Alkylation of the secondary amides 16a-f furnished the 1-alkyl derivatives 17a-f, whereas the ester 5 and the tertiary amides 16g,h gave the 4-alkyl derivatives 14a-d and 16m,n, selectively.

Full text of DOI:10.1016/j.tet.2014.09.020

Tetrahedron 70 (2014) 8267e8279
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective synthesis of 1- and 4-substituted 7-oxopyrazolo
[1,5-a]pyrimidine-3-carboxamides
a
a
,
a
a
a
ꢀ
ꢀ
*
ꢀ
ꢀ
ꢀ
Miha Drev , Uros Groselj , Spela Mevec , Eva Pusavec , Janja Strekelj ,
b
a
a,
*
ꢀ a
Amalija Golobic , Georg Dahmann , Branko Stanovnik , Jurij Svete
a
ꢀ
ꢀ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, SI e 1000 Ljubljana, Slovenia
b Medicinal Chemistry, Boehringer-Ingelheim Pharma GmbH&Co. KG, 88397 Biberach, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 July 2014
Received in revised form 30 August 2014
Accepted 8 September 2014
Available online 16 September 2014
The synthesis of 7-substituted pyrazolo[1,5-a]pyrimidine-3-carboxamides was studied. First, methyl 7-
hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (5) was prepared in three steps from methyl 5-
amino-1H-pyrazole-4-carboxylate (3). Treatment of 5 with POCl3 gave the highly reactive 7-chloro de-
rivative 10, which was reacted with amines, benzyl alcohol, and phenylboronic acid in the presence of
Pd-catalyst to give the corresponding 7-substituted derivatives 11. Hydrolysis of the esters 5 and 11
followed by amidation gave the corresponding carboxamides 16aeh and 15. Regioselectivity of N-al-
kylation of 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid derivatives 5 and 16 was tunable by
the carboxy function. Alkylation of the secondary amides 16aef furnished the 1-alkyl derivatives 17aef,
whereas the ester 5 and the tertiary amides 16g,h gave the 4-alkyl derivatives 14aed and 16m,n,
selectively.
Keywords:
Pyrazolo[1,5-a]pyrimidines
Heterocycles
Cyclization
Regioselective alkylation
Amidation
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Annelated heterocycles are important scaffolds for the prepa-
ration of compound libraries for medicinal and pharmaceutical
applications.1 Among 5e6-fused systems, pyrazolo[1,5-a]pyrimi-
dine is an important heterocycle, due to biological activity of many
of its derivatives.2 For example, a literature search shows more than
100,000 known pyrazolo[1,5-a]pyrimidine derivatives with almost
5000 references and with preparation, biological study, and uses as
the predominant substance roles. For 2014 alone, over one hundred
references can be found for w15,000 pyrazolo[1,5-a]pyrimidines.
Examples of bioactive pyrazolo[1,5-a]pyrimidines include hepatitis
C virus inhibitors,3 antagonists of serotonin 5-HT6 receptors,4 ki-
nase inhibitors,5 PET tumour imaging agents,6 and inhibitors of
Fig. 1. Approved drugs containing a pyrazolo[1,5-a]pyrimidine.
Nevertheless, a more detailed literature search also reveals that 7-
alkoxy-, and 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxamides
are much less known, while their 5,6-unsubstituted analogues
are, to the best of our knowledge, unknown. In continuation of our
long-term study on utilization of enaminones as reagents and/or
key-intermediates in heterocyclic11 and combinatorial syntheses,12
we recently focused our attention on the synthesis and trans-
formations of derivatives of pyrazolo[1,5-a]pyrimidine-3-
carboxamide. Within this context, we recently reported a parallel
synthesis of 24 novel 7-(pyridin-2-yl)- and 7-pyrazinyl substituted
pyrazolo[1,5-a]pyridine-3-carboxamides from 3-(dimethylamino)-
1-(heteroaryl)prop-2-en-1-ones.12a In extension, we tried to de-
amyloid
b
-peptide 1e42 aggregation.7 Sedative agents zaleplon
and indiplon and the anxyolytic agent ocinaplon are approved
drugs containing a pyrazolo[1,5-a]pyrimidine core (Fig. 1).
Pyrazolo[1,5-a]pyrimidines are commonly available by cyclo-
condensation of a 3-aminopyrazole derivative with a 1,3-dicarbonyl
compound2,8 or its synthetic equivalent, such as a -alkoxy-9 or
b b-
amino enone.10 Due to this ease of access, a plethora of known
pyrazolo[1,5-a]pyrimidine derivatives (see above) is not surprising.
* Corresponding authors. Tel.: þ386 1 2419 254; fax: þ386 1 2419 220; e-mail
address: jurij.svete@fkkt.uni-lj.si (J. Svete).
velop another synthetic approach utilizing a pyrazolo[1,5-a]
http://dx.doi.org/10.1016/j.tet.2014.09.020
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

8268
M. Drev et al. / Tetrahedron 70 (2014) 8267e8279
pyrimidine central building block for a late-stage derivatisation at
different positions. Herein we report the results, the synthesis of
methyl 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (5) as
the central building block and its transformations into differently
substituted pyrazolo[1,5-a]pyrimidine-3-carboxamides.
due to an E/Z-equilibrium between the isomers of substitution in-
termediates 4 and 40. Probably, this equilibrium is strongly shifted
towards the thermodynamically more stable (E)-isomer 4, which
cannot easily cyclize (Scheme 1).
If the above explanation was correct, then cyclisation of 3 with
dimethyl (dimethylamino)methylidenemalonate (6a) should take
place easily,15 since one of the ester groups is always in position to
undergo cyclisation. Indeed, treatment of 3 with 6a in refluxing
acetic acid produced the cyclisation product 7a in 41% yield. Vari-
ation of solvent, temperature, and reaction time did not improve
the yield of 7a. Hydrolysis of 7a with 1e2 equivalents of aqueous
KOH in methanol under various conditions produced mixtures of
regioisomeric (semi)hydrolysed products, whereas the reaction
with excess LiOH$H2O gave the diacid 8a, which decarboxylated
2. Results and discussion
2.1. Synthesis of target compounds
The initial idea was to prepare the central intermediate 5 in two
steps from methyl propiolate (1) via 1,4-addition of diethylamine to
give the enaminone 213 followed by cyclisation with methyl 5-
amino-1H-pyrazole-4-carboxylate (3) in refluxing acetic acid. Al-
at 250 ꢀC for
4 h to give 7-oxo-4,7-dihydropyrazolo[1,5-a]
pyrimidine (9)10a,16 in 51% yield. To obtain the desired central in-
termediate 5, the carboxy groups in the diester 7 had to be or-
thogonally protected. The dibenzyl ester 6b was cyclized into the 6-
benzyl 3-methyl 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-
dicarboxylate (7b). Though hydrogenolytic debenzylation of 7b
gave the mono-acid 8b in 89% yield, this method was suitable only
for a small scale preparation of 10 (<3 mmol), due to extremely low
solubility of 7b and 8b in most organic solvents including DMF. On
the other hand, acidolytic debenzylation of 7b with HBr/AcOH
proceeded smoothly to give 8b in 70% yield. Finally, de-
carboxylation of 8b with Cu/quinoline at 180 ꢀC furnished 5 in 75%
yield (Scheme 2).
though numerous enaminones cyclize smoothly with
a-amino
azoles and azines under these conditions,11 the reaction of enami-
none 2 with 3-aminopyrazole 3 under the above conditions gave
a 1:3 mixture of the intermediate 4 and the product 5 in w50%
yield. Crystallization of a mixture of 4 and 5 from ethanol provided
the desired central intermediate 5 in only 10% yield. Unfortunately,
crystallization of a mixture of 4 and 5 from ethanol was not re-
producible. At best, improvement of the product ratio of 4:5 to
w1:10 was achieved. Neither did prolonged heating in acetic acid,
nor prolonged microwave-assisted heating at 180 ꢀC did not affect
the product ratio. It is noteworthy that attempts to obtain 5 from 3
and ethyl 2,2-diethoxyacetate following the literature procedure
for the synthesis of the ethyl analogue of 514 were not successful,
either. When the neat mixture of 4 and 5 was heated at 250 ꢀC for
3 h, the product ratio of 4:5 improved to w 1:5. Our difficulty to
prepare pure compound 5 in reasonable yield and purity may be
Scheme 2. Reaction conditions: (i) Compound 3, AcOH, reflux; (ii) LiOH$H2O, MeOH,
reflux; (iii) 250 ꢀC (neat), 4 h; (iv) H2 (3 bar), PdeC, DMF, rt; (v) 33% HBr/AcOH, 60 ꢀC;
(vi) quinoline, Cu (cat.), 180 ꢀC.
Scheme 1. Reaction conditions: (i) Et2NH, CH2Cl2, 0 ꢀC (Ref. 13); (ii) AcOH, reflux; (iii)
Once access to the central intermediate 5 was gained, we
studied the substitution of the oxo group. Treatment of 5 with the
250 ꢀC (neat), 3 h; (iv) crystallization from EtOH.

M. Drev et al. / Tetrahedron 70 (2014) 8267e8279
8269
standard chlorination reagents POCl3 or POCl3/PCl5 did not give the
desired chloride 10, even upon prolonged heating under reflux. On
the other hand, chlorination in the presence of N,N-dimethylaniline
or Et3N at 100 ꢀC did give 10, however, the yields were not re-
producible. The best yield was obtained by treating 5 with POCl3 in
the presence of 2 equiv of Et3N under reflux for 3 h (75% yield). The
chloride 10 was highly reactive and hydrolysed back into 5 within
two weeks unless stored under anhydrous conditions. Thus, 10 had
to be used for further transformations immediately upon isolation.
SuzukieMiyaura cross-coupling of 10 with phenylboronic acid in
the presence of a Pd-catalyst gave the 7-phenyl derivative 11a,
whereas nucleophilic substitution with benzyl(methyl)amine pro-
duced the corresponding amino derivative 11b. Attempted sub-
stitution with sodium benzylate in benzyl alcohol was not
successful and gave the hydroxy compound 5. However, reaction of
10 with excess benzyl alcohol in dichloromethane in the presence
of 1 equiv of aq NaOH and a phase-transfer catalyst afforded the 7-
benzyloxy derivative 11c in 71% yield. Finally, the esters 11aec were
hydrolysed with aq NaOH in methanol at 50 ꢀC. The hydrolysis of
11a,b with NaOH produced the desired carboxylic acids 12a,b,
whereas reaction of 11c somewhat unexpectedly proceeded pref-
erentially at position C(7) to give the central intermediate 5
(Scheme 3).
good yields. Quite surprisingly, the same treatment of the N-benzyl
analogue 13b gave a non-separable mixture of products with 14c as
the minor component. Therefore, the acid 14c was prepared in two
steps via transesterification of 13b into the benzyl ester 13e, fol-
lowed by regioselective hydrogenolytic O-debenzylation. It is
noteworthy that mild reaction conditions and a short reaction time
were essential, otherwise both benzyl groups were removed
(Scheme 4).
Scheme 4. Reaction conditions: (i) ReX, K2CO3, DMF, rt; (ii) LiOH$H2O, H2O, rt; (iii)
BnOH, DBU (1 equiv), 150 ꢀC; (iv) H2 (balloon), PdeC, rt, 15 min.
Carboxylic acids 12a,b and 14aec were amidated using
bis-(pentafluorophenyl) carbonate (BPC) as the activating reagent.
As usual, these amidations proceeded smoothly to provide the
corresponding carboxamides 15aec and 16aeq in good yields. Fi-
nally, the alkylation of different secondary and tertiary carbox-
amides 16b,deh was performed with alkyl halides in the presence
of a base. To our surprise, the regioselectivity of N-alkylation was
dependent on the carboxamide moiety. Thus, alkylation of the
secondary amides 16b,def (R2 or R3¼H) led to the 1-alkyl
regioisomers 17aef, whereas alkylation of the tertiary carbox-
amides 16g and 16h furnished the 4-alkyl derivatives 16m and 16n.
In other words, the regioselectivity of N-alkylation of 7-oxo-4,7-
dihydropyrazolo[1,5-a]pyrimidine derivatives with purely hydro-
gen bond accepting groups at position 3 (COOMe, CONR2) were
alkylated at position N(4), whereas compounds with hydrogen
bond donor/acceptor groups (CONHR) were alkylated at position
N(1) (Scheme 5, Table 1).
A plausible rationale for N(4)-selective alkylation of the ester 5
(cf. Scheme 4) and the tertiary amides 16g,h is the (4)NeH/O]C
hydrogen bond-promoted tautomerization of the 4-NH tautomer
16 into the 1-NH tautomer 160, which could form a dimeric asso-
ciate in solution. Attack of the electrophile would then take place at
the sterically more accessible and more nucleophilic sp2 nitrogen
atom N(4) to give the 4-alkyl regioisomers 16m,n. Accordingly, the
1-NH tautomers of the secondary amides 160bef could also un-
dergo (4)N/HeNeC]O promoted tautomerization into the lactim
1600 with sterically accessible and nucleophilic sp2 nitrogen atom
N(1). Consequently, attack of the electrophile would then take place
at position 1 to furnish the 1-alkyl regioisomers 17 (Scheme 6).
Scheme 3. Reaction conditions: (i) POCl3, Et3N, reflux, 3 h; (ii) PhB(OH)2, Pd(PPh3)4-
[PdCl(allyl)]2, Cs2CO3, DMF, 95 ꢀC; (iii) Bn(Me)NH, MeCN, rt; (iv) BnOH, CH2Cl2, 2 M
NaOH, Bu4NþBre (cat.), rt; (v) 2 M NaOH, MeOH, 50 ꢀC.
N-Alkylation of the central intermediate 5 with primary alkyl
halides in DMF in the presence of potassium carbonate took place
regioselectively at position 4 to afford the 4-alkyl-7-oxo-4,7-
dihydropyrazolo[1,5-a]pyrimidine-3-carboxylates
13aed
in
19e100% yields. Hydrolysis of the central intermediate 5 and the N-
methyl derivative 13a gave the corresponding acids 14a and 14b in

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M. Drev et al. / Tetrahedron 70 (2014) 8267e8279
Scheme 6. A plausible rationale for regioselective N-alkylation of carboxamides 16.
2.2. Structure determination
Scheme 5. Reaction conditions: (i) BPC, Et3N, MeCN, rt, then R2R3NH, Et3N, rt, reflux;
(ii) R1eX, K2CO3, DMF, rt.
The structures of all novel compounds 5, 7, 8, 10e17 were de-
termined by spectroscopic methods (1H NMR, 13C NMR, IR, MS,
HRMS) and by elemental analyses for C, H, and N. Compounds 5,
7a,b, 8a,b, 10, 11aec, 12a, 13a,b,e, 14aec, 16j,p,q, and 17aef were
obtained in analytically pure form, whereas the identities of com-
Table 1
Experimental data for carboxamides 15aec, 16aeq, and 17aef
pounds 12b, 13c,d, 15a,b, and 16aei,keo,r,s were confirmed by 13
C
Cpd.
R1
NR2R3
Yield (%)
NMR and HRMS. 13C NMR spectrum of compound 16g could not be
recorded due to its low solubility in DMSO-d6.
15a
15b
15c
16a
16b
16c
16d
16e
16f
16g
16h
16i
16j
16k
16l
16m
16n
16o
16p
16q
16r
16s
17a
17b
17c
17d
17e
17f
Ph
N(Bn)Me
N(Bn)Me
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Me
Bn
NH(CH2)2OMe
NH(CH2)2OMe
NH(CH2)3NMe2
NH2
NH(CH2)2OMe
NH(CH2)3NMe2
NHCH2Ph
NHCH2C6H4e4-Me
NHCH2C6H3e3,5-Cl2
NMe2
Pyrrolidin-1-yl
NH-cy-C3H5
100
66
79
92
81
94
86
90
53
84
91
60
83
94
73
The regiochemistry of N(1)-(17aef) and N(1)-alkylated com-
pounds 13aee, 14b,c, and 16ies was primarily determined by NMR
(HMBC technique). Thus, a strong correlation through three bonds
between C(5) and CH2R and between C(5)eH and CH2R in HMBC
spectra of compounds 13b and 13d strongly supported attachment
of the alkyl group at position N(4). On the other hand, strong cor-
relation between C(2)eH and CH2R HMBC spectra of the 1-alkyl
regioisomers 17a and 17b were in agreement with the proposed
structures. The regiochemistry of the rest of compounds was de-
termined on the basis of correlation of vicinal coupling constants,
3J5He6Hw7.7 Hz for the 4-alkylated compounds 13, 14, and 16 and
3J5He6Hw6.3 Hz for the 1-alkyl analogues 17 (Fig. 2, Table 2).
Finally, the structures of compounds 13b, 16o, 17a, and 17b were
unambiguously determined by X-ray diffraction (Figs. 3e6).
NHCH2Ph
NH(CH2)3OH
2-Picolylamino
NMe2
Pyrrolidin-1-yl
Morpholin-4-yl
NH-cy-C3H5
83a, 93b
79a, 96b
94a
90
76
93
82
39
64
75
86
72
NHCH2Ph
NH(CH2)3NMe2
N(Me)CH2Ph
NH(CH2)2OMe
NH(CH2)2OMe
NHCH2Ph
NHCH2C6H3e3,5-Cl2
NHCH2Ph
NHCH2C6H4e4-Me
3. Conclusion
A new synthetic method for the late-stage derivatisation of
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid scaffold was de-
veloped. First, methyl 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimi-
dine-3-carboxylate (5) was prepared as the central intermediate in
three steps starting from dibenzyl malonate and methyl 3-amino-
1H-pyrazole-4-carboxylate (3) as starting materials. Chlorination of
Bn
Bn
3-MeOeBn
3-MeOeBn
91
a
From 14 by amidation.
From 16 by alkylation.
b

M. Drev et al. / Tetrahedron 70 (2014) 8267e8279
8271
Fig. 3. The molecular structure of 13b, showing the atom labelling. The displacement
ellipsoids are drawn with 50% probability and the hydrogen atoms are shown as small
spheres of arbitrary radii.
Fig. 4. The molecular structure of 16o, showing the atom labelling. The displacement
ellipsoids are drawn with 50% probability and the hydrogen atoms are shown as small
spheres of arbitrary radii.
Fig. 2. Structure determination by 1H NMR and HMBC NMR.
Table 2
Selected 1H NMR data for compounds 13aee, 14b,c, 16ies, and 17aef
Cpd.
3J5He6H (Hz)
d (ppm)
6-H
5-H
2-H
13a
13b
13c
13d
13e
14b
14c
16i
7.8
8.0
7.8
7.8
7.8
7.7
7.7
7.7
7.7
7.7
7.7
7.7
7.6
7.7
7.7
7.8
7.7
7.7
6.3
6.3
6.3
6.3
6.3
6.3
6.00
6.07
6.06
6.10
6.14
5.98
6.10
5.89
5.90
5.89
5.91
5.92
5.86
5.97
6.02
6.04
6.00
6.03
5.95
6.01
6.01
6.09
6.07
6.06
7.96
7.43
8.06
7.94
8.15
7.94
8.12
7.91
7.92
7.91
7.92
7.49
7.91
7.35
8.21
8.20
7.49
7.71/8.11a
8.00
8.02
8.00
7.94
7.92
7.91
8.27
8.32
8.31
8.28
8.33
8.23
8.25
8.10
8.22
8.13
8.27
7.90
8.16
7.86
8.05
8.19
7.96
8.19
8.80
9.19
9.22
8.37
8.41
8.37
16j
16k
16l
Fig. 5. The molecular structure of 17a, showing the atom labelling. The displacement
ellipsoids are drawn with 50% probability and the hydrogen atoms are shown as small
spheres of arbitrary radii.
16m
16n
16o
16p
16q
16r
16s
17a
17b
17c
17d
17e
17f
a
Mixture of rotamers.
5 gave the chloro derivative 10, which was a reactive intermediate
suitable for introduction of the amino, alkoxy, and aryl function at
position 7. Alkylation of 5 took place selectively at position N(1).
Hydrolysis of the ester group followed by amidation gave the title
Fig. 6. The molecular structure of 17b, showing the atom labelling. The displacement
ellipsoids are drawn with 50% probability and the hydrogen atoms are shown as small
spheres of arbitrary radii.

8272
M. Drev et al. / Tetrahedron 70 (2014) 8267e8279
carboxamides in good yields. Regioselectivity of N-alkylation of
various 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine derivatives
was tunable by the type of carbonyl function at position 3. Thus, the
alkylation was directed to position N(4) by hydrogen bond accep-
tors (COOMe, CONR2), whereas alkylation was directed to position
N(1) by hydrogen bond donors (CONHR). In summary, the pre-
sented synthetic method is simple and allows the late-stage dec-
oration of the heterocyclic scaffold. Therefore, it should be suitable
for the preparation of combinatorial libraries of 7-oxo-4,7-
dihydropyrazolo[1,5-a]pyrimidine-3-carboxamides, which might
be interesting for various biological and pharmaceutical
applications.
10 mmol) was added and the mixture was heated under reflux for
5 h. The reaction mixture was cooled to rt and the precipitate was
collected by filtration and washed with ethanol (2ꢂ10 mL) to give
the title compound 7. The following compounds were prepared in
this manner.
4.3.1. Dimethyl 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-
dicarboxylate (7a). Prepared from dimethyl malonate via enami-
none 6a. Yield: 1.04 g (41%) of pale yellow solid; mp 270e275 ꢀC;
[Found: C, 47.61; H, 3.39; N, 16.67. C10H9N3O5 requires: C, 47.81; H,
3.61; N,16.73%]; nmax (ATR) 3157, 3113, 3060, 2964,1743,1708,1622,
1581, 1507, 1438, 1322, 1237, 1124, 1025, 958, 799, 769, 747,
631 cmꢁ1
;
dH (300 MHz, DMSO-d6) 3.79 and 3.84 (6H, 2s, 2ꢂOMe),
4. Experimental
4.1. General
8.27 (1H, s, 2-H), 8.39 (1H, s, 5-H); dC (126 MHz, DMSO-d6) 51.5,
51.8, 98.4, 101.7, 134.4, 143.3, 146.4, 152.6, 161.8, 163.6; HRMS (ESI):
MHþ, found 252.062. C10H10N3O5 requires 252.0620.
Melting points were determined on a Stanford Research Sys-
tems MPA100 OptiMelt automated melting point system. The NMR
spectra were obtained on a Bruker Avance DPX 300 at 300 MHz for
1H and 75.5 MHz for 13C and on a Bruker Avance III UltraShield 500
plus at 500 MHz for 1H and 126 MHz for 13C, using CDCl3, and
DMSO-d6 with Me4Si as the internal standard, as solvents. Mass
spectra were recorded on a Q-Tof Premier spectrometer and on
a Agilent 6224 Accurate Mass TOF LC/MS spectrometer, IR spectra
on a PerkineElmer Spectrum BX FTIR spectrophotometer. Micro-
analyses were performed on a PerkineElmer CHN Analyzer 2400 II.
Flash column chromatography (FC) was performed on silica gel
4.3.2. 6-Benzyl-3-methyl 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimi-
dine-3,6-dicarboxylate (7b). Prepared from dibenzyl malonate via
enaminone 6b. Yield: 1.30 g (40%) of white solid; mp 240e247 ꢀC;
[Found: C, 57.95; H, 3.79; N, 12.65. C16H13N3O5$¼H2O requires: C,
57.92; H, 4.10; N, 12.66%]; nmax (ATR) 3194, 3116, 3065, 2959, 2946,
1744, 1685, 1642, 1598, 1506, 1455, 1437, 1356, 1282, 1248, 1199,
1180, 1122, 1035, 975, 778, 748, 696, 631 cmꢁ1
; dH (500 MHz,
DMSO-d6) 3.85 (3H, s, OMe), 5.32 (2H, s, CH2Ph), 7.35 (1H, t,
J¼7.3 Hz, p-Ph), 7.41 (2H, t, J¼7.5 Hz, m-Ph), 7.48 (2H, d, J¼7.1 Hz, o-
Ph), 8.30 (1H, s, 2-H), 8.41 (1H, s, 5-H), 12.86 (1H, s, NH); dC
(126 MHz, DMSO-d6) 51.6, 65.8, 98.4, 101.8, 127.8, 128.0, 128.5,
136.2, 142.2, 143.3, 146.1, 152.4, 161.8, 162.9. HRMS (ESI): MHþ,
found 328.0926. C16H14N3O5 requires 328.0933.
(Fluka, Silica gel 60, particle size 35e70 mm).
Methyl propiolate (1), dibenzyl malonate (TCI Europe), and BPC
(ABCR) are commercially available. Methyl 5-amino-1H-pyrazole-
4-carboxylate (3) was prepared following the literature
procedure.17
4.4. 7-Oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-
dicarboxylic acid (8a)
4.2. Synthesis of methyl 7-oxo-4,7-dihydropyrazolo[1,5-a]py-
rimidine-3-carboxylate (5) from methyl propiolate (1)
Dimethyl ester 7a (251 mg, 1 mmol) was added to a solution of
LiOH$H2O (251 mg, 6 mmol) in 50% aq MeOH (10 mL) and the
mixture was stirred under reflux for 1.5 h. Methanol was evapo-
rated in vacuo (35 ꢀC, 50 mbar) and the aqueous residue was
acidified with 1 M aq HCl to pHw3. The precipitate was collected by
filtration and washed with ether (2ꢂ5 mL) to give the title com-
pound 8a (177 mg, 79%) as a pale yellow solid; mp 280e285 ꢀC;
[Found: C, 41.88; H, 2.33; N, 18.22. C8H5N3O5$1/3 H2O requires: C,
41.94; H, 2.49; N, 18.34%]; nmax (ATR) 3089, 2940, 2742, 1742, 1707,
1627, 1583, 1500, 1462, 1435, 1376, 1346, 1285, 1256, 1200, 1145,
Diethylamine (2.8 mL, 27 mmol) was added to a cold solution of
1 (1.8 mL, 20 mmol) in dichloromethane (60 mL) at 0 ꢀC and the so
formed solution was stirred at 0 ꢀC for 5 h and the volatile com-
ponents were evaporated in vacuo (30 ꢀC, 20 mbar). The crude
enamino ester 2, which was obtained as yellow oil, was dissolved in
acetic acid (45 mL), aminopyrazole 3 (2.8 g, 20 mmol) was added
and the mixture was heated under reflux for 24 h. Volatile com-
ponents were evaporated in vacuo (40 ꢀC, 7 mbar) and the residue
was triturated with warm water (60 ꢀC, 50 mL). The precipitate was
collected by filtration and washed with ethanol (15 mL) to give
a 1:3 mixture of 4 and 5 (w2 g). Subsequent crystallization from
ethanol afforded the title compound 5 0.40 g (10%) as a pale yellow
solid; mp 280e287 ꢀC; [Found: C, 49.67; H, 3.40; N, 21.64.
C8H7N3O3 requires: C, 49.74; H, 3.65; N, 21.75%]; nmax (ATR) 3068,
2963, 1699, 1624, 1575, 1504, 1468, 1433, 1411, 1391, 1249, 1209,
1117, 1026, 912, 862, 822, 791, 775, 714, 663, 626 cmꢁ1
; dH
(500 MHz, DMSO-d6) 8.09 (1H, s, 2-H), 8.48 (1H, s, 5-H), 2ꢂCOOH
exchanged; dC (126 MHz, DMSO-d6) 99.7, 100.9, 143.5, 144.1, 146.9,
155.2, 163.1, 164.5, HRMS (ESI): MHþ, found 224.0302. C8H6N3O5
requires 224.0307.
4.5. 3-(Methoxycarbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]
pyrimidine-6-carboxylic acid (8b)
1150, 1123, 1069, 1017, 944, 904, 876, 800, 772, 719, 631 cmꢁ1
;
dH
(500 MHz, DMSO-d6) 3.83 (3H, s, OMe), 5.95 (1H, d, J¼7.5 Hz, 6-H),
7.85 (1H, d, J¼7.5 Hz, 5-H), 8.25 (1H, s, 2-H), 12.24 (1H, br s, 4-H); dC
(126 MHz, DMSO-d6) 51.5, 96.7, 99.1, 140.6, 142.9, 143.5, 155.8;
HRMS (ESI): MHþ, found 194.0557. C8H8N3O3 requires 194.0566.
Method A. A mixture of benzyl methyl ester 7b (1.635 g, 5 mmol),
10% PdeC (164 mg), and DMF (70 mL) was hydrogenated at rt under
3 bar of hydrogen for 1 h. The catalyst was removed by filtration
through a sintered glass funnel and washed with the DMF
(2ꢂ10 mL). The combined filtrate was evaporated in vacuo to
remove most of DMF and the residue was diluted with dichloro-
methane (50 mL) and stirred at rt for 12 h. The precipitate was
collected by filtration and washed with dichloromethane (2ꢂ5 mL)
to give the title compound 8b as a white solid.
4.3. Synthesis of dialkyl 7-hydroxypyrazolo[1,5-a]pyrimidine-
3,6-dicarboxylates 7a and 7b
A mixture of dialkyl malonate (10 mmol), anhyd toluene
(25 mL), and N,N-dimethylformamide dimethylacetal (DMFDMA)
(1.6 mL, 12 mmol) was heated under reflux for 2 h, cooled, and
volatile components were evaporated in vacuo. The crude enamino
ester 6 was dissolved in acetic acid (30 mL), aminopyrazole 3 (1.4 g,
Method B. A mixture of benzyl methyl ester 7b (1.635 g, 5 mmol)
and 33% HBreAcOH (30 mL) was stirred at 60 ꢀC for 2 h and cooled
to rt. The precipitate was collected by filtration and washed with

M. Drev et al. / Tetrahedron 70 (2014) 8267e8279
8273
ethanol (5 mL) and ether (2ꢂ5 mL) to give the title compound 8b as
a white solid.
(EtOAc). Fractions containing the product were combined and
evaporated in vacuo to afford the title compound 11a (75 mg, 58%) as
a white solid; mp 150e154 ꢀC; [Found: C, 65.92; H, 4.21; N, 16.33.
Yield: 1.118 g (89%, Method A) and 830 mg (70%, Method B) of
white solid; mp 271e275 ꢀC; [Found: C, 45.81; H, 3.07; N, 17.48.
C9H7N3O5 requires: C, 45.58; H, 2.97; N, 17.72%]; nmax (ATR) 3089,
2934, 2885, 2741, 1742, 1707, 1627, 1582, 1500, 1461, 1435, 1376,
1346, 1256, 1200, 1117, 1026, 942, 912, 862, 822, 791, 775, 714, 663,
C14H11N3O2$1/10H2O requires: C, 65.93; H, 4.43; N, 16.47%]; nmax
(ATR) 3089, 3063, 3028, 2995, 2951, 1807, 1690, 1609, 1543, 1494,
1483, 1443, 1371, 1345, 1335, 1298, 1263, 1234, 1200, 1172, 1125,
1054, 1000, 958, 905, 858, 805, 858, 805, 780, 763, 681, 654, 632,
626 cmꢁ1
;
dH (500 MHz, DMSO-d6) 8.32 (1H, s, 2-H), 8.42 (1H, s, 5-
612 cmꢁ1
; dH (500 MHz, DMSO-d6) 3.18 (3H, s, NMe), 3.96 (3H, s,
H), COOH exchanged; dC (126 MHz, DMSO-d6) 51.5, 98.5, 101.8,
142.7, 143.6, 146.2, 154.3, 161.8, 164.2; HRMS (ESI): MHþ, found
238.0926. C9H8N3O5 requires 238.0933.
OMe), 5.29 (2H, s, NCH2Ph), 6.16 (1H, s, J¼5.4 Hz, 6-H), 7.20e7.26
(2H, m, 2H of Ph), 7.28e7.39 (3H, m, 3H of Ph), 8.43 (1H, d, J¼5.4 Hz,
5-H), 8.50 (1H, s, 2-H); dC (126 MHz, DMSO-d6) 39.5, 51.1, 101.6,
109.9, 128.5, 129.7, 129.9, 131.4, 146.9, 147.0, 148.2, 153.1, 162.2;
HRMS (ESI): MHþ, found 254.0924. C14H12N3O2 requires 254.0930.
4.6. Thermal decarboxylation of the dicarboxylic acid 8a.
Synthesis of 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine (9)
4.10. Methyl 7-(benzyl(methyl)amino)pyrazolo[1,5-a]pyrimi-
dine-3-carboxylate (11b)
Compound 8a (167 mg, 0.75 mmol) was heated at 250 ꢀC for 4 h
to give a 1:2 mixture of 8a and 9. Subsequent crystallization of this
mixture from aqueous EtOH gave the title compound 9 (52 mg, 51%)
as a white solid; mp 333e338 ꢀC, lit.10a mp 335e338 ꢀC, lit.16 mp
338e340 ꢀC; dH (500 MHz, DMSO-d6) 5.69 (1H, d, J¼7.0 Hz, 6-H),
6.18 (1H, d, J¼2.0 Hz, 3-H), 7.81e7.93 (2H, m, 2-H, 5-H), 12.36 (1H,
br s, 4-H); HRMS (ESI): MHþ, found 136.0503. C6H6N3O requires
136.0511.
A mixture of 10 (211 mg,1 mmol), benzyl(methyl)amine (0.5 mL,
4 mmol), and MeOH (4 mL) was stirred under reflux for 1 h. Volatile
components were evaporated in vacuo and the residue was purified
by FC (EtOAc). Fractions containing the product were combined and
evaporated in vacuo to afford the title compound 11b (310 mg, 96%)
as a white solid; mp 140e142 ꢀC; [Found: C, 64.99; H, 5.20; N,18.83.
C16H16N4O2 requires: C, 64.85; H, 5.44; N, 18.91%]; nmax (ATR) 3110,
4.7. Decarboxylation of carboxylic acid 8b. Synthesis of
methyl 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-
carboxylate (5)
3001, 2951, 2902, 1684, 1597, 1558, 1533, 1498, 1464, 1439, 1404,
1387,1364,1326,1302,1282,1249,1221,1200,1187,1167,1134,1090,
1077, 1009, 957, 894, 800, 791, 777, 759, 713, 628 cmꢁ1
; dH
(500 MHz, DMSO-d6) 4.00 (3H, s, OMe), 7.10 (1H, d, J¼4.0 Hz, 6-H),
7.51e7.67 (3H, m, m, p-Ph), 8.01 (2H, dd, J¼8.0, 2.0 Hz, o-Ph), 8.65
(1H, s, 2-H), 8.85 (1H, d, J¼4.0 Hz, 5-H); dC (126 MHz, DMSO-d6)
39.2, 51.7, 56.6, 93.9, 101.1, 127.8, 128.0, 128.9, 136.3, 146.4, 150.6,
150.7, 152.4, 163.7 HRMS (ESI): MHþ, found 297.1351. C16H17N4O2
requires 297.1352.
A mixture of 8b (2.37 g, 10 mmol), quinoline (20 mL), and Cu
powder (200 mg) was stirred at 180 ꢀC for 45 min and cooled to rt.
The precipitate was collected by filtration and washed with quin-
oline (2ꢂ25 mL) and ether (2ꢂ50 mL) to give the title compound 5
(1.45 g, 75%) as a white solid. Physical, analytical and spectral data
were identical to the data of 5 obtained from methyl propiolate (1)
(see Section 4.2).
4.11. Methyl 7-(benzyloxy)pyrazolo[1,5-a]pyrimidine-3-
carboxylate (11c)
4.8. Methyl 7-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate
(10)
Tetrabutylammonium bromide (4 mg, 12.5
BnOH (258 L, 2.5 mmol) were added to a solution of chloro
compound 10 (52 mg, 0.25 mmol) in dichloromethane (1 mL) and
the mixture was stirred for 5 min. Then, 2 M aq NaOH (125 L,
mmol, 5 mol %) and
m
A mixture of 8b (193 mg, 1 mmol), POCl3 (4 mL), and Et3N
(300
m
L, 2 mmol) was stirred under reflux for 3 h (Caution: addition
m
of Et3N to POCl3 is exothermic!). Volatile components were evapo-
rated in vacuo and the residue was triturated with crushed ice/
water (20 mL). The precipitate was collected by filtration, washed
with cold water (0 ꢀC, 5 mL), and then suspended in dichloro-
methane (10 mL). The undissolved residue was removed by filtra-
tion and the filtrate was dried over anhyd sodium sulfate, filtered,
and the filtrate was evaporated in vacuo to give the title compound
10 (159 mg, 75%) as white crystals; mp 203e208 ꢀC; [Found: C,
45.26; H, 2.54; N, 19.69. C8H6ClN3O2 requires: C, 45.41; H, 2.86; N,
19.86%]; nmax (ATR) 3061, 3003, 2952, 2848, 1715, 1608, 1542, 1507,
1466, 1437, 1382, 1272, 1247, 1206, 1156, 1090, 958, 919, 906, 859,
0.25 mmol) was added and the mixture was stirred at rt for 12 h.
Water (10 mL) was added and the product was extracted with
dichloromethane (2ꢂ5 mL). The combined organic phases were
dried over anhyd sodium sulfate, filtered, the filtrate was evapo-
rated in vacuo, and the residue was purified by FC (EtOAc). Fractions
containing the product were combined and evaporated in vacuo to
give the title compound 11c (50 mg, 71%) as a white solid; mp
175e176 ꢀC; [Found: C, 63.34; H, 4.42; N, 14.96. C15H13N3O3 re-
quires: C, 63.60; H, 4.63; N, 14.83%]; nmax (ATR) 3108, 3071, 2950,
1687,1615,1551,1537,1491,1435,1368, 1344,1312,1281,1235,1222,
1205, 1188, 1169, 1127, 1093, 1010, 948, 909, 858, 827, 800, 776, 757,
830, 798, 777, 654, 637 cmꢁ1
;
dH (300 MHz, DMSO-d6) 3.99 (3H, s,
741, 697, 656, 639 cmꢁ1
; dH (500 MHz, DMSO-d6) 3.98 (3H, s, OMe),
OMe), 7.18 (1H, d, J¼4.6 Hz, 6-H), 8.69 (1H, d, J¼4.6 Hz, 5-H), 8.70
(1H, s, 2-H); dC (126 MHz, DMSO-d6) 52.0, 104.6, 109.9, 140.5, 148.2,
148.9, 151.7, 162.5; HRMS (ESI): MHþ, found 212.0219. C8H7ClN3O2
requires 212.0227.
5.54 (2H, s, OCH2Ph), 6.44 (1H, d, J¼5.2 Hz, 6-H), 7.35e7.60 (5H, m,
Ph), 8.65 (1H, s, 2-H), 8.64 (1H, d, J¼5.2 Hz, 5-H); dC (126 MHz,
DMSO-d6) 51.8, 72.9, 77.1, 90.2, 102.8, 127.9, 129.2, 129.5, 133.0,
148.1, 149.8, 154.0, 155.5, 163.2; HRMS (ESI): MHþ, found 284.1033.
C15H14N3O3 requires 284.1035.
4.9. Methyl 7-phenylpyrazolo[1,5-a]pyrimidine-3-carboxylate
(11a)
4.12. Hydrolysis of the esters 11a and 11b. Synthesis of 7-
substituted pyrazolo[1,5-a]pyrimidine-3-carboxylic acids 12a
and 12b
A mixture of 10 (100 mg, 0.5 mmol), phenylboronic acid
(163 mg, 0.5 mmol), cesium carbonate (175 mg, 0.5 mmol),
Pd(PPh3)4 (6 mg, 0.005 mmol), [PdCl(allyl)]2 (2 mg, 0.005 mmol),
and DMF (4 mL) was stirred at 95 ꢀC for 24 h. Volatile components
were evaporated in vacuo and the residue was purified by FC
A mixture of the ester 11 (1 mmol), MeOH (3 mL), and 2 M aq
NaOH (2 mL, 4 mmol) was added and the mixture was stirred at
50 ꢀC for 1 h. Methanol was evaporated in vacuo (40 ꢀC, 50 mbar),

8274
M. Drev et al. / Tetrahedron 70 (2014) 8267e8279
water (5 mL) was added to the aqueous residue, and the solution
was acidified with 37% aq HCl. The precipitate was collected by
filtration to give the title compound 12. The following compounds
were prepared in this manner:
136.3, 142.7, 145.1, 145.8, 155.0, 161.9; HRMS (ESI): MHþ, found
284.1021. C15H14N3O3 requires 283.1030.
4.13.3. Methyl 4-ethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-
3-carboxylate (13c). Prepared from 5 and EtI (400
mL, 3 mmol).
4.12.1. 7-Phenylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (12a).
Prepared from 11a (252 mg, 1 mmol), acidification to pHw1. Yield:
232 mg (93%) of white solid; mp 224e226 ꢀC; [Found: C, 65.04; H,
3.59; N, 17.51. C13H9N3O2 requires: C, 65.27; H, 3.79; N, 17.56%]; nmax
(ATR) 3471, 3311, 3210, 3097, 3070, 2528, 1951, 1657, 1610, 1576,
1541, 1496, 1448, 1365, 1342, 1316, 1270, 1229, 1204, 1184, 1170,
1132, 1084, 1057, 997, 973, 903, 860, 833, 788, 774, 756, 699, 690,
Yield: 44 mg (20%) of white solid; mp 150e151 ꢀC; nmax (ATR) 3049,
2920, 2850,1720,1694,1561,1490,1474,1233,1217,1188, 1173,1143,
1094, 1081, 799, 767 cmꢁ1
; dH (500 MHz, DMSO-d6) 1.29 (3H, t,
J¼7.0 Hz, CH3CH2), 3.81 (3H, s, OMe), 4.63 (2H, q, J¼7.1 Hz, CH2CH3),
6.06 (1H, d, J¼7.8 Hz, 6-H), 8.06 (1H, d, J¼7.8 Hz, 5-H), 8.31 (1H, s, 2-
H); dC (126 MHz, DMSO-d6) 15.2, 49.8, 51.8, 97.7, 99.6, 142.3, 145.2,
155.0, 161.7; HRMS (ESI): MHþ, found 221.0874. C10H12N3O3 re-
quires 221.0873.
650, 633, 624 cmꢁ1
;
dH (500 MHz, DMSO-d6) 7.46 (1H, d, J¼4.4 Hz,
6-H), 7.67e7.59 (3H, m, m, p-Ph), 8.09 (2H, dd, J¼7.9, 1.6 Hz, o-Ph),
8.63 (1H, s, 2-H), 8.86 (1H, d, J¼4.4 Hz, 5-H), 12.45 (1H, br s, COOH);
dC (126 MHz, DMSO-d6) 102.6, 109.6, 128.5,129.7, 130.0, 131.3, 146.8,
147.1, 148.2, 152.6, 163.1; HRMS (ESI): MHþ, found 240.0770.
4.13.4. Methyl 4-(2-tert-butoxy-2-oxoethyl)-7-oxo-4,7-dihydro-
pyrazolo[1,5-a]pyrimidine-3-carboxylate (13d). Prepared from 5 and
tert-butyl bromoacetate (443
white solid; mp 216e217 ꢀC; nmax (ATR) 3105, 2986, 2951, 1744, 1712,
1691, 1559, 1362, 1235, 1149, 1115, 936, 855 cmꢁ1
dH (500 MHz,
mL, 3 mmol). Yield: 306 mg (100%) of
C
13H10N3O2 requires 240.0773.
;
4.12.2. 7-(Benzyl(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-
carboxylic acid (12b). Prepared from 11b (296 mg, 1 mmol),
acidification to pH w5. Yield: 158 mg (56%) of white solid; mp
60e64 ꢀC; nmax (ATR) 3637, 3398, 3025, 1648, 1598, 1551, 1495,
1451, 1430, 1404, 1369, 1333, 1278, 1229, 1202, 1182, 1093, 1073,
DMSO-d6) 1.40 (9H, s, t-Bu), 3.76 (3H, s, OMe), 5.34 (2H, s, CH2), 6.10
(1H, d, J¼7.8 Hz, 6-H), 7.96 (1H, d, J¼7.8 Hz, 5-H), 8.28 (1H, s, 2-H); dC
(126 MHz, DMSO-d6) 27.6, 21.2, 55.9, 82.1, 98.5, 99.4, 143.1, 145.0,
146.3, 154.8, 161.8, 162.3, 166.8; HRMS (ESI): MHþ, found 308.1240.
C14H18N3O5 requires 307.1241.
1011, 963, 892, 796, 762, 739, 695, 654, 630 cmꢁ1
; dH (500 MHz,
DMSO-d6) 3.40 (3H, s, OMe), 5.46 (2H, s, NCH2Ph), 6.66 (1H, d,
J¼6.6 Hz, 6-H), 7.26e7.45 (5H, m, Ph), 8.30 (1H, d, J¼6.6 Hz, 5-H),
8.57 (1H, s, 2-H), COOH exchanged; dC (126 MHz, DMSO-d6) 39.5,
55.3, 93.8, 102.9, 127.4, 127.5, 128.6, 137.0, 145.9, 149.9, 149.9,
151.5, 164.2; HRMS (ESI): MHþ, found 283.1191. C15H15N4O2 re-
quires 283.1195.
4.14. Benzyl 4-benzyl-7-oxo-4,7-dihydropyrazolo[1,5-a]py-
rimidine-3-carboxylate (13e)
A mixture of 13b (1.192 g, 4.21 mmol), BnOH (40 mL), and DBU
(0.5 mL, 3.34 mmol) was stirred at 130 ꢀC for 24 h. Volatile com-
ponents were evaporated in vacuo and the residue was purified by
FC (EtOAc). Fractions containing the product were combined and
evaporated in vacuo. The residue was triturated with Et2O (10 mL)
and the precipitate was collected by filtration to give 13e. Yield:
953 mg (63%) of light brown solid; mp 130e132 ꢀC; [Found: C,
70.40; H, 4.92; N, 11.70. C21H17N3O3 requires: C, 70.18; H, 4.77; N,
11.69%]; nmax (ATR) 3034, 3014, 1692, 1607, 1566, 1487, 1454, 1400,
1367, 1336, 1233, 1171, 1106, 1077, 1026, 984, 959, 899, 877, 802,
4.13. N-alkylation of 5. Synthesis of methyl 4-alkyl-7-oxo-4,7-
dihydropyrazolo[1,5-a]pyrimidine-3-carboxylates 13aed
A mixture of 5 (193 mg, 1 mmol), K2CO3 (414 mg, 3 mmol), and
anhyd DMF (5 mL) was stirred at rt for 30 min. Then, alkyl halide
(3e5 mmol) was added and stirring at rt was continued for 72 h.
Volatile components were evaporated in vacuo and the residue was
chromatographed (FC) over silica gel (EtOAc). The combined eluate
was evaporated in vacuo to afford the title compound 13. The fol-
lowing compounds were prepared in this manner:
783, 769, 737, 694, 639, 613 cmꢁ1
; dH (500 MHz, DMSO-d6) 5.26
(2H, s, COOeCH2ePh), 5.91 (2H, s, NeCH2ePh), 6.14 (1H, d,
J¼7.8 Hz, 2-H), 7.10e7.41 (10H, m, 2ꢂ Ph), 8.15 (1H, d, J¼7.8 Hz, 1-
H), 8.33 (1H, s, 3-H); dC (126 MHz, DMSO-d6) 56.2, 65.9, 98.3, 100.1,
126.7, 127.9, 128.0, 128.5, 128.8, 136.0, 136.1, 142.8, 145.1, 145.8,
154.9, 161.2; HRMS (ESI): MHþ, found 360.1341. C21H18N3O3 re-
quires 360.1343.
4.13.1. Methyl
dine-3-carboxylate (13a). Prepared from
4-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimi-
and MeI (312 L,
5
m
5 mmol). Yield: 54 mg (26%) of white solid; mp 204e210 ꢀC;
[Found: C, 52.44; H, 4.03; N, 19.94. C9H9N3O3 requires: C, 52.17; H,
4.38; N, 20.28%]; nmax (ATR) 3449, 3067, 2951,1726, 1697,1561,1491,
4.15. Hydrolysis of the esters 5 and 13a. Synthesis of 7-oxo-
4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acids 14a
and 14b
1385, 1433, 1234, 1191, 1173, 1147, 1077, 1010, 802 cmꢁ1
; dH
(500 MHz, DMSO-d6) 3.79 and 4.03 (6H, 2s, 1:1, 2ꢂMe), 6.00 (1H, d,
J¼7.7 Hz, 6-H), 7.96 (1H, d, J¼7.8 Hz, 5-H), 8.27 (1H, s, 2-H); dC
(126 MHz, DMSO-d6) 42.8, 51.8, 98.4, 98.9, 143.2, 144.9, 146.4, 155.0,
161.7; HRMS (ESI): MHþ, found 208.0717. C9H9N3O3 requires
208.0645.
LiOH$H2O (252 mg, 6 mmol) was added to a stirred suspension
of the ester 5 or 13a (1 mmol) in water (8 mL) the mixture was
stirred at rt for 1 h. The so formed solution was acidified with 1 M
aq HCl (w6 mL) to pHw4. The precipitate was collected by filtration
to give the title compound 14. The following compounds were
prepared in this manner:
4.13.2. Methyl
4-benzyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimi-
L,
dine-3-carboxylate (13b). Prepared from 5 and BnBr (355
m
3 mmol). Yield: 246 mg (87%) of white solid; mp 168e174 ꢀC;
[Found: C, 63.58; H, 4.41; N, 14.57. C15H13N3O3 requires: C, 63.60; H,
4.63; N, 14.83%]; nmax (ATR) 3062, 3032, 2958, 1708, 1680, 1612,
1559, 1486, 1456, 1435, 1421, 1356, 1238, 1184, 1164, 1108, 1078,
4.15.1. 7-Oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic
acid (14a). Prepared from 5 (193 mg, 1 mmol). Yield: 131 mg (73%)
of white solid; mp 255e257 ꢀC; [Found: C, 43.16; H, 3.18; N, 21.21.
C7H5N3O3$7/8H2O requires: C, 43.14; H, 3.49; N, 21.56%]; nmax (ATR)
3106, 3074, 2969, 2868, 2585, 1681, 1616, 1582, 1501, 1467, 1421,
1029, 806, 755, 706 cmꢁ1
; dH (500 MHz, DMSO-d6) 3.84 (3H, s,
OMe), 5.94 (2H, s, CH2Ph), 6.07 (1H, d, J¼8.0 Hz, 6-H), 7.32e7.40
(5H, m, Ph), 7.43 (1H, d, J¼8.0 Hz, 5-H), 8.32 (1H, s, 2-H); dC
(126 MHz, DMSO-d6) 52.0, 56.3, 98.4, 100.0, 126.8, 128.0, 128.8,
1301, 1267, 1195, 1137, 1070, 1007, 924, 883, 797, 780, 746 cmꢁ1
; dH
(500 MHz, DMSO-d6) 5.91 (1H, d, J¼7.5 Hz, 6-H), 7.79 (1H, d,
J¼7.5 Hz, 5-H), 8.18 (1H, s, 2-H), OH and NH exchanged; dC

M. Drev et al. / Tetrahedron 70 (2014) 8267e8279
8275
(126 MHz, DMSO-d6) 97.7, 98.9, 140.5, 143.2, 143.4, 155.9, 163.4;
HRMS (ESI): [MeH]ꢁ, found 179.0257. C7H6N3O3 requires 179.0258.
58.1, 71.0, 105.1, 109.2, 128.6, 129.7, 129.9, 131.6, 145.6, 146.5, 147.2,
152.0,161.2; HRMS (ESI): MHþ, found 297.1332 C16H17N4O2 requires
297.1352.
4.15.2. 4-Methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-
carboxylic acid (14b). Prepared from 13a (207 mg, 1 mmol). Yield:
106 mg (55%) of white solid; mp 220e223 ꢀC; [Found: 49.29; H,
3.51; N, 21.34. C8H7N3O3$1/10H2O requires: C, 49.29; H, 3.72; N,
21.55%]; nmax (ATR) 3000, 2919, 1711, 1651, 1564, 1492, 1455, 1426,
1365, 1334, 1240, 1216, 1182, 1149, 1088, 972, 911, 826, 801, 771, 744,
4.17.2. 7-(Benzyl(methyl)amino)-N-(2-methoxyethyl)pyrazolo[1,5-a]
pyrimidine-3-carboxamide (15b). Prepared from 12b (141 mg,
0.5 mmol) and 2-methoxyethylamine (45 mL, 0.5 mmol), FC: first
EtOAc, then 90% EtOAc/MeOH. Yield: 112 mg (66%) of white solid;
mp 97e100 ꢀC; nmax (ATR) 3357, 3315, 3026, 2996, 2977, 2929,
2892, 2864, 2830, 2650, 2570, 1646, 1598, 1558, 1535, 1510, 1453,
1439, 1415, 1384, 1352, 1327, 1302, 1257, 1232, 1192, 1180, 1154, 1117,
1095, 1077, 1058, 1002, 978, 893, 872, 831, 814, 789, 770, 748, 706,
684, 647, 635 cmꢁ1
; dH (500 MHz, DMSO-d6) 4.06 (3H, s, Me), 5.98
(1H, d, J¼7.7 Hz, 6-H), 7.94 (1H, d, J¼7.7 Hz, 5-H), 8.23 (1H, s, 2-H),
12.74 (1H, br s, CO2H); dC (126 MHz, DMSO-d6) 42.8, 98.6, 99.5,
143.0,145.4,146.3,155.13,162.8; HRMS (ESI): MHþ, found 194.0560.
C8H8N3O3 requires 194.0560.
696, 672, 633, 605 cmꢁ1
; dH (500 MHz, DMSO-d6) 3.22 (3H, s, NMe),
3.44 (3H, s, OMe), 3.64 (2H, t, J¼5.3 Hz, CH2NH), 3.74 (2H, q,
J¼5.5 Hz, OCH2), 5.33 (2H, s, NCH2), 6.11 (1H, d, J¼5.4 Hz, 6-H),
7.22e7.39 (5H, m, Ph), 8.27 (1H, d, J¼5.4 Hz, 5-H), 8.57 (1H, s, 2-H),
8.75 (1H, br t, J¼5.6 Hz, CONH); dC (126 MHz, DMSO-d6) 38.9, 39.1,
56.4, 58.8, 71.5, 92.8, 103.2, 127.7, 127.8, 128.8, 136.1, 144.7, 149.3,
150.3, 150.7, 163.7; HRMS (ESI): MHþ, found 340.1768. C18H22N5O2
requires 340.1773.
4.16. 4-Benzyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-
3-carboxylic acid (14c)
A mixture of 13e (0.5391 g, 1.5 mmol), MeOH (25 mL), and 10%
PdeC (25 mg) was hydrogenated (via balloon) at rt and the reaction
progress was monitored by TLC in 15 min intervals. Upon com-
pletion of reaction (w45 min), the catalyst was removed by filtra-
tion through a glass-sintered funnel and the filtrate was evaporated
in vacuo to give the title compound 14c. Yield: 223 mg (55%) of
white solid; mp 209e213 ꢀC; [Found: C, 62.26; H, 3.89; N, 15.52.
4.17.3. 7-(Benzyl(methyl)amino)-N-(3-(dimethylamino)propyl)pyr-
azolo[1,5-a]pyrimidine-3-carboxamide (15c). Prepared from 12b
(141 mg, 0.5 mmol) and 3-(dimethylamino)propylamine (64
mL,
0.5 mmol), FC: first EtOAc, then 75% CHCl3/MeOH containing 3%
Et3N. Yield: 145 mg (79%) of brownish oil; nmax (ATR) 3307, 3031,
2944, 1641, 1601, 1546, 1494, 1453, 1410, 1365, 1325, 1295, 1234,
1180, 1151, 1107, 1076, 1002, 978, 908, 895, 832, 776, 729, 707, 696,
C
14H11N3O3 requires: C, 62.45; H, 4.12; N, 15.61%]; nmax (ATR) 3084,
3012, 2887, 2822, 2756, 2710, 2592, 2568, 2527, 2471, 1710, 1646,
1596,1543,1482,1457,1416,1338,1323,1259,1213,1160,1118,1009,
965, 901, 823, 767, 739, 708, 695, 656, 634, 617 cmꢁ1
;
dH (500 MHz,
629, 612 cmꢁ1
; dH (300 MHz, DMSO-d6) 1.94e2.13 (2H, m,
DMSO-d6) 6.01 (2H, s, CH2Ph), 6.10 (1H, d, J¼7.7 Hz, 2-H), 7.10e7.41
(5H, m, Ph), 8.12 (1H, d, J¼7.7 Hz, 1-H), 8.25 (1H, s, 3-H), 12.89 (1H,
br s, COOH); dC (126 MHz, DMSO-d6) 56.1, 99.6, 99.7, 126.8, 127.9,
128.7, 136.5, 142.5, 146.0, 155.0, 163.1; HRMS (ESI): MHþ, found
270.0874. C14H12N3O3 requires 270.0873.
CH2CH2CH2), 2.63 (6H, s, Me2N), 2.86e3.02 (2H, m, Me2NCH2), 3.22
(3H, s, NMe), 3.58 (2H, q, J¼6.4 Hz, CH2NH), 5.35 (2H, s, CH2Ph), 6.10
(1H, d, J¼5.4 Hz 6-H), 7.15e7.49 (5H, m, Ph), 8.20 (1H, d, J¼5.4 Hz, 5-
H), 8.51 (1H, br t, J¼6.4 Hz, NHCH2), 8.52 (1H, s, 2-H); dC (75 MHz,
DMSO-d6) 26.7, 36.6, 39.5, 41.2, 44.0, 56.6, 56.9, 93.1, 103.7, 128.0,
128.2, 129.2, 136.6, 145.1, 149.6, 150.8, 150.9, 163.9; HRMS (ESI):
MHþ, found 367.2242. C20H27N6O requires 367.2248.
4.17. Amidation of pyrazolo[1,5-a]pyrimidine-3-carboxylic
acids 12a,b and 14aec. General procedure for the synthesis of
carboxamides 15aec and 16aeq
4.17.4. 7-Oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide
(16a). Prepared from 14a (90 mg, 0.5 mmol) and excess NH3 (gentle
bubbling for 15 min into the reaction mixture after activation of 14a
with BPC; addition of Et3N was omitted). The precipitate was col-
lected by filtration to give the title compound 16a (82 mg, 92%) as
a greyewhite solid; mp 305e318 ꢀC; nmax (ATR) 3328, 3190, 2996,
2890, 1659,1637, 1581, 1542,1522, 1459, 1408,1350, 1310, 1236, 1213,
A mixture of carboxylic acid 12 or 14 (0.5 mmol), anh. DMF
(5 mL), and Et3N (70 mL, 0.5 mmol) was stirred at room temperature
for 5 min. Then, BPC (197 mg, 0.5 mmol) was added and the mixture
was stirred at rt for 1 h (activation of carboxylic acid). Next, amine
(0.5 mmol) and Et3N (70 mL, 0.5 mmol) were added and stirring at rt
was continued for 24 h. Volatile components were evaporated in
vacuo (2 mbar, 50 ꢀC), dichloromethane (5 mL) was added, and the
mixture was evaporated in vacuo (first at 2 mbar/50 ꢀC, then at 0.01
mbar/80 ꢀC) to give 15 or 16. The crude product was purified by FC
(silica gel, first EtOAc/hexanes to elute the non-polar impurities,
then EtOAc/MeOH, CHCl3/MeOH, or CHCl3/MeOH/Et3N to elute the
product). Fractions containing the product were combined, and
evaporated in vacuo to give the purified carboxamide 15 or 16. The
following compounds were prepared in this manner:
1162,1132,1005, 886, 874, 810, 774, 724, 686, 625 cmꢁ1
; dH (500 MHz,
DMSO-d6) 5.55 (1H, d, J¼5.9 Hz, 6-H), 6.88 (1H, s, NH), 7.14 (1H, br s,
NH), 7.79 (1H, d, J¼5.9 Hz, 5-H), 7.96 (1H, br s, NH), 7.97 (1H, s, 2-H); dC
(126MHz, DMSO-d6) 95.2,101.2,141.8,150.1,150.5,157.9,164.6; HRMS
(ESI): MHþ, found 179.0563. C7H7N4O2 requires 179.0564.
4.17.5. N-(2-Methoxyethyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrim-
idine-3-carboxamide (16b). Prepared from 14a (90 mg, 0.5 mmol)
and 2-methoxyethylamine(45mL, 0.5 mmol); FC: first EtOAc, then 90%
CHCl3/MeOH. Yield: 96 mg (81%) of greyewhite solid; mp
229e234 ꢀC;nmax (ATR)3315,3201, 3069,2925,1684,1614,1556,1533,
1489, 1454, 1397, 1361, 1292, 1241, 1211, 1163, 1149, 1117, 1092, 1062,
4.17.1. N-(2-Methoxyethyl)-7-phenylpyrazolo[1,5-a]pyrimidine-3-
carboxamide (15a). Prepared from 12a (120 mg, 0.5 mmol) and 2-
methoxyethylamine (45
mL, 0.5 mmol), FC: 67% EtOAc/hexanes,
1032 cmꢁ1
; dH (500 MHz, DMSO-d6) 3.27 (3H, s, OMe), 3.41e3.47 (4H,
then 90% EtOAc/MeOH. Yield: 149 mg (100%) of white solid; mp
110 ꢀC (decomp.); nmax (ATR) 3354, 3088, 3059, 2981, 2928, 2834,
2814, 1935, 1799, 1740, 1649, 1606, 1544, 1516, 1492, 1445, 1403,
1374, 1340, 1324, 1272, 1258, 1197, 1186, 1174, 1158, 1105, 1081, 1052,
1029, 1013, 996, 952, 902, 860, 821, 768, 709, 689, 651, 632,
m, CH2CH2), 5.80 (1H, d, J¼6.9 Hz, 6-H), 7.79(1H, d, J¼7.1 Hz, 5-H), 8.34
(1H, s, 2-H), 8.48 (1H, t, J¼5.1Hz,NHCH2); dC (126MHz,DMSO-d6)38.1,
58.0, 70.9, 97.5, 100.2, 141.0, 143.9, 156.6, 162.1, 168.6; HRMS (ESI):
MHþ, found 237.0983. C10H13N4O4 requires 237.0982.
618 cmꢁ1
;
dH (500 MHz, DMSO-d6) 3.31 (3H, s, OMe), 3.50 (2H, t,
4.17.6. N-(3-(Dimethylamino)propyl)-7-oxo-4,7-dihydropyrazolo
J¼5.3 Hz, OCH2), 3.56 (2H, q, J¼5.3 Hz, CH2NH), 7.48 (d, J¼4.5 Hz, 6-
H), 7.61e7.68 (3H, m, o,p-Ph), 8.09e8.16 (2H, m, m-Ph), 8.21 (1H, t,
J¼5.7 Hz, NHCH2), 8.62 (1H, s, 2-H). dC (126 MHz, DMSO-d6) 38.2,
[1,5-a]pyrimidine-3-carboxamide (16c). Prepared from 14a (90 mg,
0.5 mmol) and 3-(dimethylamino)propylamine (64
mL, 0.5 mmol),
FC: first EtOAc, then 75% CHCl3/MeOH containing 3% Et3N to elute

8276
M. Drev et al. / Tetrahedron 70 (2014) 8267e8279
the product. Yield: 125 mg (94%) of brownish semi-solid; nmax (ATR)
106 mg (91%) of beige solid; mp >300 ꢀC (decomp.); nmax (ATR)
3291, 3023, 2944, 2702, 2657, 2485, 1624, 1524, 1344, 1227, 1151,
3284, 3140, 3056, 2974, 2875, 1681, 1662, 1619, 1583, 1505, 1452,
998, 794, 619 cmꢁ1
;
dH (500 MHz, CDCl3) 1.99e2.08 (2H, m,
1434, 1349, 1325, 1243, 1179, 1161, 1149, 1064, 1021, 898, 810 cmꢁ1
;
CH2CH2CH2), 2.71 (6H, s, NMe2), 3.08 (2H, br t, J¼7.4 Hz, OCH2), 3.48
(2H, br q, J¼6.2 Hz, CH2NH), 5.80 (1H, br d, J¼5.7 Hz, 6-H), 7.91 (1H,
br d, J¼5.7 Hz, 5-H), 8.15 (1H, br s, 2-H), 8.48 (1H, br t, J¼6.0 Hz,
NHCH2), 9.91 (1H, br s, NH); dC (126 MHz, DMSO-d6) 26.5, 35.9, 43.8,
56.4, 95.6, 102.0, 142.6, 149.8, 151.5, 159.6, 164.6; HRMS (ESI): MHþ,
found 264.1456. C12H18N5O2 requires 264.1455.
dH (500 MHz, DMSO-d6) 1.76e1.86 (4H, m, 2ꢂ CH2), 3.00e3.10 (2H,
m, CH2N), 3.44 and 3.73 (2H, 2 br s, 1:1, CH2N), 5.61 (1H, d, J¼7.5 Hz,
6-H), 7.76 (1H, d, J¼7.5 Hz, 5-H), 8.31 (1H, s, 2-H); dC (126 MHz,
DMSO-d6) 23.8, 44.5, 103.9, 113.4, 141.3, 142.7, 156.9, 160.7, 171.7;
HRMS (ESI): MHþ, found 233.1029. C11H13N4O2 requires 233.1033.
4.17.12. N-Cyclopropyl-4-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]
4.17.7. N-Benzyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-
pyrimidine-3-carboxamide (16i). Prepared from 14b (97 mg,
carboxamide (16d). Prepared from 14a (90 mg, 0.5 mmol) and
0.5 mmol) and cyclopropylamine (36 mL, 0.5 mmol), FC: FC: first
benzylamine (56
m
L, 0.5 mmol), FC: first EtOAc, then 90% CHCl3/
EtOAc, then 90% CHCl3/MeOH. Yield: 70 mg (60%) of white solid;
mp 286e290 ꢀC; nmax (ATR) 3302, 3045, 3011, 2948, 1703, 1678,
1630, 1584, 1525, 1489, 1451, 1412, 1366, 1336, 1286, 1219, 1165,
1143, 1102, 1025, 997, 944, 882, 853, 825, 796, 770, 695, 676, 640,
MeOH. Yield: 116 mg (86%) of white solid; mp 277e290 ꢀC; nmax
(ATR) 3277, 1696, 1619, 1604, 1592, 1566, 1493, 1454, 1412, 1362,
1299,1244,1192,1151,1071,1048,1018, 950, 907, 875, 800, 788, 770,
737, 720, 696, 636, 611 cmꢁ1
;
dH (500 MHz, DMSO-d6) 4.50 (2H, d,
622 cmꢁ1
; dH (500 MHz, DMSO-d6) 0.53e0.57 and 0.67e0.71 (4H,
J¼6.0 Hz, CH2NH), 5.82 (1H, d, J¼7.2 Hz, 6-H), 7.21e7.27 (1H, m, p-
Ph), 7.29e7.42 (4H, m, o,m-Ph), 7.78 (1H, d, J¼7.2 Hz, 5H), 8.38 (1H,
s, 2-H), 8.93 (1H, t, J¼6.0 Hz, NHCH2), 12.02 (1H, br s, NH); dC
(126 MHz, DMSO-d6) 41.9, 97.8, 100.0, 126.8, 127.4, 128.4, 139.7,
140.8, 141.7, 143.9, 156.3, 162.0; HRMS (ESI): MHþ, found 269.1034.
2m, 1:1, CH2CH2), 2.79 (1H, octet, J¼4.0 Hz, CHNH), 3.90 (3H, s, Me),
5.89 (1H, d, J¼7.6 Hz, 6-H), 7.91 (1H, d, J¼7.6 Hz, 5-H), 8.10 (1H, s, 2-
H), 8.46 (1H, br d, J¼4.1 Hz, NH); dC (126 MHz, DMSO-d6) 5.7, 22.8,
41.7, 97.3, 103.0, 141.0, 142.8, 145.8, 155.3, 162.4; HRMS (ESI): MHþ,
found 233.1031. C11H12N4O2 requires 233.1033.
C
14H13N4O2 requires 269.1033.
4.17.13. N-Benzyl-4-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrim-
4.17.8. N-(4-Methylbenzyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimi-
idine-3-carboxamide (16j). Prepared from 14b (97 mg, 0.5 mmol)
dine-3-carboxamide (16e). Prepared from 14a (90 mg, 0.5 mmol)
and benzylamine (56 mL, 0.5 mmol), FC: first EtOAc, then 90% CHCl3/
and 4-methylbenzylamine (65
mL, 0.5 mmol), FC: first 67% EtOAc/
MeOH. Yield: 118 mg (83%) of white solid; mp 197e199 ꢀC; [Found:
C, 64.09; H, 4.94; N,19.68. C15H14N4O2 requires: C, 63.82; H, 5.00; N,
19.85%]; nmax (ATR) 3270, 3046, 1704, 1676, 1620, 1578, 1538, 1484,
1452, 1413, 1390, 1367, 1350, 1334, 1308, 1234, 1145, 1110, 1082,
1062, 1035, 1018, 991, 969, 876, 860, 797, 780, 732, 690, 664,
hexanes, then 90% CHCl3/MeOH. Yield: 128 mg (90%) of white solid;
mp 255e270 ꢀC; nmax (ATR) 3288, 3071, 1689,1616,1534, 1515, 1491,
1454, 1411, 1358, 1281, 1235, 1212, 1148, 1075, 1059, 979, 910, 883,
795, 739, 723, 677, 626, 607 cmꢁ1
; dH (500 MHz, DMSO-d6) 2.26
(3H, s, Me), 4.45 (2H, d, J¼5.9 Hz, CH2NH), 5.80 (1H, d, J¼7.1 Hz, 6-
H), 7.12 and 7.22 (4H, 2d, 1:1, J¼7.7 Hz, C6H4), 7.79 (1H, d, J¼7.1 Hz,
5-H), 8.35 (1H, s, 2-H), 8.88 (1H, t, J¼6.2 Hz, NHCH2), 11.53 (1H, br s,
OH); dC (126 MHz, DMSO-d6) 20.7, 41.6, 97.4, 100.3, 127.4, 128.9,
135.9, 136.7, 141.0, 142.9, 144.7, 156.5, 162.1; HRMS (ESI): MHþ,
found 283.1190. C15H15N4O2 requires 283.1190.
626 cmꢁ1
; dH (500 MHz, DMSO-d6) 3.90 (3H, s, Me), 4.45 (2H, d,
J¼5.9 Hz, CH2Ph), 5.90 (1H, d, J¼7.6 Hz, 6-H), 7.37e7.23 (5H, m, Ph),
7.92 (1H, d, J¼7.7 Hz, 5-H), 8.22 (1H, s, 2-H), 9.01 (1H, br t, J¼6.0 Hz,
NH); dC (126 MHz, DMSO-d6) 41.8, 42.5, 97.4, 102.9, 126.8, 127.1,
128.3, 139.4, 141.3, 142.8, 145.8, 155.3, 161.4; HRMS (ESI): MHþ,
found 283.1186. C15H15N4O2 requires 283.1190.
4.17.9. N-(3,5-Dichlorobenzyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]py-
4.17.14. N-(3-Hydroxypropyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]py-
rimidine-3-carboxamide (16f). Prepared from 14a (90 mg,
rimidine-3-carboxamide (16k). Prepared from 14b (97 mg,
0.5 mmol) and 3,5-dichlorobenzylamine (70
mL, 0.5 mmol), FC: first
0.5 mmol) and 3-hydroxypropylamine (38 mL, 0.5 mmol), FC: first
EtOAc, then 90% CHCl3/MeOH. Yield: 89 mg (53%) of white solid;
mp 240e260 ꢀC; nmax (ATR) 3277, 1702, 1618, 1587, 1570,1489, 1455,
1431, 1411, 1347, 1290, 1209, 1192, 1101, 1068, 1046, 1021, 956, 903,
EtOAc, then 90% CHCl3/MeOH. Yield: 118 mg (94%) of white solid;
mp 228e232 ꢀC; nmax (ATR) 3404, 3269, 3090, 3055, 2926, 2898,
2873, 1682, 1657, 1633, 1579, 1555, 1484, 1449, 1391, 1373, 1316,
1286, 1230, 1205, 1155, 1112, 1063, 995, 941, 877, 832, 794, 737, 725,
855, 801, 784, 769, 738, 719, 695, 637 cmꢁ1
; dH (500 MHz, DMSO-
d6) 4.48 (2H, d, J¼5.8 Hz, CH2NH), 5.83 (1H, d, J¼7.2 Hz, 6-H), 7.38
(1H, d, J¼2.0 Hz, p-C6H3), 7.47 (1H, t, J¼1.9 Hz, o-C6H3), 7.78 (1H, d,
J¼7.2 Hz, 5-H), 8.40 (1H, s, 2-H), 9.09 (1H, br t, J¼5.8 Hz, NHCH2),
12.01 (s, 1H); dC (126 MHz, DMSO-d6) 41.1, 97.9, 99.8, 126.2, 126.4,
133.9, 140.9, 141.6, 144.0, 144.3, 156.3, 162.2; HRMS (ESI): MHþ,
found 337.0258. C14H11Cl2N4O2 requires 337.0254.
694, 667, 642, 625 cmꢁ1
; dH (500 MHz, DMSO-d6) 1.67 (2H, br
quintet, J¼6.6 Hz, CH2CH2CH2), 3.27 (2H, br q, J¼6.7 Hz, OCH2), 3.47
(2H, br q, J¼6.0 Hz, CH2NH), 3.89 (3H, s, Me), 4.48 (1H, t, J¼5.1 Hz,
OH), 5.89 (1H, d, J¼7.7 Hz, 6-H), 7.91 (1H, d, J¼7.7 Hz, 5-H), 8.13 (1H,
s, 2-H); dC (126 MHz, DMSO-d6) 32.3, 36.4, 41.6, 58.5, 97.2, 103.2,
141.0, 142.7, 145.7, 155.3, 161.3; HRMS (ESI): MHþ, found 251.1142.
C11H15N4O3 requires 251.1139.
4.17.10. N,N-Dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-
3-carboxamide (16g). Prepared from 14a (90 mg, 0.5 mmol) and
4.17.15. 4-Methyl-7-oxo-N-(pyridin-2-ylmethyl)-4, 7-
dimethylamine (5.6 M in EtOH, 300
m
L, 1.68 mmol), FC: first EtOAc,
dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide
from 14b (97 mg, 0.5 mmol) and 2-picolylamine (50 m
(16l). Prepared
L, 0.5 mmol),
then 90% CHCl3/MeOH. Yield: 87 mg (84%) of greyewhite solid; mp
>300 ꢀC (decomp.); nmax (ATR) 3269, 3141, 3054, 2923, 1673, 1583,
1514, 1400, 1342, 1279, 1184, 1056, 1010, 902, 836, 764, 680,
FC: first EtOAc, then 75% CHCl3/MeOH containing 3% Et3N. Yield:
103 mg (73%) of white solid; mp 167e170 ꢀC; nmax (ATR) 3258,
3050, 2960, 2925, 1705, 1677, 1629, 1577, 1541, 1478, 1435, 1365,
1350, 1293, 1268, 1225, 1147, 1114, 1095, 1072, 1051, 1018, 993, 958,
608 cmꢁ1
; dH (500 MHz, DMSO-d6) 3.08 (br s, 3H, NMe2), 3.21 (6H,
br s, NMe2), 5.87 (1H, d, J¼7.4 Hz, 6-H), 7.79 (1H, d, J¼7.4 Hz, 5-H),
8.28 (s, 1H, 2-H), 12.10 (br s, 1H, NH); HRMS (ESI): MHþ, found
207.0876. C9H11N4O2 requires 207.0877.
875, 797, 754, 723, 664, 624 cmꢁ1
; dH (500 MHz, DMSO-d6) 3.90
(3H, s, Me), 4.54 (2H, d, J¼6.0 Hz, CH2NH), 5.91 (1H, d, J¼7.7 Hz, 6-
H), 7.28 (1H, dd, J¼7.0, 5.0 Hz, 50-H), 7.38 (1H, d, J¼7.8 Hz, 30-H), 7.78
(1H, td, J¼7.7, 1.8 Hz, 40-H), 7.92 (1H, d, J¼7.7 Hz, 5-H), 8.27 (1H, s, 2-
H), 8.52 (1H, d, J¼4.4 Hz, 60-H), 9.08 (1H, br t, J¼5.9 Hz, NH); dC
(126 MHz, DMSO-d6) 41.9, 44.6, 97.4, 102.9, 120.8, 122.1, 136.7, 141.3,
4.17.11. 3-(Pyrrolidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-
one (16h). Prepared from 14a (90 mg, 0.5 mmol) and pyrrolidine
(43 mL, 0.5 mmol), FC: first EtOAc, then 90% CHCl3/MeOH. Yield:

M. Drev et al. / Tetrahedron 70 (2014) 8267e8279
8277
142.8, 145.8, 148.8, 155.3, 158.5, 161.6; HRMS (ESI): MHþ, found
284.1143. C14H13N5O2 requires 284.1142.
1153, 1100, 1065, 1031, 980, 910, 874, 828, 794, 752, 699, 678, 651,
624 cmꢁ1
;
dH (500 MHz, DMSO-d6) 4.41 (2H, d, J¼5.9 Hz, CH2NH),
5.85 (2H, s, CH2N), 6.04 (1H, d, J¼7.7 Hz, 6-H), 7.04e7.34 (10H, m,
2ꢂ Ph), 8.19 (1H, s, 2-H), 8.20 (1H, d, J¼7.7 Hz, 5-H), 8.95 (1H, br t,
J¼5.9 Hz, NH); dC (126 MHz, DMSO-d6) 42.5, 55.6, 98.3, 102.9, 126.8,
126.9, 127.3, 127.8, 128.3, 128.7, 136.1, 139.2, 140.6, 143.1, 145.6,
155.2, 161.5; HRMS (ESI): MHþ, found 359.1502. C21H19N4O2 re-
quires 359.1503.
4.17.16. N,N,4-Trimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimi-
dine-3-carboxamide (16m). Prepared from 14b (97 mg, 0.5 mmol)
and dimethylamine (5.6 M in EtOH, 300 mL, 1.68 mmol), FC: first
EtOAc, then 90% CHCl3/MeOH. Yield: 91 mg (83%) of grey-white
solid; mp 231e235 ꢀC; nmax (ATR) 3060, 2921, 1682, 1584, 1510,
1480, 1441, 1412, 1400, 1344, 1257, 1214, 1154, 1134, 1076, 992, 887,
808, 751, 678, 656, 635, 613 cmꢁ1
;
dH (500 MHz, DMSO-d6) 3.14 and
4.17.21. 4-Benzyl-N-(3-(dimethylamino)propyl)-7-oxo-4,7-
dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide (16r). Prepared
from 14b (97 mg, 0.5 mmol) and 3-(dimethylamino)propylamine
3.19 (6H, 2s, 1:1, NMe2), 3.83 (3H, s, 4-Me), 5.92 (1H, d, J¼7.7 Hz, 6-
H), 7.49 (1H, d, J¼7.7 Hz, 5-H), 7.90 (1H, s, 2-H); dC (126 MHz,
DMSO-d6) 35.3, 39.8, 41.4, 98.4, 101.3, 141.0, 141.8, 143.9, 155.9,
163.2; HRMS (ESI): MHþ, found 221.1035. C10H13N4O2 requires
221.1033.
(64 mL, 0.5 mmol), FC: first EtOAc, then 70% CHCl3/MeOH. Yield:
164 mg (93%) of white solid; mp 202e205 ꢀC; nmax (ATR) 3306,
3062, 2942, 2859, 2814, 2760, 1710, 1685, 1630, 1607, 1575, 1538,
1495, 1481, 1446, 1420, 1385, 1359, 1334, 1292, 1262, 1232, 1216,
1185, 1154, 1140, 1103, 1076, 1043, 1024, 1002, 980, 954, 887, 842,
4.17.17. 4-Methyl-3-(pyrrolidine-1-carbonyl)pyrazolo[1,5-a]pyr-
imidin-7(4H)-one (16n). Prepared from 14b (97 mg, 0.5 mmol) and
807, 769, 739, 730, 691, 665, 641, 717 cmꢁ1
; dH (500 MHz, DMSO-d6)
pyrrolidine (43
m
L, 0.5 mmol), FC: first EtOAc, then 90% CHCl3/
1.65e1.72 (2H, m, CH2CH2CH2), 2.21 (6H, s, NMe2), 2.44 (2H, t,
J¼5.9 Hz, OCH2), 3.43 (2H, q, J¼5.7 Hz, NHCH2), 5.81 (2H, s, CH2Ph),
6.00 (1H, d, J¼7.7 Hz, 6-H), 7.12e7.16 and 7.28e7.33 (5H, 2m, 2:3,
Ph), 7.49 (1H, d, J¼7.7 Hz, 5-H), 7.96 (1H, s, 2-H), 8.39 (1H, t,
J¼4.9 Hz, NH); dC (126 MHz, DMSO-d6) 24.8, 40.6, 45.2, 57.4, 59.1,
99.3, 104.2, 127.4, 128.5, 129.1, 135.3, 140.9, 142.7, 143.7, 156.1, 162.0;
HRMS (ESI): MHþ, found 354.1925. C19H24N5O2 requires 354.1925.
MeOH. Yield: 98 mg (79%) of grey-white solid; mp 205e208 ꢀC;
nmax (ATR) 3106, 3061, 3034, 2953, 2872, 1686, 1587, 1497, 1435,
1405, 1340, 1321, 1266, 1256, 1210, 1164, 1144, 1102, 1038, 973, 913,
888, 843, 806, 754, 732, 706, 657, 638, 618 cmꢁ1
; dH (500 MHz,
DMSO-d6) 1.87 (4H, br octet, J¼6.6 Hz, CH2CH2), 3.44e3.51 (4H, m,
2ꢂ CH2N), 3.73 (3H, s, 4-Me), 5.86 (1H, d, J¼7.6 Hz, 6-H), 7.91 (1H, d,
J¼7.6 Hz, 5-H), 8.16 (1H, s, 2-H); dC (126 MHz, DMSO-d6) 24.1, 25.6,
40.6, 45.6, 48.6, 96.9, 102.7, 140.4, 141.5, 145.3, 155.4, 160.9; HRMS
(ESI): MHþ, found 247.119. C12H14N4O2 requires 247.119.
4.17.22. N,4-Dibenzyl-N-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]
pyrimidine-3-carboxamide (16s). Prepared from 14b (97 mg,
0.5 mmol) and 3-(dimethylamino)propylamine (64 mL, 0.5 mmol),
4.17.18. 4-Methyl-3-(morpholine-4-carbonyl)pyrazolo[1,5-a]pyr-
imidin-7(4H)-one (16o). Prepared from 14b (97 mg, 0.5 mmol) and
FC: first EtOAc, then 90% CHCl3/MeOH. Yield: 164 mg (93%) of
greyewhite solid; mp 196e200 ꢀC; nmax (ATR) 3098, 2965, 1698,
1613, 1588, 1496, 1472, 1445, 1425, 1406, 1370, 1355, 1336, 1318,
1294, 1260, 1235,1220, 1183, 1166, 1146, 1086, 1036, 1028, 1001, 964,
morpholine (43
mL, 0.5 mmol), FC: first EtOAc, then 90% CHCl3/
MeOH. Yield: 123 mg (94%) of grey-white solid; mp 189e191 ꢀC;
nmax (ATR) 3075, 2956, 2925, 2860, 1690, 1622, 1561, 1451, 1428,
1411, 1359, 1347, 1303, 1265, 1242, 1194, 1176, 1153, 1100, 1065, 1031,
931, 895, 801, 756, 737, 729, 711, 692, 660, 641, 609 cmꢁ1
; dH
(500 MHz, DMSO-d6) mixture of rotamers 2.42 and 2.70 (3H, 2br s,
2:1, NMe), 3.78 and 4.49 (2H, 2br s, 1:2, NCH2Ph), 5.51 (2H, br s,
N(4)-CH2Ph), 6.03 (1H, d, J¼7.7 Hz, 6-H), 6.95e7.44 (10H, m, 2ꢂ Ph),
7.71 and 8.11 (1H, 2s, 1:2, 2-H), 8.19 (d, J¼7.7 Hz, 5-H); dH (500 MHz,
CDCl3) mixture of rotamers 2.42 and 2.86 (3H, 2br s, 1:1, NMe), 3.80
and 4.52 (2H, 2br s, 1:1, NCH2Ph), 5.47 (2H, br s, N(4)-CH2Ph), 6.03
(1H, d, J¼7.7 Hz, 6-H), 6.93e7.10 and 7.19e7.40 (10H, 2m, 3:7, 2ꢂ
Ph), 7.54 (1H, d, J¼7.7 Hz, 5-H), 7.61 and 7.78 (1H, 2s, 1:1, 2-H); dC
(126 MHz, CDCl3) mixture of rotamers 33.5 and 36.9 (NMe), 51.0
and 54.8 (NCH2Ph), 57.0 and 57.1 (N(4)eCH2Ph), 99.0 and 99.1 (6-C),
102.2 and 102.3 (3-C), 126.2, 126.7, 127.8, 127.8, 128.5, 128.6, 128.7,
128.9, 129.0, and 129.1 (o,m,p-C of 2ꢂ Ph), 134.6, 134.9, 136.0, and
136.3 (i-C of 2ꢂ Ph), 140.4 and 140.4 (3a-C), 141.1 and 142.0 (2-C),
143.7 and 143.8 (5-C), 156.0 and 156.1 (7-C), 163.8 and 164.5 (C(3)e
C]O); HRMS (ESI): MHþ, found 373.1660. C22H21N4O2 requires
373.1559.
980, 910, 874, 828, 794, 752, 699, 678, 651, 624 cmꢁ1
; dH (500 MHz,
DMSO-d6) 3.75 (8H, br s, 4ꢂ CH2), 3.83 (3H, s, 4-Me), 5.97 (1H, d,
J¼7.7 Hz, 6-H), 7.35 (1H, d, J¼7.7 Hz, 5-H), 7.86 (1H, s, 2-H); dC
(126 MHz, DMSO-d6) 41.7, 66.9, 76.8, 77.1, 99.1, 100.6, 141.8, 143.6,
155.8, 162.2; HRMS (ESI): MHþ, found 263.1138. C12H14N4O3 re-
quires 263.1139.
4.17.19. 4-Benzyl-N-cyclopropyl-7-oxo-4,7-dihydropyrazolo[1,5-a]
pyrimidine-3-carboxamide (16p). Prepared from 14b (97 mg,
0.5 mmol) and cyclopropylamine (36 mL, 0.5 mmol), FC: first EtOAc,
then 90% CHCl3/MeOH¼10:1. Yield: 138 mg (90%) of greyewhite
solid; mp 288e291 ꢀC; [Found: C, 66.26; H, 5.04; N, 18.01.
C
17H16N4O2 requires: C, 66.22; H, 5.23; N, 18.17%]; nmax (ATR) 3075,
2956, 2925, 2860, 1690, 1622, 1561, 1451, 1428, 1411, 1359, 1347,
1303, 1265, 1242, 1194, 1176, 1153, 1100, 1065, 1031, 980, 910, 874,
828, 794, 752, 699, 678, 651, 624 cmꢁ1
; dH (500 MHz, DMSO-d6)
0.45 (2H, td, J¼4.2, 6.1 Hz, CH2CH2), 0.68 (2H, br dt, J¼5.0, 7.0 Hz,
CH2), 2.73 (1H, br octet, J¼3.9 Hz, CHNH), 5.80 (2H, s, CH2Ph), 6.02
(1H, d, J¼7.7 Hz, 6-H), 7.11e7.34 (5H, m, Ph), 8.05 (1H, s, 2-H), 8.21
(1H, d, J¼7.7 Hz, 5-H), 8.38 (1H,br d, J¼3.9 Hz, NH), dC (126 MHz,
DMSO-d6) 5.6, 22.8, 55.6, 98.1, 103.2, 127.0, 128.0, 128.7, 136.1, 140.2,
143.0, 145.5, 155.2, 162.7; HRMS (ESI): MHþ, found 309.1348.
4.18. N-alkylation of carboxamides 16b,deh. Regioselective
synthesis of 4-alkyl- (16m,n) and 1-alkyl 7-oxo-4,7-
dihydropyrazolo[1,5-a]pyrimidine-3-carboxamides 17aef
C
17H16N4O2 requires 309.1346.
Alkyl halide (2.5 mmol) was added to a stirred mixture of car-
boxamide 16b,deh (0.5 mmol), anhyd DMF (5 mL), and anhyd
K2CO3 (345 mg, 2.5 mmol) and the mixture was stirred at rt for 24 h.
Volatile components were evaporated in vacuo and the residue was
purified by FC (silica gel, first EtOAc/hexanes to elute the non-polar
impurities, then EtOAc or CHCl3/MeOH to elute the product).
Fractions containing the product were combined and volatile
components evaporated in vacuo to give the title compound 16 or 17.
The following compounds were prepared in this manner:
4.17.20. N,4-Dibenzyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-
3-carboxamide (16q). Prepared from 14b (97 mg, 0.5 mmol) and
benzylamine (56 mL, 0.5 mmol), FC: first EtOAc, then 90% CHCl3/
MeOH. Yield: 137 mg (76%) of greyewhite solid; mp 242e246 ꢀC;
[Found: C, 69.60; H, 4.83; N, 15.19. C21H18N4O2$1/5H2O requires: C,
69.68; H, 5.12; N, 15.48%]; nmax (ATR) 3075, 2956, 2925, 2860, 1690,
1622, 1561, 1451, 1428, 1411, 1359, 1347, 1303, 1265, 1242, 1194, 1176,

8278
M. Drev et al. / Tetrahedron 70 (2014) 8267e8279
4.18.1. N,N,4-Trimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-
3-carboxamide (16m). Prepared from 16g (103 mg, 0.5 mmol) and
1655, 1576, 1557, 1507, 1437, 1418, 1314, 1261, 1200, 1173, 1101, 1010,
929, 867, 847, 804, 775, 733, 708, 700, 670, 621 cmꢁ1
dH (500 MHz,
;
MeI (156
m
L, 2.5 mmol), FC: first EtOAc, then 90% CHCl3/MeOH.
DMSO-d6) 4.59 (2H, d, J¼6.2 Hz, CH2NH), 6.05 (2H, s, CH2N), 6.09
(1H, d, J¼6.3 Hz, 6-H), 7.21e7.25 (3H, m, 3H of Arl), 7.30e7.37 (5H,
m, 5H of Arl), 7.94 (1H, d, J¼6.3 Hz, 5-H), 8.37 (1H, s, 2-H), 9.01 (1H,
t, J¼6.2 Hz, NHCH2); dC (126 MHz, DMSO-d6) 42.1, 57.2, 103.7, 106.3,
126.0, 127.6, 128.8, 129.42, 129.45, 133.2, 135.2, 139.8, 142.1, 150.7,
153.1, 157.3, 160.6; HRMS (ESI): MHþ, found 427.0723.
Yield: 102 mg (93%) of greyewhite solid. Physical, analytical and
spectral data were identical to the data of 16m obtained by ami-
dation of 14b (see Section 4.17.16).
4.18.2. 4-Methyl-3-(pyrrolidine-1-carbonyl)pyrazolo[1,5-a]pyr-
imidin-7(4H)-one (16n). Prepared from 16h (116 mg, 0.5 mmol) and
C21H17Cl2N4O2 requires 427.0722.
MeI (156
mL, 2.5 mmol), FC: first EtOAc, then 90% CHCl3/MeOH.
Yield: 118 mg (96%) of greyewhite solid. Physical, analytical and
spectral data were identical to the data of 16n obtained by ami-
dation of 14b (see Section 4.17.17).
4.18.7. N-Benzyl-1-(3-methoxybenzyl)-7-oxo-1,7-dihydropyrazolo
[1,5-a]pyrimidine-3-carboxamide (17e). Prepared from 16d
(134 mg, 0.5 mmol) and 3-methoxybenzyl bromide (356 L,
m
2.5 mmol), FC: first 33% EtOAc/hexanes, then EtOAc. Yield: 140 mg
(72%) of white solid; mp 148e150 ꢀC; [Found: C, 67.88; H, 4.86; N,
14.04. C22H20N4O3 requires: C, 68.03; H, 5.19; N, 14.42%]; nmax (ATR)
3269, 3058, 1677, 1654, 1573, 1512, 1440, 1322, 1297, 1258, 1172,
4.18.3. N-(2-Methoxyethyl)-1-methyl-7-oxo-1,7-dihydropyrazolo
[1,5-a]pyrimidine-3-carboxamide
(17a). Prepared
from
16b
(118 mg, 0.5 mmol) and MeI (156
mL, 2.5 mmol), FC: first EtOAc,
then 90% CHCl3/MeOH. Yield: 49 mg (39%) of greyewhite solid; mp
160e161 ꢀC; [Found: C, 52.88; H, 5.56; N, 22.39. C11H14N4O3 re-
quires: C, 52.79; H, 5.64; N, 22.39%]; nmax (ATR) 3301, 3052, 2920,
1686,1644,1574,1553,1512,1473,1445,1310,1276,1118,1087,1025,
1048, 931, 774, 740, 698, 658, 630 cmꢁ1
; dH (500 MHz, DMSO-d6)
3.76 (3H, s, OMe), 4.66 (2H, d, J¼5.8 Hz, CH2NH), 5.99 (2H, s, CH2N),
6.07 (1H, d, J¼6.3 Hz, 6-H), 6.84e6.87 (3H, m, 3H of Arl), 7.22e7.28
(2H, m, 2H of Arl), 7.30e7.37 (4H, m, 4H of Arl), 7.92 (1H, d, J¼6.3 Hz,
5-H), 8.41 (1H, s, 2-H), 8.94 (1H, br t, J¼5.8 Hz, NHCH2); dC
(126 MHz, DMSO-d6) 43.1, 55.4, 56.9, 103.5, 106.7, 114.3, 114.7, 120.7,
127.4, 127.6, 128.7, 130.4,134.7, 138.4, 140.0, 150.7, 153.1, 157.4, 160.2,
160.4; HRMS (ESI): MHþ, found 389.1585. C22H21N4O3 requires
389.1608.
944, 867, 791, 771, 695 cmꢁ1
; dH (500 MHz, DMSO-d6) 3.28 (3H, s,
OMe), 3.45 (2H, br t, J¼5.4 Hz, OCH2), 3.51 (2H, br q, J¼5.4 Hz,
NCH2), 4.35 (3H, s, NMe), 5.95 (1H, d, J¼6.3 Hz, 6-H), 8.00 (1H, d,
J¼6.3 Hz, 5-H), 8.54 (1H, br t, J¼5.4 Hz, NH), 8.80 (1H, s, 2-H), dC
(126 MHz, DMSO-d6) 38.1, 40.8, 58.1, 70.8, 101.5, 103.9, 141.2, 149.6,
153.1, 156.4, 159.9; HRMS (ESI): MHþ, found 251.1141. C11H15N4O3
requires 251.1139.
4.18.8. 1-(3-Methoxybenzyl)-N-(4-methylbenzyl)-7-oxo-1,7-
dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide
from 16e (141 mg, 0.5 mmol) and 3-methoxybenzyl bromide
(356 L, 2.5 mmol), FC: first 33% EtOAc/hexanes, then 67% EtOAc/
(17f). Prepared
4.18.4. 1-Benzyl-N-(2-methoxyethyl)-7-oxo-1,7-dihydropyrazolo[1,5-
a]pyrimidine-3-carboxamide (17b). Prepared from 16b (118 mg,
m
0.5 mmol) and BnBr (303
m
L, 2.5 mmol), FC: EtOAc. Yield: 104 mg
hexanes. Yield: 183 mg (91%) of white solid; mp 162e164 ꢀC;
[Found: C, 68.92; H, 5.65; N,13.71. C23H22N4O3 requires: C, 68.64; H,
5.51; N,13.92%]; nmax (ATR) 3269, 3056,1673,1650,1575,1556,1510,
1490, 1439, 1420, 1375, 1344, 1325, 1299, 1257, 1176, 1157, 1088,
1059, 996, 936, 899, 816, 800, 774, 755, 739, 709, 693, 649,
(64%) of greyewhite solid; mp 138e140 ꢀC; [Found: C, 62.76; H,
5.35; N, 17.12. C17H18N4O3 requires: C, 62.57; H, 5.56; N, 17.17%];
nmax (ATR) 3290, 3056, 2990, 1683, 1645, 1580, 1552, 1510, 1495,
1441, 1426, 1320, 1265, 1200, 1175, 1119, 1094, 1026, 966, 769 cmꢁ1
;
dH (500 MHz, DMSO-d6) 3.27 (3H, s, OMe), 3.43e3.47 and
3.48e3.53 (4H, 2m, 1:1, CH2CH2), 6.01 (1H, d, J¼6.3 Hz, 6-H), 6.04
(2H, s, NCH2Ph), 7.21e7.24 and 7.26e7.35 (5H, 2m, 2:3, Ph), 8.02
(1H, d, J¼6.3 Hz, 5-H), 8.55 (1H, t, J¼5.7 Hz, NH), 9.19 (1H, s, 2-H); dC
(126 MHz, DMSO-d6) 38.2, 55.5, 58.1, 70.7, 102.5, 105.7, 127.6, 128.4,
128.8, 135.1, 141.8, 150.3, 153.2, 156.2, 159.6; HRMS (ESI): MHþ,
found 327.1435. C17H19N4O3 requires 327.1452.
629 cmꢁ1
; dH (500 MHz, DMSO-d6) 2.32 (3H, s, Me), 3.76 (3H, s,
OMe), 4.61 (2H, d, J¼5.9 Hz, CH2NH), 5.99 (2H, s, NCH2), 6.06 (1H, d,
J¼6.3 Hz, 6-H), 6.83e6.88 (3H, m, 3H of Arl), 7.13 (2H, d, J¼7.7 Hz,
2H of Arl), 7.22e7.27 (3H, m, 3H of Arl), 7.91 (1H, d, J¼6.3 Hz, 5-H),
8.37 (1H, s, 2-H), 8.88 (1H, t, J¼5.9 Hz, NHCH2); dC (126 MHz, DMSO-
d6) 21.2, 42.9, 55.4, 57.0, 103.5, 106.8, 114.3, 114.7, 120.7, 127.7, 129.4,
130.4, 134.7, 135.4, 137.1, 139.9, 150.7, 153.2, 157.4, 160.2, 160.3;
HRMS (ESI): MHþ, found 403.1753. C23H23N4O3 requires 403.1765.
4.18.5. N,1-Dibenzyl-7-oxo-1,7-dihydropyrazolo[1,5-a]pyrimidine-3-
carboxamide (17c). Prepared from 16d (134 mg, 0.5 mmol) and
BnBr (303
m
L, 2.5 mmol), FC: first 33% EtOAc/hexanes, then EtOAc.
4.19. X-ray structure analysis for compounds 13b, 16o, 17a and
17b
Yield: 129 mg (75%) of white solid; mp 180e183 ꢀC; [Found: C,
68.95; H, 4.96; N, 14.81. C21H18N4O2 requires: C, 70.38; H, 5.06; N,
15.63%]; nmax (ATR) 3276, 3060, 2924, 1693, 1644, 1577, 1555, 1508,
1451, 1421, 1357, 1327, 1263, 1202, 1179, 1099, 1079, 1051, 1026, 939,
Single crystal diffraction data for compounds 13b, 16o, 17a and
17b have been collected on an Agilent SuperNova dual source dif-
897, 837, 825, 788, 773, 722, 710, 692, 638, 627, 604 cmꢁ1
;
dH
fractometer with an Atlas detector with Cu Ka radiation (1.54184 A).
ꢁ
(500 MHz, DMSO-d6) 4.57 (2H, d, J¼6.1 Hz, CH2NH), 6.01 (1H, d,
J¼6.3 Hz, 6-H), 6.05 (2H, s, CH2N), 7.21e7.36 (10H, m, 2ꢂ Ph), 8.00
(1H, d, J¼6.3 Hz, 5-H), 8.85 (1H, br t, J¼6.1 Hz, NHCH2), 9.22 (1H, s,
2-H); dC (126 MHz, DMSO-d6) 43.1, 57.0, 103.5, 106.7, 127.4, 127.6,
128.66, 128.72, 129.29, 129.30, 133.4, 138.4, 140.0, 150.7, 153.1, 157.3,
160.4; HRMS (ESI): MHþ, found 359.1503. C21H19N4O2 requires
359.1503.
For 13b, 16o and 17a data were collected at room temperature and
for 17b at 150(1) K, respectively. The diffraction data were pro-
cessed using CrysAlis PRO software.18
All structures were solved by direct methods, using SIR97.19
A
full-matrix least-squares refinement on F2 was employed with
anisotropic displacement parameters for all non-hydrogen atoms.
H atoms were placed at calculated positions and treated as riding.
SHELXL97 software20 was used for structure refinement and in-
terpretation. Drawings of the structures were produced using
ORTEP-3.21 Structural and other crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 1007397eCCDC
1007400, for 13b, 16o, 17a and 17b, respectively. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/
4.18.6. 1-Benzyl-N-(3,5-dichlorobenzyl)-7-oxo-1,7-dihydropyrazolo
[1,5-a]pyrimidine-3-carboxamide (17d). Prepared from 16f (169 mg,
0.5 mmol) and BnBr (303 mL, 2.5 mmol), FC: first 33% EtOAc/hex-
anes, then EtOAc. Yield: 185 mg (86%) of white solid; mp
181e183 ꢀC; [Found: C, 59.09; H, 3.70; N, 12.70. C21H16Cl2N4O2 re-
quires: C, 59.03; H, 3.77; N, 13.11%]; nmax (ATR) 3297, 3062, 1687,

M. Drev et al. / Tetrahedron 70 (2014) 8267e8279
8279
10090e10107; (b) Asano, T.; Yamazaki, H.; Kasahara, C.; Kubota, H.; Kontani, T.;
Harayama, Y.; Ohno, K.; Mizuhara, H.; Yokomoto, M.; Misumi, K.; Kinoshita, T.;
Ohta, M.; Takeuchi, M. J. Med. Chem. 2012, 55, 7772e7785; (c) Kosugi, T.;
Mitchell, D. R.; Fujino, A.; Imai, M.; Kambe, M.; Kobayashi, S.; Makino, H.;
Matsueda, Y.; Oue, Y.; Komatsu, K.; Imaizumi, K.; Sakai, Y.; Sugiura, S.; Taken-
ouchi, O.; Unoki, G.; Yamakoshi, Y.; Cunliffe, V.; Frearson, J.; Gordon, R.; Harris,
C. J.; Kalloo-Hosein, H.; Le, J.; Patel, G.; Simpson, D. J.; Sherborne, B.; Thomas, P.
S.; Suzuki, N.; Takimoto-Kamimura, M. J. Med. Chem. 2012, 55, 6700e6715.
6. Xu, J.; Liu, H.; Li, G.; He, Y.; Ding, R.; Wang, X.; Feng, M.; Zhang, S.; Chen, Y.; Li,
S.; Zhao, M.; Li, Y.; Qi, C. Z. Naturforsch. 2012, 67B, 827e834.
7. Lopez, L. C.; Dos-Reis, S.; Espargaro, A.; Carrodeguas, J. A.; Maddelein, M.-L.;
Ventura, S.; Sancho, J. J. Med. Chem. 2012, 55, 9521e9530.
8. Hajos, G.; Riedl, Z.. In Aza Analogues of Pyrazolo[1,5-a]pyridines Containing
Additional Nitrogen Atoms in the Sixmembered Ring in Science of Synthesis,
HoubeneWeyl: Methods of Molecular Transformations, Neier, R., Ed.; Thieme:
Stuttgart, Germany, Vol. 12, pp 667e678.
retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2
1EZ, UK; fax: þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgements
The financial support from the Boehringer-Ingelheim Pharma
(Biberach, Germany) and from the Slovenian Research Agency
through grant P1-0179 is gratefully acknowledged. We also thank to
EN-FIST Centre of Excellence (Ljubljana, Slovenia) for using the
SuperNova diffractometer.
Supplementary data
9. (a) Bruni, F.; Selleri, S.; Costanzo, A.; Guerrini, G.; Casilli, M. L.; Giusti, L. J.
Heterocycl. Chem. 1995, 32, 291e298; (b) Gregg, B. T.; Tymoshenko, D. O.;
Razzano, D. A.; Johnson, M. R. J. Comb. Chem. 2007, 9, 507e512.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.09.020.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
ꢀ
ꢀ
ꢀ
10. (a) Japelj, B.; Recnik, S.; Cebasek, P.; Stanovnik, B.; Svete, J. J. Heterocycl. Chem.
ꢀ
ꢀ
2005, 42, 1167e1173; (b) Cebasek, P.; Bevk, D.; Pirc, S.; Stanovnik, B.; Svete, J. J.
Comb. Chem. 2006, 8, 95e102.
11. (a) Svete, J.; Stanovnik, B. Chem. Rev. 2004, 104, 2433e2480; (b) Svete, J. Mon-
atsh. Chem. 2004, 125, 629e647.
12. (a) Ahmetaj, S.; Velikanje, N.; Groselj, U.; Sterbal, I.; Prek, B.; Golobic, A.; Kocar,
ꢀ
References and notes
ꢀ
ꢀ
ꢀ
D.; Dahmann, G.; Stanovnik, B.; Svete, J. Mol. Divers. 2013, 17, 731e743; (b)
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Baskovc, J.; Dahmann, G.; Golobic, A.; Groselj, U.; Kocar, D.; Stanovnik, B.; Svete,
1. (a) Dolle, R. E. Solid-phase Synthesis of Heterocyclic Systems (Heterocycles
Containing One Heteroatom) InNicolaou, K. C., Hanko, R., Hartwig, W., Eds..
Handbook of Combinatorial Chemistry. Drugs, Catalysts, Materials; Wiley-VCH
GmbH: Weinheim, Germany, 2002; Vol. 2, pp 643e684; (b) Pernerstorfer, J.
Molecular Design and Combinatorial Compound InNicolaou, K. C., Hanko, R.,
Hartwig, W., Eds.. Handbook of combinatorial chemistry. Drugs, catalysts, mate-
rials; Wiley-VCH GmbH: Weinheim, Germany, 2002; Vol. 2, pp 725e742; (c)
Dolle, R. E.; Le Bourdonnec, B.; Worm, K.; Morales, G. A.; Thomas, C. J.; Zhang,
W. J. Comb. Chem. 2009, 12, 765e806; (d) Patrick, G. L. Introduction to Medicinal
Chemistry, 4th ed.; Oxford University: Oxford, UK, 2009.
2. (a) Regan, A. C. In Pyrazolo[1,5-c]pyrimidine (73) in Comprehensive heterocyclic
chemistry III, Katritzky, A. R.; Ramsden, C. A., Scriven E. F. V., Taylor, R. J. K., Eds.;
Elsevier Science Ltd.: Oxford, UK, 2008; Vol. 11, Cossy, J., Ed.; pp 577e577; and
references cited therein; (b) Elnagdi, M. H.; Elmoghayar, M. R. H.; Elgemeie, G.
E. H. Adv. Heterocycl. Chem. 1987, 41, 319e376.
ꢀ
ꢀ
J. ACS Comb. Sci. 2012, 14, 513e519; (c) Perdih, P.; Baskovc, J.; Dahmann, G.;
Groselj, U.; Kocar, D.; Novak, A.; Stanovnik, B.; Svete, J. Synthesis 2011, 17,
2822e2832 and references cited therein.
ꢀ
ꢀ
13. (a) Irlapati, N. R.; Baldwin, J. E.; Adlington, R. M.; Pritchard, G. J.; Cowley, A. Org.
Lett. 2013, 5, 2351e2354; (b) Irlapati, N. R.; Baldwin, J. E.; Adlington, R. M.;
Pritchard, G. J.; Cowley, A. Tetrahedron 2006, 62, 4603e4614; (c) Pirc, S.; Bevk,
ꢀ
D.; Golobic, A.; Stanovnik, B.; Svete, J. Helv. Chim. Acta 2006, 89, 30e44.
14. (a) Cheng, W.; Gu, Z.; Tang, J.; Jia, H. CN 102603752, Chem. Abstr. 2012, 157,
261872; (b) Tung, R.; Harbeson, S. WO2008005471; Chem. Abstr. 2008, 148,
144785; (c) Sorbera, L. A.; Castaner, J.; Martin, L. Drugs Future 2003, 28,
739e746.
ꢀ
15. Kusar, M.; Svete, J.; Stanovnik, B. J. Heterocycl. Chem. 1996, 33, 1041e1046.
ꢂ
16. Reimlinger, H.; Pieren, M. A.; Merenyi, R. Chem. Ber. 1970, 103, 3252e3265.
17. Nitz, T. J.; Salzwedel, K., Finnegan, C.; Wild, C.; Brunton, S.; Flanagan, S.; Mon-
talbetti, C.; Coulter, T. S.; Kimber, M.; Magaraci, F.; Johnston D. WO 2008134035,
Chem. Abstr. 2008, 149, 534234.
3. Hwang, J. Y.; Windisch, M. P.; Jo, S.; Kim, H. C.; Kim, S.; Kim, H.; Lee, M. E.; Park,
D.-S.; Park, E.; Ahn, S.; Cechetto, J.; Kim, J.; Liuzzi, M.; No, Z.; Lee, J. Bioorg. Med.
Chem. Lett. 2012, 22, 7297e7301.
18. Agilent Technologies. CrysAlis PRO. Version 1.171.35.11; Agilent Technologies:
Yarnton, Oxfordshire, England, 2011.
4. Ivashchenko, A. V.; Golovina, E. S.; Kadieva, M. G.; Kysil, V. M.; Mitkin, O. D.;
19. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.; Giacovazzo, C.; Gua-
gliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. J. Appl. Crystallogr. 1999,
32, 115e119.
20. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112e122.
21. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565e565.
Okun, I. M. Pharm. Chem. J. 2012, 46, 406e410.
5. (a) Hanan, E. J.; van Abbema, A.; Barrett, K.; Blair, W. S.; Blaney, J.; Chang, C.;
Eigenbrot, C.; Flynn, S.; Gibbons, P.; Hurley, C. A.; Kenny, J. R.; Kulagowski, J.;
Lee, L.; Magnuson, S. R.; Morris, C.; Murray, J.; Pastor, R. M.; Rawson, T.; Siu, M.;
Ultsch, M.; Zhou, A.; Sampath, D.; Lyssikatos, J. P. J. Med. Chem. 2012, 55,