Synthesis of tetrahydropyrazolo[1,5- C ]pyrimidine-2,7(1 H,3 H)-diones

Article abstract of DOI:10.1055/s-0032-1318107

A series of tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones 3a-h as the first representatives of the so far unexplored saturated heterocyclic system have been synthesized, formally in 12 steps from methyl acrylate (4). The synthesis comprises a four-step preparation of methyl N-Cbz-5-alkylamino-3- oxopentanoates 9a-c, their three-step transformation into 5-{2-[(alkyl) (benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones 12a-c, three-step selective alkylation of the amidic N-2 to give 2-alkyl-5-{2-[(alkyl)(benzyloxycarbonyl) amino]ethyl}pyrazolidin-3-ones 16b-h, followed by hydrogenolytic Cbz-deprotection and subsequent cyclization of the intermediate 1,4-diamine with CDI to furnish the title compounds 3. Most of the synthetic steps were performed as a one-pot transformation. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1318107

PAPER
▌639
paper
Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones
Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidines
Uroš Grošelj,*a Anja Podlogar,a Ana Novak,a Georg Dahmann,b Amalija Golobič,a Branko Stanovnik,a Jurij Svete*a
a
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, P. O. Box 537, 1000 Ljubljana, Slovenia
Fax +386(1)2419220; E-mail: jurij.svete@fkkt.uni-lj.si
b
Boehringer Ingelheim Pharma GmbH & Co. KG, Medicinal Chemistry, 88397 Biberach, Germany
Received: 22.11.2012; Accepted after revision: 27.12.2012
Dedicated to Professor Emeritus Volker Jäger, Institut für Organische Chemie, Universität Stuttgart, on the occasion of his 70th birthday.
synthesis
2,7(1H,3H)-diones 3.
of
tetrahydropyrazolo[1,5-c]pyrimidine-
Abstract: A series of tetrahydropyrazolo[1,5-c]pyrimidine-
2,7(1H,3H)-diones 3a–h as the first representatives of the so far un-
explored saturated heterocyclic system have been synthesized, for-
mally in 12 steps from methyl acrylate (4). The synthesis comprises
a four-step preparation of methyl N-Cbz-5-alkylamino-3-oxopen-
tanoates 9a–c, their three-step transformation into 5-{2-[(al-
kyl)(benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones 12a–c,
three-step selective alkylation of the amidic N-2 to give 2-alkyl-5-
{2-[(alkyl)(benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones
16b–h, followed by hydrogenolytic Cbz-deprotection and subse-
quent cyclization of the intermediate 1,4-diamine with CDI to fur-
nish the title compounds 3. Most of the synthetic steps were
performed as a one-pot transformation.
R2
7
4
1
8
N
R1
N
6 N
N
N
N
2
5
3a
3
1
2
2-aminoethyl moiety
3-pyrazolidinone moiety
O
R2
R1
N
N
N
O
Key words: pyrazolo[1,5-c]pyrimidines, cyclization, saturated het-
erocycles, 3-pyrazolidinones
3
Figure 1 Pyrazolo[1,5-c]pyrimidine (1), 1,6-disubstituted octahy-
dropyrazolo[1,5-c]pyrimidines 2, and 1,6-disubstituted tetrahydro-
pyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones 3
Heterocyclic systems are important scaffolds in medicinal
chemistry, catalysis, and material science.1 In this context,
pyrazolo[1,5-c]pyrimidine (1) (Figure 1) belongs to a
group of less explored systems with approximately 600
derivatives synthesized and 60 references, mostly patents,
with almost one half of them prepared for use in biological
studies.2 Thus, biologically active pyrazolo[1,5-c]pyrimi-
dine derivatives exhibit kinase inhibition,3 antiviral,4 anti-
cancer,5 and GPR119 modulatory activity.6 They also
possess high affinity for transforming growth factor β type
I receptor (Alk 5) and activin receptor type I (Alk 4).7 Fur-
ther, 2,5-diarylpyrazolo[1,5-c]pyrimidine-7(6H)-thiones
inhibit corrosion of ferrous alloys,8 while related pyrazo-
lo[1,5-c]pyrimidinones are used as photographic materi-
als.9 In contrast to hundreds of known pyrazolo[1,5-
c]pyrimidine derivatives, their fully saturated analogues,
octahydropyrazolo[1,5-c]pyrimidines 2 (Figure 1) are, to
the best of our knowledge, unknown.
Herein, we report the synthesis of 1,6-dialkyltetrahydro-
pyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones 3a–h as
the first representatives of this partially saturated bicyclic
system.
Following a literature example,11c solvent-free 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU)-catalyzed Michael
addition of benzylamine (5a), 1-butylamine (5b), and 1-
propylamine (5c) to methyl acrylate (4) gave methyl β-al-
aninates 6a–c, which were Cbz-protected, and the so
formed N-alkyl-N-Cbz-β-alanine esters 7a–c were hydro-
lyzed to afford N-alkyl-N-Cbz-β-alanines 8a–c12 in 34–
51% yields over three steps. Masamune–Claisen conden-
sation of 8a–c with monomethylmagnesium malonate
was carried out according to the literature procedure for
the homologation of closely related amino acid
derivatives11,13 to give the corresponding β-keto esters 9a–
c in 87–92% yields. Reduction of 9a–c with NaBH4, me-
sylation of the alcohols 10a–c, and cyclization of the me-
sylates 11a–c with hydrazine hydrate furnished 5-{2-
[(alkyl)(benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-
ones 12a–c in 43–61% yields over three steps (Scheme 1,
Table 1).
In continuation of our previous work on the chemistry of
3-pyrazolidinones10 and the pyrazole analogues of hista-
mine,11 it became apparent to us to study the synthesis of
tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones
3 as interesting type of heterocyclic compounds consist-
ing of the 3-pyrazolidinone and the 2-aminoethyl moiety.
To our pleasant surprise, the literature search revealed,
that also this particular subclass of heterocycles was un-
known. This prompted us to focus our attention on the
Unfortunately, attempts to prepare N-2-substituted pyr-
azolidinones by cyclization of the mesylate 11a with cy-
clohexyl-, tert-butyl-, and phenylhydrazine failed. As it
became clear that introduction of the other N-substituent
(cf. Figure 1, R2 in title compounds 3) by cyclization of 11
with monosubstituted hydrazines was not feasible, a dif-
ferent, somewhat longer approach was investigated. First,
SYNTHESIS 2013, 45, 0639–0650
Advanced online publication: 24.01.2013
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1
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DOI: 10.1055/s-0032-1318107; Art ID: SS-2012-Z0909-OP
© Georg Thieme Verlag Stuttgart · New York

640
U. Grošelj et al.
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the pyrazolidinone 12a was treated with ClCO2Bn to af- analogues of 13a readily underwent alkylation of the
ford the Cbz-protected derivative 13a in 70% yield. How- amidic nitrogen N-2. The Boc-protected pyrazolidinones
ever, subsequent N-methylation of 13a with MeI (14a) 13b–d were prepared by treatment of 12a–c with Boc2O
did not proceed to completion and the N-methylated inter- in 73–97% yields and then alkylated with alkyl halides
mediate 15a was obtained in only 18% yield. Quite ex- 14a–d to give the fully substituted intermediates 15b–h in
pectedly, subsequent removal of both Cbz groups by 49–73% yields. Acidolytic removal of the Boc group led
catalytic hydrogenation, cyclization of the intermediate to 1-unsubstituted pyrazolidinones 16b–h in 77–99%
1,4-diamine with 1,1′-carbonyldiimidazole (CDI), and yields. Subsequent hydrogenolytic removal of the Cbz
chromatographic workup furnished the first final product group followed by cyclization of the so formed free 1,4-
3a in 30% yield over two steps (Path A, Scheme 2, Table diamine with CDI, and chromatographic workup fur-
1). Despite the ineffective N-2 alkylation of the pyrazolid- nished the title compounds 3b–h in 28–65% yields over
inone 13a, the above transformations confirmed the feasi- the last two steps (Path B, Scheme 2, Table 1).
bility of our synthetic approach. To our delight, 1-Boc
Table 1 Experimental and Analytical Data for Title Compounds 3a–h and Intermediates 8–13, 15, and 16
Product
R
R1
R2
Yield
Appearance
mp (°C)
Molecular formula
Elemental analysis
ESI-MS m/z
ESI-HRMS m/z
8a
8b
H
H
Bn
Bu
–
–
32.1 g (51%)
26.0 g (47%)
brown oil
brown oil
C18H19NO4
C15H21NO4
280 [M + H]+
266 [M + H]+
370 [M + H]+
336 [M + H]+
322 [M + H]+
372 [M + H]+
338 [M + H]+
324 [M + H]+
450 [M + H]+
416 [M + H]+
402 [M + H]+
354 [M + H]+
320 [M + H]+
306 [M + H]+
488 [M + H]+
454 [M + H]+
Calcd: 280.1543
Found: 280.154
8c
9a
H
Pr
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
18.1 g (34%)
34.0 g (92%)
29.2 g (87%)
28.6 g (89%)
30.2 g (98%)
24.0 g (86%)
26.2 g (98%)
30.4 g (94%)
22.2 g (74%)
25.9 g (90%)
11.6 g (66%)
10.9 g (68%)
9.82 g (64%)
11.9 g (70%)
11.6 g (73%)
brown oil
C14H19NO4
C21H23NO5
C18H25NO5
C17H23NO5
C21H25NO5
C18H27NO5
C17H25NO5
C22H27NO7S
Calcd: 266.1387
Found: 266.1388
Bn
Bu
Pr
colorless oil
yellowish oil
yellowish oil
brownish oil
yellow oil
Calcd: 370.1649
Found: 370.1679
9b
Calcd: 336.1805
Found: 336.1816
9c
Calcd: 322.1649
Found: 322.1645
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
H
Bn
Bu
Pr
Calcd: 372.1805
Found: 372.1806
H
Calcd: 338.1962
Found: 338.1965
H
yellow oil
Calcd: 324.1805
Found: 324.1802
Ms
Ms
Ms
Bn
Bu
Pr
brown oil
Calcd: 450.1593
Found: 450.1588
red-brown oil C19H29NO7S
Calcd: 416.1737
Found: 416.1739
brown oil
C18H27NO7S
Calcd: 402.1581
Found: 402.1585
Bn
Bu
Pr
red-brown oil C20H23N3O3
red-brown oil C17H25N3O3
red-brown oil C16H23N3O3
Calcd: 354.1812
Found: 354.1805
Calcd: 320.1969
Found: 320.1966
Calcd: 306.1812
Found: 306.1810
Cbz
Boc
Bn
Bn
yellow oil
brown oil
C28H29N3O5
C25H31N3O5
Calcd: 488.218
Found: 488.2179
Calcd: 454.2342
Found: 454.2345
Synthesis 2013, 45, 639–650
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidines
641
Table 1 Experimental and Analytical Data for Title Compounds 3a–h and Intermediates 8–13, 15, and 16 (continued)
Product
R
R1
R2
Yield
Appearance
mp (°C)
Molecular formula
Elemental analysis
ESI-MS m/z
ESI-HRMS m/z
13c
13d
15a
15b
15c
15d
15e
15f
Boc
Boc
Cbz
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Bu
Pr
–
14.2 g (97%)
13.4 g (95%)
0.453 g (18%)
1.183 g (49%)
1.283 g (57%)
1.468 g (68%)
1.595 g (71%)
1.638 g (69%)
1.853 g (73%)
1.516 g (72%)
1.120 g (98%)
1.314 g (99%)
0.876 g (88%)
0.981 g (94%)
1.098 g (98%)
0.945 g (77%)
0.883 g (92%)
0.156 g (30%)
yellow oil
C22H33N3O5
C21H31N3O5
C29H31N3O5
C27H35N3O5
C32H37N3O5
C23H35N3O5
C24H37N3O5
C26H41N3O5
C29H39N3O5
C22H33N3O5
C22H27N3O3
C27H29N3O3
C18H27N3O3
C19H29N3O3
C21H33N3O3
C24H31N3O3
C17H25N3O3
420 [M + H]+
406 [M + H]+
502 [M + H]+
482 [M + H]+
544 [M + H]+
434 [M + H]+
448 [M + H]+
476 [M + H]+
510 [M + H]+
420 [M + H]+
382 [M + H]+
444 [M + H]+
334 [M + H]+
348 [M + H]+
376 [M + H]+
410 [M + H]+
320 [M + H]+
260 [M + H]+
Calcd: 420.2498
Found: 420.2486
–
yellow oil
Calcd: 406.2336
Found: 406.2324
Bn
Bn
Bn
Bu
Bu
Bu
Bu
Pr
Me
Et
yellow oil
Calcd: 502.2342
Found: 502.2344
yellowish oil
yellowish oil
colorless oil
yellow oil
Calcd: 482.2655
Found: 482.2647
Bn
Me
Et
Calcd: 544.2811
Found: 544.2818
Calcd: 434.2655
Found: 434.2651
Calcd: 448.2811
Found: 448.2806
Bu
Bn
Me
Et
yellowish oil
yellowish oil
colorless oil
yellowish oil
yellowish oil
yellowish oil
yellowish oil
yellow oil
Calcd: 476.3124
Found: 476.3128
15g
15h
16b
16c
16d
16e
16f
Calcd: 510.2968
Found: 510.2965
Calcd: 420.2493
Found: 420.2494
Bn
Bn
Bu
Bu
Bu
Bu
Pr
Calcd: 382.2131
Found: 382.2120
Bn
Me
Et
Calcd: 444.2282
Found: 444.2284
Calcd: 334.2125
Found: 334.2126
Calcd: 348.2282
Found: 348.2283
Bu
Bn
Me
Me
Calcd: 376.2595
Found: 376.2595
16g
16h
3aa
yellowish oil
yellowish oil
Calcd: 410.2438
Found: 410.2439
Calcd: 320.1969
Found: 320.1969
Bn
white solid
94–97
C14H17N3O2
Calcd: 260.1394
Found: 260.1394
Calcd: C, 64.85; H, 6.61; N,
6.20. Found: C, 64.62; H, 6.37;
N, 15.95
3ba
3ca
3d
Bn
Bn
Bu
Et
0.153 g (28%)
0.293 g (44%)
0.292 g (65%)
white solid
66–70
C15H19N3O2
274 [M + H]+
Calcd: 274.1550
Found: 274.1568
Calcd: C, 65.91; H, 7.01; N,
15.37. Found: C, 65.55; H, 7.32;
N, 15.40
Bn
Me
beige solid
64–68
C20H21N3O2·½H2O Calcd: C, 336 [M + H]+
69.75; H, 6.44; N, 12.20.
Found: C, 69.57; H, 6.46; N,
12.26
Calcd: 336.1707
Found: 336.1702
yellowish oil
C11H19N3O2
226 [M + H]+
Calcd: 226.1550
Found: 226.1551
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 639–650

642
U. Grošelj et al.
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Table 1 Experimental and Analytical Data for Title Compounds 3a–h and Intermediates 8–13, 15, and 16 (continued)
Product
R
R1
R2
Yield
Appearance
mp (°C)
Molecular formula
Elemental analysis
ESI-MS m/z
ESI-HRMS m/z
3e
3f
Bu
Bu
Bu
Pr
Et
0.265 g (55%)
0.282 g (53%)
0.314 g (52%)
0.191 g (45%)
yellowish oil
yellow oil
yellow oil
C12H21N3O2
C14H24N3O2
C17H23N3O2
240 [M + H]+
268 [M + H]+
302 [M + H]+
212 [M + H]+
Calcd: 240.1707
Found: 240.1709
Bu
Bn
Me
Calcd: 268.2020
Found: 268.2021
3g
3ha
Calcd: 302.1863
Found: 302.1864
beige solid
74–78
C10H17N3O2
Calcd: 212.1394
Found: 212.1394
Calcd: C, 56.85; H, 8.11; N,
19.89. Found: C, 56.55; H, 8.17;
N, 19.61
a Elemental analysis for C, H, and N was within ± 0.4% deviation from the theoretical values.
1
This somewhat tedious twelve-step synthesis of title com- Their identities were confirmed by H NMR, 13C NMR,
pounds 3a–h was simplified by performing it, as much as and/or HRMS. The identities of the intermediates 8c, 10c–
possible, in a one-pot manner. Each transformation was 12c, 13d, 15a, 16g, and 16h were established by 1H NMR
followed by simple workup, such as evaporation, extrac- and HRMS; intermediate 9c was characterized by HRMS,
tion, and/or FC without additional purification of interme-
diates.
H
H
N
N
O
R
O
ii
i
The structures of all title compounds 3a–h and the repre-
sentative intermediates 8b, 9a,b–12a,b, 13a–c, 15b–g,
and 16b–f were determined by spectroscopic methods (1H
and 13C NMR, MS, HRMS, IR) and elemental analyses
for C, H, and N. Only four solid final products, 3a, 3b, 3c,
and 3h, were obtained in analytically pure form. The oily
intermediates 6–13, 15, and 16, as well as the oily prod-
ucts 3d–g were not obtained in analytically pure form.
HN
N
R2X
14a–d
R1
R1
N
N
Cbz
12a–c
Cbz
13a–d
R2
O
7
R2
1
Path A
iii, iv
R1
8
N
N
N
R
O
6N
2
N
COOMe
COOR
O
5
iv
R = Cbz
i
3a
3
4
R1NH2
3a–h
4
R1
N
5a–c
R1
N
R'
Cbz
6a–c (R = Me, R' = H)
7a–c (R = Me, R' = Cbz)
8a–c (R = H, R' = Cbz)
R2
N
ii
15a–h
iii, iv
iii
O
v
Path B
R = Boc
HN
H
COOMe
COOMe
OR
N 2
1
HN
R1
N
O
vii
v
3
Cbz
16b–h
O
5
4
1'
R1 R2
2'
R
Compound transformation
R1
N
R1
N
R1
N
12a 13a 15a
3a
Cbz Bn Me
Boc Bn Et
Boc Bn Bn
Boc Bu Me
Boc Bu Et
Boc Bu Bu
Boc Bu Bn
Boc Pr Me
Cbz
Cbz
Cbz
12a–c
12a 13b 15b 16b 3b
12a 13b 15c 16c 3c
12b 13c 15d 16d 3d
12b 13c 15e 16e
12b 13c 15f 16f
9a–c
10a–c (R = H)
11a–c (R = Ms)
vi
5a–12a (R1 = Bn)
5b–12b (R1 = Bu)
5c–12c (R1 = Pr)
3e
3f
12b 13c 15g 16g 3g
12c 13d 15h 16h 3h
Scheme 1 Reagents and conditions: (i) BnNH2 (5a) or BuNH2 (5b) or
PrNH2 (5c), DBU (cat.), r.t.; (ii) ClCO2Bn, CH2Cl2, Et3N, 0–20 °C;
(iii) aq NaOH, MeOH, r.t.; (iv) CDI, THF, r.t., then potassium mono-
methyl malonate, MgCl2, r.t.; (v) NaBH4, MeOH, 0–20 °C; (vi) MsCl,
pyridine, 0–20 °C; (vii) hydrazine hydrate, MeOH, r.t.
Scheme 2 Reagents and conditions: (i) ClCO2Bn or Boc2O, 1,4-diox-
ane–H2O, Na2CO3, r.t.; (ii) MeI (14a) or EtI (14b) or BuBr (14c) or
BnBr (14d), DMF, K2CO3, r.t.; (iii) H2, Pd/C, MeOH, r.t.; (iv) CDI,
DMF, r.t.; (v) TFA–CH2Cl2, r.t.
Synthesis 2013, 45, 639–650
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidines
643
whereas the known compound 8a12 was characterized rahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-dione
only by 1H NMR spectroscopy (Tables 1 and 2).
system must both adopt a half-chair conformation where
C-3 and C-4 are pointing out of the plane of the system
and where 3-Ha, 3a-H, 4-Ha, and 5-Hb are axial (Figure
2, Table 3).
1H and 13C NMR spectra of the intermediates 6–13, 15,
and 16 exhibited broad and/or double signals for most of
the nuclei. This broadening and/or doubling of signals are
explainable by slow conformer equilibration due to the
branched structure of these compounds. On the other
hand, 1H and 13C NMR spectra of conformationally con-
strained final products 3a–h exhibited well resolved sig-
nals for all nuclei (see Supporting Information). A more
detailed 3D structure of title compounds 3a–h was also
established on the basis of characteristic vicinal coupling
R2
O
R16N
Ha
1
H
8
N
a N
7
2
4
5
Ha
O
3Hb
Hb
3a
H
Hb
Compounds 3a–h
3J3Ha-3aH
=
3J4Ha-5Hb = 12.5 Hz (trans, a-a)
3J4Ha-3aH = 10.5 Hz (trans, a-a)
3J4Hb-5Ha = 3.5 Hz (trans, e-e)
3
3
constants, JH-H. Large coupling constants, J3Ha-3aH
=
3J3Hb-3aH
=
3J4Hb-3aH = 7 Hz (cis, e-a)
3J4Ha-5Hb = 12.5 Hz and J4Ha-3aH = 10.5 Hz are in agree-
ment with antiperiplanar trans-orientation of these nuclei.
Accordingly, the pyrimidine and the pyrazole part of tet-
3
3J4Ha-5Ha = 4 Hz (cis, a-e)
1
Figure 2 Structure determination of title compounds 3a–h by H
NMR spectroscopy
Table 2 Spectral Data for Title Compounds 3a–h and Intermediates 8–13, 15, and 16
Product IR (cm–1)
1H NMR (500 MHz, δH) and 13C NMR (126 MHz, δC)a
8a
8b
–
δH = 2.42–2.53 (2 H, m, 2-CH2), 3.31–3.47 (2 H, m, 3-CH2), 4.46–4.53 (2 H, m, NCH2Ph), 5.11 and
5.14 (2 H, 2 s, OCH2Ph), 7.22–7.42 (10 H, m, 2 × C6H5), 12.28 (1 H, br s, CO2H)
3059, 3028, 2959, 2874, 2599, δH = 0.79–0.92 (3 H, m, CH3 of Bu), 1.15–1.28 and 1.40–1.50 (4 H, 2 m, 1:1, 2 × CH2 of Bu), 2.45–
2358, 1734, 1702, 1481, 1425, 2.54 (2 H, m, 2-CH2), 3.39–3.49 (2 H, m, NCH2), 3.23 (2 H, t, J = 7.4 Hz, NCH2), 5.08 (2 H, s, OCH2),
1370, 1293, 1226, 1140, 1091, 7.28–7.39 (5 H, m, C6H5), 12.23 (1 H, br s, CO2H)
1030, 770, 734, 698, 667
δC = 13.7, 19.5, 29.8/30.5, 33.0/33.7, 42.7/43.5, 46.7/46.9, 66.2, 127.5/127.5, 127.8, 128.4/128.4,
137.1/137.1, 155.2/155.2, 172.9/173.0
8c
9a
–
δH = 0.81–0.94 (3 H, m, CH3), 1.49–1.63 (2 H, m, CH2), 2.56–2.70 (2 H, m, CH2), 3.21–3.32 (2 H, m,
CH2), 3.50–3.62 (2 H, m, CH2), 5.13 (2 H, s, CH2Ph), 7.12–7.40 (5 H, m, C6H5), 10.15 (br s, 1 H,
CO2H)
3064, 3031, 2953, 2362, 2334, δH = 2.77–2.86 (2 H, m, 4-CH2), 3.39 (2 H, t, J = 6.9 Hz, 5-CH2), 3.54–3.66 (5 H, m, 2-CH2 and
1962, 1876, 1747, 1698, 1655, OCH3), 4.42–4.50 (2 H, m, NCH2Ph), 5.08–5.16 (2 H, m, OCH2), 7.16–7.43 (10 H, m, 2 × C6H5)
1604, 1583, 1537, 1496, 1470, δC = 40.8/41.0, 41.3/42.0, 48.7, 50.0, 51.8, 66.4/66.5, 127.1, 127.2, 127.4, 127.5, 127.8, 128.4/128.4,
1454, 1432, 1422, 1367, 1315, 128.5, 136.8/136.9, 138.0/138.0, 167.6, 202.4/202.5
1238, 1177, 1108, 1028, 1002,
915, 810, 768, 736, 700
9b
3395, 2956, 2930, 2873, 2358, δH = 0.80–0.93 (3 H, m, CH3 of Bu), 1.16–1.28 and 1.40–1.49 (4 H, 2 m, 1:1, 2 × CH2 of Bu), 2.82 (2
1748, 1698, 1476, 1423, 1378, H, t, J = 7.1 Hz, 4-CH2), 3.20 (2 H, t, J = 7.2 Hz, NCH2), 3.37–3.46 (2 H, m, NCH2), 3.57–3.70 (5 H,
1290, 1224, 1157, 1088, 1003, m, 2-CH2 and OCH3), 5.07 (2 H, s, OCH2), 7.30–7.40 (5 H, m, C6H5)
769, 738, 698, 668
δC = 13.7, 19.4, 29.7/30.3, 41.1/41.2, 41.7/42.0, 46.5/46.8, 48.7, 51.8, 66.1, 127.4, 127.8, 128.4,
137.0, 155.1/155.2, 167.6, 202.4/202.6
10a
3438, 3059, 3031, 3951, 2360, δH = 1.50–1.60 (1 H, m, 4-Ha), 1.63–1.72 (1 H, m, 4-Hb), 2.28–2.46 (2 H, m, 2-CH2), 3.17–3.28 and
2326, 1735, 1698, 1607, 1581, 3.28–3.38 (2 H, 2 m, 1:1, 5-CH2), 3.57 (3 H, s, OCH3), 3.78–3.88 (1 H, m, 3-H), 4.40–4.41 (2 H, m,
1540, 1496, 1475, 1436, 1421, NCH2Ph), 4.85 (1 H, s, OH), 5.07–5.18 (2 H, m, OCH2Ph), 7.15–7.43 (10 H, m, 2 × C6H5)
1364, 1236, 1173, 1123, 1072, δC = 34.8/35.4, 42.3, 43.3/44.1, 49.7/49.9, 51.2, 65.1, 66.3, 127.0/127.1, 127.3, 127.4/127.4, 127.8,
1034, 1016, 1003, 985, 949,
736, 699, 666
128.4, 128.5, 136.9/137.1, 138.2, 155.3/155.8, 171.5
10b
10c
3451, 2955, 2930, 2872, 2363, δH = 0.79–0.92 (3 H, m, CH3 of Bu), 1.23 (2 H, br s, CH2 of Bu), 1.45 (2 H, quint, J = 7.3 Hz, 2-CH2),
1737, 1698, 1677, 1479, 1425, 1.55 (1 H, br s, 1 H of CH2), 1.63–1.72 (1 H, m, 1 H of CH2), 2.31–2.49 (2 H, m, CH2), 3.13–3.27 (3
1367, 1292, 1224, 1167, 1074, H, m, 3 H of 2 × NCH2), 3.31 (1 H, br s, 1 H of NCH2), 3.58 (3 H, br s, OCH3), 3.80–3.90 (1 H, m,
1009, 770, 738, 699
3-H), 4.48 (1 H, br s, OH), 5.07 (2 H, s, CH2Ph), 7.28–7.40 (5 H, m, C6H5)
δC = 13.7, 19.4, 29.8/30.4, 35.2/35.9, 42.3, 43.5/44.1, 46.3/46.7, 51.2, 65.2/66.0, 127.3, 127.4, 127.7,
128.4, 137.2, 155.3, 171.6
–
δH = 0.83–0.92 (3 H, m, CH3), 1.40–1.83 (4 H, m, 2 × CH2), 2.39–2.58 (2 H, m, CH2), 3.0–3.44 (4 H,
m, 2 × CH2), 3.69 (3 H, s, CO2CH3), 3.96–4.03 (1 H, m, 3-H), 2.13 (2 H, s, CH2Ph), 7.13–7.38 (5 H,
m, C6H5), OH exchangeable with D2O
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 639–650

644
U. Grošelj et al.
PAPER
Table 2 Spectral Data for Title Compounds 3a–h and Intermediates 8–13, 15, and 16 (continued)
Product IR (cm–1) 1H NMR (500 MHz, δH) and 13C NMR (126 MHz, δC)a
11a
11b
3059, 3030, 2952, 2358, 1739, δH = 1.96 (2 H, br s, 4-CH2), 2.67–2.87 (2 H, m, 2-CH2), 3.06–3.20 (3 H, m, SO2CH3), 3.20–3.43 (2
1698, 1605, 1584, 1496, 1474, H, m, NCH2), 3.53–3.66 (3 H, m, OCH3), 4.37–4.56 (2 H, m, NCH2Ph), 4.87–4.98 (1 H, m, CH), 5.13
1438, 1423, 1355, 1227, 1172, (2 H, s, OCH2Ph), 7.16–7.49 (10 H, m, 2 × C6H5)
1126, 1070, 1031, 998, 973,
δC = 32.2/32.8, 37.9, 38.6, 42.3/43.0, 49.6/49.8, 51.5/51.6, 51.7, 66.5, 77.0/77.2, 127.3, 127.4/127.5,
910, 819, 802, 768, 736, 701, 127.8, 128.4, 128.5/128.6, 136.8, 137.9, 155.4/155.6, 169.9/169.9
668
3462, 3028, 2956, 2930, 2873, δH = 0.80–0.92 (3 H, m, CH3), 1.16–1.28 (2 H, m, CH2), 1.46 (2 H, quint, J = 7.4 Hz, CH2), 1.97 (2
2363, 1739, 1697, 1478, 1425, H, br q, J = 7.4 Hz, CH2), 2.72–2.90 (2 H, m, CH2), 3.08–3.33 (5 H, m, 2 × CH2 and SO2CH3), 3.36
1355, 1258, 1224, 1173, 1091, (2 H, br s, CH2), 3.62 (3 H, s, OCH3), 4.94 (1 H, br quint, J = 6.0 Hz, 3-H), 5.07 (2 H, s, OCH2Ph),
972, 910, 809, 770, 739, 699 7.28–7.39 (5 H, m, C6H5)
δC = 13.7, 19.4, 29.7/30.2, 32.5/33.2, 37.9, 38.6, 42.4/43.0, 46.1/46.6, 51.7, 66.1, 77.2/77.4, 127.4,
127.8, 128.4, 137.0, 155.0/155.3, 170.0
11c
12a
–
δH = 0.83–0.93 (3 H, m CH3), 1.56 (2 H, br s, CH2), 1.97–2.11 (2 H, br m, CH2), 2.95 and 3.06 (3 H,
2 br s, 1:2, SO2CH3), 3.01–3.08 (2 H, m, CH2), 3.16–3.28 (2 H, m, NCH2), 3.30–3.38 and 3.39–3.43
(2 H, 2m, 1:1, NCH2), 3.67–3.72 (3 H, m, CO2CH3), 5.05 (1 H, br s, 3-H), 5.12 (2 H, s, CH2Ph), 7.13–
7.38 (5 H, m, C6H5)
3059, 3030, 2952, 2358, 1739, δH = 1.56–1.76 (2 H, m, 2-CH2), 1.84–2.04 and 2.26–2.44 (2 H, 2 m, 1 H, 4-CH2), 3.14–3.43 (3 H, m,
1698, 1605, 1584, 1496, 1474, 5-H, 1′-CH2), 4.47 (2 H, s, NCH2Ph), 5.07–5.29 (1 H, br s, NH), 5.11 and 5.14 (2 H, 2 s, 1:1,
1438, 1423, 1355, 1227, 1172, OCH2Ph), 7.11–7.45 (10 H, m, 2 × C6H5), 8.97 (1 H, s, NH)
1126, 1070, 1031, 998, 973,
δC = 31.4/32.0, 37.9, 43.6/44.5, 49.7/49.9, 55.2/55.4, 66.3/66.4, 127.1/127.2, 127.4/127.5, 127.5,
910, 819, 802, 768, 736, 701, 127.8, 128.4/128.4, 128.5/128.5, 128.5, 136.9/138.2, 155.4/155.8, 175.6/175.6
668
12b
3221, 2958, 2925, 2873, 2359, δH = 0.79–0.92 (3 H, m, CH3), 1.22 (2 H, br s, CH2 of Bu), 1.45 (2 H, quint, J = 7.3 Hz, CH2 of Bu),
1694, 1478, 1452, 1424, 1365, 1.58–1.72 (2 H, m, 1′-CH2), 1.87–2.01 and 2.30–2.42 (2 H, 2 m, 1:1, 4-CH2), 3.12–3.30 (4 H, m, CH2
1295, 1226, 1173, 1090, 1005, of Bu, 1-CH2), 3.31–3.41 (1 H, m, 5-H), 5.06 (2 H, s, OCH2Ph), 5.21 (1 H, br s, NH), 7.28–7.40 (5 H,
769, 698, 667
m, C6H5), 8.97 (1 H, s, NH)
δC = 13.7, 19.4, 29.7/30.4, 31.6/32.4, 37.9, 43.8/ 44.5, 46.2/46.7, 55.3/55.5, 66.0, 127.4, 127.8, 128.4,
137.1, 155.2, 175.7
12c
13a
–
δH = 0.75–0.86 (3 H, m, CH3), 1.48 (2 H, sept, J = 7.5 Hz, CH2), 1.58–1.73 (2 H, m, CH2), 1.86–2.03
and 2.31–2.24 (2 H, 2 m, 1:1, 4′-CH2), 3.09–3.31 (4 H, m, 2 × CH2), 3.32–3.41 (1 H, m, 5-H), 5.07 (2
H, s, CH2Ph), 5.21 (1 H, s, 1-H), 7.28–7.40 (5 H, m, C6H5), 8.97 (1 H, s, 2-H)
3246, 3032, 2943, 1698, 1610, δH = 1.64–1.75 and 1.75–1.85 (2 H, 2 m, 1:1, 1′-CH2), 1.96–2.12 and 2.81–3.01 (2 H, 2 m, 1:1, 4-
1584, 1496, 1474, 1454, 1422, CH2), 3.13–3.45 (2 H, m, 2′-CH2), 4.30–4.53 (3H, m, NCH2Ph, 5-H), 5.01–5.20 (4 H, m, 2 ×
1323, 1287, 1234, 1158, 1118, OCH2Ph), 7.09–7.45 (15 H, m, 3 × C6H5), 10.63 (1 H, s, NH)
1080, 1028, 974, 914, 742,
698, 666
δC = 32./32.9, 35.8/36.0, 42.8/43.8, 49.6/49.7, 55.9/56.0, 65.2/65.8, 66.3, 67.1, 127.0, 127.1, 127.5,
127.6, 127.8/128.0, 128.1, 128.4, 128.5, 136.1, 136.8/136.9, 137.9/138.0, 155.1/155.2, 155.1/155.2,
171.1/171.2
13b
13c
13d
3488, 3231, 3065, 3032, 2979, δH = 1.36 and 1.38 (9 H, 2 s, 1:1, CH3 of Boc), 1.62–1.74 and 1.74–1.86 (2 H, 2 m, 1:1, 1′-CH2), 1.94–
2930, 2356, 1964, 1694, 1680, 2.11 and 2.77–2.94 (2 H, 2 m, 1:1, 4-CH2), 3.15–3.24 and 3.24–3.34 (2 H, 2 m, 2′-CH2), 4.16–4.30 (1
1496, 1473, 1454, 1423, 1368, H, m, 3-H), 4.42–4.54 (2 H, m, NCH2Ph), 5.12 and 5.15 (2 H, 2 s, OCH2Ph), 7.14–7.49 (10 H, m,
1334, 1295, 1234, 1159, 1118, C6H5), 10.46 (1 H, br s, NH)
1078, 1028, 998, 943, 860,
765, 734, 700, 667
δC = 27.8, 32.6/33.3, 36.0/36.1, 43.0/43.8, 49.7, 55.3/55.5, 66.4, 80.9, 127.1, 127.2, 127.5,
127.8/128.6, 128.4, 128.5, 136.9/136.9, 138.0, 154.2, 155.3/155.7, 170.5/170.7
3231, 2960, 2930, 2868, 2362, δH = 0.78–0.92 (3 H, m, CH3), 1.22 (2 H, br s, CH2 of Bu), 1.45 (11 H, m, CH3 of Boc, CH2 of Bu),
1694, 1477, 1455, 1424, 1368, 1.63–1.72 and 1.75–1.84 (2 H, 2 m, 1:1, 1′-CH2), 2.00–2.13 and 2.78–2.95 (2 H, 2 m, 1:1, 4-CH2),
1294, 1224, 1164, 860, 769,
698
3.14–3.35 (4 H, m, 2 × NCH2), 4.25 (1 H, br s, 5-H), 5.07 (2 H, s, OCH2Ph), 7.29–7.41 (5 H, m, C6H5),
10.44 (1 H, s, NH)
δC = 13.7, 19.4, 27.8, 29.7/30.4, 32.9/33.6, 35.9/36.0, 43.1/43.9, 46.2/46.5, 55.4/55.5, 66.0, 80.8,
127.4, 127.8, 128.4, 137.1, 154.2, 155.1/155.2, 170.6/170.7
–
δH = 0.80 (3 H, br s, CH3), 1.35–1.52 (11 H, m, CH3 of Boc and CH2 of Pr), 1.62–1.71 and 1.75–1.84
(2 H, 2 m, 1:1, 1′-CH2),1.99–2.12 and 2.78–2.94 (2 H, 2 m, 1:1, 4-CH2), 3.10–3.25 (3 H, m, 3 H of
2 × NCH2), 3.27–3.39 (1 H, m, 1 H of 2 × NCH2), 4.25 (1 H, br s, 5-H), 5.08 (2 H, s, CH2Ph), 7.28–
7.39 (5 H, m, C6H5), 10.43 (1 H, s, 2-H)
Synthesis 2013, 45, 639–650
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidines
645
Table 2 Spectral Data for Title Compounds 3a–h and Intermediates 8–13, 15, and 16 (continued)
Product IR (cm–1) 1H NMR (500 MHz, δH) and 13C NMR (126 MHz, δC)a
15a
3483, 3290, 3063, 3032, 2947, δH = 1.35–1.54 and 1.54–1.73 (2 H, 2 m, 1:1, CH2), 1.92–2.12 (1 H, m, 4-Ha), 2.80–3.36 (6 H, m, 4-
1700, 1602, 1586, 1496, 1473, Hb, 2-CH3, and 2′-CH2), 4.25–4.57 (3 H, m, 5-H and NCH2Ph), 4.95–5.24 (4 H, m, 2 × OCH2Ph),
1454, 1422, 1380, 1335, 1294, 6.94–7.48 (15 H, m, 3 × C6H5)
1236, 1167, 1117, 1081, 1029,
1002, 912, 820, 736, 699, 668
15b
3592, 3394, 3063, 3031, 2977, δH = 0.86 and 0.99 (3 H, 2 br t, 1:1, J = 6.2 Hz, CH3CH2), 1.37 and 1.40 (9 H, 2 br s, 1:1, CH3 of Boc),
2930, 2342, 1703, 1605, 1586, 1.63 (2 H, br s, CH2), 1.90–2.03 (1 H, m, 4-Ha), 2.86–3.03 (1 H, m, 4-Hb), 3.13–3.30 (2 H, m, 2′-Ha
1496, 1474, 1454, 1419, 1368, and 1 H of CH3CH2), 3.30–3.39 (1 H, m, 2′-Hb), 3.70–3.88 (1 H, m, 1 H of CH3CH2), 4.22–4.34 (1
1310, 1231, 1157, 1119, 1083, H, m, 5-H), 4.39–4.58 (2 H, m, NCH2Ph), 5.13 (2 H, s, OCH2Ph), 7.16–7.42 (10 H, m, 2 × C6H5)
1029, 1003, 916, 849, 821,
767, 740, 701, 665, 610
δC = 11.2/11.3, 27.6, 31.9/32.4, 36.0/36.1, 43.2/44.1, 49.7, 56.1, 66.3/66.5, 81.6, 127.0, 127.2, 127.4,
127.5, 127.8, 128.3, 128.4, 136.8, 137.9/137.9, 155.2/155.7, 155.8/155.8, 170.4
15c
3571, 3400, 3085, 3059, 3028, δH = 0.96–1.08 (1 H, m, 1′-Ha), 1.25–1.46 (10 H, m, 1′-Hb, CH3 of Boc), 1.94–2.08 (1 H, m, 4-Ha),
2977, 2930, 2360, 1704, 1496, 2.57–2.66 (1 H, m, 2′-Ha), 2.88–3.07 (2 H, m, 4-Hb, 2′-Hb), 3.90 (1 H, d, J = 15.6 Hz, 1 H of
1473, 1454, 1420, 1368, 1311, NCH2Ph), 4.11–4.34 (3 H, m, 1 H of NCH2Ph, 5-H, 1 H of NCH2Ph), 5.00–5.13 (3 H, m, 1 H of
1236, 1163, 1117, 1082, 1031, NCH2Ph, OCH2Ph), 6.97–7.09 and 7.12–7.42 (15 H, 2 m, 2:13, 3 × C6H5)
1000, 949, 912, 850, 768, 739, δC = 27.7, 32.0/32.5, 35.9/35.9, 42.8/44.0, 47.8, 49.6, 55.8, 66.2/66.4, 81.9, 126.8/127.1, 127.1, 127.5,
699
127.8/127.8, 128.0, 128.3, 128.4, 128.4, 129.0, 135.7, 136.8/136.8, 137.8/137.9, 155.2/155.6, 155.8,
170.7
15d
15e
15f
15g
2959, 2932, 2873, 2362, 1705, δH = 0.89–0.93 (3 H, m, CH3), 1.17–1.23 (2 H, m, CH2 of Bu), 1.35–1.51 (11 H, m, CH3 of Boc and
1476, 1455, 1422, 1368, 1334, CH2 of Bu), 1.59–1.70 (2 H, m, 1′-CH2), 1.97–2.11 (1 H, m, 4-Ha), 2.92 and 3.07 (3 H, 2 s, 1:1, 2-
1304, 1253, 1220, 1166, 1109, CH3), 2.87–3.03 (1 H, m, 4-Hb), 3.13–3.28 (3 H, m, CH2 of Bu, 2′-Ha), 3.28–3.42 (1 H, m, 2′-Hb),
1005, 849, 769, 699, 668
4.23–4.36 (1 H, m, 5-H), 5.06 (2 H, s, OCH2Ph), 7.29–7.40 (5 H, m, C6H5)
δC = 13.7, 19.4, 27.7, 29.8/30.4, 32.7/33.3, 33.5, 35.7, 43.4/44.0, 46.3/46.6, 56.5/56.6, 66.1, 81.8,
127.5, 127.8, 128.4, 137.0, 155.1/155.2, 156.1/156.2, 170.9/171.0
3299, 2960, 2933, 2872, 2361, δH = 0.81–0.95 and 1.01–1.09 (6 H, 2 m, 3:1, 2 × CH3), 1.17–1.29 (2 H, m, CH2 of Bu), 1.35–1.52 (11
1703, 1476, 1455, 1422, 1368, H, m, CH3 of Boc and CH2 of Bu), 1.55–1.70 (2 H, m, 1′-CH2), 1.95–2.08 and 2.89–3.04 (2 H, 2 m,
1308, 1223, 1165, 1113, 1014, 1:1, 4-CH2), 3.17–3.26 (4 H, m, 2 × NCH2), 3.30–3.44 and 3.73–3.92 (2 H, 2 m, 1:1, NCH2), 4.26–
917, 851, 769, 742, 698
4.38 (1 H, m, 5-H), 5.06 (2 H, s, OCH2Ph), 7.28–7.41 (5 H, m, C6H5)
δC = 11.3/11.4, 13.7, 19.4, 27.7, 27.7/28.1, 29.7/30.4, 32.2/32.9, 36.1/36.1, 43.5/44.2, 46.3/46.5, 56.2,
66.0, 81.7, 127.5, 127.8, 128.4, 137.0, 155.0/155.2, 155.9, 170.5
2959, 2933, 2872, 2362, 1702, δH = 0.77–0.93 (6 H, m, 2 × CH3), 1.13–1.35 (4 H, m, 2 × CH2 of Bu), 1.35–1.58 (13 H, m, CH3 of
1476, 1456, 1421, 1368, 1297, Boc and 2 × CH2 of Bu), 1.58–1.71 (2 H, m, 1′-CH2), 2.01–2.12 and 2.88–3.04 (2 H, 2 m, 1:1, 4-CH2),
1222, 1163, 1111, 851, 768,
736, 698
3.15–3.40 and 3.70–3.88 (6 H, 2 m, 5:1, 3 × NCH2), 4.31 (1 H, br s, 5-H), 5.07 (2 H, s, OCH2Ph),
7.29–7.40 (5 H, m, C6H5)
δC = 13.5, 13.7, 19.4, 19.5/19.6, 27.7, 27.9/28.0, 29.7/30.4, 32.5/33.2, 36.0/36.1, 43.4/44.2, 43.6,
46.2/46.5, 56.2, 66.0, 81.7, 127.2/127.4, 127.7, 128.3, 137.0, 155.0/155.2, 156.1, 170.3/170.3
3291, 3032, 2958, 2932, 2873, δH = 0.75–0.92 (3 H, m, CH3), 0.95–1.07 (1 H, br s, 1′-Ha), 1.07–1.30 [4 H, m, 1′-Hb, 3 H of
2358, 1704, 1496, 1477, 1455, CH3(CH2)2CH2], 1.30–1.54 [10 H, m, 1 H of CH3(CH2)2CH2, CH3 of Boc], 1.97–2.10 (1 H, m, 4-Ha),
1421, 1368, 1305, 1254, 1225, 2.46–2.59 (1 H, m, 2′-Ha), 2.63–2.75 [1 H, m, 1 H of CH3(CH2)2CH2], 2.90–3.08 (2 H, m, 4-Hb, 2′-
1158, 1083, 1028, 849, 822,
768, 739, 701, 667, 610
Hb), 3.13–3.26 [1 H, m, 1 H of CH3(CH2)2CH2], 4.14–4.25 (1 H, m, 5-H), 4.25–4.36 (1 H, m, 1 H of
NCH2Ph), 4.96–5.15 (3 H, m, 1 H of NCH2Ph, OCH2Ph), 7.26–7.41 (10 H, m, 2 × C6H5)
δC = 13.7, 19.3, 27.7, 29.7/30.4, 32.2/32.8, 35.8/35.9, 43.0/44.0, 46.1/46.3, 47.8, 56.0, 66.0, 81.9,
127.4, 127.8, 128.0, 128.4, 128.4, 129.1, 135.8, 137.0, 155.0/155.1, 155.8, 170.7
15h
16b
–
δH = 0.77–0.85 (3 H, m, CH3 of Pr), 1.40–1.52 (10 H, m, CH3 of Boc and 1 H of CH2), 1.64 (1 H, br
s, 1 H of CH2), 1.97–2.10 (1 H, m, 4-Ha), 2.72–2.80 (1 H, m, 4-Hb), 2.91 and 3.07 (3 H, 2 br s, 1:1,
2-CH3), 3.12–3.24 and 3.27–3.41 (6 H, 2 m, 1:1, 3 × CH2), 4.23–4.34 (1 H, m, 5-H), 5.01–5.09 (2 H,
m, OCH2Ph), 7.28–7.39 (5 H, m, C6H5)
3454, 3211, 3030, 2937, 2359, δH = 0.91–1.17 (3 H, m, CH3 of Et), 1.51–1.72 (2 H, m, 1′-CH2), 1.88–2.05 and 2.41–2.56 (2 H, 2 m,
1687, 1496, 1470, 1454, 1420, 1:1, 4-CH2), 3.11–3.36 (5 H, m, CH2 of Et, 2′-CH2, 5-H), 4.38–4.54 (2 H, m, NCH2Ph), 5.11 and 5.13
1366, 1293, 1235, 1161, 1122, (2 H, 2 s, 1:1, OCH2Ph), 5.51 (1 H, s, NH), 7.21–7.38 (10 H, m, 2 × C6H5)
1028, 977, 910, 767, 736, 699 δC = 12.4, 31.4/32.0, 37.7, 38.4, 43.6/44.4, 49.8/49.9, 52.0/52.2, 66.3/66.4, 127.0/127.1, 127.4/127.4,
127.5, 127.8, 128.4, 128.5, 136.9, 138.1, 155.3/155.8, 170.7
16c
3441, 3221, 3063, 3031, 2932, δH = 1.52–1.66 (2 H, m, 1′-CH2), 1.99–2.17 and 2.48–2.64 (2 H, 2 m, 1:1, 4-CH2), 3.09–3.23 (2 H, m,
2362, 1694, 1606, 1584, 1496, 1′-CH2), 3.28–3.36 (1 H, m, 5-H), 4.31–4.45 (4 H, m, 2 × NCH2Ph), 5.09 and 5.11 (2 H, 2 br s,
1473, 1454, 1420, 1360, 1290, OCH2Ph), 5.53 (1 H, br s, NH), 7.14–7.36 (15 H, m, 3 × C6H5)
1230, 1157, 1120, 1082, 1028, δC = 31.3/31.9, 38.0, 43.5/44.4, 47.0, 49.7/49.8, 52.2/52.5, 66.3/66.4, 127.0, 127.1, 127.4, 127.5,
982, 910, 821, 768, 735, 699, 127.6, 127.8, 128.3, 128.4, 128.4, 136.9, 137.2, 138.1, 155.3/155.7, 171.8
665
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Table 2 Spectral Data for Title Compounds 3a–h and Intermediates 8–13, 15, and 16 (continued)
Product IR (cm–1) 1H NMR (500 MHz, δH) and 13C NMR (126 MHz, δC)a
16d
16e
3462, 3210, 2956, 2925, 2868, δH = 0.78–0.94 (3 H, m, CH3 of Bu), 1.17–1.29 and 1.41–1.49 (4 H, 2 m, 1:1, 2 × CH2 of Bu), 1.57–
2359, 1690, 1477, 1423, 1392, 1.70 (2 H, m, 1′-CH2), 1.96–2.12 and 2.40–2.53 (2 H, 2 m, 1:1, 4-CH2), 2.80 and 2.83 (3 H, 2 s, 1:1,
1294, 1222, 1172, 1130, 1088, 2-CH3), 3.15–3.41 (5 H, m, CH2 of Bu, 5-H, 2′-CH2), 5.07 (2 H, s, OCH2), 5.59 (1 H, br s, NH), 7.30–
1024, 1008, 769, 737, 699
7.39 (5 H, m, C6H5), NH exchangeable with D2O
δC = 13.7, 19.4, 29.8/30.4, 30.7, 31.9/32.6, 38.0, 43.7/44.4, 46.3/46.7, 51.9/52.1, 66.0, 127.4, 127.8,
128.4, 137.1, 155.2/155.2, 171.2
3462, 3210, 2956, 2925, 2868, δH = 0.78–0.88 (3 H, m, CH3 of Bu), 0.95–1.06 (3 H, m, CH3 of Et), 1.17–1.30 (2 H, m, CH2 of Bu),
2359, 1690, 1477, 1423, 1392, 1.43–1.49 (2 H, m, CH2 of Bu), 1.54–1.72 (2 H, m, 1′-CH2), 1.94–2.09 and 2.45–2.58 (2 H, 2 m, 1:1,
1294, 1222, 1172, 1130, 1088, 4-CH2), 3.19–3.37 (7 H, m, CH2 of Bu, CH2 of Et, 2′-CH2, 5-H), 5.06 (2 H, s, OCH2), 5.55 (1 H, br s,
1024, 1008, 769, 737, 699.
NH), 7.30–7.39 (5 H, m, C6H5).
δC = 12.4, 13.7, 19.4, 29.8/30.4, 31.7/32.4, 37.8, 38.5, 43.8/44.4, 46.3/46.7, 52.1/52.2, 66.0, 127.4,
127.8, 128.4, 137.1, 155.2, 170.8
16f
3434, 3220, 3034, 2958, 2932, δH = 0.78–0.94 (6 H, m, 2 × CH3 of Bu), 1.17–1.30 and 1.37–1.49 (8 H, 2 m, 1:1, 4 × CH2 of Bu),
2873, 2356, 1683, 1478, 1424, 1.56–1.69 (2 H, m, 1′-CH2), 1.95–2.09 and 2.44–2.58 (2 H, 2 m, 1:1, 4-CH2), 3.12–3.37 (7 H, m, 2 ×
1368, 1296, 1225, 1205, 1175, CH2 of Bu, 2′-CH2, 5-H), 5.07 (2 H, s, OCH2), 5.53 (1 H, br s, NH), 7.30–7.39 (5 H, m, C6H5)
1134, 1090, 1008, 909, 836,
801, 769, 735, 698
δC = 13.6, 13.7, 19.4, 19.5, 28.8, 29.8/30.4, 31.8/32.5, 38.4, 42.3, 43.8/44.5, 46.3/46.7, 52.0/52.3,
66.0, 127.4, 127.8, 128.4, 137.1, 155.2, 171.1
16g
3468, 3236, 3028, 2957, 2925, δH = 0.77–0.92 (3 H, m, CH3), 1.13–1.28 (2 H, m, CH2 of Bu), 1.37 (2 H, quint, J = 7.4 Hz, CH2 of
2863, 2360, 1693, 1477, 1454, Bu), 1.53–1.62 (2 H, m, 1′-CH2), 2.03–2.19 and 2.53–2.65 (2 H, 2 m, 1:1, 4-CH2), 3.03–3.34 (5 H, m,
1422, 1293, 1224, 1168, 1084, CH2 of Bu, 2′-CH2, 5-H), 4.31–4.47 (2 H, m, NCH2Ph), 5.01–5.11 (2 H, m, OCH2Ph), 5.57 (1 H, br
736, 698, 667
s, NH), 7.19–7.40 (10 H, m, 2 × C6H5)
16h
3a
–
δH = 0.76–0.85 (3 H, m, CH3), 1.49 (2 H, sept, J = 7.3 Hz, CH2), 1.58–1.72 (2 H, m, CH2), 1.96–2.11
and 2.38–2.53 (2 H, 2 m, 1:1, CH2), 2.80 and 2.83 (2 H, 2 br s, 1:1, CH2), 3.08–3.38 (6 H, m, 2-CH3,
5-H, and CH2), 5.07 (2 H, s, CH2Ph), 5.59 (1 H, s, NH), 7.26–7.40 (5 H, m, C6H5)
3472, 3029, 2928, 2362, 1781, δH = 1.63 (1 H, dddd, J = 4.0, 10.6, 12.3, 13.4 Hz, 4-Ha), 2.31 (1 H, tdd, J = 2.7, 7.0, 13.5 Hz, 4-Hb),
1697, 1664, 1480, 1434, 1422, 2.49 (1 H, dd, J = 12.4, 15.6 Hz, 3-Ha), 2.63 (1 H, dd, J = 7.1, 15.8 Hz, 3-Hb), 3.18 (1 H, td, J = 3.5,
1392, 1372, 1343, 1287, 1219, 12.7 Hz, 5-Ha), 3.32 (1 H, dt, J = 2.3, 12.5 Hz, 5-Hb), 3.37 (3 H, s, 1-CH3), 4.26 (1 H, tdd, J = 7.0,
1176, 1135, 1079, 1029, 991, 10.5, 12.3 Hz, 3a-H), 4.52 and 4.65 (1 H, 2 d, 1:1, J = 15.0 Hz, NCH2Ph), 7.20–7.40 (5 H, m, C6H5)
967, 874, 746, 702, 672, 641, δC = 29.8, 33.8, 39.4, 43.0, 51.1, 58.3, 127.7, 128.0, 128.8, 137.2, 157.3, 170.7
610
3b
3c
3502, 2973, 2933, 2868, 2360, δH = 1.20 (3 H, t, J = 7.1 Hz, CH3CH2), 1.64 (1 H, dddd, J = 4.0, 10.6, 12.2, 13.2 Hz, 4-Ha), 2.31 (1
1698, 1667, 1482, 1451, 1420, H, tdd, J = 2.8, 6.9, 13.5 Hz, 4-Hb), 2.49 (1 H, dd, J = 12.4, 15.8 Hz, 3-Ha), 2.60 (1 H, dd, J = 7.0,
1376, 1345, 1286, 1233, 1209, 15.8 Hz, 3-Hb), 3.18 (1 H, td, J = 3.6, 12.7 Hz, 5-Ha), 3.33 (1 H, dt, J = 2.3, 12.5 Hz, 5-Hb), 3.73 and
1178, 1140, 1080, 1029, 998, 4.08 (1 H, 2 × sext, J = 7.0 Hz, CH3CH2), 4.17 (1 H, tdd, J = 7.0, 10.6, 12.5 Hz, 3a-H), 4.52 and 4.65
973, 932, 875, 832, 745, 702, (2 H, 2 d, 1:1, J = 15.0 Hz, NCH2Ph), 7.24–7.39 (5 H, m, C6H5)
668, 642, 608
δC = 12.1, 29.9, 39.7, 41.0, 43.0, 51.1, 58.9, 127.7, 128.0, 128.8, 137.3, 157.0, 170.7
3487, 3059, 3030, 2928, 2868, δH = 1.63 (1 H, dddd, J = 4.3, 10.4, 11.9, 13.3 Hz, 4-Ha), 2.21 (1 H, tdd, J = 2.7, 6.8, 12.7 Hz, 4-Hb),
2360, 1700, 1665, 1494, 1481, 2.52 (1 H, dd, J = 12.5, 15.9 Hz, 3-Ha), 2.63 (1 H, dd, J = 7.0, 15.9 Hz, 3-Hb), 3.07 (1 H, ddd, J = 3.0,
1439, 1419, 1403, 1374, 1344, 4.3, 12.6 Hz, 5-Ha), 3.13 (1 H, dt, J = 2.3, 12.3 Hz, 5-Hb), 3.91 (1 H, tdd, J = 6.9, 10.6, 12.6 Hz, 3a-
1287, 1228, 1203, 1184, 1080, H), 4.49 and 4.65 (2 H, 2 d, 1:1, J = 15.1 Hz, NCH2Ph), 4.76 and 5.37 (2 H, 2d, 1:1, J = 14.6 Hz,
1028, 976, 738, 701, 676, 644, NCH2Ph), 7.18–7.23 and 7.25–7.38 (10 H, 2 m, 1:4, 2 × C6H5)
627
δC = 29.7, 39.5, 43.0, 49.1, 51.1, 58.6, 127.6, 127.81, 127.84, 128.5, 128.78, 128.80, 136.4, 137.3,
156.7, 171.0
3d
3e
3496, 2958, 2930, 2871, 2358, δH = 0.94 [3 H, t, J = 7.4 Hz, CH3(CH2)3], 1.33 [2 H, sept, J = 7.4 Hz, CH3CH2(CH2)2], 1.52 and 1.53
1702, 1672, 1481, 1422, 1373, (2 H, 2 × br quint, CH3CH2CH2CH2), 1.70 (1 H, dddd, J = 3.5, 10.6, 12.6, 13.2 Hz, 4-Ha), 2.39 (1 H,
1342, 1297, 1274, 1218, 1198, br tdd, J = 2.2, 7.1, 13.2 Hz, 4-Hb), 2.48 (1 H, dd, J = 12.5, 15.8 Hz, 3-Ha), 2.61 (1 H, dd, J = 7.1,
1144, 1109, 966, 756, 694, 668 15.8 Hz, 3-Hb), 3.22 (1 H, dt, J = 3.5, 12.7 Hz, 5-Ha), 3.28 [1 H, ddd, J = 6.7, 8.2, 14.3 Hz, 1 H of
CH3(CH2)2CH2], 3.32 (3 H, s, 1-CH3), 3.40 (1 H, td, J = 2.2, 12.6 Hz, 5-Hb), 3.45 (1 H, ddd, J = 6.8,
8.1, 14.0 Hz, 1 H of CH3CH2CH2CH2), 4.24 (1 H, tdd, J = 7.1, 10.4, 12.3 Hz, 3a-H)
δC = 13.9, 20.0, 29.9, 30.2, 33.6, 39.3, 43.6, 47.7, 58.0, 157.0, 170.6
3501, 2958, 2932, 2872, 2358, δH = 0.94 [3 H, t, J = 7.4 Hz, CH3(CH2)3], 1.17 (3 H, t, J = 7.1 Hz, CH3CH2), 1.33 [2 H, sept, J = 7.4
1700, 1672, 1483, 1421, 1406, Hz, CH3CH2(CH2)2], 1.53 and 1.54 (2 H, 2 × br quint, CH3CH2CH2CH2), 1.72 (1 H, dddd, J = 3.9,
1376, 1344, 1296, 1232, 1209, 10.6, 12.6, 13.5 Hz, 4-Ha), 2.40 (1 H, br tdd, J = 2.6, 7.0, 12.8 Hz, 4-Hb), 2.48 (1 H, dd, J = 12.6, 15.8
1149, 1111, 1080, 971, 748,
695
Hz, 3-Ha), 2.59 (1 H, dd, J = 7.0, 15.8 Hz, 3-Hb), 3.23 (1 H, dt, J = 3.7, 12.7 Hz, 5-Ha), 3.29 [1 H,
ddd, J = 6.5, 7.9, 14.1 Hz, 1 H of CH3(CH2)2CH2], 3.42 (1 H, dt, J = 2.4, 12.7 Hz, 5-Hb), 3.45 [1 H,
ddd, J = 7.0, 8.1, 14.0 Hz, 1 H of CH3(CH2)2CH2], 3.66 and 4.03 (2 H, 2 × sext, J = 7.1 Hz, CH3CH2),
4.24 (1 H, tdd, J = 7.0, 10.4, 12.5 Hz, 3a-H)
δC = 12.0, 13.9, 20.0, 30.0, 30.2, 39.6, 40.7, 43.6, 47.7, 58.7, 156.8, 170.7
Synthesis 2013, 45, 639–650
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Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidines
647
Table 2 Spectral Data for Title Compounds 3a–h and Intermediates 8–13, 15, and 16 (continued)
Product IR (cm–1) 1H NMR (500 MHz, δH) and 13C NMR (126 MHz, δC)a
3f
3491, 2957, 2931, 2872, 2363, δH = 0.92 and 0.94 [6 H, 2 t, 1:1, J = 7.4 Hz, 2 × CH3(CH2)3], 1.25–1.38 [4 H, m, 2 × CH3CH2(CH2)2],
1698, 1482, 1421, 1377, 1343, 1.48–1.63 (4 H, m, 2 × CH3CH2CH2CH2), 1.71 (1 H, dtd, J = 3.9, 10.4, 12.3, 13.5 Hz, 4-Ha), 2.39 (1
1297, 1272, 1224, 1196, 1150, H, ddd, J = 2.6, 7.2, 12.8 Hz, 4-Hb), 2.46 (1 H, br dd, J = 12.6, 15.7 Hz, 3-Ha), 2.61 (1 H, dd, J = 6.9,
1112, 984, 752
15.8 Hz, 3-Hb), 3.23 (1 H, td, J = 3.5, 12.7 Hz, 5-Ha), 3.29 [1 H, ddd, J = 6.6, 7.9, 14.2 Hz, 1 H of
CH3(CH2)2CH2], 3.40 (1 H, br dt, J = 2.7, 12.4 Hz, 5-Hb), 3.45 [1 H, ddd, J = 6.7, 7.5, 14.1 Hz, 1 H
of CH3(CH2)2CH2], 3.64 [1 H, ddd, J = 5.5, 7.6, 13.5 Hz, 1 H of CH3(CH2)2CH2], 4.02 [1 H, td, J =
7.9, 13.5 Hz, 1 H of CH3(CH2)2CH2], 4.16 (1 H, tdd, J = 7.1, 10.3, 12.5 Hz, 3a-H)
δC = 13.9, 14.0, 20.09, 20.10, 28.7, 30.1, 30.3, 39.8, 43.7, 45.3, 47.8, 58.5, 156.9, 170.8
3g
3483, 2958, 2930, 2871, 2359, δH = 0.94 [3 H, t, J = 7.3 Hz, CH3(CH2)3], 1.30 [2 H, sext, J = 7.3 Hz, CH3CH2(CH2)2], 1.49 and 1.50
1700, 1668, 1481, 1422, 1405, (2 H, 2 × quint, J = 7.4 Hz, CH3CH2CH2CH2), 1.68 (1 H, dddd, J = 4.0, 10.4, 12.3, 13.5 Hz, 4-Ha),
1376, 1344, 1296, 1227, 1194, 2.29 (1 H, tdd, J = 2.6, 7.0, 12.5 Hz, 4-Hb), 2.50 (1 H, dd, J = 12.5, 15.8 Hz, 3-Ha), 2.62 (1 H, dd,
1114, 1028, 752, 702
J = 6.9, 15.9 Hz, 3-Hb), 3.13 (1 H, td, J = 3.6, 12.6 Hz, 5-Ha), 3.24 (1 H, br dt, J = 2.6, 12.6 Hz, 5-
Hb), 3.24 [1 H, br td, J = 7.3, 13.7 Hz, 1 H of CH3(CH2)2CH2], 3.49 [1 H, td, J = 7.3, 13.7 Hz, 1 H of
CH3(CH2)2CH2], 3.91 (1 H, tdd, J = 7.0, 10.5, 12.5 Hz, 3a-H), 4.70 and 5.33 (2 H, 2 d, 1:1, J = 14.7
Hz, NCH2Ph), 7.25–7.33 (5 H, m, C6H5)
δC = 13.9, 20.0, 29.8, 30.3, 39.5, 43.5, 47.6, 48.9, 58.4, 127.7, 128.4, 128.7, 136.5, 156.6, 171.0
3h
–
δH = 0.88 [3 H, t, J = 7.4 Hz, CH3(CH2)2], 1.54 (2 H, d of sept, J = 3.3, 7.3 Hz, CH3CH2CH2), 1.67 (1
H, dddd, J = 3.9, 10.5, 12.5, 12.7 Hz, 4-Ha), 2.36 (1 H, tdd, J = 2.6, 7.1, 12.5 Hz, 4-Hb), 2.44 (1 H,
dd, J = 12.7, 15.8 Hz, 3-Ha), 2.57 (1 H, dd, J = 7.1, 15.8 Hz, 3-Hb), 3.15–3.22 (2 H, m, 1 H of
CH3CH2CH2 and 5-Ha), 3.28 (3 H, s, 1-CH3), 3.37 (1 H, dt, J = 2.5, 12.5 Hz, 5-Hb), 3.38–3.45 (1 H,
m, 1 H of CH3CH2CH2), 4.21 (1 H, tdd, J = 7.1, 10.5, 12.4 Hz, 3a-H)
δC = 11.2, 21.4, 29.9, 33.6, 39.3, 43.7, 49.5, 58.0, 157.1, 170.6
a Unless otherwise stated, all NMR spectra were recorded in DMSO-d6.
Table 3 Correlation of Characteristic NMR Data for Compounds 3a–h
Product δ
3-Ha
3JH-H (Hz)
3a-3a 3b-3a 4a-3a 4b-3a 4a-5a
3-Hb 3a-H
4-Ha
4-Hb 5-Ha
5-Hb
4a-5b
4b-5a
4b-5b
3a
3b
3c
3d
3e
3f
2.49
2.49
2.52
2.48
2.48
2.46
2.50
2.44
2.63
2.60
2.63
2.61
2.59
2.61
2.62
2.57
4.26
4.17
3.91
4.24
4.24
4.16
3.91
4.21
1.63
1.64
1.63
1.70
1.72
1.71
1.68
1.67
2.31
2.31
2.21
2.39
2.40
2.39
2.29
2.36
3.18
3.18
3.07
3.22
3.23
3.23
3.13
3.32
3.33
3.13
3.40
3.42
3.40
3.24
12.4
12.4
12.5
12.6
12.5
12.5
12.5
12.7
7.1
7.0
7.0
7.1
7.0
6.9
6.9
7.1
10.6
10.6
10.4
10.6
10.6
10.4
10.4
10.5
7.0
7.0
6.8
7.1
7.0
7.2
7.0
7.1
4.0
4.0
4.3
3.9
3.9
3.9
4.0
3.9
12.4
12.2
12.5
12.6
12.6
12.3
12.3
12.5
3.5
3.6
3.0
3.5
3.7
3.5
3.6
~3a
2.3
2.3
2.3
2.2
2.4
2.7
2.6
2.5
3g
3h
~3.2a 3.37
a Overlapped by other signals.
Finally, the structures of compounds 3a, 3c, and 3h were glance, the synthesis sequence is well feasible, since often
also determined by X-ray diffraction (Figures 3–5). The subsequent steps can be carried out as one-pot transforma-
X-ray structures of compounds 3a, 3c, and 3h were in tions. This synthetic method opens the gate to this so far
agreement with the general 3D structure of tetrahydropyr-
azolo[1,5-c]pyrimidine-2,7(1H,3H)-diones 3a–h that has
been proposed by NMR analysis (cf. Figure 2).
In conclusion, a twelve-step synthesis of 1,6-dialkyltetra-
hydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones was
developed. A series of eight tetrahydropyrazolo[1,5-c]py-
rimidine-2,7(1H,3H)-diones 3a–h have been prepared. To
the best of our knowledge, compounds 3a–h are the first
examples of the fully saturated octahydropyrazolo[1,5-
c]pyrimidine system. Though somewhat lengthy at first
Figure 3 ORTEP14 view of compound 3a
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 639–650

648
U. Grošelj et al.
PAPER
(100 mL) was added and most of the MeOH was removed by careful
evaporation at 35 °C/80 mbar. The aqueous residue was extracted
with Et2O (3 × 200 mL) to remove the nonpolar impurities, acidified
with 6 M aq HCl (100 mL, 600 mmol), and the product was extract-
ed with EtOAc (4 × 150 mL). The combined organic phases were
dried (Na2SO4), filtered, and the filtrate was evaporated in vacuo to
give the crude oily 8a–c, which were used for further transforma-
tions without purification. Spectral data for the known compound
8a were in agreement with the literature data.12
Methyl 5-[(Alkyl)(benzyloxycarbonyl)amino]-3-oxopentano-
ates 9a–c; General Procedure
Under argon atmosphere, 1,1′-carbonyldiimidazole (CDI, 21.3 g,
118 mmol) was added to a solution of 8a–c (100 mmol) in anhyd
THF (200 mL) and the mixture was stirred at r.t. for 2 h. Then, a sol-
id mixture of anhyd MgCl2 (9 g, 93 mmol) and potassium mono-
methyl malonate (22.5 g, 144 mmol) was added under argon in one
portion via a powder funnel, which was rinsed with anhyd THF (50
mL), and the mixture was stirred under argon at r.t. for 20 h. Vola-
tile components 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 (100 mL). The organic
phase was dried (Na2SO4), filtered, and the filtrate was evaporated
in vacuo to give 9a–c, which were used for further transformations
without purification.
Figure 4 ORTEP14 view of compound 3c
Methyl 5-[(Alkyl)(benzyloxycarbonyl)amino]-3-hydroxypen-
tanoates 10a–c; General Procedure
NaBH4 (3.4 g, 90 mmol) was added slowly to a stirred solution of
β-keto ester 9a–c (83 mmol) in MeOH (80 mL) at 0 °C and the mix-
ture was stirred at 0 °C for 10 min and then at r.t. for 1 h. H2O (50
mL) was added, MeOH was removed by evaporation at 35 °C/80
mbar, and solid NaCl was added to the stirred aqueous phase until a
saturated solution was obtained. The product was extracted with
EtOAc (2 × 100 mL), the combined organic phases were dried
(Na2SO4), filtered, and the filtrate was evaporated in vacuo. The res-
idue was dissolved in toluene (100 mL) and evaporated in vacuo to
give 10a–c, which were used for further transformations without
purification.
Figure 5 ORTEP14 view of compound 3h
unknown group of saturated heterocyclic compounds
which may be useful in various applications.
Melting points were determined on a Kofler micro hot stage. The
NMR spectra were obtained on a Bruker Avance III UltraShield 500
1
plus at 500 MHz for H and 126 MHz for 13C nucleus, using ace-
tone-d6, acetonitrile-d3, 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; IR spectra on a Perkin
Elmer Spectrum BX FTIR spectrophotometer. Microanalyses were
performed on a PerkinElmer CHN Analyzer 2400 II. Flash column
chromatography (FC) was performed on silica gel (Fluka, silica gel
60, particle size 0.035–0.070 mm).
Methyl 5-[(Alkyl)(benzyloxycarbonyl)amino]-3-(methylsulfo-
nyloxy)pentanoates 11a–c; General Procedure
Under argon atmosphere, MsCl (7.3 mL, 94 mmol) was added slow-
ly to a stirred solution of 10a–c (72 mmol) in anhyd pyridine (70
mL) at 0 °C and the mixture was stirred at 0 °C for 15 min and then
at r.t. for 2 h. EtOAc (200 mL) and brine (100 mL) were added, the
mixture was cooled to 0 °C on an ice-bath, and then acidified slowly
and carefully while stirring at 0 °C (neutralization was exothermic!)
with 10% aq citric acid until pH ~3. The biphasic system was trans-
ferred into a separatory funnel, shaken, and the phases were separat-
ed. The organic phase was washed with brine (2 × 50 mL) and sat.
aq NaHCO3 (25 mL), dried (Na2SO4), filtered, and the filtrate was
evaporated in vacuo. The residue was dissolved in toluene (100 mL)
and evaporated in vacuo to give 11a–c, which was used for further
transformations without purification.
Experimental and characterization data for the final products 3a–h
and the intermediates 6–13, 15, and 16 are given in Tables 1 and 2.
Compounds 8a–c were prepared following the one-pot literature
procedure for the synthesis of closely related compounds.11c
3-[(Alkyl)(benzyloxycarbonyl)amino]propanoic Acids 8a–c;
General Procedure
DBU (1.5 g, 1.5 mL, ~10 mmol) was added to a cooled (0 °C) stirred
mixture of methyl acrylate (4; 17.4 g, 18.1 mL, 200 mmol) and
amine 5a–c (202 mmol). The resulting mixture was stirred at 0 °C
for 15 min and then at r.t. for 12 h to give the crude oily methyl N-
alkyl-β-alaninates 6a–c in quantitative yield. This crude material
was dissolved in CH2Cl2 (200 mL), Et3N (31 mL, 220 mmol) was
added, and the solution was cooled to 0 °C. Benzyl chloroformate
(28 mL, 188 mmol) was added slowly to the stirred reaction mixture
at 0 °C, and the mixture was stirred at r.t. for 12 h. Then, 1 M aq HCl
(40 mL) was added, the mixture was stirred at r.t. for 5 min, trans-
ferred into a separatory funnel, and the phases were separated. The
organic phase was washed with brine (100 mL), dried (Na2SO4), fil-
tered, and the filtrate was evaporated in vacuo to give the crude oily
N-alkyl-N-benzyloxycarbonyl-β-alaninates 7a–c. This crude mate-
rial was dissolved in MeOH (300 mL), 2 M aq NaOH (300 mL, 600
mmol) was added, and the mixture was stirred at r.t. for 2 h. H2O
Methyl 5-{2-[(Acyl)(alkyl)amino]ethyl}pyrazolidin-3-ones 12a–
c; General Procedure
A mixture of mesylate 11a–c (50 mmol), MeOH (100 mL), and hy-
drazine hydrate (7.9 mL, 163 mmol) was stirred at r.t. for 48 h. Vol-
atile components were evaporated in vacuo and the residue was
purified by CC (first EtOAc–hexanes, 1:1 to elute the nonpolar im-
purities, then EtOAc–MeOH, 10:1 to elute the product). Fractions
containing the product were combined and evaporated in vacuo to
give 12a–c.
Alkyl 5-{2-[(Alkyl)(benzyloxycarbonyl)amino]ethyl}-3-oxopyr-
azolidine-1-carboxylates 13a–d; General Procedure
Compound 12a–c (35 mmol) was dissolved in a mixture of 1,4-di-
oxane (50 mL) and H2O (100 mL) containing Na2CO3 (4.3 g, 41
mmol). Then, Boc2O (9.6 g, 44 mmol) or ClCO2Bn (6.18 mL, 41
Synthesis 2013, 45, 639–650
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidines
649
mmol) was added and the mixture was stirred at r.t. for 24 h. Most
of the 1,4-dioxane was removed by evaporation in vacuo at
35 °C/50 mbar. EtOAc (200 mL) and brine (100 mL) were added to
the aqueous residue, the biphasic system was transferred into a sep-
aratory funnel, shaken, and the phases were separated. The organic
phase was washed with brine (2 × 50 mL), dried (Na2SO4), filtered,
and the filtrate was evaporated in vacuo. The residue was purified
by column chromatography (EtOAc–hexanes, 1:1). Fractions con-
taining the product were combined and evaporated in vacuo. The
residue was dissolved in toluene (100 mL) and evaporated in vacuo
to give 13a–d.
independent and 5444 observed reflections, Rint = 0.039, ω scans,
refinement on F2, R[F2 > 2σ(F2)] = 0.052, wR(F2) = 0.142, 10641
contributing reflections, 925 parameters, Δρmax = 0.13 e Å−3,
Δρmin = −0.14 e Å−3.
3h: C10H17N3O2, Mr = 211.27, Dx = 1.275 Mg m−3, orthorhombic,
Pna21, a = 9.2315(3), b = 17.4469(7), c = 6.8315(2) Å, V =
1100.29(7) Å3, Z = 4, prism, 0.4 × 0.4 × 0.3 mm, colorless, T = 293
K, MoKα radiation, λ = 0.7107 Å, SuperNova-Atlas single-crystal
diffractometer, 9912 measured, 1677 independent and 1388 ob-
served reflections, Rint = 0.051, ω scans, refinement on F2, R[F2 >
2σ(F2)] = 0.049, wR(F2) = 0.144, 1677 contributing reflections, 138
parameters, Δρmax = 0.16 e Å−3, Δρmin = −0.16 e Å−3.
Alkyl 2-Alkyl-5-{2-[(alkyl)(benzyloxycarbonyl)amino]ethyl}-3-
oxopyrazolidine-1-carboxylates 15a–h
Under argon atmosphere, K2CO3 (691 mg, 5 mmol) and alkyl halide
14a–d (15 mmol) were added to a solution of 13a–d (5 mmol) in an-
hyd DMF (25 mL) and the mixture was stirred at r.t. for 72 h. In al-
kylations with 1-butyl bromide, KI (144 mg, 0.89 mmol) was also
added as catalyst. Volatile components were evaporated in vacuo,
EtOAc (100 mL) was added to the residue, and the mixture was
washed with brine (first 1 × 40 mL, then 2 × 20 mL). The organic
phase was dried (Na2SO4), filtered, and the filtrate was evaporated
in vacuo. The residue was purified by column chromatography
(EtOAc–hexanes, 1:1). Fractions containing the product were com-
bined and evaporated in vacuo to give 15a–h.
Acknowledgment
The financial support from Boehringer Ingelheim Pharma (Bibe-
rach, Germany) and from the Slovenian Research Agency through
grant P1-0179 is gratefully acknowledged. We also thank EN-FIST
Centre of Excellence (Ljubljana, Slovenia) for using SuperNova
diffractometer.
Supporting Information for this article containing copies of
1H and 13C spectra of compounds 3, 8–13, 15, and 16 is available
online at http://www.thieme-connect.com/ejournals/toc/synthesis.SunogIpifrmntiratoSpIug
n
opifomirtnat
2-Alkyl-5-{2-[alkyl(benzyloxycarbonyl)amino]ethyl}pyrazoli-
din-3-ones 16b–h; General Procedure
To a solution of Boc-pyrazolidinone 15b–h (3 mmol) in CH2Cl2 (20
mL) was added TFA (5 mL) and the mixture was stirred at r.t. for
24 h. Volatile components were evaporated in vacuo, EtOAc (150
mL) and brine (50 mL) were added, and the biphasic system was
made alkaline by the slow addition of solid K2CO3 until pH 8–9 was
reached. The mixture was stirred at r.t. for 5 min and the phases
were separated. The organic phase was washed with brine (2 × 10
mL), dried (Na2SO4), filtered, and the filtrate was evaporated in
vacuo. The residue was purified by column chromatography
(EtOAc–MeOH, 10:1). Fractions containing the product were com-
bined and evaporated in vacuo to give 16b–h.
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X-ray Structure Analysis15
3a: C14H17N3O2, Mr = 259.31, Dx = 1.279 Mg m−3, monoclinic,
P21/n, a = 12.4810(9), b = 6.4892(4), c = 16.6917(11) Å, β = 95.147
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flections, 173 parameters, Δρmax = 0.16 e Å−3, Δρmin = −0.14 e Å−3.
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and 3c, respectively. A copy of the data can be obtained, free
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Cambridge, CB2 1EZ, UK (fax: +44(0)1223336033 or
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Synthesis 2013, 45, 639–650
© Georg Thieme Verlag Stuttgart · New York