Synthesis of pyrazolo[3,4- D]-4,5-Dihydropyrimidines through [5+1] cyclocondensation

Article abstract of DOI:10.1055/s-0033-1340158

Twenty-five diverse pyrazolo[3,4-d]-4,5-dihydropyrimidines were synthesized in 73-91% yield through TMS-promoted [5+1] heterocyclization of aldehydes with pyrazolylamidines. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340158

LETTER
▌2675
lSetyternthesis of Pyrazolo[3,4-d]-4,5-dihydropyrimidines through [5+1] Cyclo-
condensation
Pyrazolo[3,4-d]-4,5-dihydropyrimidines
Sergey V. Ryabukhin,*a,b Dmitry S. Granat,b Andrey S. Plaskon,b Dmitriy M. Volochnyuk,c Alexander N. Shivanyuk*a
a
The Institute of High Technologies, Kyiv National Taras Shevchenko University, 4 Glushkov str., Building 5, 03187, Kyiv, Ukraine
Fax +380506424763; E-mail: s.v.ryabukhin@gmail.com; E-mail: a.shivanyuk@univ.kiev.ua
b
Department of Chemistry, Kyiv National Taras Shevchenko University, 62 Volodymyrska str., 01033, Kyiv, Ukraine
c
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska str., 02094, Kyiv, Ukraine
Received: 06.08.2013; Accepted after revision: 25.09.2013
ing materials II can be synthesized via the acylation of
Abstract: Twenty-five diverse pyrazolo[3,4-d]-4,5-dihydropyrimi-
3-aminopyrazoles IV with imidoylchlorides V.
dines were synthesized in 73–91% yield through TMS-promoted
[5+1] heterocyclization of aldehydes with pyrazolylamidines.
Amidines 3a–k were obtained in 52–67% yield through
the previously described acylation of aminopyrazoles
1a,b with imidoylchlorides 2a–g (Table 1).7
Key words: heterocycles, cyclization, fused-ring systems, alde-
hydes, ring closure
Table 1 Synthesis of Compounds 3
R2
R2
Imidazolo[3,4-d]pyrimidine (purine) is a building block
of DNA, RNA, NAD, ATP, purine alkaloids, and synthet-
ic drugs.1 Isomeric to purine pyrazolo[3,4-d]- and pyrazo-
lo[4,3-d]pyrimidine units are found in the structures of
such active pharmaceutical ingredients (API) as allopuri-
nol and sidenafil.2 Some functionalized pyrazolo[3,4-
d]pyrimidines possess different activities, such as antipro-
liferative,3 antitumor,4 and anti-inflamatory.5 In this con-
text we considered pyrazolo[3,4-d]-4,5-dihydro-
pyrimidines I (Scheme 1) as highly promising molecular
scaffold for rational design of biologically active com-
pounds. To the best of our knowledge compounds I (with
R5 = Ar, Het and R6 = H, Alk) have not been synthesized
yet and this research has been undertaken in order to es-
tablish facile and versatile methods of their synthesis.6
R4
R3
R4
Et3N, CH2Cl2
HN
N
+
N
N
R1
N
N
R1
r.t. to 4 °C, 4 h
R3
NH2
N
Cl
1a,b
2a–g
3a–k
Entry 1
R1
R2
2
R3
R4
3
Yield (%)
1
2
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1b i-Pr
1b i-Pr
1b i-Pr
1b i-Pr
1b i-Pr
Me 2a Ph
Me 2b Ph
Me
3a 67
3b 64
3c 58
3d 56
3e 64
c-Pr
3
Me 2c
2-FC6H4 Me
4
Me 2d 2-FC6H4 c-Pr
5
Me 2e
Me 2f
4-FC6H4 Me
4-FC6H4 c-Pr
Me
6
3f
62
R2
R5
N
R2
R6
7
H
H
H
H
H
2a Ph
2b Ph
2g Ph
3g 52
3h 55
R4
R3
R4
R3
R6
R5
HN
8
c-Pr
i-Pr
N
N
R1
N
N
R1
+
O
N
N
9
3i
3j
53
53
I
II
III
10
11
2e
2f
4-FC6H4 Me
4-FC6H4 c-Pr
3k 56
R1 = Alk, Ar
R2 = H, Me
R3 = Ar, Het
R2
R4
R3
N
N
N
R1
+
The condensation of 3a–k with aldehydes 4a–d in DMF
in the presence of TMSCl as activator of the C=O group
and water scavenger8 gave pyrazolo[3,4-d]-4,5-dihydro-
pyrimidines 5 in 73–91% yield (Table 2). Compounds 5
are stable white solids well soluble in DMF and poorly
soluble in alcohols. They were purified by simple precip-
itation with water and recrystallization from MeCN. In
most cases the sufficiently pure compounds 5 were isolat-
ed after washing the crude product with MeOH and
MeCN and vacuum drying.
R
R
R
4 = Alk, Ar, Het
5 = Ar, Het
6 = H, Alk
Cl
NH2
V
IV
Scheme 1 Retrosynthetic analysis of 4,5-dihydropyrazolo-[3,4-d]-
pyrimidines
Retrosynthetic analysis revealed that molecules I
(Scheme 1) can be assembled through condensation of
pyrazoloamidines II with carbonyl compounds III. Start-
Composition and structure of compounds 5 were con-
firmed by LC–MS, elemental analysis, 1H NMR and 13
C
SYNLETT 2013, 24, 2675–2678
Advanced online publication: 07.11.2013
DOI: 10.1055/s-0033-1340158; Art ID: ST-2013-D0759-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
NMR spectroscopy, and NOE correlations. For example,
the irradiation of the methine proton in the position 4 of

2676
S. V. Ryabukhin et al.
LETTER
O
O
O
O
O
NH
R2
R2
O
O
N
O
R4
R3
R2
H
R4
6
7
HN
N
N
N
R1
N
N
R1
N
Me3SiCl, DMF
Me3SiCl, DMF
N
N
R3
N
N
R4
R1
R3
9a,b
3a,b
N
8a
H
Scheme 2 Reactions with ketones
the pyrimidine ring of 5aa resulted in positive NOE with
both C–Me (3.96%) and N–Me (10.77%) groups and pro-
tons in the ortho positions of the closest phenyl ring
(21.32%). This pattern unambiguously proves 4,5-dihy-
dropyrazolo[3,4-d]pyrimidine structure of compounds 5
(Figure 1).
Table 2 Synthesis of Compounds 5
R5
N
R2
R2
R4
N
R4
R3
H
R5
Me3SiCl
DMF
HN
+
N
N
R1
N
N
R1
O
R3
N
3a–k
4a–d
5(a–k)(a–d)
Entry Amidine 3 Aldehyde 4 R5
Product 5 Yield
H
H
(%)
H
H3C
N
CH3
N
1
2
3a
3a
3a
3a
3b
3b
3b
3b
3c
3c
3d
3e
3e
3f
4a
4b
4c
4d
4a
4b
4c
4d
4a
4b
4a
4b
4d
4a
4b
4d
4a
4b
4b
4c
4c
4a
4a
4b
Ph
5aa
5ab
5ac
5ad
5ba
5bb
5bc
5bd
5ca
5cb
5da
5eb
5ed
5fa
88
84
91
90
87
82
87
88
84
79
81
80
85
86
77
85
75
73
77
82
78
76
76
73
4-MeOC6H4
4-ClC6H4
2-thienyl
Ph
N
N
3
4
Figure 1 1H–1H NOE correlations in 5aa
5
6
4-MeOC6H4
4-ClC6H4
2-thienyl
Ph
Izatine 6 also reacted with amidines 3a,b (DMF, TMSCl)
to give spiro-4,5-dihydropyrazolo[3,4-d]pyrimidine 8a
(73% yield), whereas cyclohexanone (7) was converted
into pyrazoloamidines 9a,b (76% and 72% yield, respec-
tively) under the same conditions (Scheme 2).
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4-MeOC6H4
Ph
All the synthetic results described above can be explained
by the suggested mechanism (Scheme 3)9 of an activation
of carbonyl compounds by TMSCl, N-silylation, and al-
kylation of compounds 3 in position 5 followed by elimi-
nation of HMDS that may result in dipolar intermediate C.
Zwitterion C can be stabilized either through intermolec-
ular ion recombination (for 4 and 6) or proton transfer to
N– (for 7).
4-MeOC6H4
2-thienyl
Ph
3f
4-MeOC6H4
2-thienyl
Ph
5fb
5fd
5ga
5gb
5hb
5hc
5ic
3f
A simple two-step procedure readily gives new pyrazo-
lo[3,4-d]-4,5-dihydropyrimidines 5 which are structural
isomers of purine.10,11 The pyrazolo[3,4-d]-4,5-dihydro-
pyrimidine scaffold has four points of variation which al-
low to generate combinatorial libraries of potentially
biologically active compounds.
3g
3g
3h
3h
3i
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
Ph
All chemicals were obtained from commercially available sources
and used without further purification (Aldrich, Fluka, Enamine
Ltd.). All solvents and reagents for the reactions and purification
(DMF, CH2Cl2, i-PrOH, MeCN) were freshly distilled and dried by
standard methods, monitoring of the water concentration in solvents
(all solvents had <0.05%, usually 0.02% of water) was performed
using a Mettler Toledo DL31 KF Titrator. Column chromatography
was performed using Kieselgel Merck 60 (230–400 mesh) as the
stationary phase. Melting points were measured on a Buchi melting
3j
5ja
3k
3k
Ph
5ka
5kb
4-MeOC6H4
Synlett 2013, 24, 2675–2678
© Georg Thieme Verlag Stuttgart · New York

LETTER
Pyrazolo[3,4-d]-4,5-dihydropyrimidines
2677
R6
R6
Cl
Cl
Me3SiCl
R5
O
R5
4, 6, 7
O
SiMe3
SiMe3
O
R5
R6
O
R5
R6
A
Me3Si Cl
OSiMe3
R5
R6
R6
R5
R2
SiMe3
R5
R6
N
R2
R4
R4
R3
R2
R2
R4
R3
N
N
R4
HN
Me3SiCl
recombination
N
N
R1
N
N
R3
N
R3
N
N
A
– (Me3SiO)2O
N
R1
N
N
R1
N
N
R1
5, 8
C (for 4 and 6)
B
3
– (Me3SiO)2O
R2
R2
N
R4
R3
proton transfer
N
N
N
N
N
R1
N
R4
R3
R1
C (for 7)
N
H
9
Scheme 3 TMSCl-promoted [5+1] heterocyclization
point apparatus and are uncorrected. The 1H NMR spectra were re-
corded on a Bruker Avance DRX 500 using DMSO-d6 as a solvent
and TMS as an internal standard. LC–MS spectra were recorded on
Agilent 1100 HPLC equipped with a diode matrix and mass-selec-
tive detector Agilent LC/MSD SL. Column: Zorbax SB-C18, 1.8
μm, 4.6 mm × 15 mm. Eluent A: MeCN–H2O with 0.1% of TFA
(95:5); eluent B: H2O with 0.1% of TFA; flow rate: 1.8 mL/min.
The volume of the injected sample was 1 μL. UV detectors operate
at λ = 215, 254, and 265 nm; ionization method: chemical ionization
under atmospheric pressure (APCI); ionization mode: simultaneous
scanning of positive and negative ions in the mass range of m/z =
80–1000. According to HPLC/MS data all the synthesized com-
pounds have a purity ≥95%.
(4) (a) Rashad, A. E.; Mahmoud, A. E.; Ali, M. M. Eur. J. Med.
Chem. 2011, 1019. (b) Ibrahim, D. A. Eur. J. Med. Chem.
2009, 44, 2776.
(5) (a) Kota, R. K.; Kompelly, K. K.; Surampudi, R.; Kulakarni,
R. J. Chem. Pharm. Res. 2011, 3, 848. (b) Youssef, A. M.;
Neeland, E. G.; Villanueva, E. B.; White, M. S.; El-
Ashmawy, I. M.; Patrick, B.; Klegeris, A.; Abd-El-Aziz, A.
S. Bioorg. Med. Chem. 2010, 18, 5685. (c) Raffa, D.;
Maggio, B.; Plescia, F.; Cascioferro, S.; Raimondi, M. V.;
Plescia, S.; Cusimano, M. G. Arch. Pharm. 2009, 342, 321.
(6) (a) Higashino, T.; Sato, S.; Miyashita, A.; Katori, T. Chem.
Pharm. Bull. 1987, 35, 4803. (b) Miyashita, A.; Sato, S.;
Taido, N.; Tanji, K.; Oishi, E.; Higashino, T. Chem. Pharm.
Bull. 1990, 38, 230.
(7) (a) Volochnyuk, D. M.; Kovaleva, S. A.; Chernega, A. N.;
Chubaruk, N. G.; Kostyuk, A. N.; Pinchuk, A. M.;
Tolmachev, A. A.; Schmutzler, R. Synthesis 2006, 1613.
(b) Ryabukhin, S. V.; Granat, D. S. Plaskon A. S.;
Shivanyuk, A. N.; Tolmachev, A. A.; Volovenko, Y. M.
ACS Comb. Sci. 2012, 14, 465.
(8) (a) Volochnyuk, D. M.; Ryabukhin, S. V.; Plaskon, A. S.;
Grygorenko, O. O. Synthesis 2009, 3719. (b) Ryabukhin, S.
V.; Plaskon, A. S.; Ostapchuk, E. N.; Volochnyuk, D. M.;
Tolmachev, A. A. Synthesis 2007, 417. (c) Ryabukhin, S. V.;
Plaskon, A. S.; Ostapchuk, E. N.; Volochnyuk, D. M.;
Shishkin, O. V.; Shivanyuk, A. N.; Tolmachev, A. A. Org.
Lett. 2007, 9, 4215. (d) Ryabukhin, S. V.; Plaskon, A. S.;
Bondarenko, S. S. Ostapchuk E. N.; Grygorenko, O. O.;
Shishkin, O. V.; Tolmachev, A. A. Tetrahedron Lett. 2010,
51, 4229. (e) Ryabukhin, S. V.; Plaskon, A. S.; Boron, S. Y.;
Volochnyuk, D. M.; Tolmachev, A. A. Mol. Diversity 2011,
15, 189.
(9) See also: (a) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk,
D. M.; Pipko, S. E.; Shivanyuk, A. N.; Tolmachev, A. A.
J. Comb. Chem. 2007, 9, 1073. (b) Ryabukhin, S. V.;
Naumchik, V. S.; Plaskon, A. S.; Grygorenko, O. O.;
Tolmachev, A. A. J. Org. Chem. 2011, 76, 5774.
(10) General Procedure for the Synthesis of Amidines 3
To a stirred solution of aminopyrazole 1 (0.01 mol) and Et3N
(1.53 mL, 0.011 mol) in CH2Cl2 (30 mL) at 0 °C a solution
of imidoyl chloride 2 (0.01 mol) in CH2Cl2 (30 mL) was
added. The reaction mixture was left to stand for 1 h at r.t.
Acknowledgment
The authors thank Mr. Vitaliy V. Polovinko for NMR measure-
ments.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
maotrin
r
t
References
(1) Pacher, P.; Nivorozhkin, A.; Szabó, C. Pharm. Rev. 2006,
58, 87.
(2) (a) Kumar, R.; Darpan Sharma, S.; Singh, R. Exp. Opin.
Therap. Pat. 2011, 21, 1071. (b) Davidson, G. S. Int. J.
Pharm. Comp. 2006, 10, 405. (c) Shukla, N.; Jones, R.;
Persad, R.; Angelini, G. D.; Jeremy, J. Y. Eur. J. Pharm.
2005, 517, 224.
(3) (a) Radi, M.; Dreassi, E.; Brullo, C.; Crespan, E.; Tintori, C.;
Bernardo, V.; Valoti, M.; Zamperini, C.; Daigl, H.;
Musumeci, F.; Carraro, F.; Naldini, A.; Filippi, I.; Maga, G.;
Schenone, S.; Botta, M. J. Med. Chem. 2011, 54, 2610.
(b) Carraro, F.; Naldini, A.; Pucci, P.; Locatelli, G. A.;
Maga, G.; Schenone, S.; Bruno, O.; Ranise, A.; Bondavalli,
F.; Brullo, C.; Fossa, P.; Menozzi, G.; Mosti, L.; Modugno,
M.; Tintori, C.; Manetti, F.; Botta, M. J. Med. Chem. 2006,
49, 1549.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2675–2678

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S. V. Ryabukhin et al.
LETTER
and then heated at 40 °C for 4 h. The solvent was evaporated
in vacuo, and the residue was triturated with H2O and
crystallized from dioxane–DMF (ca. 3:1).
7.45 (m, 7 H), 8.04 (d, 2 H, 3JH,H = 8.0 Hz) ppm. 13C NMR
(125 MHz, DMSO-d6): δ = 8.9, 12.5, 13.3, 34.2, 55.6, 60.8,
103.3, 114.8, 120.8, 125.4, 128.3, 128.4, 128.5, 129.2,
129.7, 135.6, 137.9, 140.2, 143.4, 144.1, 158.5, 159.6 ppm.
MS (APCI) [M+ +1]: m/z = 435. Anal. Calcd for C28H26N4O:
C, 77.39; H, 6.03; N, 12.89. Found: C, 77.55; H, 6.19; N,
13.08.
5-Cyclopropyl-6-(4-fluoro-phenyl)-3-methyl-1-phenyl-4-
thiophen-2-yl-4,5-dihydro-1H-pyrazolo[3,4-
d]pyrimidine (5fd)
Selected Spectroscopic Data of Compounds 3
N-Methyl-N′-(5-methyl-2-phenyl-2H-pyrazol-3-yl)-
benzamidine (3a)
Yield 67%. 1H NMR (400 MHz, DMSO-d6): δ = 2.08 (s, 3
H), 3.03 (d, 3 H, 3JH,H = 4.2 Hz), 4.82 (br s, 1 H), 7.15 (t, 1
H, 3JH,H = 6.4 Hz), 7.19 (t, 1 H, 3JH,H = 7.8 Hz), 7.26–7.38 (m,
6 H), 7.54 (br s, 1 H), 7.71 (d, 2 H, 3JH,H = 7.8 Hz) ppm. APSI
MS: M++1 = 291.
Yield 85%; mp 176 °C. 1H NMR (500 MHz, DMSO-d6): δ =
0.31 (m, 1 H), 0.40 (m, 1 H), 0.81 (m, 2 H), 2.08 (s, 3 H),
2.75 (m, 1 H), 6.23 (s, 1 H), 7.08 (br s, 1 H), 7.22 (m, 2 H),
7.29 (m, 2 H), 7.42 (m, 2 H), 7.57 (m, 3 H), 8.04 (d, 2 H, 3JH,H
= 8.0 Hz) ppm. 13C NMR (125 MHz, DMSO-d6): δ = 9.2,
12.4, 13.3, 34.4, 56.6, 103.1, 115.6 (d, 2JC,F = 22.0 Hz),
120.8, 124.9, 125.6, 127.0, 127.5, 129.3, 130.4 (d, 3JC,F = 9.0
N-Cyclopropyl-N′-(5-methyl-2-phenyl-2H-pyrazol-3-yl)-
benzamidine (3b)
Yield 64%. 1H NMR (500 MHz, DMSO-d6): δ = 0.59 (br s,
2 H), 0.69 (br s, 2 H), 1.95 (s, 3 H), 2.88 (br s, 1 H), 4.65 (br
s, 1 H), 7.16 (m, 3 H), 7.32–7.36 (m, 5 H), 7.59 (br s, 1 H),
7.86 (d, 2 H, 3JH,H = 7.6 Hz) ppm. MS (APCI) [M+ +1]: m/z
= 317.
Hz), 134.0, 140.0, 143.4, 143.8, 157.1, 163.0 (d, 1JC,F
=
N-Cyclopropyl-4-fluoro-N′-(5-methyl-2-phenyl-2H-
pyrazol-3-yl)-benzamidine (3f)
248.0 Hz) ppm. MS (APCI) [M+ +1]: m/z = 429. Anal. Calcd
for C25H21FN4S: C, 70.07; H, 4.94; N, 13.07. Found: C,
70.12; H, 4.80; N, 12.89.
Yield 62%. 1H NMR (400 MHz, DMSO-d6): δ = 0.58 (br s,
2 H), 0.70 (br s, 2 H), 1.96 (s, 3 H), 2.86 (br s, 1 H), 4.71 (br
s, 1 H), 7.11 (t, 2 H, 3JH,H,F = 7.6 Hz), 7.14 (br s, 1 H), 7.16
(t, 2 H, 3JH,H,F = 7.6 Hz), 7.36 (t, 2 H, 3JH,H = 7.8 Hz), 7.62
(br s, 1 H), 7.83 (d, 2 H, 3JH,H = 7.8 Hz) ppm. MS (APCI) [M+
+1]: m/z = 335.
1-Isopropyl-5-methyl-4,6-diphenyl-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimidine (5ga)
Yield 75%; mp 118 °C. 1H NMR (500 MHz, DMSO-d6): δ =
1.35 (m, 6 H), 2.73 (s, 3 H), 4.69 (sept, 1 H, 3JH,H = 7.0 Hz),
5.84 (s, 1 H), 6.99 (br s, 1 H), 7.32 (t, 1 H, 3JH,H = 7.8 Hz),
7.38–7.45 (m, 4 H), 7.47 (br s, 5 H) ppm. 13C NMR (125
MHz, DMSO-d6): δ = 22.5, 22.9, 47.7, 63.3, 101.8, 117.2,
126.6, 128.2, 128.3, 128.9, 129.4, 129.8, 132.8, 137.2,
142.2, 144.3, 158.0 ppm. MS (APCI) [M+ +1]: m/z = 331.
Anal. Calcd for C21H22N4: C, 76.33; H, 6.71; N, 16.96.
Found: C, 76.46; H, 6.57; N, 16.83.
N-(2-Isopropyl-2H-pyrazol-3-yl)-N′-methyl-
benzamidine (3g)
Yield 52%. 1H NMR (400 MHz, DMSO-d6): δ = 1.32 (d, 6
H, 3JH,H = 7.2 Hz), 2.96 (d, 3 H, 3JH,H = 4.8 Hz), 4.45 (s, 1 H),
4.74 (sept, 1 H, 3JH,H = 7.2 Hz), 6.88 (s, 1 H), 7.15 (m, 2 H),
7.33–7.41 (m, 4 H) ppm. MS (APCI) [M+ +1]: m/z = 243.
N-Cyclopropyl-N′-(2-isopropyl-2H-pyrazol-3-yl)-
benzamidine (3h)
5-Cyclopropyl-1-isopropyl-4-(4-methoxy-phenyl)-6-
phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine (5hb)
Yield 77%; mp 134 °C. 1H NMR (400 MHz, DMSO-d6): δ =
0.24 (m, 2 H), 0.71 (m, 2 H), 1.36 (d, 6 H, 3JH,H = 6.7 Hz),
2.55 (m, 1 H), 3.71 (s, 3 H), 4.73 (sept, 1 H, 3JH,H = 6.7 Hz),
8.78 (s, 1 H), 6.96 (d, 2 H, 3JH,H = 8.6 Hz), 7.02 (s, 1 H), 7.25
(d, 2 H, 3JH,H = 8.6 Hz), 7.43 (m, 5 H) ppm. 13C NMR (125
MHz, DMSO-d6): δ = 8.9, 13.4, 22.7, 22.8, 34.1, 47.9, 55.6,
61.1, 102.8, 114.7, 127.9, 128.3, 128.4, 129.5, 132.5, 136.5,
138.1, 142.1, 157.7, 159.4 ppm. MS (APCI) [M+ +1]: m/z =
387. Anal. Calcd for C24H26N4O: C, 74.58; H, 6.78; N,
14.50. Found: C, 74.74; H, 6.51; N, 14.34.
Spiro[3,5-dimethyl-1,6-diphenyl-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimidine-4,3′-(7′,8′-dihydro-1′H,6′H-
5′,9′-dioxa-1′-aza-cyclohepta[f]indene]-2′-one (8a)
Yield 73%; mp 294 °C. 1H NMR (400 MHz, DMSO-d6): δ =
1.58 (s, 3 H), 2.10 (m, 2 H), 3.30 (s, 3 H), 4.08 (m, 2 H), 4.17
(m, 2 H), 6.57 (s, 1 H), 7.11 (s, 1 H), 7.22 (t, 1 H, 3JH,H = 8.9
Hz), 7.41 (t, 2 H, 3JH,H = 7.8 Hz), 7.51 (m, 5 H), 7.95 (d, 2 H,
3JH,H = 7.8 Hz), 10.71 (s, 1 H) ppm. MS (APCI) [M+ +1]: m/z
= 492. Anal. Calcd for C29H25N5O3: C, 70.86; H, 5.13; N,
14.25. Found: C, 71.03; H, 5.02; N, 14.34.
Yield: 55%. 1H NMR (400 MHz, DMSO-d6): δ = 0.59 (br s,
2 H), 0.71 (br s, 2 H), 1.34 (d, 6 H, 3JH,H = 6.5 Hz), 2.96 (br
s, 1 H), 4.46 (s, 1 H), 4.77 (sept, 1 H, 3JH,H = 6.5 Hz), 6.83 (s,
1 H), 7.17 (m, 2 H), 7.35–7.43 (m, 4 H) ppm. MS (APCI)
[M+ +1]: m/z = 269.
(11) General Procedure for the Synthesis of
Pyrazolodihydropyrimidines 5
DMF (1 mL), amidine 3 (1 mmol), TMSCl (3 mmol), and
carbonyl compound (1.1 mmol) were placed in a sealed tube
(10 mL). The tube was heated at 100 °C for 4–8 h. Than the
reaction mixture was diluted by H2O (8 mL) and sonicated at
r.t. for 1–2 h (BRANSON 2510E-MT). The precipitate
formed was filtered and washed with of 5% aq NaHCO3
(8 mL), then i-PrOH (1 mL) and MeCN (1 mL).
Selected Spectroscopic Data of Compounds 5
3,5-Dimethyl-1,4,6-triphenyl-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimidine (5aa)
Yield 88%; mp 162 °C. 1H NMR (400 MHz, DMSO-d6): δ =
1.89 (s, 3 H), 2.75 (s, 3 H), 5.88 (s, 1 H), 7.17 (t, 1 H, 3JH,H
=
7.4 Hz), 7.41 (m, 3 H), 7.47 (m, 9 H), 8.01 (d, 2 H, 3JH,H
=
7.6 Hz) ppm. 13C NMR (125 MHz, DMSO-d6): δ = 12.6,
N-(4-Cyclohex-1-enyl-5-methyl-2-phenyl-2H-pyrazol-3-
yl)-N′-methyl-benzamidine (9a)
63.0, 102.1, 120.8, 121.3, 125.4, 127.2, 128.3, 128.7, 129.0,
129.2, 129.5, 130.0, 130.2, 137.0, 140.2, 143.5, 144.4, 158.7
ppm. MS (APCI) [M+ +1]: m/z = 379. Anal. Calcd for
C25H22N4: C, 79.34; H, 5.86; N, 14.80. Found: C, 79.21; H,
5.98; N, 14.68.
Yield 76%; mp 131 °C. 1H NMR (400 MHz, DMSO-d6): δ =
1.50 (s, 4 H), 1.73 (br s, 2 H), 1.97 (m, 5 H), 2.89 (s, 3 H),
5.08 (s, 1 H), 6.98 (d, 2 H, 3JH,H = 6.3 Hz), 7.19 (t, 1 H, 3JH,H
= 6.3 Hz), 7.24 (t, 2 H, 3JH,H = 7.5 Hz), 7.31 (m, 1 H), 7.40
5-Cyclopropyl-4-(4-methoxy-phenyl)-3-methyl-1,6-
diphenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine
(5bb)
(t, 2 H, 3JH,H = 7.8 Hz), 7.51 (br s, 1 H), 7.74 (d, 2 H, 3JH,H
7.8 Hz) ppm. 13C NMR (125 MHz, DMSO-d6): δ = 14.2,
22.2, 23.0, 25.6, 27.8, 29.0, 111.1, 121.8, 124.6, 125.1,
127.8, 128.2, 129.0, 129.9, 130.3, 135.2, 140.8, 143.2,
145.8, 160.5 ppm. MS (APCI) [M+ +1]: m/z = 371. Anal.
=
Yield 82%; mp 154 °C. 1H NMR (400 MHz, DMSO-d6): δ =
0.32 (m, 2 H), 0.81 (m, 2 H), 1.96 (s, 3 H), 2.55 (m, 1 H),
3.77 (s, 3 H), 5.80 (s, 1 H), 7.00 (d, 2 H, 3JH,H = 8.3 Hz), 7.20
(t, 1 H, 3JH,H = 7.2 Hz), 7.36 (d, 2 H, 3JH,H = 8.3 Hz), 7.41–
Calcd for C24H26N4: C, 77.80; H, 7.07; N, 15.12. Found: C,
78.02; H, 6.97; N, 14.98.
Synlett 2013, 24, 2675–2678
© Georg Thieme Verlag Stuttgart · New York