Chlorotrimethylsilane-promoted condensation of ketones and aminoazoles

Article abstract of DOI:10.1002/jhet.972

Chlorotrimethylsilane-promoted reaction of ketones and aminoazoles (i.e., 3-amino-1,2,4-triazoles, 5-aminotetrazole) at 2: 1 ratio resulted in the formation of 4,5-dihydroazolo[1,5-a]pyrimidine derivatives as the single regioisomers in 35 - 71% yields. In the case of tert-butylmethylketone and 5-aminotetrazole as the starting materials, the solvent (dimethylformamide) entered the reaction instead of the second ketone molecule.

Full text of DOI:10.1002/jhet.972

September 2012
Chlorotrimethylsilane-Promoted Condensation of Ketones
1147
and Aminoazoles
a
a,b
Sergey V. Ryabukhin,a,b Vasiliy S. Naumchik, Oleksandr O. Grygorenko,
*
and Andrey A. Tolmacheva,b
aEnamine Ltd., Oleksandra Matrosova Street, 23, Kyiv 01103, Ukraine
bDepartment of Chemistry, Kyiv National Taras Shevchenko University, 64 Volodymyrska str., Kyiv 01601, Ukraine
*
E-mail: Ryabukhin@mail.enamine.net
Received December 24, 2010
DOI 10.1002/jhet.972
Published online 26 October 2012 in Wiley Online Library (wileyonlinelibrary.com).
Chlorotrimethylsilane-promoted reaction of ketones and aminoazoles (i.e., 3-amino-1,2,4-triazoles,
5-aminotetrazole) at 2 : 1 ratio resulted in the formation of 4,5-dihydroazolo[1,5-a]pyrimidine derivatives
as the single regioisomers in 35 – 71% yields. In the case of tert-butylmethylketone and 5-aminotetrazole
as the starting materials, the solvent (dimethylformamide) entered the reaction instead of the second ketone
molecule.
J. Heterocyclic Chem., 49, 1147 (2012).
INTRODUCTION
no regioselective synthesis of the compounds of general
formula 3 was reported to date.
Dihydropyrimidines represent a remarkable class of
potential biologically active compounds. This can be
explained by properties of the substituted dihydropyrimi-
dine fragment which are commonly associated with
“drug-likeliness” of the compounds, i.e., hydrophilicity,
nonflattened structure and chirality [1]. Dihydropyrimidine
derivatives exhibit a range of biological activities; their
representatives include calcium channel modulators,
mitotic kinesine inhibitors, adrenergic receptor antagonists,
antibacterial and antiviral agents [2]. Modern methods for
synthesis of dihydropyrimidines allow preparation of the
compounds with almost any substitution pattern [3–20].
On the contrary, fused dihydropyrimidine derivatives are
much less explored.
It was demonstrated previously by our group and
others that chlorotrimethylsilane is an efficient promoter
of various condensations involving carbonyl compounds,
e.g., Knoevenagel, Friedlander, Biginelli and many other
reactions [21–28]. As a part of our ongoing research on
TMSCl-promoted reactions, we have turned our atten-
tion to the reaction of ketones 1 and aminoazoles 2 at
2:1 ratio resulting in the formation of azolopyrimidine
derivatives 3 and/or 4 (Scheme 1). Although this trans-
formation has been reported previously, mixtures of 3
and 4 were obtained in most cases; moreover, rather
harsh conditions were used (150 – 190 °C; DMF [29],
AcOH (or HCl) – DMF [30], ZnCl2 – no solvent [31,32]).
Apart from the single examples described in [29] and [31],
In this work, we wish to report our results on chloro-
trimethylsilane-promoted reaction of ketones 1a–c and
aminoazoles 2a–c at 2 : 1 ratio. It was found that tria-
zoles 2a,b and tetrazole 2c reacted with 2 eq of aceto-
phenone (1a) in the presence of TMSCl (5 eq) – DMF
at 100°C for 8 h to form the corresponding dihydroazo-
lopyrimidine derivatives 3aa – 3ac in good yields
(Table 1). Analogous reactions of cyclohexanone (1b)
afforded the corresponding spiroheterocycles 3ba – 3bc,
although with diminished outcome of the product. In all
the cases, the condensation proceeded in a regioselective
manner: no products 4 were detected in the crude reaction
mixture.
The structure of the products 3 was confirmed by
NOESY experiments performed with the compound 3aa.
First, 5- and 7-phenyl substituents were distinguished
using correlation of ortho-protons with 5-methyl group,
which is possible only for 5-phenyl. The correlation
between 4-NH proton and ortho-protons of 7-phenyl group
clearly confirm the structure 3aa as it is impossible in the
case of isomer 4aa (Fig. 1).
Reaction of tetrazole 2c with 2 eq of ketone 1c under
the conditions described led to the formation of tetrazolo
[1,5-a]pyrimidine 5 in 78% yield (Scheme 2). In this case,
due to the steric effect of tert-butyl substituent,
dimethylformamide enters the reaction instead of the
second molecule of tert-butylmethylketone. The structure
of 5 was confirmed by comparison of chemical shifts in
© 2012 HeteroCorporation

1148
S. V. Ryabukhin, V. S. Naumchik, O. O. Grygorenko, and A. A. Tolmachev
Vol 49
Scheme 1
13C NMR with the literature data for the corresponding
analogues 6 – 8 (Table 2) [33]. The chemical shift of the
C-5 signal for the compound 5 is higher than that in the case
of 8; this is observed for 4-tert-butyl-substituted pyrimidines
(see, for example, [34] and [35]). Moreover, vicinal
Figure 1. Significant NOESY correlations for the compound 3aa.
1
coupling constant between protons at 6-C and 7-C in H
for the synthesis of azolo[1,5-a]pyrimidine derivatives. Using
of chlorotrimethylsilane allows to obtain the corresponding
products in a regiospecific manner and to perform the reaction
under relatively mild conditions comparing to the procedures
reported previously. The corresponding products are obtained
as single isomers in 35–71% yields.
NMR spectra (7.3 Hz) is also consistent with the literature
data for the analogues (6.9 – 7.3 Hz, while for the alternative
isomers—4.2 – 4.8 Hz [36]).
The structure of 5 and the literature data [29,37,38] allows us
to assume that the reaction of aminoazoles with ketones starts
with electrophilic attack of the carbonyl group of the activated
ketone molecule 9 at the amino group of the silylated aminoa-
zole derivative 10 [21] (Scheme 3). Silylation of the starting
aminoazole at the endocyclic nitrogen atom prevents attack
of the ketone at this site, hence the reaction proceeds in a
regiospecific manner. The second ketone molecule (or
dimethylformamide, as in the case of the formation of 5) reacts
then with the imine intermediate 11 formed to accomplish the
heterocyclization. It is interesting to note that the products anal-
ogous to 5 were also detected by LC–MS in the crude reaction
mixtures obtained from ketones 1a and 1b and aminoazoles
2a–c as the starting compounds. Unfortunately, replacing the
DMF with other solvents to avoid these side reactions was
unfruitful.
EXPERIMENTAL
Solvents were purified according to the standard procedures.
Compound 2b was prepared by the procedure described in the
literature [39]. All other starting materials were purchased from
Acros, Merck, and Fluka. Melting points were measured on
MPA100 OptiMelt automated melting point system. Analytical
TLC was performed using Polychrom SI F254 plates. Column
chromatography was performed using Kieselgel Merck 60
1
(230–400 mesh) as the stationary phase. H, 13C NMR, and all
2D NMR spectra were recorded on a Bruker 170 Avance 500
spectrometer (at 499.9 MHz for protons, 124.9 MHz for carbon-
13) and Varian Unity Plus 400 spectrometer (at 400.4 MHz for
protons, 100.7 MHz for carbon-13). Chemical shifts are reported
in ppm downfield from TMS (1H, 13C) as an internal standard.
HPLC-MS analyses were done on an Agilent 1100 LCMSD SL
instrument (chemical ionization (CI)) and Agilent 5890 Series II
5972 GCMS instrument (electron impact ionization (EI)).
Elemental analyses were performed at the Laboratory of Organic
Analysis, Department of Chemistry, Kyiv National Taras
Shevchenko University.
In conclusion, chlorotrimethylsilane-promoted reaction of
ketones and aminoazoles at 2:1 ratio is an efficient method
Table 1
Chlorotrimethylsilane‐promoted reaction of ketones 1a–c and aminoa-
zoles 2a–c.
General procedure for the reaction of ketones 1a–c and
aminoazoles 2a–c. A mixture of ketone 1 (0.4 mmol) and
aminoazole 2 (0.2 mmol) was dissolved in dry DMF (1 mL) in
an ace pressure tube, and then chlorotrimethylsilane (1 mmol)
was added dropwise. The tube was sealed and heated on a
steam bath for 8 h, then cooled and diluted with water (6 mL).
The resulting mixture was sonicated for 2 h at 40°C, the
precipitate was filtered and washed with a small amount of
Entry
No.
Yield,
%
Reagents Product R1
R2
X
Scheme 2
1
2
3
4
5
6
1a
1a
1a
1b
1b
1b
2a
2b
2c
2a
2b
2c
3aa
3ab
3ac
3ba
3bb
3bc
Ph
Ph
Ph
(CH2)4
(CH2)4
(CH2)4
Me
Me CCF3
Me
CH
65
62
71
40
35
46
N
CH
CCF3
N
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Chlorotrimethylsilane-Promoted Condensation of Ketones and Aminoazoles
1149
Table 2
Significant chemical shifts in 13C NMR spectra of the compounds 5 – 8.
5-Methyl-5,7-diphenyl-2-(trifluoromethyl)-4,5-dihydro[1,2,4]
triazolo[1,5-a]pyrimidine 3ab. Yield 62%. Mp 183 °C. 1H NMR
(500 MHz, DMSO-d6), δ: 1.80 (s, 3H), 5.87 (s, 1H), 7.29 (m, 1H),
7.40–7.46 (m, 5H), 7.56–7.60 (m, 4H), 8.93 (s, 1H). 13C NMR
(125 MHz, DMSO-d6), δ: 31.1, 58.1, 115.6, 119.9 (q, J = 270.3 Hz),
125.3, 127.7, 128.7, 128.9, 129.1, 129.9, 131.4, 132.9, 147.7, 150.3
(q, J = 38.4 Hz), 154.8. APCI MS: 357 (MH+). Anal. calcd. for
C19H15F3N4 C 64.04, H 4.24, N 15.72. Found C 64.29, H 4.03, N 15.97.
5-Methyl-5,7-diphenyl-4,5-dihydrotetrazolo[1,5-a]pyrimidine
3ac. Yield 71%. Mp 214 °C. 1H (500 MHz, DMSO-d6), δ: 2.21
(s, 3H), 5.41 (s, 1H), 7.30–7.45 (m, 8H), 7.65 (m, 2H), 10.56
(s, 1H). 13C NMR (125 MHz, DMSO-d6), δ: 39.5, 63.3, 103.4,
125.7, 126.5, 128.3, 129.1, 129.2, 129.8, 133.9, 134.1, 145.0,
Entry no.
1
Compound
13C NMR, δ
5
153.6 (3a-C), 179.8 (5-C),
111.7 (6-C), 134.7 (7-C)
158.9 (3a-C), 158.4 (5-C),
112.4 (6-C), 146.8 (7-C)
156.0 (3a-C), 154.4 (5-C),
110.1 (6-C), 148.1 (7-C)
158.9 (3a-C), 165.7 (5-C),
111.2 (6-C), 135.0 (7-C)
151.2. APCI MS: 290 (MH+). Anal. calcd. for C17H15N5
70.57, H 5.23, N 24.20. Found C 70.80, H 5.17, N 24.59.
C
2
3
4
6
7
8
6’,7’,8’,9’-Tetrahydro-4’H-spiro(cyclohexane-1,5’-[1,2,4]
triazolo[1,5-a]quinazoline) 3ba. Yield 40%. Mp 225 °C.1H
NMR (500 MHz, DMSO-d6), δ: 1.15 (m, 1H), 1.45 (m, 2H),
1.58–1.76 (m, 10H), 2.09 (m, 2H), 2.44 (m, 2H), 3.12 (m,
1H), 7.19 (br. s, 1H), 7.40 (s, 1H). 13C NMR (125 MHz,
DMSO-d6), δ: 19.9, 21.6, 22.7, 23.2, 23.7, 25.3, 33.9, 56.8,
118.0, 127.2, 149.3, 152.7. APCI MS: 245 (MH+). Anal.
calcd. for C14H20N4 C 68.82, H 8.25, N 22.93. Found C
69.06, H 8.44, N 23.27.
2’-(Trifluoromethyl)-6’,7’,8’,9’-tetrahydro-4’H-spiro
(cyclohexane-1,5’-[1,2,4]triazolo[1,5-a]quinazoline) 3bb. Yield
35%. Mp 158 °C. 1H NMR (500 MHz, DMSO-d6), δ: 1.12
(m, 1H), 1.44 (m, 2H), 1.59–1.72 (m, 10H), 2.07 (m, 2H), 2.41
(m, 2H), 3.34 (m, 1H), 7.98 (s, 1H). 13C NMR (125 MHz,
DMSO-d6), δ: 19.8, 21.4, 22.5, 23.2, 23.4, 25.1, 34.0, 57.3, 120.1
(q, J = 269.3 Hz), 120.4, 126.8, 149.8 (q, J = 37.4 Hz), 153.6.
APCI MS: 313 (MH+). Anal. calcd. for C15H19F3N4 C 57.68, H
6.13, N 17.94. Found C 57.91, H 5.88, N 17.92.
iPrOH. The crude product was purified by flash chromatography
(Hexane – EtOAc (9:1) as an eluent).
5-Methyl-5,7-diphenyl-4,5-dihydro[1,2,4]triazolo[1,5-
1
a]pyrimidine 3aa. Yield 65%. Mp 174 °C. H NMR (500 MHz,
DMSO-d6), δ: 2.09 (s, 3H), 5.29 (s, 1H), 7.26 (m, 3H), 7.34 (m,
3H), 7.41 (m, 2H), 7.61 (m, 2H), 7.69 (s, 1H), 9.97 (s, 1H). 13C
NMR (125 MHz, DMSO-d6), δ: 28.7, 62.5, 103.4, 125.6, 126.3,
127.6, 128.8, 129.0, 129.4, 134.1, 134.5, 146.5, 150.0, 150.1.
APCI MS: 289 (MH+). Anal. calcd. for C18H16N4 C 74.98, H
5.59, N 19.43. Found C 75.14, H 5.31, N 19.24.
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1150
S. V. Ryabukhin, V. S. Naumchik, O. O. Grygorenko, and A. A. Tolmachev
Vol 49
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1
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MHz, DMSO-d6), δ: 29.2, 40.8, 111.5, 134.8, 154.4, 179.9.
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6.26, N 39.52. Found C 53.87, H 6.41, N 39.60.
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Acknowledgments. The authors thank to Mr. Vitaliy V. Polovinko
for NMR measurements and to Mrs. Olga V. Manoylenko for
chromatographic separations.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet