Synthesis of 3-trialkylsilyl pyrazoles from β-oxo acylsilanes

Article abstract of DOI:10.1016/S0040-4039(00)01724-X

The synthesis of β-oxo acylsilanes via cyclic sulfates is described and applied to carbohydrates. These compounds are used for the synthesis of new silylated pyrazoles linked to a carbohydrate moiety by the addition of hydrazines. The regiochemistry of the reaction was determined by NMR analyses (¹H/¹³C and ¹H/¹⁵N correlations). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01724-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9791–9795
Synthesis of 3-trialkylsilyl pyrazoles from b-oxo acylsilanes
Ste´phane Ge´rard,a Richard Plantier-Royon,a,* Jean-Marc Nuzillardb and Charles Portellaa,*
aLaboratoire ꢀRe´actions Se´lectives et Applicationsꢁ, Associe´ au CNRS (UMR 6519), Universite´ de Reims,
Faculte´ des Sciences, B.P. 1039, 51687 Reims Cedex 2, France
bLaboratoire de Pharmacognosie, Associe´ au CNRS (UMR 6013), Universite´ de Reims, Faculte´ des Sciences,
B.P. 1039, 51687 Reims Cedex 2, France
Received 15 June 2000; accepted 1 October 2000
Abstract
The synthesis of b-oxo acylsilanes via cyclic sulfates is described and applied to carbohydrates. These
compounds are used for the synthesis of new silylated pyrazoles linked to a carbohydrate moiety by the
addition of hydrazines. The regiochemistry of the reaction was determined by NMR analyses (1H/13C and
1H/15N correlations). © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: carbohydrates; pyrazoles; silicon heterocycles; acylsilanes; 15N-NMR.
Acylsilanes have considerable interest in organic chemistry1 and numerous syntheses of these
compounds are available in the literature. Recently, we reported a general strategy for the
synthesis of functionalized and carbohydrate-derived acylsilanes (b-hydroxy, b-oxo, a,b-unsatu-
rated) by ring opening of an epoxide2 or substitution of a leaving group3 with a silylcarbonyl
anion equivalent: 2-lithio-2-trimethylsilyl-1,3-dithiane (LTD). On the other hand, several routes
are available for the synthesis of trimethylsilyl heteroarenes.4 Introduction of a trimethylsilyl
group onto a pyrazole heterocycle takes place selectively at the 4-position by a Friedel–Crafts
reaction and at the 5-position by activation with a base. However, the synthesis of alkyl-3-
(trimethylsilyl)pyrazoles is not well described. To our knowledge, the methods which are
available to obtain these compounds are: 1,3-dipolar cycloaddition reaction of a diazo com-
pound with an alkynylsilane,5 or reaction of lithium trimethylsilyldiazomethane with
ketenimines6 or a,b-unsaturated nitriles.7 The presence of a trimethylsilyl group is interesting
owing to the possibility of its substitution by different electrophilic groups.8
In this paper, we report a new approach for the formation of functionalized acylsilanes from
a-diols via a cyclic sulfate.9 This methodology was successfully applied to b-oxo acylsilanes
derived from diacetone
D
-glucose: 3-O-benzyl-1,2-O-isopropylidene-a-
-glucofuranose,10 3-O-
D
* Corresponding author. Fax: 33 3 26 91 31 66; e-mail: charles.portella@univ-reims.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01724-X

9792
benzyl-1,2-O-isopropylidene-a-
D
-allofuranose11 and 3-deoxy-1,2-O-isopropylidene-a-
-ribohexo-
D
furanose.12 Condensation of these b-oxo acylsilanes with hydrazines led to silylated pyrazoles
bearing a carbohydrate moiety.
Cyclic sulfites 2a–d were prepared by reaction of hexane-1,2-diol 1a or sugars 1b–d with SOCl2
in the presence of Et3N. The best results were obtained using a freshly prepared thionyl
diimidazole SO(Im)2 solution.13 Scheme 1 exemplifies the synthetic pathway in carbohydrates
series. The diastereomeric mixtures of cyclic sulfites were directly used in the oxidation reaction
with the NaIO4/RuCl3 system14 to give efficiently cyclic sulfates 3a–d. The key step of this
synthesis is the regiospecific opening of these cyclic sulfates with LTD to give dithioketals 4a–d
after a mild acid-catalyzed hydrolysis.15 Dethioketalization using iodine in a buffered medium
converted compounds 4 to the b-hydroxy acylsilanes 5a–d with excellent yields. Swern oxidation
of the resulting b-hydroxy acylsilanes using trifluoroacetic anhydride16 led to compounds 6a–d.
As previously observed,2 compounds 6a–d are totally enolized [singlet at 14.45 (l ppm/TMS) in
1H NMR and two carbonyl groups at 193 and 199 (l ppm/TMS) in 13C NMR].
HO
HO
O
O
O
O
O
O
S
O S
SO(Im)2
Ref. 14
O
O
O
R2
R1
R2
R1
R2
R1
80-86 %
63-95 %
O
O
O
O
O
O
2b-d
3b-d
1b R1 = H, R2 = OBn
1c R1 = H, R2 = H
1d R1 = OBn, R2 = H
1) LTD
2) Ref. 16
68-88 %
SiMe3
O
O
S
S
Me3Si
HO
H
Me3Si
HO
I2/CaCO3
Ref 16
O
O
O
O
R2
R1
R2
R2
THF/H2O
60-84 %
O
O
O
R1
R1
O
85-95 %
O
O
6b-d
5b-d
4b-d
Scheme 1.
These b-oxo acylsilanes were converted into the corresponding silylated pyrazoles by reaction
with hydrazines in ether at room temperature (Scheme 2 and Table 1).17,18 The b-oxo acylsilane
R'
R'
H
N
N
N
N
O
O
R'-NH-NH2
Et2O
+
R
SiMe3
R
SiMe3
R
SiMe3
Major
7-16
Minor
O
R2
R1
7-16
R = C4H9
O
O
6a
6b-d
Scheme 2.

9793
with the alkyl chain 6a, upon addition of different hydrazines, gave the corresponding
pyrazoles with good yields (entries 1–3).
Table 1
Formation of silylated pyrazole heterocycles
Entry
b-Oxo acylsilane
R%
Pyrazole (%)
Maj./Min.
1
2
3
4
5
6
7
8
9
6a
6a
6a
6b
6b
6b
6c
6d
6d
6d
Me
H
Ph
Me
H
Ph
Me
Me
H
7 (60)
8 (82)
85/15
–
88/12
100/0
–
9 (74)19
10 (73)
11 (72)
12 (0)19
13 (90)
14 (36)19
15 (97)
16 (0)19
100/0
100/0
–
10
Ph
In the case of substituted hydrazines, two regioisomers were obtained with a good regioselec-
1
tivity (5.7/1, ratio determined by H NMR). Under the same conditions, carbohydrate-derived
b-oxo acylsilanes 6b–d led, with quite good yields, to the pyrazoles (entries 4, 5, 7, 8, 9), except
with phenylhydrazine, which gave formation of side-products (entries 6, 10).19 The limited
reactivity of phenylhydrazine with these compounds could be explained by the steric hindrance
of phenylhydrazine with the furanose moiety. Owing to the lowest nucleophilicity of phenyl-
hydrazine, a longer reaction time is needed favouring the formation of the hydrodesilylation
by-product. Reactions with methylhydrazine yielded only one regioisomer of the expected
pyrazole. In order to determine the regiochemistry of the addition of hydrazines on b-oxo
acylsilanes, NMR analyses were performed.
For pyrazole 13, a 13C–1H HMBC spectrum showed a correlation between C3 (140 ppm) and
the methyl groups of SiMe3 and between C5 (152 ppm) and the methyl group of the hydrazine
moiety. In the case of pyrazole 9, a 15N–1H HMBC spectrum showed a correlation between N1
and the CH2 group of the butyl chain and aromatic proton. These observations confirm that the
major isomers are the 3-trimethylsilyl-5-alkylpyrazoles depicted in Fig. 1.
H
H
Me
H
SiMe3
Si Me
3
2
1
N
N
N
N
H
5
O
H
H
H
O
H
H
O
9
13
Figure 1. NMR correlations in compounds 9 and 13

9794
According to previously reported works, the formation of the pyrazole ring should proceed by
initial nucleophilic attack of the less hindered and more nucleophilic primary nitrogen of the
hydrazine at the most electrophilic carbonyl group.20 The observed regioselectivity indicates that
the carbonyl group of the acylsilane moiety should be the most reactive. This is in accordance
with some physico-chemical data reported for the acylsilane function.2b,21 The steric hindrance
of the TMS group is balanced by a longer CꢀSi bond (1.926 A).2b Spectroscopic (IR, NMR) and
,
basicity studies21a about acylsilanes showed an enhanced polarity of the carbonyl group
compared to classical ketones due to the inductive effect of the silicon atom that stabilizes the
positive charge on the carbon of the CꢁO bond. The favoured reaction pathway leads to the
formation of the observed 3-trimethylsilyl pyrazoles.
This preliminary study on the synthesis of silylated pyrazoles illustrates the usefulness of
acylsilanes in carbohydrate and heterocyclic chemistry. This methodology could be applied to
the formation of different heterocycles and could lead to -C-nucleosides analogues.
L
Acknowledgements
We are grateful to H. Baillia for his precious help during the NMR studies.
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9795
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1
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