Regioselective benzylation of an indazolyl-substituted pyrazole under the influence of inorganic solid supported bases

Article abstract of DOI:10.1039/a808310j

The benzylation of an indazolyl-substituted pyrazole under the influence of KOH-Al₂O₃, KF-Al₂O₃ and CsF-Al₂O₃ is investigated.

Full text of DOI:10.1039/a808310j

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274 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 274^275y
Regioselective Benzylation of an Indazolyl-
substituted Pyrazole under the Influence of
Inorganic Solid Supported Basesy
aInstitute of Elemento-Organic Chemistry, Nankai-University, 300071 Tianjin, P.R. China
bOrganisch-Chemisches Institut, Ruprecht-Karls-Universitat, INF 270, 69120, Heidelberg,
Germany
M. W. Branco,a R. Z. Cao,a L. Z. Liu*a and G. Egeb
The benzylation of an indazolyl-substituted pyrazole under the influence of KOH Al2O3, KF Al2O3 and CsF Al2O3
is investigated.
Many alkylation reactions on pyrazole1 have been investigated
and described as not being selective. Only in a few cases has
regioselectivity has been described for special pyrazole
derivatives and special reaction conditions, e.g. if
diazomethane1 or phase-transfer catalysts2 are used. An alky-
lation of pyrazoles under the in£uence of inorganic solid
supported bases has not been described until now. But in
the literature this method has been used for the alkylation
of imidazole3 and benzotriazole.4 In the case of
benzotriazole a regioselectivity that depends on the choice
of the solvent has been described.4 In a recently published
bond with the surface of the base (Scheme 2, II)5 With a
shift of double bonds around the pyrazole ring, the alkylation
takes place at the nitrogen neighbouring the methyl group
(Scheme 2, III).5
Our interest was in whether the described reaction is still
regioselective in the case of smaller aryl groups. Therefore,
the benzylation of the analogous, indazolyl-substituted
pyrazole 1 was investigated (Scheme 3).
work5 this method was used for the alkylation of
a
Me
naphthoindazolyl pyrazole and has shown
regioselectivity (Scheme 1).
a
100%
Ph
N
N
+
BrCH2Ph
Me
Me
N
N
Me
Ph
N
Ph
N
N
H
N
H
CH2Ph
1
Base Solvent
N
N
N
O
N
25 ˚C
3 h
BnBr
Me
Me
KF–Al2O3
DMF
Ph
N
N
Ph
N
N
O
98% yield
+
(100% regioselective)
N
N
Me
Me
N
N
Scheme 1 Selective benzylation of a pyrazole derivative5
Ph
CH2Ph
2
3
The regioselectivity was explained by an adsorptive
substrate mechanism. In this mechanism the aryl substituent
adsorbs on the Al2O3-surface, while the pyrazole twists
out of the plane of the aryl group and is ¢xed by a hydrogen
Scheme 3
Me
Ph
Me
Ph
N
R
R
N
H
N
C
N
N
N
O
N
N
O
H
Ph
Me
O
N
N
F
R
N
2
N
R
–Br –
R2CHBr
C
H
H
Br
H
F
F
KF–Al2O3
KF–Al2O3
KF–Al2O3
1
I
II
III
1: Adsorption of the aryl group on the Al2O3 surface, 2: hydrogen bond
Scheme 2 Alkylation mechanism under the influence of inorganic solid supported bases5
The benzylation has been investigated under the in£uence
of KOH Al2O2, KF Al2O3 and CsF Al2O3. The ratio
of the isomers 2 and 3 was determined via the intensities
of the methylene peaks in the 1H NMR spectra. To judge
* To receive any correspondence.
y This is a Short Paper as de¢ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is
therefore no corresponding material in J. Chem. Research (M).

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J. CHEM. RESEARCH (S), 1999 275
Table 1 Benzylation of 1 under various reaction conditions
No.
Solvent
Amount/ml
Base
2 (%)a
3 (%)a
1
2
Acetone
10
30
30
10
15
10
10
30
30
10
15
10
10
30
30
10
15
10
10
15
15
15
KOH Al2O3
KOH Al2O3
KOH Al2O3
KOH Al2O3
KOH Al2O3
KOH Al2O3
KF Al2O3
KF Al2O3
KF Al2O3
KF Al2O3
KF Al2O3
KF Al2O3
CsF Al2O3
CsF Al2O3
CsF Al2O3
CsF Al2O3
CsF Al2O3
CsF Al2O3
K2CO3
60
40
10
Ethyl acetate
Acetonitrile
THF
90
3
Decomposision
4
87
13
9
35
30
10
5
1,4-Dioxane
DMF
Acetone
Ethyl acetate
Acetonitrile
THF
1,4-Dioxane
DMF
Acetone
Ethyl acetate
Acetonitrile
THF
1,4-Dioxane
DMF
Acetone
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
91
6
65
7
70
8
90
9
Decomposision
10
11
12
13
14
15
16
17
18
19
20
21
22
85
100
63
70
15
0
37
30
0
100
Decomposision
100
100
84
0
0
16
42
38
30
40
58
K2CO3
62
KOH
Et3N
70
60
a The ratio of isomers 2 and 3 were determined according to the intensities of the methylene peaks (2: d ˆ 5:41, 3, d ˆ 5:11† in the 1H
NMR spectra (CDCl3).
1.83 g CsF Al2O3† was added. After 5 min of stirring at room tem-
perature 0.1ml (0.14 g, 0.8 mmole) of benzyl bromide were added with
a syringe. The mixture was stirred at room temperature for 4 h. It
was then ¢ltered and the ¢lter and base were washed with solvent.
The solvent was removed from the ¢ltrate. The oily residue was
dissolved in 50 ml of ethyl acetate; 50 ml of water and 3 ml of
triethylamine were added and the mixture was stirred vigorously for
1h. The two layers separated. The organic layer was washed 3 times
with water and then dried over MgSO4 . After removal of the solvent
the product remained as a colourless solid residue. It was dried under
the vacuum of the belt drive pump for 1h and then investigated by
1H NMR ꢀCDCl3) (see Table 1).
the regioselectivity, the products have also been produced in
the presence of bases without a support. By comparison,
benzylation under the in£uence of inorganic solid supported
bases appeared to be highly selective. The results are listed
in Table 1.
As seen in Table 1, the use of acetone and acetonitrile is
disadvantageous to the reaction. Acetonitrile is not useful
because it leads to decomposition of the products. On the
other hand, ethyl acetate, THF and 1,4-dioxane support
the selectivity.
The activity of the inorganic solid supported bases
The two isomers
2 and 3 have been separated via column
decreases
in
the
order
CsF Al2O3 > KF Al2O3
chromatography (SiO2/CH2Cl2 : Et2O ˆ 30 :1) and identi¢ed by NOE.
2: mp 130 8C, Rf (SiO2/CH2Cl2 : Et2O ˆ 30 : 1): 0.52; dHꢀCDCl3†
2.30 (s, 3 H, 3-CH3), 2.57 (s, 3 H, 1-C-5-CH3), 5.41 (s, 2 H,
1-N-1-CH2), 7.12±7.32 (m, 13 H, 5,6,7-H ‡ 1-C-4-C-2,3,4,5,6-H ‡
1-N-CH2-C-2,3,4,5,6-H), 7.62 (d, 1 H, 4-H); dCꢀCDCl3† 10.15, 11.56,
53.23, 110.39, 114.97, 119.53, 120.10, 123.50, 126.11, 126.29, 126.54,
127.33, 127.78, 128.35, 128.66, 131.45, 136.01, 137.03, 140.74, 143.40.
144.24. (Found: C, 78.95; H, 5.68; N, 14.67. Required: C, 79.34; H,
5.86; N, 14.80%).
3: mp 133 8C, Rf ꢀSiO2=CH2Cl2 : Et2O ˆ 30 : 1): 0.43; dHꢀCDCl3†
2.44 (s, 3 H, 3-CH3), 2.62 (s, 3 H, 1-C-5-CH3), 5.11 (s, 2 H,
1-N-1-CH2), 6.70 (d, 1 H, 7-H), 7.07±7.11 (m, 12 H,
5,6-H ‡ 1-C-4-C-2,3,4,5,6-H ‡ 1-N-CH2-C-2,3,4,5,6-H), 7.59 (d,
1 H, 4-H); dC (CDCl3) 11.57, 13.19, 52.45, 109.26, 116.71, 119.59,
120.55, 123.31, 126.06, 126.85, 127.14, 127.79, 131.07, 133.59, 135.72,
141.37, 145.15, 145.33. (Found: C, 79.27; H, 5.65; N, 14.44.
Required: C, 79.34; H, 5.65; N, 14.44%).
> KOH Al2O3. This is explainable by decreasing strength
of the hydrogen bond between the pyrazole and the surface
of the base.
Other than in usual alkylation reactions, the used solvents
have not been puri¢ed. Only 1,4-dioxane was stored over
sodium metal, to prevent the formation of peroxides. As
in all cases, the overall yield was between 90 and 100%,
and traces of water seem not to disturb the reaction.
Experimental
1-(5-Methyl-4-phenyl-1H-pyrazol-3-yl)-3-methylindazole (1).ö15 ml
conc. H2SO4 was cooled to 15 8C in a 50 ml ¯ask. At this tem-
perature a solution of 1 g (3.5 mmole) 3,6-dimethyl-3,7-diphenyl-3H-
pyrazolo[5,1-c][1,2,4]triazole6 in 5 ml ethyl acetate was slowly added.
This solution was stirred at 15 8C for 2.5 h. It was then poured
on 300 ml of crushed ice and neutralized with K2CO3 to pH 5. The
organic material was extracted with ethyl acetate. The solution was
dried over MgSO4 and the solvent removed until 20 ml remained.
The product precipitated overnight as colourless needles. It was
®ltered off by suction, washed with light petroleum (bp 60±90 8C)
and dried over P4O10. Yield: 0.6 g (60%); mp 203 8C, Rf SiO2=Et2O
0.54, Rf ꢀSiO2=CH2Cl2): 0.02; dH ꢀCDCl3† 1.96 (s, 3 H, 3-CH3),
2.55 (s, 3 H, 1-C-5-CH3), 6.98±7.24 (m, 8 H, 5,6,7-H ‡
1-C-4-C-2,3,4,5,6-H), 7.61 (d, 1 H, 4-H), 10.65 (s, 1 H, N-H); dC
ꢀCDCl3) 10.58, 11.55, 110.35, 113.29, 120.13, 120.48, 123.19, 126.13,
126.83, 128.11, 128.28, 131.81, 137.48, 141.06, 142.59, 144.75.
(Found: C, 75.03; H, 5.47; N, 19.61. Required: C, 74.98; H, 5.59;
N, 19.43%).
To remove the toxicity from the KF Al2O3 and the CsF Al2O3,
which remained in the ¢lter, it was suspended in 200 ml of water
and CaCl2 was added. Thus it was transformed into insoluble CaF2
and was no longer bioavailable.
Received, 27th October 1998; Accepted, 5th January 1999
Paper E/8/08310J
References
1
K. Scho¢eld, M. R. Grimmet and B. R. T. Keene,
Heteroaromatic Nitrogen Compounds ``The Azoles'' Cambridge
University Press, London, New York, Melbourne, 1976, S. 73.
S. Vega, E. Arranz, J. A. D|az, E. Morante and C. Perez, J.
Heterocycl. Chem., 1996, 33, 151.
2
3
4
CsF Al2O3,3, KF Al2O3 and KOH Al2O3 were produced
3
4
L. Wang and X. H. Sun; Huaxue Tongbao, 1993, 3 8.
Y. H. Zheng, F. N. Wang, G. H. Deng and G. M. Li, Xiangtan
Dexue Ziran Kexue Xuebao, 1991, 13, 75.
according to the literature.
1-(1-Benzyl-5-methyl-4-phenyl-1H-pyrazol-3-yl)-3-methylindazole
(2) and 1-(1-Benzyl-3-methyl-4-phenyl-1H-pyrazol-5-yl)-3-methyl-
indazole (3). 0.1g (0.35 mmol) of 1 was dissolved in a 50 ml £ask in
the amount of solvent listed inTable1.Then a12-fold excess of inorganic
solid supported base (4.2 mmole; 0.81g KOH Al2O3, 1.1g KF^Al2O3,
5
6
M. W. Branco, Dissertation Universitat Heidelberg, 1997, G.
Ege and M. W. Branco, in preparation.
G. Ege, K. Gilbert and R. Heck, Chem. Ber., 1984, 117, 1726.