A convenient and rapid approach for the synthesis of 1-benzyl-3-heterocyclic pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2009.07.062

A variety of 1-benzyl-3-heterocyclic pyrazoles were rapidly assembled by a two-step N-benzylation/Suzuki coupling sequence. A one-pot variation of this sequence is demonstrated.

Full text of DOI:10.1016/j.tetlet.2009.07.062

Tetrahedron Letters 50 (2009) 5479–5481
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A convenient and rapid approach for the synthesis of
1-benzyl-3-heterocyclic pyrazoles
*
Michael P. Curtis, Matthew F. Sammons, David W. Piotrowski
Pfizer Global Research and Development, Groton/New London Laboratories, Pfizer Inc, Groton, CT 06340, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of 1-benzyl-3-heterocyclic pyrazoles were rapidly assembled by a two-step N-benzylation/
Suzuki coupling sequence. A one-pot variation of this sequence is demonstrated.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 2 December 2008
Revised 10 July 2009
Accepted 13 July 2009
Available online 16 July 2009
1. Introduction
sition of the pyrazole ring and the two protons on the phenyl ring
ortho to the carbon linker was observed upon irradiation of the
Regiocontrolled access to small, polar heterocycles has become
an increasingly important part of a medicinal chemist’s repertoire
to examine structure–activity relationships (SARs) and adjust
physicochemical properties of lead molecules. As part of a medic-
inal chemistry program, we were interested in rapidly evaluating
an N-benzyl-3-heterocyclic pyrazole lead compound. Recently,
methods to access (het)aryl-substituted imidazoles and pyrazoles
via the corresponding boronic acids or esters have been pub-
lished.1,2 Herein, we disclose a method to rapidly prepare 1-ben-
zyl-3-heterocyclic pyrazole analogs (1) derived from commercially
available 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyr-
azole (2) (see Fig. 1).
methylene protons of the benzyl group.4 Similar regioselectivity
O
B
O
Het
N
N
N
H
N
Ar
2
1
Figure 1. N-Benzyl-3-heterocylic pyrazoles.
2. Results and discussion
In order to explore the SAR of a lead 3-(4-pyrimidinyl)pyrazole
1, we wished to survey a range of N-substituents as well as a range
of heterocycles at the 3-position. Initial exploration of the benzyl
moiety of 1 while maintaining 4-pyrimidine constant at the 3-po-
sition was facilitated by the commercial availability of 1-(pyrimi-
din-4-yl)ethanone (3). Thus, 3 was treated with DMFÁDMA in
refluxing DMF to provide intermediate 4.3 Subsequent ring closure
with hydrazine hydrate in EtOH at room temperature afforded
compound 5 in 75 % yield. Benzylation of 5 was first accomplished
using 4-chlorobenzyl bromide and Cs2CO3 in DMF. After aqueous
work-up and flash chromatography, the reaction yielded two dis-
tinct regioisomers (1a and 6a) in roughly 10:1 ratio (Scheme 1).
NOESY analysis of the major isolate confirmed benzylation at the
N-1 position. A strong correlation between the proton at the 5-po-
O
O
N
b
a
N
N
N
N
3
4
N
N
N
N
c
N
N
N
N
H
N
N
N
H
N
H
5
R
R
n.O.e.
observed
1a-f
6
Scheme 1. Reagents and conditions: (a) DMFÁDMA, DMF, 150 °C 18 h, 87%; (b)
* Corresponding author. Tel.: +1 860 686 0271; fax: +1 860 686 6627.
E-mail address: david.w.piotrowski@pfizer.com (D.W. Piotrowski).
hydrazine hydrate, EtOH, rt 18 h, 75%; (c) R-benzyl bromide Cs2CO3, MeCN, 80 °C
2 h.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.062

5480
M. P. Curtis et al. / Tetrahedron Letters 50 (2009) 5479–5481
Table 1
Table 2
3-(4-Pyrimidinyl)-N-benzylpyrazoles obtained by benzylation of 5.
3-Heteroaryl-N-benzylpyrazoles obtained by Suzuki coupling of crude 7
Compd
R
% Yield
O
B
O
B
1a
1b
1c
1d
1e
1f
4-Cl
H
3-Cl
2-Cl
3-CF3
3-CH3
48
47
41
70
43
62
O
O
Het
a
b
N
N
N
N
N
H
N
R
R
7
2
1g-r
Compd
Het
R
X
% Yield
was also observed for the benzylation of other analogs. In addition,
the chemical shift of the benzylic protons of 1 typically appeared
0.6 ppm upfield when compared to benzylic protons of 6, and thus
served as diagnostic protons for identification of the desired
regioisomer.5
Simplification of the benzylation procedure by replacement of
DMF with acetonitrile allowed for filtration, concentration and
purification by chromatography. Using this methodology we were
able to rapidly synthesize a variety of substituted benzyl analogs in
moderate to good yields (Table 1, compounds 1a–f).
A facile, parallel-enabled approach to altering the pyrazole 3-
substituent that did not rely on the three-step method depicted
in Scheme 1 was sought. However, few methods to make 3-hetero-
cyclic pyrazoles are amenable to parallel synthesis.6 Thus, benzyla-
tion of 2 followed by Suzuki cross-coupling would allow for rapid
generation of 3-heterocyclic pyrazole analogs. Early attempts to ef-
fect N-benzylation of 2 provided less than 10 % of desired product 7
(R = H) after aqueous work-up and chromatography. Although
these results were discouraging, we believed the reaction was pro-
gressing, and that the boronate-ester group of the pyrazole was
undergoing protodeboronation7 or hydrolysis during aqueous
work-up and/or silica gel purification. To better understand the
fate of boronate 7, the crude reaction mixture was filtered, concen-
trated and subjected to LC–MS, GC–MS, and NMR analysis. Reverse
phase LC–MS showed only the boronic acid hydrolysis product of 7.
However, GC–MS and NMR analysis confirmed complete conver-
sion of 2 into 7, ca. 8 % of the undesired regioisomer and a trace
of protodeboronated product. To avoid this decomposition, the
crude reaction products 7 were used directly in the Suzuki cross-
coupling.
F
N
1g
1h
1i
H
Cl
Br
Cl
22
28
44
N
2-Pyrimidinyl
3-CF3
3-CF3
N
N
O
F
N
1j
3-CF3
3-CF3
Cl
Cl
43
51
N
N
1k
CH3
1l
2-Pyridazinyl
phenyl
3-CF3
3-CF3
Cl
41
48
1m
Br
F
1n
1o
1p
3-CF3
3-CF3
3-CF3
Br
Cl
Br
50
51
20
N
S
N
O
1q
1r
2-Thiazolyl
3-CF3
3-CF3
Br
Br
22
35
2-Furyl
Conditions: (a) R-benzyl bromide, Cs2CO3, MeCN, 80 °C 2 h; (b) Het-X, Pd(PPh3)4
Na2CO3, iPrOH/toluene/H2O, 80 °C 18 h.
To our satisfaction, Suzuki reaction of crude 7 with 5-fluoro-2-
chloropyrimidine gave the desired product 1g in 22 % yield over
two steps. Although this yield was less than optimal, higher yields
were achieved with more activated heterocycles. Most impor-
tantly, we now had a method to readily access heterocycles at
the 3-position of the pyrazole core. This process was further opti-
mized by preparing intermediate 7 on scale and using the crude
boronate ester for a series of Suzuki reactions. With this in place,
a number of 3-heterocyclic pyrazole analogs were synthesized in
parallel (Table 2, compounds 1g–r).
We believed that this pyrazole benzylation/Suzuki coupling ap-
proach to compounds 1 could be simplified even further if both
steps were carried out in a one-pot reaction sequence. Indeed, it
was found that compounds 1 could be prepared directly from 2
in one pot through initial benzylation of 1 in the presence of excess
Cs2CO3 followed by addition of 5 mol % Pd(PPh3)4 and aryl halide
(Table 3).
Table 3
3-Heteroaryl-N-benzylpyrazoles obtained by one-pot alkylation/Suzuki coupling of
boronate ester 2
Het
O
B
O
N
a
N
N
N
H
R
2
1
Compd
Het
R
% Yield
In conclusion, we have described a rapid and convenient meth-
od to prepare 1-benzyl-3-heterocyclic pyrazole analogs (1) derived
from commercially available 3-(4,4,5,5-tetramethyl-[1,3,2]dioxa-
borolan-2-yl)-1H-pyrazole (2). This two-step sequence is amena-
ble to a one-pot synthesis, allowing for variation of substituents
at two positions of the pyrazole and rapid examination of the series
SAR.
1a
1c
1d
1s
1t
4-Pyrimidinyl
4-Pyrimidinyl
4-Pyrimidinyl
2-Pyridinyl
4-Cl
3-Cl
2-Cl
4-Cl
2-Cl
47
43
49
36
27
2-Pyridinyl
Conditions: (a) (i) R-benzyl bromide, Cs2CO3 (3 equiv), MeCN, 80 °C 2 h; (ii) het-
erocyclic-Cl, Pd(PPh3)4 , H2O, 80 °C 18 h.

M. P. Curtis et al. / Tetrahedron Letters 50 (2009) 5479–5481
5481
0.77 mmol) in acetonitrile (2 mL) was added 4-chlorobenzyl bro-
mide (53 mg, 0.26 mmol). The reaction mixture was heated at
80 °C for 2 h. Pd(PPh3)4 (15 mg, 0.013 mmol), 2-chloropyridine
3. Experimental
3.1. Typical experimental procedure for preparation and Suzuki
coupling of 7
(25 lL, 0.27 mmol), and 50 lL water were added. The reaction mix-
ture was stirred at 80 °C for 18 h. After cooling to room tempera-
ture, the mixture was filtered through Celite and concentrated.
Purification by flash chromatography eluting with a 0–50% EtOAc
in heptane gradient gave 1s (25 mg, 36%) as a colorless solid. 1H
NMR (CDCl3, 400 MHz) d 5.34 (s, 2H) 6.89 (d, J = 2.35 Hz, 1H)
7.15–7.21 (m, 3H) 7.27–7.33 (m, 2H) 7.39 (d, J = 2.35 Hz, 1H)
7.69 (m, 1H) 7.86–7.96 (m, 1H) 8.58–8.65 (m, 1H); m/z (CI) 270
([M+H]+, 100%).
To a solution of 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
yl)-1H-pyrazole(1.0 g, 5.1 mmol)in acetonitrile (35 mL)were added
3-(trifluoromethyl)benzyl bromide (1.23 g, 5.2 mmol) and cesium
carbonate (2.5 g, 7.7 mmol). The reaction mixture was heated at
80 °C for 2 h. The reaction mixture was cooled, filtered, and concen-
trated to provide 7 as a yellow solid. To a solution of crude 7 (125 mg,
0.36 mmol) in toluene/iPrOH/water (7 mL) were added 2-chloro-
benzothiazole (61 mg, 0.36 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol),
and sodium carbonate (95 mg, 0.9 mmol). The reaction mixture was
heated at 80 °C for 18 h. After cooling to room temperature, the mix-
ture was concentrated and purified using flash chromatography,
eluting from 10:90 EtOAc/heptane to 50:50 EtOAc/heptane afford-
ing 1o (65 mg, 51 %) as a colorless solid. 1H NMR (CDCl3, 400 MHz)
d 5.45 (s, 2H), 7.05 (d, J = 2.4 Hz, 1H), 7.37 (t, J = 7.2 Hz, 1H), 7.42–
7.50 (m, 4H), 7.54 (s, 1H), 7.58, (d, J = 4.0 Hz, 1H), 7.89 (d,
J = 8.0 Hz, 1H), 8.06 (d, J = 8.4, 1H); 13C NMR (CDCl3 100.51 MHz) d
56.13, 106.13, 121.89, 123.20, 124.66, 125.51, 126.44, 129.75,
131.23, 131.59, 134.60, 137.04, 147.30, 153.90, 161.97 ppm; m/z
(CI) 360 ([M+H]+, 100%); Anal. Calcd for C18H12F3N3S: C, 60.16; H,
3.37; N, 11.69. Found: C, 59.94; H, 3.04; N, 11.56.
References and notes
1. McLaughlin, M.; Marcantonio, K.; Chen, C.; Davies, I. W. J. Org. Chem. 2008, 73,
4309.
2. Primas, N.; Mahatsekake, C.; Bouillon, A.; Lancelot, J.-C.; Sopkovà-de Oliveira
Santos, J.; Lohier, J.-F.; Rault, S. Tetrahedron 2008, 64, 4596.
3. Wang, L.; Woods, K. W.; Li, Q.; Barr, K. J.; McCroskey, R. W.; Hannick, S. M.;
Gherke, L.; Credo, R. B.; Hui, Y.; Marsh, K.; Warner, R.; Lee, J. Y.; Zielinski-Mozng,
N.; Frost, D.; Rosenberg, S.; Sham, H. L. J. Med. Chem. 2002, 45, 1697.
4. Price, S.; Bordogna, W.; Bull, R. J.; Clark, D. E.; Crackett, P. H.; Dyke, H. J.; Gill, M.;
Harris, N. V.; Gorski, J.; Lloyd, J.; Lockey, P. M.; Mullett, J.; Roach, A. G.; Roussel,
F.; White, A. B. Bioorg. Med. Chem. Lett. 2007, 17, 370.
5. The benzylic protons for 1a = d 5.37 ppm and 6a = d 6.01 ppm; 1b = 5.40 ppm
and 6b = d 6.05 ppm; 1e = d 5.46 ppm; 1g = d 5.45 ppm; 1l = d 5.47 ppm.
6. (a) Patel, M.; Bacheler, L. T.; Rayner, M. M.; Cordova, B. C.; Klabe, R. M.; Erickson-
Viitanen, S.; Seitz, S. P. Bioorg. Med. Chem. Lett. 1998, 8, 823; (b) Pavlik, W.;
Kurzweil, E. M. J. Heterocycl. Chem. 1992, 29, 1357; (c) Balle, T.; Perregaard, J.;
Ramirez, M. T.; Larsen, A. K.; SØby, K. K.; Liljefors, T.; Andersen, K. J. Med. Chem.
2003, 46, 265.
3.2. Typical experimental procedure for the one-pot
benzylation/Suzuki coupling of 2
7. (a) Campeau, L.; Fagnou, K. Chem. Soc. Rev. 2007, 36, 1058; (b) Tyrrell, E.;
Brookes, P. Synthesis 2003, 469.
To a suspension of 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-
2-yl)-1H-pyrazole (50 mg, 0.26 mmol) and Cs2CO3 (273 mg,