One-pot copper-catalyzed synthesis of N-functionalized pyrazoles from boronic acids

Article abstract of DOI:10.1016/j.tetlet.2010.07.077

A straight-forward route to prepare a diverse set of N-aryl pyrazoles via a one-pot copper-catalyzed boronic acid coupling and cyclization protocol is presented. A variety of aryl and heteroaryl N-functionalized pyrazoles not easily accessible by other means were formed in good yield from readily available boronic acid precursors in an operationally simple procedure.

Full text of DOI:10.1016/j.tetlet.2010.07.077

Tetrahedron Letters 51 (2010) 5005–5008
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot copper-catalyzed synthesis of N-functionalized pyrazoles
from boronic acids
*
Ramsay E. Beveridge , Dilinie Fernando, Brian S. Gerstenberger
Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Groton, CT, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A straight-forward route to prepare a diverse set of N-aryl pyrazoles via a one-pot copper-catalyzed boro-
nic acid coupling and cyclization protocol is presented. A variety of aryl and heteroaryl N-functionalized
pyrazoles not easily accessible by other means were formed in good yield from readily available boronic
acid precursors in an operationally simple procedure.
Received 23 June 2010
Revised 13 July 2010
Accepted 13 July 2010
Available online 16 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Pyrazoles represent an important class of heterocycles as constit-
uents of agro-chemicals,1 polymeric materials2 and as a unique
ligand class3 but are perhaps most prevalent as constituents of
active pharmaceutical compounds.4 Considering the lack of natu-
rally occurring pyrazole-containing molecules, it is interesting that
there are an extensive number of synthetic pyrazoles with profound
biological activity5 including the COX-2 inhibitor drug Celecoxib
(Celebrex)™. In our ongoing drug discovery research efforts, we
are interested in the development of efficient and general methods
to access N-functionalized pyrazoles under mild conditions.
Typically, the construction of pyrazole compounds is performed
via cyclocondensation of hydrazines and 1,3-dicarbonyls, or by di-
rect N-functionalization of pre-formed 1H-pyrazoles by either
nucleophilic substitution or metal-catalyzed/mediated C–N cross-
coupling methods.6–10 In regards to the latter, while transition-me-
tal-catalyzed coupling or direct nucleophilic substitution of simple
pyrazoles is known, these examples are limited to pyrazoles devoid
of potentially useful halo-substitutions. In addition, while transition
metal-catalyzed/mediated C–N bond formation routes have wit-
nessed considerable advances in generality, 1H-pyrazoles remain
difficult substrates in these reactions.6 The cyclocondensation
method can also be restricted in regards to the availability of the
requisite hydrazine precursors. For example, a number of common
heterocyclic hydrazines are not known, and preparation of
multi-substituted aryl hydrazines can be difficult to access using
conventional methods.11 For these reasons, a general method for
the preparation of these interesting pharmaceutically active cores
from readily available materials with improved functional group
scope (e.g., formation of halo-containing pyrazoles) is a desirable
goal.
prepared in a simple one-pot protocol from aryl-bromides.12 This
reaction involves initial metal-halo exchange generating a reactive
aryl-lithium species which reacts rapidly with di-tert-butylazodi-
carboxylate13 providing a di-N-boc-protected aryl hydrazide inter-
mediate which in the presence of a 1,3-dicarbonyl compound and
in situ deprotection generated a number of useful N-aryl pyrazoles
in good yield (Fig. 1).
While useful, the metallation conditions employed is not
compatible with aryl-bromides containing sensitive groups. For
R2
Boc
O
O
R1
Ar
n-BuLi
N
N
Br
R3
R1
R3
N
Ar
HCl/dioxane
one-pot
N
Boc
R2
Figure 1. One-pot formation of N-aryl pyrazoles from aryl halides.
Cl
N
Br
Cl
N
conditions
A-C
N
N
HN
N
N
N
1
not observed
Cl
N
N
N
1) 1.1 eq. n-BuLi
-78ºC THF
2) 4N HCl/dioxane
reflux
N
N
Br
Boc
O
O
N
N
N
N
N
N
N
Boc
Cl
1
2
Recently, we have reported that a number of N-aryl pyrazoles,
including those with pyrazole-ring halo-substituents, can be
not observed
62% by LC-MS
Scheme 1. Unsuccessful attempts towards a 5-pyrazole-pyrimidine synthesis from
5-bromo-pyrimidine. Reagents and conditions: (A) 1.2 equiv pyrazole, 1.5 equiv
iPr2NEt, DMSO 110 °C 24 h; (B) 1.8 equiv pyrazole, 5% Cu powder, 5% CuI 20% rac-
BINOL, 2.3 equiv Cs2CO3, DMF 110 °C 24 h; (C) 1.5 equiv pyrazole, 10% CuO, 30%
Fe(acac)3, 2 equiv Cs2CO3, DMF 90 °C 24 h.
* Corresponding author.
E-mail addresses: ramsay.beveridge@pfizer.com, ramsaybeveridge@hotmail.com
(R.E. Beveridge).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.077

5006
R. E. Beveridge et al. / Tetrahedron Letters 51 (2010) 5005–5008
example, we considered the potential to access chloro-functional-
Cl
HO
OH
ized-5-pyrazole-substituted pyrimidines such as 1 via this method
since the corresponding 5-hydrazine-pyrimidine is not known,
and attempts at direct substitution of 5-bromo-pyrimidine with
4-chloro-3,5-dimethyl-1H-pyrazole14 under conventional 1H-pyra-
zole cross-coupling conditions were unsuccessful.8h,9 However, in
the event, 5-Br-pyrimidine under our typical one-pot metallation/
condensation conditions resulted in the undesired formation of a
dimerized pyrimidine species 2 with no trace of the pyrazole prod-
uct 1 by LC–MS analysis of the crude reaction mixture (Scheme 1).
Alternatively, we investigated whether the commercially avail-
able 5-pyrimidine-boronic acid would be compatible in a copper-
mediated approach towards pyrazoles of type 1. As shown in
Scheme 2, the oxidative Chan-Lam-type coupling of 5-pyrimi-
dine-boronic acid and 4-chloro-3,5-dimethyl-1H-pyrazole in the
presence of stoichiometric copper was unsuccessful.10 Considering
that our one-pot metallation strategy to pyrazoles involved initial
B
B
Cl
1eq. Cu(OAc)2H2O
2eq. pyridine
N
N
N
3mL CH2Cl2
air, rm. temp. 4days
N
N
HN
N
N
O
1
not observed
Cl
O
HO
OH
BocHN
Boc
Cl
N
NBoc
N
N
4N HCl
5% Cu(OAc)2H2O
N
N
dioxane
80ºC 10min
Solvent
N
N
N
Boc
65ºC, 1hr
N
N
1
3
Solvent = THF, 0% yield
not isolated
MeOH, 72% yield
HO
N
OH
N
NHBoc
NBoc
B
1eq. Cu(OAc)2H2O
2eq. pyridine
Boc
HN
NH
N
3mL CH2Cl2
air, rm. temp. 4days
Boc
N
3
not observed
Scheme 2. A one-pot copper-catalyzed 5-pyrazole-pyrimidine synthesis from 5-
pyrimidine boronic acid.
Table 1
One-pot copper-catalyzed N-functionalized pyrazole synthesis from boronic acidsa,22
R2
Boc
O
O
R1
R
5% Cu(OAc2)H2O
HO
B
R
N
N
R3
R1
R3
OH
N
HCl/dioxane
one-pot
N
Boc
R2
Entry
Boronic acid
Dicarbonyl
Productb (% yield)
O
O
Cl
Cl
Br
B(OH)2
B(OH)2
N
Br
O
1a
N
Cl
(53%)
O
O
O
O
N
1b
1cc
1d
N
Cl
(75%)
O
O
N
Cl
N
B(OH)2
NH2
O
H2N
Cl
O
(40%)
O
O
Cl
O
B(OH)2
N
MeO
N
MeO
Cl
(63%)
O
S
O
O
O
Cl
Cl
O
B(OH)2
O
S
1e
N
N
O
(78%)
O
Br
MeO
F3C
B(OH)2
MeO
N
1f
N
Br
F3C
(61%)
N
O
O
O
O
Cl
HO
B(OH)2
B(OH)2
HO
1g
N
Cl
(74%)
H2N
Cl
N
1h
1i
N
Cl
O
H2N
Me
(32%)
O
Cl
Me
O2N
N
B(OH)2
N
N
Cl
O2N
(45%)
O
O
N
Cl
Cl
B(OH)2
N
N
N
1j
N
(45%)

R. E. Beveridge et al. / Tetrahedron Letters 51 (2010) 5005–5008
5007
Table 1 (continued)
Entry
Boronic acid
Dicarbonyl
Productb (% yield)
O
O
Cl
B(OH)2
O
N
N
H
O
N
1k
1l
Cl
O
N
H
O
(78%)
Cl
B(OH)2
O
O
O
Ph
Br
N
N
N
N
Ph
Cl
(67%)
B(OH)2
O
N
N
N
Br
1m
N
(53%)
Br
Bn
Bn
O
O
B(OH)2
B(OH)2
N
N
Bn
Bn
N
1n
1o
1p
N
N
N
Br
(78%)
O
O
Cl
N
N
N
N
N
N
Cl
(60%)
N
Bn
O
O
B(OH)2
N
N
N
N
N
Cl
Bn
(65%)
N
Cl
O
O
O
B(OH)2
O
F
N
O
1qd
N
H
O
F
N
H
(72%)
O
O
Cl
NC
B(OH)2
NC
N
1r
N
Cl
(63%)
a
Boronic acid (0.75 mmol), DBAD (115 mg, 0.5 mmol) and Cu(OAc)2H2O (5.1 mg, 0.025 mmol) were combined in 3 mL MeOH and placed in a 65 °C heating block for 1 h.
Cooled to rt, added the dicarbonyl (0.75 mmol) and 2 mL 4 N HCl in dioxane, stirred at rt for 10 min then heated at 80 °C for 10 min.
b
Isolated yield.
MeOH removed before addition of 4 N HCl in dioxane.
72% Combined yield of a 1.4:1 mixture of regio-isomers in favour of the one shown.
c
d
formation of an intermediate hydrazide species, we re-focused our
efforts towards the formation of the N,N-diBoc hydrazide species 3.
Recently, aryl-boronic acids have been reported to undergo effi-
cient copper-catalyzed coupling with di-tert-butylazodicarboxy-
late (DBAD) and related diazo-species generating a number of
new N,N-difunctionalized hydrazide derivatives.15,16 Subsequently,
we considered the potential that readily available pyrimidine 5-
boronic acid could be used in an analogous one-pot copper-cata-
lyzed DBAD coupling and condensation towards pyrazoles of type
1.
While copper-catalyzed boronic acid and diazo-dicarboxylate
coupling has been reported to occur using both MeOH15a and
THF15b as solvent, we did not observe the formation of the hydra-
zide intermediate 3 in THF (Scheme 2). However, we were
pleased to observe efficient Cu(OAc)2-catalyzed coupling of this
substrate with DBAD in MeOH under the literature conditions re-
sulted in the rapid in situ conversion to the desired N,N-di-boced
intermediate 3 (vide infra). Direct treatment of 3 with the 1,3-
dicarbonyl compound and HCl in dioxane produced the desired
pyrimidine-5-pyrazole 1 in good isolated yield in one-pot without
pre-isolation of the intermediate hydrazide or hydrazine
(Scheme 2).17 It is interesting to note that copper-mediated
Chan-Lam-type conditions of this boronic acid with di-tert-butyl
hydrazido-formate failed to provide the requisite hydrazide inter-
mediate precursor 3.
With this result in hand, we sought to explore this method to-
wards the development of a general one-pot method to construct
a variety of N-functionalized pyrazoles from readily available boro-
nic acid precursors. Potentially, the commercial availability of a
range of boronic acids and their ready synthetic access via mild
and functional group tolerant methods18–21 make these attractive
precursors to pyrazoles. As shown in Table 1, a variety of commer-
cially available aryl- and heteroaryl-boronic acid substrates were
converted in a simple one-pot protocol in the presence of 5 mol %
Cu(OAc)2 to a variety of new N-functionalized pyrazoles.22
The mild reaction conditions shown here demonstrate an
improvement in scope over our initially developed aryl metallation
strategy. For example, boronic acids containing sensitive bromo-,
carbonyl, nitrile, amide, nitro, sulfone, amino and hydroxylfunc-
tionalities were all found to generate pyrazole products in good
yield. In addition, a variety of heterocyclic boronic acids were
found to be compatible including pyrazole, quinoline and sensitive
structures such as 2-Cl-pyridine and pyrimidine. Importantly, this
reaction can generate species with reactive pyrazole-ring halogen
substitutions; a non-trivial transformation via traditional C–N cou-
pling methods, and allows for further modification of these cores

5008
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Chem. 2008, 19, 208–241; (c) Withbroe, G. J.; Singer, R. A.; Sieser, J. E. Org.
OH
O
HO
O
B
S
Process Res. Dev. 2008, 12, 480–489; review on cross-coupling with azoles
containing two or more hetero-atoms: (d) Schnurch, M.; Flasik, R.; Khan, A. F.;
Spina, M.; Mihovilovic, M. D.; Stanetty, P. Eur. J. Org. Chem. 2006, 15, 3283–
3307.
O
O
Boc
N
N
F3C
Boc
7. Pd-cat. pyrazole coupling: Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman, R.
A.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 6523–6527.
NH2
5% Cu(OAc)2
one-pot
8. Cu-cat. pyrazole coupling: (a) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald,
S. L. J. Org. Chem. 2004, 69, 5578–5587; (b) Antilla, J. C.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 11684–11688; (c) Cristau, H.-J.; Cellier, P. P.;
Spindler, J.-F.; Taillefer, M. Eur. J. Org. Chem. 2004, 695–709; (d) Cristau, H.-J.;
Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607–5622; (e)
Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7727–7729; (f) Zhu, L.; Guo, P.; Li, G.; Lan, J.; Xie, R.; You, J. J. Org. Chem. 2007,
72, 8535–8538; (g) Zhu, L.; Li, G.; Luo, L.; Guo, P.; Lan, J.; You, J. J. Org. Chem.
2009, 74, 2200–2202; (h) Zhu, D.; Wang, R.; Mao, J.; Xu, L.; Wu, F.; Wan, B. J.
Mol. Catal. A: Chem. 2006, 256–260.
9. Iron-cat. pyrazole coupling: (a) Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2007,
46, 8862–8865; (b) Guo, D.; Huang, H.; Xu, J.; Jiang, H.; Liu, H. Org. Lett. 2008,
10, 4513–4516; (c) Correa, A.; Elmore, S.; Bolm, C. Chem. Eur. J. 2008, 14, 3527–
3529; (d) Correa, A.; Bolm, C. Adv. Synth. Catal. 2008, 350, 391–394; (e) Taillefer,
M.; Xia, N.; Ouali, A. Angew. Chem., Int. Ed. 2007, 46, 934–936; (f) Lee, H. W.;
Chan, A. S. C.; Kwong, F. Y. Tetrahedron Lett. 2009, 50, 5868–5871.
10. Oxidative Cu-mediated/catalyzed 1H-pyrazole coupling with boronic acids: (a)
Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998,
39, 2933–2936; (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M.
P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941–2944; (c)
Deagostino, A.; Prandi, C.; Zavattaro, C.; Venturello, P. Eur. J. Org. Chem. 2007, 8,
1318–1323; (d) Tanitame, A.; Oyamada, Y.; Ofuji, K.; Fujimoto, M.; Iwai, N.;
Hiyama, K. S.; Ito, H.; Terauchi, H.; Kawasaki, M.; Nagai, K.; Wachi, M.;
Yamagishi, J. J. Med. Chem. 2004, 47, 3693–3696.
F3C
N
N
CF3
O
N
N
O
S
S
H2N
O
O
H2N
4
35% Yield (4+ 5)
2:1 ratio (4:5)
5
Celecoxib
(Celebrex)TM
Scheme 3. Celecoxib synthesis via copper-catalyzed one-pot pyrazole formation.
towards more complex products. It is particularly interesting to
note the compatibility of boronic acids containing hydroxyl, amino,
amide and carbamate functionalities since these groups can be
reactive towards C–N (or C–O) bond formation with boronic acids
in the presence of copper salts.10
As an example of the potential utility of this pyrazole N-func-
tionalization strategy, we considered whether the pyrazole-con-
taining drug Celecoxib (Celebrex)™ could be prepared under our
one-pot conditions. We were pleased to find that commercially
available 4-sulfonamide-phenyl boronic acid, in the presence of
5 mol % Cu(OAc)2H2O, underwent a clean DBAD coupling and cycli-
zation providing a 35% isolated yield of a 2:1 mixture of regio-iso-
mers in favour of the desired Celecoxib pyrazole material 4
(Scheme 3).
11. A recent review: Begtrup, M.; Rasmussen, L. K. Sci. Synth. 2007, 31b, 1773–
1826.
12. Gerstenberger, B. S.; Rauckhorst, M. R.; Starr, J. T. Org. Lett. 2009, 11, 2097–
2100.
13. Demers, J. P.; Klaubert, D. H. Tetrahedron Lett. 1987, 28, 4933–4934.
14. Prepared according to: Zhao, Z.-G.; Wang, Z.-X. Synth. Commun. 2007, 37, 137–
147.
15. (a) Kisseljova, K.; Tšubrik, O.; Sillard, R.; Mäeorg, S.; Mäeorg, U. Org. Lett. 2006,
8, 43–45; (b) Uemura, T.; Chatami, N. J. Org. Chem. 2005, 70, 8631–8634.
16. A copper-catalyzed addition of aryl-bismuth reagents to diazo-dicarboxylates:
Tšubrik, O.; Kisseljova, K.; Mäeorg, U. Synlett 2006, 2391–2394.
In summary, we have shown that a variety of N-functionalized
pyrazoles can be prepared in a simple one-pot copper-catalyzed
procedure from readily available boronic acids. The reaction is tol-
erant to a variety of common functional groups, does not require
pre-isolation of the hydrazine and provides ready access to struc-
tures containing useful pyrazole-ring halogen substitutions.
17. One example of using copper-catalyzed boronic acid addition to DBAD in a
multi-step fashion to form pyrazoles has been reported: Allan, M.; Manku, S.;
Therrien, E.; Nguyen, N.; Styhler, S.; Robert, M.-F.; Goulet, A.-C.; Petschner, A. J.;
Rahil, G.; MacLeod, A. R.; Deziel, R.; Besterman, J. M.; Nguyen, H.; Wahhab, A.
Bioorg. Med. Chem. Lett. 2009, 19, 1218–1223.
18. Boronic acids from pinacol boronates: (a) Yuen, A. K. L.; Hutton, C. A.
Tetrahedron Lett. 2005, 46, 7899–7903; (b) Pennington, T. E.; Kardiman, C.;
Hutton, C. A. Tetrahedron Lett. 2004, 45, 6657–6660; (c) Nakamura, H.;
Fujiwara, M.; Yamamoto, Y. J. Org. Chem. 1998, 63, 7529–7530; (d) Song, Y.-
L.; Morin, C. Synlett 2001, 266–268; (e) Tzschucke, C. C.; Murphy, J. M.;
Hartwig, J. F. Org. Lett. 2007, 9, 761–764; (f) Murphy, J. M.; Tzschucke, C. C.;
Hartwig, J. F. Org. Lett. 2007, 9, 757–760.
19. Recent examples of boronic ester synthesis via hydroboration: (a) Noh, D.;
Chea, H.; Ju, J.; Yun, J. Angew. Chem., Int. Ed. 2009, 48, 6062–6064; (b)
PraveenGanesh, N.; d’Hondt, S.; Chavant, P. Y. J. Org. Chem. 2007, 72, 4510–
4514; (c) Wang, Y. D.; Kimball, G.; Prashad, A. S.; Wang, Y. Tetrahedron Lett.
2005, 46, 8777–8780.
Acknowledgements
We thank Justin Stroh for HRMS support, Andrew Butler for
NMR support and Guoqiang Wang for helpful discussions.
Supplementary data
20. Typical procedure for Pd-catalyzed synthesis of aryl pinacol boronates from
aryl halides: Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508–
7510.
21. Direct Ir-catalyzed pinacol-borylation of arenes: (a) Ishiyama, T.; Nobuta, Y.;
Hartwig, J. F.; Miyaura, N. Chem. Commun. 2003, 2924–2925; (b) Ishiyama, T.;
Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc.
2002, 124, 390–391; (c) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura,
N. Tetrahedron Lett. 2002, 43, 5649–5651.
22. General procedure for copper-catalyzed pyrazole formation from boronic acids:
4-Bromophenylboronic acid (150 mg, 0.75 mmol, 1.5 equiv), di-tert-butyla-
zodicarboxylate ‘DBAD’ (115 mg, 0.5 mmol, 1.0 equiv) and Cu(II)OAc-H2O
(5.1 mg, 0.025 mmol, 0.05 equiv) were combined in MeOH (3 mL) in a 20-mL
scintillation vial and heated for 1 h at 65 °C. The mixture was then cooled to
room temperature and 2-chloro-malonaldehyde (80 mg, 0.75 mmol, 1.5 equiv)
was added followed by the addition of 4 N HCl in dioxane (2 mL) and the
reaction mixture was stirred for 10 min at room temperature and then heated
for 10 min at 80 °C. The mixture was cooled to room temperature and volatiles
were removed in vacuo to give a crude oil. To the crude oil was added water
(15 mL) followed by dropwise addition of satd aq NaHCO3 until pH ꢀ7.
Organics were extracted with ethyl acetate (100 mL), dried over MgSO4,
filtered and concentrated in vacuo. The crude residue was purified by flash
chromatography through silica gel using ethyl acetate in heptanes to
elute providing 1-(4-bromophenyl)-4-chloro-1H-pyrazole (Table 1, entry 1a)
(68 mg, 53%) as a yellow solid. 1H NMR (400 MHz, CDCl3) d = 7.47–7.51 (m,
2H), 7.53–7.57 (m, 2H), 7.62 (s, 1H), 7.85 (s, 1H). 13C NMR (101 MHz, CDCl3)
d = 113.1, 120.5, 120.5, 124.9, 132.8, 138.9, 140.0. HRMS (M+H) for C9H6BrClN2,
calcd: 256.9475, found: 256.9479.
Supplementary data (experimental procedures, and 1H and 13C
NMR data and spectra for all new compounds) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.07.077.
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