Facile microwave assisted decarbonylation of 4-formyl group in 5-alkyl amino substituted pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2008.02.020

Facile decarbonylation of the 4-formyl group in 5-alkyl amino pyrazoles was seen when reacted with catalytic p-toluene sulfonic acid in methanol under microwave irradiation to provide parent 4-H pyrazoles in good yields.

Full text of DOI:10.1016/j.tetlet.2008.02.020

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2280–2282
Facile microwave assisted decarbonylation of 4-formyl
group in 5-alkyl amino substituted pyrazoles
a,
a
a
b,
*
Subas M. Sakya , Barbara Abrams , Sheri L. Snow , Bryson Rast
a CNS Chemistry Department, Pfizer Global Research and Development, Pfizer Inc, Groton, CT 06340, United States
b Veterinary Medicine Research and Development, Pfizer Inc, Groton, CT 06340, United States
Received 1 October 2007; revised 4 February 2008; accepted 5 February 2008
Available online 9 February 2008
Abstract
Facile decarbonylation of the 4-formyl group in 5-alkyl amino pyrazoles was seen when reacted with catalytic p-toluene sulfonic acid
in methanol under microwave irradiation to provide parent 4-H pyrazoles in good yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Pyrazoles are an important class of compounds used in
Cl
the pharmaceutical and the agrochemical industry. Drug
discovery efforts have led to important pyrazole drugs,
such as COX-2 inhibitor celecoxib1 for treating inflamma-
tion and pain and cannabinoid receptor 1 (CB-1) antago-
nist rimonabant2 as an anti-obesity agent (Fig. 1). More
closely related 5-amino pyrazoles have also been shown
to have anti-tumour activity.3 Our own recent efforts in
the search for canine COX-2 selective agents resulted in a
potent and selective COX-2 lead (9) for canine and feline
use (Fig. 1).4 Towards that effort we developed a synthetic
route to prepare 5-alkyl amino and ether substituted pyr-
azoles using a mild reaction protocol utilizing parallel syn-
thesis to produce a large number of compounds.5,6
During the synthesis of 5-alkyl amino pyrazoles with
4-nitrile substitution, our attempts to convert the 4-formyl
group to an oxime with hydroxyl amine hydrochloride in
methanol resulted in a significant decarbonylation side
product 4-H pyrazole. Under the oxime forming reaction
conditions, we observed decarbonylation in up to 60%
yields.7 We surmised that the decarbonylation was due to
the acid present in the reaction condition since the decarb-
onylation of 4-formyl pyrazoles has been reported intermit-
SO2NH2
Cl
Cl
N
N
O
N
N
HN
N
F3C
Celecoxib
Rimonabant
SO2CH3
N
N
O
N
N
HF2C
9 Canine COX2 active Lead
CN
Fig. 1. Lead COX-2 inhibitors and synthetic targets.
tently in the literature under thermal and acidic
conditions.8 However, a majority of unsubstituted pyra-
zoles at the 4-position are generally accessed via decarbox-
ylation methodology.9 Thus, an alternate facile and mild
approach to decarbonylate the 4-formyl group of 5-amino
*
Corresponding author. Tel.: +1 860 715 0425; fax: + 1 860 715 7312.
E-mail address: subas.m.sakya@pfizer.com (S. M. Sakya).
Currently at Array Biophama.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.020

S. M. Sakya et al. / Tetrahedron Letters 49 (2008) 2280–2282
2281
Table 1
Amino pyrazoles 6
pyrazoles under microwave condition would present a use-
ful alternative.
In our studies, the substitution of the 5-chloro-4-formyl
pyrazoles, easily obtained in multigram-scale quantities,
provides an ideal way to make 5-amino or ether substituted
pyrazoles. The formyl group is generally inert to reaction
with both primary and secondary amines and alcohols.
With easy access to 5-amino-4-formyl pyrazole precursors,
this decarbonylation procedure provides access to 5-alkyl-
amino 4-H (unsubstituted) pyrazole analogs which, based
on our own experience,10 are fairly difficult to access.
The desired 5-amino 4-formyl pyrazoles 3 were synthe-
sized as shown in Scheme 1 according to our recently
reported procedures (See Scheme 2).4
R
N
NR3R4
N
R1
R2
Entry
3a, 6a
3b, 6b
NR3R4
R
R1
Yield (%)
Yielda (%)
(R2 = CHO) (R2 = H)
Pyridyl sulfone CF3 NDb
Pyridyl sulfone CF3 NDb
85.9
99.3
N
NH
The substitution of the chloropyrazoles with amines
with either N-heteroaryl sulfone, N-aryl sulfone or N-alkyl
groups works quite well (Table 1). The amino substitution
yield is low only in the case of cyclobutyl amine substitu-
tion of 3n for reasons that are not quite clear.
3c, 6c
3d, 6d
Pyridyl sulfone CF3 66.4
Pyridyl sulfone CF3 NDb
66
NH
78.4
N
Initial studies to decarbonylate the 4-formyl group in 3g
were performed under various acidic conditions. Use of
1 M HCl in dioxane and catalytic p-toluene sulfonic acid
in refluxing toluene overnight gave the decarbonylated
product 6g in 45% and 89% yields, respectively.10 However,
the use of p-TsOHÁH2O in MeOH under microwave irradi-
ation provided the 4-H pyrazoles 6g in good yields (76%)
and in much shorter time (120 °C, 20 min). Expanding this
protocol to other amines demonstrated that the pyrazoles
undergo decarbonylation with good yields (Table 1).
NH
3e, 6e
3f, 6f
Pyridyl sulfone CF3 70.9
Phenyl sulfone CF3 81
82.2
83
N
3g, 6g
3h, 6h
3i, 6i
Phenyl sulfone CF3 54
Phenyl sulfone CF3 70.4
Phenyl sulfone CF3 70
76.2
75.8
69.3
NH
NH
SO2CH3
SO2CH3
NH
O
O
a
SO2CH3
F3C
c
OEt
X
N
X
N
X
3j, 6j
Phenyl sulfone CF3 76.9
82.5
47
N
b
N
N
N
NR3R4
CHO
Cl
NHNH2
F3C
CHO
F3C
3k, 6k
Methyl
CH3 78
2
1
3
N
X = CH, N
3l, 6l
Phenyl
Phenyl
Phenyl
CH3 84
CH3 NDb
CH3 13
60
50
80
Scheme 1. Reagents and conditions: (a) EtOH, reflux, ꢀ16 h; 2 equiv
NaOH, EtOH, 30 min, >80%; (b) POCl3, 4 equiv DMF, 80 °C, 4 h, 60–
80%; (c) CsF, R3R4NH, DMSO, rt or 80 °C.
NH
3m, 6m
NH
3n, 6n
R
N
R
N
a
NR3R4
CHO
NR3R4
N
a
N
Isolated yields.
b
The aldehyde substrate obtained from Pfizer sample bank.
R1
R1
H
5
6
Besides the N-heteroaryl sulfone, others such as the N-
phenyl sulfone (6f–i), N-phenyl (6l–n) and N-Me (6k)
groups are also tolerated. Having both N-Me and 3-methyl
substitution (6k) did however result in lower decarbonyl-
ation yield (47%).
R = pyridyl sulfone, phenylsulfone, Me
R1 = CF3, Me
Scheme 2. Reagents and conditions: (a) p-TsOHÁH2O, MeOH, MW,
120 °C, 20 min.

2282
S. M. Sakya et al. / Tetrahedron Letters 49 (2008) 2280–2282
Ph
N
Ph
O
O
N
O
N
O
N
p-TsOH.H2O
MeOH, MW
N
N
CHO
145 ºC
N
N
7
8
Scheme 3. Reagents and conditions: p-TsOHÁH2O, MeOH, MW, 145 °C, 45 min.
Ferrara, P.; Soubrie, P.; Breliere, J. C.; Le Fur, G. FEBS Lett. 1994,
350, 240.
3. Park, H.-J.; Lee, K.; Park, S.-J.; Ahn, B.; Lee, J.-C.; Cho, H. Y.; Lee,
K.-I. Bioorg. Med. Chem. Lett. 2005, 15, 3307.
4. Sakya, S. M.; Demello, K. M. L.; Minich, M. L.; Rast, B.; Shavnya,
A.; Rafka, R. J.; Koss, D. A.; Cheng, H.; Li, J.; Jaynes, B. H.; Ziegler,
C. B.; Mann, D. W.; Petras, C. F.; Seibel, S. B.; Silvia, A. M.; George,
D. M.; Lund, L. A.; St. Denis, S.; Haven, M. L.; Lynch, M. P. Bioorg.
Med. Chem. Lett. 2006, 16, 288.
5. Sakya, S. M.; Rast, B. Tetrahedron Lett. 2003, 44, 7629.
6. Shavnya, A.; Sakya, S. M.; Minich, M. L.; DeMello, K. L.; Jaynes, B.
H. Tetrahedron Lett. 2005, 46, 6887.
7. Sakya, S. M.; Hou, X.; Minich, M. L.; Rast, B.; Shavnya, A.;
Demello, K. M. L.; Cheng, H.; Li, J.; Jaynes, B. H.; Mann, D. W.;
Petras, C. F.; Seibel, S. B.; Haven, M. L. Bioorg. Med. Chem. Lett.
2007, 17, 1067.
8. (a) Ohsawa, A.; Wada, I.; Igeta, H. Chem. Pharm. Bull. 1986, 34,
1023; (b) Eltsov, O. S.; D’yachenko, E. V.; Glukhareva, T. V.;
Morzherin, Y. Y. Mendeleev Commun. 2005, 119; (c) El-Shekeil, A.;
Babaqi, A.; Hassan, M.; Shiba, S. Acta Chim. Hungarica 1989, 126,
813.
9. (a) Guerrini, G.; Costanzo, A.; Ciciani, G.; Bruni, F.; Selleri, S.;
Costagli, C.; Besnard, F.; Costa, B.; Martini, C.; De Siena, G.;
Malmberg-Aiello, P. Bioorg. Med. Chem. 2006, 14, 758; (b) Meegalla,
S. K.; Doller, D.; Sha, D.; Soll, R.; Wisnewski, N.; Silver, G. M.;
Dhanoa, D. Bioorg. Med. Chem. Lett. 2004, 14, 4949; (c) Bondavalli,
F.; Botta, M.; Bruno, O.; Ciacci, A.; Corelli, F.; Fossa, P.;
Lucacchini, A.; Manetti, F.; Martini, C.; Menozzi, G.; Mosti, L.;
Ranise, A.; Schenone, S.; Tafi, A.; Trincavelli, M. L. J. Med. Chem.
2002, 45, 4875; (d) Seneci, P.; Nicola, M.; Inglesi, M.; Vanotti, E.;
Resnati, G. Synth. Commun. 1999, 29, 311; (e) Frigola, J.; Colombo,
A.; Pares, J.; Martinez, L.; Sagarra, R.; Roser, R. Eur. J. Med. Chem.
1989, 24, 435.
In an unrelated project, we were required to make 5-
amino pyrazoles without substitution at the 4-position as
exemplified by compound 8. Thus the preparation of the
intermediate 7 using benzyl hydrazine and pyridyl keto-
ester gave 5-chloro-4-formyl pyrazole, which was substi-
tuted with 2-methoxyphenyl substituted morpholine in
80% yield. Subjecting pyrazole 7 to catalytic amount of
p-TsOHÁH2O at 120 °C for 20 min resulted in no reaction,
with only starting material recovered. However subjecting
the same reaction to 145 °C for 45 min in the microwave
showed almost complete reaction (Scheme 3). Additional
time under the microwave did not progress the reaction
any further. However adding an additional 1 equiv of
p-TsOHÁH2O and subjecting the resulting mixture to
145 °C for 45 min in the microwave resulted in complete
reaction, providing product (5c) in 80% isolated yield.11
In summary, we have developed a very efficient micro-
wave assisted decarbonylation of 4-formyl pyrazole to
provide the parent 4-H pyrazoles. This should be
complementary to the standard decarboxylation of acids
to make 5-amino substituted pyrazoles.
Acknowledgements
Our sincere thanks to Ms. Jiemin Lu for the synthesis of
compound 7 using our previously reported condition. Our
thanks also go to Dr. Christopher O’Donnell for his many
helpful suggestions to this article.
10. Unpublished results of initial efforts.
11. General sample decarbonylation procedure: A mixture of 3b (50.9 mg,
0.131 mmol) and p-TsOHÁH2O (0.2 equiv, 5.0 mg, 0.026 mmol) in
methanol (1 ml) was microwaved to 120 °C for 20 min. The reaction
mixture was concentrated and purified by preparative TLC (What-
man 1000 lm plate) with 20% EtOAc/hexane as eluant to give the
desired pyrazole 6d (46.9 mg, 99.3% yield) as white solid. 1H NMR
(400 MHz, CDCl3) d 8.93 (s, 1H), 8.28 (d, 1H, J = 8.7 Hz), 8.18 (d,
1H, J = 8.7 Hz), 7.94 (br s, 1H, NH), 5.56 (s, 1H, 4-H), 3.87 (p, 1H,
J = 7.9 Hz, NCH), 3.13 (s, 3H, CH3), 2.50 (m, 2H, CH2), 2.02 (m, 2H,
CH2), 1.84 (m, 2H, CH2); MS (m/z) 361.2 (M+H).
References and notes
1. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins,
P. W.; Doctor, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson,
G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;
Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.;
Isakson, P. C. J. Med. Chem. 1997, 40, 1347.
´
2. Rinaldi-Carmona, M.; Barth, F.; Heaulme, M.; Shire, D.; Calandra,
B.; Congy, C.; Martinez, S.; Maruani, J.; Neliat, G.; Caput, D.;