Conjugate base catalysed one-pot synthesis of pyrazoles from β-formyl enamides

Article abstract of DOI:10.1016/j.tetlet.2005.10.145

A novel one-pot synthesis of pyrazoles has been accomplished by the reaction of β-formyl enamides with hydroxylamine hydrochloride catalysed by potassium dihydrogenphosphate in acid medium.

Full text of DOI:10.1016/j.tetlet.2005.10.145

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 43–46
Conjugate base catalysed one-pot synthesis of pyrazoles
from b-formyl enamides
Anil Saikia, Madan G. Barthakur, Moyurima Borthakur, Chandan J. Saikia,
Utpal Bora and Romesh C. Boruah*
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat 785006, India
Received 25 August 2005; revised 14 October 2005; accepted 25 October 2005
Available online 14 November 2005
Abstract—A novel one-pot synthesis of pyrazoles has been accomplished by the reaction of b-formyl enamides with hydroxylamine
hydrochloride catalysed by potassium dihydrogenphosphate in acid medium.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The synthesis of pyrazoles has received considerable
attention because of their applications in pharmaceuti-
cal and agrochemical industries being due to their anti-
pyretic, anti-inflammatory, herbicidal, insecticidal and
fungicidal properties.1 More recently, extensive studies
have focused on aryl pyrazoles for exhibiting cyclooxy-
genase-2 (COX-2) and non-nucleoside HIV-1 reverse
transcriptase inhibitory properties.2,3 Among several
methods available for the preparation of pyrazoles, the
condensation of hydrazine with 1,3-dicarbonyl com-
pounds4 and the nitrene insertion reaction5 are widely
employed strategies. However, the generality of these
reactions is vitiated by the severe reaction conditions
or multi-step sequences usually required to access the
starting materials.6 As a result, efforts have been and
are still being made to find and develop more general
and versatile synthetic methodologies for pyrazoles.7
The biological activities of heterosteroids8,9 make
them important targets for synthetic chemists. Research
efforts in our laboratory towards the synthesis of newer
heterosteroids afforded b-formyl enamides as organic
synthons.10 In continuation of our interest in the use
of b-formyl enamides in organic synthesis, we report
herein a novel, simple and high yielding one-pot synthe-
sis of pyrazoles from the reaction of b-formyl enamides
with hydroxylamine hydrochloride catalysed by potas-
sium dihydrogenphosphate in acid medium.
In a typical reaction, 3b-acetoxy-17-acetamido-16-form-
yl-androst-5,16-diene 1a11 and hydroxylamine hydro-
chloride were mixed with potassium dihydrogen-
phosphate in ethanol and the mixture stirred at room
temperature for 1 h. Work-up of the reaction did not
yield the expected aldoxime 2a, rather it afforded
a cyclised pyrazolo-androsteroid 3a in 94% yield
(Scheme 1). The product was characterised by spectral
and analytical analysis.12 The 1H NMR spectrum of
3a exhibited a characteristic singlet proton signal at
R2
R2
R1
R2
CH=NOH
CHO
NH2OH.HCl
KH2PO4
R1
N
N
NHAc
2a-k
R1
1a-k
NHAc
Ac
3a-k
Scheme 1.
Keywords: b-Formyl enamide; Conjugate base; Hydroxylamine hydrochloride; Pyrazole.
*
Corresponding author. Tel.: +91 376 2370327; fax: +91 376 2370011; e-mail: rc_boruah@yahoo.co.in
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.145

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
44
A. Saikia et al. / Tetrahedron Letters 47 (2006) 43–46
d = 8.38 for the aromatic pyrazole proton. The ESI
mass spectra showed a molecular ion peak at m/z 419
(M++Na). Examination of Table 1 shows that the reac-
tion occurred in good yields in all cases examined,
varying from 79–94% and affording pyrazoles as sole
products. It is noteworthy that steroidal, alicyclic, ali-
phatic and aromatic b-formyl enamides 1b–i all gave rise
to the corresponding pyrazoles 3b–i in high yields (Table
1).
afforded the corresponding aldoxime 2a without forma-
tion of pyrazole 3a.13
A KH2PO4-mediated treatment of aldoxime 2a was con-
ducted successively in acidic, neutral and basic condi-
tions. It was observed that in acidic medium (pH 6),
the cyclised product 3a was obtained in excellent yield
(92%), whereas, reaction attempted at pH 7 or pH 8
failed to afford 3a.
The reaction of b-formyl enamide 1a with hydroxyl-
amine hydrochloride was similarly catalysed by dipotas-
sium hydrogenphosphate or sodium acetate to afford 3a
in excellent yield. However, replacement of KH2PO4
with pyridine or sodium methoxide led to the corre-
sponding aldoxime 2a, exclusively, without formation
of 3a. The use of pyrrolidine or morpholine gave 3a as
a minor product. On the other hand, the reaction of
1a with hydroxylamine hydrochloride without base led
to a mixture of products 2a and 3a. However, when
the oximation of b-formyl enamide 1a was carried with
a 50% aqueous solution of hydroxylamine or a mixture
of equimolar equivalents of NH2OHÁHCl–Et3N, it
A possible mechanism for pyrazole formation is shown
in Scheme 2. Under acidic conditions, aldoxime 2a
undergoes protonation to form intermediate A, abstrac-
tion of the amide NH proton being facilitated by the
conjugate base H2POÀ. Intramolecular attack of the
4
nucleophilic nitrogen onto the electron-deficient imine
nitrogen followed by loss of water led to cyclised prod-
uct 3a. The failure of aldoxime 2a to react with potas-
sium dihydrogenphosphate under neutral conditions
supports the requirement for acid mediation.
In conclusion, we have developed an efficient synthesis
of pyrazoles from b-formyl enamides employing a con-
Table 1. Reaction of b-formyl enamides with hydroxylamine hydrochloridea
Entry
b-Formyl enamide
Time (h)
Product
Yieldb
94
Ac
NHAc
CHO
l
1a, R = Ac
1b, R = Bz
2
3a
3b
N
N
2
3
2
2
86
RO
RO
OHC
N
N
1c
3c
85
AcNH
Ac
4
5
6
1d
1e
1f
2
2
3
3d
3e
3f
84
87
81
Ac
Ac
AcNH
N
N
CHO
NHAc
CHO
N N
Ac
NHAc
CHO
N
N
Ph
NHAc
CHO
Ac
Ph
N
N
7
1g
2
3g
93
H
Ac
NHAc
CHO
N N
X
8
9
1h, X = H
1i, X = Cl
2
2
3h
3i
79
82
X
a Reactions were carried using potassium dihydrogenphosphate as catalyst.
b Isolated yields.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
A. Saikia et al. / Tetrahedron Letters 47 (2006) 43–46
45
R2
R1
R2
R1
7. (a) Majid, T.; Hopkins, C. R.; Pedgrift, B.; Collar, N.
Tetrahedron Lett. 2004, 45, 2137–2139; (b) Yadav, J. S.;
Reddy, B. V. S.; Satheesh, G.; Lakshmi, P. N.; Kumar, S.
K.; Kunwar, A. C. Tetrahedron Lett. 2004, 45, 8587–8590;
(c) Kim, M.; Wiemer, D. F. Tetrahedron Lett. 2004, 45,
4977–4980; (d) Hanamoto, T.; Hakoshima, Y.; Egashira,
M. Tetrahedron Lett. 2004, 45, 7573–7576; (e) Singh, S.
K.; Reddy, M. S.; Shivaramakrishna, S.; Kavitha, D.;
Vasudev, R.; Babu, J. M.; Sivalakshmidevi, A.; Rao, Y.
K. Tetrahedron Lett. 2004, 45, 7679–7682; (f) Ahmed, S.;
Longchar, M.; Boruah, R. C. Ind. J. Chem. 1999, 38B,
125–127.
8. (a) Hong, C. I. In Antitumor Steroids; Blickenstaff, R. T.,
Ed.; Academic Press: New York, 1992; pp 1–142; (b)
Potter, G. A.; Barrie, S. E.; Jarman, M.; Rowland, M. G.
J. Med. Chem. 1995, 38, 2463–2471; (c) Jarman, M.;
Barrie, S. E.; Llera, J. M. J. Med. Chem. 1998, 41, 5375–
5381; (d) Pettit, G. R.; Inoue, M.; Kamano, Y.; Herald, D.
L.; Arm, C.; Dufresne, C.; Christie, N. D.; Schmidt, J. M.;
Doubek, D. L.; Krupa, T. S. J. Am. Chem. Soc. 1988, 110,
2006–2007.
9. (a) Njar, V. C. O.; Klus, G. T.; Brodie, A. M. H. Bioorg.
Med. Chem. Lett. 1996, 6, 2777–2782; (b) Li, J.; Li, Y.;
Son, C.; Brodie, A. M. H. J. Med. Chem. 1996, 39, 4335–
4339; (c) Ling, Y.; Li, J.; Liu, Y.; Kato, K.; Klus, G. T.;
Brodie, A. J. Med. Chem. 1997, 40, 3297–3304.
10. (a) Boruah, R. C.; Ahmed, S.; Sharma, U.; Sandhu, J. S. J.
Org. Chem. 2000, 65, 922–925; (b) Sharma, U.; Ahmed, S.;
Boruah, R. C. Tetrahedron Lett. 2000, 41, 3493–3495; (c)
Ahmed, S.; Boruah, R. C. Tetrahedron Lett. 1996, 37,
8231–8232; (d) Chetia, A.; Longchar, M.; Lekhok, K. C.;
Boruah, R. C. Synlett 2004, 1309–1311.
CH=NOH
NHAc
CHO
NH2OH.HCl
NHAc
2a
1a
_
H2PO4
R2
R2
R1
CH
N
+
O
H
H
R1
N
N
N
Ac
_
H
Ac
H2PO4
3a
A
Scheme 2.
jugate base catalysed intramolecular cyclisation reaction
in acidic medium. We have demonstrated that the
incorporation of an acetamido group adjacent to an
aldoxime moiety facilitated the cyclisation to afford
the pyrazole in a one-pot reaction. The methodology
reported herein represents a new preparation of pyra-
zoles and is expected to be a general route for one-pot
combinatorial synthesis of a wide range of annelated
pyrazoles.
Acknowledgements
11. Steroidal D-ring and cyclic b-formyl enamides were
prepared by Vilsmeier reaction of the corresponding
conjugated oximes following a reported procedure: Bor-
uah, R. C.; Ahmed, S.; Sharma, U.; Sandhu, J. S. Ind. J.
Chem. 1999, 38B, 274–282; Steroidal A-ring and acyclic
b-formyl enamides were prepared by Vilsmeier reactions
of the corresponding enamides in turn accessible from 3-
ketocholestanone and acetophenone, respectively, fol-
lowing a reported procedure: Boar, R. B.; McGhie, J. F.;
Robinson, M.; Barton, D. H. R.; Horwell, D. C.; Stick,
R. V. J. Chem. Soc., Perkin Trans. 1 1975, 1237–1241.
12. Illustrative experimental procedure. Pyrazolo-androster-
oid 3a: To a solution of 3b-acetoxy-17-acetamido-16-
formyl-androst-5,16-diene (1a, 0.327 g, 0.82 mmol) in
ethanol (40 ml) was added hydroxylamine hydrochloride
(0.112 g, 1.62 mmol) and potassium dihydrogenphosphate
(0.220 g, 1.62 mmol) and the reaction mixture was stirred
at room temperature for 2 h. The solvent was removed
under reduced pressure and the residue was poured into
ice-cold water (50 ml), neutralised with aqueous NaHCO3
solution, extracted with dichloromethane (2 · 25 ml), the
extract washed with water and dried over anhydrous
sodium sulfate. Removal of the solvent and column
chromatography of the residue over silica gel using ethyl
acetate/hexane (8/2) as eluant afforded pyrazolo-andros-
teroid 3a, yield 0.305 g (94%), mp 206–207 ꢁC; IR (CHCl3)
We are grateful to the Department of Science and Tech-
nology, New Delhi for financial support and the Direc-
tor, R. R. L. Jorhat for his keen interest in this work.
References and notes
1. (a) Elguero, J. In Comprehensive Heterocyclic Chemistry;
Katritzky, A., Ed.; Pergamon Press: Oxford, 1984; Vol. 5,
pp 291–298; (b) Elguero, J. In Comprehensive Heterocyclic
Chemistry; Katritzky, A., Rees, C. W., Scriven, E. F. V.,
Eds.; Elsevier Science Ltd.: Oxford, 1996; Vol. 3, pp 1–75.
2. (a) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter,
J. S.; Collins, P. W.; Docter, 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, 1347–1365; (b) Hashimoto, H.;
Imamura, K.; Haruta, J.; Wakitani, K. J. Med. Chem.
2002, 45, 1511–1517; (c) Habeeb, A. G.; Rao, P. N. P.;
Knaus, E. E. J. Med. Chem. 2001, 44, 3039–3042; (d)
Price, M. L. P.; Jorgensen, W. L. J. Am. Chem. Soc. 2000,
122, 9455–9466.
3. Genin, M. J.; Biles, C.; Keiser, B. J.; Poppe, S. M.;
Swaney, S. M.; Tarpley, W. G.; Yagi, Y.; Romero, D. L.
J. Med. Chem. 2000, 43, 1034–1040.
4. Kost, A. N.; Grandberg, I. I. Adv. Heterocycl. Chem.
1966, 6, 347–429.
5. Moody, C. J. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 7, pp 21–28.
6. (a) Almirante, N.; Cerri, A.; Fedrizzi, G.; Marazzi, G.;
Santagostino, M. Tetrahedron Lett. 1998, 39, 3287–3290;
(b) Luca, L. D.; Giacomelli, G.; Masala, S.; Porcheddu, A.
Synlett 2004, 2299–2302.
1
m 1734 cmÀ1; H NMR (300 MHz, CDCl3) d 8.38 (1H, s),
5.42 (1H, br s), 4.61 (1H, m), 2.71 (3H, s), 2.04 (3H, s),
1.10 (3H, s), 1.00 (3H, s), 2.92–1.02 (17H, m); 13C NMR
(CDCl3) d 170.96, 170.40, 158.15, 141.91, 140.58, 133.65,
121.96, 74.05, 56.27, 50.56, 45.73, 38.44, 37.20, 33.17,
31.50, 31.11, 30.07, 28.56, 28.04, 21.81, 20.74, 20.32, 19.70,
17.26; Mass spectra: m/z 419 (M++Na), 397 (M++1);
Anal Calcd for C24H32N2O3: C, 72.70; H, 8.13; N, 7.06%.
Found: C, 72.60; H, 8.28; N, 6.96%.
13. 3b-Acetoxy-17-acetamido-androst-5,16-dieno-16-aldoxime
2a, mp 167–169 ꢁC; IR (CHCl3) m 3405, 2940, 1730,

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
46
A. Saikia et al. / Tetrahedron Letters 47 (2006) 43–46
1625 cmÀ1; 1H NMR (300 MHz, CDCl3) d 7.80 (1H, s), 7.48
34.08, 31.90, 31.37, 31.22, 28.97, 27.67, 21.76, 20.21, 20.13,
19.55, 17.86; Mass spectra: m/z 413 (M+À1), 395
[(M+À1)À18], 353, 335, 293; Anal. Calcd for
C24H34N2O4: C, 69.54; H, 8.27; N, 6.76%. Found: C,
69.85; H, 8.12; N, 6.96%.
(1H, br s), 5.35 (1H, br s), 4.60 (1H, m), 2.15 (3H, s), 2.06
(3H, s), 1.12 (3H, s), 1.04 (3H, s), 2.75–0.95 (17H, m); 13
C
NMR (CDCl3) d 172.45, 171.90, 153.53, 144.82, 141.35,
136.55, 120.43, 75.10, 57.20, 50.88, 44.32, 39.74, 38.52,