Hydrazine-mediated cyclization of Ugi products to synthesize novel 3-hydroxypyrazoles

Article abstract of DOI:10.1016/j.tetlet.2012.03.033

This report discloses a novel concise synthesis of a series of 3-hydroxypyrazoles 5 via a tandem Ugi/debenzylation /hydrazine-mediated cyclization sequence. Herein, n-butyl isocyanide 4b was utilized as an alternative to classical convertible isocyanides enabling high yielding hydrazine-mediated cyclization. Taken together, a novel class of 3-hydroxypyrazoles 5a-5i was synthesized with a potential to be of interest in future library enrichment strategies.

Full text of DOI:10.1016/j.tetlet.2012.03.033

Tetrahedron Letters 53 (2012) 2592–2594
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Hydrazine-mediated cyclization of Ugi products to synthesize novel
3-hydroxypyrazoles
Arthur Y. Shaw a, Jonathan A. McLaren a, Gary S. Nichol b, Christopher Hulme a,b,
⇑
a Department of Pharmacology and Toxicology, College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd., Oro Valley, AZ 85737, USA
b Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This report discloses a novel concise synthesis of a series of 3-hydroxypyrazoles 5 via a tandem
Ugi/debenzylation /hydrazine-mediated cyclization sequence. Herein, n-butyl isocyanide 4b was utilized
as an alternative to classical convertible isocyanides enabling high yielding hydrazine-mediated cycliza-
tion. Taken together, a novel class of 3-hydroxypyrazoles 5a–5i was synthesized with a potential to be of
interest in future library enrichment strategies.
Received 23 February 2012
Accepted 8 March 2012
Available online 24 March 2012
Keywords:
Multicomponent reaction
Ugi reaction
Ó 2012 Elsevier Ltd. All rights reserved.
3-Hydroxypyrazole
Hydrazine-mediated cyclization
In spite of scarcity in nature,1 the pyrazole scaffold has been
significantlystudied mainly due to the discoveryof interestingprop-
erties exhibited by a great number of its derivatives. Pyrazole, a five-
membered heterocycle containing two adjacent nitrogen atoms, is a
motif found in a number of small molecules that possess a broad
spectrum of pharmaceutical activities.2 Particularly noteworthy is
celecoxib, containing a 1-arylpyrazole motif which is a selective
cyclooxygenase-2 (COX-2) inhibitor for the treatment of a plethora
of indications that include osteoarthritis, rheumatoid arthritis, acute
pain, and others.3 As a consequence, a variety of methodologies to
develop pyrazole derivatives have been intensively explored in the
past decade.4
Multi-component reactions (MCRs) are powerful transforma-
tions in which three or more starting materials are incorporated
in a one-pot fashion to produce highly functionalized products.
Isocyanide-based multicomponent reactions (IMCRs) are of partic-
ular interest thanks in part to the large number of commercially
available starting materials and a wide range of readily accessible
pharmacologically relevant scaffolds.5 The most well-known IMCR,
the Ugi reaction, is carried out through the reaction of an amine,
carbonyl compound, carboxylic acid, and isocyanide, which under-
go a condensation step to afford the corresponding functionalized
a
-acylamino amide.6 The usefulness of such a process as a power-
ful diversity generating step has been demonstrated by numerous
MeO
OMe
NH2
R1
OH
+
Ar
1. Ugi Reaction
O
NH
N
1
O
2
2. Debenzylation
+
R1
N
H
O
OH
3. N2H4-mediated cyclization
CN R2
+
Ar
5
O
3
4
Scheme 1. Synthesis of 3-hydroxypyrazoles 5.
⇑
Corresponding author.
E-mail address: hulme@pharmacy.arizona.edu (C. Hulme).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.033

A. Y. Shaw et al. / Tetrahedron Letters 53 (2012) 2592–2594
2593
OMe
O
MeO
OMe
NH2
HO
+
Br
MeOH, rt
43%
NH
N
MeO
OMe
Br
O
NH
2a
1
+
N
N
N2H4 HCl/EtOH
10% TFA / DCE
82%
O
N
N
H
HN
OH
CN
µw, 120 °C, 20 min
O
O
OH
MeO
+
45%
O
O
O
6a
Br
7a
4a
Br
5a
3a
Scheme 2.
subsequently generate new molecular diversity.9 Herein we would
like to report a novel hydrazine-mediated cyclization of the Ugi
condensation product that affords unique 3-hydroxypyrazoles 5
via a tandem Ugi/debenzylation/hydrazine-mediated cyclization
sequence, Scheme 1.
Initial optimization studies focused on 4-tert-butyl cyclohexen-
1-yl isocyanide 4a, employed as a convertible isocyanide to
increase the acid catalyzed electrophilicity of the isocyanide
derived amide carbonyl which in turn was expected to promote
the key cyclization step.10 Thus Ugi product 6a was initially pre-
pared (MeOH, rt, 36 h, 43%) utilizing 2,4-dimethoxybenzenylamine
1,11 4-bromobenzoic acid 2a, phenylglyoxal 3a, and 4-tert-butyl
cyclohexen-1-yl isocyanide 4a, Scheme 2.
a
HO
N
O
NH
N
H
Br
5a
Subsequent treatment of 6a with hydrazine mono-hydrochlo-
ride in ethanol (accelerated via microwave irradiation) successfully
afforded the 3-hydroxypyrazole 7a in 45% isolated yield. At this
stage the unaccounted for mass balance seemed to be composed
of several unidentified side products. Removal of the 2,4-dime-
thoxybenzyl moiety from 7a was successfully carried out at 80 °C
for 10 min under microwave irradiation in 10% TFA/DCE solution
to afford the corresponding 3-hydroxypyrazole 5a (82% isolated
yield) which was characterized by X-ray crystallographic analysis,
Figure 1a. Interestingly, an intra-molecular hydrogen bond was
observed between the 3-hydroxyl group and the carboxamide
carbonyl of 5a, Figure 1b.
b
Not satisfied with the first two steps of the sequence (both
<50%), attempts to further optimize yields were undertaken
through replacement of 4a with n-butyl isocyanide 4b, and an
alteration in the order of the reaction sequence Scheme 3.12
Consequently, the Ugi product 6b was prepared in improved yields
(6a, 43%, 6b, 57%) and debenzylation was conducted prior to pyra-
Figure 1. (a) Crystal structure of 5a. (b) Depiction of intra-molecular H-bonds
between the pyrazole 3-hydroxyl group and amide carbonyl. In addition inter-
molecular bonds are seen between methanol and both the hydroxyl pyrazole (–OH)
and pyrazole nitrogen (N).
zole formation to afford the N-acyl-
a
-aminoketone 8, Scheme 3.
-aminoketone 8 was sub-
Without further purification, N-acyl-
a
jected to hydrazine-mediated cyclization conditions to give the
desired 3-hydroxypyrazole 5a with improved conversion (56% iso-
lated yield in two steps).13
With satisfactory conditions in place, a small array of 3-hydrox-
ypyrazoles was thus synthesized with diversity being generated
through the utilization of various carboxylic acids 2 and arylglyoxals
3 to establish the scope of the methodology. Indeed, the new tandem
Ugi/debenzylation/hydrazine-mediated cyclization sequence furnished
applications in the synthesis of potential drug-like libraries of
small molecules.5c,7 Indeed recently, we have successfully devel-
oped a concise synthesis of 2,4,5-trisubstituted oxazoles via a
tandem Ugi/Robinson-Gabriel sequence.8 Of particular relevance
to this Letter are the extensive studies performed by Krasavin
et al. who often employs hydrazines as the amine equivalent to
OMe
O
NH2
+
O
HO
O
H
N
O
NH
N
MeO
O
10% TFA / DCE
Br
N2H4 HCl/ EtOH
1
+
H
N
Br
MeOH, rt
57%
N
2a
HN
O
N
H
µw, 120 °C, 20 min
56% in two steps
O
Br
OH
O
+
O
CN
8
4b
O
OMe
MeO
5a
Br
6b
3a
Scheme 3.

2594
A. Y. Shaw et al. / Tetrahedron Letters 53 (2012) 2592–2594
O
N
H
N
H
H
N
H
N
N
N
N
N
N
HN
HN
OH
OH
HN
HN
OH
OH
O
O
O
O
N
HN
O
O2N
5b,54%,60%
5c, 45%, 47%
5d, 55%, 61%
5e, 51%, 54%
Cl
H
N
CF3
Cl
Br
N
O
O
H
N
H
N
H
N
HN
O
OH
N
N
N
HN
OH
HN
HN
Br
OH
OH
O
O
O
N
N
OCF3
5g, 57%, 58%
5f, 58%, 62%
5h, 44%, 38%
5i, 54%, 57%
Figure 2. Structures of 3-hydroxypyrazoles 5b–5i (Ugi% isolated yield, debenzylation/N2H4-mediated cyclization% isolated yield for two steps).
Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.;
Isakson, P. C. J. Med. Chem. 1997, 40, 1347.
4. Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes, S. Chem. Rev. 2011,
111, 6984.
Ugi products and 3-hydroxypyrazoles with yields ranging from 44%
to 58% and 38–62%, respectively, Figure 2.
In summary, a series of novel 3-hydroxypyrazoles 5a–5i were
synthesized in three steps employing a tandem Ugi/debenzylation/
hydrazine-mediated cyclization sequence and n-butyl isocyanide
4b was an effective replacement for 4-tert-butyl cyclohexen-1-yl
isocyanide 4a for the hydrazine-mediated cyclization step. The
novel class of 3-hydroxypyrazoles is fully expected to be of high
interest in medicinal chemistry groups, in particular those involved
in kinase inhibitor design.
5. (a)For relevant reviews see: Multicomponent Reactions; Zhu, J., Bienayme, H.,
Eds.; Wiley-VCH: Weinheim, 2005; (b) Hulme, C.; Gore, V. Curr. Med. Chem.
2003, 10, 51; (c) Dömling, A. Chem. Rev. 2006, 106, 17; (d) Hulme, C.; Nixey, T.
Curr. Opin. Drug Discovery Dev. 2003, 6, 921; (e) El Kaim, L.; Grimaud, L.
Tetrahedron 2009, 65, 2153; (f) Banfi, L.; Riva, R.; Basso, A. Synlett 2010, 23.
6. (a) Ugi, I. Angew. Chem. 1962, 74, 9; (b) Ugi, I.; Steinbrucker, C. Chem. Ber. 1961,
94, 734; (c) Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8; (d) Ugi, I.; Domling, A.;
Horl, W. Endeavor 1994, 18, 115.
7. Akritopoulou-Zanze, I. Curr. Opin. Chem. Biol. 2008, 12, 324.
8. Shaw, A. Y.; Xu, Z.; Hulme, C. Tetrahedron Lett. 2012, 53, 1998.
9. (a) Krasavin, M.; Bushkova, E.; Parchinsky, V.; Shumsky, A. Synthesis 2010, 6,
933; (b) Bushkova, E.; Parchinsky, V.; Krasavin, M. Mol. Diversity 2010, 41, 493.
10. Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574.
11. Sheehan, S. M.; Masters, J. J.; Wiley, M. R.; Young, S. C.; Liebeschuetz, J. W.;
Jones, S. D.; Murray, C. W.; Franciskovich, J. B.; Engel, D. B.; Weber, W. W.;
Marimuthu, J.; Kyle, J. A.; Smallwood, J. K.; Farmen, M. W.; Smith, G. F. Bioorg.
Med. Chem. Lett. 2003, 13, 2255.
Acknowledgments
We would like to thank the Office of the Director, NIH, and the
National Institute of Mental Health for funding (1RC2MH090878-
01). Particular thanks to N. Schechter (PSM) for copy editing.
12. Hulme, C.; Chappeta, S.; Dietrich, J. Tetrahedron Lett. 2009, 50, 4054.
13. For the preparation of Ugi product 6b and general library protocol: To a
References and notes
solution of 2,4-dimethoxybenzenylamine
1
(334.2 mg, 2.0 mmol), 4-
bromobenzoic acid 2a (398 mg, 2.0 mmol), phenylglyoxal monohydrate 3a
(304 mg, 2.0 mmol) and n-butyl isocyanide 4b (166 mg, 2.0 mmol) in methanol
(3 mL), the resulting mixture was stirred at room temperature for 36 h. The
reaction solution was concentrated in vacuo and the residue was purified by
column chromatography (ethyl acetate/hexane, 1/9 to 1/3) to obtain the Ugi
product 6b (645 mg, 57%). For the preparation of 3-hydroxypyrazole 5a and
general library protocol: To a solution of Ugi product 6b (566 mg, 1.0 mmol) in
10% TFA/DCE solution (3 mL), the resulting mixture was heated at 80 °C for
10 min under microwave irradiation to obtain ketoamide 10. The reaction
solution was evaporated in vacuo and the residue was dissolved in ethyl
acetate (20 mL), washed with 1 N NaOH (20 mL) and brine (20 mL), dried over
1. Parameswaran, P. S.; Naik, C. G.; Hegde, V. R. J. Nat. Prod. 1997, 60, 802.
2. (a) Mowbray, C. E.; Burt, C.; Corbau, R.; Gayton, S.; Hawes, M.; Perros, M.; Tran,
I.; Price, D. A.; Quinton, F. J.; Selby, M. D.; Stupple, P. A.; Webster, R.; Wood, A.
Bioorg. Med. Chem. Lett. 2009, 19, 5857; (b) Wyatt, P. G.; Woodhead, A. J.;
Berdini, V.; Boulstridge, J. A.; Carr, M. G.; Cross, D. M.; Davis, D. J.; Devine, L. A.;
Early, T. R.; Feltell, R. E.; Lewis, E. J.; MsMenamin, R. L.; Navarro, E. F.; O’Brien,
M. A.; O’Reilly, M.; Reule, M.; Saxty, G.; Seavers, L. A.; Smith, D.-M.; Squires, M.;
Trewartha, G.; Walker, M. T.; Woolford, A. J.-A. J. Med. Chem. 2008, 51, 4986; (c)
Wickens, P.; Kluender, H.; Dixon, J.; Brennan, C.; Achebe, F.; Bacchiocchi, A.;
Bankston, D.; Bierer, D.; Brands, M.; Braun, D.; Brown, M. S.; Chuang, C.-Y.;
Dumas, J.; Enyedy, I.; Hofilena, G.; Hong, Z.; Housley, T.; Jones, B.; Khire, U.;
Kreiman, C.; Kumarasinghe, E.; Lowinger, T.; Ott-Morgan, R.; Perkins, L.;
Phillips, B.; Schoenleber, R.; Scott, W. J.; Sheeler, R.; Redman, A.; Sun, X.; Taylor,
I.; Wang, L.; Wilhelm, S.; Zhang, X.; Zhang, M.; Sullivan, E.; Carter, C.; Miglarese,
M.; Levy, J. Bioorg. Med. Chem. Lett. 2007, 17, 4378; (d) de Paulis, T.; Hemstapat,
K.; Chen, Y.; Zhang, Y.; Saleh, S.; Alagille, D.; Baldwin, R. M.; Tamagnan, G. D.;
Conn, P. J. J. Med. Chem. 2006, 49, 3332; (e) Bekhit, A. A.; Abdel-Aziem, T. Bioorg.
Med. Chem. 2004, 12, 1935; (f) Tanitame, A.; Oyamada, Y.; Ofuji, K.; Fujimoto,
M.; Suzuki, K.; Ueda, T.; Terauchi, H.; Kawasaki, M.; Nagai, K.; Wachi, M.;
Yamagishi, J.-I. Bioorg. Med. Chem. 2004, 12, 5515; (g) Zhou, H.-B.; Carlson, K. E.;
Stossi, F.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Bioorg. Med. Chem.
Lett. 2009, 19, 108; (h) Chimenti, F.; Fioravanti, R.; Bolasco, A.; Manna, F.;
Chimenti, P.; Secci, D.; Befani, O.; Turini, P.; Ortuso, F.; Alcaro, S. J. Med. Chem.
2007, 50, 425.
MgSO4 and evaporated in vacuo to get N-acyl-a
-aminoketone 8b. 1H NMR
(400 MHz, CDCl3) d 8.11–8.01 (m, 2H), 7.78–7.70 (m, 2H), 7.61 (ddq, J = 5.2, 2.6,
1.2 Hz, 3H), 7.54–7.46 (m, 2H), 6.81 (s, 1H), 6.06–6.00 (m, 1H), 3.33–3.14 (m,
2H), 1.52–1.39 (m, 2H), 1.35–1.20 (m, 3H), 0.93–0.81 (m, 3H) ppm. 13C NMR
(100 MHz, CDCl3) d 192.86, 166.54, 166.11, 134.50, 134.24, 132.06, 131.78,
128.86, 128.83, 127.18, 60.21, 39.65, 31.31, 19.88, 13.62 ppm. For the
preparation of 3-hydroxypyrazole 5a and general library protocol: Without
further purification, a mixture of N-acyl-a-aminoketone 8b and NH2NH2 HCl
(343 mg, 5.0 mmol) in ethanol (3 mL) heated under microwave irradiation at
120 °C for 20 min. The reaction solution was evaporated in vacuo and the
residue was purified by column chromatography (eluent, ethyl acetate/hexane,
1/4 to 9/1) to afford 3-hydroxypyrazole 5a (214 mg, 56% in two steps). 1H NMR
(400 MHz, DMSO-d6) d 9.58 (s, 1H), 7.95–7.86 (m, 2H), 7.76–7.68 (m, 2H), 7.60
(dt, J = 6.2, 4.0 Hz, 2H), 7.38 (dd, J = 10.3, 4.7 Hz, 2H), 7.33–7.25 (m, 1H), 3.28 (s,
2H) ppm. 13C NMR (100 MHz, DMSO-d6) d 166.16, 133.87, 131.81, 130.18,
129.09, 128.35, 126.15, 125.64 ppm.
3. 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.;