A general method for the preparation of 3-acyl-4-cyano-5-amino-pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2006.05.173

This letter describes a general synthesis for N1-substituted 3-acyl-4-cyano-5-amino-pyrazoles.

Full text of DOI:10.1016/j.tetlet.2006.05.173

Tetrahedron Letters 47 (2006) 5797–5799
A general method for the preparation of
3-acyl-4-cyano-5-amino-pyrazoles
Min Ge,* Eric Cline and Lihu Yang
Merck & Co., Rahway, NJ 07065, USA
Received 24 February 2006; revised 24 May 2006; accepted 30 May 2006
Available online 27 June 2006
Abstract—This letter describes a general synthesis for N1-substituted 3-acyl-4-cyano-5-amino-pyrazoles.
Ó 2006 Elsevier Ltd. All rights reserved.
Pyrazoles and their derivatives are widely used as phar-
maceuticals and agrochemicals.1 There is significant
interest in the preparation of 5-amino-4-cyanopyrazoles,
with a wide array of groups at N-1. This class of com-
pounds has been reported to be selective Cox-2 inhibitors,
cyclooxygenase inhibitors, pesticides, and antihyperten-
sive agents.2 Furthermore, they are also extensively used
in the synthesis of fused heterocyclic systems, which are
purine antagonists.1a
CN
CN
O
R1
O
+
N2
a
CN
NH2
R1
N
N
R2
b
O
CN
CN
R2
Br
then
R1
Recently we were interested in a series of 3-acyl-4-cyano-
5-amino-pyrazoles. This type of pyrazoles is usually
synthesized using the diazonium salt of aniline (Fig. 1,
routes a and b).3 Obviously, the success of both methods
depends on the stability and reactivity of the diazonium
salts. Because the diazonium salts of alkyl amines are often
unstable, the N-1 substituents of the pyrazoles are limited
to phenyl groups. For broader N-1 substituent changes, a
general method is desired. In this sense, the third method
(Fig. 1, route c) seems to be an attractive method because
of many available substituted hydrazines.
O
O
CN
NH2
H2N
CN
c
R1
NH
R2
R1
+
N
O
N
CN
R2
Figure 1. Methods for the synthesis of 3-acyl-5-amino-pyrazoles.
hydrazine 2 was formed as the major side product, along
with extensive decomposition of the starting material 1.
This suggests that hydrazone formation is disfavored
during the condensation step, probably because malono-
nitrile is an excellent leaving group (Fig. 2).
While there are some reports on the synthesis of 3-acyl-
4-H-5-amino-pyrazoles through hydrazines, this method
has not been reported for 3-acyl-4-cyano-5-amino-pyr-
azoles.1d,e In fact, few such pyrazoles with non-aryl
N-1 substitutions have been reported, highlighting the
difficulties in the synthesis of this type of pyrazoles.
We thought that converting the hydroxyl group to a
better leaving group should favor the formation of the
desired hydrazone intermediate.4 However, an interme-
diate such as 4 (Scheme 1) has not been reported before.
Attempts to alkylate the enolate 1 under various condi-
tions (NaH, MeI, or Me2SO4) failed to give the desired
methyl enol ether, possibly due to the low reactivity of
enolate 1. After extensive experimentation, we found
that treating 1 in refluxing POCl3 for 1 h and then
quenching the reaction mixture with methanol gave a
Indeed, it was found that the reaction of 1 with 4-chloro-
aniline did not give any desired product (Fig. 2). Careful
analysis of the reaction mixture indicated that acyl
*
Corresponding author. Tel.: +1 732 594 3587; fax: +1 732 594
3007; e-mail: min_ge@merck.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.173

5798
M. Ge et al. / Tetrahedron Letters 47 (2006) 5797–5799
Table 1.
CN
CN
EtOOC
+Na-O
H
CN
EtOOC
N
O
EtOOC
HO
O
NH
Cl
CN
NH2
Et3N
1
CN
NH
O
favored
CN
CN
H
HN
EtO
+
R N NH2
EtO
MeO
+
EtOH
N
N
R
H2N
2
4
NH
Cl
5
Entry
R–NHNH2
Product (yield, %)a,b
Cl
1
2
3
4
H3C–
Et–
i-Pr–
t-Bu–
5a (78)
5b (72)
5c (78)
5d (73)
disfavored
CN
CN
O
5
5e (75)
EtOOC
CN
EtO
N
N
NH2
NH
N
6
5f (80)
O
N
HN
7
8
5g (66)
5h (87)
Cl
N
Cl
Figure 2. Proposed mechanism for the formation of side-product 2.
Cl
F
O
O
O
9
5i (79)
5j (73)
5k (54)
5l (58)
CN
CN
CN
MeOH
POCl3
110 oC
CN
CN
EtO
EtO
+Na-O
F
EtO
MeO
Cl
CN
O
10
11
12
S
1
3
4
O
Scheme 1. Synthesis of methyl vinyl enol ether 4.
HN
N
relatively stable product, which was identified to be the
desired methyl enol ether 4 by 1H and 13C NMR
(Scheme 1).5–7
N
N
H
As we expected, the reactions between 4 and substituted
hydrazines in ethanol provided the desired 5-amino-pyr-
azoles cleanly in good to modest yields.8 A wide variety
of substituents can be incorporated, including alkyl,
aryl, sulfonyl, and heterocycles (Table 1). In most cases,
the desired pyrazoles are precipitated out of the reaction
solution and analytically pure products can be isolated
by simple filtration.
N
13
14
15
5m (46)
5n (67)
5o (83)
NH
N
N
N
Cl
Br
These 5-amino-pyrazoles are very versatile intermediates
for the synthesis of many biologically important scaf-
folds. For example, direct reaction of pyrazole 5c with
N-hydroxycarboximidamides can give the oxadiazole
such as 8 (Scheme 2, route a). Or, after basic hydrolysis,
pyrazole acid 6 can be coupled to various amines to
give amides such as 9 (Scheme 2, route c). Acid 6 can
also be converted to the Weinreb amide, followed by
the treatment of Grignard reagents (or organolithium
reagents) to provide pyrazoles with further variation at
C-3 (such as 7, Scheme 2). These pyrazoles can be
further converted to fused heterocycles such as pyrazol-
opyrimidine, pyrazolopyrimidinones, and pyrazolo-
pyridazines using known chemistry.3a
N
N
16
17
18
5p (80)
5q (78)
5r (75)
N
N
N
O
O
19
20
5s (65)
5t (70)
S
O
O
S
O
This method can also be used in the one-pot formation
of 3-aryl/alkyl-4-cyano-5-amino-pyrazoles (Scheme 3).
Thus, treatment of enolate 11 with POCl3 in methylene
chloride at room temperature, followed by methanol
a Isolated yield.
b The regiochemistry of the products was assigned by NMR analysis as
well as comparison to the known compound 5h.3

M. Ge et al. / Tetrahedron Letters 47 (2006) 5797–5799
5799
References and notes
N
O
O
N
CN
NH2
1. (a) Cheng, C. C.; Robins, R. K. J. Org. Chem. 1956, 21,
1240–1256; (b) Hainzl, D.; Cole, L. M.; Casida, J. E. Chem.
Res. Toxicol. 1998, 11, 1529–1535; (c) Zhang, J.; Didier-
laurent, S.; Fortin, M.; Lefrancois, D.; Uridat, E.; Vevert,
J. P. Bioorg. Med. Chem. Lett. 2000, 10, 2575–2578; (d)
Vanotti, E.; Fiorentini, F.; Villa, M. J. Heterocycl. Chem.
1994, 31, 737–739; (e) Straub, A.; Stasch, J.; Alonso-Alija,
C.; Benet-Buchholz, J.; Ducke, B.; Feurer, A.; Furstner, C.
Bioorg. Med. Chem. Lett. 2001, 11, 781–784.
N
CN
NH2
a
c
f
EtO
N
N
N
8
5c
b
O
O
CN
NH2
CN
NH2
2. (a) Minich, M. L.; Rast, B.; Sakya, S. M.; Sahvnya, A. WO
2003037874 A1, 2003; (b) Heil, M.; Erdelen, C. DE
19532066 A1, 1997; (c) Gustavsson, A.; Jendeberg, L.;
Beierlein, K.; Lindqvist, B. WO 2003053976 A1, 2003.
3. (a) Abdelhamid, A. O.; Negm, A. M.; Abbsa, I. M. J.
Prakt. Chem. 1989, 1, 31–36; (b) Shawali, A. S.; Abdelh-
amid, A. O. Bull. Chem. Soc. Jpn. 1976, 49, 321–324.
4. This strategy has been used for the synthesis of 3-aryl-5-
amino-pyrazoles, where pre-formed methyl enol ether led to
the facile formation of the desired pyrazoles. See: Hanefeld,
U.; Rees, C. W.; White, A. J. P.; Williams, D. J. J. Chem.
Soc., Perkin Trans. 1 1996, 1545–1552.
5. We are not certain about the identity of the intermediate
because both vinyl chloride 3 and compound 3a can lead to
the corresponding enol ether 4 after methanol treatment.
This intermediate is too unstable to be isolated. However,
there is one report supporting vinyl chloride as the
intermediate. See: Friedrich, K.; Thieme, H. K. Synthesis
1973, 5, 111.
HO
N
N
N
N
O
N
6
9
d, e
H2N
N
O
N
CN
NH2
N
N
N
N
10
7
Scheme 2. Reagents and conditions: (a) NaH, N-hydroxyl benzam-
idine, 80 °C, 2 h, 65%; (b) LiOH, MeOH, 12 h, rt, 100%; (c) piperidine,
EDC, CH2Cl2, 4 h, rt, 78%; (d) MeONHMeÆHCl, EDCÆHCl, CH2Cl2,
NEt3, 82%; (e) C7H7MgBr, THF, À78 to 0 °C, 2 h, 88%; (f) HCONH2,
HCOOH, DMF, reflux, 73%.
EtOOC
CN
Cl2OPO
CN 3a
CN
Et3NH+
O-
O
OMe
6. The enol ether 4 is quite stable under acidic conditions but
a
b
N
c
NH2
N
CN
CN
12
quickly decomposes under basic conditions.
7. Experimental for enol ether synthesis: To
CN
CN
11
Cl
1 (7.2 g,
38.3 mmol) was added POCl3 (10.7 mL, 115 mmol) at
room temperature. After stirring for 15 min, this dark
solution was warmed up to 110 °C over 30 min and kept at
110 °C for another 30 min. The solution was then cooled to
room temperature and concentrated to a solid at 10 Torr.
With cooling in an ice bath, methanol (200 mL) was added
to this solid slowly. After addition, the brown suspension
was concentrated to an oil at 20 Torr. This oil was purified
by flash chromatography (eluting with 50% EtOAc/
hexanes) to give enol ether 4 (3.0 g, 44%) as a yellow
liquid. Avoid excess transfer because the pure material is
13
Cl
Scheme 3. Reagents and conditions: (a) malononitrile, Et3N, EtOAc,
90%; (b) POCl3, CH2Cl2, rt, 10 min, then MeOH; (c) 4-chloro-
phenylhydrazineÆHCl, Et3N, MeOH, 71%.
quenching, provided the corresponding methyl enol
ether 12 as a methanolic solution, which can be used di-
rectly to yield the desired pyrazole 13 after the addition
of triethylamine and corresponding hydrazine. This one-
pot procedure complements the reported method using
Me2SO4 as alkylating reagent,4 and is especially suitable
for sterically hindered or base sensitive substrates when
alkylation becomes difficult.
1
not very stable. Rf = 0.6 (50% EtOAc/hexanes); H NMR
(500 MHz, DMSO-d6) d 4.40 (q, J = 7.1 Hz, 2H), 4.24
(s, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (125
MHz, DMSO-d6) 172.1, 158.2, 112.2, 111.8, 64.9, 63.8,
14.1.
8. To a suspension of i-propylhydrazine HCl salt (765 mg,
6.9 mmol) in ethanol (10 mL) was added triethylamine
(7.6 mmol, 1.1 mL), followed by a solution of 4 (1.5 g,
8.3 mmol) in ethanol (1.5 mL) at room temperature.
Reaction was completed within 15 min as indicated by
LC–MS. The reaction was concentrated in vacuo. The
resulted oil was purified by flash chromatography, eluting
with a gradient from 0% to 20% EtOAc/CH2Cl2 to give the
desired pyrazole 5c (1.21 g, 78%) as a yellow solid.
Rf = 0.34 (20% EtOAc/CH2Cl2); 1H NMR (500 MHz,
DMSO-d6) d 6.80 (s, 2H, NH2), 4.50 (q, J = 6.4 Hz,
1H), 4.26 (q, J = 7.1 Hz, 2H), 1.29–1.25 (m, 9H). LC–MS
(ES+) calcd for C10H15N4O2 [M+H+] 223.1, found
223.1.
In summary, we have developed a general method for
the synthesis of N-1 substituted 3-acyl-5-amino-pyraz-
oles. We envision that this method will be very useful
in the construction of small molecule libraries with pyr-
azole core structures.
Acknowledgments
We would like to thank Drs. Songnian Lin and Christo-
pher Thompson for critical reading and helpful
discussions.