One-pot synthesis of 5-(substituted-amino)pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2004.04.017

An efficient and mild one-pot synthesis of substituted 5-alkylamino and/or 5-(arylamino)pyrazoles is described. A suitably decorated β-ketoamide, an aryl or alkyl hydrazine and Lawesson's reagent are suspended in THF/Py and gently heated to yield the requisite 5-aminopyrazoles.

Full text of DOI:10.1016/j.tetlet.2004.04.017

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4265–4267
One-pot synthesis of 5-(substituted-amino)pyrazoles
Dharmpal S. Dodda,b, and Rogelio L. Martinez
b
*
aEarly Discovery Chemistry, Bristol-Myers, Squibb Pharmaceutical Research Institute, PO Box 4000,
Princeton, NJ 08543-4000, USA
bNew Leads Chemistry-Applied Biotechnology, Bristol-Myers, Squibb Pharmaceutical Research Institute,
PO Box 4000, Princeton, NJ 08543-4000, USA
Received 5 March 2004; revised 6April 2004; accepted 6April 2004
Abstract—An efficient and mild one-pot synthesis of substituted 5-alkylamino and/or 5-(arylamino)pyrazoles is described. A suit-
ably decorated b-ketoamide, an aryl or alkyl hydrazine and Lawesson’s reagent are suspended in THF/Py and gently heated to yield
the requisite 5-aminopyrazoles.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Compounds containing the 5-alkyl/arylamino substi-
tuted pyrazole moiety (1, Fig. 1) have been exploited in
the design of pharmaceutical1 and agrochemical agents.2
Although a number of methods for the synthesis of
5-alkyl/arylamino substituted pyrazoles have been
reported,1–3 we found that none were suitable for our
purposes4 and thus sought a general solution phase
method that could also be applied to solid-supported
synthesis. The known protocols required harsh reaction
conditions3;4a or were limited to a defined set of starting
materials having special electronic requirements.1a;2;4b
The most versatile method1b;c;d involves the reaction
of mono-substituted hydrazines with pregenerated
b-ketothioamides to accomplish the cyclization but, as
such, was not suitable for solid-phase synthesis. We
herein describe a modification of the latter method1b–d
that allows for the efficient installation of mono- and
di-substituted-5-amino groups on pyrazole core 1 in a
single final step. This protocol avoids the pregeneration
of the b-ketothioamides and it is amendable to solid-
supported synthesis.
The 5-aminopyrazoles 1 (Scheme 1) are furnished by
heating a mixture of the b-ketoamide,5 aryl or alkyl
hydrazines and Lawesson’s reagent (L.R.) in dry THF/
pyridine (95/5) at 55–60 ꢁC.6;7 The reaction proceeds by
an initial formation of the intermediate hydrazone7e;8
3
followed by the reaction of the amide carbonyl with
Lawesson’s reagent. The reaction times range from 5 to
48 h8 depending on the nature of the substrate but, in
general, the reactions are complete within 12 h.6–8 In
those reactions that failed to give 1 in decent yields,
pyrazolone 4 was identified as the major side product.7b
In all cases only a single isomer was isolated.6b The
R2
N
R2
N
R3
R3
R3
R4
R4
R4
a
R2
L. R.
R1
R1
N
N
R1
N
R5
O
O
O
N
NHR5
R3
R4
2
3
1
R2
N
N
N
R1
R5
1
R3
R4
N
O
Figure 1. Substituted 5-(alkyl/arylamino)pyrazoles.
N
R5
4
Keywords: 5-Aminopyrazoles; 5-Alkylaminopyrazoles; b-ketoamides.
* Corresponding author. Tel.: +1-609-252-5273; fax: +1-609-252-7446;
e-mail: dharmpal.dodd@bms.com
Scheme 1. Reagents and conditions: (a) 1.1 equiv R5NHNH2 · HCl,
1.1 equiv Lawesson’s reagent, THF/Py (95/5), 50–55 ꢁC.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.017

4266
D. S. Dodd, R. L. Martinez / Tetrahedron Letters 45 (2004) 4265–4267
method was found to be extremely versatile and can be
applied to a diverse range of b-ketoamides and mono-
substituted hydrazines.
when reacted with phenylhydrazine, gave product 1a in
95% yield, whereas substrate 2b (R4 ¼ Ph) reacted with
phenylhydrazine to give product 1c in only 65% yield.
The initial transient hydrazone 3, formed from the
substrates where R4 is Ph, took longer to cyclize and
usually gave more of the pyrazoloneside product 4.7d;e
The results of a representative study examining the
reactivity of various secondary and tertiary amides
(Table 1) with phenylhydrazine and benzylhydrazine are
reported in Table 2.
In general, phenyl hydrazine gave slightly better
yields with C-2 (R3) unsubstituted b-ketoamides (2a–f)
than did benzylhydrazine. Whereas, benzylhydrazine
appeared to give slightly better yields with C-2 substi-
tuted substrates (2g–m) than did phenylhydrazine.
Furthermore, it was noticed that the reaction with
benzylhydrazine proceeded faster than with phenyl-
hydrazine.
In all cases the C-2 unsubstituted b-ketoamides 2a–f, in
which R3 is H, consistently gave higher yields (respective
products 1a–l, Table 2) than their counterparts 2g–m,
where R3 is Me or Ph (products 1m–u, Table 2). Though
the number of examples is limited, substrate 2g, in which
R3 is Me, gave significantly better yields (products 1o
and 1p) than substrate 2m, where R3 is a Ph8 (product
1m and 1n, Table 2). As a general rule b-ketoamides
where R4 is Me (alkyl) reacted much faster and generally
gave higher yields than substrates in which R4 is Ph
(aryl).7c As an example, b-ketoamide 2a (R4 ¼ Me),
As for the substituents on the amide nitrogen or sec-
ondary versus tertiary amides 2, the effect is not so clear
cut and no trends were apparent. N-Aryl and N-alkyl
substituents were tolerated equally well and the substi-
tution pattern and the nature of the groups at C-2 (R3)
and C-4 (R4) on the b-ketoamides appear to determine
the fate of the reaction.
Table 1. The b-ketoamides 2 used in the study5
Compound
R1
R2
R3
R4
In summary, a mild one-pot procedure for the prepa-
ration of 5-N-mono- or 5-N,N-disubstituted-aminopyr-
azoles has been presented.9 This protocol negates the
need for pregeneration of b-ketothioamides as described
previously1b;c;d and is thus easily adaptable for auto-
mated parallel synthesis. The versatility and mild nature
of this method has also been exploited for the solid-
2a
2b
2c
2d
2e
2f
Et
Et
Et
Et
H
H
Me
Ph
H
Bn
Bn
Ph
Ph
Et
H
Me
Ph
H
H
H
H
Me
Ph
H
H
2g
2h
2i
Et
Et
H
Me
Me
Me
Me
Me
Me
Ph
Me
Ph
Et
supported
amino)pyrazoles and will be reported in due course.
synthesis
of
5-(N-mono-substituted-
Bn
Bn
Ph
Ph
Et
Me
Ph
2j
H
2k
2l
Me
Me
Et
Me
Ph
2m
Me
Acknowledgements
The authors would like to acknowledge Sarah C. Trae-
ger of Discovery Analytical Sciences-BMS for her con-
tributions in establishing the regiochemistry of the
5-aminopyrazoles and Dr. Cullen Cavallaro for a thor-
ough review of this manuscript.
Table 2. Yields of 5-aminopyrazoles 1
Compound R1
R2
R3
R4
R5
Yield
(%)a;b
1a
1b
1c
1d
1e
1f
Et
Et
Et
Et
Et
Et
H
H
Me
Me
Ph
Ph
Bn
Ph
Bn
Ph
Bn
Ph
Bn
Ph
Ph
Ph
Ph
Ph
Bn
Ph
Bn
Ph
Ph
Ph
Ph
Ph
95
87
65
52
91
87
67
50
95
45
92
40
13
15
55
60
32
55
43
30
26
H
Et
Et
H
H
Ph
Bn
Bn
Bn
Bn
Ph
Ph
Ph
Ph
Et
H
Me
Me
Ph
References and notes
H
H
1g
1h
1I
1j
H
H
1. For some recent reports see: (a) Sakya, S. M.; Rast, B.
Tetrahedron Lett. 2003, 44, 7629; (b) Tang, J.; Shewchuk,
L. M.; Sato, H.; Hasegawa, M.; Washio, Y.; Nishigaki, N.
Bioorg. Med. Chem. Lett. 2003, 13, 2985; (c) Cooper, C. B.;
Helal, C. J.; Sanner, M. A.; Wagner, T. T. PCT WO 02/
18346A1, 2002; (d) Schenone, S.; Bruno, O.; Ranise, A.;
Bondavalli, F.; D’Amico, M.; Filippelli, W.; Falcone, G.;
De Novellis, V. Il Farmaco 1995, 50, 179.
H
H
Ph
H
H
Me
Ph
H
H
1k
1l
Me
Me
Et
Et
Et
Et
Et
H
H
Me
Ph
H
1m
1n
1o
1p
1q
1r
1s
1t
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Et
Et
2. (a) Ancel, J. E.; El Kam, L.; Gadras, A.; Grimaud, L.; Jana,
N. K. Tetrahedron Lett. 2002, 43, 8319; (b) Atlan, V.; El
Et
Et
€
Kaım, L.; Grimaud, L.; Jana, N. K.; Majee, A. Synlett
2002, 352; (c) Atlan, V.; Buron, C.; El Kaım, L. Synlett
Bn
Bn
Ph
Ph
Me
Ph
€
H
2000, 489; (d) Palacios, F.; Aparicio, D.; de los Santos, J.
M. Tetrahedron 1996, 52, 4123.
H
Me
Ph
1u
H
~
ꢀ
3. (a) Moreno-Manas, M.; Sebastian, R. M.; Vallribera, A.;
Carini, F. Synthesis 1999, 157; (b) Abdel-Rahman, R. M.;
Seada, M.; Fawzy, M.; El-Baz, I. Pharmazie 1994, 49, 729.
a Purified using reverse phase preparative HPLC.
b Yield averaged from two runs.

D. S. Dodd, R. L. Martinez / Tetrahedron Letters 45 (2004) 4265–4267
4267
4. (a) Method described in Ref. 3 requires the reaction of b-
ketoamide with mono-substituted hydrazines under very
harsh acidic conditions and/or very high temperatures to
accomplish the cyclization in poor to moderate yields; (b)
Method outlined in Refs. 2a,b,c, though very useful, is
limited by the necessity of starting hydrazones that must be
conjugated to an electron withdrawing group, to yield 5-(N-
alkylamino)pyrazoles with electron-withdrawing groups at
the C-4 position; (c) The method described in Refs. 1b,c,d
J ¼ 7:14 Hz); LCMS (m=z) 230 (Mþ+H); (b) The regio-
13C HMQC/HMBC and 1H–15N HMQC/HMBC as well as
COSY and PSNOESY NMR experiments.
1
chemistry of the R5 group was established using (2D) H–
7. (a) Reactions also proceeded without the use of pyridine,
but it was noticed that yields were slightly higher when
pyridine was used as an additive, particularly for sluggish
reactions. Dioxane can be substituted for THF; (b) The
formation of the corresponding 5-pyrazolones 4 are mon-
itored by LCMS; (c) For example, C-2 unsubstituted
(R3 ¼ H) substrates such as 2a, 2c and 2e with methyl
groups at C-4 (R4) reacted within as little as 5 h at 55 ꢁC,
where as substrates 2b, 2d and 2f with phenyl at C-4 (R4)
required reaction times >12 h. For uniformity, all reactions
were heated for 24 h;8; (d) Increasing reaction temperature
did not enhance the yield. In fact, in some cases a decreased
yield was observed due to an increase in the formation of
the corresponding 5-pyrazolone 4; (e) The hydrazones 3
were apparent by LCMS. Conversions to the thioamide
intermediates were not observed.
8. It was noticed that the initial hydrazone intermediates 3
that are formed from 2m are extremely stable (particularly
those formed from phenylhydrazine). The reaction took
>48 h at 60 ꢁC to go to completion and resulted in a
significant amount of the corresponding 5-pyrazolones 4.
Increasing the reaction temperatures (using 1,4-dioxane as
the solvent) did not enhance the yield.
takes
advantage
of
the
reaction
between
a
2-oxocarbo-thioamides (b-ketothioamides) with mono-
substituted hydrazines to afford 5-(N-alkylamino)pyrazoles
in good yield.
5. Some useful methods for the preparation of b-ketoamides
include: (a) Miriyala, B.; Williamson, J. S. Tetrahedron
Lett. 2003, 44, 7957; (b) Railard, S. P.; Chen, W.; Sullivan,
E.; Bajjalieh, W.; Bhandari, A.; Baer, T. A. J. Comb. Chem.
2002, 4, 470; (c) Witzemanard, J. S.; Nottingham, W. D. J.
Org. Chem. 1991, 56, 1715.
6. (a) Typical reaction conditions: To a mixture of the b-
ketoamide 2a (16mg, 0.10 mmol), phenylhydrazine hydro-
chloride (16mg, 0.11 mmol) and Lawesson’s reagent
(45 mg, 0.11 mmol) in a 1 dram vial was added 1.0 mL of
dry THF/pyridine (95/5) solution. The reaction was stirred
at room temperature for 15 min and the vial was transferred
to a heating block. The vial was heated at 55 ꢁC for 14 h and
the solvents removed in vacuo. The resulting oil was
resuspended in 1.0 mL of (1/4) DCE/heptane and loaded on
a 500 mg prepacked silica cartridge and flushed with 6–
7 mL of 1/1 diethyl ether/heptane. The filtrate is condensed
in vacuo and purified using reverse-phase preparative
HPLC to give 1a (22 mg, 95%): 1H NMR (400 MHz,
CDCl3) d 7.57–7.55 (m, 2H), 7.51–7.44 (m, 3H), 5.71 (s,
3H), 3.00 (q, 4H, J ¼ 7:14 Hz), 2.37 (s, 3H), 1.01 (t, 6H,
9. The reactivity of both electron rich and electron deficient
hydrazines and b-ketoamides have also been examined.
Though there were some combinations of hydrazines and b-
ketoamides that were not compatible, on the whole most
electronically diverse reagents were tolerated and gave
reasonable yields and purity. The regioselectivity was
independent of the electronic nature of the reactants.