Studies towards the synthesis of Fipronil analogues: Improved decarboxylation of α-hydrazonoacid derivatives

Article abstract of DOI:10.1016/S0040-4039(02)01977-9

The Mannich reaction of hydrazones coupled with a [4+1] cycloaddition with isocyanides has been used for the synthesis of aminopyrazole analogues of Fipronil. The starting cyanohydrazone was prepared with new experimental conditions for efficient diazonium coupling in fluorinated solvents followed by a new sodium cyanide catalysed decarboxylation.

Full text of DOI:10.1016/S0040-4039(02)01977-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8319–8321
Studies towards the synthesis of Fipronil® analogues: improved
decarboxylation of a-hydrazonoacid derivatives
J. E. Ancel,a L. El Ka¨ım,b,* A. Gadras,a L. Grimaudb and N. K. Janab
aCRIT-Rhones-Poulenc Industrialisation, 24 av. Jean Jaure´s, 69153 De´cines Charpieu Cedex, France
bLaboratoire Chimie et Proce´de´s, Ecole Nationale Supe´rieure de Techniques Avance´es, 32 Bd Victor, 75015 Paris, France
Received 26 July 2002; revised 11 September 2002; accepted 13 September 2002
Abstract—The Mannich reaction of hydrazones coupled with a [4+1] cycloaddition with isocyanides has been used for the
synthesis of aminopyrazole analogues of Fipronil®. The starting cyanohydrazone was prepared with new experimental conditions
for efficient diazonium coupling in fluorinated solvents followed by a new sodium cyanide catalysed decarboxylation. © 2002
Published by Elsevier Science Ltd.
Fipronil® F (Scheme 1, R=H) is a new fluorinated
pyrazole with high insecticide activity;1 in the search for
new methods for the synthesis of Fipronil® analogues,
we were interested in evaluating the use of the Man-
nich/[4+1] cycloaddition reactions of hydrazones
recently disclosed in our research group.2,3 The starting
cyanohydrazone 3a could be obtained by diazotation of
aniline 6 followed by coupling with methylcyanoac-
etate, saponification and decarboxylation (Scheme 1).
Unexpected problems using this approach eventually
led us to define original conditions for the diazonium
coupling with methylcyanoacetate as well as a new
catalysed decarboxylation of a-hydrazonoacids.
with t-butyl nitrite in a mixture of trifluoroacetic acid
and trifluoroethanol (3/2) as solvent, followed by addi-
tion of methyl cyanoacetate and neutralisation with
potassium hydroxide (as a 1/1 concentrated solution in
water). The cyanohydrazone 5 was thus obtained in a
83% isolated yield (Scheme 2). The choice of this com-
plex solvent system was dictated by the need of a large
excess of acid for the diazotation process without any
solidification of the mixture during the diazonium cou-
pling in basic medium. Saponification of ester 5 in 2N
aqueous NaOH led to the corresponding acid 4a in
good yields (Scheme 2).
Attempted thermal decarboxylation of cyanohydra-
zonoacid 4a as described for N-phenylcyanohydrazone
failed to give any isolated product.4 The decarboxyla-
tion of electronwithdrawing group substituted aryl-
cyanohydrazonoacids is known to be difficult due to
competing formation of dicyanogen with elimination of
Diazotation of electronwithdrawing group substituted
anilines often requires the use of large excess of acid to
prevent the triazene formation associated with incom-
plete protonation of the aniline. Optimal one pot diazo-
tation–diazonium coupling of aniline 6 was obtained
Scheme 1.
* Corresponding author. Fax: 33-1-45-528322; e-mail: elkaim@ensta.fr
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01977-9

8320
J. E. Ancel et al. / Tetrahedron Letters 43 (2002) 8319–8321
Scheme 2.
substituted anilines.4 The catalytic effect of tri-
butylphosphine for the room temperature decarboxyla-
tion of various a-imino and a-hydrazono acids has been
described by Barton et al.;5 under these conditions, the
decarboxylated hydrazone 3a was obtained in a moder-
ate 48% isolated yield. As suggested by Barton et al, a
possible mechanism implies the addition–elimination of
the phosphine on the hydrazone to allow the decar-
boxylation on a quaternary center. In our case, the
leaving group properties of the cyano substituent may
alter the catalytic cycle involving the phosphine
(Scheme 3).
nations. Indeed when hydrazone 4a was treated with
sodium cyanide in DMSO at room temperature, the
decarboxylated hydrazone 3a was now obtained in a
62% isolated yield (Table 1). As shown by the examples
described in Table 1, the interest of this procedure is
not restricted to cyano substituted hydrazones as
phenylglyoxylic acid hydrazone 4c was equally decar-
boxylated under cyanide catalysis. The behaviour of
oximes 4e is close to the one of hydrazone 4c; with less
electronwithrawing groups tethered on the hydrazone,
heating is required for the decarboxylation to proceed.
With this improved decarboxylation reaction in hand,
we were very pleased to observe efficient Mannich
coupling with formation of 2a without any competing
elimination of the cyanide under piperazine treatment
(Scheme 4). Alternatively, the dimethylamino substi-
We postulate that cyanide anion could compete
efficiently with tributylphosphine as a catalyst in this
reaction, offering furthermore the advantage of degen-
erative pathways in the various possible cyanide elimi-
Scheme 3.
Table 1. Decarboxylation of a-hydrazono and a-oximinoacids
Entry
Starting 1
Catalyst
Temperature
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
4a
4a
4b
4b
4c
4c
4d
4e
NaCN
PBu3
NaCN
PBu3
NaCN
PBu3
NaCN
NaCN
rt
rt
rt
rt
65°C
65°C
rt
0.5
3
0.5
3
12
12
0.5
1
62
48
60
45
50
30
70
45
65°C
a To a solution of acid 4 (1 mmol) in DMSO (3 ml) was added sodium cyanide (1 mmol) and the mixture stirred for the time and temperature
shown in Table 1. Comparative reactions with tributylphosphine were performed with 0.5 equiv. phosphine in the same conditions.

J. E. Ancel et al. / Tetrahedron Letters 43 (2002) 8319–8321
8321
Scheme 4.
tuted hydrazone 2b could be obtained in a 90% isolated
yield by treatment with tetramethyldiaminomethane.
The aminohydrazone 2b was then easily converted to
aminopyrazoles 1 by a [4+1] cycloaddition reaction
with isocyanides. The azoalkene precursor was
obtained in this case by a mere thermal treatment in
toluene and trapped in situ by t-butylisocyanide or
4-chlorobenzylisocyanide to give the expected pyrazoles
1a and 1b in a 50 and 52% isolated yield respectively
(Scheme 4).
Acknowledgements
We thank Aventis CropSciences for financial support.
References
1. Fipronil® (CAS No. 120068-37-3) patented by Aventis is
one of the leading pesticides for crop and pet protection.
2. Atlan, V.; Bienayme´, H.; El Ka¨ım, L.; Majee, A. Chem
Commun. 2000, 1585–1586.
3. Atlan, V.; El Ka¨ım, L.; Grimaud, L.; Jana, N. K.; Majee,
In conclusion, we have disclosed an expedient access to
N-substituted analogues of Fipronil® from cyanohydra-
zone 3a. This was made possible by the new experimen-
tal conditions defined for the diazonium coupling and
the decarboxylation reaction to prepare 3a. The interest
and scope of these procedures will be studied further.
A. Synlett 2002, 352–354.
4. Grundmann, C.; Fulton, M. B. Chem. Ber. 1964, 97,
566–574.
5. Barton, D. H. R.; Taran, F. Tetrahedron Lett. 1998, 39,
4777–4780.