Synthesis of tetrasubstituted pyrazoles through different cyclization strategies; Isosteres of imidazole fungicides

Article abstract of DOI:10.1055/s-0033-1338433

Formerly unknown 3-chloro-4,5-diaryl-1-methylpyrazoles have been prepared through two different synthesis pathways, one of which starts from 2,3-diarylacrylonitriles, the second from 3,3-dichloro-1,2-diarylpropenones. Both approaches rely on the cyclocondensation of diarylated three-carbon synthons with hydrazine derivatives and possess some unique features. One route uses a cyclization reaction, during which a chlorine atom is directly installed at the pyrazole ring that normally would be introduced in subsequent halogenation steps. The second pathway applies the Sandmeyer reaction to introduce this chloro substituent; an approach that is rarely described at the pyrazole nucleus. The obtained tetrasubstituted pyrazoles are isosteres of highly active imidazole fungicides and show good control of Uncinula necator (grape powdery mildew). Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338433

1150▌
LETTER
lSetyternthesis of Tetrasubstituted Pyrazoles through Different Cyclization Strate-
gies; Isosteres of Imidazole Fungicides
Synthesis of Tetrasubstituted Pyrazoles through Different Cyclization Strategies; Isosteres of Imidazole Fungicides
Raphael Dumeunier,* Clemens Lamberth,* Stephan Trah
Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland
Fax +41(62)8660860; E-mail: clemens.lamberth@syngenta.com
Received: 07.03.2013; Accepted after revision: 28.03.2013
Cl
Cl
Abstract: Formerly unknown 3-chloro-4,5-diaryl-1-methylpyr-
azoles have been prepared through two different synthesis path-
ways, one of which starts from 2,3-diarylacrylonitriles, the second
from 3,3-dichloro-1,2-diarylpropenones. Both approaches rely on
the cyclocondensation of diarylated three-carbon synthons with hy-
drazine derivatives and possess some unique features. One route
uses a cyclization reaction, during which a chlorine atom is directly
installed at the pyrazole ring that normally would be introduced in
subsequent halogenation steps. The second pathway applies the
Sandmeyer reaction to introduce this chloro substituent; an ap-
proach that is rarely described at the pyrazole nucleus. The obtained
tetrasubstituted pyrazoles are isosteres of highly active imidazole
fungicides and show good control of Uncinula necator (grape pow-
dery mildew).
F
F
O
O
N
N
N
F
N
F
Cl
Cl
1
2
Figure 1 Imidazole fungicide 1 and its pyrazole analogue 2
We realized that 3,3-dichloro-1,2-diarylpropenones, such
as 7, are perfectly suited for heterocyclization to pyrazoles
(Scheme 1). The starting material 3,3-dichloro-2-(2,4,6-
trifluorophenyl)acryloyl chloride (6), which we previous-
ly used for the synthesis of imidazo[2,1-b][1,3]thiazin-5-
ones,10 can be easily prepared by Corey–Fuchs type
dichlorovinylation11 of ethyl 2,4,6-trifluorophenylglyox-
ylate (4), subsequent ester saponification and acid chlo-
ride formation. The transformation of 6 with anisole in the
presence of aluminum trichloride delivers the diaryl-sub-
stituted 3,3-dichloropropenone 7. Friedel–Crafts acyla-
tions of 3,3-dichloroacryloyl chlorides have never been
described before. The next step required the heterocycli-
zation of 7 with a hydrazine derivative. Hereby, one of the
vinylic chlorine atoms in 7 is substituted during the ring
closure reaction by a hydrazine nitrogen atom, the second
remains in the molecule. We first attempted the conver-
sion with methylhydrazine with the hope that it would di-
rectly deliver 11. Unfortunately, the undesired
regioisomer 1-methyl-5-chloropyrazole 8 was the only
product that could be isolated. We, therefore decided to
apply a hydrazine derivative with a protecting group that
could be cleaved after the heterocyclization. Our reagent
of choice was benzylhydrazine dihydrochloride, which
delivered the 1-benzyl-5-chloropyrazole 9. This cycliza-
tion product could be converted by removal of the benzyl
protecting group under reductive conditions and subse-
quent methylation into 1-methyl-3-chloropyrazole 11, to-
gether with its regioisomer 8. Finally, regioselective
replacement of the fluorine atom in the para-position of
the phenyl ring by a methoxy group led to the desired tar-
get compound 12.12 Although ring closure reactions with
hydrazines have already been described with other 3,3-
chloropropenones,13 we succeeded in the first ring closure
reactions of 1,2-diaryl-3,3-dichloropropenones to diary-
lated 3-chloropyrazoles.
Key words: pyrazole, heterocycles, cyclization, Sandmeyer reac-
tion, fungicides
The tubulin polymerization promoters are a class of ex-
perimental fungicides that was discovered in the 1990s
with the synthesis of special biheterocyclic compounds,
such as trisubstituted [1,2,4]triazolo[1,5-a]pyrimidines1
and pyrido[2,3-b]pyrazines.2 More recently, similar sub-
stituted analogues with monoheterocyclic scaffolds have
been the focus of agrochemical research, such as tetrasu-
bstituted pyridazines3 and imidazoles.4 Imidazole 1 (Fig-
ure 1) is highly active against a broad range of
phytopathogens, such as Botrytis cinerea (grey mould),
Uncinula necator (grape powdery mildew), Mycosphaer-
ella graminicola (wheat leaf blotch) and Alternaria solani
(potato and tomato early blight).4 We decided to prepare
pyrazole analogues with a similar substitution pattern be-
cause pyrazoles are well-known privileged structures in
medicinal5 and crop-protection chemistry6 and are also re-
gioisomeric diazole equivalents of imidazoles. Tremen-
dous effort has already been invested in the preparation of
a range of pyrazole derivatives,7 and several tetrasubsti-
tuted pyrazoles have also been reported.8,9 However,
when we started our research program, fully substituted
pyrazoles bearing an alkyl group at one of the ring nitro-
gen atoms, two aryl or heteroaryl rings in positions 4 and
5 and a halogen substituent in position 3, such as 2, had
not been described in the literature (Figure 1). We there-
fore designed a new synthesis pathway to obtain the en-
visaged target compounds.
SYNLETT 2013, 24, 1150–1154
Advanced online publication: 18.04.2013
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9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338433; Art ID: ST-2013-B0211-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Tetrasubstituted Pyrazoles
1151
Cl
Cl
O
Cl
Cl
O
F
O
F
F
F
F
1. KOH
2. SOCl2
anisole
AlCl3
i-PrMgCl
(CO2Et)2
O
O
Cl
Br
CCl4, Ph3P
O
50 %
F
F
F
F
F
F
F
3
4
5
6
O
O
O
O
Cl
Cl
O
O
F
F
F
F
F
BnNHNH2⋅2HCl
Pd(OH)2/C
cyclohexene
1. K2CO3
2. MeI
O
F
F
F
NaOMe
K2CO3
92%
84%
F
F
N
N
N
N
N
N
F
N
F
F
HN
F
7
Cl
Cl
Cl
Cl
9
10
12
11
MeNHNH2
90%
33%
(+ 40%
regioisomer 8)
O
F
F
N
N
F
Cl
8
Scheme 1 Synthesis of the tetrasubstituted pyrazole 12 via 3,3-dichloro-1,2-diarylpropenone 7 (Method A)
On one hand, our synthesis route to 12 can be considered manner. Instead of the 3,3-dichloro-1,2-diarylprope-
as efficient because it is one of the very few syntheses of nones, we turned our attention to 2,3-diarylacrylonitriles
3-chloropyrazole derivatives in which the halogen atom is as more appropriate starting materials. Such diarylated
introduced simultaneously during the ring closure reac- α,β-unsaturated nitriles can be easily prepared by base-
tion without any need for a (subsequent) chlorination step. catalyzed aldol condensation of an arylacetonitrile with an
However, if the application of methylhydrazine could de- aromatic aldehyde.14 This is demonstrated by the reaction
liver the desired 1-methyl-3-chloropyrazole and not, as of (2,4,6-trifluorophenyl)acetonitrile (13) with 4-chloro-
found, the regioisomeric 1-methyl-5-chloropyrazole 8, benzaldehyde to give acrylonitrile 14, during which the
the last two steps of the reaction sequence (deprotection fluorine atom in the para-position of the phenyl ring is
and alkylation) would not be required. Furthermore, the also replaced by a methoxy group (Scheme 2). This key
Friedel–Crafts acylation of 3,3-dichloro-2-arylacryloyl intermediate is then transformed with methylhydrazine
chlorides such as 6 seems to be limited to benzene deriv- into the tetrasubstituted pyrazoline 15. This is the first ex-
atives with electron-donating substituents.
ample of a ring closure reaction of a 2,3-diarylacryloni-
trile with a hydrazine to a pyrazoline derivative. Only two
cases have been reported in which acrylonitriles have
We therefore looked for an alternative synthesis to pyr-
azoles such as 2 that could be applicable in a more general
N
Cl
F
F
4-ClC6H4CHO
K2CO3, MeOH
MeNHNH2
Et3N
N
30%
F
F
O
F
13
14
Cl
Cl
Cl
F
F
F
1. HCl, NaNO2
2. CuCl
O
O
O
MnO2
22%
from 14
51%
N
N
N
N
N
F
F
N
F
NH2
NH2
Cl
15
16
2
Scheme 2 Synthesis of the tetrasubstituted pyrazole 2 via 2,3-diarylacrylonitrile 14 (Method B)
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1150–1154

1152
R. Dumeunier et al.
LETTER
been cyclized with hydrazonoyl chlorides to completely Both approaches allowed the synthesis of several novel
different 5-cyanopyrazolines.15 The aminopyrazoline 15 tetrasubstituted pyrazoles from diverse 3,3-dichloro-1,2-
is then converted in two further steps by aromatization diarylpropenones and 2,3-diarylacrylo-nitriles (Table 1).
and subsequent chlorodediazoniation into the desired pyr- According to the structure-activity relationship require-
azole 2. Such Sandmeyer type transformations of 3-ami- ments of the analogues imidazole fungicides, they all bear
nopyrazoles via their diazonium salts into 3- a methyl group in the 1-position, a chloro substituent in
chloropyrazoles have been only rarely described in the lit- the 3-position and two aryl or heteroaryl rings in the 4-
erature.16
and 5-positions. Such benzene and pyridine rings are sub-
stituted by electron-donating as well as electron-with-
drawing groups.
Table 1 Novel Tetrasubstituted Pyrazoles
Entry Intermediate for heterocyclisation Product
1H NMR (CDCl3)
LC-MS
Method
O
Cl
Cl
O
O
3.73 (s, 3 H), 3.76 (s, 3 H), 6.58 (t,
J = 7.91 Hz, 2 H), 6.82 (d,
J = 8.79 Hz, 2 H), 7.09 (d,
J = 8.77 Hz, 2 H)
F
F
Rt = 1.99 min; MS:
m/z = 353 [M + 1]+,
355 [M + 3]+
F
1
A
N
F
F
N
F
Cl
O
Cl
Cl
O
O
F
3.77 (s, 3 H), 3.79 (s, 3 H), 3.82 (s,
3 H), 6.43 (d, J = 9.13 Hz, 2 H), 6.90
(d, J = 8.83 Hz, 2 H), 7.18 (d,
J = 8.76 Hz, 2 H)
F
Rt = 1.96 min; MS:
m/z = 365 [M + 1]+,
367 [M + 3]+
O
2
3
4
A
B
B
N
F
F
N
F
Cl
Cl
N
Cl
F
F
3.79 (s, 3 H), 3.81 (s, 3 H), 6.43 (d,
Rt = 2.12 min; MS:
O
J = 9.2 Hz, 2 H), 7.19 (d, J = 8.49 Hz, m/z = 369 [M + 1]+,
2 H), 7.46 (d, J = 8.48 Hz, 2 H)
371 [M + 3]+
N
O
F
N
F
Cl
O
N
N
N
3.71 (s, 3 H), 3.74 (s, 3 H), 3.90 (s,
N
O
F
F
3 H), 6.37 (d, J = 9.15 Hz, 2 H), 6.69 Rt = 1.93 min; MS:
O
(d, J = 8.48 Hz, 1 H), 7.38 (dd,
J = 2.4, 8.59 Hz, 1 H), 8.00 (d,
J = 2.2 Hz, 1 H)
m/z = 366 [M + 1]+,
368 [M + 3]+
O
F
N
F
Cl
O
N
3.83 (s, 3 H), 3.94 (s, 3 H), 6.73 (d,
J = 8.5 Hz, 1 H), 7.12 (d, J = 8.3 Hz,
1 H), 7.22 (dd, J = 2.1, 8.3 Hz, 1 H),
7.38 (dd, J = 2.4, 8.57 Hz, 1 H), 7.41
(d, J = 2.1 Hz, 1 H), 8.02 (d,
N
N
N
O
Cl
Rt = 2.09 min; MS:
m/z = 368 [M + 1]+,
370 [M + 3]+
Cl
5
B
Cl
J = 2.0 Hz, 1 H)
N
Cl
Cl
Synlett 2013, 24, 1150–1154
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Tetrasubstituted Pyrazoles
1153
Table 1 Novel Tetrasubstituted Pyrazoles (continued)
Entry Intermediate for heterocyclisation Product
1H NMR (CDCl3)
LC-MS
Method
Cl
N
Cl
Cl
3.83 (s, 3 H), 6.95 (d, J = 9.1 Hz, 1 H), Rt = 2.12 min; MS:
7.04 (d, J = 8.58 Hz, 2 H), 7.08–7.17 m/z = 355 [M + 1]+,
(m, 2 H), 7.32 (d, J = 8.51 Hz, 2 H)
F
6
B
B
357 [M + 3]+
N
F
N
Cl
Cl
N
Cl
Cl
3.76 (s, 3 H), 7.11 (dd, J = 2.63,
8.12 Hz, 2 H), 7.19–7.23 (m, 4 H),
7.40–7.44 (m, 3 H)
Rt = 1.18 min; MS:
m/z = 303 [M + 1]+,
305 [M + 3]+
7
N
N
Cl
Online 2010, 5. (e) McDonald, E.; Jones, K.; Brough, P. A.;
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In conclusion, we have established two different reaction
pathways for the preparation of novel 3-chloro-1-methyl-
4,5-diarylpyrazoles, which are analogues of highly active
imidazole fungicides.17 Both approaches rely on the cy-
clocondensation of a diarylated three-carbon synthon with
a hydrazine derivative. One type of reagent, 3,3-dichloro-
propenones, allows a ring closure reaction that directly
leads to chlorinated pyrazoles, because only one of the
two vinylic chlorine atoms is required for pyrazole forma-
tion. However, the condensation of 3,3-dichloroprope-
nones with methyl hydrazine leads to the undesired 1-
methyl-5-chloropyrazole. 2,3-Diarylacrylonitriles, the
second kind of diarylated three-carbon synthons applied,
facilitated a more direct approach to the desired fully sub-
stituted pyrazoles, because their transformation into the
target compounds was possible in only three steps, the last
one being a rarely described Sandmeyer reaction at a pyr-
azole nucleus. Several of the fully substituted pyrazoles
described here showed excellent activity against Uncinula
necator (grape powdery mildew) in whole-plant assays.
(6) For some reviews on agrochemically active pyrazoles, see:
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F. M. J. Heterocycl. Chem. 2004, 41, 109. (g) Kashima, C.
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(8) For a review on tetrasubstituted pyrazoles, see: Dadiboyena,
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(10) Lamberth, C.; Querniard, F. Tetrahedron Lett. 2008, 49,
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References and Notes
(1) Montel, F.; Lamberth, C.; Jung, P. M. J. Tetrahedron 2008,
64, 6372.
(2) Crowley, P. J.; Lamberth, C.; Müller, U.; Wendeborn, S.;
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T.; Kempf, H.-J.; Godwin, J.; Schneiter, P.; Dobler, M. R.
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(3) Lamberth, C.; Trah, S.; Wendeborn, S.; Dumeunier, R.;
Courbot, M.; Godwin, J.; Schneiter, P. Bioorg. Med. Chem.
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(4) Lamberth, C.; Dumeunier, R.; Trah, S.; Wendeborn, S.;
Godwin, J.; Schneiter, P.; Corran, A. Bioorg. Med. Chem.
2013, 21, 127.
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D.; Bolasco, A.; Chimenti, P.; Carradori, S. Curr. Med.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1150–1154

1154
R. Dumeunier et al.
LETTER
methyl-1H-pyrazol-3-ylamine (16): Et3N (0.16 g, 1.6
Org. Chem. 2003, 39, 1069. (d) Levskovskaya, G. G.;
Bozhenkov, G. V.; Larina, L. I.; Mirskova, A. N. Russ. J.
Org. Chem. 2002, 38, 1501.
mmol) and methylhydrazine (0.75 g, 16 mmol) were added
consecutively to a solution of 14 (0.5 g, 1.6 mmol) in MeOH
(10 mL). The reaction mixture was heated to reflux for 72 h,
then cooled and concentrated under reduced pressure to
obtain 15 (0.44 g, 1.3 mmol), which was dissolved in CHCl3
(10 mL). MnO2 (1.1 g, 13 mmol) was added and the reaction
mixture was stirred for 2 h at r.t., then diluted with EtOAc
and filtered over Celite. The filtrate was concentrated under
reduced pressure and the residue was purified by column
chromatography on silica gel (EtOAc–cyclohexane, 3:2), to
deliver 16 (0.12 g, 0.35 mmol, 22% from 14). 1H NMR
(CDCl3): δ = 3.69 (s, 3 H), 3.77 (s, 3 H), 6.41 (d, J = 9.08 Hz,
2 H), 7.15 (d, J = 8.9 Hz, 2 H), 7.33 (d, J = 8.45 Hz, 2 H).
LC-MS: Rt = 1.84 min; MS: m/z = 350 [M]+, 352 [M + 2]+.
3-Chloro-5-(4-chlorophenyl)-4-(2,6-difluoro-4-
(14) (a) Yue, Y.; Fang, H.; Wang, M.; Wang, Z.; Yu, M. J. Chem.
Res. 2009, 377. (b) Oh, K.-B.; Kim, S.-H.; Lee, J.; Cho, W.-
J.; Lee, T.; Kim, S. J. Med. Chem. 2004, 47, 2418.
(c) Zupancic, B.; Kokalj, M. Synthesis 1981, 913. (d) Kulp,
S. S.; Caldwell, C. B. J. Org. Chem. 1980, 45, 171.
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Phosphorus, Sulfur Silicon Relat. Elem. 1998, 133, 103.
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E.; Algharib, M. S. J. Chem. Res. 1994, 286.
(16) (a) da Silva, D.; Samadi, A.; Chioua, M.; do Carmo
Carreiras, M.; Marco-Contelles, J. Synthesis 2010, 2725.
(b) Reimlinger, H.; Van Overstraeten, A. Chem. Ber. 1966,
99, 3350.
(17) Typical Procedures:
methoxyphenyl)-1-methyl-1H-pyrazole (2): Compound
16 (60 mg, 0.17 mmol) was dissolved in concd HCl (0.5 mL)
and cooled to 0 °C. A solution of NaNO2 (12 mg, 0.17
mmol) in H2O (0.1 mL) was then added dropwise. A solution
of CuCl (17 mg, 0.17 mmol) in concd HCl (0.3 mL) was
added and the reaction mixture was heated to 60 °C for
30 min, then the reaction mixture was neutralized by the
addition of NaOH and diluted with EtOAc. The phases were
separated and the aqueous phase was extracted twice with
EtOAc and the combined organic layer was dried over
Na2SO4, filtered, and evaporated under reduced pressure.
The residue was purified by chromatography on silica gel
(EtOAc–hexane, 1:9), to deliver 2 (32 mg, 0.08 mmol, 51%).
(Z)-3-(4-Chlorophenyl)-2-(2,6-difluoro-4-methoxy-
phenyl)acrylonitrile (14): K2CO3 (2.42 g, 17 mmol) was
added to a solution of (2,4,6-trifluorophenyl)-acetonitrile
(2.5 g, 14 mmol) and 4-chlorobenzaldehyde (2.0 g, 14 mmol)
in MeOH (30 mL). The reaction mixture was heated to reflux
for 16 h, cooled, poured into H2O and filtered. The solid was
washed twice with H2O and twice with heptane, and dried
under vacuum to obtain 14 (1.28 g, 4.2 mmol, 30%). 1H
NMR (CDCl3): δ = 3.84 (s, 3 H), 6.55 (d, J = 9.15 Hz, 2 H),
7.22 (s, 1 H), 7.43 (d, J = 8.51 Hz, 2 H), 7.82 (d, J = 8.74 Hz,
2 H). LC-MS: 1.69, 305 [M+], 307 [M++2].
5-(4-Chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-1-
Synlett 2013, 24, 1150–1154
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