Synthesis of tetra-substituted pyrazoles

Article abstract of DOI:10.1016/j.tet.2012.07.069

A set of highly substituted pyrazoles bearing different functional groups on the pyrazole core was developed. Employing a suitable protecting group strategy we could regioselectively introduce various substituents in position 1, 3 and 4 of the pyrazole. T

Full text of DOI:10.1016/j.tet.2012.07.069

Tetrahedron 68 (2012) 8823e8829
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Tetrahedron
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Synthesis of tetra-substituted pyrazoles
a
b
a,
*
€
€
Anne J. Ruger , Martin Nieger , Stefan Brase
a Karlsruhe Institute of Technology (KIT), Institute for Organic Chemistry, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
b Department of Chemistry, Laboratory of Inorganic Chemistry, P.O. Box 55, FIN-00014 University of Helsinki, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 May 2012
Received in revised form 9 July 2012
Accepted 19 July 2012
Available online 7 August 2012
A set of highly substituted pyrazoles bearing different functional groups on the pyrazole core was de-
veloped. Employing a suitable protecting group strategy we could regioselectively introduce various
substituents in position 1, 3 and 4 of the pyrazole. This enabled the synthesis of various derivatives of
a pyrazoleebiscarboxamide with insecticidal activity. During the optimization process we focused on the
precise exchange of carboxamide as well as other functional groups based on the concept of
bioisosterism.
Keywords:
Insecticide
Ó 2012 Elsevier Ltd. All rights reserved.
Pyrazole
Amide bond mimic
1. Introduction
Me
O
HN
Br
Since insects, fungi and other threats for agriculture become
resistant against common pesticides there is an urgent need for
novel agrochemicals ensuring the maintenance of world’s pop-
ulation with food. Using the concept of bioisosterismdthat de-
rivatives with close geometric and electronic properties should
show similar effects in biological systemsdthe optimization of lead
structures towards pesticidal agents focuses on physicoechemical
properties and metabolic stability.1e3 Amide bonds are a prevalent
motif in natural products as well as other biologically active com-
pounds. Accordingly it’s not surprising that several agrochemicals
include amides, e.g., the pyrazoles Rynaxypyr (1, insecticide) or
Sedaxane (2, fungicide) Fig. 1.4 Although amides are easily acces-
sible via simple chemical reactions they can be unstable towards
hydrolysis in vivo. For this reason numerous possibilities for the
bioisosteric replacement of amides with amide bond mimics have
been investigated.5,6 Due to the requirement for absorption of
pesticides into plants, water solubility of the derivatives plays an
important role in the optimization process.7
F
O
H
N
F
NH
N
N
Cl
O
N
Cl
N
N
Me
Rynaxypyr (1)
insecticide,
Sedaxane (2)
fungicide,
DuPont
Syngenta
Fig. 1. Modern pesticides with pyrazole core.
When optimizing this insecticide we focused on bioisosteric
replacement of the amide-bonds because this might enhance
metabolic stability or activity. Amide bond mimics, as well as the
introduction of heterocyclic substituents, affect intra- and in-
termolecular H-bonds the derivatives can form, which might have
a positive effect on water solubility.
Herein we present synthetic studies towards different bio-
isosters based on the insecticidal pyrazolebiscarboxamide
3
2. Results and discussion
(Fig. 2).8 This lead structure already has a moderately strong in-
secticidal effect on chewing insects (e.g., spodoptera), but a low
solubility in water (1.2 mg/L), which might be the reason for the
limited biological activity.
For mimicking the amide-bonds we targeted the retro-amide-
4, urea- 5 and ester-moiety 6, as well as amine 7 and oxo-
methylene 8, which are shown exemplarily at position four of the
pyrazole (Fig. 3, top row). Beside those modifications we regar-
ded pyridine 9 and the 1,3-dioxanes 10 and 11 as suitable bio-
isosteres bearing a heterocyclic moiety (Fig. 3, bottom row).
* Corresponding author. Fax: þ49 721608 48581; e-mail addresses: stefan.braese@
€
kit.edu, braese@kit.edu (S. Brase).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.069

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A.J. Ruger et al. / Tetrahedron 68 (2012) 8823e8829
8824
corresponding esters 20 and 23 can act as precursors for the syn-
thesis of several bioisosteres of the lead structure.
2.2. Amide-mimicseesters
We were able to convert carboxylic acid 24 in moderate yield to
the first target structure, ester 26, using the same protocol as per
amide synthesis (Scheme 3). Aromatic esters are generally not that
stable towards hydrolysis, which may be one reason for the mod-
erate yield. Furthermore phenols show a rather low nucleophilicity.
Employing the same pathway to the alternate ester 6 was less
successful and did not lead to the desired product in reasonable
Fig. 2. Insecticidal lead structure 3 (H-bonding network derived from the X-ray crystal
structure).
Fig. 3. Target structures, modified at position four of the pyrazole.
time (Scheme 4), suggesting that alcohol 27 is only poorly nucle-
ophilic. Using EDC with 4-(N,N-dimethylamino)pyridine (DMAP) as
additive in dichloromethane lead primarily to a bicyclic imide 28
through intramolecular ring closure.13 Presumably deprotonation
of the amideenitrogen occurs, which is then nucleophilic enough
to attack the activated carboxylic acid. Due to the formation of the
by-product 28 we decided to use the Mitsunobu-reaction for the
formation of ester 6.14 It does not matter that inversion of the al-
cohol occurs because alcohol 27 was used as a mixture of isomers
and we are interested in both diastereomers, i.e., cis and trans 6.
Unfortunately the yield was also low for this reaction and neither
elongated reaction time nor higher temperature (40 ꢀC) improved
the efficiency of this reaction.
Fig. 4. Orthogonally protected pyrazolebiscarboxylic acids 12 and 13.
2.1. Synthesis of precursors
Regioselective syntheses of tetra-substituted pyrazoles are
subject of ongoing research, but mainly deal with cores bearing
alkyl and/or aryl substituents next to at most one functional
group.9e11 Thus synthetic routes for all amide-mimics and 1,3-
dioxanes have been designed, which use functional group trans-
fer as a main tool and are based on common precursorsdthe
contrarily protected pyrazolebiscarboxylic acids 12 and 13 (Fig. 4).
While methyl carboxylate 12 was provided by Bayer CropScience
(BCS), ethyl carboxylate 13 was synthesized in very good yields
using a method developed by Veronese et al. for the synthesis of
pyrazolebiscarboxylates (Scheme 1).12 This synthesis proceeded
regioselectively as only one isomer, pyrazole-3,4-dicarboxylate 18,
occurred. Its structure was confirmed by X-ray crystallography of
the free carboxylic acid 13 (Fig. 5).
The pyrazolecarboxylates, 12 and 13, were reacted with 3-(tri-
fluoromethoxy)aniline 19 and 4-(trifluoromethyl)cyclohexanamine
22, respectively, using N-(3-dimethylaminopropyl)-N0-ethyl-
carbodiimide hydrochloride (EDC) as coupling reagent. After sa-
ponification free carboxylic acids 21 and 24 were obtained in
excellent yields over two steps (Scheme 2, for an X-ray structure
of acid 21 see Supplementary data). These acids and the
Scheme 1. Synthesis of ethyl pyrazolecarboxylate 13.

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A.J. Ruger et al. / Tetrahedron 68 (2012) 8823e8829
8825
Scheme 4. Synthesis of ester 6 and cyclic by-product 28. Reagents and conditions: (a)
EDC, cat. DMAP, CH2Cl2, rt, 3d; (b) PPh3, DIAD, THF, rt, 20 h to 3 days.
Fig. 5. X-ray crystal structure of carboxylic acid 13. Displacement parameters are
drawn at 50% probability level.
Scheme 5. Synthesis of bromides 30 and 32. Reagents and conditions: (a) NaBH4,
MeOH, rt, 1d; (b) CBr4, PPh3, MeCN, 65 ꢀC, 14 h; (c) PBr3, pyridine, Et2O, 0 ꢀC rt, 5e15 h.
Scheme 2. Synthesis of precursors 20, 21, 23 and 24.
Scheme 3. Synthesis of ester 26.
2.3. Amide-mimicseamines and ethers
To access more bioisosters of the lead structure we performed
a functional group conversion on precursors 20 and 23 with the
goal of introducing a leaving group into the pyrazolic system
(Scheme 5). To this end we reduced both carboxylates 20 and 23 to
alcohols 29 and 31 in quantitative yield, followed by bromination.15
These bromides 30 and 32 should serve as starting material for
the synthesis of both amines and ethers in one-step. As the syn-
thesis of amine 7 proceeded in a reasonable yield we applied
similar conditions to the synthesis of ether 8, as shown in Scheme 6.
Scheme 6. Conversion of bromide 30 with different nucleophiles. Reagents and con-
ditions: (a) K2CO3, DMF, 90 ꢀC, 1.5 h, 65%; (b) Cs2CO3, DMF, 90 ꢀC, 1.5 h, 70%; (c) NaH,
DMF, rt ꢁ80 ꢀC, 30 min, 5%.

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Again the amide functionality showed a high nucleophilicity, be-
cause intramolecular cyclization was faster than addition of mod-
erately nucleophilic alcohol 27 and yielded the bicyclic system 33 in
good yield. Changing the base to potassium carbonate also led to
the intramolecular addition albeit in lower yield (33%). The use of
the stronger base sodium hydride led to a coupled product 34 in
a small amount and in addition caused defluorination at the
trifluoroethyl-unit. Due to low yield only one isomer (cis or trans) of
compound 34 could be isolated and identified, though a mixture of
isomers was employed for alcohol 27.
As it is shown in Scheme 9 further steps for the synthesis of both
retroamides proceeded in good to excellent yields. We were able to
get an X-ray of the cis isomer of target structure 4, which helped us
once more to determine the configuration of the cyclohexyl-
substituents. The solid state structure of this bisamide is surpris-
ing since both carbonyl groups point in a similar direction (Fig. 7).
Importantly, there are no intramolecular hydrogen bonds between
the amide groups, thus we assume the structure to be less rigid
than is the case for the lead structure 3, which we hoped would
enhance water solubility.
The second bromide 32 could easily be employed for the syn-
thesis of amine 35 and ether 36 without degradation or other side
reactions (Scheme 7). To facilitate substitution with phenol 25 we
added tetrabutylammonium iodide to the reaction mixture.
2.5. Amide-mimicseurea derivatives
Besides retroamides urea derivatives were accessible via Curtius
rearrangement too.16 Again starting from carboxylic acids 12 and 13
the significant moiety was introduced within one step. Whereas
urea formation at position 3 of the pyrazole occurred at room
temperature we observed amide synthesis at position 4 using the
same reaction conditions. Therefore we heated the reaction mix-
ture to 90 ꢀC before adding the amine to facilitate rearrangement of
the azide to the intermediate isocyanate (Scheme 10).
Saponification of ester 46 led directly to the bicyclic pyr-
imidinedione 49. The free acid 48 was only obtained as a side
product. Deprotection in acidic media or under nucleophilic con-
ditions using lithium iodide did not lead to free acid 48 either
(Scheme 11). Therefore we decided to convert ester 46 directly into
an amide using a protocol described by Weinreb.17 Trimethylalu-
minium allows the one step conversion of esters into amides
through activation of the corresponding amine in situ. Thus we
were able to synthesize urea 50 in low yield, but unreacted ester 46
could be recovered after column chromatography.
A standard protocol using EDC was used for the synthesis of the
other urea derivative 5. Employing saponification of ester 47 fol-
lowed by amide-synthesis we were able to synthesize urea 5 in
medium yield over two steps (Scheme 12).
Scheme 7. Synthesis of amine 35 and ether 36. Reagents and conditions: (a) K2CO3,
DMF, 90 ꢀC, 5 he17 h, up to 46%; (b) K2CO3, Bu4NI, DMF, 90 ꢀC, 17 h to days, up to 77%.
2.4. Amide-mimicseretroamides
For the synthesis of retroamides 4 and 43 nitrogen substituted
pyrazoles were needed. Those could easily be obtained from car-
boxylic acids 12 and 13 through Curtius rearrangement.16 After
saponification both Boc-protected amino carboxylic acids 38 and 40
were synthesized in good yields and readily crystallized (see
Scheme 8, X-ray crystal structures shown in Fig. 6).
2.6. Other bioisosteres
In order to improve the water solubility of the lead structure, we
introduced
a pyridine-moiety as a replacement for the tri-
fluoromethyl group. Since this position is easily accessible we
derivatized the functional group on the central pyrazole core. As
was the case for the synthesis of trifluoroethyl substituted pyrazole
18 we obtained only one regioisomer 53 in the condensation of
b
-enaminoketone 16 with hydrazine 52 (Scheme 13).12 Further
deprotection and coupling steps provided pyrazolebiscarboxamide
9 in good to excellent yields (48% overall, 5 steps).
Another approach to enhance water solubility is the in-
troduction of further heteroatoms. Thus we regarded acetals 10 and
11 as interesting targets, whose syntheses are based on diol 58,
which can be obtained in good yield from acid 21 (Scheme 14).
There is very little literature available about the synthesis of acetals
derived from trifluoroacetaldehyde and we initially followed
a route via activation of the diol as described by Smithers.18 With
tosylchloride we did not achieve monotosylation of the diol, and
instead the bicyclic product 59 was isolated (Scheme 14).
Scheme 8. Synthesis of amino carboxylic acids 38 and 40.
Since the linear route did not succeed, we examined a building
block approach with protected serinol 60 (Scheme 15).18,19 It was
possible to cyclize activated diol 61 with in situ generated fluoral
63, but the products obtained were supposed to be oxazolidines 65,
not acetals 64, as determined by NMR spectroscopy. It appears that
the reaction is not reproducible and not suitable for the synthesis of
those oxazolidines or acetals, such as 64.
Amide formation with carboxylic acid 38 led to amide 41, which
could also be crystallized (Fig. 6). The X-ray crystal structure of
amide 41 (pure trans isomer crystallized) proofed the configuration
of the cyclohexane moiety to be correct, which was determined by
comparison of 1H NMR spectra with the data for the lead com-
pound 3 before. Thus we continued to elucidate cis or trans con-
figurations via NMR analyses.
Other approaches for the synthesis of acetal 64 employing the
ethyl hemiacetal of trifluoroacetaldehyde, which is easier to handle,

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A.J. Ruger et al. / Tetrahedron 68 (2012) 8823e8829
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Fig. 6. X-ray structure of carboxylic acids 40 (left) and 38 (middle) as well as amide 41 (right). Displacement parameters are drawn at 50% probability level.
Scheme 9. Synthesis of retroamides 4 and 43. Reagents and conditions: (a) EDC, HOBt, DMF, 80 ꢀC, 7 h to 3 days; (b) TFA, H2O, CH2Cl2, rt, 20e50 min.
Fig. 7. Solid state structure of retroamide 4. Displacement parameters are drawn at
50% probability level, only the major part of the disordered trifluoroethyl group is
shown.
Scheme 10. Curtius rearrangement towards ureas 46 and 47. Reagents and conditions:
(a) NEt3, DPPA, DMF, 0 ꢀC to rt, 3e18 h; (b) NEt3, DPPA, DMF, 90 ꢀC, 3 h, then 22, 0 ꢀC to
rt, 2.5 h.

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Scheme 14. Isolation of a bicyclic product on the route to acetal 10. Reagents and
conditions: (a) EDC, HOBt, DMF, 80 ꢀC, 2.5d; (b) pTsCl, NEt3, CH2Cl2, 0 ꢀC rt, 3d.
Scheme 11. Synthesis of urea 50.
Scheme 15. Synthesis of trifluoromethyl substituted oxazolidine 65. Reagents and
conditions: (a) pTsCl, NEt3, CH2Cl2, 0 ꢀC to rt, 1d; (b) in situ generated 63, THF, ꢁ78 ꢀ
C
to rt, 4 h, then K2CO3, 55 ꢀC, 15 h.
Scheme 12. Synthesis of urea 5. Reagents and conditions: (a) LiOH, THF/H2O, rt, 21 h,
99%; (b) EDC, HOBt, DMF, 80 ꢀC, 1d.
Overall we were able to synthesize nine amide bond-mimics of
the lead structure as well as two isosteres with a pyridine moiety.
These and all precursors and side products are currently under
investigation for their biological activity.
under various conditions did not succeed. Nor did the conversion of
this hemiacetal into its tosylate give any advantage.20,21
Since the synthesis of acetal 10 had failed, we decided to in-
troduce a dioxane and pyridine moiety simultaneously to give ac-
etal 11. We recently reported the synthesis for 5-amino-1,3-dioxane
66 and for this reason we decided to compare the linear approach
with a building block strategy for the synthesis of acetal 11
(Scheme 16).22
The building block strategy using 66 is feasible, but the overall
yield starting from acid 21 and serinol 57 is higher for the linear
route (32% vs 27%). Furthermore only two steps instead of four are
necessary in this pathway, since no building block has to be syn-
thesized beforehand.
3. Conclusions
In the present study the design and synthesis of highly
substituted pyrazoles is reported. Central amide bonds of an in-
secticidal lead structure were converted into a retroamide-, urea-
and ester-moiety, as well as an amine- and oxomethylene-group,
based on the concept of bioisosterism. Furthermore pyridine sub-
stituents were introduced. Due to the high nucleophilicity of the
EtO C
CO Bn
2
2
O
N
O
O
N
O
O
N
O
O
N
O
R
NH
R
NH
OBn
EtO
OH
EtO
EtO
HO
H N
2
22
O
16
d)
a)
b)
c)
N
N
N
N
+
NH
2
87%
85%
98%
92%
N
H
N
N
N
N
N
55
56
52
53
54
19
OCF3
CF3
c)
72%
O
N
O
N
H
NH
N
=
N
9
Scheme 13. Synthesis of pyridinomethylpyrazole 9. Reagents and conditions: (a) ClCH2CH2Cl, 0 ꢀC to rt, 15 h; (b) H2, Pd/C, EtOAc, rt, 21 h; (c) EDC, HOBt, DMF, 70 ꢀC, 3e4 d; (d) LiOH,
THF/H2O, rt, 1d.

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4 (CCDC-813080), 13 (CCDC-813081), 21 (CCDC-813082), 38 (CCDC-
813083), 40 (CCDC-813084) and 41 (CCDC-813085).
Acknowledgements
We acknowledge Bayer CropScience for funding.
References and notes
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ꢀ
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Scheme 16. Synthesis of pyridine acetal 11. Reagents and conditions: (a) EDC, HOBt,
DMF, 80 ꢀC, 2.5d; (b) NBS, MgSO4, toluene, 130 ꢀC, 2d; (c) EDC, HOBt, DMF, 80 ꢀC 15 h.
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14497e14506.
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aromatic amide, interesting bicyclic products with 5-, 6- and
8-membered rings were also obtained and are currently being ex-
amined for their biological activity.
4. Experimental section
€
21. Bremer, M.; Kirsch, P.; Pauluth, D.; Schoen, S.; Tarumi, K.; Lussem, G.; Heckmeier,
M.; Krause, J. Ger. Offen. 2002. DE 10134299 A1, p 34.
€ €
22. Ruger, A. J.; Nieger, M.; Es-Sayed, M.; Brase, S. Eur. J. Org. Chem. 2010, 3837e3846.
Supplementary data: Experimental details and spectroscopic data
of all newcompoundsand X-raycrystal structure data of compounds