Synthesis of functionalized cyanopyrazoles via magnesium bases

Article abstract of DOI:10.1021/ol502977a

4-Alkyl- and 4-H-pyrazoles were sequentially metalated using TMPMgCl·LiCl, and their reaction with electrophiles afforded 3-aryl-4-alkyl-5-cyanopyrazoles.

Full text of DOI:10.1021/ol502977a

Letter
pubs.acs.org/OrgLett
Synthesis of Functionalized Cyanopyrazoles via Magnesium Bases
Allan Dishington,* J. Lyman Feron, Kathryn Gill, Mark A. Graham, Ian Hollingsworth, Jennifer H. Pink,
Andrew Roberts, Iain Simpson, and Matthew Tatton
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
S
* Supporting Information
ABSTRACT: 4-Alkyl- and 4-H-pyrazoles were sequentially metalated using
TMPMgCl·LiCl, and their reaction with electrophiles afforded 3-aryl-4-
alkyl-5-cyanopyrazoles.
n a recent drug discovery project, we became interested in
the synthesis of a series of 3-cyano-4-methyl-5-arylpyrazoles
Scheme 1, we embarked on a reinvestigation of the synthetic
protocols where we wished to address synthetic efficiency and
scaleability.
I
(Figure 1). Our work has shown that the 3-cyano group is
essential for biological activity, and the C4-methyl, as well as
other C4-alkyl groups, is very interesting. Therefore, we wanted
to develop a synthetic methodology that would allow late-stage
variation of the C5-aryl ring, ideally where the 3-cyano-4-
methyl substitution was pre-established or where the C4
substitution could also be varied.
A timely addition to the literature6 came from Knochel and
co-workers, who demonstrated that substituted pyrazoles could
be prepared via a deprotonation with the tetramethylpiper-
idinylmagnesium chloride lithium chloride (TMP-MgCl·LiCl)
base 7 followed by reaction of the resultant magnesium anion
with a range of electrophiles. The scope of this work was
limited to 4-H-pyrazoles but offered the possibility to us of
shorter routes to 4-methyl-5-cyanopyrazoles 9 (R = Me, R1 =
CN) as well as opening up the later investigation of differing
substituents in the pyrazole 4-position 11 (Scheme 2). We
reasoned that if we could develop Knochel’s work to 4-
alkylpyrazoles 8 (R = alkyl) then substitution into the 5-
position of 4-alkylpyrazoles could be achieved via magnesiation
to give compounds of type 9 (R = alkyl). This would be
followed by 3-position magnesiation, transmetalation with
zinc(II), and then cross-coupling to afford alkylpyrazoles 10
(R = alkyl) with suitably functionalized aryl groups at the 3-
position. The single example of this deprotonation−Negishi
protocol introduced an aromatic system into an unsubstituted
pyrazole,6 whereas we were looking to extend this chemistry to
sterically and electronically complex pyrazoles. This approach
would ensure that a range of substituted aryl groups could be
introduced in the last step of the sequence, enabling us to
synthesize a diverse range of medicinally important pyrazoles.
We would have to demonstrate that the magnesiation
chemistry could be advanced to include 4-alkylpyrazoles as
well as develop a previously unreported magnesiation−Negishi
coupling between aromatic sulfonamides and 4,5-disubstituted
pyrazoles. To this end we set about developing a new synthetic
route for the production of a range of 4-methylpyrazoles.
Commercially available 4-methylpyrazole 12 was treated with
sodium hydride in N,N-dimethylformamide for 1 h and then
was treated with silylethoxymethyl chloride to give the SEM-
protected pyrazole 13 in 81% yield. The methylpyrazole 13 in
tetrahydrofuran was magnesiated at position 5 with TMP−
Trisubstituted pyrazoles1 are generally obtained either by the
addition of hydrazines to 1,3-dicarbonyl compounds1 or 1,3-
dipolar cycloadditions.2
We anticipated that the pyrazole nonaflate 5 could undergo a
metal-catalyzed cross-coupling with a range of organometallics
to give the arylpyrazoles.3 The nonaflate 5 could be prepared
according to known procedures,4a and we were able to prepare
multiple gram of the nonaflate 5 but via conditions that were
not ideal. Treatment of the diester 1 with hydrazine gave the
pyrazole 2 in 66% yield, and protection gave the ester 3 as a
single regioisomeric N-protected THP ether. The conversion of
the ester 3 to the nitrile 4 with lithium hexamethyldisilazide was
only possible in sodium-distilled tetrahydrofuran under micro-
wave irradation or in a sealed vessel at 140 °C and then only in
32% isolated yield.5 The alcohol 4 was treated with sodium
hydride and nonaflyl fluoride to give the nonaflate 5.4b
However, the major disadvantages of this chemistry were the
yields for the subsequent Suzuki coupling of the nonaflate 5
with arylboronic acids and esters. When the nonaflate 5 in
dioxane containing the boronic acid, potassium carbonate, and
tetrakis(triphenylphoshine)palladium (0) was heated at 120 °C
for 30 min, the typical isolated yields for the arylpyrazoles 6
Figure 1. 3-Cyano-4-methyl-5-arylpyrazoles.
were in the 10−40% range after chromatography. An extensive
catalyst and solvent screen only confirmed these to be the best
coupling conditions. Given the limitation of the route in
Received: October 9, 2014
© XXXX American Chemical Society
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Scheme 1. Preparation and Coupling of the Pyrazole Nonaflate 5
Scheme 2. Successive Functionalization of Pyrazoles Using
Scheme 4. 4-Alkylpyrazoles via Magnesiation
TMPMgCl·LiCl (Knochel6)
MgCl·LiCl at room temperature. The progress of deprotona-
tion was followed by the iodination of a small aliquot of the
reaction mixture and analysis by LCMS.7 After 6 h, complete
reaction was confirmed and the mixture was treated with
phenylsulfonyl cyanide. The 2-cyano-3-methylpyrazole 14 was
isolated in 87% yield after silica gel chromatography (Scheme
3).
Scheme 3. Successive Functionalisation of Pyrazoles Using
TMPMgCl·LiCl 7
With the cyanopyrazole 14 in hand, we were able to look at
CH functionalization of the C5-position. We envisioned a
Negishi cross-coupling may be applicable in this situation.
When 14 was treated with base 7 in THF at −16 °C, full C5
magnesiation was observed after 5 h. Zinc chloride (1.0 M in
diethyl ether) was added, the reaction mixture was allowed to
warm to ambient temperature, and an aryl bromide in N,N-
dimethylformamide followed by catalyst was added. The
mixture was heated at 70 °C for 2 h, and following treatment
of the crude product with aqueous sulfuric acid, we were
pleased to isolate the arylpyrazole 15 after silica gel
chromatography. Yields were generally good (Table 1);
however, aryl sulfones (entries 2 and 4) were superior coupling
partners compared to the aryl sulfonamides (entries 1 and 3) as
it appears that an acidic N−H partially quenches the
organometallic reagent to give recovery of starting material.
This reliable chemistry improved the preparation of pyrazole
15c from a five-step 5% sequence via the nonaflate 5 to three
steps in 57% via the magnesium base technology and represents
the first application of this methodology to 4-alkylpyrazoles. Of
particular note is the coupling of aryl sulfonamides; we were
easily able to execute this chemistry on larger scale to prepare
13 g of the pyrazole 15a.
Table 1. Negishi Cross-Coupling of 4-Methylpyrazoles with
Aryl Bromides
We next wished to explore the SAR around 4-position alkyl
groups in a cyanopyrazole, which necessitated the synthesis of
3-cyano-4-alkyl-5-arylpyrazoles. The absence of literature would
indicate that preparation of these compounds is not trivial, and
we were able to prepare only a limited number of 4-halo
derivatives by established methods. Ideally, we required carbon
substituents in the 4-position. Once again, we were able to
apply sequential pyrazole deprotonation methodology to
prepare this substitution pattern (Scheme 4).6
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LiCl 7, and quenching with tosyl cyanide gave the nitrile 18 in
73% yield after silica gel chromatography. This material was
subjected to the same base 7, and the anion was quenched with
either iodine or tetrabromodichloroethane to afford the 3-iodo-
19a (65%) or 3-bromopyrazole 19b (74%).
Table 2. Preparation of 4-Alkylpyrazoles and Coupling to
Bromoarenes
The literature observes that the third deprotonation in the 4-
position of disubstituted pyrazoles requires the more basic
TMP2Mg·2LiCl unless substitution includes a carboxylate
group.6 We found that the weaker TMP−MgCl·LiCl 7 was
capable of this deprotonation at −13 °C over 1.5 h, and we
were able to quench the magnesium anion with electrophiles to
afford a range of 4-alkyl-substituted pyrazoles 20 (entries 1, 2,
and 8, Table 2). When iodide 19a was metalated under these
conditions and treated with excess iodomethane at 20 °C, the
methylpyrazole 20a was isolated in 67% yield (entry 1). The
same metalated iodide 19a also reacted with morpholine-4-
carbaldehye to give the aldehyde 20b in 61% yield (entry 2).
The metalated bromide 19b reacted with morpholine-4-
carbaldehyde to give the aldehyde 20g in 48% yield (entry 8).
While the scope of this reaction will be explored further with
a wider range of electrophiles, we desired to elaborate further
the existing 4-position substituents. The aldehyde 20b could be
reduced with sodium borohydride to the alcohol 20c in 72%
yield (entry 3) or reacted with methylmagnesium bromide
(40%) to give the alcohol 20d (entry 5). The bromoaldehyde
20g gave the difluoromethylene pyrazole 20i in 69% yield when
treated with Deoxo-fluor (entry 10). The 4-ethylpyrazole 20h
was prepared in 41% from the aldehyde 20g in two steps
(Wittig methylenation followed by hydrogenation) (entry 9).
The alcohol 20d could be oxidized under Swern conditions to
give the ketone 20e (86%) (entry 6), which on methylenation
via a Wittig reaction (77%) gave alkene 20f (entry 7). With a
range of 3-halo-4-alkylpyrazoles in hand, we were finally able to
attempt aryl substitution at the 3-position (the aldehydes 20b
and 20g were excluded from this coupling). Gratifyingly, the 3-
halopyrazoles were coupled with a suitable boronic acid under
palladium catalysis to afford the synthetically challenging 3-aryl-
4-alkylpyrazoles 15a and 21 in 56−88% yield. Removal of the
SEM group was readily achieved by treatment with aqueous
sulfuric acid or tetrabutylammonium fluoride.
In summary, we have prepared a range of 3-cyano-4-alkyl-5-
arylpyrazoles via the application of regioselective magnesium
amide base protocols and have demonstrated that this
previously unknown biologically privileged structure is readily
accessible to the medicinal chemist. In a significant advance-
ment to the established methods, we have shown that 4-
alkylpyrazoles can now be deprotonated with magnesium bases
and that after deprotonation disubstituted pyrazoles can be
readily functionalized with complex aromatic groups. The aryl
group was introduced by either a Suzuki coupling or by a direct
deprotonation−zincation Negishi reaction.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
Pyrazole 16 in N,N-dimethylformamide was treated with
sodium hydride and silylethoxymethyl chloride to give the
SEM-protected pyrazole 17 in 86% yield. Magnesiation in the
5-position was achieved at 20 °C over 1 h with TMP−MgCl·
*E-mail: allan.dishington@astrazeneca.com.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank Howard Beeley and David Whittaker (Oncology
Innovative Medicines, AstraZeneca) for NMR spectroscopy,
Paul Davey (Oncology Innovative Medicines, AstraZeneca) for
mass spectrometry, and Caroline McMillan and Becky Burton
(Oncology Innovative Medicines, AstraZeneca) for purification
services.
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