Two convenient regioselective syntheses of 1-N-alkyl-3-aryl-4-[pyrimidin-4-yl]-pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2008.12.113

Two regioselective synthetic routes for 1-N-alkyl-3-aryl-4-[pyrimidin-4-yl]-pyrazoles of generic formula 1 were developed. These highly efficient and scalable routes circumvent the generally observed poor regioselectivity for the pyrazole alkylation.

Full text of DOI:10.1016/j.tetlet.2008.12.113

Tetrahedron Letters 50 (2009) 1377–1380
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Tetrahedron Letters
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Two convenient regioselective syntheses of 1-N-alkyl-3-aryl-4-[pyrimidin-4-yl]-
pyrazoles
*
Jeffrey M. Ralph , Thomas H. Faitg, Domingos J. Silva, Yanhong Feng,
Charles W. Blackledge, Jerry L. Adams
Medicinal Chemistry, Oncology CEDD, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Two regioselective synthetic routes for 1-N-alkyl-3-aryl-4-[pyrimidin-4-yl]-pyrazoles of generic formula
1 were developed. These highly efficient and scalable routes circumvent the generally observed poor reg-
ioselectivity for the pyrazole alkylation.
Received 19 September 2008
Revised 19 December 2008
Accepted 22 December 2008
Available online 13 January 2009
Published by Elsevier Ltd.
The aurora kinases are a family of serine/threonine kinases,
which play crucial roles in the cell cycle. Deregulation of Aurora ki-
nase activity can result in mitotic abnormality and genetic instabil-
ity, leading to defects in spindle assembly, chromosome alignment
and cytokinesis. Both the expression and the kinase activity of Aur-
ora kinase are found to be up-regulated in many human cancers.
Taken together, these data suggest the potential utility of Aurora
kinase inhibitors as novel agents to treat cancer. Our quest for a
Aurora kinase inhibitor as a potential agent to treat cancer led us
to the investigation of a pyrazole template as an interesting
scaffold.
One scaffold we investigated in pursuit of novel Aurora kinase
inhibitors was the 1-N-alkyl-3-aryl-4-[pyrimidin-4-yl]-pyrazoles,
such as 1. This scaffold allows for the arrangement of three diver-
sity elements around the central pyrazole core. However, at the
start of our investigation, to the best of our knowledge, there
was no published report of a concise, scalable and regioselective
synthesis of such compounds. This Letter summarizes our explora-
tion into the regioselective synthesis of these trisubstituted
pyrazoles.
Commercially available ethyl para-amino-benzoate 2 was acylated,
and then reacted with the lithium anion of 4-methyl-2-thiomethyl-
pyrimidine to afford ketone 3. Treatment of 3 with the dimethyl ace-
tal of dimethylformamide (DMF–DMA), followed by reaction with
hydrazine, yielded pyrazole 4. Oxidation of the sulfide afforded the
sulfone 5. Alkylation of the 1H-pyrazole core resulted in a 1:1 mixture
of the desired b-isomer 6b and the a-regioisomer 6a.
The mixture of regioisomers was then reacted with aniline, in
the presence of sodium hexamethyldisilazide at low temperature,
to afford a 1:1 mixture of regioisomers 7a and 7b. Separation of
the regioisomers (6a/6b or 7a/7b) was possible, but the ease of
separation was compound dependent and required development
of the appropriate chromatographic method. Furthermore, the lack
of regioisomeric control in the alkylation automatically reduces the
overall yield, hampering any scale-up campaign required for effec-
tive SAR investigation.
Facing these challenges, we explored alternative synthetic ap-
proaches to the desired b-isomer. Few regioselective synthetic pro-
cedures favoring the b-substituted 1-N-alkyl-3,4-diaryl-pyrazole
have been reported in the literature.1b Most of them are based on
the formylation of an arylbenzylketone, followed by reaction with
monosubstituted hydrazine (R2NHNH2) and spontaneous cycliza-
tion to form the b-R2-substituted pyrazole ring.1b,2 This approach
was successful for R2 = acyl and aryl, but failed for R2 = alkyl, limit-
ing the scope of our SAR.
H
R1
N
α
N
O
β
N R2
Building on the chemistry displayed in Scheme 1, we initially
attempted to identify conditions that would favor the b-alkylation
of a 3-aryl-4-[pyrimidin-4-yl]-1-N-H-pyrazole such as 5. The direct
alkylation of 1-N-H-pyrazoles with alkyl halides in the presence of
inorganic base was generally non-selective, as previously reported
for the case of 3,4-diaryl pyrazoles and confirmed in our hands
(data not shown).3 Use of different alkylating agents (halides or tri-
flates) and bases (sodium hydride, cesium carbonate, or potassium
t-butoxide) afforded 1:1 mixtures of isomers.4
N
N
1
HN
R3
Our initial synthesis of 1-N-alkyl-3-aryl-4-[pyrimidin-4-yl]-pyra-
zoles following published procedures1,2 is summarized in Scheme 1.
* Corresponding author. Tel.: +1 610 917 7989.
E-mail address: Jeffrey.M.Ralph@gsk.com (J.M. Ralph).
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.12.113

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J. M. Ralph et al. / Tetrahedron Letters 50 (2009) 1377–1380
O
O
HN
HN
H2N
i, ii
iii, iv
O
OEt
N
NH
O
N
N
N
N
3
4
2
SCH3
SCH3
O
O
N
HN
HN
v
α
vi
N
N
N
CH3
NH
β
N
N
N
SO2CH3
SO2CH3
5
6a (α) / 6b (β)
vii
O
HN
N
CH3
N
N
N
N
HN
N
7a (α) / 7b (β)
Scheme 1. Reaction conditions: (i) cyclopropylcarbonyl chloride, NEt3, CH2Cl2, 93%; (ii) 4-methyl-2-thiomethyl-pyrimidine, LiHMDS, À78 °C to 10 °C, THF, 98%; (iii) DMF-
DMA; (iv) N2H4ÁH2O, EtOH, 70% (two steps); (v) mCPBA, CH2Cl2, 22%; (vi) KOt-Bu, MeI, DMF, 0 °C, 58% (1:1); (vii) 3-(4-methyl-piperazin-1-yl)aniline, NaHMDS, À78 to 20 °C,
(67% for 7a, 64% for 7b).
Since the alkylation of 3,4-disubstituted pyrazoles proceeds
without selectivity, we decided to explore the regioselectivity for
the alkylation of a related substrate, 3-aryl-4-H-pyrazoles. We
hoped that the distinct electronic environment of the ring system
would allow for more selective alkylations. Such 3-aryl-4-H-pyra-
zoles would also be highly attractive from a synthetic standpoint,
since they can be easily prepared from commercially available ace-
tophenones. Furthermore, substitution at C4 could be easily intro-
duced by regiospecific halogenation of the pyrazole ring, followed
by borylation and Suzuki coupling. The retrosynthetic scheme for
the synthesis of 1 using 3-aryl-4-H-pyrazoles as intermediates is
shown in Scheme 2.
The synthetic route that is shown in Scheme 3 was thus imple-
mented. Commercially available acetophenone 8 was sequentially
treated with DMF–DMA and hydrazine, affording pyrazole 9 in 96%
yield. Alkylation of 9 using MeI in the presence of Cs2CO3, followed
by recrystallization from ethanol, afforded the pure desired b-iso-
mer 10 in 68% yield. We were pleasantly surprised that this reac-
tion not only afforded mostly the desired b-isomer but also was
easily performed in multigram scale.5 Bromination of 10 using bro-
mine afforded the desired pure 4-bromo regioisomer 12 in 68%
yield. Alternatively, 9 could be reacted with NBS to afford 4-bromo
pyrazole 11. Alkylation of 11 was also highly regioselective and
scalable (up to at least 20 g), affording 12 in 85% yield. Pyrazole
R1N
O2N
O2N
O2N
N
N
N
N
N R2
N H
N R2
N R2
O
B
regioselective
alkylation?
O
N
N
NHR3
Scheme 2.

J. M. Ralph et al. / Tetrahedron Letters 50 (2009) 1377–1380
1379
O2N
O2N
O2N
i, ii
iii
CH3
N
N
68%
N CH3
NH
O
8
9
10
v
vi
99%
68%
O2N
O2N
iv
N
N
85%
NH
N CH3
Br
Br
vii
11
12
O2N
O2N
viii
N
N
N CH3
N CH3
O
B
N
N
O
13
14
Cl
ix
O2N
N
N
x, xi
N
O
N
N CH3
N CH3
N
N
N
N
N
N
HN
N
N
HN
15
16
Scheme 3. Reaction conditions: (i) DMF–DMA, DMF, 80 °C; (ii) N2H4ÁH2O, EtOH, 70 °C, 96% (two steps); (iii) MeI, Cs2CO3, DMF, 68%; (iv) MeI, NaH, DMF, 0 °C, 85%; (v) NBS,
DMF, 68%; (vi) Br2, CHCl3, 68%; (vii) pinacol boronate ester, PdCl2(PPh3)2, KOAc, dioxane, 100 °C, 61%; (viii) 2,4-dichloropyrimidine, PdCl2(PPh3)2, Na2CO3, EtOH, water, 75%;
(ix) 3-(4-methyl-piperazin-1-yl)aniline, HCl, i-PrOH, 120 °C, 99%; (x) Sn, 6 N HCl, EtOH, 92%; (xi) phosgene, diethylamine, THF, 58%.
12 was converted to the pinacol boronate ester 13, and then was
coupled to 2,4-dichloropyrimidine under the standard Suzuki con-
ditions to form 14, a versatile intermediate containing two orthog-
onal diversity points. As shown in Scheme 3, nucleophilic
displacement of the chloride with aniline under thermal conditions
afforded compound 15. Reduction of the nitro group, followed by
treatment with phosgene and an amine, afforded compound 16.
The route that is shown in Scheme 3 affords the desired 3-aryl-
4-[pyrimidin-4-yl]-1-alkyl-pyrazoles with excellent regioselectivity.
It also allows for the late orthogonal introduction of two diversity
elements through the use of intermediate 14. This route was then
used to explore the SAR of 1.
The high regioselectivity seen in the alkylation of 9 allows for
an alternative route to 1, as outlined in Scheme 4. The pyrimi-
dine ring could be formed by condensation of a guanidine and
an enaminone.6,7 The enaminone would be derived from a 4-
acetyl-3-aryl-1-N-alkyl pyrazole, which could be formed from
the regioselective acetylation of the previously described 3-
aryl-1-N-alkyl pyrazole.
The validation of this second route is represented in Scheme 5.
Compound 10 was treated with acetic anhydride in the presence of
sulfuric acid to afford 17,8 which was converted to the enaminone
18 in 91% yield.9,10 Condensation of 18 with the guanidine 1911 in
anhydrous conditions gave pyrimidine 15. Reduction of the nitro
R1
O2N
O2N
O2N
R2
N
R2
N
N
N
N R2
N
N R2
N
O
O
CH3
N
N
NHR3
N
CH3
H3C
Scheme 4.

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J. M. Ralph et al. / Tetrahedron Letters 50 (2009) 1377–1380
O2N
O2N
N
ii
i
N
N CH3
N
CH3
O
CH3
17
10
O2N
O2N
N
iii
N
N CH3
N CH3
O
CH3
H2N
HN
NH
N
CH3
N
N
N
N
N
HN
N
CH3
H3C
19
18
15
Scheme 5. Reaction conditions: (i) Ac2O, concd H2SO4 (cat), 64%; (ii) DMF di-t-butylacetal, DMF, 91%; (iii) K2CO3, DMF, 62%.
Adams, J. L.; Faitg, Thomas, H.; Ralph, J. M.; Silva, D. J. Int. Patent
WO2007024843, 2007.
2. (a) Rheinheimer, J.; Eicken, K.; Rose, I.; Grote, T.; Ammermann, E.; Speakman, J.
-B.; Strathmann, S.; Lorenz, G. Int. Patent WO2001030154, 2001.; (b) Mueller,
U.; Eberle, M.; Pillonel, C. Int. Patent WO 2003049542, 2003.
3. (a) Schofield, K.; Grimmet, M. R.; Keene, B. R. T.. In Heteroaromatic Nitrogen
Compounds. In The Azoles; Cambridge University Press: London, 1976; (b)
Bailey, D. M.; Hansen, P. E.; Hlavac, A. G.; Baizman, E. R.; Pearl, J.; DeFelice, A. F.;
Feigenson, M. E. J. Med. Chem. 1985, 28, 256; (c) Olivera, R.; SanMartin, R.;
Dominguez, E. J. Org. Chem. 2000, 65, 7010.
4. Interestingly, reaction of the 1-H-N-pyrazole with isocyanates or acyl chlorides
afforded the beta isomer preferentially, in a 10:1 ratio or greater.
5. HPLC analysis of the crude reaction mixture showed a b-to-a ratio of 11:1.
6. (a) Bredereck, H.; Effenberger, F.; Bosch, H. B. Dtsch. Chem. Ges. 1964, 97, 3397;
(b) Gudmundsson, K.; Johns, B. Org. Lett. 2003, 5, 1369.
group, followed by urea formation, afforded the desired target 16.
This second route is highly convergent, consisting of eight linear
steps from 8 (plus the required synthesis of the guanidine 19) with
very good overall yield.
In summary, two novel, highly efficient, and scalable routes to
trisubstituted 1-alkyl-3-aryl-4-[pyrimidin-4-yl]-pyrazoles were
developed. Both the routes are based on the highly regioselective
b-alkylation of 1-H-3-aryl-4-H-pyrazoles, eliminating the need
for potentially cumbersome isomer separation. In addition, the
synthetic routes described allow for convenient introduction of
diversity at the R1 and R3 positions. Detailed biological data for
this class of compounds will be published elsewhere.
Two novel, regioselective, and scalable routes to trisubstituted
1-alkyl-3-aryl-4-[pyrimidin-4-yl]-pyrazoles have been developed.
These routes allow for the easy isolation of the desired b-substi-
tuted pyrazole and for the efficient SAR exploration around the
central core.
7. (a) Johns, B. A.; Gudmundsson, K. S.; Turner, E. M.; Allen, S. H.; Jung, D. K.;
Sexton, C. J.; Boyd, F. L.; Peel, M. R. Tetrahedron 2003, 59, 9001; (b) Stevens, K.
L.; Jung, D. K.; Alberti, M. J.; Badiang, J. G.; Peckham, G. E.; Veal, J. M.; Cheung,
M.; Harris, P. A.; Chamberlain, S. D.; Peel, M. R. Org. Lett. 2005, 7, 4753.
8. Compound 17 was also prepared from 9 in similar overall yield using a longer
synthetic sequence based on the 4-iodo pyrazole intermediate shown below:
1. Cu, PdCl2(PPh3)2
1. NIS, DMF
TMS-acetylene,
toluene, Et3N
2. TFA, water, CH2Cl2
2. MeI, NaH
3. recrystallization
from EtOH
Supplementary data
O2N
17
9
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.12.113.
N
98% (2 steps)
65% (over 3 steps)
N
CH3
I
9. Tavares, F. X.; Boucheron, J. A.; Dickerson, S. H.; Griffin, R. J.; Preugschat, F.;
Thomson, S. A.; Wang, T. Y.; Zhou, H.-Q. J. J. Med. Chem. 2004, 47, 4716.
10. The enaminone was also prepared by reaction of the arylmethylketone with
DMF–DMA as the solvent, but the yield was lower.
11. Guanidine 19 was prepared by treating 3-(4-methyl-piperazin-1-yl)-aniline
with 1,3-bis(tert-butoxy-carbonyl)guanidine, followed by deprotection with
12 N HCl.
References and notes
1. (a) Fraley, M. E.; Peckham, J. P.; Arrington, K. L.; Hoffman, W. F.; Hartman, G. D.
Int. Patent WO2003011837, 2003.; (b) Furet, P.; Imbach, P.; Ramsey, T. M.;
Schlapbach, A.; Scholz, D.; Caravatti, G. Int. Patent WO2004005282, 2004.; (c)
Ledeboer, M.; Salituro, F.; Moon, Y.-C. Int. Patent WO 2002046184, 2002.; (d)