Phenoxide leaving group SNAr strategy for the facile preparation of 7-amino-3-aryl pyrazolo[1,5-a]pyrimidines from a 3-bromo-7-phenoxypyrazolo[1,5-a]pyrimidine intermediate

Article abstract of DOI:10.1016/j.tetlet.2015.09.068

We have discovered a 3-bromo-7-phenoxypyrazolo[1,5-a]pyrimidine intermediate that allows for the direct sequential funtionalization of the 3-position and 7-position of a pyrazolo[1,5-a]pyrimidine scaffold. The intermediate and general method described herein offer an improvement over prior methods, particularly in cases where multiple unique 3-aryl substituents are to be incorporated in conjunction with multiple unique 7-amino substituents.

Full text of DOI:10.1016/j.tetlet.2015.09.068

Tetrahedron Letters 56 (2015) 6077–6079
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Phenoxide leaving group SNAr strategy for the facile preparation
of 7-amino-3-aryl pyrazolo[1,5-a]pyrimidines from
a 3-bromo-7-phenoxypyrazolo[1,5-a]pyrimidine intermediate
a
a
a
b
John G. Catalano a, , Vishwanath Gaitonde , Mallesh Beesu , Anna L. Leivers , J. Brad Shotwell
⇑
a GlaxoSmithKline, 5 Moore Dr, RTP, NC 27709, USA
b Abbvie Discovery Chemistry and Technology, North Chicago, IL 60064, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We have discovered a 3-bromo-7-phenoxypyrazolo[1,5-a]pyrimidine intermediate that allows for the
direct sequential funtionalization of the 3-position and 7-position of a pyrazolo[1,5-a]pyrimidine scaf-
fold. The intermediate and general method described herein offer an improvement over prior methods,
particularly in cases where multiple unique 3-aryl substituents are to be incorporated in conjunction
with multiple unique 7-amino substituents.
Received 14 August 2015
Revised 14 September 2015
Accepted 16 September 2015
Available online 21 September 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazolo[1,5-a]pyrimidine
Heterocycle
Phenoxide
SNAr
Suzuki
Introduction
core. Unfortunately, direct conversion of intermediate 6 to
intermediates 5 via Suzuki conditions proved to be problematic.
Palladium-catalyzed coupling of 6 with aryl boronic acids/esters
often resulted in substitution at both the 7-chloro and 3-bromo
functionalities and gave complex mixtures of regioisomers as well
as bis-substituted products. Intermediate 6 was, however, effec-
tively reacted with amines to achieve precursors 7. Regrettably,
direct conversions of 7 to 3 under Suzuki conditions were often
also problematic. Other researchers appear to have had similar
problems with Suzuki chemistry on these substrates and have
employed a t-butylcarbamate protection scheme to facilitate the
desired coupling.6 In our hands, Boc-protected intermediates 8
readily reacted with aryl boronic acids/esters to give intermediates
The pyrazolo[1,5-a]pyrimidine heterocyclic core is an impor-
tant scaffold for medicinal chemists. In particular, 7-amino-3-
aryl-pyrazolo[1,5-a]pyrimidine derivatives have found utility as
agents against NYP1, CRF, kinases, and other targets.1–4
A common method utilized for synthesizing 7-amino-3-aryl
pyrazolo[1,5-a]pyrimidines employs aryl-substituted acetonitrile
precursors such as 4 (Scheme 1).1–4 Intermediates 4 are converted
to 7-chloro-3-aryl precursors 5 in four steps and then subsequently
treated with amines to give final targets 3. Method A is quite effi-
cient for derivatization of the 7-amino position in cases where the
3-aryl substituent is held constant. The utility of this method is
greatly reduced, however, in cases where 7-amino substitution
and 3-aryl substitution need to be explored concurrently, for
example when multiple unique 3-aryl substituents will be studied
in conjunction with multiple unique 7-amino substituents.
Method A
R1 R2
Cl
N
N
1
4-steps
Another
general
method
employed
to
synthesize
N
R1R2NH
7
N
N
N
N
7-amino-3-aryl pyrazolo[1,5-a]pyrimidines analogs is shown in
Scheme 2. Upon preliminary inspection, intermediate 65 would
appear to be an ideal precursor for the sequential funtionalization
of the 3-position and 7-position of a pyrazolo[1,5-a]pyrimidine
Ar
DMSO,
iPr2NEt,
heat
N
3
Ar
Ar
4
5
3a, 3d
88% - 92%
⇑
Scheme 1. 7-Amino-3-aryl pyrazolo[1,5-a]pyrimidines from aryl-substituted
acetonitrile precursors. Experimental details included in Supplemental material.
Corresponding author. Tel.: +1 (919) 483 6264.
E-mail address: john.g.catalano@gsk.com (J.G. Catalano).
http://dx.doi.org/10.1016/j.tetlet.2015.09.068
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

6078
J. G. Catalano et al. / Tetrahedron Letters 56 (2015) 6077–6079
Table 1
Method B
7-Amino-3-aryl pyrazolo[1,5-a]pyrimidines analogs
O
N
R1
R1
R2
N
Cl
NH
R1
N
N
N
N
O
N
R1-NH2
Boc2O
N
N
N
N
N
DMAP,
dioxane
75%
DMSO,
iPr2NEt,
heat
N
N
Br
Br
R3
Br
6
7b
8b
86%
Compound
R1R2NH
R3
Method (% yield)a
Suzuki
Ar-B(OR)2
69%
Suzuki
Ar-B(OR)2
Suzuki
Ar-B(OR)2
A [5 steps from 4] (86%)
C [2 steps from 1] (89%)
3a
NH2
O
O
R1
O
Cl
4M HCl
in dioxane
R1
NH
N
N
O
N
R1-NH2
N
N
B [4 steps from 6]
C [2 steps from 1] (92%)
N
N
N
N
N
DMSO,
iPr2NEt,
heat
THF
86%
N
H
N
N
3b
Ar
Ar
Ar
NH2
NH2
Cl
O
O
5
3b
9b
Scheme 2. 7-Amino-3-aryl pyrazolo[1,5-a]pyrimidines from 3-bromo-7-chloropy-
razolo[1,5-a]pyrimidine precursor. Experimental details included in Supplemental
material.
O
3c
3d
3e
3f
C (76%)
S
N
H
Cl
O
O
O
O
O
A (92%)
C (88%)
N
9. Deprotection under acidic conditions then provided desired
products 3. Method B allowed for efficient derivatization at the
3-position with a 2-step enumeration from intermediate 8. As with
method A, however, the utility of method B is greatly diminished
when both the 7-amino position and the 3-aryl position need to
be derivatized in direct sequence.
Neither method A nor method B was very efficient for succes-
sive functionalization at the 3-aryl and 7-amino positions. For
method A, the 3-aryl substituent is incorporated in the first step
of the 5 step sequence. For method B, the 7-amino substituent is
incorporated in the first step of the respective 4 step sequence.
As such, we desired a late-stage intermediate with reactive groups
at the 3-position and 7-position that could be functionalized in
direct succession.
NH2
O
O
O
O
O
N
C (82%)
C (86%)
C (85%)
C (75%)
NH2
N
H
3g
3h
Useful bifunctional intermediate for the facile preparation of
7-amino-3-aryl-pyrazolo[1,5-a]pyrimidine derivatives
NH2
NH2
Phenoxy is an atypical leaving group for SNAr reactions and has
been utilized sparingly for these types of displacements. Use of
phenoxy as a leaving group at the 7-position of a pyrazolo[1,5-a]
pyrimidine core, such as for intermediate 10, has not been previ-
ously reported. Intermediate 6 was readily converted to the 7-phe-
noxy intermediate 1 by displacement of chloro with phenoxide ion.
As expected, intermediate 1 readily reacted with boronic acids/
esters under Suzuki conditions to give clean substitution at the
3-position. Phenoxide was then displaced by amines to give
desired products 3. In this manner, method C initially generated
the three compounds 3a–3c (Table 1). Each analog required just
two steps from common intermediate 1, which equated to 6 total
chemistry experiments for all three compounds. For comparison,
method A and method B minimally required a total of 15 and 12
chemistry experiments respectively to achieve the same three
compounds. The benefit of method C over method A and method
B increases as arrays become larger.
We additionally synthesized compounds 3d–3h (Table 1) by
method C in order to more thoroughly explore the reactivity and
limitations of the phenoxide displacement. In general, the phenox-
ide leaving group was readily displaced by unbranched 3a–d and
moderately branched 3e amines. Phenoxide displacements to
achieve 3a–3e were largely complete in a few hours between
80 °C and 90 °C, although we regularly allowed the displacement
a
Isolated yield of amine displacement product in final step of the respective
method. Experimental details included in Supplemental material.
reaction to run overnight without observing decomposition or
by-products. The secondary amine 3f, aniline 3g, and sterically
encumbered t-butylamine 3h proved significantly less reactive
during the phenoxy displacements and required higher tempera-
tures, additional reagent, and prolonged reaction times to give
roughly the same conversion. Phenoxide displacement with aniline
gave no conversion at 90 °C. However, upon increasing the temper-
ature to 130 °C and adding an extra equivalent of aniline, the dis-
placement was complete within 36 hours to form 3g in good
yield. Reaction of 10 with dipropylamine was also sluggish at
90 °C and required additional reagent, time, and heat to effect dis-
placement of the phenoxide, but ultimately gave 3f in good yield.
Displacement of phenoxide 10 with t-butylamine did proceed
slowly at 90 °C, but ultimately required additional amine, higher
temperature, and longer reaction times to achieve conversion to
3h. Significant decomposition impurities were not observed at
elevated temperatures or prolonged reaction times and therefore

J. G. Catalano et al. / Tetrahedron Letters 56 (2015) 6077–6079
6079
Method C
R1 R2
N
O
N
O
N
R1R2NH
Phenol,
Ar-B(OR)2
N
N
N
6
N
N
N
N
NaH,
DMF
68%
DMSO,
iPr2NEt,
heat,
PdCl2-DCM,
1,4-dioxane,
heat
Ar
Ar
Br
1
10a-h
3a-h
75% - 92%
77% - 94%
Scheme 3. 7-Amino-3-aryl pyrazolo[1,5-a]pyrimidines from a 3-bromo-7-phenoxypyrazolo[1,5-a]pyrimidine precursor. Experimental details included in Supplemental
material.
intermediate and method are robust with few limitations and
offers a significant improvement over previous methods where lar-
ger sets of diverse 7-amino-3-aryl-pyrazolo[1,5-a]pyrimidines
O
N
i. nBuLi,
- 78 oC
O
N
O
N
N
were produced.
Ar-Br
N
N
N
N
N
PdCl2-DCM,
1,4-dioxane,
heat
ii.
O
Acknowledgments
B
O
B
O
O
Ar
Br
O
The authors wish to acknowledge the members of the Antiviral
Discovery Performance Unit, as well as the Analytical and Separa-
tions groups at GlaxoSmithKline for their support and camaraderie.
This work was financially supported by GlaxoSmithKline.
60%
1
11
10i
50%
Scheme
4. 7-Phenoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo
[1,5-a]pyrimidine precursor. Experimental details included in Supplemental mate-
rial. Ar = 3-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-4-chlorophenyl.
Supplementary data
Supplementary data (experimental procedures and analytical
data for intermediates and products found in Schemes 1–4 and
Table 1) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2015.09.068. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
we believe that the reaction times might be reduced simply by
increasing temperature, amine equivalents, and/or reaction mix-
ture concentration. We also considered that an electron deficient
phenoxy moiety might potentially be a more reactive leaving
group, but ultimately did not explore this possibility.
It is interesting to note that intermediate 1 was also readily con-
verted to the boronic ester 11 (Scheme 4) and subsequently
reacted with aryl bromides via a ‘reverse’ Suzuki reaction to give
penultimate intermediate 10. Intermediate 11 was a convenient
starting point when the desired aryl boronic acids/esters used for
the Suzuki reaction in Scheme 3 were not readily available. Yield
and scope of the ‘reverse’ Suzuki illustrated in Scheme 4 compared
satisfactorily to the Suzuki reactions exemplified in Scheme 3.
References and notes
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McElroy, J.; Smith, M. A.; Shen, H.-S. L.; Saye, J.; Christ, D.; Trainor, G.; Robertson,
D. W.; Hartig, P. Bioorg. Med. Chem. 2000, 8, 181–189.
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44958, 2006.
Conclusion
We have discovered a useful approach using intermediate 1 to
achieve direct sequential functionalization at the 3-position and
7-position of
6. Murphy, F.; Hayes, I.; James, T.R. WO2007/17678, 2007.
a
pyrazolo[1,5-a]pyrimidine scaffold. The