Divergent and Regioselective Synthesis of Pyrazolo[1,5- a]pyridines and Imidazo[1,5- a]pyridines

Article abstract of DOI:10.1021/acs.orglett.1c01431

Nitrogenous heterocycles are ubiquitous in pharmaceuticals and drug-like compounds; however, regioselective synthesis has proved challenging. Herein we report our efforts to develop a regioselective method for the synthesis of pyrazolo[1,5-a]pyridines and the serendipitous discovery of a protocol for the regioselective formation of imidazo[1,5-a]pyridines. Together, these transformations allow for the rapid and selective formation of two important heterocyclic motifs from a common intermediate.

Full text of DOI:10.1021/acs.orglett.1c01431

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Letter
Divergent and Regioselective Synthesis of Pyrazolo[1,5‑a]pyridines
and Imidazo[1,5‑a]pyridines
Katrina M. Mennie,* Michael H. Reutershan,* Catherine White,* Bruce Adams, Bridget Becker,
James Deng, Jason D. Katz, Elisabeth LaBlue, Kaila Margrey, and Josep Saurí
Cite This: Org. Lett. 2021, 23, 4694−4698
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ABSTRACT: Nitrogenous heterocycles are ubiquitous in pharmaceuticals and drug-like compounds; however, regioselective
synthesis has proved challenging. Herein we report our efforts to develop a regioselective method for the synthesis of pyrazolo[1,5-
a]pyridines and the serendipitous discovery of a protocol for the regioselective formation of imidazo[1,5-a]pyridines. Together,
these transformations allow for the rapid and selective formation of two important heterocyclic motifs from a common intermediate.
itrogen-containing heterocycles are common motifs in
U.S. Food and Drug Administration (FDA)-approved
literature attracted our attention. The first strategy described
by Stevens21 utilizes 2-methylketopyridines 7 to construct two-
substituted pyrazolopyridines regioselectively. (See Scheme
1C.) The conversion of 7 to the azirine 8 followed by heating
delivered the desired pyrazolopyridines 9. However, this
strategy was not amenable to our desired three-substituted
analogs.
N
drugs and promising investigational compounds.1−3 Among
these, pyrazolo[1,5-a]pyridines4−13 and imidazo[1,5-a]-
pyridines14−17 are particularly prevalent. (See Scheme 1A.)
However, the regioselective synthesis of substituted analogs
has proved challenging. Therefore, the development of
regioselective methods to access these heterocycles has the
potential to drive advancement in the drug discovery process.
The traditional synthesis of pyrazolo[1,5-a]pyridine deriva-
tives 5 or 6 involves the amination of a pyridine 1 followed by
a 1,3-dipolar cycloaddition between an N-amino-pyridinium
salt 3 and an alkynylester 4.18 (See Scheme 1B.) One potential
drawback of the initial bond-forming step is the lack of
regiocontrol when starting from asymmetric N-amino-
pyridinium salts (3, R1 ≠ R3), where a mixture of regioisomers
5 and 6 is formed. Whereas there are a number of reports in
the literature detailing the effects of various parameters on the
regioselectivity of this reaction,19,20 only one report by Stevens
offers a method to reliably control the regioselectivity.21
We were interested in an “unsymmetrical” pyrazolo[1,5-
a]pyridine core as a novel scaffold for several kinase programs,
and the inability to control the regioselectivity limited the
access to analogs of the core. This prompted us to investigate
methods to access this ring formation with the control of
regiochemistry. Two particular synthetic strategies in the
The second strategy, which was developed initially by Lin22
and subsequently modified by Balsells (see Scheme 1C),23 was
invoked in the synthesis of [1,2,4]triazolo[1,5-a]pyridines 11.
Lin discovered that triazolopyridines 11 could be prepared via
the condensation of aminopyridines 10 with DMF−DMA
followed by treatment of the DMF−DMA adduct with
hydroxylamine-O-sulfonic acid. In addition, Balsells discovered
that a two-step protocol involving an initial treatment with
hydroxylamine followed by trifluoroacetic anhydride (TFAA)
delivered the desired triazolopyridines 11 in moderate to good
yields.
Received: April 26, 2021
Published: May 26, 2021
https://doi.org/10.1021/acs.orglett.1c01431
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4694−4698
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overall yield of the ring closure. Whereas DCM provided the
best overall yield, both DMF and THF were tolerated (entries
4 and 6, respectively), whereas MeOH, DMSO, and dioxane
were suboptimal (entries 3, 5, and 7). In our attempts to
optimize the nitrogen source, we applied the conditions
described by Balsells (hydroxylamine, then TFAA) to enamine
13 (Table 1, entry 8).23 Unexpectedly, we observed the
significant formation of imidazo[1,5-a]pyridine 15a (entry 8,
35%). Excited by the ability to form two different heterocyclic
systems from a common enamine intermediate, we inves-
tigated other nitrogen sources in an attempt to improve the
yield. However, reagents such as T3P and PPA gave reduced
yields of the imidazo[1,5-a]pyridine system (entries 9 and 10,
respectively). Moreover, other reagents including POCl3, TsCl,
and MsCl failed to provide either ring system.
Scheme 1. Examples of Drugs Featuring Pyrazolo- and
Imidazopyridines and the Synthesis of Pyrazolo[1,5-
a]pyridines
To understand the scope of the pyrazolopyridine formation,
we tested this synthetic sequence on a variety of commercially
available 2-pyridyl acetates. In general, low to moderate yields
of the corresponding pyrazolo[1,5-a]pyridines were isolated.
(See Table 2.) Moderate yields (∼50%) were obtained for 4-,
Table 2. Pyrazolo[1,5-a]pyridine Scope
entry substrate
R1
R2
R3
R4
R5
product 14 (%)
1
2
3
4
5
6
7
8
12a
12b
12c
12d
12e
12f
12g
12h
12i
H
H
H
Br
H
H
Br
H
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
F
H
H
H
H
Br
H
H
H
H
H
H
Me
Et
Et
Me
Et
Et
Me
Et
Et
Et
Me
87
55
55
46
0
We sought to adapt these strategies as a means to exert
regiocontrol in the synthesis of our pyrazolo[1,5-a]pyridine
system. (See Scheme 1D.) As an initial experiment, we
condensed the commercially available methylpyridin-2-ylace-
tate 12a with DMF−DMA to afford enamine 13a (Table 1,
entry 1). Subsequent treatment with O-(mesitylsulfonyl)-
hydroxylamine 2 afforded the desired pyrazolopyridine 14a
in good yield (87%). The speed of this reaction is notable, as
the corresponding cycloaddition previously described (3 → 5)
often takes several days to go to completion at ambient
temperature.24
H
a
OMe
Me
CN
H
H
OMe
24
55
66
28
28
9
10
11
12j
12k
Cl
Br
b
30
a
b
Step 2 stirred for 72 h. Step 2 stirred overnight.
We observed a reduction in yield when a substituted pyridyl
acetate was subjected to our two-step pyrazolopyridine
protocol (5-bromopyridyl acetate, Table 1, entry 2). We
therefore screened various solvents to assess its effect on the
5-, and 6-bromopyrazolo[1,5-a]pyridines 14b−d. Unfortu-
nately, the corresponding enamine 13e derived from 6-bromo
2-pyridyl acetate (entry 5) did not undergo intramolecular
Table 1. Optimization of Regiocontrolled Synthesis toward Pyrazolo[1,5-a]pyridines
entry
substrate
R1
R2
nitrogen source
H2NOSO2Mes
H2NOSO2Mes
H2NOSO2Mes
H2NOSO2Mes
H2NOSO2Mes
H2NOSO2Mes
H2NOSO2Mes
solvent
product 14 (%)
product 15 (%)
1
2
3
4
5
6
7
8
9
12a
12b
12b
12b
12b
12b
12b
12a
12a
12a
Me
Et
Et
Et
Et
Et
Et
Me
Me
Me
H
DCM
DCM
MeOH
DMF
DMSO
THF
dioxane
THF
THF
87
55
0
33
0
Br
Br
Br
Br
Br
Br
H
28
nd
a
b
H2NOH-HCI and TFAA
H2NOH-HCI and T3P
H2NOH-HCI and PPA
35
b
H
H
11
b
10
THF
4
6
a
b
Partial conversion to product observed. Reaction was messy, and product was not isolated. Reaction warmed to room temperature.
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cyclization. This was not surprising given the likely decreased
nucleophilicity of the nitrogen and the increased steric
hindrance around the nitrogen. Instead, two unidentified
bromine-containing side products were observed via LC−MS.
We found that both electron-withdrawing and electron-
donating substituents were tolerated at the four-position of
the pyrazolo[1,5-a]pyridine. Methoxy-, methyl-, and cyano-
substituted pyrazolo[1,5-a]pyridines were obtained in low to
moderate yields (entries 6, 7, and 8, respectively). Fluoro and
chloro substituents were tolerated at the R3 position, although
yields were lower than that for the corresponding bromo
substituent (entries 9, 10, and 2, respectively). In addition to
monosubstituted pyridines, this method enabled the synthesis
of the unsymmetrical disubstituted pyrazolo[1,5-a]pyridine
(entry 11). The modest yields are the result of side-product
formation, specifically hydrolysis of the enamine intermediate
(13), rather than low conversion. However, despite the yields,
this method allows for complete regiocontrol, as demonstrated
by entries 2, 4, and 6−11, where R1 ≠ R3. This feature
represents a major advantage over the existing, nonregiose-
lective methods.
tion at R2 and R3 was tolerated to give imidazo[1,5-a]pyridines
15c and 15d, respectively, in ∼20% yield, enamines with
bromine substitution at R1 and R4 did not undergo the desired
intramolecular cyclization. Cyano and fluoro substituents were
also tolerated (entries 6 and 7, respectively). Nevertheless,
despite the low to modest yields, this method represents a
simple, regioselective route to complex, valuable heterocycles
that are difficult to access otherwise.
Nearly exclusive formation of nitrile side product 16 was
observed for substrates where R1 ≠ H. NMR spectroscopic
evidence of an intramolecular hydrogen bond between the
resulting amine and the ester carbonyl was observed. (See the
Supporting Information.) It is likely that the steric effect of
substitution at this position restricts the rotation of the ester
bond and that this, together with the stabilizing intramolecular
hydrogen bond, promotes the formation of 16 over 15.
We envision two plausible mechanisms for the formation of
the pyrazolo[1,5-a]pyridines. (See Scheme S3 in the
Supporting Information for more details.) The reaction likely
proceeds with O-(mesitylsulfonyl)hydroxylamine acting as
either a nucleophile by displacing dimethylamine or an
electrophile whereby it aminates the pyridine ring. With
regard to the mechanism for the formation of the imidazo[1,5-
a]pyridines, we speculate the involvement of a reactive azirine
intermediate. (See Scheme S4 in the Supporting Information
for more details.)
We also investigated the preparation of aza analogs and
tricyclic fused ring systems. (See Figure 1.) A 4-pyrimidinyl
To demonstrate the utility of this regioselective trans-
formation to readily access complex heterocyclic compounds,
we applied standard Suzuki cross-coupling reaction conditions
(see the Supporting Information) to a number of bromo-
substituted pyrazolo- and imidazo[1,5-a]pyridine products.
(See Figure 2.) Overall, the corresponding phenyl-substituted
Figure 1. Heterocyclic and fused ring systems.
acetate afforded pyrazolo[1,5-c]pyrimidine-3-carboxylate in
low yield (14l, 18% yield), whereas fused dihydronaphthyr-
idine and 2-quinolinyl acetate afforded tricyclic
dihydropyrazolo[1,5-a][1,5]naphthyridine and pyrazolo[1,5-
a]quinoline in low to moderate yields (14m and 14n,
respectively). Despite the modest yields of this transformation,
it allows regioselective access to complex polycyclic com-
pounds in merely two steps from simple, commercially
available starting materials.
To understand the scope of the imidazopyridine formation,
we subjected commercially available pyridyl acetates to the
hydroxylamine/TFAA conditions. (See Table 3.) In general,
yields were lower than those observed for the corresponding
pyrazolo[1,5-a]pyridines due to the substrate-dependent
formation of pyrazolo (14) or nitrile (16) side-products.
(See the Supporting Information.) Whereas bromo substitu-
Table 3. Initial Imidazo[1,5-a]pyridine Scope
Figure 2. Derivatization of bromo-substituted pyrazolo- and imidazo-
[1,5-a]pyridines.
entry substrate
R1
R2
R3
R4
R5
product 14 (%)
derivatives 17a−f were obtained in good yields, showcasing the
value of this method in enabling the rapid expansion of the
structure−activity relationship (SAR)in pyrazolo- and imidazo-
[1,5-a]pyridines.
In conclusion, we have identified a versatile enamine
intermediate that allows for regioselective cyclization to both
pyrazolo[1,5-a]- and imidazo[1,5-a]pyridines in low to
moderate yields. Despite the modest yields, this method
1
2
3
4
5
6
7
13a
13b
13c
13d
13e
13f
H
Br
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
Br
H
H
H
H
H
Br
H
H
Me
Et
Et
Et
Et
Et
Et
49
0
20
22
0
CN
F
10
24
13g
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allows for regioselective synthesis from simple starting
materials with improved reaction times. Additional optimiza-
tion efforts are ongoing and will be disclosed in due course.
Elisabeth Hennessy (Merck & Co., Inc., Boston, MA, USA) for
helpful discussions during the preparation of this manuscript.
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■
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AUTHOR INFORMATION
Corresponding Authors
■
Katrina M. Mennie − Merck & Co., Inc., Boston,
Massachusetts 02115, United States; orcid.org/0000-
0002-6960-2144; Email: katrina.mennie@merck.com
Michael H. Reutershan − Merck & Co., Inc., Boston,
Massachusetts 02115, United States;
Email: michael_reutershan@merck.com
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Murata-Tai, K.; Fujisawa, M.; Ino, M.; Shibata, H.; Yonaga, M.
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Catherine White − Merck & Co., Inc., Boston, Massachusetts
02115, United States; orcid.org/0000-0003-1168-1289;
Email: catherine_white@merck.com
Authors
Bruce Adams − Merck & Co., Inc., Boston, Massachusetts
02115, United States; Present Address: B.A.: Department
of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139, United States
Bridget Becker − Merck & Co., Inc., Boston, Massachusetts
02115, United States; Present Address: B.B.: Covance,
Inc., Madison, Wisconsin, 53704, United States.
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Jason D. Katz − Merck & Co., Inc., Boston, Massachusetts
02115, United States; Present Address: J.D.K.: IFM
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States
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Elisabeth LaBlue − Merck & Co., Inc., Boston, Massachusetts
02115, United States; Present Address: E.L.: Emmanuel
College, Boston, Massachusetts, 02115, United States.
Kaila Margrey − Merck & Co., Inc., Boston, Massachusetts
02115, United States
Josep Saurí − Merck & Co., Inc., Boston, Massachusetts
02115, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01431
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank Lisa Nogle, David Smith, Mark Pietrafitta, Miroslawa
Darlak, and Adam Beard for their help with the purification as
members of the Separation Sciences Team (Merck & Co., Inc.,
Boston, MA, USA). We also thank Foster Tenkorang for
assistance with HRMS (Merck & Co., Inc., Rahway, NJ, USA).
Finally, we thank Alec Christian, Andrew Musacchio, and
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