Development of a late-stage diversification strategy for the 4- And 5-Positions of 4,5,6-trisubstituted indazoles

Article abstract of DOI:10.1021/acs.orglett.0c03440

Indazoles represent a privileged motif in drug discovery. However, the formation of highly substituted indazoles can require the execution of lengthy synthetic routes with minimal opportunities to introduce diversity. In this report, we disclose the development of a late-stage diversification strategy for the 4- and 5-positions of 4,5,6-trisubstituted indazoles. A regioselective C-H functionalization and subsequent nucleophilic aromatic substitution provide two sequential points of diversification. The synthetic sequence delivers rapid access to an array of 4,5,6-trisubstituted indazoles in only four steps from readily available starting materials.

Full text of DOI:10.1021/acs.orglett.0c03440

pubs.acs.org/OrgLett
Letter
Development of a Late-Stage Diversification Strategy for the 4- and
5‑Positions of 4,5,6-Trisubstituted Indazoles
́
Joyann S. Barber, Alexander Burtea, Michael R. Collins, Michelle Tran-Dube, Ryan L. Patman,
Stephanie Scales, Graham Smith, Jillian E. Spangler, Fen Wang, Wei Wang, Shouliang Yang, JinJiang Zhu,
and T. Patrick Montgomery*
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ABSTRACT: Indazoles represent a privileged motif in drug
discovery. However, the formation of highly substituted indazoles
can require the execution of lengthy synthetic routes with minimal
opportunities to introduce diversity. In this report, we disclose the
development of a late-stage diversification strategy for the 4- and 5-
positions of 4,5,6-trisubstituted indazoles. A regioselective C−H
functionalization and subsequent nucleophilic aromatic substitu-
tion provide two sequential points of diversification. The synthetic
sequence delivers rapid access to an array of 4,5,6-trisubstituted
indazoles in only four steps from readily available starting materials.
itrogen-containing heterocycles are ubiquitous in medic-
The syntheses of indazoles have utilized a wide array of
chemical methods.16−18 Traditionally, indazoles have been
synthesized through the cyclization of o-toluidine diazonium
salts19,20 or the intramolecular cyclization of arylhydrazones.21
Transition-metal-catalyzed/mediated formations of 1H-inda-
zoles are also prevalent in the literature.22 Much of this work
focuses on the formation of mono- and disubstituted indazoles;
however, Tsui and co-workers reported the synthesis of highly
substituted indazoles using a palladium-catalyzed cycloaddition
of alkynes with pyrazoles to form 4,5,6,7-tetrasubstituted
indazoles.23
The late-stage functionalization of indazoles generally
requires the early introduction of a cross-coupling handle
that can survive the indazole formation step.24−26 The
development of methods beyond cross-coupling strategies for
the derivatization of indazoles has remained largely unex-
plored, with the majority of reported methodologies taking
advantage of the inherent reactivity at the C3-position.27,28
Direct alkenylation of both 1H- and 2H-indazoles at the C3-
and C7-positions has been achieved using palladium and
rhodium catalysis.29,30 Methods for direct C−H functionaliza-
tion of the arene ring of indazoles have remained somewhat
elusive. Herein, we report the synthesis of 4,5,6-trisubstituted
N
inal chemistry and marketed pharmaceuticals.1 Indazoles
represent an important class of bicyclic heterocycles due to
their 1,2-donor−acceptor arrangement. A prodigious amount
of research has focused on the construction and application of
indazoles in biologically active molecules.2−5 Although
observed sparingly in nature,6−8 indazole-containing com-
pounds have been utilized in an array of therapeutic areas,
including as antibacterial,9 anticancer,10−12 anti-inflamma-
tory,13 antiprotozoal,14 and antiviral15 agents (Figure 1).
Given the utility of the indazole scaffold, the ability to
incorporate a range of diversity, in a unified manner, would
greatly facilitate the examination of structure−activity and
structure−property relationships in a drug discovery program
possessing this core.
Received: October 14, 2020
Figure 1. Representative examples of bioactive compounds containing
the indazole motif.
https://dx.doi.org/10.1021/acs.orglett.0c03440
© XXXX American Chemical Society
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A

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Scheme 1. Initial Efforts Towards the Synthesis of 4,5,6-Trisubstituted Indazoles Compared with a More Unified Route
indazoles via the unification of direct C−H functionalization
methodology and a late stage-diversification strategy.
With the requisite 4,6-disubstituted indazoles in hand, our
attention turned to the regioselective C−H functionalization of
the C5-position. Although 1H NMR analysis indicated that the
C7-proton is likely most acidic,33 we speculated that the C4-
fluorine could serve as a directing group to achieve
deprotonation at the C5-position.34−41 Quenching the anion
with an electrophilic chlorinating agent would provide desired
indazole 3c.
Our interest in the syntheses of a diverse array of 4,5,6-
trisubstituted indazoles stemmed from a recent need to
broadly evaluate the structure−activity relationship (SAR) of
this motif as a key pharmacophore in one of our lead-
optimization campaigns. Regrettably, the syntheses of these
functionalized indazoles proved to be lengthy and inefficient.
Moreover, each synthesis had to be tailor-made for the specific
indazole-containing target (Scheme 1A). It became evident
that a unified synthesis of 4,5,6-trisubstituted indazoles with
the potential for late-stage diversification at the 4- and 5-
positions would be highly enabling.
We took inspiration in our route design from the broad
availability of 2,6-difluorobenzaldehydes (Scheme 1B). More-
over, the C2 symmetry of these molecules permits their
cyclization with hydrazine to the corresponding 4,6-disub-
stituted indazoles without a need to establish regiocontrol.
Direct C−H functionalization at the C5-position would serve
as our first point of diversification. Subsequent nucleophilic
aromatic substitution at C4 would further expand the
collection of indazoles that can be accessed through this
synthetic sequence.
Our initial efforts using indazole 2c employed magnesium
bases due to the lower propensity of aryl-magnesium species to
form benzyne at elevated temperatures (Table 1, entries 1−
3).42 Unfortunately, no product was detected when using
Mg(NiPr2)2 or TMPMgCl·LiCl (entries 1 and 2). Using
(TMP)2Mg·2LiCl as the base (entry 3) delivered the desired
chlorination product in low conversion. We then assessed
lithium bases and found that LDA performed well, delivering
the desired product in 44% yield (entry 4) with a high level of
regioselectivity (>20:1, 3c:3c′). Complete consumption of the
starting material was critical for purification as separation of 2c
and 3c was challenging. The use of hexachloroacetone as the
electrophilic chlorinating agent (entry 5) proved unfruitful, as
3c was isolated in diminished yield. It is known that LiCl can
aid in the reduction of aggregates in lithiation reactions.43−46
The addition of LiCl in this transformation provided a cleaner
reaction profile, furnishing the desired product in 68% yield,
while maintaining high levels of regioselectivity (entry 6).
Employing n-BuLi as the base flipped the regioselectivity to
favor chlorination at the 7-position (entry 7), delivering 3c′ as
the major regioisomer in good yield. It is known that THP
protecting groups have demonstrated the ability to serve as o-
directing groups in o-lithiations.47,48 Additionally, due to steric
effects of the THP group, the 7-position could be more
accessible to nBuLi than LDA. Finally, a slight exotherm was
observed upon addition of the electrophile, which we
speculated could impact the stability of the anion. As such,
inverse addition, wherein the indazole anion was added to a
precooled solution of the electrophile, was applied (entry 8).
This protocol provided a moderate increase in yield and an
improved reaction profile to deliver 3c in 81% isolated yield.
Additional optimization studies focused on reducing the
loading of reagents to deliver a more process-friendly protocol.
With optimized conditions in hand, the scope of the
regioselective C−H chlorination was evaluated (Scheme 3).
Chlorination of indazoles containing either electron-with-
drawing or electron-donating C6-functional groups was
successful (3a−d), with 3c being obtained on >40 g scale.
We subsequently found that the lithiated species could be
quenched with a variety of electrophiles to achieve C5-
Our initial efforts focused on optimizing the formation of
1H-indazoles 2a−d (Scheme 2) from the corresponding 2,6-
Scheme 2. Formation of Indazoles 2a−d Using Aryl
Aldehydes and Hydrazine Followed by THP-Protection
difluorobenzaldehyde starting material. Inspired by the work of
Lukin and co-workers,21 a one-pot, two-step sequence was
examined. The aryl hydrazone is preformed in tetrahydrofuran
(THF) followed by solvent exchange to dimethyl sulfoxide
(DMSO) and ring closure to furnish our desired indazole. By
adapting previously reported conditions for a one-step
hydrazone formation, ring closure provided access to the
target indazole using 1,4-dioxane as solvent.31 Subsequent
THP-protection provided the protected 1H-indazole.32 This
sequence was successful with both electron-withdrawing (2a−
2c) and electron-donating (2d) groups at the C4-postion,
albeit with depreciated yield for the electron-rich substrate.
B
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a b c
, ,
Table 1. Selected Conditions for Optimization of the Directed Lithiation and Anion Quenching with Chlorinating Reagent
a
b
c
Reported yields are of isolated material. Ratios of starting material: product (2:3) determined by 1H NMR analysis of crude material. Ratio of
d
1
regioselectivity (c:c′) determined by H NMR analysis of crude material. Inverse addition performed.
nucleophiles (Scheme 4). Utilizing 3b as the indazole
Scheme 3. Substrate Scope of the Regioselective Directed
a b
,
Lithiation and Electrophilic Quenching
substrate, it was found that heteroaryl amines undergo
nucleophilic substitution (4a−h). Using benzimidazole,
substitution product 4a was isolated in 90% yield.49 Employing
1H-indazole as the nucleophile delivered desired product 4b in
good yield as the major isomer,50 with small amounts of the
product of N-2 substitution detected.32,51 Using pyrazole and
2-methylimidazole delivered the desired substitution products,
4d and 4e, in >95% yield and 90% yield, respectively. 1,2,4-
Triazoles also served as functional nucleophiles, delivering 4f
and 4g in good yield. It is postulated that, in the deprotonated
form, a destabilizing effect from the adjacent lone pair amplifies
the nucleophilicity of N-1, favoring reactivity at this position.
To our delight, 4g was crystalline, which permitted us to
obtain an X-ray crystal structure, allowing unambiguous
assignment of both the N-selectivity of the triazole and the
regioselectivity on the indazole fluorine of 3b. It is reasoned
the 4-position of the indazole is more electrophilic due to
electronics of the carbonyl-like C3-position. The regioselectiv-
ities of the other products were assigned in accordance with
this result. Using 3-aminopyrazole as the nucleophile delivered
4h in 70% yield as the major isomer, with minor isomers of
nitrogen substitution occurring. Surveying amides led to the
evaluation of 2-pyrrolidinone, which provided 4i in 82% yield
with N-selectivity. Extrapolation of our standard reaction
conditions (Cs2CO3, room temperature) to aliphatic amines
proved unsuccessful. However, it was found that the desired
SNAr reaction occurred at an elevated temperature (90 °C)
with excess amine (no exogenous base) to provide the
corresponding products 4j and 4k in moderate yield.
Hydroxylation of 3b with water delivered 4l in >95% yield.
Aliphatic alcohols served as nucleophiles in this trans-
formation, furnishing 4m−o in excellent yields. Employing
3c as the indazole provided similar reactivity and selectivity as
observed with 3b. Again, we saw good reactivity from
heteroaryl N-based nucleophiles (5a−h). When using 4-
azaindazole as the nucleophile, product 5c was formed with
a
b
Reported yields are of isolated material. Unless otherwise noted,
c
reactions were conducted on 1.0 mmol scale. Reaction to produce 3c
was conducted on 49 g scale.
diversification. Bromination with dibromoethane and fluorina-
tion with NFSI provided 3e and 3f, in 37% and 40% yield,
respectively. Methylation with iodomethane delivered 3g in
66% yield. Formylation with DMF proceeded in moderate
yield (3h). Borylation with trimethylborate delivered 3i in 64%
yield, providing a functional group handle for subsequent
cross-coupling reactions.
We next turned our attention to the nucleophilic aromatic
substitution of the 4-fluoro group with N- and O-based
C
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aromatic substitution at the C4-position delivers an additional
handle for regioselective functionalization with N- and O-based
nucleophiles. These transformations offer two sequential
points of diversification and obviate the need for tailor-made
indazole syntheses. This approach is highly enabling for rapid
SAR determination thus further enhancing medicinal chemists’
synthetic toolbox. Further studies evaluating the regioselectiv-
ity in the directed lithiation are ongoing in our laboratory.
Scheme 4. Substrate Scope of Substitution Reaction with N-
and O-Based Nucleophiles
a b
,
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03440.
Experimental procedures and characterization data for
all novel compounds (PDF)
Accession Codes
CCDC 2038443 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
T. Patrick Montgomery − Pfizer Oncology Medicinal
Chemistry, San Diego, California 92121, United States;
orcid.org/0000-0003-0975-088X;
Email: Timothy.Montgomery@pfizer.com
a
b
Reported yields are of isolated material. Unless otherwise noted,
c
reactions were conducted on 0.3 mmol scale. 5 equiv of the amine
was used and the reactions were conducted at 90 °C. Reactions
conducted on 1 mmol scale.
Authors
d
Joyann S. Barber − Pfizer Oncology Medicinal Chemistry, San
Diego, California 92121, United States
Alexander Burtea − Pfizer Oncology Medicinal Chemistry,
the same regiochemistry (N-1 attack) as seen when using
indazole (4b and 5b).52 As before, 2-pyrrolidinone attack
proceeded to form 5i in 65% yield. It was also observed that
aliphatic amines required the same reaction parameter
adjustment as before, furnishing 5j and 5k in diminished
yields. O-Based nucleophiles participated in the transformation
with 3c to similar levels as observed with 3b, delivering
substitution products 5l−o in high yields.
San Diego, California 92121, United States
Michael R. Collins − Pfizer Oncology Medicinal Chemistry,
San Diego, California 92121, United States
́
Michelle Tran-Dube − Pfizer Oncology Medicinal Chemistry,
San Diego, California 92121, United States
Ryan L. Patman − Pfizer Oncology Medicinal Chemistry, San
Diego, California 92121, United States; orcid.org/0000-
0003-2363-8368
Lastly, facile deprotection of 5l using strong acid delivered
4,5,6-trisubstituted indazole 6a in quantitative yield (Scheme
5).
Stephanie Scales − Pfizer Oncology Medicinal Chemistry, San
Diego, California 92121, United States
Graham Smith − Pfizer Oncology Medicinal Chemistry, San
Diego, California 92121, United States
Jillian E. Spangler − Pfizer Oncology Medicinal Chemistry,
San Diego, California 92121, United States
Fen Wang − Pfizer Oncology Medicinal Chemistry, San Diego,
California 92121, United States
In conclusion, we have developed a route to access a variety
of highly functionalized 4,5,6-trisubstituted indazoles in only
four steps from commercially available materials. Central to
this approach is the regioselective C−H functionalization of
the C5-position with a variety of electrophiles. Nucleophilic
Wei Wang − Pfizer Oncology Medicinal Chemistry, San Diego,
California 92121, United States; orcid.org/0000-0003-
2611-8210
Scheme 5. Deprotection To Furnish 4,5,6-Trisubstituted
Indazole 6a
Shouliang Yang − Pfizer Oncology Medicinal Chemistry, San
Diego, California 92121, United States
JinJiang Zhu − Pfizer Oncology Medicinal Chemistry, San
Diego, California 92121, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03440
D
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors would like to thank Prof. E. J. Corey (Harvard
University) for helpful discussions, Dr. Alex Yanovsky (Pfizer),
Dr. Milan Gembicky (UCSD), and Dr. Arnold L. Rheingold
(UCSD) for X-ray structure support, Jason Ewanicki (Pfizer)
and Igor Landa (Pfizer) for NMR support, and Jeff Elleraas
(Pfizer) and Loanne Chung (Pfizer) for purification support.
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Org. Lett. XXXX, XXX, XXX−XXX