Oxidative Cyclization Approach to Benzimidazole Libraries

Article abstract of DOI:10.1021/acscombsci.9b00189

An efficient approach to the parallel synthesis of benzimidazoles from anilines is described. Library approaches to vary the N1 and C2 vectors of benzimidazoles are well established; however, C4-C7 variation has traditionally relied on 1,2-dianiline build

Full text of DOI:10.1021/acscombsci.9b00189

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Letter
Oxidative Cyclization Approach to Benzimidazole Libraries
Eric P Arnold, Prolay K. Mondal, and Daniel C. Schmitt
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.9b00189 • Publication Date (Web): 20 Dec 2019
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Oxidative Cyclization Approach to Benzimidazole
Libraries
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Eric P. Arnold, Prolay K. Mondal, and Daniel C. Schmitt*
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340,
United States
Keywords: parallel synthesis, oxidative cyclization, benzimidazoles, C-H amination, amidines,
PIDA
ABSTRACT: An efficient approach to the parallel synthesis of benzimidazoles from anilines is
described. Library approaches to vary the N1 and C2 vectors of benzimidazoles are well
established; however, C4-C7 variation has traditionally relied on 1,2-dianiline building blocks,
providing limited chemical space coverage. We have developed an amidine formation / oxidative
cyclization sequence that enables anilines as a diversity set for benzimidazole C4-C7 SAR
generation in parallel format. The amidine annulation was achieved using PIDA or Cu-mediated
oxidation to access both NH and Nalkyl benzimidazoles. This library protocol has now been
utilized for analog production on four medicinal chemistry projects. Additionally, the synthesis
of aza-benzimidazoles from aminopyridines was achieved via an analogous sequence.
1) LiHMDS
NC Ar
N
NH2
H
A
A
A
A
Ar
N
H
Cu(OAc)2
2)
A
A
DMSO/HOAc
diversity set:
(hetero)aryl-amines
diverse (aza)-benzimidazoles
in parallel format
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Access to new drug design space via parallel synthesis is imperative to the advancement of
medicinal chemistry.1-2 The formation of heteroaromatic rings is a useful strategy for efficient
establishment of structure-activity relationships (SAR), but is an underutilized tactic in library
synthesis, constituting only 3% of drug discovery libraries.3 Benzimidazoles are the second most
common fused heteroaromatic ring system found in small molecule drugs, behind only indoles,
and serve as central cores in marketed proton pump inhibitors, anthelminthics, anti-cancer agents,
and vasodilators (Figure 1).4 As a result, protocols for the parallel synthesis of benzimidazoles are
numerous, permitting variation of the N1-vector from amines5 and the C2-vector from carboxylic
acids6; however, the C4-C7 vectors are seldom explored in library format due to the limited
availability of the requisite 1,2-dianiline building blocks, which afford restricted design space.7
Recognizing the deficiency of extant methods, we sought to identify a more abundant diversity set
for the parallel synthesis of benzimidazoles.
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O
S
N
N
N
O
N
N
H
Me
OMe
S
MeO
N
H
O
N
H
esomeprazole
proton pump inhibitor
Br
Me
F
cambendazole
anthelminthic
F
N
Me
OMe
HN
H
N
N
N
H
HO
N
N
O
O
N
pimobendan
vasodilator
Me
H
O
binimetinib
anti-cancer
Figure 1. Benzimidazoles in approved drugs.
Intramolecular CH amination of N-phenyl amidines to form benzimidazoles has been
widely reported in academic literature,8-20 but has remained underutilized in the pharmaceutical
industry. While N-phenyl amidines are not widely available, they may be accessed directly from
anilines which are significantly more abundant than 1,2-dianilines (Scheme 1). Recently
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Punniyamurthy has reported the one-pot conversion of anilines to benzimidazoles using Cu
catalysis and azide; however, these approaches cannot directly provide N1-alkyl benzimidazoles
(N1-H only) or aza-benzimidazoles (aminopyridine reactants were unreactive).21-23 The synthesis
of aza-benzimidazoles via oxidative cyclization of N-pyridyl amidines would represent a
convenient entry into a desirable heterocyclic system but is far less established. To date, known
examples require either pre-isolation of an N-Cl amidine intermediate24 or electrochemical
oxidation25, rendering them operationally complex for library applications. Herein, we describe
an amidine formation / oxidative cyclization sequence for the synthesis of both N1-H and N1-alkyl
benzimidazoles in library format from diverse anilines. Aminopyridine and aminopyrimidine
building blocks were also found to be compatible with the sequence, providing azabenzimidazoles
and purines respectively.
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Scheme 1. Parallel approaches to benzimidazole C4-C7 libraries.
Standard Library Approach
O
R
R
H
R
NH2
NH2
N
N
R''
AcOH
HO
R''
R''
amidation
N
H
O
R'
R'
NH2
R'
1,2-dianilines
limited design space
limited availability
This Library Approach
R''
R
H
R
R
NH2 N
oxidative
cyclization
N
R''
NH
N
LiHMDS
R''
N
H
R'
R'
R'
anilines
abundant & diverse
expanded design space
The goal of our initial experiments was to determine if oxidative cyclization could be
achieved on an unpurified N-aryl amidine intermediate resulting from aniline addition to a nitrile.
Amidine synthesis was achieved by treatment of anilines with LiHMDS or NaH in the presence of
benzonitrile at ambient temperature. Without aqueous workup or purification, the oxidative
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cyclization of the crude N-aryl amidine was tested using (diacetoxyiodo)benzene (PIDA),
(Bis(trifluoroacetoxy)iodo)benzene (PIFA)12, and Cu(II)/O2. The Cu(OAc)2-catalyzed oxidative
cyclization reported by Buchwald11 was found to provide the highest yields for the cyclization of
crude N-aryl amidines. To render the cyclization more amenable to parallel synthesis, we ran the
reactions in vials open to air, rather than under an O2 atmosphere as reported by Buchwald. Under
air atmosphere, highest conversion was achieved using 2 equivalents of Cu(OAc)2, which is not
an issue for small-scale library synthesis.
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Using the optimized conditions, we explored the scope of the sequence with respect to the
aniline diversity set. 2-, 3-, and 4- substituted anilines were all competent in the library sequence,
as were multi-substituted and fused-ring anilines, providing benzimidazoles in suitable yields
following high throughput purification by HPLC (on 0.1 mmol library scale >5% yield can
typically provide sufficient material for our biological assays). 3-Substituted anilines generated
separable regiosiomers, with cyclization typically favoring the less-hindered CH (2g, 2i, 2n).
Notably, meta-F (1f), meta-S (1o), and meta-amido (1h, 1p) substituted anilines favored
cyclization to the 7-substituted benzimidazoles 2f, 2h, 2o, and 2p, indicating a heteroatom lone-
pair directing effect. While electron-rich and neutral anilines provided the highest yields, electron-
withdrawing groups were surprisingly tolerated, including sulfone 2g, nitrile 2i, and pyridine 2m;
trifluoro and 2-sulfonyl anilines only provided trace amounts of product (2c and 2d). The most
problematic anilines were sterically hindered ortho to the amine, which would not participate in
the initial amidine formation.
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Scheme 2. Synthesis of N1-H benzimidazoles from anilines.
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8
R1
R1
NC
R2
R3
NH2
R2
R3
N
Cu(OAc)2 / air
1.0 equiv
DMSO/AcOH (6:1)
110 °C
LiHMDS
THF, 23 °C
N
H
R4
(1.0 equiv)
R4
9
1
2
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O
O
OMe
F
F
Me
S
F
F
N
N
N
N
Ph
Ph
Ph
Ph
N
H
N
H
, 7%
N
H
N
H
2a
2b
2c <5%
2d, <5%
, 29%
,
O
O
Me
S
N
N
N
Me
Ph
Ph
Ph
N
H
N
H
N
H
Me
2e
F
2f
2g
, 15%
>20:1 regioselectivity
, 14%
8:1 regioselectivity
, 28%
N
Ph
NC
N
N
N
H
O
Ph
Ph
N
N
N
H
, 15%
MeO
H
2h
2i
, 9%
2j
, 42%
>20:1 regioselectivity
2:1 regioselectivity
N
N
N
Boc
N
Ph
Ph
Ph
N
N
H
N
N
H
Me
Me
H
2k
2l
2m
, 13%
, 12%
, 15%
N
N
Ph
N
Ph
N
H
N
Ph
N
H
N
N
H
N
N
Bn
O
S
2o
2n
2p
, 35%
, 46%
, 33%
5:1 regioselectivity
17:1 regioselectivity
>20:1 regioselectivity
We next sought to extend the chemistry to access N1-substituted benzimidazoles. To
minimize the number of library steps we elected to utilize N-alkyl imidoyl triflate as the template
to provide N-aryl-N’-methyl amidine 3, which would be cyclized to N1-methyl benzimidazoles
4a-e. Whereas Cu(II)-mediated cyclization was preferred for the N1-H benzimidazoles (Scheme
2), PIDA was optimal for cyclization of N-aryl-N’-methyl amidines 3 to N1-methyl
benzimidazoles 4. Electron-rich, -neutral, and -poor anilines were all found to be effective in the
library sequence (Scheme 3). Given the modest yields for the one-pot sequence, we wanted to
verify that hit follow up could be achieved using the same method on larger scale with improved
yield. On >2.5 mmol scale, both NH and N-Me benzimidazoles could be accessed in enhanced
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yield following chromatographic purification of the amidine intermediate (Scheme 4). Further
yield optimization could be possible by screening solvent and base combinations in the amidine
formation step.
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Scheme 3. Synthesis of N1-methyl benzimidazoles from anilines.
TfO
R1
R1
R1
R2
R3
NH2
N
R2
R3
R2
R3
N
N
1.0 equiv
Me
PIDA (2 equiv)
HN
MeCN
100 °C
2,6-lutidine
CH2Cl2
23 °C
N
Me
R4
, 1.2 equiv
R4
R4
Me
1
3
4
F
OMe
N
Me
N
N
N
N
Ph
Ph
Ph
Ph
Ph
N
N
N
N
N
MeO
Me
Me
Me
Me
, 20%
Me
Me
4c
F
4d
4a
4b
4e
, 51%
, 47%
, 11%
, 46%
Scheme 4. Preparative scale amidine formation / oxidative cyclization sequence.
NC
H
PIDA (1.1 equiv)
Me
Cs2CO3 (1.1 equiv)
Me
NH2
Me
N
Ph
N
1.0 equiv
Ph
NH
N
H
LiHMDS (1.0 equiv)
THF, 23 °C
78%
CF3CH2OH
0 °C
Me
Me
Me
71%
2e
1.0 equiv
350 mg
340 mg scale
O
H
N
Ph
NH2
N
MeHN
Ph
PIDA (2 equiv)
1.0 equiv
Ph
NMe
N
MeCN, 100 °C
2,6-lutidine (2 equiv)
Tf2O (1.1 equiv)
0 °C to 23 °C
MeO
MeO
MeO
Me
4e
907 mg
51% yield
over 2 steps
1.2 equiv
1.1 g scale
To fully explore C4-C7 SAR, the incorporation of nitrogen atoms at various positions
would be highly desirable. Aza-benzimidazoles provide an additional hydrogen bond acceptor
and possess inherently lower cLogP than benzimidazoles; however, oxidative cyclization of
electron-poor heterocyclic amidines to aza-benzimidazoles has proven largely elusive to date.25
Nonetheless, we sought to test the compatibility of our amidine formation / oxidative cyclization
sequence with aminopyridine building blocks. Starting with 4-aminopyridine, amidine formation
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was achieved by aminopyridine addition to benzonitrile. Initial cyclization attempts with PIDA
resulted in decomposition, but switching to Cu(OAc)2/air conditions, oxidative cyclization was
achieved, affording 6a. The scope was then evaluated with a set of heteroaryl amine building
blocks (Scheme 5). 2-Aminopyridines are unsuccessful in the oxidative cyclization step,
potentially due to 2-pyridyl-amidine chelation to Cu. Interestingly, 3-aminopyridine cyclizes
selectively ortho- to the pyridine nitrogen, providing 4-azabenzimidazole as a single regioisomer
(6b). The fluorine directing effect, previously observed with 2f and 4d, inverts the inherent 3-
aminopyridine regioselectivity, as 3-amino-5-fluoropyridine favors cyclization adjacent to F (6g).
Remarkably, even electron-deficient pyrimidine rings were susceptible to Cu-mediated oxidative
cyclization, providing a new route to substituted purines (6h, 6i).
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Scheme 5. Aza-benzimidazole and purine scope.
NC
A
A
NH2
A
A
N
A
A
A
A
1.0 equiv
Cu(OAc)2 (2 equiv)
DMSO/AcOH (6:1)
air, 110 °C
LiHMDS, THF
23 °C
N
H
5
, 1.0 equiv
6
N
N
N
N
Ph
Ph
Ph
N
N
N
H
N
H
N
H
6c, 0%
6a
6b
, 22%
, 13%
>20:1 regioselectivity
O
Me
N
N
N
Ph
N
Ph
Ph
N
N
N
N
H
Me
N
H
H
6d
6f
, 12%
, 22%
6e
, 15%
2:1 regioselectivity
>20:1 regioselectivity
F
N
N
N
N
N
Ph
Ph
Ph
N
N
H
, 18%
N
H
, 15%
N
N
i-Pr
N
H
6g
6h
6i,
12%
4:1 regioselectivity
This parallel sequence provides a dramatic enhancement in available library design space.
Whereas only 141 dianilines are available for traditional benzimidazole synthesis via
cyclocondensation, there are 10,265 available ortho CH anilines, a >72 fold increase.26 For
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visualization purposes a theoretical library based on the marketed benzimidazole drug
cambendazole was enumerated using both the dianiline and aniline diversity sets, capping product
MW < 320 (Figure 2). Principal component analysis of the chemical fingerprints of the
benzimidazoles derived from the dianilines (red) and anilines (green) illustrates the enhanced
spatial coverage afforded by this protocol relative to traditional cyclocondensation.
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R1
R2
R3
N
N
N
N
O
S
S
N
H
N
H
O
N
H
R4
theoretical C4-C7 library
cambendazole
R1
R1
diversity source
R2
R3
NH2
R2
R3
NH2
NH2
vs.
H
R4
R4
dianiline diversity set
aniline diversity set
Figure 2. Chemical space plot of cambendazole derivatives.
In conclusion, we have developed a parallel protocol for the rapid synthesis of
benzimidazoles using anilines as the diversity source via PIDA- or Cu-mediated oxidative
cyclization. In addition to anilines, the reaction sequence was found to be compatible with
heteroaryl amines to provide a novel, concise route to azabenzimidazoles and purines. While
benzimidazole N1- and C2- variation libraries are routinely utilized in medicinal chemistry, C4-
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C7 libraries are rarely pursued due to the deficiencies of the 1,2-dianiline diversity set. Enablement
of plentiful aniline building blocks for C4-C7 variation in parallel format significantly accelerates
thorough SAR generation on these often-critical vectors. This method has been used on four drug
discovery projects to date, so far only in the context of lead generation; however, the protocol
could also be utilized to enrich screening sets via hit-finding libraries. This methodology
demonstrates the immense utility of CH functionalization in parallel synthesis by rendering
abundant, mono-functional building blocks capable of multiple bond constructions.
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
1H NMR, 13C NMR, and LRMS of all new compounds
AUTHOR INFORMATION
Corresponding Author
*Phone: 1-860-441-4147. E-mail: daniel.schmitt@pfizer.com
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
ACKNOWLEDGMENT
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The authors thank Dr. David Blakemore for manuscript review and Kathleen Farley for helpful
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