Enantioselective C2-Allylation of Benzimidazoles Using 1,3-Diene Pronucleophiles

Article abstract of DOI:10.1021/acs.orglett.1c00306

Although substituted benzimidazoles are common substructures in bioactive small molecules, synthetic methods for their derivatization are still limited. Previously, several enantioselective allylation reactions of benzimidazoles were reported that functionalize the nucleophilic nitrogen atom. Herein we describe a reversal of this inherent selectivity toward N-allylation by using electrophilic N-OPiv benzimidazoles with readily available 1,3-dienes as nucleophile precursors. This CuH-catalyzed approach utilizes mild reaction conditions, exhibits broad functional-group compatibility, and exclusively forms the C2-allylated product with excellent stereoselectivity.

Full text of DOI:10.1021/acs.orglett.1c00306

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Letter
Enantioselective C2-Allylation of Benzimidazoles Using 1,3-Diene
Pronucleophiles
James Levi Knippel, Yuxuan Ye, and Stephen L. Buchwald*
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ABSTRACT: Although substituted benzimidazoles are common
substructures in bioactive small molecules, synthetic methods for
their derivatization are still limited. Previously, several enantiose-
lective allylation reactions of benzimidazoles were reported that
functionalize the nucleophilic nitrogen atom. Herein we describe a
reversal of this inherent selectivity toward N-allylation by using
electrophilic N-OPiv benzimidazoles with readily available 1,3-
dienes as nucleophile precursors. This CuH-catalyzed approach utilizes mild reaction conditions, exhibits broad functional-group
compatibility, and exclusively forms the C2-allylated product with excellent stereoselectivity.
he development of effective small-molecule therapeutics
often requires the evaluation of a library of compounds
products.4 Approaches for the asymmetric functionalization of
benzimidazoles predominantly involve bond formation at the
nucleophilic nitrogen. For example, Hartwig and Breit have
independently demonstrated that enantioenriched N-allylated
benzimidazoles can be prepared from allyl carbonates or
allenes, and chiral iridium or rhodium catalysts (Figure 2A).5
Of the few reported examples of the enantioselective C2-
functionalization of benzimidazoles,6 most rely on an intra-
molecular cyclization of an N1-tethered alkene (Figure 2B).7
Our laboratory and others have previously shown that CuH-
based catalysts can reliably convert olefins to chiral alkyl
copper intermediates, which can be utilized to form new bonds
stereoselectively.8 This chemistry has enabled a variety of C−
N and C−C bond-forming reactions, including the hydro-
acylation,9 hydroamidation,10 and formal hydrocyanation11 of
olefins as well as the allylations of both imines12 and ketones.13
Recently, we have employed this hydrofunctionalization
strategy to alkylate indole electrophiles with divergent site
selectivity, enabling C- or N-alkylation depending on the
supporting ligand that is selected (Figure 2C).14a A similar tack
has also enabled the C3-allylation of indazoles.14b We reasoned
that by using an electrophilic N-OPiv benzimidazole as a
substrate, we might be able to extend this chemistry to achieve
asymmetric addition to the C2 position of benzimidazoles
(Figure 2D).
T
containing diverse chemical structures.1 Thus the discovery of
new methods for the rapid derivatization of substructures
commonly represented in biologically active molecules is an
important goal for organic synthesis. Benzimidazoles are one
such class of heterocycles found in a variety of pharmaceuticals
and interesting natural products.2 In many of these
compounds, the benzimidazole core is functionalized at C2
with a chiral substituent (Figure 1).3 However, despite the
We began by investigating the reaction of potential alkene
coupling partners with N-OPiv benzimidazole (6) using (S,S)-
Figure 1. Representative C2-functionalized benzimidazoles.
Received: January 26, 2021
Published: March 1, 2021
prevalence of these substructures in bioactive molecules,
methods for their synthesis are limited, especially in an
enantioselective manner. Most protocols for the syntheses of
C2-substituted benzimidazoles involve late-stage construction
of the imidazole ring and often require the use of harsh
reaction conditions, being limited to the synthesis of achiral
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© 2021 American Chemical Society
Org. Lett. 2021, 23, 2153−2157
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Information for details). Several chiral bisphosphines were
examined as supporting ligands, and high enantioselectivity
was observed employing (R,R)-QuinoxP* (L2), (R)-DTBM−
SEGPHOS (L3), and (S,S)-Ph-BPE (L4) (Table 1, entries 1−
4). Although the utilization of either L3 or L4 provided
comparable enantioselectivities, the use of L4 provided 8 in the
highest yield. A comparison of solvents (entries 5−8) revealed
that the reaction was most efficient in MTBE. The use of
silanes other than DMMS led to a decrease in the product yield
(entries 9−11).15
We next explored the scope of this method by examining the
use of an assortment of benzimidazole electrophiles (Table 2).
The reaction proceeded efficiently with both electron-rich and
electron-poor benzimidazoles, giving the C2-allylated products
in good yields with good enantioselectivities (9, 10). The
reaction also worked well with halogenated benzimidazoles
(12, 13). The stereochemical assignment of 13 was confirmed
by X-ray crystallography. We note that we were also able to
utilize the 4-thiophenyl-substituted N-OPiv benzimidazole to
synthesize 11, a substructure of the histone deacetylase
inhibitor 3 (Figure 1),3c in excellent yield and enantioselec-
tivity.
Figure 2. (A) Hartwig and Breit’s asymmetric N1-allylation. (B)
Cyclization of N1-tethered alkenes to generate C2-alkylated
benzimidazoles. (C) Our group’s divergent C- or N-alkylation of
indoles. (D) CuH-catalyzed C2-allylation of benzimidazoles.
Next, we evaluated a number of 1-aryl-1,3-butadienes as
pronucleophiles. The use of reagents containing electron-rich
arenes generated the allylated benzimidazoles in good yields
with high e.r. (14, 16, 17). Additionally, heterocycle-
containing dienes could be utilized, allowing us to obtain
products such as indole 18. Aryl groups substituted with
strongly electron-withdrawing groups such as p-CF3 were
found to give significantly diminished e.r. (19). A modest level
of enantioselectivity was obtained with the more moderately
electron-poor 1-(3-bromophenyl)-1,3-butadiene, which al-
lowed access to 20, which contains both aryl chloride and
Ph-BPE (L4) as a ligand and (MeO)2MeSiH (DMMS) as the
silane. Our initial results with p-phenylstyrene were unsat-
isfactory, giving only 18% yield and poor e.r. (See the
Supporting Information for details.) However, with (E)-1-
1
phenyl-1,3-butadiene (7), we observed a 65% H NMR yield
of the allylated product (8) with 95:5 e.r. It was found, not
unexpectedly, that the use of geometrically pure (E)-
butadienes was critical, as employing an E/Z mixture resulted
in decreased enantioselectivity. Notably, the product obtained
was almost exclusively the Z-isomer, regardless of the geometry
of the diene starting material (>20:1 Z/E; see the Supporting
a
Table 1. Optimization of the Synthesis of 8
a
Reactions were performed using 0.15 mmol of 6. All yields were determined by 1H NMR with 1,1,2,2-tetrachloroethane as an internal standard.
Enantiomeric ratios were determined using supercritical fluid chromatography (SFC) employing chiral columns.
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Whereas overall, this C2-allylation protocol shows generally
good functional group tolerance, we did find that substrates
containing N-tosyl protecting groups performed poorly,
oftentimes forming a precipitate during the reaction and
giving products in poor yield. Investigating the use of alkyl-
substituted dienes, such as 1-cyclohexyl-1,3-butadiene and
myrcene, suggested that these types of pronucleophiles are
poorer substrates.
Table 2. Substrate Scope for the CuH-catalyzed C2-
allylation of N-OPiv Benzimidazoles
a
On the basis of our previous studies on the addition of allyl
copper species to indazoles, we believe the allylation of
benzimidazoles may proceed as depicted in Figure 3.14b The in
Figure 3. Proposed mechanism for the copper-hydride-catalyzed C2-
allylation of N-OPiv benzimidazoles.
situ generated (S,S)-Ph-BPE-ligated copper hydride I under-
goes a hydrocupration of diene 7 to generate isomeric allyl
copper intermediates IIa and IIb which are presumably in
equilibrium.13,14b,18 These engage with 6 in a process that
likely proceeds through a six-membered transition state in
which the methyl group occupies the endocyclic axial position
(TSA), leading to the dearomatized intermediate III. The
corresponding transition state leading to the minor E-isomer
(TSB) would require the methyl group to adopt an equatorial
orientation, resulting in a steric interaction between the methyl
group and the large Ph-BPE ligand, perhaps explaining the
allylation’s observed Z selectivity. Next, a net loss of copper
pivalate generates 8a, which may isomerize to 8 following a
1,5-hydride shift. The active CuH species I is then regenerated
after the σ-bond metathesis of IV with DMMS. Alternatively, it
is conceivable that intermediate III may undergo a σ-bond
metathesis followed by oxidation to generate the desired
product 8. In-depth mechanistic studies to shed light on these
proposed elementary steps are ongoing.
In conclusion, we have developed a method for the
asymmetric synthesis of C2-allylated benzimidazoles utilizing
1,3-diene pronucleophiles. The method allows for the
preparation of substituted benzimidazoles bearing either aryl
or methyl groups at the stereogenic center as well as
quaternary stereocenters. The reaction tolerates benzimida-
zoles and dienes with a variety of electron-rich, electron-poor,
and heterocyclic substituents, which we have utilized to
generate several substructures found in biologically active
compounds.
a
All yields and enantiomeric ratios reported represent the average of
at least two runs on a 0.5 mmol scale. Enantiomeric ratios were
determined by HPLC and SFC analysis employing chiral columns.
b
Average of two runs on a 1.00 mmol scale.
aryl bromide functional groups as potential sites for further
diversification. We also found that 1,1-disubstituted butadienes
furnished benzimidazoles bearing a C2-adjacent quaternary
center with high enantioselectivity (15). Of note, 15 was the
only allylation product obtained as the predominately E-
isomer, and both the E- and Z- isomers of 15 were found to be
highly enantioenriched.
Additionally, through the use of 2-aryl-1,3-butadiene
pronucleophiles, we could access C2-substituted benzimida-
zole products bearing a methyl-substituted stereogenic center
and a 1,1-disubstituted alkene (21).16 The reaction proceeded
well with 2-substituted butadienes containing electron-rich aryl
groups, furnishing products such as indole 23 and compound
25. Electron-poor benzimidazoles could also be utilized to
obtain C2-substituted products with high enantioselectivity
(24); however, we found that the use of electron-poor 2-
substituted butadienes resulted in severely diminished yields
(22).17
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00306.
■
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Experimental details and characterization of the products
and starting materials (PDF)
Accession Codes
CCDC 2058945 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.
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AUTHOR INFORMATION
Corresponding Author
■
Stephen L. Buchwald − Department of Chemistry,
Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States; orcid.org/0000-
0003-3875-4775; Email: sbuchwal@mit.edu
Authors
James Levi Knippel − Department of Chemistry,
Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States; orcid.org/0000-
0002-3867-4372
Yuxuan Ye − Department of Chemistry, Massachusetts
Institute of Technology, Cambridge, Massachusetts 02139,
United States; orcid.org/0000-0003-3516-5270
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00306
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the NIH under MIRA grant R35-
GM122483, the NSF Graduate Research Fellowship Program
under grant 1122374 (J.L.K.), and an NIH Diversity
Supplement Fellowship under grant R35-GM122483-03S
(J.L.K.). We thank the National Institutes of Health for a
supplemental grant for the purchase of supercritical fluid
chromatography (SFC) equipment (GM058160-17S1). Any
opinions, findings, conclusions, or recommendations expressed
in this material are those of the authors and do not necessarily
reflect the views of the NSF or NIH. We thank Solvias and
Nippon Chemical, respectively, for their generous donations of
JosiPhos and QuinoxP* ligands. We thank Dr. Peter Muller
̈
(MIT) for his assistance in the acquisition of X-ray diffraction
data. We also thank Drs. Alex Schuppe (MIT), Richard Liu
(MIT), Scott McCann (MIT), and Christine Nguyen (MIT)
for their advice during the preparation of this manuscript.
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