Catalytic, Enantioselective C2-Functionalization of 3-Aminobenzofurans Using N-Heterocyclic Carbenes

Article abstract of DOI:10.1021/acs.orglett.0c01112

N-Heterocyclic carbene catalyzed enantioselective functionalization of 3-aminobenzofurans at the C2-position was realized using 2-bromoenals as the coupling partner. The reaction proceeds via generation of chiral α,β-unsaturated acylazoliums and follows a

Full text of DOI:10.1021/acs.orglett.0c01112

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Letter
Catalytic, Enantioselective C2-Functionalization of
3‑Aminobenzofurans Using N‑Heterocyclic Carbenes
Shilpa Barik, Sayan Shee, Arghya Ghosh, and Akkattu T. Biju*
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ABSTRACT: N-Heterocyclic carbene catalyzed enantioselective
functionalization of 3-aminobenzofurans at the C2-position was
realized using 2-bromoenals as the coupling partner. The reaction
proceeds via generation of chiral α,β-unsaturated acylazoliums and
follows an aza-Claisen rearrangement. The initially formed
dihydropyridinone undergoes ring-opening catalyzed by Mg to
afford the δ-amino acid derivatives. The reaction worked with 3-
aminobenzothiophenes as well, and the C2-alkylated products were formed in moderate to high yields and selectivity.
Scheme 1. NHC-Catalyzed Reaction of Enals with
Vinylogous Amides
ransition-metal-catalyzed chelation-assisted functionaliza-
tion of the inert C−H bonds has emerged as a powerful
T
and flexible synthetic strategy for the rapid access to complex
molecules from simple starting materials.1 A wide range of
transition-metal catalysts were developed over the past years
for the selective proximal and distal functionalization of C−H
bonds.2 With the proper choice of chiral ligands attached to
the metal center, the corresponding enantioselective C−H
bond functionalization reactions could be possible leading to
enantiomerically pure products.3 Intriguingly, the transition-
metal-free, enantioselective functionalization of inert C−H
bonds for the derivatization of arenes and heteroarenes has
received only scant attention.4 Herein, we report the N-
heterocyclic carbene (NHC)-catalyzed enantioselective func-
tionalization of 3-aminobenzofurans/benzothiophenes at the
C2-position, where the reaction proceeds via the carbene-
bound chiral α,β-unsaturated acylazolium intermediates.
the hemiaminal B, which is poised for an enantiodetermining
aza-Claisen rearrangement to form C (Scheme 2).13−15
Tautomerization of intermediate C could generate the NHC-
azolium D, which undergoes lactamization to 4 followed by
ring-opening to afford the C2-functionalized benzofuran 3.
Following this background, herein, we report a general,
catalytic and enantioselective C2-functionalization of 3-amino-
Scheme 2. Envisioned C2-Functionalization of 3-
Aminobenzofurans Using NHC Catalysis
Catalysis using NHCs are widely utilized for the (un)-
conventional access to various carbocycles, heterocycles and
acyclic molecules and in many cases with remarkable
enantioselectivity.5 Among the various modes of carbene
reactivity, the generation of α,β-unsaturated acylazoliums from
various α,β-unsaturated aldehydes/acid derivatives is one of
the important nonumpolung pathway.6 The catalytically
generated α,β-unsaturated acylazoliums are employed in the
enantioselective synthesis of several heterocycles.7,8 Nucleo-
philes could add to the α,β-unsaturated acylazoliums in a 1,4-
pathway (proposed by Studer)9 or in a 1,2-manner (suggested
by Bode).10 In 2011, Bode and co-workers demonstrated the
NHC-catalyzed oxidative annulation of enals with vinylogous
amides for the enantioselective synthesis of dihydropyridi-
nones, and the reaction proceeds via the generation of α,β-
unsaturated acylazolium intermediates (Scheme 1).11,12 We
envisioned that the hard nitrogen center of 3-aminobenzofur-
ans 1 could add to the hard carbonyl center of α,β-unsaturated
acylazolium intermediate A in a 1,2-pathway thus generating
Received: March 27, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01112
© XXXX American Chemical Society
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A

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a
benzofurans and benzothiophenes, and the δ-amino acid
derivatives are formed in good yield and selectivity.
Scheme 3. Scope of 2-Bromoenals in the Reaction
The present studies were initiated by treating the N-tosyl 3-
aminobenzofuran 1a with 2-bromoenal 2a in the presence of
the carbene generated from the chiral triazolium salt 516 using
DABCO as the base and LiOAc·2H2O and 4 Å MS as additives
followed by treatment with catalytic amount of Mg in
methanol. Delightfully, under these conditions, the C2-
alkylated benzofuran derivative 3a was formed in 94% isolated
yield and 98:2 enantiomeric ratio (Table 1, entry 1).17 The
a
Table 1. Optimization of the Reaction Conditions
b
c
entry variation of the standard conditions yield of 3a (%) er of 3a (%)
1
2
3
4
5
6
7
8
none
6 instead of 5
7 instead of 5
95 (94)
88
84
83
81
84
85
87
68
70
71
<5
87
98:2
95:5
93:7
99:1
98:2
98:2
98:2
99:1
63:37
62:38
97:3
nd
without 4 Å MS and LiOAc.2H2O
5 mol % of 5 instead of 10 mol %
1,4-dioxane instead of toluene
THF instead of toluene
CH2Cl2 instead of toluene
Cs2CO3 instead of DABCO
Et3N instead of DABCO
DMAP instead of DABCO
DBU instead of DABCO
5 mol % Mg instead of 20 mol %
9
a
General conditions: 1a (0.25 mmol), 2 (0.375 mmol), 5 (10 mol %),
DABCO (0.425 mmol), LiOAc·2H2O (20 mol %), 4 Å MS (50 mg),
toluene (2.5 mL) 25 °C and 12 h followed by Mg (20 mol %) in
MeOH (5.0 mL), 25 °C and 12 h. Yields of isolated products are
given and the er value was determined by HPLC analysis on a chiral
stationary phase.
10
11
12
13
98:2
releasing, -neutral, and -withdrawing groups at the 4-position
of the β-aryl ring are well tolerated under the present
conditions, and in all cases, the C2-alkylated product was
formed in good yields and er values (3a−3h). However, with
the −CF3 group, the yield and selectivity were only moderate.
Moreover, 2-bromoenals having substitution at the 2-position
and 3-position as well disubstitution underwent smooth C2-
functionalization, and the desired products are formed in
moderate to good yield and high selectivity (3i−3r). In
addition, substitution at the β-position of enal with heteroaryl
moiety did not affect the outcome of the reaction and the
corresponding furyl and thienyl products 3s and 3t were
formed in good yield and selectivity. Furthermore, challenging
aliphatic 2-bromoenals also worked under the optimized
conditions leading to the desired C2-alkylated products in
good yields (3u, 3v).
Next, we evaluated the variation on 3-aminobenzofurans
(Scheme 4). Benzofurans having Me, OMe, and halogen
substitution at the 5-position are well tolerated under the
present conditions to furnish the δ-amino acid derivatives in
good yield and excellent er values (3w−3aa). Moreover, 6-
fluoro-substituted substrate afforded the desired product 3ab
in 83% yield and 97:3 er. Interestingly, the present reaction is
not limited to benzofurans, but instead 3-amino benzothio-
phenes also underwent smooth carbene-catalyzed reaction
followed by ring-opening to deliver the C2-alkylated
benzothiophenes in good yield and er values (3ac−3ae).18
Disappointingly, the reactions performed using N-protected 3-
a
Standard conditions: 1a (0.1 mmol), 2a (0.15 mmol), 5 (10 mol
%), toluene (1.0 mL), LiOAc·2H2O (20 mol %), 4 Å MS (25 mg), 25
°C, 12 h, followed by Mg (20 mol %) in methanol (2.0 mL) at 25 °C,
12 h. The yields were determined by H NMR analysis of crude
reaction mixture using CH2Br2 as the internal standard. Isolated yield
was provided in parentheses. The er values were determined by
b
1
c
HPLC analysis on a chiral stationary phase.
carbene generated from the triazolium salts 6 and 7 also
showed good reactivity, but the yield and selectivity are less
compared to the carbene generated from 5 (entries 2, 3). The
additives are required for the excellent reactivity (entry 4), and
lowering the loading of 5 to 5 mol % reduced the reactivity
maintaining the high selectivity (entry 5). Toluene was found
to be the optimal solvent for this transformation as the
reactions performed in other solvents afforded 3a in reduced
yields (entries 6−8). The reactions performed in bases such as
Cs2CO3, Et3N, DMAP, and DBU returned inferior results,
indicating that DABCO is the best base for this reaction
(entries 9−12). Moreover, reducing the loading of Mg to 5
mol % reduced the yield of 3a to 87% (entry 13).
Having the optimized conditions in hand, we then focused
our attention on the substrate scope of the C2-functionaliza-
tion reaction. Initially, the variation on 2-bromoenals was
studied (Scheme 3). A series of 2-bromoenals bearing electron-
B
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Moreover, β-heteroaryl as well as β-alkyl-substituted 2-
bromoenals also furnished the target benzofuran-fused
dihydropyridinone in moderate to good yields and er values
(4h, 4i, and 4n). In the case of the 4-Br (4e) and 4-Cl
derivatives (4f), the structure and the absolute stereochemistry
of the chiral center was confirmed using single-crystal X-ray
analysis. The structure and stereochemistry of the δ-amino acid
derivatives 3 were concluded in analogy with 4e and 4f. Finally,
the 5-bromo- and 5-iodo-substituted benzofuran substrates
also worked fine to afford the tricyclic products in moderate to
good yields and high selectivity (4o, 4p).
Scheme 4. Variation of 3-Amino Benzofurans
To gain insight into the mode of addition of 3-amino-
benzofuran 1a to the catalytically generated α,β-unsaturated
acylazoliums A, a reaction of 1a with 2a under the present
conditions in the presence of iPr-OH was conducted.
Interestingly, the C2-alkylated product 8a possibly derived
from the 1,4-addition from the C2-position of 1a to A was not
observed, and the desired dihydropyridinone 4a was isolated in
59% yield along with the cinnamyl ester 9a in 25% yield
(Scheme 6). The absence of the formation of 1,4-addition
a
General conditions: 1 (0.25 mmol), 2a (0.375 mmol), 5 (10 mol %),
DABCO (0.425 mmol), LiOAc·2H2O (20 mol %), 4 Å MS (50 mg),
toluene (2.5 mL) 25 °C and 12 h followed by Mg (20 mol %) in
b
MeOH (5.0 mL), 25 °C and 12 h. 1.0 equiv of Mg was used and the
reaction mixture stirred for 36 h.
aminoindoles did not afford the desired C2-alkylated products
under the optimized reaction conditions.
Scheme 6. Study toward the Mechanism of the Reaction
Interestingly, when the NHC-catalyzed reaction was
performed without the treatment of Mg, the intermediate
dihydropyridinone derivative was indeed isolable. Thus, the
treatment of 1a with 2a in the presence of NHC generated
from 5 afforded the tricyclic dihydropyridinone 4a in 74% yield
and 98:2 er (Scheme 5). The dihydropyridinone formation was
taking place with a series of electronically different 2-
bromoenals. Substitution was well tolerated at the 4-position
and 2-position of the β-aryl ring (4b−4g and 4j−4m).
Scheme 5. Enantioselective Synthesis of
a
Dihydropyridinones
product 8a and the formation of 4a is likely an evidence for the
initial 1,2-addition operating in the present case. Control
experiments indicated that 4a cannot be converted into 8a in
the presence of iPr-OH with or without Mg. Notably, related
1,4-addition product in the reaction of dimethyl malonate to A
was demonstrated by Studer and co-workers.9a Moreover,
intermolecular competition experiments carried out between
1a and methyl (Z)-3-aminobut-2-enoate indicated that 1a
reacts ∼65 times faster than the acyclic vinylogous amide,
which likely sheds light on the high nucleophilicity of 1a.17
A proposed mechanism of the reaction is presented in
Scheme 7. The nucleophilic attack of the NHC generated from
5 to the 2-bromoenal 2 followed by the proton transfer
generates the Breslow intermediate I,19 which is converted into
the key α,β-unsaturated acylazolium II via bromide elimi-
nation.6 The 1,2-addition of 1 to intermediate II generates the
hemiaminal III, which undergoes an aza-Claisen rearrange-
ment to form IV.10a−c,11 The intermediate IV could undergo a
tautomerization to generate the NHC-azolium V, which
undergoes a facile lactamization to form the dihydropyridinone
4, which is subsequently ring-opened to afford the C2-
functionalized benzofuran 3. Notably, related ring-opening of
dihydropyridinones using Mg was reported by Ye and co-
workers.10e
The δ-amino acid derivative synthesized using the present
method can be easily N-arylated under transition-metal-free
conditions using arynes as the aryl source.20 Thus, treatment of
3a with benzyne generated from the triflate 10a using KF (in
the presence of 18-crown-6 as additive) afforded the N-
a
General conditions: 1 (0.25 mmol), 2 (0.375 mmol), 5 (10 mol %),
DABCO (0.425 mmol), LiOAc·2H2O (20 mol %), 4 Å MS (50 mg),
toluene (2.5 mL), 25 °C and 12 h.
C
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Scheme 7. Tentative Mechanism of the Reaction
AUTHOR INFORMATION
Corresponding Author
■
Akkattu T. Biju − Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560012, India; orcid.org/
0000-0002-0645-8261; Email: atbiju@iisc.ac.in
Authors
Shilpa Barik − Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560012, India
Sayan Shee − Department of Organic Chemistry, Indian Institute
of Science, Bangalore 560012, India
Arghya Ghosh − Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560012, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01112
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support by the Science and Engineering
Research Board, Government of India (File No. EMR/2016/
007021), is gratefully acknowledged. S.B. and S.S. thank IISc
for the fellowships, and A.G. thanks CSIR for the research
fellowship. We thank Mr. Apurba Kumar Pal (IPC-IISc) for
the help in collecting the X-ray data, Ms Arya Karumanthra
(OC-IISc) for performing some initial experiments, and Dr.
Subrata Mukherjee (CSIR-NCL) for helpful discussions.
arylated product 11a in 92% yield, preserving the enantiopurity
(Scheme 8).
Scheme 8. N-Arylation Using Arynes as Aryl Source
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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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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(14) It seems very unlikely that the 3-aminobenzofuran undergoes
1,4-addition to α,β-unsaturated acylazoliums because this has to break
the aromaticity of benzofuran moiety, and the presence of a tosyl
group is likely to make the N−H harder for the 1,2-addition.
E
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