De Novo Synthesis of Highly Functionalized Benzimidazolones and Benzoxazolones through an Electrochemical Dehydrogenative Cyclization Cascade

Article abstract of DOI:10.1002/anie.201904931

Benzimidazolone and benzoxazolone moieties are important scaffolds in a variety of pharmaceutical molecules. These bicyclic heterocycles are usually prepared from a benzene derivative through the construction of an additional five-membered heterocyclic ri

Full text of DOI:10.1002/anie.201904931

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Accepted Article
Title: De Novo Synthesis of Highly Functionalized Benzimidazolones
and Benzoxazolones by an Electrochemical Dehydrogenative
Cyclization Cascade
Authors: Fan Xu, Hao Long, Jinshuai Song, and Hai-Chao Xu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201904931
Angew. Chem. 10.1002/ange.201904931
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10.1002/anie.201904931
Angewandte Chemie International Edition
RESEARCH ARTICLE
De Novo Synthesis of Highly Functionalized Benzimidazolones
and Benzoxazolones by an Electrochemical Dehydrogenative
Cyclization Cascade
Fan Xu,a,+ Hao Long,a,+ Jinshuai Song,b and Hai-Chao Xua,*
Abstract: Benzimidazolone and benzoxazolone moieties are
important scaffolds in a variety of pharmaceutical molecules. These
bicyclic heterocycles are usually prepared from a benzene derivative
through the construction of an additional five-membered heterocyclic
ring. We report herein a methodology that enables the efficient
synthesis of highly substituted benzimidazolone and benzoxazolone
derivatives by building both the benzene and the heterocyclic rings via
a dehydrogenative cyclization cascade. Readily available arylamine-
tethered 1,5-enynes undergo biscyclization/dehydrogenation cascade
to afford functionalized benzanellated heterocycles in a single step
with complete control of regioselectivity. These electricity-powered
oxidative transformations proceed via H2 evolution, obviating the need
for transition metal-based catalysts and oxidizing reagents.
strategy under electrochemical conditions. Herein, we report the
electrochemical synthesis of benzimidazolones and
benzoxazolones by constructing both the benzene ring and the
five-membered heterocyclic ring in a single step from arylamine-
tethered 1,5-enynes (Scheme 1d). Our synthetic strategy
provides facile access to highly functionalized benzoheterocycles
with diverse substitution patterns with complete regiocontrol. In
addition, the electrochemical dehydrogenative reactions proceed
via H2 evolution, which obviates the need for sacrificial oxidizing
reagents and proton acceptors.
Many FDA drugs, including droperidol, pimozide, domperidone
and chlorzoxazone, contain a benzimidazolone or benzoxazolone
scaffold (Scheme 1a).[1] The construction of these structural cores
generally relies on the functionalization of benzene derivatives
such as carbonylation of o-phenylenediamine[2] or 2-
aminophenol[3] and cyclization of
a functionalized aniline
derivative (Scheme 1b).[4] An obvious limitation is that the
structural diversity of the synthesized benzimidazolone and
benzoxazolone derivatives is limited due to the narrow range of
starting substrates that can be used.
Organic electrochemistry is an enabling and inherently green
synthetic technology that employs traceless electric current to
promote redox reactions[5] Compared to conventional synthetic
methods, electrosynthesis obviates the use of potentially
hazardous redox reagents, and demonstrates remarkable
reaction versatility toward a wide range of organic substrates
thanks to tunable electrode potentials.[6] We[7] have previously
reported the electrochemical synthesis of N-heterocycles through
amidyl radical[8] cyclization reactions. These results prompted us
to boldly speculate that an electrochemically enabled radical
cyclization cascade could be employed to prepare
benzoheterocycles through de novo construction of the bicyclic
scaffold. Despite that it is difficult to obtain the 6,5-fused ring
system through radical cyclization of enynes under reductive
conditions (Scheme 1c),[9] we have successfully implemented the
[a]
F. Xu, H. Long, Prof. Dr. H.-C. Xu
State Key Laboratory of Physical Chemistry of Solid Surfaces,
College of Chemistry and Chemical Engineering, Xiamen University,
Xiamen 361005 (P. R. China)
Scheme 1. Synthesis of benzimidazolones and benzoxazolones.
E-mail: haichao.xu@xmu.edu.cn
Web: http://chem.xmu.edu.cn/groupweb/hcxu/
Dr. J. Song
College of Chemistry and Molecular Engineering, Zhengzhou
University, Zhengzhou 450001 (P. R. China)
F.X. and H.L. contributed equally to this work
[b]
[+]
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201904931
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 1. Optimization of reaction conditions.[a]
effective in promoting the product formation compared to the
original choice of RVC and Pt.
The scope of the electrochemical synthesis of
benzimidazolones was explored by varying the substituents of the
urea substrate (Scheme 2, Ar and R1–R5). In addition to the
electron-rich PMP substituent, the reaction was shown to tolerate
not only unsubstituted benzene (3), but also a broad range of
functionalized phenyl moieties with diverse electronic properties,
including those bearing a Me (4), F (5) or CN group (6) on the
terminal urea nitrogen. On the other hand, the Me group on the
linking nitrogen could be replaced with a removable Bn (6–8), nBu
(9) or Ph (10). The terminal alkynyl position (R2) could be
functionalized with a 2-thiophenyl (13) or cyclohexenyl (18)
substituent. Alternatively, R2 could also be installed with a primary
(14, 15, and 19–21), secondary (22), or tertiary (23) alkyl group.
It is worth noting that a terminal alkyne (R2 = H) led to the
formation of the desired product (16), albeit in a low yield (20%).
The electrochemical reaction also demonstrated broad
compatibility with different substituents on the alkenyl positions
(R3, R4). For example, 1,1-disubstituted alkenes bearing a
sterically bulky tBu substituent (11) or an alkynyl group (12) could
be converted to the corresponding benzimidazolone products in
moderate yields. Similarly, trisubstituted alkenes were shown to
be excellent substrates for the synthesis of benzimidazolone
derivatives bearing a penta-substituted benzene ring (17–23). In
addition to acyclic olefins, alkenes embedded in a 5- (24), 6- (25–
28) or 7- (29) membered ring were also well tolerated.
Remarkably, our method could be used to efficiently synthesize a
panel of fully substituted benzimidazolones (30–35). Finally, the
alkenyl moiety could be replaced with an aryl group such as a
phenyl (36) or a naphthyl ring (37), providing facile access to
naphthyl- and phenanthryl-fused imidazolidinones.
Entry
Deviation from standard conditions
Yield [%][b]
[a] Reaction conditions: reactions run on a 0.2 mmol scale (janode = 0.15 mA
cm−2 for entry 1), RVC (1 cm x 1 cm x 1.2 cm), Pt plate (1 cm x 1 cm), solvent
(6 mL), argon, 2.7 h (5.0 F mol−1). [b] Determined by 1H NMR analysis using
1,3,5-trimethoxybenzene as the internal standard. Unreacted
parenthesis. [c] Yield of isolated 2. PMP, p-methoxyphenyl; DMF,
1 in
dimethylformamide; DMA, dimethylacetamide; TFE, 2,2,2-trifluoroethanol.
We first investigated the electrochemical dehydrogenative
cyclization of an easily available urea substrate 1 in a three-
necked round-bottomed flask equipped with two electrodes
(Table 1). Base additives were specifically avoided due to the
susceptibility of 1 to base-promoted ionic hydroamidation (Figure
S1). On the other hand, the substrate is stable under acid
conditions. After reaction optimization, we obtained the target
benzimidazolone product 2 in 83% yield by performing the
electrolysis at 100 °C and a constant current of 10 mA, with a
reticulated vitreous carbon (RVC) anode, a platinum plate
cathode, 1 equiv of trifluoroacetic acid (TFA) as acid additive, and
DMF as solvent (entry 1). The oxidation potential of the product 2
(Ep/2 = 1.26 V vs SCE) was higher than that of starting material 1
We next investigated whether our electrochemical cyclization
cascade could be used to prepare functionalized benzoxazolones
from propargylic carbamates (Scheme 3). We first tested the
same reaction conditions that we used earlier for
benzimidazolone synthesis, which unfortunately resulted in poor
yield (18% for 38) probably due to acid induced decomposition of
the propargylic carbamate substrate. However, conducting the
electrolysis in refluxing TFE (80 °C) with AcOH (5 equiv) as the
acid additive led to significant yield improvement. Subsequent
studies found the reaction to be compatible with a variety of 1,1-
substituted alkenes carrying alkyl groups with different steric
properties and aryl groups， such as Me (38 and 39), cyclohexyl
(40), tBu (41) and p-chlorophenyl (42). Fully substituted
benzoxazolones, such as 43, could also be synthesized in
satisfactory yield. Similar to what was observed in the
benzimidazolone synthesis, substitution of the alkene moiety with
an aryl group afforded naphthyl- and even phenanthrenyl-fused
oxazolidones efficiently (44–47).
(Ep/2
= 0.96 V vs SCE), which prevented the oxidative
decomposition of 2 during the electrolysis. The inclusion of TFA
was found to significantly improve the yield of 2 (entry 2), likely by
facilitating cathodic proton reduction[27] and avoiding base-
promoted side reactions mentioned above. Lowering the reaction
temperature to 50 °C (entry 3) or replacing DMF with another
solvent such as DMA (entry 4), DMSO (entry 5) or TFE (entry 6),
all resulted decreased product formation. We speculated that
heating was necessary for the urea substrate 1 to overcome the
energy barrier of a conformational change from its preferred (trans,
trans)-conformation to the (trans, cis)-conformation required for
its cyclization (Figure S2).[10] Alternative anode materials, such as
Pt (entry 7) and graphite (entry 8), as well as cathode materials
with greater overpotential for proton reduction, such as Ni (entry
9), stainless steel (entry 10) and RVC (entry 11), were all less
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10.1002/anie.201904931
Angewandte Chemie International Edition
RESEARCH ARTICLE
Scheme 2. Scope of benzimidazolone synthesis. [a] Yield refers to isolated yield of purified product (0.2 mmol scale), 4.2–9.2 F mol−1. [b] No TFA. [c] AcOH (5
equiv) instead of TFA. Bn, benzyl; TBDPS, tert-butyldiphenylsily.
Scheme 3. Scope of benzoxazolone synthesis. [a] Yield refers to isolated yield of purified product (0.2 mmol scale), 4.0–6.7 F mol−1
.
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10.1002/anie.201904931
Angewandte Chemie International Edition
RESEARCH ARTICLE
successful synthesis of 5.9 g of benzimidazolone 20 from 10.4 g
of 48 (57% yield). In addition, 20 could subsequently be
converted to chlorobenzimidazole 49 by chemoselectively
removing its N-Bn group and then reacting with POCl3. The
remaining hydrogen on the penta-substituted benzene ring of 20
could be substituted by a bromine (50) or an iodine (51) to
provide a functional group handle for further derivatization. The
side chains could also be chemoselectively functionalized. For
example, the OBn group on the alkyl chain could be orthogonally
deprotected (52), or converted to an acetoxy (53) or chloro (54)
group.
We have previously reported the electrocatalytic formation of
amidyl radicals using ferrocene as a mild redox catalyst.[7a] Under
these conditions, the carbamate substrate 55 could be converted
to cyclohexadiene 56 (20%) and monocyclized 1,5-diene 57
(12%), together with a trace amount of benzoxazolone 41
(Scheme 5a). Importantly, electrochemical dehydrogenation of
56 in TFE afforded 41 in 67% yield. Overall, these results
strongly supported
Scheme 4. Gram-scale synthesis and chemoselective derivatization of
benzimidazolone 20. Reaction conditions: a. i) BuOK, O2, DMSO, rt, 72%; ii)
POCl3, 110 °C, 52%. b. NBS, HBr, CH3CN, rt, 82%. c. I2, Ag2SO4, EtOH, 85 °C,
53%. d. Pd(OH)2/C, H2, MeOH, rt, 88%. e. AcCl, AlCl3, CH2Cl2, 0 °C, 65%. f.
POCl3, DMF, 80 °C, 99%.
t
The electrochemical cyclization reaction could be applied on
a decagram scale (Scheme 4), as demonstrated by the
Scheme 5. Mechanistic investigations and proposal.
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10.1002/anie.201904931
Angewandte Chemie International Edition
RESEARCH ARTICLE
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dehydrogenative radical cyclization of acyclic precursors. These
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benzimidazolones and benzoxazolones, including fully
substituted benzoheterocycles, with complete control of
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Keywords:
electrochemistry
•
benzimidazolones
•
benzoxazolones • dehydrogenative cyclization cascade • radical
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10.1002/anie.201904931
Angewandte Chemie International Edition
RESEARCH ARTICLE
RESEARCH ARTICLE
Fan Xu, Hao Long, Jinshuai Song, and
Hai-Chao Xu*
Page No. – Page No.
De Novo Synthesis of Highly
Functionalized Benzimidazolones and
Benzoxazolones
Electrochemical
Cyclization Cascade
by
an
Report herein is an electricity-powered synthesis of highly substituted
benzimidazolone and benzoxazolone derivatives by de novo construction of the
benzene and the heterocyclic ring via a dehydrogenative cyclization cascade. The
electrosynthesis method proceeds via H2 evolution, obviating the need for oxidizing
reagents and proton acceptors.
Dehydrogenative
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