Amidinyl Radical Formation through Anodic N?H Bond Cleavage and Its Application in Aromatic C?H Bond Functionalization

Article abstract of DOI:10.1002/anie.201610715

We report herein an atom-economical and sustainable approach to access amidinyl radical intermediates through the anodic cleavage of N?H bonds. The resulting nitrogen-centered radicals undergo cyclizations with (hetero)arenes, followed by rearomatization,

Full text of DOI:10.1002/anie.201610715

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201610715
German Edition: DOI: 10.1002/ange.201610715
Electrochemistry
Hot Paper
ꢀ
Amidinyl Radical Formation through Anodic N H Bond Cleavage and
Its Application in Aromatic C H Bond Functionalization
ꢀ
Huai-Bo Zhao, Zhong-Wei Hou, Zhan-Jiang Liu, Ze-Feng Zhou, Jinshuai Song, and Hai-
Chao Xu*
Abstract: We report herein an atom-economical and sustain-
able approach to access amidinyl radical intermediates through
ꢀ
the anodic cleavage of N H bonds. The resulting nitrogen-
centered radicals undergo cyclizations with (hetero)arenes,
followed by rearomatization, to afford functionalized tetracy-
clic benzimidazoles in a highly straightforward and efficient
ꢀ
ꢀ
manner. This metal- and reagent-free C H/N H cross-cou-
pling reaction exhibits a broad substrate scope and proceeds
with high chemoselectivity.
N
-Heterocycles are ubiquitous motifs that play a critical
role in both medicinal chemistry and biology.[1] As a result,
the development of simple, efficient, and sustainable methods
for their synthesis from easily available building blocks is an
important research focus for organic chemists. In recent years,
the cyclization of reactive nitrogen-centered radicals (NCRs),
such as amidyl and iminyl radicals, onto unsaturated systems
has been actively pursued for the construction of N-hetero-
cycles.[2] The conventional approach for the preparation of
Scheme 1. Formation and cyclization of NCRs.
access to a series of structurally complex and diverse
polycyclic benzimidazoles, as well as pyridoimidazoles.[9]
Benzimidazoles and pyridoimidazoles are ubiquitous
structural motifs in pharmaceuticals and materials.[10] They
are generally synthesized either from ortho-functionalized
anilines,[10a] or more recently, through transition-metal-cata-
ꢀ
NCRs involves the cleavage of an N X (X = O, N, etc.) bond
to give an iminyl radical intermediate (Scheme 1a).[2,3] The
ꢀ
ꢀ
ꢀ
generation of NCRs through cleavage of N H bonds is an
inherently more atom- and step-economical method and has
lyzed or hypervalent-iodine-mediated C H/N H cross-cou-
pling of N-arylamidines.[11] However, these C H functional-
ꢀ
attracted much attention recently.[4] Despite these advances,
the reported methods involving N H bond scission are
ization methods are often limited in scope and ill-suited to the
preparation of the synthetically more difficult pyridoimid-
azoles. In addition, it is highly desirable, yet challenging, to
develop metal-[12] and reagent-free[13] dehydrogenative cross-
coupling processes with reduced environmental impact and
safety concerns.
We first optimized the electrolysis conditions for the
cyclization of 2a, which was prepared in one step from 2-
(benzylamino)benzonitrile (1). Extensive experimentation
indicated that conducting the electrolysis in a three-necked
round-bottomed flask containing an electrolyte solution of
Et4NPF6 in refluxing MeOH, combined with the use of
a reticulated vitreous carbon (RVC) anode and a platinum
ꢀ
limited in utility to the generation of amidyl or sulfonamidyl
radicals. We have previously reported[5] electrochemical
methods[6] for the generation of amidyl radicals from N H
ꢀ
amides. With our continued interest in the NCR-mediated
synthesis of N-heterocycles,[5,7] we report herein an unprece-
dented electrochemical method for the generation of ami-
ꢀ
dinyl radicals through anodic cleavage of N H bonds
(Scheme 1b). The resultant NCR intermediates subsequently
undergo cyclizations[8] with (hetero)arenes to give benzimid-
ꢀ
azoles and pyridoimidazoles. This metal- and reagent-free C
H/N H cross-coupling reaction offers rapid and sustainable
ꢀ
cathode
with
a
constant
current
of
10 mA
(janodeffi0.13 mAcmꢀ2), resulted in the highest yield (94%)
for the benzimidazole product 3a (Table 1, entry 1). While
a lower current of 5 mA showed no negative effect on the
reaction efficiency (entry 2), a reduction in yield was
observed when the reaction was performed at 20 mA
(entry 3), thus suggesting that a relatively low current density
is potentially important. Other electrolytes such as nBu4NBF4
or Et4NOTs could also be used without affecting the yield or
current efficiency (entry 4). However, reacting 2a in MeCN
(entry 5) or lowering the reaction temperature to RT
(entry 6) were found to be detrimental to the cyclization
process. The choice of electrode material proved critical; no
[*] H.-B. Zhao, Z.-W. Hou, Z.-J. Liu, Z.-F. Zhou, Prof. Dr. H.-C. Xu
iChEM, State Key Laboratory of Physical Chemistry of Solid Surfaces
Key Laboratory of Chemical Biology of Fujian Province and
College of Chemistry and Chemical Engineering
Xiamen University, Xiamen 361005 (P.R. China)
E-mail: haichao.xu@xmu.edu.cn
Homepage: http://chem.xmu.edu.cn/groupweb/hcxu/
Dr. J. Song
Fujian Institute of Research on Structure of Matter
Chinese Academy of Sciences, Fuzhou 350002 (P.R. China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201610715.
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Table 1: Optimization of reaction conditions.[a]
Entry
Electrolysis conditions[b]
Yield [%][c]
1
2
3
4
5
6
7
8
9
10
MeOH, Et4NPF6 (1 equiv), reflux, 10 mA
5 mA
20 mA
nBu4NBF4 or Et4NOTs as electrolyte
MeCN as solvent
Reaction at RT
94
93[d]
82[e]
91
7 (53)[f]
26 (41)
NR
Pt plate as anode
Graphite rod as anode
Graphite rod as cathode
Reaction run under air
50 (33)[f]
30 (25)[f]
90
[a] Reaction conditions: RVC anode (100 PPI, 1.2 cmꢀ1 cmꢀ1 cm), Pt
plate cathode (1 cmꢀ1 cm), 2a (0.3 mmol), electrolyte (0.3 mmol),
solvent (9 mL), reflux, argon, 3 h (3.7 F). [b] Conditions as for entry 1
except for the change noted. [c] Yield of isolated product. [d] Reaction
time=6 h. [e] Reaction time=1.5 h. [f] Yield determined by 1H-NMR
analysis using 1,3,5-trimethoxybenzene as the internal standard.
NR=no reaction.
product formation was detected when we used a Pt anode
(entry 7), and a dramatically lower amount of 3a was afforded
when either the anode or the cathode was graphite based
(entry 8,9). Meanwhile, the reaction showed little sensitivity
to oxygen and could be run under atmospheric conditions
(entry 10).
We subsequently investigated the effects of various func-
tional groups on the efficiency of the electrochemical
cyclization reaction (Scheme 2). A host of polar function-
alities, including alcohol (3aa), ester (3ac), carbamate (3ad),
sulfonamide (3ae, 3af), and tert-butylcarbonyl (Boc)-pro-
tected amine (3ag) or aminoester (3ah) groups were found to
be well tolerated. The reaction also demonstrated excellent
compatibility with a series of amidine reactants containing
substituents with different electronic and steric properties at
the para or meta position of the reacting A ring (3ai–am and
3c–e). Densely decorated benzimidazoles can be easily
synthesized from substrates with a multisubstituted A ring
(3i–p). It is worth noting that all meta-substituted amidines
that we tested furnished a 1:1 mixture of regioisomers (3 f–h),
whereas the cyclization of para,meta-disubstituted substrates
such as 2i and 2j led to benzimidazoles 3i and 3j as single
regioisomers.[14] The reaction of a 2-aminonaphthalene-
derived substrate also exhibited strict regioselectivity (3k).
Further investigation revealed that the C ring of the bicyclic
amidine could be functionalized with a halogen (3q, 3s, 3t),
a methyl group (3r), or even a nitrogen atom (3u).
Scheme 2. Scope of benzimidazole formation. [a] Reaction conditions:
constant current=10 mA (janodeffi0.13 mAcmꢀ2), 2 (0.3 mmol), Et4NPF6
(0.3 mmol), MeOH (9 mL), 3–4 h (3.7–5 F). [b] Yield of isolated
product. [c] 10 F. [d] 20 F. [e] Partially separable. TBS=tert-butyldime-
thylsilyl, Ts=4-toluenesulfonyl, Boc=tert-butoxycarbonyl.
Functionalized pyridoimidazoles remained difficult to
ꢀ
synthesize, even with the development of C H functionaliza-
tion methods.[10] However, as shown in Scheme 3, pyridoimid-
azoles could easily be prepared through the electrolysis of 4-
and 3-aminopyridine-derived substrates. In particular, the
products when using the latter (5d–k) were formed with
excellent regioselectivity (see the Supporting Information for
Scheme 3. Scope of pyridoimidazole synthesis. Reaction conditions
were the same as those of Scheme 2. [a] Yield of isolated product.
2
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a possible explanation). In contrast, a previously reported
cyclization of iminyl radicals afforded low selectivity.[15]
ꢀ
ꢀ
The synthetic potential of our C H/N H cross-coupling
method was further demonstrated by conducting the elec-
trolysis reaction on a gram scale (Scheme 4). For instance, we
electrolyzed 1.04 g (3 mmol) of 2ak using a constant current
of 90 mA and obtained the desired benzimidazole 3ak in
86% yield, which was on a par with what was obtained in
a 0.3 mmol reaction (92% yield).
Scheme 6. Mechanistic studies.
probed the cyclization of two ortho-substituted amidines (13
and 15; Scheme 6). Iminyl radicals are known to undergo
homolytic aromatic substitution of carbon–carbon as well as
carbon–heteroatom bonds.[15,18] Under standard conditions,
we isolated benzimidazoles 14 and 17, which were formed as
Scheme 4. Gram-scale synthesis.
ꢀ
ꢀ
a result of C Cl and C C bond cleavage, respectively (see the
Supporting Information for additional mechanistic studies).
Taken together, these studies provide strong evidence for the
The electrochemical cross-coupling reaction could also be
used for the construction of other heterocycles of medicinal
importance, such as the simple 1,2-disubstituted benzimid-
azole (7),[10a] benzo[4,5]imidazo[1,2-c]quinazoline (10),[16] and
phenanthridine (12;[17] Scheme 5) from easily available ami-
ꢀ
mechanistic involvement of a NCR intermediate in the C H/
ꢀ
N H cross-coupling process.
In summary, we have demonstrated for the first time that
amidinyl radicals can be generated conveniently through
anodic cleavage of N H bonds. The electrochemically formed
NCRs undergo efficient cyclizations onto (hetero)arenes to
afford a diverse range of polycyclic benzimidazoles and
pyridoimidazoles. Further studies to apply these anode-
generated NCRs in the synthesis of other N-heterocycles
are underway in our laboratory.
ꢀ
Acknowledgements
Financial support of this research from MOST
(2016YFA0204100), NSFC (No. 21402164, 21672178,
21603227), the “Thousand Youth Talents Plan” (K08004),
XMU (X170300109), Fujian province (Z0230106), and
Xiamen (Z0330104).
Conflict of interest
Scheme 5. Extension of the current method. Energies are in kcalmolꢀ1
.
The authors declare no conflict of interest.
Keywords: benzimidazoles · cyclization · electrochemistry ·
dines 6, 9, and 11, respectively. For the electrolysis of 6 and 9,
a mixed solvent of THF/MeOH (5:1) was found to improve
the yield. It is worth emphasizing that the favored formation
of a six-membered ring was the driving force for the
regioselective generation of phenanthridine (12). Density
functional theory (DFT) calculations confirmed that the 6-
endo-trig cyclization (path a) of the NCR intermediate to
form a six-membered ring was both kinetically and thermo-
dynamically preferred over the alternative five-membered-
ring formation (pathb).
heterocycles · radicals
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Manuscript received: November 2, 2016
Final Article published: && &&, &&&&
4
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H.-B. Zhao, Z.-W. Hou, Z.-J. Liu,
Z.-F. Zhou, J. Song,
H.-C. Xu*
&&&& — &&&&
Amidinyl Radical Formation through
Power trip: A conceptually new method
alization reactions to give benzimid-
ꢀ
Anodic N H Bond Cleavage and Its
for the generation of amidinyl radicals
azoles and pyridoimidazoles. This metal-
and reagent-free transformation exhibits
a broad scope and proceeds with high
chemoselectivity.
ꢀ
ꢀ
Application in Aromatic C H Bond
through the anodic cleavage of N H
Functionalization
bonds was developed and applied to the
ꢀ
development of aromatic C H function-
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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