Electrochemical Synthesis of Imidazo-Fused N-Heteroaromatic Compounds through a C?N Bond-Forming Radical Cascade

Article abstract of DOI:10.1002/anie.201711876

We have developed a unified strategy for preparing a variety of imidazo-fused N-heteroaromatic compounds through regiospecific electrochemical (3+2) annulation reaction of heteroarylamines with tethered internal alkynes. The electrosynthesis employs a novel tetraarylhydrazine as the catalyst, has a broad substrate scope, and obviates the need for transition-metal catalysts and oxidizing reagents.

Full text of DOI:10.1002/anie.201711876

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Accepted Article
Title: Electrochemical Synthesis of Imidazo-Fused N-Heteroaromatics
via C-N Bond Forming Radical Cascade
Authors: Zhong-Wei Hou, Zhong-Yi Mao, Yared Yohannes Melcamu,
Xin Lu, and Hai-Chao Xu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201711876
Angew. Chem. 10.1002/ange.201711876
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http://dx.doi.org/10.1002/ange.201711876

10.1002/anie.201711876
Angewandte Chemie International Edition
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Electrochemical Synthesis of Imidazo-Fused N-Heteroaromatics
via C–N Bond Forming Radical Cascade
Zhong-Wei Hou,+ Zhong-Yi Mao,+ Yared Yohannes Melcamu, Xin Lu* and Hai-Chao Xu*
Abstract: We have developed a unified strategy for preparing a
variety of imidazo-fused N-heteroaromatics through regiospecific
electrochemical (3+2) annulation reaction of heteroarylamines with
tethered internal alkynes. The electrosynthesis employs a novel
tetraarylhydrazine as the catalyst, has a broad substrate scope, and
obviates the need for transition-metal catalysts and oxidizing reagents.
forming cyclization cascade (Scheme 1b). Our electrolytic
approach employs a traceless linker to enable the regiospecific
(3+2) annulation of internal alkynes.
The development of more efficient and sustainable methods for
constructing C–N bonds has always been a major focus of
synthetic organic chemistry due to the critical roles of N-
containing compounds in pharmaceutical, agrochemical and
material industries.[1] Despite the recent resurgence of interests in
organic radical chemistry, radical C–N bond formation reactions
remain underdeveloped.[2] Lately, many research groups
including us have succeeded in creating C–N bonds by cyclizing
N-centered radicals with alkenes (Scheme 1a).[3] In comparison,
there have only been a few studies on the cyclization of N-
centered radicals with alkynes,[4] probably due to the lack of
versatile radical initiation methods and the competing ionic
cyclization reaction[5] when using a N–H based radical precursor.
On the other hand, there is also a lack of C–N bond forming
cyclization reactions employing C-centered radicals,[6] which
show a strong preference for reaction with the carbon instead of
the nitrogen in N-containing -systems.[7]
Imidazo-fused heteroaromatics are important scaffolds as
they are featured in numerous bioactive compounds including
commercialized drugs such as Zolpidem, Olprinone and
Cefozopran.[8] The oxidative (3+2) annulation of arylamines with
alkynes is one of the most attractive strategies to access these
structures because of the easy availability of starting materials
and the inherent atom- and step-economical features. However,
the reported methods employ only terminal alkynes or alkynes
substituted with halogen or electron-withdrawing groups to
provide sufficient reactivity and regioselectivity.[9]
Scheme 1. Design of radical cyclization cascade for the synthesis of imidazo-
fused N-heteroaromatics.
The first aim of our study was to develop an electrochemical
process that could be used to efficiently generate amidyl radicals
from N–H precursors without the need for transition-metal
catalysts. To this end, we chose the readily accessible carbamate
2 as a model substrate and screened a variety of different
electrolysis conditions employing an undivided cell equipped with
a reticulated vitreous carbon (RVC) anode and a platinum
cathode (Table 1 and Table S1). The optimal results were
obtained when 2 was electrolyzed at a constant current in a mixed
solvent of MeCN/H2O (9:1) under reflux in the presence of 10
mol % of tetraarylhydrazine 1 as catalyst. Despite their easy
availability, the use of tetraarylhydrazines as redox catalyst has
not been reported.[13] Under these conditions, the desired
Organic electrochemistry is a powerful and attractive tool for
organic synthesis because it employs electrons as “reagents” and
is tunable in the activation of small molecules to generate reactive
intermediates.[10,11] In this context, few methods have been
developed for preparing amidyl radicals via direct[12] or
indirect[3g,4b,4c] electrolysis of N–H bearing precursors. Here we
report an electrochemical synthesis of imidazo-fused N-
heteroaromatics through an unprecedented radical C–N bond-
imidazopyridine 3 was isolated in 89% yield (entry 1).
Table 1. Optimization of reaction conditions.[a]
Entry
Deviation from standard conditions
Yield [%][b]
[*]
Z.-W. H,+ Z.-Y. Mao,+ Y. Y. Melcamu, Prof. Dr. X. Lu, Prof. Dr. H.-C.
Xu
State Key Laboratory of Physical Chemistry of Solid Surfaces,
iChEM, and College of Chemistry and Chemical Engineering,
Xiamen University
Xiamen 361005 (P. R. China)
E-mail: xinlu@xmu.edu.cn; haichao.xu@xmu.edu.cn
Homepage: http://chem.xmu.edu.cn/groupweb/hcxu/
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201711876
Angewandte Chemie International Edition
COMMUNICATION
performance. Stringent removal of oxygen from the reaction
system was not needed as performing the electrolysis under
atmospheric conditions also produced the desired 3 in 75% yield
(entry 9). Note that we did not observe the generation of 4, which
would indicate the occurrence of carbophilic cyclization, under
any circumstances.
We investigated the substrate scope first by testing different
aminoheteroarene moieties (Scheme 2). Generally, annulation of
a 2-aminopyridine derivative demonstrated broad tolerance
toward a wide range of substituents with diverse electronic
properties at the C6 (10, 11), C5 (12–15), C4 (16–19) but not the
C3 (20) position of the pyridyl ring. Substrates with multiple
substituents afforded densely functionalized imidazopyridines
(21–25). Furthermore, replacement of the 2-aminopyridine moiety
with a host of aminodiazine structures was also shown to be
possible. The reaction proceeded smoothly in all instances
regardless of the nitrogen positions, leading to the formation of
imidazo[1,2-b]pyridazines (26–28), imidazo[1,2-c]pyrimidine (30),
imidazo[1,2-a]pyrazines (31–34) and imidazo[1,2-a]pyrimidine
(35). The synthesis of imidazo[1,2-c]pyrimidine 30 required the
use of Na2CO3 as the base and MeOH/THF (1:3) as the solvent
(See Table S2 for details). Medicinally important imidazo[2,1-b]
benzothiazoles (36, 37) could also be prepared by the electrolytic
method.
[a] Reaction conditions: undivided cell, RVC anode, Pt cathode, 2 (0.3
mmol), H2O (1 mL), MeCN (9 mL), Et4NBF4 (0.3 mmol), NaHCO3 (0.6 mmol),
7.5 mA (janode = 0.1 mA cm−2), 3.7 h (3.5 F mol−1). [b] determined by 1H NMR
analysis, unreacted 1 in parenthesis. [c] Yield of isolated 3.
The organic catalyst (entry 2), NaHCO3 (entry 3) and heating
(entry 4) were all found to be essential for the reaction to achieve
the optimal yield. Other tetraarylhydrazines with similar (entry 5)
or higher oxidation potentials (entry 6), common triarylamines
(entry 7) and ferrocene[3g,4b,4c] (entry 8) all showed poor catalytic
Scheme 2. Substrate scope using a carbamate linkage. Reaction conditions: Table 1, entry 1, substrate (0.3 mmol), 3.7 h (3.5 F mol−1). All yields are isolated yields.
[a] Reaction run with 1 (5 mol %) and Na2CO3 (0.3 mmol) in refluxing MeOH/THF (1:3, 9 mL). [b] 0.5 equiv of NaHCO3.
We next varied the propargyl group in the starting substrate
(Scheme 2). The reaction was shown to be compatible with
methyl (38) and tert-butyl (39) on the propargylic position. On the
other hand, the benzene ring at the terminus of the alkyne could
be functionalized with a variety of substituents with diverse
electronic and steric properties (40–48). While the alkyne could
also be terminally substituted with 1-naphthyl (49), 2-thiophenyl
(50) or cyclohexenyl group (51), the installation of an alkyl group
did not result in the generation of the corresponding
imidazopyridine product in MeCN/H2O; alternatively, the
hydroamidation product 52 was isolated when the reaction was
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10.1002/anie.201711876
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conducted in MeOH/THF, a solvent system with better H-atom
donating ability.
We speculated that the terminal alkyl substituent caused the
intermediate vinyl radical to favor H-atom abstraction from the
solvent over the azaphilic cyclization. To address this problem, we
drew inspiration from our recent findings that the formation of a
six-membered ring in the first step of the amidyl radical cyclization
cascade could greatly facilitate the subsequent construction of the
five-membered ring.[4b] To our delight, the urea-linked substrates,
especially those carrying an alkyl-capped alkyne, exhibited
significantly improved reaction compatibility and furnished
imidazopyridines 53–60 even when only 5 mol % of 1 was added
(Scheme 3). In all cases, the starting compound was electrolyzed
in MeOH, which installed a methoxycarbonyl substituent on the
amino group of the corresponding product to protect it from
oxidative decomposition.
Scheme 4. Mechanistic studies and rationale. DFT (UB3LYP/6-31G*)
calculated energetics (kcal mol−1) are Gibbs free energies in the gas phase.
Energies of C–F are relative to C. ACCN, 1,1′-azobis(cyclohexanecarbonitrile).
Based on the studies above, a possible mechanism for the
electrolytic (3+2) annulation reaction was proposed using model
substrate 2 (Scheme 4). The reaction begins with the anodic
oxidation of tetraarylhydrazine 1 (Ep/2 = 0.68 V vs SCE), which
produces a stable radical-cation intermediate A. Meanwhile,
hydroxide is generated from the reduction of H2O at the cathode
and it deprotonates 2 to afford the anion B, whose oxidation
potential is significantly lower than that of 2 (Ep/2 = 1.76 V for 2,
0.66 V for B, vs SCE). Because of the continuous generation of
the requisite base at low concentration, base-promoted ionic
cyclization[5] of 2 is avoided (Scheme S1). A single electron
transfer then occur from B to A, which results in the formation of
amidyl radical C and the regeneration of 1. The 5-exo-dig
cyclization of C affords vinyl radical D, which then reacts
regioselectively with the pyridyl nitrogen to generate a tricyclic
radical intermediate E. The ensuing one-electron oxidation of E,
followed by the hydrolysis of its carbonyl linker, forms the
imidazopyridine product 3 (Ep/2 = 1.20 V), which has an oxidation
potential lower than that of the starting carbamate 2. The use of a
redox catalyst instead of direct electrolysis protects the product
from oxidative decomposition.
Scheme 3. Substrate scope using a urea linkage. Reaction conditions, urea
substrate (0.3 mmol), 1 (0.015 mmol), Et4NBF4 (0.3 mmol), Na2CO3 (0.3 mmol),
MeOH/THF (1:3, 9 mL), reflux, 7.5 mA, 4–8.5 h (3.7–8 F mol−1).
As further evidence for the application potential of our method,
we first demonstrated that the synthesis of 3 could be performed
on a decagram scale with similarly high yield as that of the small-
scale reaction (Eq. 1). Furthermore, enantioenriched (−)-2 was
shown to afford (−)-3 without racemization (Eq. 1).
The cascade radical cyclization was further examined by DFT
(density functional theory) calculations (Scheme 4). The formation
of E via the C–N bond-forming pathway is thermodynamically and
kinetically favored over the alternative C–C bond-forming
pathway to give F. Detailed NBO (natural bonding orbital)
analyses (Schemes S2 and S3) revealed that the regioselectivity
of the cyclization reaction toward C–N bond formation was due to
the n(pyridine)p(C1) interaction being much more energetically
favorable than that of (pyridine)p(C1). This was consistent with
the observation that the dihedral angle N5–C4–N3–C2 (20.3) in
TS1 is much smaller than C6–C4–N3–C2 (30.1) in TS2.
To shine light on the reaction mechanism, cyclic carbamate
61 containing a C(sp2)–I bond was employed as the vinyl radical
precursor and reacted to produce the imidazopyridine product 3
in 30% yield when treated with ACCN and nBu3SnH (Scheme 4).
These results lent support to the hypothesis that 3 was generated
from the azaphilic cyclization of a vinyl radical intermediate. In
comparison, the reaction of the alkyl-substituted 63 afforded only
the reduced product 52, suggesting that the alkyl-substituted vinyl
radical favored H-atom abstraction over cyclization.
In summary, we have reported a regiospecific electrochemical
[3+2] annulation reaction of heteroarylamines with internal
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[11] Selected recent examples: a) R. Hayashi, A. Shimizu, J. I. Yoshida, J.
Am. Chem. Soc. 2016, 138, 8400–8403; b) B. Johnson, R. Francke, R.
D. Little, L. A. Berben, Chem. Sci. 2017, 8, 6493–6498; c) E. J. Horn, B.
R. Rosen, Y. Chen, J. Tang, K. Chen, M. D. Eastgate, P. S. Baran,
Nature 2016, 533, 77–81; d) Q.-Q. Wang, K. Xu, Y.-Y. Jiang, Y.-G. Liu,
B.-G. Sun, C.-C. Zeng, Org. Lett. 2017, 19, 5517-5520; e) Q. L. Yang, Y.
Q. Li, C. Ma, P. Fang, X. J. Zhang, T. S. Mei, J. Am. Chem. Soc. 2017,
139, 3293–3298; f) P. Wang, S. Tang, P. Huang, A. Lei, Angew. Chem.
Int. Ed. 2017, 56, 3009–3013; Angew. Chem. 2017, 129, 3055–3059; g)
L. Schulz, M. Enders, B. Elsler, D. Schollmeyer, K. M. Dyballa, R. Franke,
S. R. Waldvogel, Angew. Chem. Int. Ed. 2017, 56, 4877–4881; Angew.
Chem. 2017, 129, 4955–4959; h) A. J. J. Lennox, J. E. Nutting, S. S.
Stahl, Chem. Sci. 2018, DOI: 10.1039/C7SC04032F; i) N. Fu, G. S.
Sauer, A. Saha, A. Loo, S. Lin, Science 2017, 357, 575–579.
alkynes that is applicable to the synthesis of a host of imidazo-
fused N-heteroaromatics. This electrosynthesis is enabled by the
development of a tetraarylhydrazine as the catalyst to generate
the amidyl radicals and by uncovering novel reactivities of N- and
C-centered radicals for C–N bond formation.
Acknowledgements
Financial
support
of
this
research
from
MOST
(2016YFA0204100), NSFC (No. 21402164, 21672178).
[12] a) T. Gieshoff, A. Kehl, D. Schollmeyer, K. D. Moeller, S. R. Waldvogel,
J. Am. Chem. Soc. 2017, 139, 12317–12324; b) T. Gieshoff, D.
Schollmeyer, S. R. Waldvogel, Angew. Chem. Int. Ed. 2016, 55, 9437–
9440; Angew. Chem. 2016, 128, 9587–9590; c) H.-C. Xu, J. M. Campbell,
K. D. Moeller, J. Org. Chem. 2014, 79, 379–391.
Keywords: electrochemistry • heterocycles • radical • annulation
• alkyne
[1]
[2]
E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257–
10274.
[13] Selected recent examples of organocatalyzed organic electrosynthesis:
a) C.-C. Zeng, N.-T. Zhang, C. M. Lam, R. D. Little, Org. Lett. 2012, 14,
1314-1317; b) P. Röse, S. Emge, C. A. König, G. Hilt, Adv. Synth. Catal.
2017, 359, 1359; c) X.-Y. Qian, S.-Q. Li, J. Song, H.-C. Xu, ACS Catal.
2017, 7, 2730-2734.
a) S. Z. Zard, Chem. Soc. Rev. 2008, 37, 1603–1618; b) J. R. Chen, X.
Q. Hu, L. Q. Lu, W. J. Xiao, Chem. Soc. Rev. 2016, 45, 2044–2056; c)
M. D. Kärkäs, ACS Catal. 2017, 7, 4999–5022.
[3]
Selective recent examples: a) J. Davies, T. D. Svejstrup, D. F. Reina, N.
S. Sheikh, D. Leonori, J. Am. Chem. Soc. 2016, 138, 8092–8095; b) D.
C. Miller, G. J. Choi, H. S. Orbe, R. R. Knowles, J. Am. Chem. Soc. 2015,
137, 13492–13495; c) X. Q. Hu, X. T. Qi, J. R. Chen, Q. Q. Zhao, Q. Wei,
Y. Lan, W. J. Xiao, Nat. Commun. 2016, 7, 11188; d) J. C. Walton, Acc.
Chem. Res. 2014, 47, 1406–1416; e) Z. Li, L. Song, C. Li, J. Am. Chem.
Soc. 2013, 135, 4640–4643; f) P. Xiong, H.-H. Xu, H.-C. Xu, J. Am. Chem.
Soc. 2017, 139, 2956–2959; g) L. Zhu, P. Xiong, Z. Y. Mao, Y. H. Wang,
X. Yan, X. Lu, H.-C. Xu, Angew. Chem. Int. Ed. 2016, 55, 2226–2229;
Angew. Chem. 2016, 128, 2266–2269.
[4]
a) N. Fuentes, W. Kong, L. Fernandez-Sanchez, E. Merino, C. Nevado,
J. Am. Chem. Soc. 2015, 137, 964–973; b) Z. W. Hou, Z. Y. Mao, H. B.
Zhao, Y. Y. Melcamu, X. Lu, J. Song, H.-C. Xu, Angew. Chem. Int. Ed.
2016, 55, 9168–9172; Angew. Chem. 2016, 128, 9314–9318; c) Z.-W.
Hou, Z.-Y. Mao, J. Song, H.-C. Xu, ACS Catal. 2017, 7, 5810–5813; d)
D. F. Reina, E. M. Dauncey, S. P. Morcillo, T. D. Svejstrup, M. V.
Popescu, J. J. Douglas, N. S. Sheikh, D. Leonori, Eur. J. Org. Chem.
2017, 2108–2111; e) X.-X. Peng, D. Wei, W.-J. Han, F. Chen, W. Yu, B.
Han, ACS Catal. 2017, 7, 7830–7834.
[5]
[6]
R. Ramesh, Y. Chandrasekaran, R. Megha, S. Chandrasekaran,
Tetrahedron 2007, 63, 9153–9162.
a) C. T. Falzon, I. Ryu, C. H. Schiesser, Chem. Commun. 2002, 2338–
2339; b) S. Tang, K. Liu, Y. Long, X. L. Gao, M. Gao, A. W. Lei, Org. Lett.
2015, 17, 2404-2407; c) M. El Qacemi, L. Ricard, S. Z. Zard, Chem.
Commun. 2006, 4422–4424; d) H. Ishibashi, T. Sato, M. Ikeda, Synthesis
2002, 695-713; e) G. K. Friestad, Tetrahedron 2001, 57, 5461-5496.
a) I. Ryu, S. Ogura, S. Minakata, M. Komatsu, Tetrahedron Lett. 1999,
40, 1515–1518; b) D. C. Harrowven, B. J. Sutton, S. Coulton,
Tetrahedron Lett. 2001, 42, 9061–9064; c) J. Xie, P. Xu, H. M. Li, Q. C.
Xue, H. M. Jin, Y. X. Cheng, C. J. Zhu, Chem. Commun. 2013, 49, 5672–
5674.
[7]
[8]
[9]
A. K. Bagdi, S. Santra, K. Monir, A. Hajra, Chem. Commun. 2015, 51,
1555–1575.
a) C. He, J. Hao, H. Xu, Y. Mo, H. Liu, J. Han, A. Lei, Chem. Commun.
2012, 48, 11073–11075; b) J. Zeng, Y. J. Tan, M. L. Leow, X. W. Liu,
Org. Lett. 2012, 14, 4386–4389; c) Y. Gao, M. Yin, W. Wu, H. Huang, H.
Jiang, Adv. Synth. Catal. 2013, 355, 2263–2273.
[10] Selected recent reviews on electroorganic synthesis: a) R. Francke, R.
D. Little, Chem. Soc. Rev. 2014, 43, 2492–2521; b) J. Yoshida, K.
Kataoka, R. Horcajada, A. Nagaki, Chem. Rev. 2008, 108, 2265–2299;
c) H. J. Schäfer, C. R. Chim. 2011, 14, 745–765; d) M. Yan, Y. Kawamata,
P. S. Baran, Chem. Rev. 2017, 117, 13230–13319; e) Y. Jiang, K. Xu, C.
Zeng, Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.7b00271.
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10.1002/anie.201711876
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Zhong-Wei Hou, Zhong-Yi Mao, Yared
Yohannes Melcamu, Xin Lu*, Hai-Chao
Xu*
Page No. – Page No.
Electrochemical Synthesis of
Imidazo-Fused N-Heteroaromatics via
C–N Bond Forming Radical Cascade
A regiospecific electrochemical [3+2] annulation reaction of heteroarylamines with
tethered internal alkynes has been developed for the preparation of a variety of
imidazo-fused N-heteroaromatics. The electrosynthesis employs a novel
tetraarylhydrazine as the catalyst, has a broad substrate scope, and obviates the
need for transition-metal catalysts and oxidizing reagents.
This article is protected by copyright. All rights reserved.