Reagent-Free C?H/N?H Cross-Coupling: Regioselective Synthesis of N-Heteroaromatics from Biaryl Aldehydes and NH3

Article abstract of DOI:10.1002/anie.201707192

An unprecedented synthesis of N-heteroaromatics from biaryl aldehydes and NH₃ through reagent-free C?H/N?H cross-coupling has been developed. The electrosynthesis uses NH₃ as an inexpensive and atom-economic nitrogen donor, requires no oxidizing agents, and allows efficient and regioselective access to a wide range of phenanthridines and structurally related polycyclic N-heteroaromatic products.

Full text of DOI:10.1002/anie.201707192

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Accepted Article
Title: Reagent-Free C-H/N-H Cross-Coupling: Regioselective
Synthesis of N-Heteroaromatics from Biaryl Aldehydes and NH₃
Authors: Huai-Bo Zhao, Zhan-Jiang Liu, Jinshuai Song, and Hai-Chao
Xu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707192
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10.1002/anie.201707192
Angewandte Chemie International Edition
COMMUNICATION
Reagent-Free C–H/N–H Cross-Coupling: Regioselective Synthesis
of N-Heteroaromatics from Biaryl Aldehydes and NH3
Huai-Bo Zhao,†[a] Zhan-Jiang Liu,†[a] Jinshuai Song,*[b] Hai-Chao Xu*[a]
Abstract: An unprecedented synthesis of N-heteroaromatics from
biaryl aldehydes and NH3 through reagent-free C–H/N–H cross-
coupling has been developed. The electrosynthesis uses NH3 as an
inexpensive and atom-economic nitrogen donor, requires no oxidizing
agents, and allows efficient and regioselective access to a wide range
of phenanthridines and structurally related polycyclic N-
heteroaromatic products.
hardly any studies on electrochemical C–H/N–H cross-coupling
reactions. Little reported an efficient iodide-mediated C–H/N–H
cross-coupling of benzoxazoles and secondary amines.[11c] We
have recently reported the synthesis of benzimidazoles by anodic
cyclization of amidines.[12a] With our continued interest in
electrochemical dehydrogenative annulation reactions,[12] we
report herein the synthesis of N-heteroaromatic products through
anodic condensation between biaryl aldehydes and NH3 (Scheme
1b). Despite the propensity of aryl aldimines toward
dehydrogenation to form aryl nitriles under chemical[13] and
electrochemical[14] conditions, our electrolytic reaction proceeds
via C–H/N–H cross-coupling to produce functionalized polycyclic
heteroaromatic compounds in a chemo- and regioselective
manner.
The importance of nitrogen-containing molecules as natural
products, pharmaceuticals and functional materials makes the
development of efficient and sustainable C–N bond-forming
reactions a long-standing priority to organic synthesis.[1] In this
context, cross-coupling between C–H and N–H bonds, which
offers several potential advantages such as wide availability of
starting materials and high atom economy, represents one of the
most attractive strategies for constructing C–N bonds.[2] However,
the overwhelming majority of these coupling reactions that have
been developed so far require chemical oxidants and/or
transition-metal catalysts.[2,3] Hence, the invention of metal- and
oxidizing agent-free C–H/N–H cross-coupling methods would
represent a significant step toward achieving lower cost, greater
environmental sustainability and operational safety in the
preparation of nitrogen-containing compounds.[4]
Phenanthridine and the structurally related pyridine-fused
polycyclic aromatic structures form the core scaffold of numerous
natural products and bioactive compounds.[5] A number of recent
elegant studies have employed radical-mediated chemical or
photochemical reactions to prepare phenanthridines from biaryl
aldehydes or ketones via a vinyl azide[6] (Scheme 1a, top) or
oxime[7] intermediate (Scheme 1a, bottom). A common feature of
these methods is the requirement of a pre-installed leaving group
for radical generation.[8] NH3 is one of the simplest and most
attractive nitrogen donor due to its low cost and high atom
economy. Despite these potential advantages, few syntheses
have employed NH3 as the nitrogen source in C–H
functionalization reactions.[9] Particularly, there has been no
literature report on the synthesis of phenanthridines employing
NH3 as the nitrogen donor.
Scheme 1. Synthesis of phenanthridines through C–N bond-forming cyclization.
Our reaction setup for the oxidative condensation of biaryl
aldehyde 1 with NH3 comprised an undivided cell (a three-necked
round-bottomed flask) equipped with a reticulated vitreous carbon
(RVC) anode and a Pt plate cathode. We first tested different
solvent systems and achieved the highest yield, 94%, by
performing electrolysis at room temperature in a mixed solvent of
hexafluoro-2-propanol (HFIP)/MeOH (5:1) (entry 1). We found our
solvent of choice sufficiently conductive, which was likely due to
the in-situ generation of ions through the acid-base equilibrium
Electroorganic synthesis,[10] which employs electrons as
oxidizing or reducing “reagents”, has emerged as a useful tool for
C–H functionalization.[11] However, we noticed that there are
[a]
H.-B. Zhao, Z.-J. Liu, Dr. J. Song, 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
+
between HFIP (pKa = 9.3) and NH3 [pKa (NH4 ) = 9.2], to eliminate
the need for supporting electrolytes, thereby lowering the amount
of solid wastes generated and facilitating subsequent purification.
Furthermore, the use of HFIP as a co-solvent also played a critical
role in ensuring efficient product formation, as replacing it with
MeOH or 2,2,2-trifluoroethanol (TFE) led to dramatic yield
reduction (entries 2–3). Further investigation centered on the
manipulation of the electrolysis conditions. It seemed that a
relatively low current density and a proper choice of electrode
Xiamen 361005 (P. R. China)
E-mail: jssong@fjirsm.ac.cn; haichao.xu@xmu.edu.cn
Web: http://chem.xmu.edu.cn/groupweb/hcxu/
Fujian Institute of Research on Structure of Matter, Chinese
Academy of Sciences
[b]
Fuzhou 350002 (P. R. China)
†
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.201707192
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material were important as increasing the current to 10 (entry 4)
or 30 mA (entry 5) or replacing RVC with Pt (entry 6) or graphite
plate (entry 7) with reduced surface area all resulted in lower
yields. Stringent removal of oxygen from the reaction system is
not necessary as conducting the electrolysis under air also
produced the desired product 2 in 79% yield (entry 8).
Table 1. Optimization of reaction conditions.[a]
Entry
Deviation from standard conditions
Yield [%][b]
[a] Reaction conditions: Undivided cell, RVC anode (100 PPI, 1.2 cm x 0.8
cm x 1 cm, j  0.08 mA cm−2), 1 (0.3 mmol), HFIP (5 mL), NH3 (7 M in MeOH,
1 mL), argon, 4 h (2.5 F). [b] Yield determined by 1H-NMR analysis using
1,3,5-trimethoxybenzene as the internal standard, unreacted
parenthesis. [c] Isolated yield.
1 in
We next explored the reaction scope by varying the aromatic
rings A and B (Scheme 2). The phenyl ring A could be substituted
with OMe (3), alkyl groups (4–7), halogens (8–10) and OCF3 (11),
but not with the highly electron-withdrawing CO2Et (12), in which
case an aryl nitrile was formed in 44% yield. Importantly, when
the A ring of the starting substrate was substituted at the meta
position, the reaction proceeded with good to excellent
regioselectivity in favor of cyclization at the para position of the
substituent (13–20). This selectivity was in contrast to iminyl
radical cyclization under chemical or photochemical conditions,
which would typically show a moderate bias toward the ortho
position of the substituent.[6d,7a,e] Substrates substituted at both
the meta and para positions underwent the reaction with excellent
regioselectivity (21–23).[15] Interestingly, the directing effect of the
meta-substituted Me group was enhanced when a OMe was
present at the para position (> 20:1 for 24 vs 7:1 for 14). When
both meta positions carried functionalities, the electron-rich OMe
was found to dictate and direct the regioselectivity of the
cyclization to its para position (25–26). The regioselectivity did not
seem to be affected by the electronic properties of the B ring (27).
The reaction exhibited considerable tolerance of biaryl substrates
with a multisubstituted (28–32) or a heterocyclic A ring such as 3-
indole (33–34), 2- (35) or 3-thiophene (36), 2-benzothiophene
(37) and 3-benzofuran (38). On the other hand, the B ring of the
substrate could be substituted
Scheme 2. Substrate scope. Reaction conditions: Table 1, entry 1, aldehyde
(0.3 mmol), 4–6 h (2.5–3.7 F). [a] Isolated yield, regioisomeric ratio in
parenthesis. [b] The corresponding aryl nitrile was obtained in 44% yield. [c]
Yield of the major product. [d] NH3 (7 M in MeOH, 0.5 mL) was employed. [e]
Pre-formed ketimine was used as the substrate. TBS = tert-butyldimethylsilyl.
Ts = p-toluenesulfonyl.
at position 7 (39) or 8 (40–43) but not at position 9 (44).
Alternatively, the B ring could be replaced by a naphthyl (45),
pyridinyl (46–47), or benzothiophenyl (48) moiety.
Biaryl ketones were found unreactive in our electrochemical
reaction probably due to their reduced propensity toward imine
formation compared to the aldehydes. However, the pre-formed
ketimines could undergo the electrolytic annulation to form the
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10.1002/anie.201707192
Angewandte Chemie International Edition
COMMUNICATION
corresponding phenanthridine products 49 and 50 in 53% and
66% yield, respectively (Scheme 2).
functional theory (DFT) calculations suggested that cyclization
through a radical cation was favored both kinetically and
thermodynamically over the alternative pathway that involved a
radical intermediate (Scheme 4A vs 4B). The theoretical study
also suggested that the iminyl radical cation was more likely to
attack the para position, rather than the ortho position, of the
meta-substituent (Scheme 4A), whereas the opposite trend was
observed in cyclization with iminyl radicals (Scheme 4B). This was
consistent with earlier findings that iminyl radical cyclization
showed moderate selectivity toward the ortho position.[6d,7a,e]
Taken together, we concluded that the anodic cyclization of biaryl
aldehydes with NH3 most likely proceeded via a radical cation
intermediate, and that the observed regioselectivity could be
attributed to the disparity in activation energy between different
cyclization pathways.
Scheme 3. Decagram scale synthesis and preparation of nonitidine.
Scheme 5. Proposed mechanism.
Based on the experimental and theoretical studies, a possible
reaction mechanism was proposed (Scheme 5). As a start, the
condensation between the aldehyde substrate and NH3 produces
aldimine intermediate 61, which subsequently loses an electron
on the anode to generate radical cation 62.[17] Cyclization of 62
leads to the formation of 63, which then loses an electron and two
protons to generate the phenanthridine product 2. The analysis of
the radical orbital (single occupied natural orbital) of 62 and 63
suggests that the spin densities move from the B ring and the
iminyl nitrogen to the A ring during the ring closure (Page S23,
Figure S2 of the Supporting Information for details).
Scheme 4. DFT (M062x/6-31G*) calculated energetics (kcal mol−1) in the mixed
solvent of HIFP/MeOH (5:1).
In summary, we have demonstrated for the first time that a
range of pyridine-fused polycyclic N-heteroaromatic compounds
could be synthesized through anodic condensation of biaryl
aldehydes and NH3. The electrochemical synthesis requires no
metal catalysts, oxidizing agents or salt additives, and provides
regioselective, efficient and scalable access to a range of N-
heteroaromatic molecules.
To further establish the synthetic utility of our method, we
subjected 10 g of 1 to the electrochemical cyclization and
successfully obtained phenanthridine 2 in 81% yield. Next, we
applied the method to the synthesis of nonitidine, which contained
a phenanthridine scaffold (Scheme 3).[16] Our initial attempt ended
up with the over-oxidation of the dioxolane methylene carbon in
nonitidine. To address this problem, controlled-potential
electrolysis was conducted at 1.50 V vs SCE, which is slightly
lower than the oxidation potential of nonitidine (Ep/2 = 1.57 V vs
SCE). The adjustment led to the formation of nonitidine in 72%
yield.
Acknowledgements
To understand why the regioselectivity of the electrochemical
cyclization process that we developed in this study was
significantly different from that of previously reported iminyl
radical-based cyclization reactions,[6d,7a,e] we estimated the
activation energies and ∆G of different cyclization reactions of
radical cations 53–56 and iminyl radicals 57–60. Density
Financial
support
of
this
research
from
MOST
(2016YFA0204100), NSFC (No. 21402164, 21672178,
21603227), the “Thousand Youth Talents Plan”, XMU.
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Keywords: electrochemistry • phenanthridines • radical cation •
ammonia • cross-coupling
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COMMUNICATION
COMMUNICATION
Hui-Bo Zhao, Zhan-Jiang Liu, Jinshuai
Song, Hai-Chao Xu*
Page No. – Page No.
Reagent-Free C–H/N–H Cross-
Coupling: Regioselective Synthesis
of N-Heteroaromatics from Biaryl
Aldehydes and NH3
An unprecedented synthesis of N-heteroaromatics from biaryl aldehydes and NH3
through reagent-free C–H/N–H cross-coupling has been developed. The
electrosynthesis uses NH3 as an inexpensive and atom-economic nitrogen donor,
requires no oxidizing agents, and allows efficient and regioselective access to a
wide range of phenanthridines and structurally related polycyclic N-heteroaromatic
products.
This article is protected by copyright. All rights reserved.