Modular synthesis of phenanthridine derivatives by oxidative cyclization of 2-isocyanobiphenyls with organoboron reagents

Article abstract of DOI:10.1002/anie.201206115

Where HAS you been? A manganese-mediated annulation of 2-isocyanobiaryls with organoboronic acids is developed for the synthesis of a broad range of phenanthridine derivatives (see scheme). Mechanistic studies indicate that the reaction proceeds by the intramolecular homolytic aromatic substitution (HAS) of an imidoyl radical intermediate. Copyright

Full text of DOI:10.1002/anie.201206115

Angewandte
Chemie
DOI: 10.1002/anie.201206115
Heterocycle Synthesis
Modular Synthesis of Phenanthridine Derivatives by Oxidative
Cyclization of 2-Isocyanobiphenyls with Organoboron Reagents**
Mamoru Tobisu,* Keika Koh, Takayuki Furukawa, and Naoto Chatani*
Homolytic aromatic substitution (HAS) by an aryl radical and
related processes[1,2] have recently attracted considerable
utility of this intramolecular HAS could be considerably
expanded if a radical generated by the intermolecular
addition of an external radical could undergo a HAS type
cyclization (Scheme 1b). Herein, we report the development
of a reaction guided by this hypothesis for the synthesis of
phenanthridine framework.[4]
To realize the intramolecular HAS reaction depicted in
Scheme 1b, an isocyano group was selected as a radical
acceptor (A in Scheme 1b) because intermolecular radical
addition to isocyanide, forming an imidoyl radical, occurs at
a sufficiently fast rate to maintain the efficiency of the overall
process.[5] Furthermore, the potential for an imidoyl radical
intermediate to participate in a HAS reaction is partly
supported by the report that a fragment radical derived from
an initiator (such as, AIBN) can induce the radical cyclization
of isocyanide by a HAS process.[6]
À
attention as alternatives to transition-metal-catalyzed C H
bond arylation[3] for the construction of biaryl motifs. These
HAS reactions have several advantages over the conventional
methodology, including unique chemo- and regioselectivity as
well as avoiding the requirement for precious-metal catalysts
and ligands. Mechanistically, it has been proposed that the
HAS reaction proceeds by the addition of an aryl radical to an
arene, followed by the oxidative re-aromatization of the
resulting cyclohexadienyl-type radical.[1,2] Although there has
been only limited application of the intermolecular HAS to
the synthesis of biaryl systems because of issues associated
with low levels of efficiency and selectivity, the application in
intramolecular settings largely alleviates these issues and
allows for straightforward access to biaryl moieties embedded
in polycyclic system (Scheme 1a). It was envisioned that the
After examining several radical precursors (see Support-
ing Information for details), the phenyl radical generated
from phenylboronic acid and a manganese salt[7] was identi-
fied as promoting the desired cyclization (Scheme 2). Thus,
the reaction of isocyanide 1a with phenylboronic acid (2a) in
À
Scheme 1. C H bond functionalization by intramolecular homolytic
aromatic substitution, see text for details.
Scheme 2. Manganese(III) mediated annulation of 1a with 2a.
[*] K. Koh, T. Furukawa, Prof. Dr. N. Chatani
Department of Applied Chemistry, Faculty of Engineering, Osaka
University
the presence of [Mn(acac)3] (3 equiv) gave phenanthridine
3aa in 77% yield under relatively mild conditions (808C,
1 h).[8] The only byproduct detected in the reaction mixture
was phenanthridine 4a (7%).[9] The use of more than two
equivalents of the manganese salt was required for the
complete conversion of 1a.[10] This result is particularly
relevant to the reaction mechanism.
Suita, Osaka 565-0871 (Japan)
E-mail: chatani@chem.eng.osaka-u.ac.jp
Dr. M. Tobisu
Center for Atomic and Molecular Technologies, Graduate School of
Engineering
Osaka University, Suita, Osaka 565-0871 (Japan)
E-mail: tobisu@chem.eng.osaka-u.ac.jp
As revealed in Table 1, a broad range of arylboronic acids
were successfully coupled with isocyanide 1b to give the
corresponding phenanthridine bearing substituents adjacent
to the ring nitrogen atom.[11] Ethers, esters, fluorides, chlor-
[**] This work was supported, in part, by a Grant-in-Aid for Scientific
Research on Innovative Areas of “Molecular Activation Directed
toward Straightforward Synthesis” from MEXT (Japan). We thank
Prof. Kei Ohkubo and Prof. Shunichi Fukuzumi for obtaining EPR
spectra. We also thank the Instrumental Analysis Center of the
Faculty of Engineering at Osaka University for their assistance with
HRMS.
ides, and bromides are readily tolerated (entries 2–6).[12]
A
sterically hindered 2-tolyl group was also incorporated with-
out significant loss in the yield (entry 7). Fused arene and
heteroaromatic systems, including an indole, a pyridine, and
a thiophene, were also compatible with the reaction condi-
tions (entries 8–11), which represented a significant outcome
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206115.
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Table 1: Scope of boronic acid.
Table 2: Scope of the annulation of isocyanides with 2a.
[a] Yield of isolated product based on 1b. [b] Run for 2 h. [c] Boronic acid
(3 equiv) was used. [d] Run for 24 h. [e] Run for 15 h. [f] Run for 3 h.
given the utility of these substructures in medicinal chemistry.
Notably, alkyl boronic acids were found to be suitable
coupling partners. Pleasingly, primary, branched, and cyclic
alkylboronic acids uniformly produced the corresponding
phenanthridine derivatives (entries 12–16). It is worthy of
note that a bromoalkyl moiety remained intact under these
conditions, demonstrating the mild nature of the reaction
conditions (entry 13).
The cyclocoupling method was also successfully applied to
a variety of different 2-isocyanobiaryl compounds, which can
themselves be readily prepared from the parent anilines
(Table 2). Electronically and sterically different isocyanides
underwent annulation with 2a successfully (Table 2,
entries 2–6). The method was readily applied to the synthesis
of 1,5-naphthyridine ring system by using heteroaryl isocya-
nide 1h (Table 2, entry 7). When an isocyanide bearing a 2-
naphthyl group was used, the cyclization occurred exclusively
at the 1-position to furnish 3ia, with none of the 3-position
regioisomer being detected (Table 2, entry 8). The regiose-
lectivity observed in this particular case is a characteristic
outcome of HAS.[13] In contrast, it is worthy of note that the
corresponding transition-metal-mediated reactions invariably
provide a mixture of regioisomers.[14] Further extension of p-
system was readily accomplished by modifying the 2-aryl
group in the starting isocyanide, as in 1j, enabling the
assembly of the otherwise difficult to access pentacyclic
azaarene 3ja (Table 2, entry 9).
[a] Yield of isolated product based on 1. [b] Run for 2 h.
MnIII salt generates aryl or alkyl radical B,[7] which undergoes
intermolecular addition to isocyanide C to form the imidoyl
radical D.[5] Intramolecular attack of the imidoyl radical on
the pendant aromatic ring subsequently provides a cyclo-
hexadienyl-type radical E, which ultimately aromatizes to
afford phenanthridine G. Although there are several possi-
A mechanistic pathway for the current manganese(III)-
mediated annulation of 2-isocyanobiphenyl with boronic acid
is depicted in Scheme 3. The reaction of boronic acid A with
Scheme 3. Proposed reaction mechanism.
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bilities,[1] it was envisaged that the re-aromatization pro-
ceeded via cationic intermediate F through single-electron
oxidation by MnIII followed by deprotonation, on the basis of
the observation that more than two equivalents of MnIII were
required to drive the reaction to completion. Several experi-
ments were performed to provide support for the proposed
mechanism. One such experiment involved the addition of
2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO) to effectively
quench the reaction, and the putative alkyl radical inter-
mediate was intercepted by TEMPO (See Supporting Infor-
mation). In a separate experiment, the use of 5-hexenylbor-
onic acid (2q) exclusively afforded phenanthridine bearing
a cyclopentylmethyl group, indicating that a rapid 5-exo
process preceded the intermolecular addition to isocyanide
(See Supporting Information).[15]
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Itami, ChemCatChem 2011, 3, 827; f) A. Studer, D. P. Curran,
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[2] Recent leading works on HAS and related processes for
(hetero)biaryl synthesis: a) K.-i. Fujita, M. Nonogawa, R.
Yamaguchi, Chem. Commun. 2004, 1926; b) D. P. Curran, A. I.
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Wang, F. Y. Kwong, A. Lei, J. Am. Chem. Soc. 2010, 132, 16737;
j) Y. Fujiwara, V. Domingo, I. B. Seiple, R. Gianatassio, M.
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Chem. Commun. 2011, 47, 9813; n) N. Uchiyama, E. Shirakawa,
R. Nishikawa, T. Hayashi, Chem. Commun. 2011, 47, 11671;
o) G.-P. Yong, W.-L. She, Y.-M. Zhang, Y.-Z. Li, Chem.
Commun. 2011, 47, 11766; p) B. S. Bhakuni, A. Kumar, S. J.
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2838; q) W.-C. Chen, Y.-C. Hsu, W.-C. Shih, C.-Y. Lee, W.-H.
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To further demonstrate the value of the current two-
component cyclization, we implemented this method in the
synthesis of phenanthridine derivative 8, which displays
in vivo antitumor activity (Scheme 4).[16] Our synthetic
scheme features a late-stage introduction of a C6 substituent
À
[3] Selected Reviews on catalytic C H bond functionalization: a) F.
Kakiuchi, T. Kochi, Synthesis 2008, 3013; b) X. Chen, K. M.
Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. 2009, 121, 5196;
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Scheme 4. Application in the synthesis of 8.
as well as amide at C4, allowing for rapid access to the product
diversity required for structure–activity relationship studies.
In conclusion, we have developed a novel bimolecular
coupling of 2-isocyanobiaryls with organoboronic acids by
a formal HAS. The method enables the rapid divergent
synthesis of phenanthridine and its p-extended analogues
bearing aryl, heteroaryl and alkyl groups at the C6 position
from readily accessible starting materials and a promoter.
Further efforts are currently underway to develop synthetic
methods capable of exploiting HAS and related processes in
[4] Synthesis of cyclic compounds other than phenanthridines by
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À
the transformation of C H bonds.
Received: July 31, 2012
Revised: September 8, 2012
Published online: October 10, 2012
Keywords: boronic acid · homolytic aromatic substitution ·
.
isocyanide · manganese · phenanthridine
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[15] Involvement of organomanganese species in all bond-forming
steps cannot fully be excluded at this point. For our work on
catalytic reactions that involve imidoyl–metal species, see: a) M.
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b) M. Tobisu, H. Fujihara, K. Koh, N. Chatani, J. Org. Chem.
2010, 75, 4841. EPR measurement of the frozen reaction mixure
indicated the formatin of an organic radical. See Supporting
Information for details.
[9] 4a was formed in 6% yield when the reaction was conducted in
the absence of 2a. The same cyclization was also promoted by
AlCl3, in place of [Mn(acac)3], indicating that 4a is formed by
a Lewis acid mediated pathway. M. Tobisu, S. Yamaguchi, N.
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[10] [Mn(acac)3] from TCI Co., Inc. costs approximately $0.82 per
gram.
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anthridine: a) M. Tobisu, I. Hyodo, N. Chatani, J. Am. Chem.
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