Copper-Catalyzed Selective ortho-C-H/N-H Annulation of Benzamides with Arynes: Synthesis of Phenanthridinone Alkaloids

Article abstract of DOI:10.1021/acs.orglett.7b00442

An efficient and convenient copper-catalyzed method has been developed to achieve direct ortho-C-H/N-H annulation to synthesize phenanthridinones with arynes. This method highlights an emerging strategy to transform inert C-H bonds into versatile functional groups in organic synthesis and provides a new way to synthesize phenanthridinone alkaloids efficiently.

Full text of DOI:10.1021/acs.orglett.7b00442

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Selective ortho-C−H/N−H Annulation of
Benzamides with Arynes: Synthesis of Phenanthridinone Alkaloids
Ting-Yu Zhang,† Jun-Bing Lin,† Quan-Zhe Li,† Jun-Chen Kang,§ Jin-Long Pan,† Si-Hua Hou,†
Chao Chen,† and Shu-Yu Zhang*,†,‡
†School of Chemistry and Chemical Engineering, ‡Sixth People’s Hospital South Campus, and §Zhiyuan College, Shanghai Jiao Tong
University, Shanghai 200240, P. R. China
S
* Supporting Information
ABSTRACT: An efficient and convenient copper-catalyzed
method has been developed to achieve direct ortho-C−H/N-H
annulation to synthesize phenanthridinones with arynes. This
method highlights an emerging strategy to transform inert C−
H bonds into versatile functional groups in organic synthesis
and provides a new way to synthesize phenanthridinone
alkaloids efficiently.
henanthridinones are very important core structural units
and occur widely in a variety of alkaloids and biologically
Scheme 1. Approaches for the Synthesis of
Phenanthridinones via C−H Activation
P
active pharmaceutical agents (Figure 1).1 While many classical
Figure 1. Alkaloids containing phenanthridinone skeletons.
transformations have been established to form phenanthridi-
none skeletons, the development of more efficient and novel
formation methods continues to be intensively investigated in
synthetic chemistry.
interest because of its high efficiency and directness.9 In 2014,
the Jeganmohan9a and Xu9b groups independently reported a
Pd-catalyzed intermolecular ortho-C(sp2)−H activation with
arynes and N-methoxyamide to synthesize phenanthridinones
(Scheme 1B).
However, although Pd-catalyzed aryne annulation via C−H
activation has been significantly advanced,9−11 to date, ligand-
controlled, Cu-catalyzed,12 intermolecular unactivated direct
C(sp2)−H annulation processes with arynes to synthesize
phenanthridinones have not yet been discovered. From our
continuing interest and effort in developing efficient and
selective unactivated C−H functionalizations and applying
them in the synthesis of natural biological products,13 we
describe herein the first copper-catalyzed selective ortho-C−H/
N−H annulation to synthesize the tricyclic core with arynes
under mild conditions (Scheme 1C). This method offers a
practical and environmentally friendly strategy for the rapid
synthesis of phenanthridinones from simple starting materials.
Transition-metal-catalyzed direct selective conversion of
unactivated C−H bonds has emerged as an attractive and
arguably ideal new strategy to synthesize heterocyclic
molecules.2 The use of an intramolecular dehydrogenative
annulation strategy to form phenanthridinones has been
significantly developed in recent decades.3 In 2011, a
challenging intermolecular cascade using Pd- or Rh-catalyzed
C−H/N−H activation and cyclization to build both C−N and
C−C bonds in one pot was achieved by the Wang4a and
Cheng4b,c groups as an important and more efficient new
approach to the synthesis of phenanthridinones (Scheme 1A).
In addition, Pd-catalyzed synthesis of phenanthridinones via
oxidative carbonylation of o-arylanilines with CO has also been
documented.5 More recently, the Jiao group reported a Pd-
catalyzed domino process employing arylcarbamic chlorides
and aryl iodides for phenanthridinone derivatives.6a An
overview of the synthetic strategy toward phenanthridinones,
in particular, the use of highly reactive arynes7,8 as a component
in the one-pot synthesis of phenanthridinones, has attracted
Received: February 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00442
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Letter
a,b
Our initial attempt was the intermolecular annulation of the
model substrate N-quinolylbenzamide 1a14 with Kobayashi
benzyne precursor 2a (Table 1).15 After an initial screening of
Scheme 2. Substrate Scope of Benzamides
a
Table 1. Optimization of the Cu-Catalyzed Annulation
a
Reaction conditions: benzamide (0.2 mmol), 2a (0.4 mmol),
Cu(OAc)2 (35 mol %), CsF (0.24 mmol), and TBAI (0.1 mmol) in
b
DMF/MeCN (1:1, 2 mL) at 80 °C under O2 for 12 h. Isolated yields.
a
c
d
All screening reactions were carried out in a 10 mL glass vial with a
2 equiv of Cu(OAc)2 was used under air for 12 h. 1 equiv of TBAI
b
1
PTFE-lined cap on a 0.2 mmol scale. Yields are based on HNMR
analysis. Isolated yield in parentheses. 20 mol % Cu(OAc)2 was
used. See the Supporting Information for more reaction conditions.
was used; see the Supporting Information for more reaction
conditions.
c
d
excellent yields. Subsequently, the o-, m-, and p-methyl-
substituted benzamine substrates (4a, 5a, and 6a) were used
to examine the effects of sterics (4−6). It is clear that the lower
steric hindrance of the para-substituted N-quinolylbenzamides
(6a) gave the best yield. The meta-substituted substrates (7a−
13a) demonstrated that this approach has high regioselectivity,
and only the less hindered ortho-C−H bond could be activated
to give the desired phenanthridinone products 7−13 without
regioisomers. The regioselectivity of the annulation product
was confirmed by X-ray crystallography of compound 11.
Moreover, the effect of electron-donating and electron-
withdrawing groups on the benzamides was further studied. It
was found that benzamides with electron-donating groups
(alkyl, OMe, etc.) or weakly electron-withdrawing groups (Cl,
Br, I, etc.) produced the corresponding products in good to
excellent yields. Comparatively, the benzamides with strong
electron-withdrawing groups (CF3, NO2, etc.) could be utilized
to afford the annulation products in moderate to good yield
(11, 18, and 24). To our delight, the yield could be increased
by using more copper in the reaction system. Multisubstituted
benzamides also reacted efficiently to furnish the sterically
favored polysubstituted phenanthridinones 26 and 27. In
addition, the interesting polycyclic or poly heterocyclic
compounds 28−31 could be synthesized in the copper-
catalyzed system. For 28 and 29, the annulation demonstrated
a high regioselectivity but only achieved 55% and 37% yields
the copper-catalyzed system, promising results demonstrated
the feasibility of this reaction. The desired phenanthridinone
product 3 was obtained in a 24% yield by using catalytic
amounts of Cu(OAc)2, CsF (1.2 equiv), and TBAB (0.5 equiv)
at 80 °C in dioxane under O2 as oxidant for 12 h (Table 1,
entry 1). A detailed screening of various solvents revealed that
the reaction could achieve higher conversions using DMF/
MeCN (1:1) as the mixture solvent (entry 4). To promote the
circulation of this reaction system, further studies surveyed a
series of fluoride sources and additives (entries 5−8). We were
delighted to find that an 83% isolated yield of 3 was obtained
under the optimized reaction conditions: Cu(OAc)2 (35 mmol
%), CsF (1.2 equiv), and TBAI (0.5 equiv) at 80 °C in DMF/
MeCN (1:1) under O2 for 12 h (entry 8). Interestingly, O2, as a
clean and green oxidant, appeared to significantly improve the
copper catalysis cycle.13d In comparison, when argon was used
instead of O2, the desired reaction was inhibited, resulting in a
diminished 21% yield (entry 9).
With an optimized set of conditions in hand, we then probed
the substrate scope of N-quinolylbenzamides to survey their
general reactions. As shown in Scheme 2, benzamides
substituted with a variety of functional groups such as alkyl,
aryl, ether, ester, halogens, CF3, NO2, CN, and NMe2 were well
tolerated under the copper-catalyzed system and gave the
phenanthridinone derivative annulation products in good to
B
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due to steric and electronic effects. The annulation efficiency
could also be improved to 81% and 60% yields under the use of
2 equiv of Cu(OAc)2.
Scheme 4. Applications of Copper-Catalyzed ortho-C−H/
N−-H Annulation in the Alkaloid Synthesis of Phenaglydon
and Crinasiadine
We next examined the scope of functionalized aryne
precursors as the general annulation partner for this reaction.
As shown in Scheme 3, a variety of substituted benzamide
a,b
Scheme 3. Substrate Scope of Benzamides and Arynes
not inhibited by the addition of 2 equiv of the radical scavenger
TEMPO, and 1a still gave product 3 in 76% isolated yield. This
experiment suggested that a SET was unlikely involved in this
reaction. A Cu(III) intermediate was proposed for the ortho-
C−H annulation.19
On the basis of the above experiments and literature
precedents,13,18,19 a plausible mechanism for this annulation
reaction with arynes is proposed below in Scheme 5. First,
Scheme 5. Proposed Reaction Pathway
a
Reaction conditions: benzamide (0.2 mmol), aryne precursors (0.4
mmol), Cu(OAc)2 (35 mol %), CsF (0.24 mmol), and TBAI (0.1
mmol) in DMF/MeCN (1:1, 2 mL) at 80 °C under O2 for 12 h.
Isolated yields. 2 equiv of Cu(OAc)2 was used under air for 12 h.
50% of Cu(OAc)2 and 1 equiv of TBAI were used.
b
c
d
substrates were reacted with electron-donating or electron-
withdrawing arynes (2,3-naphthalyne precursor (2c), 4,5-
dimethoxybenzyne precursor (2d), 4,5-methylenedioxybenzyne
precursor (2e), and 4,5-difluorobenzyne precursor (2f)) and
gave good to excellent annulation yields (32−47). Interestingly,
many of the annulation products, such as 6, 26, 42, and 44, are
important subunits in biologically and pharmaceutically active
phenanthridinone alkaloids or their analogues.16 To demon-
strate the application of our non-noble metal copper-catalyzed
ortho-C−H/N−H annulation method, two phenanthridinone
alkaloids phenaglydon and crinasiadine were synthesized under
these mild conditions (Scheme 4). Previous work has reported
that the 8-amino-5-methoxyquinoline (MQ) can be used
instead of 8-aminoquinoline for its easy extraction property.17a
The N-MQ amides 48 and 51 first gave rise to 49 in 91% and
52 in 62% yield under the general conditions. The phenaglydon
50 and crinasiadine 53 alkaloids could then be synthesized
under simple conditions17b in 62% and 55% isolation yields,
respectively.
coordination of the amide 1a reacted with the Cu(OAc)2
generated anionic complex I ligated by an N,N-bidentate
directing group. Subsequently, complex I underwent an acetate-
assisted intramolecular C−H concerted metalation−deproto-
nation to give the key five-membered complex II, which then
underwent carbocupration with the aryne generated from the
silyl triflate to give rise to intermediate III. An experiment was
conducted here; when unsymmetrical aryne 2g was used in this
reaction, two regioisomers were obtained with a ratio of
approximately 1.2:1, which also indicated the formation of
aryne intermediates in this reaction. Finally, reductive
elimination of III afforded the desired annulation production
3, and the copper catalyst could be regenerated by oxygen for
the next cycle.
In summary, we have developed the first copper-catalyzed
intermolecular ortho-C−H/N−H annulation of benzamides
with arynes. These reactions are operationally simple and
robust, avoiding the use of sensitive and expensive noble
metals. The reaction also demonstrated broad substrate scope
for both benzamides and arynes. The directing group can be
easily removed under simple conditions, granting an efficient
and straightforward strategy for the synthesis of phenanthridi-
none alkaloids such as phenaglydon and crinasiadine.
Since C−H activation is involved in this reaction to form the
annulation products, a primary intermolecular kinetic isotope
effect experiment was conducted. A KIE value of 5.7 was
observed. This value suggested that the Cu-catalyzed C−H
activation step is the rate-determining step.18 In addition, a
radical-trapping experiment was performed. The reaction was
C
DOI: 10.1021/acs.orglett.7b00442
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00442.
Experimental procedures, NMR spectra, and X-ray and
analytical data for all new compounds (PDF)
X-ray data for compounds 6 (CIF)
X-ray data for compounds 11 (CIF)
X-ray data for compounds 29 (CIF)
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W. J. Am. Chem. Soc. 1953, 75, 3290.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhangsy16@sjtu.edu.cn.
ORCID
Jin-Long Pan: 0000-0002-1085-4566
Shu-Yu Zhang: 0000-0002-1811-4159
Notes
(10) For the selected Pd-catalyzed cycloaddition reaction of arynes,
see: (a) Gerfaud, T.; Neuville, L.; Zhu, J.-P. Angew. Chem., Int. Ed.
2009, 48, 572. (b) Wang, W.-G.; Peng, X.-L.; Qin, X.-Y.; Zhao, X.-Y.;
Ma, C.; Tung, C.-H; Xu, Z.-H. J. Org. Chem. 2015, 80, 2835. (c) Feng,
M.-H.; Tang, B.-Q.; Wang, N.-Z.; Xu, H.-X.; Jiang, X.-F. Angew. Chem.,
Int. Ed. 2015, 54, 14960.
The authors declare no competing financial interest.
(11) For the Ni-catalyzed cycloaddition reaction of arynes, see: Qiu,
Z.-Z.; Xie, Z.-W. Angew. Chem., Int. Ed. 2009, 48, 5729.
ACKNOWLEDGMENTS
■
This work was supported by the “Thousand Youth Talents
Plan”, NSFC (21672145), the Shuguang program from the
Shanghai Education Development Foundation and the
Shanghai Municipal Education Commission, and startup
funds from Shanghai Jiao Tong University. We thank Prof.
Gong Chen (Nankai University) for helpful suggestions and
comments on this manuscript.
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