Synthesis of Naphthoquinolizinones through Rh(III)-Catalyzed Double C(sp2)-H Bond Carbenoid Insertion and Annulation of 2-Aryl-3-cyanopyridines with α-Diazo Carbonyl Compounds

Article abstract of DOI:10.1021/acs.orglett.7b00839

An unprecedented Rh(III)-catalyzed double C(sp²)-H bond carbenoid insertion and annulation of 2-aryl-3-cyanopyridines with α-diazo carbonyl compounds is presented. Through this cascade reaction, a series of naphthoquinolizinone derivatives with a large π-system were efficiently prepared. The reactions could selectively afford naphthoquinolizinones with either an amine or an amide unit attached on the 11-position depending on the nature of the solvent and the additive used. Compared with literature methods, this is a more efficient, convenient, and atom-economic way to provide polycyclic heteroaromatic compounds through direct π-extension of simple aromatics via inert C-H bond activation and functionalization.

Full text of DOI:10.1021/acs.orglett.7b00839

Letter
pubs.acs.org/OrgLett
Synthesis of Naphthoquinolizinones through Rh(III)-Catalyzed
Double C(sp2)−H Bond Carbenoid Insertion and Annulation of
2‑Aryl-3-cyanopyridines with α‑Diazo Carbonyl Compounds
Beibei Zhang, Bin Li, Xinying Zhang,* and Xuesen Fan*
School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan Province for Green Manufacturing of
Fine Chemicals, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, Henan Normal University, Xinxiang, Henan 453007, China
S
* Supporting Information
ABSTRACT: An unprecedented Rh(III)-catalyzed double
C(sp2)−H bond carbenoid insertion and annulation of 2-
aryl-3-cyanopyridines with α-diazo carbonyl compounds is
presented. Through this cascade reaction, a series of
naphthoquinolizinone derivatives with a large π-system were
efficiently prepared. The reactions could selectively afford
naphthoquinolizinones with either an amine or an amide unit attached on the 11-position depending on the nature of the solvent
and the additive used. Compared with literature methods, this is a more efficient, convenient, and atom-economic way to provide
polycyclic heteroaromatic compounds through direct π-extension of simple aromatics via inert C−H bond activation and
functionalization.
ransition-metal-catalyzed C−H bond activation is rapidly
prevailing as it can remarkably enhance the efficiency and
initiated by carbenoid insertion, N-cyclization vs C-cyclization,
we were curious that 2-phenyl-3-cyanopyridine, bearing both the
pyridinyl and the cyano moieties, would follow the reaction
pattern as shown by 2-phenylpyridine to give benzoquinolizi-
none (A, Scheme 1-3) via N-cyclization or the reaction pattern as
shown by 2-phenyl-3-cyanoindole to give benzo[h]quinoline (B,
Scheme 1-3) through C-cyclization upon treatment with an α-
diazo carbonyl compound. Herein, we report our detailed
studies.
Our study was initiated by treating 2-phenylnicotinonitrile
(1a) with ethyl 2-diazo-3-oxo-3-phenylpropanoate (2a) using
[RhCp*Cl2]2 as a catalyst and AgOAc as an additive in CH3CN
at 80 °C for 6 h. From this reaction, neither the proposed N-
cyclization product (A) nor the C-cyclization product (B,
Scheme 1-3) was obtained. Instead, two naphthoquinolizinones,
3a and 4a, were obtained in yields of 6 and 15%, respectively
(Table 1, entry 1).
This unexpected finding is no less interesting and promising.
First, formation of 3a/4a directly from 1a and 2a indicated that
an unprecedented cascade process of double C(sp2)−H bond
carbenoid insertion followed by C-cyclization and N-cyclization
took place spontaneously. Second, naphthoquinolizine deriva-
tives such as 3a and 4a belong to the biologically and optically
significant azapyrene derivatives with a large π-system and thus
hold the potential to find wide applications in the fields of
material science and medicinal chemistry.9 Although the design
and synthesis of novel polycyclic heteroaromatic compounds has
already been intensively pursued, general and easy-to-run
synthetic approaches toward azapyrene derivatives are still
T
atom-economy of the desired transformations by avoiding
tedious preactivation of the starting materials and minimizing
the production of unwanted byproducts.1 As one of the powerful
strategies for C−H bond activation, carbenoid insertion into the
challenging arene C(sp2)−H bonds is a well-established method
for the construction and functionalization of aromatics.2−5 In this
regard, Zhao et al. reported a Co(III)-catalyzed C−H bond
coupling between 2-phenylpyridine and α-diazo malonate
followed by a Lewis acid promoted intramolecular nucleophilic
addition of the N-atom of the pyridinyl unit onto the ester moiety
to give benzoquinolizinones (Scheme 1-1).6 Meanwhile, our
recent study on carbene chemistry showed that 2-phenyl-3-
cyanoindole reacted with α-diazo carbonyl compounds under
Rh(III) catalysis to give benzo[a]carbazoles via carbenoid
insertion, intramolecular nucleophilic addition of an enolate
onto the cyano unit followed by a deacylation (Scheme 1-2).7 As
the above examples revealed two distinct annulation patterns
Scheme 1. Carbenoid Insertions and Annulations
Received: March 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00839
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Letter
a
a b
,
Table 1. Optimization Studies
Scheme 2. Substrate Scope for the Synthesis of 3
b
yield (%)
entry
solvent
additive (equiv)
t (°C)
3a 4a
c
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
AgOAc (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
80
80
80
80
80
80
80
80
80
80
80
80
80
100
60
6
15
32
44
d
2
12
18
3
e
4
5
trace
17
8
trace
45
6
AgOAc (0.5)
AgOAc (0.5)
AgOAc (0.5)
AgOAc (0.5)
AgSbF6 (0.5)
Cu(OAc)2 (0.5)
HOAc (0.5)
PivOH (0.5)
HOAc (0.5)
HOAc (0.5)
7
61
8
acetone
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
25
62
50
55
82
61
63
72
43
9
20
10
11
12
13
14
15
15
12
trace
trace
trace
trace
a
Conditions: 1a (0.3 mmol), 2a (0.9 mmol), [RhCp*Cl2]2 (0.015
b
c
mmol), additive, solvent (2 mL), 6 h. Isolated yield. 2a (0.36 mmol).
d
e
2a (0.6 mmol). Without [RhCp*Cl2]2.
limited.6,8−10 Therefore, this new reaction deserves a detailed
study to develop it into an efficient and practical synthetic
approach toward azapyrenes and to enrich the chemistry of diazo
compounds as carbene precursors.
Reaction conditions for the formation of 3a and 4a were
optimized. It was found that increasing the amount of 2a from 1.2
to 2 or 3 equiv could improve the yields of 3a and 4a to 12 and
32% or 18 and 44%, respectively (entries 2 and 3). Control
experiments indicated that either the catalyst or the additive was
indispensible (entries 4 and 5). In addition, reducing the amount
of AgOAc from 1 to 0.5 equiv could give similar yields of 3a and
4a (entry 6). Next, study of the effect of different solvents
including CH3CN, DCE, acetone, and CH3OH revealed that
DCE is the most efficient for the formation of 4a whereas
CH3OH is more effective than other solvents for the formation of
3a (entries 6−9). Next, with CH3OH as the solvent, AgSbF6,
Cu(OAc)2, HOAc, and PivOH were tried as additives to replace
AgOAc (entries 10−13). Using HOAc as an additive could
remarkably enhance the efficiency and selectivity for the
formation of 3a in that the yield of 3a increased to 82% while
4a was formed in trace amount (entry 12). Further study showed
that temperature higher or lower than 80 °C resulted in
diminished efficiency (entries 14 and 15). Thus, the following
conditions for the formation of 3a were established for
subsequent studies: [RhCp*Cl2]2 (5 mol %) and HOAc (0.5
equiv) in CH3OH at 80 °C under air for 6 h.
With the optimized reaction conditions, the scope and
generality for the synthesis of 3 were explored, and the results
are listed in Scheme 2. First, using 1a as a model substrate, the
reaction of different α-diazo carbonyl compounds (2) was
studied. It was found that 2-diazo-3-oxo-3-phenylpropanoates
with various functional groups attached on the phenyl ring
underwent this reaction efficiently to give 3a−3g in 78−90%
yields, and the electronic nature of the phenyl moiety rendered a
slight effect on this reaction in that substrates bearing electron-
withdrawing groups (EWGs) on the phenyl ring generally gave
a
Conditions: 1 (0.3 mmol), 2 (0.9 mmol), [RhCp*Cl2]2 (0.015
b
mmol), HOAc (0.15 mmol), CH3OH (2 mL), 80 °C, 6 h. Isolated
yield.
higher yields than those bearing electron-donating groups
(EDGs). 2-Diazo-3-oxo-3-(thiophen-2-yl)propanoate and 2-
diazo-3-(naphthalen-1-yl)-3-oxopropanoate were also suitable
for this reaction, affording 3h and 3i in yields of 56 and 76%,
respectively. When two alkyl-substituted α-diazo carbonyl
compounds were used, the reactions proceeded successfully to
give 3j and 3k in reasonably good yields. Just like ethyl 2-diazo-3-
oxo-3-phenylpropanoate, the reaction of methyl 2-diazo-3-oxo-
3-phenylpropanoate was equally successful to give 3l in 81%
yield. Next, with 2a as a model substrate, different 2-aryl-3-
cyanopyridines (1) were tested. All of them took part in this
reaction smoothly to give 3m−3u in good yields. Generally,
yields of 3 were affected by the electronic nature of 1 in that 1
with EWGs attached on the 2-phenyl ring generally gave higher
yields than those with EDGs. Dimethyl 2-diazo malonate was
found to be suitable for this reaction to afford 3v in good yield.
With the synthesis of 3 accomplished, we studied the
preparation of 4. After some trials and errors, the following
conditions were found to be optimal, giving 4a in 66% yield:
[RhCp*Cl2]2 (5 mol %) and AgOAc (0.5 equiv) in DCE at 80 °C
for 10 h. Under these conditions, the substrate scope for the
synthesis of 4 was explored (Scheme 3). First, it was found that 2
bearing various R2 and R3 units reacted with 1a smoothly to give
4a−4j in moderate yields. Next, reactions of 1 bearing a different
R1 group were also studied using 2a as a model substrate. They
could undergo this reaction to give 4k−4r in moderate yields.
B
DOI: 10.1021/acs.orglett.7b00839
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ab c
, ,
densation to form VI, from which VII is formed through addition
of methanol onto the imine moiety followed by aromatization via
eliminating a methyl benzoate molecule.12 In the second stage of
this cascade process, Rh(III)-catalyzed C(sp2)−H bond
carbenoid insertion of VII with 2a followed by an intramolecular
N-cyclization affords 3a via formation of intermediates VIII−XI.
The mechanism shown in Scheme 4 is partly supported by the
following experiments. First, the proposed rhodacycle I could be
prepared separately by directly reacting 1a with [RhCp*Cl2]2 in
the presence of NaOAc in CH2Cl2 at ambient temperature.11
Next, reacting 1a with 2a in the presence of 5 mol % of I and
HOAc in methanol afforded 3a in 85% yield. When the reaction
was carried out in the absence of HOAc, 3a was obtained in a
decreased yield of 65%. Direct treatment of stoichiometric
amount of I, instead of 1a, with 2a in the presence of HOAc in
methanol afforded 3a in 83% yield (Scheme 5), indicating that in
addition to being able to act as an active catalyst, I could also be
used as the substrate for formation of 3a.
Scheme 3. Substrate Scope for the Synthesis of 4
Scheme 5. Preparation and Reaction of Rhodacycle I
a
Conditions: 1 (0.3 mmol), 2 (0.9 mmol), [RhCp*Cl2]2 (0.015
b
mmol), AgOAc (0.15 mmol), DCE (2 mL), 80 °C, 10 h. Isolated
yield. Yields in parentheses refer to those of compound 3. 24 h.
Second, 2-(2-fluorophenyl)nicotinonitrile (5), in which one of
the two C(2)−H bonds of the 2-phenyl unit is replaced by a C−F
bond, and therefore only one C(sp2)−H bond carbenoid
insertion would be possible, was treated with 2a under standard
conditions. From this reaction, 6, the C-cyclization product, was
obtained in a yield of 58%. Formation of the plausible N-
cyclization product (7) was not observed (Scheme 6). This result
indicated that after the initial C(sp2)−H bond carbenoid
insertion, C-cyclization occurred preferentially to N-cyclization.
c
d
Substrates bearing EDGs on the 2-phenyl moiety of 1 generally
resulted in yields higher than those bearing EWGs, and this is in
contrast to what had been observed in the synthesis of 3. Note
that the functional groups attached on different sites of the newly
formed naphthoquinolizinone skeleton might be used as
synthetic handles for azodination, alkylation, reduction, etc. to
tune their photophysical or other properties.
Based on reports,6,11 a plausible mechanism for the formation
of 3a is proposed in Scheme 4. First, a C−H bond cleavage of 1a
assisted by [RhCp*Cl2]2 takes place to form five-membered
rhodacycle I or II. Next, I or II reacts with 2a to afford a
rhodium−carbene III by dediazonization. Migratory insertion of
carbene into the Rh−C bond affords IV. Next, protonolysis of IV
leads to formation of V and allows the Rh complex to start a new
catalytic cycle. Then, V undergoes an intramolecular con-
Scheme 6. Reaction of 5 with 2a
Third, a kinetic isotopic effect value of 2.03 was observed in the
competitive reactions of an equimolar mixture of 1a and 1a-d5
with 2a (Scheme 7). This result showed that an arene C(sp2)−H
bond cleavage might involve the rate-limiting step of this cascade
process.
Scheme 4. Proposed Mechanism for the Formation of 3a
For the pathway leading to formation of 4a, it is postulated that
when the reaction of 1a and 2a is carried out in the non-
Scheme 7. Competitive Reactions of 1a and 1a-d5 with 2a
C
DOI: 10.1021/acs.orglett.7b00839
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nucleophilic DCE, an intramolecular version of nucleophilic
addition occurs with intermediate VI to give XII featured with
the formation of a four-membered ring. XII undergoes an
aromatization-driven ring opening to give XIII. C(sp2)−H bond
carbenoid insertion of XIII with 2a gives XIV. Finally, N-
cyclization of XIV, a process similar that described in Scheme 4
(from intermediate IX to 3a), occurs to afford 4a (Scheme 8).
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (NSFC) (Grant No. 21572047), Program for Innovative
Research Team in Science and Technology in Universities of
Henan Province (15IRTSTHN003), and Program for Science
and Technology Innovation Talents in Universities of Henan
Province (15HASTIT005) for financial support.
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Scheme 8. Proposed Mechanism for the Formation of 4a
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Scheme 9. Control Experiments
In summary, we developed a novel and efficient synthesis of
naphthoquinolizinone derivatives through Rh(III)-catalyzed
double C(sp2)−H bond carbenoid insertion and annulation of
2-aryl-3-cyanopyridines with α-diazo carbonyl compounds. This
should be the first example in which two distinct aromatic
systems are efficiently constructed in one pot via double C(sp2)−
H bond carbenoid insertion and annulation of simple substrates.
Compared with previous reports, this new protocol provides an
alternative approach toward naphthoquinolizinones with advan-
tages such as easily obtainable substrates, good functional group
tolerance, tunable chemoselectivity, and high efficiency.
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ASSOCIATED CONTENT
* Supporting Information
■
S
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̧ ien, M.; Gonka, E.; Zyła, M.; Sprutta, N. Chem. Rev. 2017, 117,
(9) Step
3479.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00839.
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(12) GC-MS study showed that methyl benzoate was formed (see
Supporting Information for details).
Experimental procedure, characterization data and NMR
spectra of all products, X-ray crystal structures and data of
4a and I (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xinyingzhang@htu.cn.
*E-mail: xuesen.fan@htu.cn.
ORCID
Xuesen Fan: 0000-0002-2040-6919
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.7b00839
Org. Lett. XXXX, XXX, XXX−XXX