Palladium-Catalyzed Domino Alkenylation/Amination/Pyridination Reactions of 2-Vinylanilines with Alkynes: Access to Cyclopentaquinolines

Article abstract of DOI:10.1021/acs.orglett.7b03164

A novel domino oxidative annulation of 2-vinylanilines with internal alkynes was developed to constitute a rare class of cyclopentaquinoline derivatives. This transformation encompasses four σ bonds formation, one quaternary carbon center construction, and pyridination steps in one pot under identical conditions, which fascinatingly increases the molecular complexity from easily available starting materials.

Full text of DOI:10.1021/acs.orglett.7b03164

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Domino Alkenylation/Amination/Pyridination
Reactions of 2‑Vinylanilines with Alkynes: Access to
Cyclopentaquinolines
Dejun Li and Fanlong Zeng*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry & Materials
Science, Northwest University, 1 Xuefu Road, Xi’an, Shaanxi 710127, P. R. China
S
* Supporting Information
ABSTRACT: A novel domino oxidative annulation of 2-vinylanilines with internal alkynes was developed to constitute a rare
class of cyclopentaquinoline derivatives. This transformation encompasses four σ bonds formation, one quaternary carbon center
construction, and pyridination steps in one pot under identical conditions, which fascinatingly increases the molecular complexity
from easily available starting materials.
Scheme 1. Pd-Catalyzed Vinylic C−H Bond Activation of 2-
challenge for modern organic synthesis is the creation of
Aefficient processes that can provide the maximum molecular
complexity and diversity with a minimum number of purification
steps1 and chemical waste.2 Domino reactions, which typically
bestow the formation of multiple new bonds in one step under
identical reaction conditions, are an attractive alternative to reach
this near ideal goal. In past decades, myriad efforts have been
devoted to the development of efficient domino reactions, from
academia to industry.3
Recently, cascade oxidative annulations based on transition-
metal-catalyzed C−H bond activation involving insertion of one
or two unsaturated bonds have attracted considerable attention
due to their outstanding ability to construct benzoheterocycles
from readily available starting materials.4 In particular, for 2-
vinylphenols and 2-vinylanilines, oxidative annulations employ-
ing alkynes, allenes, carbon monoxide, isocyanides, and carbon
dioxide as cycloaddition partners were developed to generate
benzoxepine,5 chromene,6 coumarin,7 quinolinone,8 benzoaze-
pine,9 2-aminoquinoline,10 indole,11 and spirocylic derivatives.12
Our group is interested in exploring new transformations of 2-
vinylanilines to potentially useful nitrogen-containing hetero-
cycles through palladium-catalyzed oxidative heteroannulation
reactions.9a,10a Importantly, during the investigation, we found
that the vinylic C(sp2)−H bond is activated probably via
nucleophilic attack of the conjugated alkene on the electrophilic
palladium(II) followed by a base-assisted deprotonation process
(Scheme 1),9a,10a which offers the possibility to sequentially
difunctionalize the terminal vinyl group of 2-vinylanilines in one
Vinylanilnes
pot. We herein disclose a novel domino oxidative annulation of 2-
vinylanilines with internal alkynes via difunctionalization of the
terminal vinyl group. The transformation is suggested to
encompass the consecutive formation of two C(sp2)−C(sp2)
and one C(sp3)−N bonds, 1,2-migration of an aryl group, and
elimination of a tosyl group in a single step under identical
reaction conditions.
Initially, the reaction of free amine 1a and 1,2-bis(4-
methoxyphenyl)acetylene (2a) was tested under anticipated
conditions for oxidative annulation, Pd(OAc)2/Cu(OAc)2 in
acetonitrile at 90 °C. Only a trace amount of the product was
formed. Successful amine-directed C−H bond activation
normally requires a strong electron-withdrawing group to
modulate the nucleophilicity of the nitrogen.13 Therefore, the
substrates with different electron-withdrawing protecting groups,
such as Ac, Bz, Ts, and Ms were next investigated. Delightfully,
the substrate 1e, employing tosyl as the protecting group,
Received: October 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03164
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
afforded 3ea in 63% isolated yield (Table 1, entry 5). Overdose of
alkyne 2a or Cu(OAc)2 was not beneficial to the yield of
are summarized in Table 2. The substrates with alkyl groups, e.g.,
Me, iPr, and tBu, para to the nitrogen on the aniline moiety,
a
a
Table 1. Optimization of Reaction Conditions
Table 2. Scope of 2-Vinylanilines
b
entry
1
oxidant
solvent
yield (%)
1
2
3
4
5
1a
1b
1c
1d
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1f
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Ag2CO3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
dixone
PhMe
DMF
trace
0
trace
0
63
55
57
16
15
78
15
8
c
6
d
7
8
9
10
11
12
DMSO
DCE
e
13
iPrOH
CH3NO2
DMF
12
19
50
60
57
46
trace
trace
46
41
0
14
15
16
17
18
19
20
1e
1e
1e
1e
1e
1e
1e
1e
1e
DMF
AgOAc
DMF
Ag2O
DMF
PhI(OAc)2
DMF
BQ
DMF
f
21
Cu(OAc)2·H2O(30%) + O2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
DMF
g
22
DMF
a
All reactions were carried out with 0.3 mmol of 1, 0.6 mmol of 2a, 10
h
23
DMF
mol % of Pd(OAc)2, 3.0 equiv of Cu(OAc)2, 5 mL of DMF, sealed
i
b
24
DMF
0
flask, 90 °C, 12 h. Isolated yield.
a
All reactions were carried out with 0.3 mmol of 1, 0.6 mmol of 2a, 10
mol % of Pd(OAc)2, 3.0 equiv of [Cu2+], [Ag+], PhI(OAc)2, or BQ, 5
furnished the corresponding products 3ga, 3ha, and 3ia in 62%,
68%, and 62% yield, respectively, demonstrating alkyl sub-
stituents para to the nitrogen slightly impede the reaction
efficiency. Strong electron-donating group MeO para to the
nitrogen was well tolerated, giving the desired product 3ja in 79%
yield. Strong electron-withdrawing substituents, such as CO2Et
(3ka) and NO2 (3la), located on the same position, hampered
the performance of this process, and especially, the para-nitro
product (3la) was only obtained in 38% yield. The above results
clearly show that an electron-rich aniline moiety facilitates this
transformation.
The reaction was also compatible with halogen substituents,
e.g., Cl (3ma) and Br (3na), which is interesting because the
carbon−halogen bond is susceptible to further structural
elaboration. When R2 was p-Me-phenyl, m-Me-phenyl, p-MeO-
phenyl, m-MeO-phenyl p-Cl-phenyl, p-F-phenyl, and 1-naph-
thyl, the corresponding products 3oa−3ua were obtained in
moderate yields (56−79%), indicating no direct correlation
exists between the yield and the electron density of the aryl
group. The substrate with a thienyl group produced the
anticipated product 3va in poor yield (35%), probably due to
the strong coordination and absorption properties of the sulfur
atom with transition metals. The substrates were smoothly
converted to the desired products when R1 was a substituent
b
c
mL of solvent, sealed flask, 90 °C, 12 h. Isolated yield. 3.0 equiv of
d
e
f
2a. 4.5 equiv of [Cu2+]. DCE = dichloroethane. 0.3 equiv of [Cu2+]
g
h
and 1.0 atm of O2. 5 mol % of Pd(OAc)2. 5 mol % of [Ru(p-
cymene)Cl2]2. 5 mol % of [Cp*RhCl2]2.
i
quinoline 3ea (Table 1, entries 6 and 7). The choice of solvent
had a dramatic impact on the reaction efficiency, and the optimal
DMF provided quinoline 3ea in 78% yield (Table 1, entries 8−
14). Employing Ms as the protecting group instead of Ts resulted
in a significant drop in yields (Table 1, entry 15). The
performance of this transformation also relied significantly on
the nature of oxidants, and copper acetate was proven to be
optimal. The employment of silver salts, such as Ag2CO3,
AgOAc, and Ag2O, offered the product in moderate yields, while
the utilization of two organic oxidants, PhI(OAc)2 and BQ,
merely resulted in trace amount of the product. Engaging O2 as
oxidant or lowering the loading of Pd(OAc)2 delivered inferior
yields (Table 1, entries 21 and 22). Surprisingly, the rhodium
complex [Cp*RhCl2]2 and ruthenium complex [Ru(p-cymene)-
Cl2]2 did not show catalytic activity in this transformation.
With the optimized reaction conditions established, the
reactivity of other 2-vinylanilines with 1,2-bis(4-
methoxyphenyl)acetylene (2a) was explored, and the results
B
DOI: 10.1021/acs.orglett.7b03164
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
rather than an H atom and R2 was a functionalized phenyl group
(1w and 1x). When R2 was a methyl or i-propyl, rather than an
aromatic group, the reaction did not occur (Table 2, entry 20).
The catalytic system is also applicable to the 2-vinylnaphthalen-
1-amine derivatives. The substrate 1z offered the corresponding
product 3za in acceptable yields (46%). The structures of 3oa,
3qa, and 3wa were determined by X-ray diffraction analysis.
The scope of alkynes was next examined by the reaction of N-
tosyl-2-(1-phenyl-vinyl)aniline (1e) with a range of alkynes
(Table 3). The symmetrical acetylenes 2a and 2b with two
Scheme 2. Control Experiments
a
Table 3. Scope of Alkynes
b
entry
2
R3
R4
3
yield (%)
78
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
4-MeO-Ph
4-EtO-Ph
4-MeO-Ph
4-MeO-Ph
4-Me-Ph
Ph
4-MeO-Ph
4-EtO-Ph
4-Me-Ph
Ph
3ea
3eb
3ec
3ed
3ee
3ef
69
c
c
56 (11:10)
45 (13:10)
4-Me-Ph
Ph
23
15
0
2g
2h
Ph
CO2Me
Et
3eg
3eh
Et
0
a
All reactions were carried out with 0.3 mmol of 1e, 0.6 mmol of 2, 10
mol % of Pd(OAc)2, 3.0 equiv of Cu(OAc)2, 5 mL of DMF, sealed
b
c
flask, 90 °C, 12 h. Isolated yield. Ratio of two regioisomers.
strongly electron-efficient alkoxyaryl groups reacted smoothly
and gave the corresponding products 3ea and 3eb in good yields.
The unsymmetrical acetylenes 2c and 2d with one strongly
electron-efficient alkoxyaryl group were also suitable for this
transformation and provided the anticipated products in
moderate yields, which contains two regioisomers. The sym-
metrical acetylene 2e with two weakly electron-efficient
alkylaryls and 2f with two unfunctionalized phenyls gave poor
yields of products 3ee and 3ef. The electron-deficient acetylene
2g and dialkylacetylene 2h failed to deliver the expected products
3eg and 3eh. It is noteworthy that 4,4′-(ethyne-1,2-diyl)bis(N,N-
dimethylaniline) did not participate in this transformation.
To gain mechanistic insight for the reaction, the following
control experiments were conducted (Scheme 2). Employing
HFIP (hexafluoroisopropanol) instead of DMF as solvent, the
reaction of 1e and 2a offered a mixture of 3ea (29%) and
benzazepine 3ea′ (14%) (Scheme 2, eq 1). Using Pd(OAc)2-
Ag2CO3-HFIP as the catalytic system delivered benzazepine 3ea′
as the main product (65%) at room temperature (Scheme 2, eq
1). However, unfortunately, other substrates gave inferior yields
under this condition, such as substrates 1i and 1q delivered the
corresponding benzazepines 3ia′ and 3qa′ in acceptable yields
(50% and 51%) (Scheme 2, eq 2). The above results delineate
the intermediacy of eight-membered palladacycle 6 (Scheme 3)
in this transformation. Performing the reaction of 1e and 2a
under the standard conditions in the presence of radical
scavengers, i.e., TEMPO (2,2,6,6-tetramethylpiperidine-N-
oxyl) or BHT (3,5-di-tert-butyl-4-hydroxytoluene), slightly
lowered the yields of 3ea, which disfavors the reaction via a
free-radical process (Scheme 2, eq 3).
vinylanilines,9a,10a a possible mechanism for this transformation
is presented in Scheme 3, with 1e and 2a as the model substrates.
Initially, aniline 1e reacts with Pd(II) species to form palladacycle
complex 4 via vinylic C−H bond activation. Alkyne 2a
coordinates to the palladium center of Pd(II) species 4 and
inserts to the Pd−C bond generating eight-membered pallada-
cycle 6, which is converted to intermediate 7 by acid hydrolysis
(also can be converted to benzazepine 3ea′ by reduction
elimination). The left vinylic C(sp2)−H bond (marked in red) in
species 7 is activated via nucleophilic attack of the adjacent alkene
on the electrophilic palladium(II) followed by an AcO−-assisted
deprotonation, engendering palladacycle 9. The involvement of
another alkyne 2a in a same fashion gives intermediate 10, which
cyclizes to 11 in the presence of palladium under oxidative
conditions. Compound 11 is oxidized to carboncation
intermediate 12 by Cu(OAc)2, and then 1,2-migration of the
aryl group on the adjacent quaternary carbon center produces
carbon-cation intermediate 13. The elimination of Ts+ from 13
with the assistance of the AcO− group yields the product 3ea.
In conclusion, a novel domino oxidative annulation of 2-
vinylanilines with internal alkynes has been developed based on
palladium-catalyzed sequential vinylic C−H alkenylation/
amination/pyrindination. This transformation encompasses
four bonds formation, one quaternary carbon center con-
Based on the above preliminary observations and our previous
results about palladium-catalyzed oxidative annulation of 2-
C
DOI: 10.1021/acs.orglett.7b03164
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ORCID
Scheme 3. Proposed Catalytic Cycle
Fanlong Zeng: 0000-0002-4293-5133
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Dr. Jamie Ferguson (Department of
Chemistry, Emory & Henry College) for constructive discussion,
and the National Science Foundation of China (No. 21302152)
and Northwest University for financial support.
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03164.
2017, 82, 4121. (b) Cendon
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, B.; Casanova, N.; Comanescu, C.; García-
Characterization data of new compounds, including X-ray
crystal structures of 3oa, 3qa, and 3wa, 1H and 13C NMR
spectra, and HRMS (PDF)
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Accession Codes
CCDC 1579067−1579068 and 1579070 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: fzeng@nwu.edu.cn.
D
DOI: 10.1021/acs.orglett.7b03164
Org. Lett. XXXX, XXX, XXX−XXX