Palladium-Catalyzed Multicomponent Reaction of Alkynes, Carboxylic Acids, and Isocyanides: A Direct Approach to Captodative Olefins

Article abstract of DOI:10.1021/acs.orglett.9b00137

A palladium-catalyzed multicomponent reaction of alkynes, carboxylic acids, and isocyanides has been developed with the assistance of silver salt under mild conditions. Highly functionalized captodative olefins are synthesized efficiently by this method, which can find many applications as versatile synthons in organic synthesis.

Full text of DOI:10.1021/acs.orglett.9b00137

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Multicomponent Reaction of Alkynes,
Carboxylic Acids, and Isocyanides: A Direct Approach to
Captodative Olefins
Mingchun Gao,† Minfen Zou,† Jue Wang,† Qitao Tan,† Bingxin Liu,† and Bin Xu*,†,‡
†Department of Chemistry, Innovative Drug Research Center, School of Materials Science and Engineering, Shanghai University,
Shanghai 200444, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed multicomponent reaction of alkynes, carboxylic acids, and isocyanides has been developed
with the assistance of silver salt under mild conditions. Highly functionalized captodative olefins are synthesized efficiently by
this method, which can find many applications as versatile synthons in organic synthesis.
socyanides have been proven to be versatile building blocks
product diversity under high concentrations9a or microwave
Iin organic synthesis in the past several decades due to their heating9b,c (Scheme 1). An elegant example has been disclosed
reactivities toward electrophiles, nucleophiles, and radicals.1
Therefore, isocyanide-based multicomponent reactions
(MCRs) are unparalleled in terms of effectiveness and
economy for the preparation of complicated molecules in a
single synthetic step,2 where the Passerini 3CR reaction and
Ugi 4CR reaction are two representative examples. In recent
years, palladium-catalyzed reactions involving isocyanides have
been extensively studied.3 However, reactions of unactivated
terminal alkynes with isocyanides are less studied,4 probably
due to their competitively facile homocoupling reactions.
Among them, much attention has been centered on C(sp)−H
insertion of isocyanide under the catalysis of uncommon rare
earth or actinide complexes, leading to 2-yn-1-ones or 1-aza-
1,3-enynes.5 Very recently, N-acyl propiolamides were
synthesized by a palladium-catalyzed three-component reac-
tion of alkynes, isocyanides, and sodium carboxylates through
direct isocyanide insertion of alkyne-complexed Pd species.4a
Thus, the development of facile methods to diverse product
skeletons from alkynes and isocyanide as well as their related
mechanistic study is of great value.
Captodative olefins, with both an electron-withdrawing and
an electron-donating substituent at the same α-carbon,6 have
demonstrated broad utility in cyclization reactions and
heterocycle synthesis,7 thus rendering convenient access to
them of great value and highly desirable. 2-Acyloxyacrylamides
represent a class of typical captodative olefins and useful
synthons in organic synthesis. However, only a few methods
have been introduced for their preparation.8 These reactions
mainly focused on the condensation of two molecules of the
same arylacetic acids and one of isocyanide with limited
Scheme 1. Synthesis of captodative olefins
by Basso and co-workers using a three-component tandem
reaction of isocyanides, acids, and preactivated diazonium
compounds upon irradiation to achieve the highly function-
alized captodative olefins (Scheme 1).10 In continuation of our
previous efforts on isocyanide chemistry,3h,j,11 herein we report
a novel palladium-catalyzed three-component reaction for
straightforward access to diversified captodative olefins under
mild reaction conditions (Scheme 1). To the best of our
knowledge, the given approach represents the first example for
2-acyloxyacrylamide synthesis from commercially available
alkynes, isocyanides, and carboxylic acids. Notably, the
significance of silver oxide should be highlighted, which
provides an alternative reaction pathway and affords distinct
products.4a,5
Received: January 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00137
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Organic Letters
Letter
Our preliminary investigation was started by examining the
reaction of phenylacetylene and tert-butyl isocyanide with
acetic acid in the presence of Pd(OAc)2 and Ag2O in
dichloromethane. Intriguingly, different from the previously
reported propiolamide product,4a the unexpected (Z)-3-aryl-2-
acyloxyacrylamides 4a was obtained in 64% yield (entry 1,
Table 1), and the structure was further determined by X-ray
of palladium catalyst and/or silver salt (entries 21−23), which
indicated both the palladium catalyst and silver salt were
crucial to this reaction. When alkyne 1a was added together
with other reagents from the beginning, the yield decreased
greatly owing to the undesired formation of 1,3-diyne (entry
24).
With the optimized conditions in hand, various alkynes were
examined for captodative olefin synthesis as summarized in
Scheme 2. A wide variety of substitution patterns and
a
Table 1. Optimization of Reaction Conditions
a b
,
Scheme 2. Substrate Scope of Alkynes
b
entry
Ag salt
ligand
solvent
temp (°C) yield (%)
1
2
3
4
5
6
7
8
Ag2O
Ag2CO3
AgOAc
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
DCM
DCM
DCM
DCE
THF
CH3CN
toluene
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
30
30
30
30
30
30
30
30
50
70
30
30
30
30
30
30
30
30
30
30
30
30
30
30
64
57
15
30
63
60
34
77
62
39
65
58
68
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
c
d
PPh3
P(o-tol)3
PCy3
83
59
72
71
24
X-Phos
P(tBu)3
dppp
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
e
51
56
f
g
trace
trace
g
0
h
Ag2O
36
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), 3a (0.9 mmol),
Pd(OAc)2 (5 mol %), ligand (10 mol %), Ag salt (1.5 equiv), and
solvent (1.5 mL) under N2. The alkyne 1a was added over 3 h by
syringe pump. dppp = 1,3-bis(diphenylphosphino)propane, X-Phos =
a
2-dicyclohexylph-osphino-2′,4′,6′-triisopropyl-1,1′-biphenyl, PCy3
=
Reaction conditions: alkynes 1 (0.3 mmol), isocyanide 2a (0.6
mmol), acetic acid 3a (0.9 mmol), Pd(OAc)2 (5 mol %), P(o-tol)3
(10 mol %), Ag2O (1.5 equiv), and PhCl (1.5 mL) under N2 at 30−
b
tricyclohexylphosphine, P(o-tol)3 = tri(o-tolyl)phosphine. Isolated
c
d
e
f
t
yields. Under air. Under O2. 1.5 equiv of BuNC was used. 2.0
g
h
b
equiv of HOAc was used. Without Pd(OAc)2 catalyst. Without
using syringe pump.
50 °C for 5 h. Alkyne 1 was added by syringe pump. Yields shown
c
are of the isolated products. Phenylpropiolic acid was used instead of
d
phenylacetylene 1a. The reaction was conducted on 1.0 mmol scale
over 14.5 h. At 50 °C.
e
crystallographic analysis.12 Ag2O was the best choice among
various silver salts (entries 1−3). Screening of solvents such as
DCE, THF, CH3CN, and toluene indicated PhCl to be the
most suitable one, affording the product 4a in 77% yield
(entries 4−8). The yield decreased when the temperature was
increased (entries 9 and 10) or the reaction was conducted in
air or oxygen atmosphere (entries 11 and 12). Ligands were
found to have a profound effect on this reaction (entries 13−
18) and the alkene 4a could be isolated in 83% yield in the
presence of P(o-tol)3, while the bidentate ligand (dppp)
inhibited the reaction significantly. Further investigation on the
ratio of starting materials suggested 2.0 equiv of tBuNC and 3.0
equiv of HOAc were necessary for this reaction (entries 19 and
20). Trace amounts or no product was formed in the absence
functional groups were tolerated. Aryl acetylenes containing
different substitutions, such as alkyl (4b, 4j), alkoxy (4c, 4l),
halides (4d, 4e, 4g, 4k), acyl (4f), nitro (4h), and amide (4i),
were compatible with the reaction conditions, regardless of
their different electronic properties and steric effect. Alter-
natively, olefin 4a could also be obtained in 87% yield when
phenylpropiolic acid was used instead of phenylacetylene,
which might undergo decarboxylative process. The reaction is
not only limited to simple benzene-substituted alkynes. For
example, thienyl alkyne could be transformed into the desired
product smoothly (4m), and enyne substrate could afford the
corresponding dienyl product (4n) in moderate yield. To our
B
DOI: 10.1021/acs.orglett.9b00137
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
delight, success of this conversion could be further extended to
alkyl acetylenes, providing products (4o and 4p) in good
yields. Notably, the product 4a could be obtained in good yield
when the reaction was scaled up to 1.0 mmol.
Scheme 4. Synthetic Applications of the Captodative Olefins
To further explore the scope and generality of this method,
we next applied various acids and isocyanides for this tandem
reaction under the optimized conditions (Scheme 3). It was
Scheme 3. Substrate Scope of Alkynes, Isocyanides, and
a b
,
Carboxylic acids
could be applied as the key intermediate for the analogue
synthesis of nature product Jatropham.15
To gain insight into the possible intermediates and pathway
of this multicomponent reaction, control experiments were
carried out as shown in Scheme 5. Both propiolamide 9 and
Scheme 5. Preliminary Mechanistic Studies
a
Reaction conditions: alkynes 1 (0.3 mmol), isocyanides 2 (0.6
mmol), acids 3 (0.9 mmol), Pd(OAc)2 (5 mol %), Ag2O (1.5 equiv),
and PhCl (1.5 mL) under N2 for 5−15.5 h by syringe pump, 70 °C.
b
c
d
Yields shown are of the isolated products. At 30 °C. At 50 °C.
acrylamide 10, instead of phenylacetylene 1a, were treated with
isocyanide and acetic acid under the standard conditions,
respectively (Scheme 5). However, no product 4a could be
observed for either substrate, which suggested that neither
compound 9 nor 10 was the key intermediate in this reaction.
Furthermore, based on the fact that product 4a was isolated in
68% yield in the presence of AgOAc in lieu of Ag2O and
HOAc, we speculated that AgOAc might be the effective
species in the reaction.
A plausible mechanism was proposed for this reaction as
depicted in Scheme 6. Silver acetylide A16 was formed from
Ag2O, alkyne 1, and carboxylic acid 3, along with the formation
of silver carboxylate. Attack of the carboxylic anion on the
silver acetylide center occurred to obtain complex B,17
followed by the transmetalation process with Pd(II). An
isocyanide insertion reaction happened to the generated vinyl
palladium complexes C, leading to the imidoyl palladium(II)
intermediate D. The final 2-acyloxyacrylamide product 4 or 5
was afforded after treatment with water and successive
reductive elimination process. The generated Pd(0) was
reoxidized to Pd(II) in the presence of silver salt to complete
the entire catalytic cycle.18
found that relatively higher temperature was more favorable for
other carboxylic acids (5a−f). To further demonstrate the
general applicability of isocyanides in this reaction, commer-
cially available 1-adamantyl and cyclohexyl isocyanide were
examined, respectively. The corresponding products could be
afforded in moderate to good yields (5g−m). However, when
α-acidic isocyanides, for example, isocyanoacetates, were
employed, no corresponding products could be observed.
The reason might be due to the easy formation of highly
reactive α-metalated isocyanides or isocyanide−metal com-
plexes over desired metal acetylide,13 thus rendering messy
reactions.
To illustrate the synthetic utility of the given method, we
tried to verify the application of this tandem reaction (Scheme
4). α-Ketoamides 6 was smoothly obtained in 90% yield from
produced 4a through hydrolysis (eq 1), which could be used as
inhibitor of enzyme activity.14 Interestingly, a base-promoted
rearrangement−cyclization reaction occurred from diene 4n,
leading to dihydropyrrolone derivative 7 in 57% yield instead
of the formation of ketoamide (eq 2).9b,c,10c Furthermore,
substrate 4n could also undergo the selective epoxidation
reaction and afforded epoxide 8 in good yield (eq 3), which
In summary, a palladium-catalyzed tandem reaction was
disclosed with the assistance of silver oxide for the synthesis of
C
DOI: 10.1021/acs.orglett.9b00137
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 6. Plausible Mechanism
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21672136 and 21871174) and Innovation Program of
Shanghai Municipal Education Commission (No. 2019-01-07-
00-09-E00008) for financial support. We thank Prof. Hongmei
Deng (Laboratory for Microstructures, SHU) and Mr. Hui
Wang (Department of Chemistry, SHU) for spectroscopic
measurements.
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