Visible-Light-Enabled Oxidative Coupling of Alkenes with Dialkylformamides to Access Unsaturated Amides

Article abstract of DOI:10.1021/acs.orglett.9b03870

A practical and direct method for oxidative cross-coupling of alkenes with dialkylformamides is established employing visible-light-enabled photoredox catalysis. This strategy allows efficient access to diverse unsaturated amides under mild reaction conditions. The application of an appropriate diaryliodonium salt was demonstrated to be critical to the success of this process. This catalyst system is well tolerant of a variety of useful functional groups.

Full text of DOI:10.1021/acs.orglett.9b03870

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Visible-Light-Enabled Oxidative Coupling of Alkenes with
Dialkylformamides To Access Unsaturated Amides
Maojian Lu, Zhaowei Lin, Shanyi Chen, Hongyou Chen, Mingqiang Huang, and Shunyou Cai*
†
†
†
†
†
,†,‡
†Key Laboratory of Modern Analytical Science and Separation Technology of Fujian Province, School of Chemistry, Chemical
Engineering, and Environment, Minnan Normal University, Zhangzhou 363000, China
‡
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking
University, Shenzhen 518055, China
*
S Supporting Information
ABSTRACT: A practical and direct method for oxidative cross-coupling of alkenes with dialkylformamides is established
employing visible-light-enabled photoredox catalysis. This strategy allows efficient access to diverse unsaturated amides under
mild reaction conditions. The application of an appropriate diaryliodonium salt was demonstrated to be critical to the success of
this process. This catalyst system is well tolerant of a variety of useful functional groups.
he unsaturated amide is a highly versatile structural motif
a unique and practical Pd-catalyzed intermolecular addition
reaction of formamides to terminal alkynes to synthesize a
diverse range of α,β-unsaturated amides, in which Markovni-
T
present in numerous biologically meaningful molecules,
1
proteins, and functional polymers. For example, they can be
employed as antibacterial agents, anticancer agents, and
3b
kov addition products were observed as the major product.
2
histone deacetylase inhibitors (Scheme 1). Given the
This work has subsequently fueled other studies with the
2
purpose of the direct functionalization of the inert sp C−H
Scheme 1. Unsaturated Amide Moieties in Biological
Molecules
bond of the formamides. For example, an efficient protocol
relying on the intermolecular oxidative coupling reactions of
unactivated terminal alkenes and dialkylformamides for the
preparation of unsaturated amides was disclosed by Li and
coworkers in the presence of the FeCl /DTBP catalytic system
3
3c
at a high reaction temperature.
Despite these contributions to unsaturated amide synthesis,
it is still highly desirable to develop a practical, convenient, and
straightforward method that is capable of yielding them with
readily available materials, minimal preactivations, and milder
reaction conditions. Herein we report our recent achievement
in the formation of α,β-unsaturated amides from simple
alkenes and dialkylformamides by means of visible-light-
promoted photoredox cross-dehydrogenative coupling under
mild conditions (Scheme 2).
significance of these utilities, great effort has been made to
explore new, mild, and efficient methods for the preparation of
unsaturated amides. Among them, the direct amidation of
cinnamic chlorides and amines has emerged as the most
frequently adopted route. However, multiple steps and toxic or
expensive reagents were commonly required in this method.
Strategies trying to address these drawbacks involved the
utilization of direct C−H bond functionalizations through
photocatalysis or transition-metal-catalysis, in which the need
for preactivated reaction substrates could be efficiently
4
On the basis of our recent studies on the direct
3
functionalization of the inert sp C−H bond by photoredox
5
,6
catalysis (Scheme 3), we envisioned that the diaryliodonium
7
salt possessing strong electron-donating properties as well as
large steric bulk aromatic group seems to be feasibly
functioned as a reliable and safe single-electron oxidant in
Received: October 29, 2019
3
bypassed. Within this context, Tsuji and coworkers reported
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03870
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
red
−
ox
−
Scheme 2. Photocatalytic Oxidative Coupling Strategy for
the Synthesis of Unsaturated Amides
(4CzIPN) (E
1
/2
(*P/P ) = +1.35 V, E
1/2
(P/P ) = −1.21 V
8
vs SCE) (0.02 equiv) and PIFA/1,3,5-trimethoxybenzene (A)
2.0 equiv, 0.333 mmol) under blue LED irradiation for 10 h at
(
room temperature (entry 1). Subsequently, other similar
arenes such as 1,3-dimethoxybenzene (B), anisole (C), and
1,3,5-trimethylbenzene (D) were used in place of 1,3,5-
trimethoxybenzene (A) under other otherwise identical
reaction conditions, but the product was produced in lower
yield (entries 2−4). Notably, complicated mixtures were
observed only when the 1,3,5-trimethoxybenzene was purpose-
fully removed from the reaction system (entry 5). Gratifyingly,
when a base K CO (2 equiv) was added to the reaction
Scheme 3. Visible-Light-Enabled Diaryliodonium-Salt-
Induced sp C−H Functionalization
2
2
3
system, the yield of 3a was improved to 79% (entry 6). Thus a
range of bases involving Cs CO , Na CO , and Na HPO ,
2
3
2
3
2
3
were subsequently screened under various conditions, but all of
which were found to have a negative influence on the
cinnamide formation (entries 7−9). Furthermore, the choice
of oxidant was also revealed to be crucial because the
the inert sp2 C−H bond activation because it can be
expediently converted to the relatively stable iodanly radical
with the synergistic actions of visible-light irradiation and a
photocatalyst through a single electron transfer (SET) process.
Subsequently, the in-situ-generated iodanyl radical would be
able to undergo an H-abstraction event on dialkylformamide,
thereby converting it into the corresponding carbonyl radical
species.
utilization of PhI(OAc) (PIDA), acetoxybenziodoxole (BI-
2
OAc), K S O , or even t-BuOOH (TBHP) resulted in either
2
2
8
reductions or complete inhibitions in reactivities (entries 10−
1
3). Subsequent attempts employing eosin Y or Ru(bpy) Cl
3
2
as an alternative photocatalyst also could not efficiently
improve the reactivity (entries 14 and 15). Finally, reactions
carried out in the absence of a photocatalyst, oxidant, or visible
light distinctly pointed to complete inhibitions in reactivities
(entries 16−18).
After efficient conditions for α,β-unsaturated amide
formation were determined, we next explored the substrate
scope of this transformation (Scheme 4). It was found that a
The initial oxidant screenings, carried out on a readily
available model substrate 1a, indicated that the in-situ-
generated diaryliodonium salt should be a promising starting
point, and the corresponding results are illustrated in Table 1.
We discovered that 63% yield of the desired product 3a was
obtained in the solvent of DMF in the presence of an organic
fluorophore 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene
Table 1. Optimization of the Reaction Conditions
a
b
c
entry
PC (2 mol %)
oxidant (equiv)
additive (equiv)
solvent
yield (%)
1
2
3
4
5
6
7
8
9
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
eosin Y
PIFA/A (2.0)
PIFA/B (2.0)
PIFA/C (2.0)
PIFA/D (2.0)
PIFA (2.0)
PIFA/A (2.0)
PIFA/A (2.0)
PIFA/A (2.0)
PIFA/A (2.0)
PIDA/A (2.0)
none
none
none
none
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
63
45
trace
trace
decomp
79
72
56
73
decomp
trace
trace
decomp
64
67
trace
NR
none
K CO (2.0)
2
3
Na CO (2.0)
2
3
Cs CO (2.0)
2
3
Na HPO (2.0)
2
4
10
11
12
13
14
15
16
17
18
K CO (2.0)
2
3
BI-OAc/A (2.0)
K S O /A (2.0)
K CO (2.0)
2 3
K CO (2.0)
2
2
2
8
3
TBHP/A (2.0)
PIFA/A (2.0)
PIFA/A (2.0)
PIFA/A (2.0)
none
K CO (2.0)
2 3
K CO (2.0)
2
3
Ru(bpy) Cl
none
4CzIPN
4CzIPN
K CO (2.0)
2
3
2
3
K CO (2.0)
2
3
K CO (2.0)
2 3
d
PIFA/A (2.0)
K CO (2.0)
2
NR
3
a
b
4
CzIPN = 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene. PIFA = PhI(OCOCF ) ; PIDA = PhI(OAc) ; BI-OAc = acetoxy-benziodoxole;
3
2
2
c
d
TBHP = t-BuOOH Yield of isolated product. No light.
B
DOI: 10.1021/acs.orglett.9b03870
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Reactivity Screenings on Alkenes 1
1ac, were found to be successful under our conditions, albeit in
relatively low isolated yield.
This technology could be readily extended to the scope of
other dialkylformamides 2 under the optimal reaction
conditions, and the results are illustrated in Scheme 5. The
Scheme 5. Reactivity Screenings on Dialkylformamides 2
corresponding α,β-unsaturated amides 4 were generally
furnished in moderate-to-good isolated yield (30−81%). The
formamides carrying an ethyl (2a), propyl (2b), or butyl (2c)
are comparably efficient in these instances. It was found that
cyclic formamide derivatives also proceeded smoothly to afford
the corresponding products in good isolated yield (4f−j).
These results, in conjunction with the aforementioned
observations, further demonstrated that this established
method would be widely applicable to substances carrying
different functionalities.
The synthetic application of this method was further
manifested through the straightforward preparation of
pharmaceutically active molecules. For example, the 1,1-
diarylethylene 7, derived in three steps through a sequence
of 1,2-addition, oxidation, and olefination of 5, was able to
efficiently couple to N-formylmorpholine under the standard
reaction conditions to expediently furnish the familiar
bactericide dimethomorph in good yield (Scheme 6).
series of different alkenes were well tolerated in addition to the
1
,1-diphenylethylene 2a under the optimal reaction conditions,
proceeding smoothly to afford the corresponding α,β-
unsaturated amide product 3 in good yield (42−88%). When
symmetrical 1,1-diarylethylenes were used, neither the
substitution patterns (1b and 1c) nor the electronic character-
istics (1d−h) on the aryl rings seemed to have an obvious
influence on the reactivities. The alkene 1l with a tricyclic
moiety could be efficiently converted to the corresponding
product. Furthermore, we found that a range of frequently
encountered electron-donating substituents such as methoxyl
Scheme 6. Synthetic Elaboration on the Dimethomorph
(
1j−m), tert-butyl (1n), methyl (1o−s), 2-naphthalenyl (1t),
and phenyl (1u) on the aromatic ring in the unsymmetrical
diarylethylenes were well tolerated, smoothly furnishing the
corresponding products in good yield (51−81%) and with E/Z
isomeric ratios ranging from 1.0 to 9.0. The successful
generation of 3v−y containing intact carbon−halogen bonds
would provide a useful platform for further required synthetic
editing. It should be noted that the 1,1-diaryl moieties in the
substrates were not a structural requisite for the cross-
dehydrogenative coupling previously outlined. Monoaryl
substrates were also revealed to work with comparable
efficiency, thus notably extending the synthetic utilization of
this method. For example, the alkenes with a cycloalkyl and
thienyl group could undergo this process to give 3z and 3ab,
respectively. Furthermore, simple styrenes, such as 1ab and
To get a better understanding about the potential reaction
mechanism, some control experiments were subsequently
carried out. (See the Supporting Information.) As shown in
Scheme 7, 1,3,5-trimethoxybenzene could react efficiently with
PhI(OCOCF ) to furnish the diaryliodonium salt through a
3
2
ligand exchange process. When the in-situ-generated diary-
liodonium salt was directly employed as the oxidant, the
desired α,β-unsaturated amide 3a was smoothly produced in
comparable yield. Complete inhibition of the reactivity was
C
DOI: 10.1021/acs.orglett.9b03870
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 7. Experimental Studies on the Reaction
Mechanism
biological and pharmaceutical contexts, we envision that this
dual diaryliodonium salt/photoredox catalytic system will find
broader applications in due course.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03870.
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: caishy05@mnnu.edu.cn.
ORCID
noticed when 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
was added to the reaction system, suggesting that this reaction
should include a radical step. Finally, fluorescence quenching
Shunyou Cai: 0000-0001-8959-245X
Notes
(
Stern−Volmer) experiments showed that the photoexcited
CzIPN could be quenched efficiently by diaryliodonium salt,
The authors declare no competing financial interest.
4
indicating that the diaryliodonium salt presumably participated
in a single electron transfer process in this reaction.
On the basis of the above observation and literature reports,
a plausible mechanistic network for α,β-unsaturated amide
formation was proposed in Scheme 8. Initially, the in-situ-
9
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
21502086 and 41575118), Natural Science Foundation of
Fujian Province (2019J01744 and 2015J05028), Outstanding
Youth Science Foundation of Fujian Province (2015J06009),
and Program for Excellent Talents of Fujian Province for
financial support.
■
(
Scheme 8. Mechanistic Proposal
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E
DOI: 10.1021/acs.orglett.9b03870
Org. Lett. XXXX, XXX, XXX−XXX