Stereoselective C(sp2)-H Alkylation of Enamides with Unactivated Aliphatic Carboxylic Acids via Decarboxylative Cross-Coupling Reactions

Article abstract of DOI:10.1021/acs.orglett.9b03169

An efficient and straightforward stereoselective alkylation reaction of enamides using commercially available and easily accessible unactivated alkyl carboxylic acids as alkylating agents is described, giving rise to a diverse array of synthetically impor

Full text of DOI:10.1021/acs.orglett.9b03169

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
2
Stereoselective C(sp )−H Alkylation of Enamides with Unactivated
Aliphatic Carboxylic Acids via Decarboxylative Cross-Coupling
Reactions
Jing-Yu Guo, Ting Guan, Ji-Yu Tao, Kai Zhao,* and Teck-Peng Loh*,†,‡
†
†
†
,†
†Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center
for Advanced Materials, Nanjing Tech University, Nanjing 211816, China
‡
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
*
S Supporting Information
ABSTRACT: An efficient and straightforward stereoselective alkylation reaction of enamides using commercially available and
easily accessible unactivated alkyl carboxylic acids as alkylating agents is described, giving rise to a diverse array of synthetically
important and geometrically defined β-alkylated enamides bearing primary, secondary, or tertiary alkyl moieties. This
transformation also shows excellent functional group tolerance, satisfying atom economy, and operational simplicity.
arboxylic acids are naturally abundant, inexpensive,
Scheme 1. Vinyl Alkylation Reactions Using Aliphatic
Carboxylic Acids as Alkylating Agents
C
stable, and easily accessible building blocks in modern
1
synthetic chemistry. Consequently, they have emerged as
exceptionally crucial and attractive feedstocks in cross-coupling
reactions which are superior to organohalides with respect to
2
lower cost and less hazardous waste generation. In the past
few decades, myriad efforts have been focused toward the
decarboxylative Heck-type crossing-coupling reactions of
aromatic carboxylic acids with olefinic electrophiles to achieve
3
vinyl C−H arylation, as pioneered by the group of Myers and
4
many others. Nevertheless, the vinyl C−H alkylation using
the decarboxylative cross-coupling strategy remained under-
developed due to the instability and inaccessibility of alkyl
5
metallic intermediates arising from β-H elimination. It was
not until recently that a series of significant breakthroughs for
2
3
the construction of C(sp )−C(sp ) bonds via decarboxylative
coupling of alkyl carboxylic acids with vinyl halides or alkenes
were achieved by merging transition-metal catalysis with
6
photoredox catalysis. For instance, Macmillian and co-workers
have elegantly described the coupling of secondary alkyl
carboxylic acids with vinyl halides by cooperative catalysis of a
nickel catalyst with an iridium photocatalyst (Scheme 1a).
decarboxylative cross-coupling of easily accessible alkyl acids
with olefins bearing more complicated structures remained a
challengeable and attractive topic.
Enamides are particularly versatile and crucial building
blocks in organic synthetic chemistry for the construction of
6a
Wu and co-workers have developed a Heck-type decarbox-
ylative coupling of aliphatic acids with terminal alkenes with
the cocatalysis of a metal-free photocatalyst along with a
6b
cobaloxime catalyst (Scheme 1b). Despite those pioneering
works, the development of more robust and readily available
methods for the direct C−H vinylation through the
Received: September 6, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03169
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
7
,
a b
pharmaceutically and biologically important molecules.
Table 1. Optimization of Reaction Conditions
Therefore, the regio- and stereoselective functionalization of
2
enamides on their β-C(sp )−H bond have gathered increasing
attention in the past few years, delivering a diverse array of β-
8
9
10
functionalized enamides containing alkene, alkyne, aryl,
11
12
13
trifluoro- or difluoromethyl, arylsulfonyl, carbonyl, and
many other useful functionalities. Especially, the incorpo-
14
b
entry catalyst
oxidant
base
solvent (v/v) yield (%)
2
3
ration of alkyl groups into enamides via C(sp )−C(sp )
coupling reactions is of particular interest. Previously, the
alkylation of enamides using electron-deficient secondary alkyl
bromides as the alkylating agents using photoredox catalysis or
palladium catalysis have been established by the groups led by
Yu and Loh, respectively. Dong and co-workers have
developed an alternative strategy using an iridium-catalyzed
branch-selective alkylation of enamides with terminal olefins to
give enamides bearing secondary alkyl substituents. How-
ever, those methods proved to be noneffective for the
deployment of primary or tertiary alkyl groups into enamides.
Very recently, our group demonstrated an efficient and
generally applicable stereoselective crossing-coupling reaction
of enamides with N-hydroxyphthalimide (NHP) esters derived
from aliphatic carboxylic acids, forging a diverse array of
geometrically defined enamides bearing primary, secondary, or
tertiary alkyl substituents. Nonetheless, this methodology
required the preactivation of carboxylic acids into redox-active
NHP esters and a precious iridium photocatalyst. Therefore,
the development of more concise, inexpensive, and atom-
economical approaches for the alkylation of enamides is highly
desired. We herein demonstrated the direct decarboxylative
cross-coupling reactions of enamides with unactivated and
commercially available carboxylic acids, giving rise to a broad
array of alkylated enamides bearing varying functional groups
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
AgF
AgOTf
AgOAc
K S O
NaHCO3
NaHCO3
NaHCO3
NaHCO3
5:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
10:1
2:1
MeCN
5:1
5:1
61
64
66
68
0
0
52
0
2
2
8
8
8
8
8
8
K S O
2 2
K S O
2
2
Ag CO3
K S O
2 2
2
AgI
AgNO3
K S O
NaHCO3
1
5
16
2 2
K S O
NaHCO3
NaHCO3
NaHCO3
2
2
Ag CO3
2
Na S O
8
2
2
Ag CO3
2
(NH ) S O
17
4
2
2
8
Ag CO3
2
K S O
Na CO3
64
62
0
2
2
8
2
0
1
2
3
4
5
6
7
Ag CO3
2
K S O
KHCO3
DIPEA
2
2
8
8
8
8
8
8
Ag CO3
2
K S O
2 2
Ag CO3
2
K S O
Et N
0
2
2
3
Ag CO3
2
K S O
2 2
NaHCO3
NaHCO3
NaHCO3
54
30
34
0
Ag CO3
2
K S O
2 2
Ag CO3
2
K S O
2 2
none
NaHCO3
18
2
Ag CO3
none
K S O
NaHCO3
0
2
2
8
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), catalyst (20
mol %), oxidant (0.6 mmol), base (0.9 mmol), solvent (1.0 mL).
b
Isolated yields.
With the optimal reaction conditions (Table 1, entry 4), we
commenced to investigate the generality of various enamides
Scheme 2). To our delight, enamides bearing either electron-
(
(Scheme 1c).
withdrawing groups (1b−1j) or electron-donating groups
(1k−1o) were both compatible with standard conditions,
furnishing desired products 3ba−3oa in moderate to good
yields. Notably, halide substituents such as −Cl, −Br, and − I
were well tolerated, forging 3ca−3ea, 3ha, and 3ja in
considerable yields, which were amenable to further function-
alization via cross-coupling reactions. Substrates bearing a
pharmaceutically crucial fluoro group (1b, 1i−1j) and a
trifluoromethyl group (1f) were both viable in this trans-
formation. Substrate 1g containing an ester group coupled with
2a smoothly, delivering 3ga in 72% yield. Steric variance on
the phenyl ring did not lead to an obvious influence on the
reaction efficiency; substrates bearing para- (1b−1g, 1k−1m),
ortho- (1i, 1n−1o), or meta- (1h) substituents were all eligible
to forge the desired products. Substrate 1p with a relatively
bulkier β-naphthyl substituent reacted with 2a to attain the
desired alkylated enamide 3pa in 49% yield. Uneventfully, a
heterocyclic 3-thienyl moiety in enamide 1q was tolerated,
forging 3qa in synthetically useful yields. N-Methyl substituted
substrate 1r coupled with 2a to give desired product 3ra, albeit
with a lower yield. Interestingly, enecarbamate 1s was an
eligible coupling partner of 2a, delivering 3sa in 45% yield. It
was also notable that, in all cases, the transformation
proceeded in a stereoselective manner, furnishing geometri-
cally defined E-configured alkylated enamides. The config-
uration of the resulting enamides was confirmed by the X-ray
The activation of alkyl carboxylic acids using a silver-
catalyzed decarboxylative strategy proved to be an efficacious
way for the in situ generation of an alkyl radical which could be
readily intercepted by heteroarenes, which have been referred
19
to as Minisci-type reactions. Nonetheless, the scope of the
aforementioned transformations is mainly limited to electron-
poor heterocycles. In this context, we became interested in
investigating if a similar strategy could be applied to the cross-
coupling of alkyl carboxylic acids with electron-rich enamides.
To testify this hypothesis, a model reaction of N-benzyl-N-(1-
phenylvinyl)acetamide enamide 1a with cyclohexanecarboxylic
acid 2a was investigated. Gratifyingly, the transformation
proceeded smoothly in the presence of catalytic amounts of
silver salts when employing potassium persulfate as an oxidant
and sodium bicarbonate as a base in a solvent mixture of
CH CN/H O (v/v = 5:1), giving rise to the desired product
3
2
3
aa in 61−68% yields (Table 1, entries 1−4), and silver
carbonate proved to be the catalyst of choice (Table 1, entry
). Other persulfate salts gave inferior yields in contrast to
4
potassium persulfate (Table 1, entries 7−8 vs entry 4). The
screening of bases showed that sodium carbonate and
potassium bicarbonate gave 3aa in slightly lower yields while
organic bases such as N,N-diisopropylethylamine (DIPEA)
and triethylamine failed to furnish 3aa (Table 1, entries 9−12).
Increasing or decreasing the ratio of water in the solvent
mixture led to a deterioration of the yield of 3aa (Table 1,
entries 13 and 14). The reaction in acetonitrile only produced
18,20
of 3cg in Scheme 3.
Next, we investigated the substrate scope with respect to a
diverse range of aliphatic carboxylic acids (Scheme 3).
Secondary alkanoic acids 2b−2c coupled with enamides 1a
smoothly, delivering target products 3ab−3ac in moderate to
3
aa in 34% yield (Table 1, entry 15). Unsurprisingly, the
reactions in the absence of a silver catalyst or a persulfate salts
failed to give 3aa (Table 1, entries 16 and 17).
B
DOI: 10.1021/acs.orglett.9b03169
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Organic Letters
Letter
Scheme 2. Substrate Scope of Enamidesa,b
Scheme 3. Substrate Scope of Aliphatic Carboxylic Acids
a
,
b
a
Reaction conditions: 1b−1s (0.3 mmol), 2a (0.6 mmol), Ag CO
2
3
(
20 mol %), K S O (0.6 mmol), NaHCO (0.9 mmol), solvent (1.0
2 2 8 3
b
mL). Isolated yields.
good yields. Cyclic carboxylic acids were also amenable to
standard reaction conditions to give 3ad−3ag and 3cg.
Importantly, pharmaceutically important tetrahydropyrane
and N-tosylpiperidine could be stereoselectively deployed to
the C-3 position of enamides, attaining 3af, 3ag, and 3cg in
moderate yields, respectively. This transformation was also
applicable to the preparation of enamides bearing primary alkyl
groups, delivering 3ah and 3ai in synthetically useful yields.
More importantly, a series of carboxylic acids bearing sterically
hindered tertiary alkyl groups including a structurally rigid
adamantane moiety coupled with enamides 1a efficiently,
affording 3aj−3al in 54−59% yields. Gratifyingly, the coupling
reactions of enamides 1a with amino acids 2m and 2n
proceeded smoothly to forge 3am and 3an in 44% and 52%
yields, respectively. It was worthy to note that anti-
inflammatory isoxepac reacted with 1a smoothly, giving rise
to pharmaceutically crucial molecule 3ao in considerable yield.
Natural occurring dehydrocholic acid bearing three base-
sensitive ketone moieties 2p and glycyrrhetic acid 2q (which
proved to be an efficacious component of Chinese medicine)
were all viable substrates in the transformation to forge
potentially bioactive 3ap and 3aq in 54% and 52% yields,
respectively.
a
Reaction conditions: 1a (0.3 mmol), 2b−2q (0.6 mmol), Ag CO
2
3
(
20 mol %), K S O (0.6 mmol), NaHCO (0.9 mmol), solvent (1.0
2 2 8 3
b
mL). Isolated yields.
trifluoroacetic acid, enabling us to control the stereo-
2
1
selectivities of alkylated enamides (Scheme 4b). In addition,
the alkylated enamides could undergo hydrolysis in concen-
trated HCl (aq) to furnish a series of α-alkylated ketones 4a−
4c in excellent yields (Scheme 4c). Gratifyingly, upon
treatment of m-CPBA, enamide 3aa could be converted to
α-acyloxyketone via a cascade epoxidation−intramolecular
nucleophilic addition−elimination−hydrolysis process
(Scheme 4d).
Preliminary mechanistic investigation revealed complete
inhibition of the reaction when a radical scavenger 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) was added (Scheme
22
5). Based on this observation and previous literature, we
proposed a radical involved mechanism (Scheme 6). First, the
Ag(I) catalyst is oxidized by a persulfate anion to generate a
Ag(II) species and a sulfate radical anion. Then, a single
electron oxidation of the carboxylic acid with Ag(II) followed
by the ensuing decarboxylation occurs to furnish an alkyl
radical along with the regeneration of the Ag(I) cation. Next,
the regioselective addition of the in situ generated alkyl radical
to the olefinic double bond of enamide leads to the formation
of radical intermediate A which would be subsequently
oxidized by the sulfate radical anion or peroxydisulfate to
Taking advantage of the synthetic versatility of the alkylated
enamides, a plethora of useful transformations were conducted
(Scheme 4). A gram scale reaction of enamide 1a with
carboxylic acid 2a proceeded smoothly to give 3aa without
negative effects on the reaction efficiency (Scheme 4a).
Importantly, the geometry of the alkylated E-enamides could
be easily reversed to the Z-configuration in the presence of
C
DOI: 10.1021/acs.orglett.9b03169
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Synthetic Applications
wherein the allylic strain between the alkyl group and the bulky
N-substituent is minimized, which gives rise to the E-
configured product upon deprotonation.
In conclusion, we have demonstrated a straightforward,
practical, and generally applicable silver-catalyzed alkylation
reaction of enamides with commercially available and easily
accessible carboxylic acids, affording a broad range of enamides
bearing various alkyl groups in a stereoselective manner.
Preliminary mechanistic investigation showed that the trans-
formation went through a radical pathway. Many further
transformations of the alkylated enamides including the
conversion of the stereochemistry, the hydrolysis reaction to
produce α-alkylated ketones, and the preparation of α-
acyloxyketone were conducted to showcase the synthetic
application of this method. Importantly, this approach allowed
the incorporation of primary, secondary, or tertiary alkyl
groups into enamides, which served as a crucial complement to
previous reports that were limited to the incorporation of
15,16
electron-deficient secondary alkyl groups.
The operational
simplicity and satisfying atom economy enable this method-
ology to inaugurate a new route to access synthetically crucial
alkylated enamides.
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.9b03169.
Experimental details, analytical data, and H, 13C NMR
spectra (PDF)
1
Scheme 5. Mechanistic Studies
AUTHOR INFORMATION
Corresponding Authors
■
*
*
E-mail: ias_kzhao@njtech.edu.cn.
E-mail: teckpeng@ntu.edu.sg.
ORCID
Scheme 6. Plausible Mechanism
Kai Zhao: 0000-0003-2226-806X
Teck-Peng Loh: 0000-0002-2936-337X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from Nanjing
Tech University (Start-up Grant Nos. 39837137, 39837101,
and 3827401739), the National Natural Science Foundation of
China (21372210, 21672198, and 21801129), the State Key
Program of National Natural Science Foundation of China
(
21432009), the Natural Science Research Projects in Jiangsu
higher education institutions (18KJB150018), and the grant
from Ministry of Education of Singapore MOE2016-T1-002-
043 (RG111/16).
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DOI: 10.1021/acs.orglett.9b03169
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