Manganese(I) Catalyzed α-Alkenylation of Amides Using Alcohols with Liberation of Hydrogen and Water

Article abstract of DOI:10.1021/acs.joc.1c00685

Herein, unprecedented manganese-catalyzed direct α-alkenylation of amides using alcohols is reported. Aryl amides are reacted with diverse primary alcohols, which provided the α,β-unsaturated amides in moderate to good yields with excellent selectivity. Mechanistic studies indicate that Mn(I) catalyst oxidizes the alcohols to their corresponding aldehydes and also plays an important role in efficient C═C bond formation through aldol condensation. This selective olefination is facilitated by metal-ligand cooperation by the aromatization-dearomatization process operating in the catalytic system. Biorenewable alcohols are used as alkenylation reagents for the challenging α-alkenylation of amides with the highly abundant base metal manganese as a catalyst, which results in water and dihydrogen as the only byproduct, making this catalytic transformation attractive, sustainable, and environmentally benign.

Full text of DOI:10.1021/acs.joc.1c00685

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Manganese(I) Catalyzed α‑Alkenylation of Amides Using Alcohols
with Liberation of Hydrogen and Water
Biplab Keshari Pandia and Chidambaram Gunanathan*
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ABSTRACT: Herein, unprecedented manganese-catalyzed direct α-
alkenylation of amides using alcohols is reported. Aryl amides are
reacted with diverse primary alcohols, which provided the α,β-
unsaturated amides in moderate to good yields with excellent
selectivity. Mechanistic studies indicate that Mn(I) catalyst oxidizes
the alcohols to their corresponding aldehydes and also plays an
important role in efficient CC bond formation through aldol
condensation. This selective olefination is facilitated by metal−ligand
cooperation by the aromatization−dearomatization process operating
in the catalytic system. Biorenewable alcohols are used as alkenylation reagents for the challenging α-alkenylation of amides with the
highly abundant base metal manganese as a catalyst, which results in water and dihydrogen as the only byproduct, making this
catalytic transformation attractive, sustainable, and environmentally benign.
alized unsaturated carboxylic acids.10 However, owing to such
multifaceted utilities, the development of efficient catalytic
INTRODUCTION
Alkenylation reactions leading to the construction of a new
■
protocols for α,β-unsaturated amides has drawn considerable
CC bond are an important transformation in organic
synthesis. A plethora of strategies is developed to introduce
alkene functionality in an intramolecular fashion.1 On the
contrary, classical methods to construct intermolecular CC
bonds remain limited to Wittig, Horner-Wadsworth-Emmons,
Peterson olefination, carbonyl coupling, and few other
reactions, which all suffer from the requirement of extensive
prefunctionalization and excessive toxic reagents.2 Further, due
to acidic hydrogen (N−H), amides are not compatible in these
classical olefination reactions that require basic conditions.2−4
There are only a few general catalytic protocols, such as alkene
metathesis and diazo coupling reactions, known for the
intermolecular olefination.5
α,β-Unsaturated amides are a valuable class of compounds in
organic chemistry. The unsaturated amide functionality is a
core motif in various natural products, biologically active
compounds, polymeric materials, and pharmaceuticals.4 For
example, avenanthramide exhibits anti-inflammatory and
antioxidant properties and is used as a nutrition additive,
whereas naturally abundant caffeic acid amides are known to
have antitumor, antiviral, and other biological activities.6,7
Moreover, α,β-unsaturated amides are key synthons in organic
synthesis, are reactive in nucleophilic additions and pericyclic
reactions, and also serve as raw materials for the synthesis of
valuable polyamides.8,9
interest in recent years.4a,10,11
In general, two pathways are developed for the catalytic
synthesis of α,β-unsaturated amides involving hydroaminocar-
bonylation of alkynes12−15 and aminocarbonylation of alkenes
(Scheme 1a).16,17 Ryu and co-workers reported the radical-
mediated hydroaminocarbonylation of alkynes with primary or
secondary amines, which provided branched α,β-unsaturated
amides.12 Using NH4HCO3 as an ammonia surrogate, a
palladium-catalyzed hydroaminocarbonylation resulted in
branched primary amides.13 Alper developed a highly selective
palladium catalyzed method for the synthesis of both linear
and branched α,β-unsaturated amides in which the product
selectivity is remarkably controlled by the use of different
ligands and additives.14 Iron catalyzed hydroaminocarbonyla-
tion of alkynes with primary and secondary amines to exclusive
formation of linear amides has also been reported recently.15
Beller and Lei reported the Pd/Cu catalyzed aminocarbony-
lation of alkenes to linear α,β-unsaturated amides, and the
reactions proceeded via aerobic oxidative dealkylation of tert-
amines.16 Palladium-catalyzed synthesis of linear α,β-unsatu-
rated amides was also attained using Mo(CO)6 as a carbonyl
Received: March 23, 2021
Published: July 13, 2021
Conventional synthesis of α,β-unsaturated amides employs
the nucleophilic substitution reaction of α,β-unsaturated
carboxylic acids and amines together with excess coupling
reagents, which results in undesired waste formation, and the
method also suffers from the limited availability of function-
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Scheme 1. Advances in Catalytic Synthesis of α,β-
Unsaturated Amides
RESULTS AND DISCUSSION
■
We commenced our investigation with the reaction of
acetanilide (0.5 mmol), benzyl alcohol (0.6 mmol), catalyst
1 (2 mol %), and cesium carbonate (30 mol %) in tert-amyl
alcohol at 135 °C. Upon completion and workup, analysis of
1H NMR spectra of the reaction mixture revealed 87%
conversion of acetanilide with alkenylated (2a) and alkylated
(2a′) amide products in an 85:4 ratio (entry 1, Table 1).
Table 1. Optimization for Catalytic α-Alkenylation of
a
Amides Using Benzyl Alcohols
b
c
entry cat. 1 (mol %)
base (mol %)
conv. (%)
ratio (2a:2a′)
1
2
3
4
5
6
7
8
2
5
2
2
1
2
2
2
-
Cs2CO3 (30)
Cs2CO3 (30)
Cs2CO3 (50)
Cs2CO3(100)
KOtBu (20)
NaOtBu (50)
NaOtBu (70)
NaOtBu (100)
NaOtBu (100)
-
87
99
77
79
71
87
96
89
-
85:4
60:10
76:5
72:4
74:5
76:5
83:4
>98:2
-
9
10
11
12
-
2
2
-
91
-
-
d
e
NaOtBu (100)
NaOtBu (100)
>98:2
-
a
Reaction conditions: acetanilide (0.5 mmol), benzyl alcohol (0.6
mmol), tert-amyl alcohol (2 mL), catalyst 1, and base were heated at
surrogate and nitroarene via aminocarbonylation of alkenes.17
Synthetic methods for the α,β-desaturation or dehydrogen-
ation of saturated alkyl amides to α,β-unsaturated amides were
also developed.18 Further, many methods are known for the
synthesis of such unsaturated amides.3,19 However, these
protocols suffer from the requirement of complicated starting
materials, elongated synthetic steps, toxic CO, additives, and
activating reagents.17−20 Thus, the development of a simple,
selective, and direct synthesis of α,β-unsaturated amides is
highly desirable.
Using biorenewable and abundant feedstock chemicals such
as alcohols, an assortment of sustainable organic trans-
formations have been developed through an acceptorless
dehydrogenative coupling (ADC) strategy.21 However, thus
far, only a few examples of direct alkenylation using ADC of
alcohols have been reported. Direct alkenylation of nitriles
using alcohols was established by other research groups and
us.22 Using the manganese pincer 1 developed by Kempe, we
have reported catalytic alkenylation of ketones by alcohols via
ADC.23,24 Manganese-catalyzed alkenylation of the heteroaryl
methyl group25 and aryl sulfone compounds26 have been
reported using alcohols. Achieving ADC in particular with
carbon nucleophile is highly challenging, primarily because of
the competing “borrowing hydrogen” reaction,27 which leads
to the hydrogenation of in situ formed α,β-unsaturated
compounds.28−30 Accordingly, the alkylation of amides using
alcohols is well established (Scheme 1b).29 On the contrary,
alkenylation of amides using ADC of alcohol is unknown.
Herein, we report the manganese pincer catalyzed direct
alkenylation of amides using alcohols, in which selective
synthesis of linear α,β-unsaturated amides with the liberation
of molecular hydrogen and water is attained (Scheme 1c).
b
135 °C under nitrogen flow. Conversion of acetanilide was
determined by 1H NMR analysis using methyl benzoate (0.25
c
mmol) as an internal standard. Ratio of products was calculated from
d
1H NMR spectral analysis of reaction mixture. Reaction performed at
e
150 °C, and product 2a was isolated in 79% yield. Reaction
performed at 100 °C with molecular sieves (4 Å).
Increasing the catalyst load to 5 mol % resulted in complete
conversion of acetanilide, however with lower selectivity of the
60:10 (2a:2a′) α-alkenylated product (entry 2, Table 1). At 2
mol % of catalyst load, increasing the amount of base (50 mol
%) decreased the conversion of acetanilide to 77% with 76:5
(2a:2a′) product selectivity (entry 3, Table 1). A similar
outcome was observed when 1 equiv of cesium carbonate was
used (entry 4, Table 1). In order to achieve better conversion
and selectivity, the reaction was screened with 20 mol % of
KOtBu and 1 mol % of catalyst, which resulted in 71%
conversion with a selectivity of 74:5 (2a:2a′, entry 5, Table 1).
Use of NaOtBu (50 mol %) base with 2 mol % of the catalyst
under similar reaction conditions resulted in the selectivity of
76:5 (2a:2a′) with 87% conversion of acetanilide (entry 6,
Table 1). Upon using 70 mol % NaOtBu, 96% conversion was
observed with a selectivity of 83:4 (2a:2a′, entry 7, Table 1).
Further, the use of 1 equiv of base, NaOtBu, provided the
optimal reaction condition with complete selectivity for the α-
alkenyl trans-product 2a (entry 8, Table 1). No product
formation was observed in control experiments performed by
employing only base, and without catalyst and base, indicating
that catalyst and base are essential (entries 9, 10, Table 1).
While the use of higher temperature has not much influence on
the product yield, the reaction performed using dehydrants
such as molecular sieves failed (entries 11, 12, Table 1).
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With optimal reaction conditions in hand, a wide range of
primary alcohols was subjected to the manganese-catalyzed α-
alkenylation of acetanilide (Scheme 2). With benzyl alcohol,
Reaction with 4-thiomethylbenzyl alcohol provided the α,β-
unsaturated amide 2h in 57% yield. Screening benzyl alcohols
containing electron-withdrawing substituents afforded prod-
ucts in moderate yields. With 4-phenylbenzyl alcohol, 79%
conversion of acetanilide occurred, and product 2i was isolated
in 62% yield. With halogenated compounds such as 3-fluoro-,
4-bromo-, and 3-iodobenzyl alcohols, the corresponding alkene
products 2j−2l were obtained in 56%, 68%, and 42% yields,
respectively. The reaction of acetanilide with 4-trifluorome-
thylbenzyl alcohol produced the α,β-unsaturated amide 2m in
65% yield. Notably, heteroaryl alcohols such as furfuryl alcohol
and 2-thiophenemethanol provided the corresponding prod-
ucts 2n−2o in good yields. However, an aliphatic alcohol, such
as 1-hexanol, resulted in complete alkylation of amide.
Secondary alcohols such as 1-phenylethanol failed to react
under this catalytic condition. Single-crystal X-ray analyses of
products 2m and 2n unequivocally confirmed the trans-
geometry of alkene in these α,β-unsaturated amides (Scheme
2).
Scheme 2. Manganese Catalyzed α-Alkenylation of
a
Acetanilide Using Alcohols
Encouraged by the versatility of this method, the scope of
various amides with benzyl alcohols was explored (Scheme 3).
The reaction of 2,3-dimethyl acetanilide with benzyl alcohol
under standard conditions provided the corresponding α,β-
Scheme 3. Manganese Catalyzed α-Alkenylation of Amides
a
Using Alcohols with H2 Liberation
a
Reaction conditions: arylamide (acetanilide, 0.5 mmol), alcohol (0.6
mmol), tert-amyl alcohol (2 mL), catalyst 1 (2 mol %), and NaOtBu
(1 equiv) were heated at 135 °C under nitrogen flow. Conversion of
acetanilide was determined from H NMR analysis of the reaction
1
mixture using methyl benzoate (0.25 mmol) as an internal standard
b
and given within the parentheses. Yield of the 0.5 g scale reaction,
c
performed for 36 h. Yield obtained when the reaction was carried out
using Cs2CO3 as a base; 5−8% of alkylation product was also present.
the corresponding α,β-unsaturated amide with complete
selectivity for E-alkene formation was observed, and product
2a was isolated in 83% yield. In general, benzyl alcohols
bearing electron-donating substituents afforded the corre-
sponding E-alkene products in moderate to good yields. A
methyl group at the ortho and para positions produced the
unsaturated amides 2b−2c in moderate yields. The α-
alkenylation of acetanilide with 4-isopropyl and 4-tert-butyl
benzyl alcohols afforded the corresponding products 2d−2e in
57% and 42% yields, respectively. Reaction with 2-methox-
ybenzyl alcohol and piperonyl alcohol afforded the correspond-
ing products 2f−2g in 67% and 52% yields, respectively.
a
b
Reaction conditions: same as that of footnote in Scheme 2. 10% of
c
alkylation product was also present. KOtBu (1 equiv) was used as a
base, the product isolated as E/Z mixture, and the ratio is not
determined. Catalyst 1 was used in 5 mol %.
d
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unsaturated amide 3a in 66% yield. Similarly, 2,4,6-trimethyl
acetanilide afforded the product 3b in 68% yield. High steric
hindrance present in 2,6-diisopropyl acetanilide resulted in
52% of the product 3c, and 4-methoxy substituted acetanilide
produced the alkenylation product 3d in 63% yield. When 2-
thiophenylacetanilide was subjected to α-alkenylation with
benzyl alcohol, only 20% product 3e was obtained, and the
majority of the starting amide was observed to undergo
deacylation to result in the corresponding aniline. Amides
containing electron-withdrawing groups such as 2-fluoro-, 4-
chloro-, and 4-bromo- substitutions on arene resulted in
products 3f−3i in moderate to good yields. The reaction of
2,3-dimethyl acetanilide with 4-trifluorobenzyl alcohol afforded
the α-alkenylation product 3j in 71% yield. To explore the
generality of the reaction, N,2-diphenylacetamide was reacted
with benzyl alcohol to afford the corresponding α,β-
unsaturated product 3k in 43% yield in which the alkene
formation occurred on internal carbon and both E and Z
isomers were formed in the reaction. Further, N,2-diphenyla-
cetamide was reacted with 4-trifluoromethylbenzyl alcohol and
1-napthalenemethanol, which provided products 3l and 3m in
41% and 43% yields, respectively, as an E/Z mixture. Upon
crystallization of the E/Z mixture of 3l, single-crystal X-ray
structure of the cis-product, Z-3l was obtained (Scheme 3).
When N-phenylpropionamide was subjected to alkenylation
with benzyl alcohol, 24% of unsaturated amide 3n was isolated.
To further test the scope of this catalytic method, tertiary
amide such as N-methyl acetanilide was subjected to
alkenylation with benzyl alcohol, which afforded 73% yield of
4a as a mixture of alkenylation and alkylation products in an
80:20 ratio (Scheme 4a). The reaction of N-acetyl indoline
under standard condition using NaOtBu resulted in deacyla-
tion reaction, and thus, when the reaction was performed using
Cs2CO3, 57% of products 4b and 4b′ in 50:50 ratio were
obtained (Scheme 4b). Further, the reaction of N-(2-
fluorophenyl)acetamide with benzyl alcohols leads to the
formation of N-(2-fluorophenyl)cinnamamide products (3f
and 3g), and when the reaction mixtures were further treated
with methanol, the corresponding methoxy products 5a and 5b
were obtained in 66% yields, which resulted from the SNAr
pathway (Scheme 4c).
Mechanistic Studies. To gain insights into the mecha-
nism, the reaction of benzaldehyde with acetanilide was
performed in both the absence and the presence of manganese
catalyst, which provided product 2a in 19% and 83% yields,
respectively (Scheme 5a and b). These experiments revealed
Scheme 5. Mechanistic Studies for α-Alkenylation of
Amides Using Primary Alcohols
Scheme 4. α-Alkenylation of Tertiary Amides Using Primary
Alcohols and Derivatization of α-Alkenyl 2-
Fluoroacetanilide
that catalyst 1 plays a significant role in the CC bond
formation via the aldol reaction. Further, deuterium-labeling
experiments were carried out. Upon reaction with α-deuterated
benzyl alcohol-d3, 80% deuterium incorporation was observed
exclusively at the β-position of the α,β-unsaturated amide 2a-D
(Scheme 5c). When deuterated acetanilide-d3 was reacted with
benzyl alcohol, 50% and 57% deuterium incorporation
occurred at α- and β-positions of 2a′-D due to deuterium
scrambling (Scheme 5d). When both amide and alcohol were
deuterated, α- and β-positions of product 2a″-D displayed 40%
and 88% deuterium incorporation, respectively (Scheme 5e).
These observations indicate that only when amide is
deuterated, the deuterium scrambling takes place and confirms
the aldol condensation.
On the basis of the experimental observations and
mechanistic studies performed, a reaction mechanism for the
manganese-catalyzed α-alkenylation of amides with alcohols is
proposed in Scheme 6. Complex 1 reacts with a base to
provide the dearomatized intermediate I. The coordinatively
unsaturated intermediate I reacts with alcohol via O−H
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studies indicate that the manganese pincer catalyst oxidizes
alcohols to aldehydes and plays an important role in efficient
CC bond formation through aldol condensation, which
operates through metal−ligand cooperation by the aromatiza-
tion−dearomatization process. Deuterium-labeling experi-
ments displayed that scrambling occurs only with the amide-
methyl protons confirming the involvement of aldol con-
densation. Overall, this simple, attractive, and catalytic
protocol advances the alkenylation reactions in chemical
synthesis and can further develop sustainable transformations.
Scheme 6. Proposed Mechanism for Manganese Pincer
Catalyzed α-Alkenylation of Amides Using Alcohols
EXPERIMENTAL SECTION
■
General Information. All catalytic reactions were performed
under inert atmosphere using standard Schlenk techniques. All
stoichiometric reactions were performed in nitrogen atmosphere
MBRAUN glovebox. Chemicals were purchased from Acros, Sigma-
Aldrich, Alfa-aesar, and Himedia Chemicals and used without further
purification. Dry solvents were prepared according to standard
procedures. Infrared (IR) spectra were recorded in PerkinElmer FT-
IR and Thermo-Nicolet FT-IR spectrophotometers. High-resolution
mass spectra (HRMS) were obtained on Bruker micrOTOF-Q II
Spectrometer and are reported as m/z (relative intensity). Accurate
masses are reported for the molecular ion [M + Na]+, [M + H]+, and
[M]+. Nuclear magnetic resonance spectra (1H NMR and 13C NMR)
were recorded at Bruker AV-700 (1H at 700 MHz and 13C at 175
MHz) and Bruker AV-400 (1H at 400 MHz and 13C at 100.6 MHz).
1H NMR chemical shifts are referenced in parts per million (ppm)
with respect to tetramethyl silane (TMS, δ 0.00 ppm), and 13C{1H}
NMR chemical shifts are referenced in parts per million (ppm) with
respect to CDCl3 (δ 77.160 ppm). Coupling constants are reported in
Hertz (Hz). 1H NMR spectroscopy abbreviations: s, singlet; d,
doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of
triplets; dq, doublet of quartets; td, triplet of doublets; qd, quartets of
doublets; ddd, doublets of doublets of doublets; m, multiplet; br,
broad. Assignment of spectra was done based on one-dimensional
(dept-135) NMR techniques. The catalyst 1 was prepared following
the literature procedure reported by Kempe.31
activation to provide alkoxy-ligated intermediate II. The
research groups of Milstein, Kempe, Yu, and Liu have
characterized such manganese alkoxy pincer complex-
es.25c,31−33 β-Hydride elimination from intermediate II results
in the formation of the corresponding aldehyde and Mn-
hydride complex III. Intermediate I is regenerated in the
catalytic cycle upon H2 liberation from saturated intermediate
III. All manganese intermediates in the catalytic cycle maintain
a +1 oxidation state due to the aromatization and
dearomatization metal−ligand cooperation operative in the
catalytic system, facilitating this transformation. The liberated
aldehyde then undergoes aldol condensation with amide under
the catalytic conditions to provide the α-alkenyl amide product
and water. As observed experimentally (Scheme 5b), the
catalyst also plays an important role in aldol condensation,
which leads to the efficient CC bond formation in α-
alkenylation of amides using alcohols as alkenylation reagents.
Combination of careful catalyst selection and optimized
experimental conditions are crucial for the selective synthesis
of alkenyl amides. Catalyst 1 with methyl substitution on the
pincer backbone favors the alkenyl products.23 Similar
manganese catalyst with phenyl substituent on the pincer
backbone favored the alkylation of ketones and secondary
alcohols when reacted with primary alcohols.28a
General Procedure for Synthesis of Amides. To a solution of
aniline (5 mmol) and dichloromethane (DCM, 5 mL), trimethyl-
amine (2 equiv, 10 mmol) was added under ice-cold conditions. The
mixture was allowed to stir for 10 min. Then, a solution of acetyl
chloride (10 mmol) in DCM was added dropwise over a period of 15
min. The reaction mixture was allowed to stir for 2 h. The completion
of the reaction was monitored by TLC. After completion, the reaction
mixture was quenched by the addition of water. The organic layer was
extracted using DCM, washed with brine solution, and dried using
anhydrous sodium sulfate. Solvents are removed under reduced
pressure using a rotavapor, and the resulted residue was purified by
column chromatography. The following amides were prepared and
characterized by NMR analyses and data compared with the reported
literature: N-(2,3-dimethylphenyl)acetamide,34 N-mesitylacetamide,35
N-(2,6-diisopropylphenyl) acetamide,36 N-(4-methoxyphenyl) acet-
amide,37 N-(2-(phenylthio)phenyl) acetamide,38 N-(2-fluorophenyl)
acetamide,39 N-(4-chlorophenyl)acetamide,40 N-(4-bromophenyl)-
acetamide, N-phenylpropanamide,41 and N,2-diphenylacetamide.42
General Procedure for Optimization of α-Alkenylation of
Amides Using Alcohols. To a Schlenk flask (25 mL) equipped with
a stir bar, catalyst 1 (2 mol %), NaOtBu (1 equiv), acetanilide (0.5
mmol), benzyl alcohol (0.6 mmol), and tert-amyl alcohol (2 mL) were
added under nitrogen atmosphere in a glovebox. The reaction mixture
was taken out of the glovebox, equipped with a condenser, and the
solution was heated at 135 °C (oil bath temperature) with stirring in
an open system under nitrogen flow for 24 h. After cooling, the
reaction mixture was transferred to an RB flask, and the solvent was
evaporated under reduced pressure. The resultant residue was
dissolved in chloroform, washed with water and brine. The collected
organic layer was dried over anhydrous sodium sulfate and
concentrated in a vacuum. Further, methyl benzoate (0.25 mmol)
CONCLUSION
■
In summary, this work demonstrated a strategy for α-
alkenylation of amides that uses highly abundant base metal
manganese as a catalyst and biorenewable and cheap industrial
feedstock alcohols as direct alkenylation reagents. Remarkably,
water and molecular hydrogen are the only byproducts of these
direct alkenylation reactions. The diverse substrate scope of
both amides and alcohols is demonstrated. Tertiary amides
were also amenable in this catalytic reaction, albeit providing a
mixture of alkenylation and alkylation products. Mechanistic
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was added (as an internal standard) to the mixture, dissolved in
CDCl3 (1 mL), and subjected to H NMR analysis from which the
conversion was calculated.
hexane (10:90) mixture as an eluent. White solid. Yield (58 mg, 42%).
1
MP 141−143 °C. IR (DCM): 3299, 3058, 2961, 2867, 1661, 1622,
1
1537, 1497, 1343, 980, 715 cm−1. H NMR (400 MHz, CDCl3): δ
General Procedure for α-Alkenylation of Amides Using
Alcohols. To a Schlenk flask (25 mL) equipped with a stir bar,
catalyst 1 (2 mol %), NaOtBu (1 equiv), amide (0.5 mmol), alcohol
(0.6 mmol), and tert-amyl alcohol were added under nitrogen
atmosphere in a glovebox. The reaction mixture was taken out of the
glovebox, equipped with a condenser, and the solution was heated at
135 °C (oil bath temperature) with stirring in an open system under
nitrogen flow for 24 h. After cooling, the reaction mixture was
transferred to an RB flask. The solvent was removed under reduced
pressure; the reaction mixture was dissolved in chloroform and
washed with water and brine. The collected organic layer was dried
over anhydrous sodium sulfate and concentrated in a vacuum.
Further, methyl benzoate (0.25 mmol) was added (as an internal
standard), the mixture was dissolved in CDCl3 or CD3OD (1 mL)
7.60 (d, J = 15.5 Hz, 1H), 7.49 (s, 3H), 7.31 (d, J = 7.7 Hz, 2H),
7.27−7.17 (m, 4H), 6.98 (t, J = 7.2 Hz, 1H), 6.42 (d, J = 15.5 Hz,
1H), 1.18 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3): δ 165.0,
153.2, 141.9, 138.2, 131.8, 128.9, 127.7, 126.9, 125.7, 125.4, 124.2,
120.3, 34.7, 31.3, 31.1. HRMS (ESI) m/z calcd for C19H21NONa (M
+Na)+: 302.1515, found: 302.1491.
(E)-3-(2-Methoxyphenyl)-N-phenylacrylamide (2f). This was
purified by silica-gel column chromatography using ethyl acetate/
hexane (15:85) mixture as an eluent. White solid. Yield (84 mg, 67%).
MP 160−162 °C. IR (DCM): 3438, 2935, 2837, 1657, 1623, 1598,
1488, 1343, 1180, 752 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.81 (d,
J = 15.7 Hz, 1H), 7.49−7.44 (m, 3H), 7.26 (d, J = 7.5 Hz, 1H), 7.12
(t, J = 7.5 Hz, 3H), 6.90 (t, J = 7.1 Hz, 1H), 6.71 (t, J = 9.7 Hz, 2H),
6.52 (d, J = 15.7 Hz, 1H), 3.65 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 165.2, 158.2, 138.4, 137.4, 130.9, 128.9, 128.9, 124.0,
123.5, 121.7, 120.5, 120.0, 110.9, 55.2. HRMS (ESI) m/z calcd for
C16H15NO2Na (M+Na)+: 276.0995, found: 276.0995.
1
and subjected to H NMR analysis from which the conversion was
calculated. CDCl3 was removed in vacuo, and the residue was purified
by silica gel (100−200 mesh) column chromatography using ethyl
acetate/hexane mixture as eluent. Yields were calculated for isolated
products.
(E)-3-(Benzo[d][1,3]dioxol-5-yl)-N-phenylacrylamide (2g). This
was purified by silica-gel column chromatography using ethyl
acetate/hexane (20:80) mixture as an eluent. White solid. Yield (69
mg, 52%). MP 157−159 °C. IR (DCM): 3063, 3021, 2944, 2844,
Spectral Data of α-Alkenyl Amide Products. N-Phenyl-
cinnamamide (2a).43 This was purified by silica-gel column
chromatography using ethyl acetate/hexane (10:90) mixture as an
eluent. White solid. Yield (92 mg, 83%; 635 mg, 77% for the 0.5 g
scale reaction). MP 155−157 °C. IR (DCM): 3060, 3028, 1661,
1
1668, 1603, 1551, 1482, 1313, 951, 705 cm−1. H NMR (400 MHz,
CDCl3): δ 7.92 (s, 1H), 7.62−7.50 (m, 3H), 7.23 (t, J = 7.8 Hz, 2H),
7.02 (t, J = 7.3 Hz, 1H), 6.89−6.81 (m, 2H), 6.66 (d, J = 8.0 Hz, 1H),
6.36 (d, J = 15.4 Hz, 1H), 5.89 (s, 2H). 13C{1H} NMR (101 MHz,
CDCl3): δ 164.5, 149.2, 148.2, 142.0, 138.2, 129.0, 124.3, 124.2,
120.1, 118.9, 108.5, 106.4, 101.4. HRMS (ESI) m/z calcd for
C16H13NO3Na (M+Na)+: 290.0788, found: 290.0770.
1
1626, 1596, 1578, 1539, 1495, 1351, 1248, 904, 704 cm−1. H NMR
(400 MHz, CDCl3): δ 7.67 (d, J = 15.5 Hz, 1H), 7.59−7.45 (m, 3H),
7.42 (dd, J1 = 6.5 Hz, J2 = 3.0 Hz, 2H), 7.30−7.26 (m, 3H), 7.24−
7.17 (m, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.49 (d, J = 15.5 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3): δ 164.5, 142.2, 138.1, 134.5,
129.8, 129.0, 128.8, 127.9, 124.4, 120.9, 120.2. HRMS (ESI) m/z
calcd for C15H13NONa (M+Na)+: 246.0889, found: 246.0885.
(E)-N-Phenyl-3-(o-tolyl)acrylamide (2b).44 This was purified by
silica-gel column chromatography using ethyl acetate/hexane (10:90)
mixture as an eluent. White solid. Yield (68 mg, 57%). MP 159−161
°C IR (DCM): 3063, 2944, 2844, 1668, 1603, 1542, 1482, 1313,
(E)-3-(4-(Methylthio)phenyl)-N-phenylacrylamide (2h). This was
purified by silica-gel column chromatography using ethyl acetate/
hexane (10:90) mixture as an eluent. White solid. Yield (85 mg, 57%).
MP 310−312 °C. IR (DCM): 3302, 2922, 2852, 1664, 1622, 1598,
1
1546, 1498, 1318, 1093, 754 cm−1. H NMR (700 MHz, CDCl3): δ
7.63 (d, J = 15.7 Hz, 1H), 7.55 (s, 2H), 7.38−7.27 (m, 5H), 7.19−
7.14 (m, 2H), 7.05 (s, 1H), 6.43 (d, J = 15.7 Hz, 1H), 2.43 (s, 3H).
13C{1H} NMR (176 MHz, CDCl3): δ 164.1, 141.8, 141.5, 138.1,
131.2, 129.1, 128.3, 126.1, 124.4, 119.9, 15.2. HRMS (ESI) m/z calcd
for C16H16NOS (M+H)+: 270.0947, found: 270.0953.
(E)-3-([1,1′-Biphenyl]-4-yl)-N-phenylacrylamide (2i). This was
purified by silica-gel column chromatography using ethyl acetate/
hexane (10:90) mixture as an eluent. White solid. Yield (97 mg, 62%).
MP 205−207 °C. IR (DCM): 3063, 2944, 2844, 1668, 1603, 1540,
1482, 1313, 951, 705 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J
= 15.5 Hz, 1H), 7.52 (s, 8H), 7.37 (t, J = 6.9 Hz, 3H), 7.29−7.25 (m,
3H), 7.06 (t, J = 8 Hz, 1H), 6.52 (d, J = 15.5 Hz, 1H). 13C{1H} NMR
(101 MHz, CD3OD): δ 165.3, 142.6, 140.9, 140.1, 138.6, 133.8,
128.5, 128.4, 128.1, 127.4, 127.0, 126.5, 123.9, 120.7, 119.8. HRMS
(ESI) m/z calcd for C21H17NONa (M+Na)+: 322.1202, found:
322.1194.
1
1247, 1156, 951, 705 cm−1. H (400 MHz, CD3OD): δ 8.21 (d, J =
15.6 Hz, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.84 (d, J = 7.5 Hz, 1H),
7.59−7.51 (m, 2H), 7.51−7.40 (m, 3H), 7.33 (t, J = 7.4 Hz, 1H),
6.92 (d, J = 15.6 Hz, 1H), 2.66 (s, 3H). 13C{1H} NMR (101 MHz,
CD3OD): δ 165.3, 139.0, 138.6, 137.3, 133.5, 130.4, 129.4, 128.4,
126.0, 125.8, 123.9, 121.8, 119.8, 18.4. HRMS (ESI) m/z calcd for
C16H16NO (M+H)+: 238.1226, found: 238.1222.
(E)-N-Phenyl-3-(p-tolyl)acrylamide (2c). This was purified by
silica-gel column chromatography using ethyl acetate/hexane (10:90)
mixture as an eluent. White solid. Yield (69 mg, 60%). MP 184−186
°C. IR (DCM): 3038, 2922, 2853, 1653, 1623, 1550, 1498, 1336, 810,
689 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.67−7.63 (m, 2H), 7.56
(d, J = 5.8 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 7.25 (t, J = 7.8 Hz, 2H),
7.05 (dd, J1 = 17.0 Hz, J2 = 7.4 Hz, 3H), 6.48 (d, J = 15.5 Hz, 1H),
2.28 (s, 3H). 13C{1H} NMR (101 MHz, CD3OD): δ 165.5, 141.4,
140.1, 138.6, 132.0, 129.2, 128.4, 127.5, 123.8, 119.8, 119.7, 20.0.
HRMS (ESI) m/z calcd for C16H16NO (M+H)+: 238.1226, found:
238.1231.
(E)-3-(3-Fluorophenyl)-N-phenylacrylamide (2j). This was puri-
fied by silica-gel column chromatography using ethyl acetate/hexane
(10:90) mixture as an eluent. White solid. Yield (67 mg, 56%). MP
144−146 °C. IR (DCM): 3437, 3029, 2848, 1662, 1628, 1583, 1499,
1443, 1250, 670 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H),
7.59 (d, J = 15.6 Hz, 3H), 7.23 (t, J = 7.9 Hz, 2H), 7.17 (dd, J1 = 7.8,
J2 = 6.0 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 7.03 (dd, J1 = 6.8, J2 = 5.1
Hz, 2H), 6.94 (td, J1 = 8.3, J2 = 2.1 Hz, 1H), 6.55 (d, J = 15.5 Hz,
1H). 13C{1H} NMR (101 MHz, CDCl3): δ 164.0, 162.9 (d, J = 245
Hz), 140.9, 137.9, 136.8 (d, J = 7.7 Hz), 130.3 (d, J = 8.3 Hz), 129.1,
124.6, 124.0 (d, J = 2.8 Hz), 122.4, 120.2, 116.7 (d, J = 21.4 Hz),
114.0 (d, J = 21.9 Hz). 19F NMR (377 MHz, CDCl3): δ −131.0.
HRMS (ESI) m/z calcd for C15H13FNO (M+H)+: 242.0976, found:
242.0966.
(E)-3-(4-Isopropylphenyl)-N-phenylacrylamide (2d). This was
purified by silica-gel column chromatography using ethyl acetate/
hexane (10:90) mixture as an eluent. White solid. Yield (75 mg, 57%).
MP 122−124 °C IR (DCM): 3063, 2944, 2844, 1668, 1603, 1542,
1
1482, 1313, 1247, 951, 705 cm−1. H NMR (400 MHz, CDCl3): δ
7.77 (s, 1H), 7.65 (d, J = 15.5 Hz, 1H), 7.56 (d, J = 7.2 Hz, 2H), 7.33
(d, J = 8.1 Hz, 2H), 7.24 (t, J = 7.9 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H),
7.03 (t, J = 7.3 Hz, 1H), 6.50 (d, J = 15.5 Hz, 1H), 2.82 (dt, J1 = 13.8,
J2 = 6.9 Hz, 1H), 1.16 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (101 MHz,
CDCl3): δ 164.5, 151.2, 142.3, 138.2, 132.2, 129.0, 128.1, 127.2,
126.9, 124.3, 120.0, 34.0, 23.8. HRMS (ESI) m/z calcd for
C18H19NONa (M+Na)+: 288.1359, found: 288.1353.
(E)-3-(4-Bromophenyl)-N-phenylacrylamide (2k).46 This was
purified by silica-gel column chromatography using ethyl acetate/
hexane (15:85) mixture as an eluent. White solid. Yield (103 mg,
68%). MP 184−186 °C. IR (DCM): 3033, 2838, 1652, 1558, 1506,
(E)-3-(4-(tert-Butyl)phenyl)-N-phenylacrylamide (2e). This was
purified by silica-gel column chromatography using ethyl acetate/
9999
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1485, 1326, 972, 743 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J
= 15.7 Hz, 1H), 7.56 (d, J = 6.1 Hz, 1H), 7.45−7.41 (m, 3H), 7.33−
7.28 (m, 4H), 7.21 (s, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.49 (d, J = 15.7
Hz, 1H). 13C{1H} NMR (101 MHz, CD3OD): δ 164.9, 139.9, 138.5,
134.0, 131.8, 129.2, 128.5, 124.0, 123.5, 121.8, 119.8. HRMS (ESI)
m/z calcd for C15H13BrNO (M+H)+: 302.0175, found: 302.0164.
(E)-3-(3-Iodophenyl)-N-phenylacrylamide (2l). This was purified
by silica-gel column chromatography using ethyl acetate/hexane
(15:85) mixture as an eluent. White solid. Yield (71 mg, 42%). MP
124−126 °C. IR (DCM): 3071, 3023, 2952, 2790, 1666, 1599, 1481,
(s, 2H), 6.62 (d, J = 15.7 Hz, 1H), 6.10 (d, J = 15.6 Hz, 1H), 2.19−
2.08 (m, 11H). 13C{1H} NMR (101 MHz, CDCl3): δ 164.8, 143.9,
141.6, 136.7, 136.4, 135.1, 134.8, 131.3, 129.9, 129.6, 129.2, 128.8,
128.7, 128.0, 127.9, 120.5, 115.9, 20.9, 18.5, 18.3. HRMS (ESI) m/z
calcd for C18H19NONa (M+Na)+: 288.1359, found: 288.1356.
N-(2,6-Diisopropylphenyl)cinnamamide (3c). This was purified
by silica-gel column chromatography using ethyl acetate/hexane
(10:90) mixture as an eluent. White solid. Yield (80 mg, 52%). MP
254−256 °C. IR (DCM): 3445, 3024, 2963, 1659, 1623, 1578, 1528,
1
1465, 1447, 1360, 987, 725 cm−1. The H and 13C NMR spectra of
1
1318, 952, 699 cm−1. H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H),
this compound display two set of signals for alkenyl protons and
carbons, respectively despite the presence of only E product. 1H NMR
(400 MHz, CDCl3): δ 7.68 (d, J = 15.6 Hz, 1H), 7.55 (d, J = 15.7 Hz,
1H), 7.48 (d, J = 20.8 Hz, 1H), 7.31 (t, J = 7.4 Hz, 2H), 7.25 (dd, J1 =
8.8 Hz, J2 = 5.1 Hz, 4H), 7.21−7.08 (m, 5H), 6.64 (d, J = 15.7 Hz,
1H), 6.10 (d, J = 15.7 Hz, 1H), 3.15 (dt, J1 = 13.7, J2 = 6.8 Hz, 1H),
3.06 (dt, J1 = 13.7, J2 = 6.8 Hz, 2H), 1.11 (s, 6H), 1.11−1.06 (m,
12H). 13C{1H} NMR (101 MHz, CDCl3): δ 168.2, 165.6, 147.2,
146.4, 143.8, 141.9, 134.7, 131.3, 131.3, 131.2, 129.9, 129.7, 129.1,
128.7, 128.3, 128.0, 127.9, 123.9, 123.4, 120.2, 116.1, 28.8, 28.5, 24.0,
23.6, 23.0. HRMS (ESI) m/z calcd for C21H25NONa (M+Na)+:
330.1828, found: 330.1832.
7.66−7.43 (m, 4H), 7.39 (d, J = 5.3 Hz, 1H), 7.28 (dd, J1 = 16.4, J2 =
8.6 Hz, 2H), 7.20 (s, 1H), 7.06 (dt, J1 = 7.6, J2 = 6.7 Hz, 2H), 6.49 (d,
J = 15.5 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 163.5, 140.7,
138.7, 136.8, 136.4, 130.5, 129.1, 127.4, 124.6, 122.2, 120.0, 94.7.
HRMS (ESI) m/z calcd for C15H12INONa (M+Na)+: 371.9856,
found: 371.9877.
(E)-N-Phenyl-3-(4-(trifluoromethyl)phenyl) acrylamide (2m).
This was purified by silica-gel column chromatography using ethyl
acetate/hexane (20:80) mixture as an eluent. White solid. Yield (94
mg, 65%). MP 176−178 °C. IR (DCM): 3420, 2926, 2852, 1652,
1
1595, 1498, 1324, 895, 756 cm−1. H NMR (400 MHz, CD3OD): δ
7.65 (d, J = 8.2 Hz, 2H), 7.58 (dd, J1 = 15.3 Hz, J2 = 7.2 Hz, 5H), 7.22
(t, J = 7.9 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.79 (d, J = 15.7 Hz, 1H).
13C{1H} NMR (101 MHz, CD3OD): δ 164.5, 139.4, 138.6, 138.4,
131.0, 128.5, 127.9, 125.4, 125.4, 124.1, 123.7, 119.8. 19F NMR (377
MHz, CDCl3): δ −62.8. HRMS (ESI) m/z calcd for C16H12F3NONa
(M+Na)+: 314.0763, found: 314.0764.
(E)-3-(Furan-2-yl)-N-phenylacrylamide (2n). This was purified by
silica-gel column chromatography using ethyl acetate/hexane (10:90)
mixture as an eluent. Yellow solid. Yield (87 mg, 82% (using NaOtBu
as a base), 98 mg, 92% (using Cs2CO3 as a base)). MP 123−125 °C.
IR (DCM): 3304, 3131, 2923, 2553, 2089, 1667, 1633, 1561, 1387,
883, 748 cm−1. 1H NMR (700 MHz, CDCl3): δ 7.99 (s, 1H), 7.65 (d,
J = 5.3 Hz, 2H), 7.53 (d, J = 15.2 Hz, 1H), 7.42 (s, 1H), 7.32 (t, J =
7.8 Hz, 2H), 7.12 (t, J = 7.0 Hz, 1H), 6.57 (d, J = 15.2 Hz, 1H), 6.53
(d, J = 3.2 Hz, 1H), 6.45 (dd, J1 = 3.3, J2 = 1.8 Hz, 1H). 13C{1H}
NMR (176 MHz, CDCl3): δ 164.3, 151.2, 144.2, 138.1, 129.0, 128.9,
124.3, 120.1, 118.7, 114.3, 112.2. HRMS (ESI) m/z calcd for
C13H11NO2 (M+H)+: 214.0863, found: 214.0865.
(E)-N-Phenyl-3-(thiophen-2-yl)acrylamide (2o). This was purified
by silica-gel column chromatography using ethyl acetate/hexane
(10:90) mixture as an eluent. White solid. Alkylated product is
observed in 5%. Yield (105 mg, 93%). MP 148−150 °C. IR (DCM):
3413, 3054, 2853, 2790, 1654, 1598, 1543, 1498, 1332, 858, 754
cm−1. 1H NMR (400 MHz, CDCl3): δ 8.57 (s, 1H), 7.72 (d, J = 15.3
Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.18−7.11 (m, 4H), 6.98−6.93 (m,
2H), 6.83 (dd, J1 = 5.1 Hz, J2 = 3.6 Hz, 1H), 6.43 (d, J = 15.3 Hz,
1H). 13C{1H} NMR (101 MHz, CDCl3): δ 164.6, 139.9, 138.2, 134.7,
130.6, 129.0, 128.0, 127.7, 124.4, 120.4, 120.1. HRMS (ESI) m/z
calcd for C13H11NOSNa (M+Na)+: 252.0454, found: 252.0450.
N-(2,3-Dimethylphenyl)cinnamamide (3a). This was purified by
silica-gel column chromatography using ethyl acetate/hexane (10:90)
mixture as an eluent. White solid. Yield (83 mg, 66%). MP 186−188
°C. IR (DCM): 3437, 2956, 1655, 1619, 1519, 1446, 1343, 992, 708
cm−1. 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 15.5 Hz, 1H), 7.42
(s, 3H), 7.28 (s, 4H), 7.02 (t, J = 7.6 Hz, 1H), 6.95 (s, 1H), 6.54 (d, J
= 15.5 Hz, 1H), 2.21 (s, 3H), 2.10 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 164.3, 142.1, 137.4, 135.3, 134.7, 129.8, 128.8,
127.9, 127.6, 125.9, 122.3, 120.8, 20.6, 13.9. HRMS (ESI) m/z calcd
for C17H17NONa (M+Na)+: 274.1202, found: 274.1206.
N-Mesitylcinnamamide (3b). This was purified by silica-gel
column chromatography using ethyl acetate/hexane (10:90) mixture
as an eluent. White solid. Yield (90 mg, 68%). MP 202−204 °C. IR
(DCM): 3442, 2919, 1653, 1623, 1577, 1521, 1457, 1339, 849, 710
cm−1. The 1H and 13C NMR spectra of this compound display two set
of signals for alkenyl protons and carbons, respectively, despite the
presence of only the E product. 1H NMR (400 MHz, CDCl3): δ 7.70
(d, J = 15.6 Hz, 1H), 7.57 (d, J = 15.7 Hz, 1H), 7.48 (s, 1H), 7.36
(dd, J1 = 6.5, J2 = 2.8 Hz, 2H), 7.31−7.19 (m, 5H), 6.87 (s, 1H), 6.74
N-(4-Methoxyphenyl)cinnamamide (3d). This was purified by
silica-gel column chromatography using ethyl acetate/hexane (15:85)
mixture as an eluent. White solid. Yield (80 mg, 63%). MP 139−141
°C. IR (DCM): 3438, 2948, 2830, 1657, 1624, 1549, 1509, 1457,
1
1360, 830, 779 cm−1. H NMR (400 MHz, CD3OD): δ 7.52 (d, J =
15.7 Hz, 1H), 7.46 (dd, J1 = 7.3 Hz, J2 = 5.1 Hz, 3H), 7.27 (m, 2H),
6.78 (d, J = 9.0 Hz, 2H), 6.65 (d, J = 15.7 Hz, 1H), 6.60 (s, 2H), 3.66
(s, 3H). 13C{1H} NMR (101 MHz, CD3OD): δ 165.1, 156.8, 140.9,
134.8, 131.5, 129.5, 128.6, 127.5, 121.4, 116.8, 113.6, 54.4. HRMS
(ESI) m/z calcd for C16H15NO2 (M+Na)+: 276.0995, found:
276.0989.
N-(2-(Phenylthio)phenyl)cinnamamide (3e). This was purified by
silica-gel column chromatography using ethyl acetate/hexane (10:90)
mixture as an eluent. Viscous liquid. Yield (33 mg, 20%). IR (DCM):
3350, 3057, 2924, 2849, 2303, 1682, 1629, 1578, 1510, 1477, 1288,
923, 705 cm−1. 1H NMR (700 MHz, CDCl3): δ 8.63−8.38 (m, 3H),
7.56−7.51 (m, 2H), 7.48−7.41 (m, 3H), 7.34−7.27 (m, 3H), 7.20−
7.18 (m, 2H), 7.10−7.04 (m, 3H), 6.34 (d, J = 15.5 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3): δ 163.9, 142.3, 140.2, 136.6,
135.7, 134.5, 131.1, 130.0, 129.4, 128.8, 128.0, 127.2, 126.4, 124.5,
121.0, 120.9. HRMS (ESI) m/z calcd for C21H17NOSNa (M+Na)+:
354.0923, found: 354.0923.
N-(2-Fluorophenyl)cinnamamide (3f). This was purified by silica-
gel column chromatography using ethyl acetate/hexane (10:90)
mixture as an eluent. White solid. Yield (72 mg, 60%). MP 135−137
°C. IR (DCM): 3350, 3048, 2946, 2830, 1664, 1629, 1549, 1501,
1448, 1288, 910, 705 cm−1. 1H NMR (400 MHz, CD3OD): δ 7.96 (s,
1H), 7.57 (d, J = 15.7 Hz, 1H), 7.53−7.42 (m, 2H), 7.33−7.19 (m,
3H), 7.04 (dd, J1 = 5.7 Hz, J2 = 2.1 Hz, 3H), 6.81 (d, J = 15.7 Hz,
1H). 13C{1H} NMR (101 MHz, CD3OD): δ 165.6, 155.1, 142.0,
134.7, 129.7, 128.6, 127.6, 126.0, 125.9, 125.3, 124.0, 123.9, 120.3,
115.0, 114.8. 19F NMR (377 MHz, CDCl3): δ −132.1. HRMS (ESI)
m/z calcd for C15H12FNONa (M+Na)+: 264.0795, found: 264.0795.
(E)-N-(2-Fluorophenyl)-3-(4-isopropylphenyl)acrylamide (3g).45
This was purified by silica-gel column chromatography using ethyl
acetate/hexane (10:90) mixture as an eluent. White solid. Yield (91
mg, 64%). MP 98−100 °C. IR (DCM): 3051, 2948, 2830, 1663,
1
1624, 1509, 1235, 830, 710 cm−1. H NMR (400 MHz, CDCl3): δ
8.39 (t, J = 7.5 Hz, 1H), 7.68 (d, J = 15.5 Hz, 1H), 7.50 (s, 1H), 7.41
(d, J = 8.2 Hz, 2H), 7.20−7.14 (m, 2H), 7.07 (dd, J1 = 13.2, J2 = 4.5
Hz, 1H), 7.04−6.94 (m, 2H), 6.48 (d, J = 15.5 Hz, 1H), 2.85 (dt, J1 =
13.8, J2 = 6.9 Hz, 1H), 1.18 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (101
MHz, CDCl3): δ 164.1, 151.5, 143.0, 132.1, 128.2, 127.0, 124.7,
124.6, 124.3, 124.2, 121.8, 119.4, 114.8, 114.6, 34.1, 23.8. 19F NMR
(377 MHz, CDCl3): δ −131.7. HRMS (ESI) m/z calcd for
C18H19FNO (M+H)+: 284.1445, found: 284.1426.
N-(4-Chlorophenyl)cinnamamide (3h). This was purified by silica-
gel column chromatography using ethyl acetate/hexane (15:85)
10000
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mixture as an eluent. White solid. Yield (46 mg, 36%). MP 183−185
°C. IR (DCM): 3441, 3025, 2922, 1659, 1626, 1556, 1505, 1407,
1298, 922, 684 cm−1. 1H NMR (400 MHz, CD3OD): δ 7.61 (s, 1H),
7.56 (d, J = 4.3 Hz, 2H), 7.50 (dd, J1 = 7.5 Hz, J2 = 1.8 Hz, 2H),
7.35−7.26 (m, 3H), 7.24−7.18 (m, 2H), 6.67 (d, J = 15.7 Hz, 1H).
13C{1H} NMR (101 MHz, CD3OD): δ 165.2, 141.7, 137.4, 134.7,
129.7, 128.7, 128.6, 128.6, 128.4, 127.5, 121.0, 120.6. HRMS (ESI)
m/z calcd for C15H12ClNONa (M+Na)+: 280.0500, found: 280.0489.
N-(4-Bromophenyl)cinnamamide (3i). This was purified by silica-
gel column chromatography using ethyl acetate/hexane (15:85)
mixture as an eluent. Compound isolated was mixture of alkenyl
(major) and alkylated (minor) products. White solid. Yield (90 mg,
60%). MP 195−197 °C. IR (DCM): 3419, 3023, 2921, 1674, 1645,
99 °C. IR (DCM): 3437, 2956, 2877, 1655, 1619, 1519, 1446, 1343,
1
910, 708 cm−1. H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 7.7 Hz,
3H), 7.35−7.31 (m, 5H), 7.29−7.21 (m, 4H), 7.19−7.14 (m, 1H),
7.06 (t, J = 7.4 Hz, 1H), 6.61 (s, 1H, cis isomer), 2.14 (s, 3H, trans
isomer), 2.11 (s, 3H, cis isomer). 13C{1H} NMR (101 MHz, CDCl3):
δ 167.8, 138.0, 135.8, 134.3, 132.9, 129.4, 129.1, 128.6, 128.4, 128.1,
127.0, 124.4, 120.3, 14.4. HRMS (ESI) m/z calcd for C16H16NO (M
+H)+: 238.1226, found: 238.1230.
General Procedure for Derivatization of α-Alkenyl Amides.
To a Schlenk flask (25 mL) equipped with a stir bar, catalyst 1 (2 mol
%), NaOtBu (1 equiv), 2-fluoro acetanilide (0.5 mmol), aryl alcohol
(0.6 mmol), and tert-amyl alcohol were added under nitrogen
atmosphere in a glovebox. The reaction mixture was taken out of the
glovebox, equipped with a condenser, and the solution heated at 135
°C (oil bath temperature) with stirring in an open system under
nitrogen flow for 24 h. Then, methanol was added to the reaction
mixture under nitrogen flow and further stirred for 3 h. The reaction
mixture was transferred to an RB flask, and the solvent was evaporated
under reduced pressure. The solvent was removed under reduced
pressure; the reaction mixture was dissolved in chloroform and
washed with water and brine. The collected organic layer was dried
over anhydrous sodium sulfate and concentrated in a vacuum. The
resultant residue was purified by silica gel (100−200 mesh) column
chromatography using ethyl acetate/hexane mixture as eluent. Yields
were calculated for isolated products.
1
1520, 1489, 1418, 977, 710 cm−1. H NMR (400 MHz, CDCl3): δ
7.67 (d, J = 15.5 Hz, 1H), 7.44 (s, 4H), 7.37 (d, J = 8.7 Hz, 2H), 7.31
(dd, J = 8.0, 5.0 Hz, 3H), 7.18 (s, 1H), 6.46 (d, J = 15.5 Hz, 1H), 2.97
(t, J = 7.5 Hz, 2H, alkylated), 2.58 (t, J = 7.5 Hz, 2H, alkylated).
13C{1H} NMR (101 MHz, CDCl3): δ 164.0, 142.9, 137.1, 134.5,
132.1, 130.2, 128.9, 128.0, 125.0, 121.5, 120.4. HRMS (ESI) m/z
calcd for C15H12BrNONa (M+Na)+: 323.9994, found: 323.9985.
(E)-N-(2,3-Dimethylphenyl)-3-(4-(trifluoromethyl) phenyl)-
acrylamide (3j). This was purified by silica-gel column chromatog-
raphy using ethyl acetate/hexane (20:80) mixture as an eluent. White
solid. Yield (113 mg, 71%). MP 230−232 °C. IR (DCM): 3437,
1
2956, 2854, 1655, 1625, 1510, 1440, 1343, 991, 756 cm−1. H NMR
N-Methyl-N-phenylcinnamamide (4a) and N-methyl-N,3-diphe-
nylpropanamide (4a′). These were purified by silica-gel column
chromatography using ethyl acetate/hexane (10:90) mixture as an
eluent. Viscous liquids. Yield (86 mg, 73%). IR (DCM): 2951, 2823,
(400 MHz, CD3OD): δ 7.83 (d, J = 8.1 Hz, 2H), 7.75−7.71 (m, 3H),
7.23 (d, J = 6.7 Hz, 1H), 7.15−7.10 (m, 2H), 7.01 (d, J = 15.8 Hz,
1H), 2.34 (s, 3H), 2.21 (s, 3H). 13C NMR (101 MHz, CD3OD): δ
165.3, 139.4, 138.7, 138.4, 137.4, 135.1, 131.7, 131.0, 130.7, 128.0,
127.8, 125.5, 125.4, 125.3, 123.5, 123.3, 19.1, 12.9. 19F NMR (377
MHz, CDCl3): δ −62.8. HRMS (ESI) m/z calcd for C18H16F3ON (M
+H)+: 320.1245, found: 320.1257.
1
1663, 1610, 1540, 1416, 1343, 895, 708 cm−1. H NMR (400 MHz,
CDCl3): δ 7.60 (d, J = 15.5 Hz, 1H), 7.41−7.32 (m, 2H), 7.34−7.23
(m, 3H), 7.21 (m, 6H), 7.16 (dd, J1 = 7.2 Hz, J2 = 2.1 Hz, 3H), 6.29
(d, J = 15.3 Hz, 1H), 3.34 (s, 3H), 3.17 (s, 3H, alkylated), 2.83 (t, J =
7.9 Hz, 2H, alkylated), 2.29 (t, J = 8.0 Hz, 2H, alkylated). 13C{1H}
NMR (101 MHz, CDCl3): δ 166.2, 143.6, 141.7, 135.2, 129.7, 129.6,
129.5, 128.7, 128.5, 128.4, 128.3, 127.8, 127.8, 127.6, 127.3, 127.0,
126.0, 118.8, 37.6, 36.0, 31.8. HRMS (ESI) m/z calcd for
C16H15NONa (M+Na)+: 260.1046, found: 260.1039.
N,2,3-Triphenylacrylamide (3k). This was purified by silica-gel
column chromatography using ethyl acetate/hexane (5:95) mixture as
an eluent. White solid. Yield (65 mg, 43%). MP 142−144 °C. IR
(DCM): 3420, 3047, 2926, 2852, 1652, 1598, 1510, 1324, 913, 712
1
cm−1. H NMR (400 MHz, CDCl3): δ 7.90 (s, 1H), 7.47−7.40 (m,
3H), 7.37 (d, J = 7.8 Hz, 3H), 7.31−7.27 (m, 1H), 7.27−7.25 (m,
1H), 7.24−7.18 (m, 3H), 7.16−7.04 (m, 5H), 7.04−6.98 (m, 1H),
6.98−6.92 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 165.0,
138.2, 137.8, 135.8, 134.8, 134.6, 130.5, 130.0, 129.9, 129.0, 128.9,
128.8, 128.2, 124.4, 119.9. HRMS (ESI) m/z calcd for C21H17NONa
(M+Na)+: 322.1202, found: 322.1190.
(E)-1-(Indolin-1-yl)-3-phenylprop-2-en-1-one (4b) and 1-(Indo-
lin-1-yl)-3-phenylpropan-1-one (4b′). These were purified by silica-
gel column chromatography using ethyl acetate/hexane (10:90)
mixture as an eluent. White solids. Yield (70 mg, 57%). MP 107−109
°C. IR (DCM): 2977, 2856, 1651, 1607, 1590, 1479, 1351, 991, 910,
708 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 8.18 (d, J =
8.1 Hz, 1H), 7.73 (d, J = 15.4 Hz, 1H), 7.53−7.41 (m, 2H), 7.34−
7.25 (m, 3H), 7.25−7.15 (m, 2H), 7.14−7.01 (m, 3H), 6.99−6.86
(m, 2H), 6.75 (d, J = 14.4 Hz, 1H), 4.14 (t, J = 8.5 Hz, 2H), 3.84 (t, J
= 8.5 Hz, 1H), 3.14 (d, J = 22.3 Hz, 2H), 3.06−2.91 (m, 2H), 2.67−
2.56 (m, 1H). 13C{1H} (101 MHz, CDCl3): δ 170.3, 164.2, 143.2,
141.2, 135.0, 129.9, 128.8, 128.5, 128.4, 127.9, 127.5, 127.5, 126.1,
124.5, 123.8, 123.5, 118.9, 117.5, 116.9, 47.8, 37.8, 30.7, 27.9. HRMS
(ESI) m/z calcd for C17H16NO (M+H)+: 250.1226, found: 250.1224.
N-(2-Methoxyphenyl)cinnamamide (5a). This was purified by
silica-gel column chromatography using ethyl acetate/hexane (15:85)
mixture as an eluent. White solid. Yield (76 mg, 66%). MP 135−137
°C. IR (DCM): 3441, 3025, 2922, 1659, 1626, 1505, 1407, 991, 698
cm−1. 1H NMR (700 MHz, CDCl3): δ 8.44 (s, 1H), 7.66 (d, J = 15.5
Hz, 1H), 7.48 (d, J = 7.0 Hz, 2H), 7.30 (dd, J1 = 15.3, J2 = 7.7 Hz,
3H), 7.17 (s, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H),
6.82 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 15.5 Hz, 1H), 3.83 (s, 3H).
13C{1H} NMR (101 MHz, CD3OD): δ 165.6, 149.9, 141.3, 135.3,
N,2-Diphenyl-3-(4-(trifluoromethyl)phenyl) acrylamide (3l). This
was purified by silica-gel column chromatography using ethyl acetate/
hexane (5:95) mixture as an eluent. White solid. Yield (75 mg, 41%).
MP 215−217 °C. IR (DCM): 3442, 2919, 1653, 1623, 1577, 1521,
1
1456, 1339, 892, 712 cm−1. H NMR (400 MHz, CDCl3): δ 7.47−
7.39 (m, 6H), 7.28−7.21 (m,5H), 7.16 (t, J = 7.9 Hz, 3H), 6.98 (t, J =
7.4 Hz, 1H), 6.90 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ
167.3, 140.2, 138.6, 137.3, 136.4, 129.1, 129.0, 128.9, 128.8, 127.6,
126.5, 125.6, 125.1, 120.2. 19F NMR (377 MHz, CDCl3): δ −62.7.
HRMS (ESI) m/z calcd for C22H17F3NO (M+H)+: 368.1257, found:
368.1271.
3-(Naphthalen-1-yl)-N,2-diphenylacrylamide (3m). This was
purified by silica-gel column chromatography using ethyl acetate/
hexane (5:95) mixture as an eluent. White solid. Yield (68 mg, 43%).
MP 172−174 °C. IR (DCM): 3063, 3021, 2944, 2844, 1668, 1603,
1
1547, 1482, 1313, 895, 707 cm−1. H NMR (400 MHz, CDCl3): δ
8.50 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.79−7.67 (m, 1H), 7.59 (d, J
= 8.2 Hz, 1H), 7.49−7.36 (m, 5H), 7.26−7.19 (m, 6H), 7.19−7.12
(m, 2H), 7.08−6.97 (m, 2H), 6.84 (d, J = 7.2 Hz, 1H). 13C{1H}
NMR (101 MHz, CDCl3): δ 165.1, 137.8, 137.5, 136.6, 135.4, 133.3,
132.5, 132.2, 130.3, 129.3, 129.0, 128.6, 128.6, 127.7, 126.5, 126.0,
125.0, 124.6, 124.4, 119.9. HRMS (ESI) m/z calcd for C25H19NONa
(M+Na)+: 372.1359, found: 372.1366.
(E)-2-Methyl-N,3-diphenylacrylamide (3n). This was purified by
silica-gel column chromatography using ethyl acetate/hexane (10:90)
mixture as an eluent. Compound isolated was mixture of cis (minor)
and trans (major) isomers. White solid. Yield (28 mg, 24%). MP 97−
129.5, 128.6, 128.0, 127.6, 124.8, 121.7, 121.0, 120.1, 110.3, 54.8.
HRMS (ESI) m/z calcd for C16H16NO2 (M+H)+: 254.1176, found:
254.1189.
(E)-3-(4-Isopropylphenyl)-N-(2-methoxyphenyl) acrylamide (5b).
This was purified by silica-gel column chromatography using ethyl
acetate/hexane (15:85) mixture as an eluent. White solid. Yield (97
mg, 66%). MP 122−124 °C. IR (DCM): 3443, 3028, 2934, 1662,
1
1618, 1510, 1399, 983, 704 cm−1. H NMR (400 MHz, CDCl3): δ
8.47 (d, J = 7.2 Hz, 1H), 7.89 (s, 1H), 7.66 (d, J = 15.5 Hz, 1H), 7.43
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J. Org. Chem. 2021, 86, 9994−10005

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Article
(d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.96 (dtd, J1 = 25.3 Hz,
J2 = 7.7 Hz, J3 = 1.5 Hz, 2H), 6.83 (dd, J1 = 8.0, J2 = 1.3 Hz, 1H), 6.49
(d, J = 15.5 Hz, 1H), 3.85 (s, 3H), 2.87 (dt, J1 = 13.8 Hz, J2 = 6.9 Hz,
1H), 1.20 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ
163.9, 151.1, 147.8, 142.0, 132.4, 128.1, 127.9, 126.9, 123.7, 121.2,
120.3, 120.0, 109.9, 55.7, 34.0, 23.8. HRMS (ESI) m/z calcd for
C19H21NO2 (M)+: 296.1645, found: 296.1658.
Procedure for Mechanistic Studies. Reaction of Acetanilide
with Benzaldehyde without Catalyst 1. To a Schlenk flask (25 mL)
equipped with a stir bar, NaOtBu (1 equiv), acetanilide (0.5 mmol),
benzaldehyde (0.6 mmol), and tert-amyl alcohol (2 mL) were added
under nitrogen atmosphere in a glovebox. The reaction mixture was
taken out of the glovebox and heated at 135 °C for 24 h. The reaction
mixture was transferred to an RB flask. The solvent was removed
under reduced pressure; the reaction mixture was dissolved in
chloroform and washed with water and brine. The resultant residue
was purified by silica gel (100−200 mesh) column chromatography
using ethyl acetate/hexane mixture as eluent. Yield was calculated for
the isolated product.
Reaction of Acetanilide with Benzaldehyde with Catalyst 1. To a
Schlenk flask (25 mL) equipped with a stir bar, catalyst 1 (2 mol %),
NaOtBu (1 equiv), acetanilide (0.5 mmol), benzaldehyde (0.6 mmol),
and tert-amyl alcohol (2 mL) were added under nitrogen atmosphere
in a glovebox. The reaction mixture was taken out of the glovebox,
equipped with a condenser, and the solution heated at 135 °C (oil
bath temperature) with stirring in an open system under nitrogen flow
for 24 h. Further workup and isolation were carried out as per the
general procedure.
(Cu Kα) = 0.981 mm−1, 2θmax = 77.2200, ρcalcd = 1.389 g/cm3, T =
293(2) K, 9610 Reflections collected, 8986 unique, R1 = 0.0479, WR2
= 0.1422 (all data). The structure has been deposited at the CCDC
data center and can be retrieved using the deposit number CCDC
2038569.
Crystal Data of α-Alkenyl Amide Product 2n. C13H11NO2, white
solid, M = 213.23 g/mol, orthorhombic with space group P121/n1, a
= 10.6354(6) Å, b = 8.8279(6) Å, c = 24.4301(15) Å, α = 90°, β =
90°, γ = 90°, V = 2293.72 (2) Å3, Z = 8, F(000) = 898.78, μ-(Cu Kα)
= 0.683 mm−1, 2θmax = 77.2200, ρcalcd = 1.235 g/cm3, T = 100.00(12)
K, 1883 Reflections collected, 1484 unique, R1 = 0.0634, WR2
=
0.1654 (all data). The structure has been deposited at the CCDC data
center and can be retrieved using the deposit number CCDC
2038570.
Crystal Data of α-Alkenyl Amide Product 3l. C22H16F3NO, white
solid, M = 367.36 g/mol, orthorhombic with space group Pbca, a =
8.62490(1) Å, b = 17.4341(2) Å, c = 23.5971(3) Å, α = 90°, β = 90°,
γ = 90°, V = 3548.23 (7) Å3, Z = 8, F(000) = 1520, μ-(Cu Kα) =
0.776 mm−1, 2θmax = 79.4100, ρcalcd = 1.375 g/cm3, T = 100.00(12) K,
9610 Reflections collected, 15971 unique, R1 = 0.0477, WR2 = 0.1369
(all data). The structure has been deposited at the CCDC data center
and can be retrieved using the deposit number CCDC 2038571.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00685.
■
sı
Reaction of Acetanilide with Benzyl Alcohol-d3. To a Schlenk
flask (25 mL) charged with a magnetic stir bar, catalyst 1 (2 mol %),
NaOtBu (1 equiv), acetanilide (0.5 mmol), benzyl alcohol-d3 (0.6
mmol), and tert-amyl alcohol (2 mL) were added under nitrogen
atmosphere in a glovebox. The reaction mixture was taken out of the
glovebox, equipped with a condenser, and the solution heated at 135
°C (oil bath temperature) with stirring in an open system under
nitrogen flow for 24 h. Further workup and isolation were carried out
as per the general procedure.
Reaction of Acetanilide-d3 with Benzyl Alcohol. To a Schlenk
flask (25 mL) charged with a magnetic stir bar, catalyst 1 (2 mol %),
NaOtBu (1 equiv), acetanilide-d3 (0.5 mmol), benzyl alcohol (0.6
mmol), and toluene (2 mL) were added under nitrogen atmosphere
in a glovebox. Toluene was chosen as a solvent as the deuterated
acetanilide exhibited H/D exchange with tert-amyl alcohol. The reaction
mixture was taken out of the glovebox, equipped with a condenser,
and the solution heated at 135 °C (oil bath temperature) with stirring
in an open system under nitrogen flow for 24 h. Further workup and
isolation were carried out as per the general procedure.
Reaction of Acetanilide-d3 with Benzyl Alcohol-d3. To a Schlenk
flask (25 mL) charged with a magnetic stir bar, catalyst 1 (2 mol %),
NaOtBu (1 equiv), acetanilide-d3 (0.5 mmol), benzyl alcohol-d3 (0.6
mmol), and toluene (2 mL) were added under nitrogen atmosphere
in a glovebox. Toluene was chosen as a solvent as the deuterated
acetanilide exhibited H/D exchange with tert-amyl alcohol. The reaction
mixture was taken out of the glovebox, equipped with a condenser,
and the solution heated at 135 °C (oil bath temperature) with stirring
in an open system under nitrogen flow for 24 h. Further workup and
isolation were carried out as per the general procedure.
Experimental procedures, spectral data, and copies of 1H
and 13C NMR spectra of the products (PDF)
Accession Codes
CCDC 2038569−2038571 contain the supplementary crys-
tallographic 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.
AUTHOR INFORMATION
Corresponding Author
■
Chidambaram Gunanathan − School of Chemical Sciences,
National Institute of Science Education and Research, Homi
Bhabha National Institute, Bhubaneswar 752050, India;
orcid.org/0000-0002-9458-5198; Email: gunanathan@
niser.ac.in
Author
Biplab Keshari Pandia − School of Chemical Sciences,
National Institute of Science Education and Research, Homi
Bhabha National Institute, Bhubaneswar 752050, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00685
X-ray Analysis of α-Alkenyl Amide Products 2m, 2n, and 3l.
Crystals suited for single crystal X-ray diffraction measurements were
mounted on a glass fiber. Geometry and intensity data were collected
with a Rigaku Smartlab X-ray diffractometer equipped with graphite-
monochromated Cu Kα radiation (λ = 1.54184 Å, multilayer optics).
Intensities were integrated with SAINT+47 and corrected for
absorption with SADABS.48 The structures were solved by direct
methods and refined on F2 with SHELXL-9749 using Olex-250
software.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank SERB New Delhi (EMR/2016/002517), DAE and
NISER for financial support. B.K.P. thanks NISER for a
research fellowship.
Crystal Data of α-Alkenyl Amide Product 2m. C16H12F3NO,
white solid, M = 291.27 g/mol, orthorhombic with space group
P212121, a = 16.9998(3) Å, b = 10.00910(10) Å, c = 8.18750(10) Å, α
= 90°, β = 90°, γ = 90°, V = 1393.13 (3) Å3, Z = 4, F(000) = 600, μ-
DEDICATION
■
Dedicated to Prof. Christian Bruneau for his outstanding
contributions to catalysis.
10002
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Article
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