Palladium-Catalyzed Regioselective Hydroaminocarbonylation of Alkynes to α,β-Unsaturated Primary Amides with Ammonium Chloride

Article abstract of DOI:10.1021/acs.joc.8b01405

α,β-Unsaturated primary amides have found numerous applications in drug development, organic materials, and polymer sciences. However, the catalytic synthesis of α,β-unsaturated primary amides via carbonylation of alkynes has long been an elusive endeavor. Here, we report a novel palladium-catalyzed hydroaminocarbonylation of alkynes with NH₄Cl as the amine source, enabling the highly chemo- and regioselective synthesis of α,β-unsaturated primary amides. A variety of alkynes, including aromatic alkynes, aliphatic alkynes, terminal alkynes, internal alkynes, as well as diynes with various functional groups, react well. The method turns the parasitic noncoordination ability of ammonium salts into a strategic advantage, enabling the gram-scale reaction to be performed in the presence of 0.05 mol % of catalyst with excellent selectivity.

Full text of DOI:10.1021/acs.joc.8b01405

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Article
Palladium-Catalyzed Regioselective Hydroaminocarbonylation of
Alkynes to #, #-Unsaturated Primary Amides with Ammonium Chloride
Xiaolei Ji, Bao Gao, Xibing Zhou, Zongjian Liu, and Hanmin Huang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01405 • Publication Date (Web): 28 Jun 2018
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The Journal of Organic Chemistry
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Palladium-Catalyzed Regioselective Hydroaminocarbonylation of
Alkynes to α, β-Unsaturated Primary Amides with Ammonium Chlo-
ride
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Xiaolei Ji,† Bao Gao,‡ Xibing Zhou,‡ Zongjian Liu† and Hanmin Huang*,†, ‡
†College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, 310024, China.
‡Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in
Molecular Synthesis, University of Science and Technology of China, Chinese Academy of Sciences, Hefei, 230026, P. R.
China.
ABSTRACT: α,β-Unsaturated primary amides have
found numerous applications in drug development, or-
ganic materials and polymer sciences. However, the
catalytic synthesis of α,β-unsaturated primary amides
via carbonylation of alkynes has long been an elusive
endeavor. Here, we report a novel palladium-catalyzed
hydroaminocarbonylation of alkynes with NH4Cl as the
amine source, enabling highly chemo- and regioselective synthesis of α,β-unsaturated primary amides. A variety of alkynes includ-
ing aromatic alkynes, aliphatic alkynes, terminal alkynes, internal alkynes as well as diynes with various functional groups react
well. The method turns parasitic non-coordination ability of ammonium salts into a strategic advantage, enabling the gram-scale
reaction to be performed in the presence of 0.05 mol% of catalyst with excellent selectivity
tions have been reported for the synthesis of α,β-unsaturated
primary amides.7
INTRODUCTION
The amide has long been recognized as an important synthetic
Recently, our group has disclosed a palladium-catalyzed re-
target because it participates in a variety of useful transfor-
gioselective hydroaminocarbonylation reaction between al-
mations.1 In addition, it also exists in myriad of natural prod-
ucts, pharmaceuticals, and agrochemicals with interesting bio-
logical activity.2 As such, the development of efficient meth-
ods for manipulation of amidic C-N bond has been a persistent
research area of interest for decades. Compared to catalytic
reactions employing carboxylic acid derivatives in which the
carbonyl group is preinstalled, transition-metal catalyzed hy-
droaminocarbonylation reaction has attracted much interest
due to its high atom- and step-economy as well as its use of
cheap and abundant CO as a C1 feedstock.3 In spite of the
advantages of hydroaminocarbonylation reaction, early studies
in this field with Fe, Co, Ni, and Ru as catalysts required harsh
reaction conditions and resulted in poor chemoselectivity.4
This situation has been greatly changed since the palladium
catalysis system was established. In this context, the palladi-
um-catalyzed hydroaminocarbonylation reaction initiated by
palladium-hydride species has emerged as one of the most
promising methods toward amides.5-6 However, in sharp con-
trast to the synthesis of tertiary and secondary amides,7 the
synthesis of primary amides via hydroaminocarbonylation
reaction has received little attention, although the primary
amides are more valuable building blocks in the synthesis of
biologically active molecules and functional materials. α,β-
Unsaturated primary amides are attractive precursors, and
have been utilized as very useful building blocks in a number
of important reactions.8 However, to the best of our knowledge,
no transition-metal-catalyzed hydroaminocarbonylation reac-
kene and NH4Cl in NMP,5g which provides an efficient ap-
proach toward aliphatic primary amides. Mechanistic studies
Scheme 1. Hydroaminocarbonylation of Alkynes to Prima-
ry Amides with NH4Cl
showed that the reaction was initiated by a palladium-hydride
species generated in situ via oxidative addition of NH4Cl to
Pd(0) (Scheme 1). The acylpalladium species produced via the
hydrocarbonylative process was capable of capturing the NH2-
moiety directly from the ammonium salt in the presence of CO
under the assistance of NMP (Scheme 1a). The NMP not only
acts as solvent to dissolve NH4Cl, but also functions as a base
to capture the released HCl.5g Moreover, the parasitic non-
coordination ability of ammonium salts could enable the reac-
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was carried out at 120 oC for
Page 2 of 8
tion to be performed with higher turnover number (TON). On
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the basis of this result, we surmised that alkynes could also
react with palladium-hydride species and CO under appropri-
ate reaction conditions to give the acylpalladium species,
which should be capable of capturing the NH2-moiety from the
ammonium salt to give the desired acrylamides (Scheme 1b).
However, unlike the hydroaminocarbonylation of alkenes, the
realization of such a process is more challenging, since the
intramolecular hydroaminocarbonylation or hydroamination
reaction of the produced α,β-unsaturated primary amide may
take place to compete with the desired carbonylation reaction.
We believe that the competition would be controlled by tuning
the reaction condition and palladium catalyst. Herein, we de-
scribe the first palladium-catalyzed hydroaminocarbonylation
of alkynes with NH4Cl as amine source, which provides an
efficient access to various valuable α,β-unsaturated primary
amides in excellent yields with high regioselectivities. Notably,
the reaction could be performed smoothly with lower catalyst
loading, which enhanced the practice of the present reaction.
Pd(CH3CN)2Cl2/Xantphos as the catalytic system (Table 1,
entry 1). These results indicated that the desired hydroam-
inocarbonylation of alkyne involving palladium-hydride spe-
cies was indeed possible albeit in low reactivity and selectivity.
Subsequently, further experiments were carried out to test
various phosphine ligands with Pd(CH3CN)2Cl2 as the catalyst
precursor and the results demonstrated that the branched am-
ide 2a was favored to be obtained with good regioselectivity
with DPEPhos as a ligand. Other ligands, including DPPF,
DPPH (1,2-Bis(diphenylphosphino)hexane) and DPPPen (1,2-
Bis(diphenylphosphino)pentane) could also promote the reac-
tion, but with lower yield and selectivity (Table 1, entries 1-5).
We then turned our attention to investigate the palladium pre-
cursor with DPEPhos as the ligand and found that Pd(PPh3)4
was better in terms of reactivity and selectivity. Encouraged
by these results, we attempted to optimize the reaction condi-
tions by screening of the reaction time and temperature. It was
found that the yield could be increased to 75% when the reac-
tion time was prolonged to 9 h (Table1, entry 14). To our de-
light, almost the same yield of product 2a with higher regiose-
lectivity was achieved when the reaction temperature was de-
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RESULTS AND DISCUSSION
Table 1. Optimization of the Reaction Conditionsa
o
creased to 100 C (Table1, entry 15). Moreover, further de-
o
creasing the reaction temperature to 80 C resulted in higher
regioselectivity and almost the same yield was obtained when
the reaction time was prolonged to 24 h. However, further
o
decreasing the temperature to 50 C resulted in no reaction
(Table 1, entry 18). Lowering CO pressure would lead to a
decreasing yield, however, regioselectivity was not affected.
(Table 1, entry 19).
With the optimized reaction conditions established, we
turned our attention to validating the generality of our hy-
droaminocarbonylation protocol. In general, the mild reaction
conditions allow the use of a variety of alkynes containing
different functional groups. Moreover, both aromatic alkynes
and aliphatic alkynes are compatible with the reaction condi-
tions. A variety of phenylacetylenes bearing different substitu-
ents on the aryl ring were initially surveyed. As shown in Ta-
ble 2, the electronic properties of the substituents on the aro-
matic ring of the aromatic alkynes have a strong influence on
the reactivity and selectivity. The aryl alkynes with electron-
donating groups exhibited high reactivity and selectivity. For
instance, the reactions of aryl alkynes (1b-1e), containing me-
thyl, ethyl and methoxy groups on the aromatic ring, afforded
the corresponding amides in good to excellent yields with
excellent regioselectivities (2b-2e). In contrast, installing elec-
tron-withdrawing groups on the phenyl ring of the alkynes
leading to lower reactivities and selectivities (2f -2l). The
structures of 2e and 2f were confirmed by X-ray crystallo-
graphic analysis.9 A bromo group on the phenyl ring 2k also
survives during the reaction and provides a potential synthetic
handle for further coupling reactions. In addition, the corre-
sponding amide 2m was successfully generated from hy-
droaminocarbonylation of 2-ethynyl-naphthalene in good yield
with excellent regioselectivity. Moreover, under the slightly
modified reaction conditions, we were pleased to find that the
alkyne scope can be extended from aryl alkynes to aliphatic
alkyne, although the corresponding amide (2n) was obtained
in relative lower regioselectivity. To our surprise, linear am-
ides 3o and 3p was obtained in 86% and 94% yields, respec-
tively, when the steric hindrance 3,3-dimethyl-1-butyne 1o and
trimethylsilyl acetylene 1p were subjected to the reaction con-
ditions. The regioselectivities were completely changed, which
On the basis of our previous work, the palladium-catalyzed
hydroaminocarbonylation of phenylacetylene 1a with NH4Cl
as amine source was selected as a benchmark reaction. The
reaction was conducted in the presence of 20 atm of CO with
NMP as solvent. As shown in Table 1, the desired α,β-
unsaturated primary amides 2a and 3a were obtained in com-
bined 23% yield with 70:30 regioselectivity, when the reaction
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might be attributed to the steric hindrance of the tertiary-butyl
firmed that the hydroaminocarbonylation reaction took place
at only one position among the several active sites of diynes.9
To demonstrate the synthetic utility of the present new reac-
tion, the gram-scale reaction of trimethylsilyl acetylene 1p
was conducted under 0.05 mol% of palladium catalyst
(Scheme 2). Under the slightly modified reaction conditions,
the reaction underwent smoothly to give the desired product
3p in 95% yield with excellent regioselectivity. Notably, this
result represents a
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group and trimethylsilyl group located adjacent to the alkyne
moiety.5 The solid structure of 3p was unambiguously deter-
mined by single-crystal X-ray diffraction analysis which pro-
vided solid evidence to confirm the regioselectivity.9 The re-
mote ester functional group attached in the aliphatic alkyne 1q
was tolerated to give the corresponding amide 2q in 64% iso-
lated yield with relatively lower regioselectivity. The estrone
derivative bearing a steroid scaffold 1r was also compatible
with the reaction condition to afford the corresponding amide
2r in 63% yield with high regioselectivity. As expected, the
substrate scope can be extended from terminal alkynes to in-
ternal alkynes. For example, the reaction of diphenylethyne
underwent smoothly to provide product 2s in good yield. Oth-
er internal alkynes substituted with diphenylethyne, such as 1t
and 1u, were also successfully transferred to the desired α,β-
unsaturated primary amides with this protocol to produce am-
ide 2t and 2u in 74% and 62% isolated yields, respectively.
However, under these reaction conditions, no amide products
formed from heteroaromatic alkynes, and further investiga-
tions of these substrates are currently in progress.
Table 3. Substrate Scope of Diyne a
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Table 2. Substrate Scope of Alkynea
turnover number (TON) of 1900, which is among the highest
reported for palladium-catalyzed hydroaminocarbonylation
reactions.3 The trimethylsilyl group of 3p can be easily re-
moved to produce the acrylamide which is widely used in in-
dustry to synthesize polyacrylamide (PAM).10 To the best of
our knowledge, this is the first example for the synthesis of
acrylamide by using of hydroaminocarbonylation reaction.
Moreover, the versatile trimethylsilyl group contained in this
product provided an additional handle for further derivatiza-
tion.11
Scheme 2. Synthetic Application
Figure1. Plausible Reaction Mechanism
On the other hand, diynes 4 containing various electron-rich
or –deficient phenyl rings reacted smoothly with CO and
NH4Cl to give the desired amides in high yields (Table 3). The
reaction was amenable to a range of substituted 1,4-
diphenylbuta-1,3-diynes, giving the corresponding primary
amides 5a-5f in 74-92% yields and obtained products did not
further reacted with NH4Cl, which may be attributed to steric
hindrance effect. The obtained versatile carbon-carbon triple
bond and double bond provides a potential handle for later
elaboration. The X-ray crystallographic analysis of 5f con-
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On the basis of these results and our previous work on hy-
Page 4 of 8
fume hood. The regioselectivity was measured by GC and GC-
MS, respectively. Then the corresponding reaction mixture
was purified by flash column chromatography on silica gel
and eluted with petroleum ether/ethyl acetate (50/1 - 1/1) to
give the desired products 2.
droaminocarbonylation of alkenes under palladium catalysis,5g
we propose the following catalytic mechanism (Figure 1).
Initially, the in situ formed Pd(0) undergoes oxidative addition
with NH4Cl to furnish the active palladium hydride species.
Subsequent regioselective hydropalladation of alkyne sub-
strate affords alkenylpalladium intermediate A or B, which
may depend on the electronics of the substituent on the aro-
matic ring. CO insertion leads to the corresponding acyl palla-
dium species C or D, and the resultant acylpalladium species
C or D directly reacted with NH4Cl in the presence of CO to
generate the desired amides. The key palladium-hydride spe-
cies was simultaneously generated to enter the next catalytic
cycle and the released HCl was trapped by NMP solvent to
finish the catalytic cycle.
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General Procedure B. In a glove box, a mixture of NH4Cl
(80.3 mg, 1.5 mmol), Pd(PPh3)4 (57.8 mg, 0.05 mmol),
DPEPhos (32.3 mg, 0.06 mmol) and NMP (3.0 mL) was added
into a dry glass vessel. The resulting mixture was stirred for 10
minutes at room temperature and then alkynes (1.0 mmol) was
added into the reaction mixture. The glass vessel was put into
an autoclave and then taken out from the glove box. The auto-
clave was purged for three times and charged with CO (20
atm). The reaction mixture was stirred at 120 oC for 12 hours.
After the reaction finished, the autoclave was cooled to room
temperature and the pressure was carefully released in the
fume hood. The regioselectivity was measured by GC and GC-
MS, respectively. Then the corresponding reaction mixture
was purified by flash column chromatography on silica gel
and eluted with petroleum ether/ethyl acetate (50/1 - 1/1) to
give the desired products 2.
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In summary, we have successfully developed a practical
protocol for the synthesis of α,β-unsaturated primary amides
via palladium-catalyzed hydroaminocarbonylation of alkynes
with NH4Cl as amine source in the presence of CO. A variety
of α,β-unsaturated primary amides have been obtained in high
yields with good to excellent regioselectivities, which repre-
sents the first example of the direct conversion of NH4Cl to
α,β-unsaturated primary amides. The scaled-up reaction
demonstrated that the reaction could be conducted in 0.05 mol%
of palladium catalyst, which enhanced the synthetic value of
this transformation. The success of this reaction could also
provide more evidence for the mechanism we have proposed
before that the acylpalladium species generated in the catalytic
system could directly incorporate the amine-moiety from the
ammonium salts. In addition, the use of ammonium salts as
practical alternatives to gaseous ammonia in a variety of C-N
bond-forming manifolds is proved more and more promising.
General Procedure C. In a glove box, a mixture of NH4Cl
(80.3 mg, 1.5 mmol), Pd(PPh3)4 (57.8 mg, 0.05 mmol),
DPEPhos (32.3 mg, 0.06 mmol) and NMP (3.0 mL) was added
into a dry glass vessel. The resulting mixture was stirred for 10
minutes at room temperature and then alkynes (1.0 mmol) was
added into the reaction mixture. The glass vessel was put into
an autoclave and then taken out from the glove box. The auto-
clave was purged for three times and charged with CO (20
atm). The reaction mixture was stirred at 140 oC for 12 hours.
After the reaction finished, the autoclave was cooled to room
temperature and the pressure was carefully released in the
fume hood. Then the corresponding reaction mixture was puri-
fied by flash column chromatography on silica gel and eluted
with petroleum ether/ethyl acetate (50/1 - 1/1) to give the de-
sired products 5.
EXPERIMENTALSECTION
General Information. All non-aqueous reactions and
manipulations were using standard Schlenk techniques. All
solvents before use were dried and degassed by standard
methods and stored under nitrogen atmosphere. All reactions
were monitored by TLC with silica gel-coated plates. NMR
spectra were recorded on BRUKER Avence III 400 MHz
spectrometers. Chemical shifts were reported in parts per
million (ppm) down field from TMS with the solvent
resonance as the internal standard. Coupling constants (J) were
reported in Hz and refered to apparent peak multiplications.
High resolution mass spectra (HRMS) were recorded on
Bruker MicroTOF-QII mass (ESI). GC analysis were
performed on Agilent 7890B with Hp-5 column. GS-MS
analysis were performed with Agilent 7890B/5975B GC-MS
system. Aromatic alkynes (1a-1l, 1n-1p, 1s) purchased from
Alfa Aesar or Sigma Aldrich. Alkynes (1m, 1q, 1r, 1t-1u, 5a-
5f) were known compounds and synthesized according to the
reported methods.12
Spectroscopic Data of the Products:
2-phenylacrylamide (2a): The title compound was prepared
according to the general procedure and purified by column
chromatography to give a white solid, 105.8 mg, 72% yield.
1H NMR (400 MHz, CDCl3) δ 5.68 (d, J = 0.8 Hz, 2H), 5.97
(br, 1H), 6.21 (d, J = 0.8 Hz, 1H), 7.38-7.41 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 123.2, 128.2, 128.7, 128.8, 137.1,
144.3, 169.7; HRMS (ESI) calcd. for C9H9NONa [M+Na]:
170.0576, found: 170.0584.
cinnamamide (3a): The title compound was purified as
byproduct from several reactions together by column
1
chromatography to give a white solid. H NMR (400 MHz,
CDCl3) δ 5.72 (br, 1H), 5.88 (br, 1H), 6.46 (d, J = 15.6 Hz,
1H), 7.37-7.38 (m, 3H), 7.51-7.53 (m, 2H), 7.63 (d, J = 15.6
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 119.6, 128.1, 129.0,
130.1, 134.6, 142.7, 168.0; HRMS (ESI) calcd. for C9H10NO
[M+H]: 148.0757, found: 148.0749.
2-(p-tolyl)acrylamide (2b): The title compound was
prepared according to the general procedure and purified by
column chromatography to give a white solid, 144.2 mg, 90%
yield. 1H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 5.63 (d, J =
1.2 Hz, 1H), 5.72 (br, 1H), 6.14 (s, 1H), 6.25 (br, 1H), 7.18 (d,
J = 8.0 Hz, 2H); 7.28 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 21.3, 122.7, 128.2, 129.5, 134.3, 138.6, 144.1, 169.7;
HRMS (ESI) calcd. for C10H11NONa [M+Na]: 184.0733,
found: 184.0731.
General Procedure A. In a glove box, a mixture of NH4Cl
(80.3 mg, 1.5 mmol), Pd(PPh3)4 (57.8 mg, 0.05 mmol),
DPEPhos (32.3 mg, 0.06 mmol) and NMP (3.0 mL) was added
into a dry glass vessel. The resulting mixture was stirred for 10
minutes at room temperature and then alkynes 1 (1.0 mmol)
was added into the reaction mixture. The glass vessel was put
into an autoclave and then taken out from the glove box. The
autoclave was purged for three times and charged with CO (20
o
atm). The reaction mixture was stirred at 80 C for 24 hours.
After the reaction finished, the autoclave was cooled to room
temperature and the pressure was carefully released in the
2-(m-tolyl)acrylamide (2c): The title compound was
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prepared according to the general procedure and purified by
yield. 1H NMR (400 MHz, CDCl3) δ 5.48 (br, 1H), 5.63 (d, J =
1.2 Hz, 1H), 5.95 (br, 1H), 6.47 (d, J = 1.2 Hz, 1H), 7.31-7.36
(m, 3H), 7.43-7.45 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
126.8, 127.2, 129.9, 130.1, 131.3, 133.5, 136.5, 141.9, 167.7;
HRMS (ESI) calcd. for C9H8ClNONa [M+Na]: 204.0192,
found: 204.0188.
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column chromatography to give a white solid, 119.1 mg, 74%
yield. 1H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 5.64 (s, 1H),
5.73 (br, 1H), 6.17 (s, 1H), 6.42 (br, 1H), 7.16-7.20 (m, 3H);
7.25-7.29 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 21.5, 123.1,
125.3, 128.7, 128.9, 129.4, 137.1, 138.5, 144.3, 169.7; HRMS
(ESI) calcd. for C10H11NONa [M+Na]: 184.0733, found:
184.0734.
2-(4-bromophenyl)acrylamide (2k): The title compound was
prepared according to the general procedure and purified by
column chromatography to give a white solid, 140.8 mg, 62%
2-(4-ethylphenyl)acrylamide (2d): The title compound was
prepared according to the general procedure and purified by
column chromatography to give a white solid, 143.3 mg, 82%
1
yield. H NMR (400 MHz, CDCl3) δ 5.68 (s, 1H), 5.79 (br,
9
1H), 6.11 (s, 1H), 6.62 (br, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.50
(d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 122.9,
129.8, 131.9, 135.8, 143.4, 169.5; HRMS (ESI) calcd. for
C9H9BrNO [M+H]: 225.9862, found: 225.986.
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yield. H NMR (400 MHz, CDCl3) δ 1.23 (t, J = 7.6 Hz, 3H),
2.63 (q, J = 7.6 Hz, 2H), 5.63 (s, 1H), 5.76 (br, 1H), 6.13 (s,
1H), 6.55 (br, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 15.5, 28.6, 122.3,
128.1, 128.2, 134.4, 144.2, 144.8, 170.2; HRMS (ESI) calcd.
for C11H13NONa [M+Na]: 198.0889, found: 198.0890.
2-(4-methoxyphenyl)acrylamide (2e): The title compound
was prepared according to the general procedure and purified
by column chromatography to give a white solid, 164.6 mg, 92%
yield. 1H NMR (400 MHz, CDCl3) δ 3.83 (s, 3H), 5.61 (d, J =
0.8 Hz, 1H), 5.71 (br, 1H), 5.89 (br, 1H), 6.10 (d, J = 1.2 Hz,
1H), 6.90 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 55.5, 114.2, 121.8, 129.5, 143.8,
160.0, 169.9, HRMS (ESI) calcd. for C10H11NO2Na [M+Na]:
200.0682, found: 200.0674.
2-(4-(trifluoromethyl)phenyl)acrylamide (2l): The title
compound was prepared according to the general procedure
and purified by column chromatography to give a white solid,
1
98.9 mg, 46% yield. H NMR (400 MHz, CDCl3) δ 5.71-5.77
(m, 2H), 6.21 (s, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 122.7, 124.1, 125.4,
125.7, 125.8, 125.8, 125.8, 128.6, 128.7, 130.6, 131.0, 132.2,
132.3, 140.5, 143.4, 168.9; 19F NMR (376 MHz, CDCl3) δ -
62.7; HRMS (ESI) calcd. for C10H9F3NO [M+H]: 216.0631,
found: 216.0629.
2-(naphthalen-2-yl)acrylamide (2m): The title compound
was prepared according to the general procedure and purified
by column chromatography to give a white solid, 103.7 mg, 52%
2-(4-fluorophenyl)acrylamide (2f): The title compound was
prepared according to the general procedure and purified by
column chromatography to give a white solid, 84 mg, 51%
1
yield. H NMR (400 MHz, CDCl3) δ 5.72-5.80 (m, 3H), 6.28
(d, J = 0.8 Hz, 1H), 7.50-7.53 (m, 3H), 7.84-7.89 (m, 4H); 13
C
1
yield. H NMR (400 MHz, CDCl3) δ 5.66 (s, 1H), 5.72 (br,
NMR (100 MHz, CDCl3) δ 123.7, 125.8, 126.8, 126.8, 127.6,
127.8, 128.3, 128.6, 133.2, 133.3, 134.5, 144.2, 169.3; HRMS
(ESI) calcd. for C13H11NONa [M+Na]: 220.0733, found:
220.0733.
1H), 6.14 (s, 1H), 6.32 (br, 1H), 7.06-7.10 (m, 2H), 7.37-7.41
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 115.7, 115.9, 123.0,
130.0, 130.1, 133.0, 133.0, 143.3, 161.8, 164.3, 169.7; 19F
NMR (376 MHz, CDCl3) δ -112.8; HRMS (ESI) calcd. for
C9H9FNO [M+H]: 166.0663, found: 166.0662.
2-methylenehexanamide (2n): The title compound was
prepared according to the general procedure and purified by
column chromatography to give a white solid, 91.2 mg, 72%
2-(3-fluorophenyl)acrylamide (2g): The title compound was
prepared according to the general procedure and purified by
column chromatography to give a white solid, 103.3 mg, 62%
1
yield. H NMR (400 MHz, CDCl3) δ 0.90 (t, J = 7.2 Hz, 3H),
1.33-1.50 (m, 4H), 2.29-2.33 (t, J = 7.2 Hz, 2H), 5.35 (s, 1H),
5.70 (s, 1H), 5.89 (br, 2H); 13C NMR (100 MHz, CDCl3) δ
14.0, 22.4, 30.3, 32.0, 118.8, 144.7, 171.1; HRMS (ESI) calcd.
for C7H13NONa [M+Na]: 150.0889, found: 150.0889.
(E)-4,4-dimethylpent-2-enamide (3o): The title compound
was prepared according to the general procedure and purified
by column chromatography to give a white solid, 109.3 mg, 83%
yield. 1H NMR (400 MHz, CDCl3) δ 1.07 (s, 9H), 5.72 (d, J =
15.6 Hz, 2H), 6.15 (br, 1H), 6.84 (d, J = 15.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 28.8, 33.6, 118.1, 156.2, 169.0;
HRMS (ESI) calcd. for C7H14NO [M+H]: 128.107, found:
128.1068.
1
yield. H NMR (400 MHz, CDCl3) δ 5.71 (s, 1H), 5.78 (br,
1H), 6.16 (s, 1H), 6.57 (br, 1H), 7.04-7.21 (m, 3H), 7.33-7.38
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 115.2, 115.4, 115.6,
115.8, 123.7, 123.9, 123.9, 130.4, 130.4, 139.0, 139.1, 143.3,
161.6, 164.0, 169.3; 19F NMR (376 MHz, CDCl3) δ -112.3;
HRMS (ESI) calcd. for C9H9FNO [M+H]: 166.0663, found:
166.0669.
2-(4-chlorophenyl)acrylamide (2h): The title compound
was prepared according to the general procedure and purified
by column chromatography to give a white solid, 97.7 mg, 54%
yield. 1H NMR (400 MHz, CDCl3) δ 5.69 (s, 2H), 6.14 (s, 2H),
7.36 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 123.2, 129.0,
129.6, 134.8, 135.4, 143.3, 169.2; HRMS (ESI) calcd. for
C9H9ClNO [M+H]: 182.0367, found: 182.0367.
(E)-3-(trimethylsilyl)acrylamide (3p): The title compound
was prepared according to the general procedure and purified
by column chromatography to give a white solid, 128.0 mg, 90%
1
2-(3-chlorophenyl)acrylamide (2j): The title compound was
prepared according to the general procedure and purified by
column chromatography to give a white solid, 115.2 mg, 63%
yield. H NMR (400 MHz, CDCl3) δ 0.06 (s, 9H), 5.87 (br,
1H), 6.17 (d, J = 18.8 Hz, 1H), 6.40 (br, 1H), 6.99 (d, J = 18.8
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ -1.7, 135.9, 145.7,
167.9; HRMS (ESI) calcd. for C6H14NOSi [M+H]: 144.0839,
found: 144.0838.
4-carbamoylpent-4-en-1-yl benzoate (2q): The title
compound was prepared according to the general procedure
and purified by column chromatography to give a white solid,
149.3 mg, 64% yield. 1H NMR (400 MHz, CDCl3) δ 1.94-2.01
(m, 2H), 2.48 (t, J = 7.6 Hz, 2H), 4.34 (t, J = 6.4 Hz, 2H), 5.42
(s, 1H), 5.73 (s, 1H), 6.03 (br, 2H), 7.42-7.46 (m, 2H), 7.54-
1
yield. H NMR (400 MHz, CDCl3) δ 5.70-5.78 (m, 2H), 6.15
(s, 1H), 6.55 (br, 1H), 7.27-7.36 (m, 3H), 7.41 (d, J = 0.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 123.8, 126.4, 128.3,
128.8, 130.1, 134.7, 138.8, 143.2, 169.0; HRMS (ESI) calcd.
for C9H9ClNO [M+H]: 182.0367, found: 182.0363.
2-(2-chlorophenyl)acrylamide (2j): The title compound was
prepared according to the general procedure and purified by
column chromatography to give a white solid, 106.8 mg, 59%
ACS Paragon Plus Environment

The Journal of Organic Chemistry
7.58 (m, 1H), 8.03-8.05 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 27.1, 28.8, 64.1, 119.3, 128.4, 129.5, 130.2, 132.9, 143.4,
166.6, 170.7; HRMS (ESI) calcd. for C13H16NO3 [M+H]:
234.1130, found: 234.1125.
Page 6 of 8
129.5 130.5, 131.4, 132.0, 139.6, 141.0, 143.6, 166.6; HRMS
(ESI) calcd. for C19H18NO [M+H]: 276.1383, found: 276.1371.
(E)-2-(3-methylbenzylidene)-4-(m-tolyl)but-3-ynamide (5c):
The title compound was prepared according to the general
procedure and purified by column chromatography to give a
white solid, 253.2 mg, 92% yield. 1H NMR (400 MHz, CDCl3)
δ 2.36 (s, 3H), 2.38 (s, 3H), 6.79-6.81 (m, 2H), 7.19-7.35 (m,
6H), 7.81 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 8.00 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 21.3, 21.5, 85.4, 99.6, 113.5, 122.2,
127.7, 128.5, 128.6, 130.1, 131.0, 131.3, 132.0, 134.6, 138.1,
138.5, 143.9, 166.6; HRMS (ESI) calcd. for C19H18NO [M+H]:
276.1383, found: 276.1371.
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4
5
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7
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22-((8R,9S,13S,14S)-13-methyl-17-oxo-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-
cyclopenta[a]phenanthren-3-yl)acrylamide (2r): The title
compound was prepared according to the general procedure
and purified by column chromatography to give a yellow solid,
1
203.4 mg, 63% yield. H NMR (400 MHz, CDCl3) δ 0.92 (s,
9
3H), 1.43-1.67 (m, 6H), 1.96-2.18 (m, 4H), 2.31-2.32 (m, 1H),
2.42-2.55 (m, 2H), 2.92-2.95 (m, 2H), 5.65 (s, 1H), 5.72 (br,
1H), 6.15 (s, 2H), 7.14 (s, 1H), 7.18 (d, J = 8 Hz, 1H), 7.27-
7.32 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 13.9, 21.7, 25.8,
26.5, 29.5, 31.7, 35.9, 38.2, 44.5, 48.1, 50.6, 122.7, 125.6,
125.8, 128.8, 134.7, 137.1, 140.5, 169.7, 220.9; HRMS (ESI)
calcd. for C21H26NO2 [M+H]: 324.1964, found: 324.1956.
(E)-2,3-diphenylacrylamide (2s): The title compound was
prepared according to the general procedure and purified by
column chromatography to give a white solid, 142.1 mg, 64%
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15
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17
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19
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23
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(E)-2-(4-fluorobenzylidene)-4-(4-fluorophenyl)but-3-
ynamide (5d): The title compound was prepared according to
the general procedure and purified by column chromatography
1
to give a white solid, 240.3 mg, 85% yield. H NMR (400
MHz, DMSO-d6) δ 7.33-7.42 (m, 4H), 7.60 (br, 1H), 7.69 (br,
1H), 7.79-7.82 (m, 2H), 7.88 (s, 1H), 8.15-8.18 (m, 2H); 13C
NMR (100 MHz, DMSO-d6) δ 85.2, 97.9, 115.0, 115.7, 115.9,
115.9, 116.1, 118.4, 118.4, 131.1, 131.1, 132.1, 132.1, 134.0,
134.1, 140.6, 161.1, 161.5, 163.6, 164.0, 164.7; 19F NMR (376
MHz, DMSO-d6) δ -109.7, -109.4; HRMS (ESI) calcd. for
C17H12F2NO [M+H]: 284.0881, found: 284.0884.
1
yield. H NMR (400 MHz, CDCl3) δ 5.49 (br, 1H), 6.42 (br,
1H), 7.0 (d, J = 7.2 Hz, 2H), 7.12-7.20 (m, 3H), 7.27-7.30 (m,
2H), 7.40-7.45 (m, 3H), 7.86 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 128.3, 128.6, 128.9, 129.7, 129.8, 130.6, 133.8,
134.8, 136.5, 138.1, 169.4; HRMS (ESI) calcd. for C15H14NO
[M+H]: 224.1070, found: 224.1066.
(E)-2-(3-fluorobenzylidene)-4-(3-fluorophenyl)but-3-
ynamide (5e): The title compound was prepared according to
the general procedure and purified by column chromatography
1
(E)-2,3-bis(4-methoxyphenyl)acrylamide (2t): The title
compound was prepared according to the general procedure
and purified by column chromatography to give a white solid,
to give a white solid, 251.0 mg, 89% yield. H NMR (400
MHz, CDCl3) δ 6.24 (br, 1H), 6.70 (br, 1H), 7.10-7.16 (m, 2H),
7.22-7.23 (m, 1H), 7.24-7.43 (m, 3H), 7.64 (d, J = 7.6 Hz, 1H),
7.87-7.90 (m, 1H), 8.02 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ 85.8, 98.7, 98.8, 114.6, 116.1, 116.3, 116.9, 117.1, 117.5,
117.7, 118.2, 118.5, 123.6, 123.7, 126.8, 126.8, 127.5, 127.5,
130.2, 130.3, 130.5, 130.6, 136.5, 136.6, 143.2, 143.3, 161.3,
161.5, 163.8, 164.0, 165.5; 19F NMR (376 MHz, CDCl3) δ -
112.3, -111.8; HRMS (ESI) calcd. for C17H11F2NONa [M+Na]:
306.0701, found: 306.0691.
1
209.0 mg, 74% yield. H NMR (400 MHz, CDCl3) δ 3.75 (s,
3H), 3.87 (s, 3H), 5.48 (br, 1H), 5.99 (br, 1H), 6.68 (d, J = 8.8
Hz, 2H), 6.97-7.00 (m, 4H), 7.19 (d, J = 8.4 Hz, 2H), 7.79 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 55.2, 55.3, 113.7, 115.1,
127.5, 128.7, 130.9, 131.0, 132.1, 137.7, 159.6, 160.0, 169.9;
HRMS (ESI) calcd. for C17H17NO3Na [M+Na]: 306.1101,
found: 306.1089.
(E)-2,3-bis(4-fluorophenyl)acrylamide (2u): The title
compound was prepared according to the general procedure
and purified by column chromatography to give a white solid,
(E)-2-(2-fluorobenzylidene)-4-(2-fluorophenyl)but-3-
ynamide (5f): The title compound was prepared according to
the general procedure and purified by column chromatography
1
1
160.6 mg, 62% yield. H NMR (400 MHz, CDCl3) δ 5.44 (br,
to give a white solid, 209.2 mg, 74% yield. H NMR (400
1H), 6.30 (br, 1H), 6.84-6.88 (m, 2H), 6.96-6.70 (m, 2H),
7.14-7.19 (m, 2H), 7.25-7.28 (m, 2H), 7.82 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 115.4, 115.6, 116.9, 117.1, 130.8, 130.8,
131.7, 131.7, 132.0, 132.1, 132.3, 132.4, 132.6, 137.4, 161.6,
161.6, 164.1, 169.3; 19F NMR (376 MHz, CDCl3) δ -112.1, -
110.9; HRMS (ESI) calcd. for C15H11F2NONa [M+Na]:
282.0701, found: 282.0691.
MHz, CDCl3) δ 5.88 (br, 1H), 6.83 (br, 1H), 7.11-7.23 (m, 4H),
7.37-7.44 (m, 2H), 7.46-7.50 (m, 1H), 8.34 (s, 1H), 8.56-8.60
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 90.4, 93.3, 110.9,
114.8, 115.6, 115.7, 115.8, 115.9, 122.6, 122.7, 123.9, 124.0,
124.4, 124.4, 129.2, 131.1, 131.2, 132.2, 132.3, 132.8, 135.6,
135.6, 160.2, 161.7, 162.7, 164.2, 165.0; 19F NMR (376 MHz,
CDCl3)
δ
-113.3, -109.6; HRMS (ESI) calcd. for
(E)-2-benzylidene-4-phenylbut-3-ynamide (5a): The title
compound was prepared according to the general procedure
and purified by column chromatography to give a white solid,
C17H11F2NONa [M+Na]: 306.0701, found: 306.0689.
Gram-scale reaction:
In the glove box, a mixture of trimethylsilyl acetylene 1p
(2.5 g, 25 mmol), NH4Cl (2 g, 37.5 mmol), Pd(PPh3)4 (14.5
mg, 0.0125 mmol, 0.05 mol%) with DPEPhos (8.0 mg, 0.015
mmol, 0.06 mol%), NMP (20 mL) were added to a 100 mL
round bottom flask. The round bottom flask was put into an
autoclave and then the autoclave was taken out from glove box.
The autoclave was purged for three times and charged with
CO (20 atm). The reaction mixture was stirred at 120 oC for 72
hours. After the reaction finished, the autoclave was cooled to
room temperature and the pressure was carefully released in
the fume hood. The regioselectivity were measured by GC and
GC-MS, respectively. Then the corresponding reaction
mixture was purified by flash column chromatography on
silica gel and eluted with petroleum ether/ethyl acetate (20/1 -
1
222.5 mg, 90% yield. H NMR (400 MHz, CDCl3) δ 6.18 (br,
1H), 6.77 (br, 1H), 7.39-7.46 (m, 6H), 7.53-7.55 (m, 2H),
8.03-8.06 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 85.5, 99.4,
113.6, 122.3, 128.7, 128.8, 129.4, 130.5, 130.6, 131.6, 134.7,
144.1, 166.2; HRMS (ESI) calcd. for C17H13NONa [M+Na]:
270.0889, found: 270.0888.
(E)-2-(4-methylbenzylidene)-4-(p-tolyl)but-3-ynamide (5b):
The title compound was prepared according to the general
procedure and purified by column chromatography to give a
white solid, 242.1 mg, 88% yield. 1H NMR (400 MHz, CDCl3)
δ 2.39 (s, 6H), 6.26 (br, 1H), 6.77 (br, 1H), 7.19-7.25 (m, 4H),
7.41 (d, J = 8.4 Hz, 2H), 7.94-7.99 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 21.7, 21.7, 85.2, 99.6, 112.7, 119.4, 129.4,
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The Journal of Organic Chemistry
Divito, E. B.; Cascio, M. Metabolism, Physiology, and Analyses of
1/1) to give the desired products 3p (3.4 g, 95% yield, L:B =
Primary Fatty Acid Amides. Chem. Rev. 2013, 113, 7343-7353. (g)
Noda, H.; Erős, G.; Bode, J. W. Rapid Ligations with Equimolar
Reactants in Water with the Potassium Acyltrifluoroborate (KAT)
Amide Formation. J. Am. Chem. Soc. 2014, 136, 5611–5614.
(3) For recent reviews on the synthesis of amides via carbonylation,
see: (a) Wu, X.-F.; Neumann, H.; Beller, M. Palladium-Catalyzed
Carbonylative Coupling Reactions Between Ar–X and Carbon
Nucleophiles. Chem. Soc. Rev. 2011, 40, 4986-5009; (b) Wu, X.-F.;
Neumann, H.; Beller, M. Synthesis of Heterocycles via Palladium-
Catalyzed Carbonylations. Chem. Rev. 2013, 113, 1-35; (c) Wu, X.-F.;
Fang, X.; Wu, L.; Jackstell, R.; Neumann, H.; Beller, M. Transition-
Metal-Catalyzed Carbonylation Reactions of Olefins and Alkynes: A
Personal Account. Acc. Chem. Res. 2014, 47, 1041-1053.
(4) (a) Natta, G.; Pino, P.; Ercoli, R. Hydrogen Transfer Reactions
Accompanying the Cobalt-Catalyzed Addition of Carbon Monoxide
to Olefinic Compounds. J. Am. Chem. Soc. 1952, 74, 4496-4498. (b)
Kealy, T. J.; Benson, R. E. Chemistry of Allene. IV. Carbonylation
Reactions of Allene. J. Org. Chem. 1961, 26, 3126-3130. (c) Striegler,
A.; Weber, J. Über die durch Metallcarbonylverbindungen
katalysierte Umsetzung von Olefinen mit Kohlenoxyd und Ammoniak
bzw. Aminen in Gegenwart von Wasserstoff. J. Prakt. Chem. 1965,
29, 281-295. (d) Tsuji, Y.; Ohsumi, T.; Kondo, T.; Watanabe, Y.
Dodecacarbonyltriruthenium Catalysed Carbonylation of Amines and
Hydroamidation of Olefins. J. Organomet. Chem. 1986, 309, 333-344.
(e) Lee, S. I.; Son, S. U.; Chung, Y. K. Catalytic One-Pot Synthesis of
N-Phenyl Alkyl Amides from Alkene and Aniline in the Presence of
Cobalt on Charcoal Under Carbon Monoxide. Chem. Commun. 2002,
1310-1311.
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99:1).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.xxxxxx.
Experimental procedures, crystallographic details and cop-
ies of NMR and mass spectra (PDF)
9
Crystallographic data for 2e (CCDC 1843492) (CIF)
Crystallographic data for 2f (CCDC 1843493) (CIF)
Crystallographic data for 3p (CCDC 1843495) (CIF)
Crystallographic data for 5f (CCDC 1843497) (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail: hanmin@ustc.edu.cn
Notes
X. Ji and B. Gao contribute equally to this work.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(5) (a) Zhang, G.; Gao, B.; Huang, H. Palladium-Catalyzed
Hydroaminocarbonylation of Alkenes with Amines: A Strategy to
Overcome the Basicity Barrier Imparted by Aliphatic Amines. Angew.
Chem. Int. Ed. 2015, 54, 7657-7661. (b) Zhang, G.; Ji, X.; Yu, H.;
This research was supported by the National Natural Science
Foundation of China (21790333, 21702197 and 21672199), CAS
Interdisciplinary Innovation Team, the Fundamental Research
Funds for the Central Universities and the Anhui Provincial
Natural Science Foundation (1708085MB28).
Yang,
L.;
Jiao,
P.;
Huang,
H.
Palladium-Catalyzed
Hydroaminocarbonylation of Alkenes with Amines Promoted by
Weak Acid. Tetrahedron Lett. 2016, 57, 383-386. (c) Hu, Y.; Shen, Z.;
Huang,
H.
Palladium-Catalyzed
Intramolecular
Hydroaminocarbonylation to Lactams: Additive-Free Protocol
Initiated by Palladium Hydride. ACS Catal. 2016, 6, 6785-6789. (d)
Hu, Y.; Huang, H. Highly Selective Construction of Medium-Sized
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