Hydroaminocarbonylation of Alkynes to Produce Primary α,β-Unsaturated Amides Using NH4HCO3 Dually as Ammonia Surrogate and Br?nsted Acid Additive

Article abstract of DOI:10.1002/cctc.201800791

By using NH₄HCO₃ dually as ammonia surrogate and Br?nsted acid additive, the production of primary α,β-unsaturated amides via hydroaminocarbonylation of alkynes was accomplished efficiently. The advantages of using the solid and inexpensive NH₄HCO₃ included: (1) the facile and clean manipulation without presence of stinky gaseous NH₃ or liquids organic amines, (2) the inhibition of the subsequent dehydration and hydrolysis of amides due to its weak basicity, and (3) the facilitated formation of Pd?H catalytic active species by the released H₂CO₃ serving as a weak Br?nsted acid additive. In addition, the diphopshine of Dppp with the natural bite angle (β_n) of 91° was found indispensable to spur the performance of the palladium catalyst for this reaction. Both terminal and internal phenylacetylene derivatives could be used as the substrates, affording the corresponding primary α,β-unsaturated amides in good yields along with excellent regio-selectivities to the branched ones.

Full text of DOI:10.1002/cctc.201800791

Accepted Article
Title: Hydroaminocarbonylation of alkynes to produce primary ꢀ,
ꢀ-unsaturated amides using NH4HCO3 dually as ammonia
surrogate and Brønsted acid additive
Authors: Dong-Liang Wang, Wen-Di Guo, Qing Zhou, Lei Liu, Yong Lu,
and Ye Liu
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To be cited as: ChemCatChem 10.1002/cctc.201800791
Link to VoR: http://dx.doi.org/10.1002/cctc.201800791
A Journal of
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10.1002/cctc.201800791
ChemCatChem
COMMUNICATION
Hydroaminocarbonylation of alkynes to produce primary ,-
unsaturated amides using NH4HCO3 dually as ammonia surrogate
and Brønsted acid additive
Dong-Liang Wang, Wen-Di Guo, Qing Zhou, Lei Liu, Yong Lu, Ye Liu*
Abstract: By using NH4HCO3 dually as ammonia surrogate and
Brønsted acid additive, the production of primary α,β-unsaturated
amides via hydroaminocarbonylation of alkynes was accomplished
efficiently. The advantages of using the solid and inexpensive
NH4HCO3 included: (1) the facile and clean manipulation without
presence of stinky gaseous NH3 or liquids organic amines, (2) the
inhibition of the subsequent dehydration and hydrolysis of amides
due to its weak basicity, and (3) the facilitated formation of Pd-H
catalytic active species by the released H2CO3 serving as a weak
Brønsted acid additive. In addition, the diphopshine of Dppp with the
natural bite angle (βn) of 91° was found indispensable to spur the
performance of the palladium catalyst for this reaction. Both terminal
and internal phenylacetylene derivatives could be used as the
substrates, affording the corresponding primary α,β-unsaturated
amides in good yields along with excellent regio-selectivities to the
branched ones.
elaborately, both linear and branched α,β-unsaturated amides
[6e]
could be selectively produced in good to excellent yields
.
Notably, the auxiliary acid additives such as p-TsOH (p-
toluenesulfonic acid) were universally involved to improve the
catalytic performance of the Pd-catalysts in the reported
examples [6c-e,6h,6k]. However, compared to the synthesis of
secondary and tertiary α,β-unsaturated amides, the preparation
of
primary
α,β-unsaturated
amides
through
hydroaminocarbonylation of alkynes has not been achieved up
to date.
As a more abundant and cheaper nitrogen-source compared
to the other organic amines, ammonia (NH3) has been widely
used to generate various N-containing compounds in organic
synthesis [7]. However, NH3 has been far less frequently used in
transition metal catalysis due to its propensity to generate
unreactive Lewis acid-base adducts with the transition metal
centers [7d]. An elegant alternative to gaseous or liquid ammonia
could be the employment of an easy-to-handle ammonium salt [8]
Very recently, Huang and co-workers developed an elegant
palladium-catalyzed hydroaminocarbonylation of alkenes with
solid NH4Cl to synthesize the primary amides (Scheme 1, eq 1)
.
Introduction
Pd-catalyzed one-step carbonylation of alkynes/alkenes in the
presence of NH3 or primary/secondary amine as a nucleophile,
which is defined as hydroaminocarbonylation, represents an
[9]
.
attractive approach for the production of high value-added α,β-
[1]
unsaturated amides in linear and branched forms
.
Hydroaminocarbonylation plays an indispensable role in
synthesizing amides which are difficult to prepare via
a
conventional carboxylic acidcarboxylic halidecarboxamide
route (e.g. with NH3 or bulky substituted amines as the nitrogen
sources) from easily available starting materials [2]. Although a
[3]
number of methods are known for their direct preparations
,
hydroaminocarbonylation of alkynes with NH3/organic amines
provides the most efficient and 100% atom-economic protocol to
allow for the synthesis of α,β-unsaturated amides, which are the
building blocks for various materials ranging from polymers,
flavors, and pharmaceuticals [4]. For example, cinnamamide
Scheme 1. Overview of the synthetic approaches for the amides via
aminocarbonylation
derivatives can be used as the protective agents of the brain
[5]
nerve and have remarkable effect on the treatment of stroke
.
Based on our continuous interest in utilizing the solid
ammonia source such as NH4HCO3 to synthesize the primary
amides (Scheme 1, eq 2) [10], herein we reported the first Pd-
catalyzed hydroaminocarbonylation of alkynes by using
NH4HCO3 as the ammonia surrogate for the preparation of
primary α,β-unsaturated amides. The advantages of using the
solid and inexpensive NH4HCO3 included: (1) the clean and
easy-to-handle manipulation without presence of stinky gaseous
NH3 or liquids organic amines, (2) the inhibition of the
subsequent dehydration and hydrolysis of amides due to its
weak basicity, and (3) the facilitated formation of Pd-H catalytic
active species by the released H2CO3 without the addition of any
The versatile hydroaminocarbonylation of alkynes by reacting
the organic (primary/secondary) amine to the secondary and
tertiary α,β-unsaturated amides have been documented in
literature with high chemo- and regioselectivity [6]. In Alper and
co-workers’ work, by selecting the ligands and additives
Shanghai Key Laboratory of Green Chemistry and Chemical Processes
School of Chemistry & Molecular Engineering
East China Normal University
3663 North Zhongshan Road, 200062 Shanghai (P.R. China)
Corresponding author: Ye Liu. E-mail: yliu@chem.ecnu.edu.cn
1
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10.1002/cctc.201800791
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COMMUNICATION
auxiliary acid additive. Meanwhile the phosphine was screened
to warrant the success of this reaction since the presence of a
phosphine is prerequisite for the transition metal complex
catalyst to activate small molecules such as CO in
carbonylations.
the dehydration and hydrolysis of the amides was not observed
at all due to the weak alkaline reaction environmental. The
moderate yields were also obtained over Dppe (βn = 86 ) or
o
Dppd (βn = 94 o) with the similar natural bite angle to Dppp
(Entries 3 and 5 vs 4). The further increase (Entries 6-8) or
decrease (Entry 2) of the bite angle neither led to the successful
transformation towards the corresponding α,β-unsaturated
amides. A slight increase of activity and regio-selectivity to the
branched amide was obtained when Pd(OAc)2 was used as the
palladium precursor instead of PdCl2(CH3CN)2 or Pd2(dba)3
(Entry 10 vs 4 and 9). Notably, the thermodynamic favored
branched 2-phenylacrylamide was predominantly generated due
Results and Discussion
The hydroaminocarbonylation of phenylacetylene with NH4HCO3
was initially investigated as a model reaction in the presence of
a catalytic amount of PdCl2(CH3CN)2, ligand, and p-TsOH under
1.0 MPa of CO in acetonitrile at 120oC (Table 1). Since the
auxiliary acid of p-TsOH has been universally involved in Pd-
catalyzed hydroaminocarbonylation [6c-e,6h,6k], it was also added
to find the optimal conditions herein (Entries 1-10). It was found
that the catalytic performance of Pd-catalyst was sensitive to the
natural bite angles of the applied diphosphines [11]. The best
result was obtained by using Dppp with a natural bite angle of
91⁰, resulting in 81% yield of the primary amides with B/L ratio of
97/3 (Entry 4). The formation of any by-products derived from
to the formation of a stabilized benzylic Pd-species induce by 3-
[12,13]
electron donation from the phenyl ring
as well as the
developed hydrogen-bond between hydrogen in phenyl and O in
carbonyl group to form a stable six-member ring (The single
crystal structure analysis of 2-phenylacrylamide was provided in
S. Fig. 1 and S. Table 1 of ESI).
Table 1. Optimization of the reaction conditions for Pd-catalyzed hydroaminocarbonylation of phenylacetylene [a]
.
Entry
Ligand
Natural bite angle [b] Pd-precursor
Additive
T (h)
Conv.
(%) [c]
Sel. to amides
(%) [c]
B:L [d]
(βn, o)
1
PPh3
--
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
Pd2(dba)3
p-TsOH
2
2
2
2
2
2
2
2
2
2
2
5
5
0
--
--
2
Dppm
Dppe
73
86
91
94
99
108
p-TsOH
0
--
--
3
p-TsOH
65
81
53
trace
0
100
100
100
--
93:7
93:7
90:10
--
4
Dppp
p-TsOH
5
Dppb
p-TsOH
6
Dppf
p-TsOH
7
Xantphos
p-TsOH
--
--
8
Nixantphos 114
p-TsOH
0
--
--
9
Dppp
Dppp
Dppp
Dppp
Dppe
91
91
91
91
86
p-TsOH
79
86
10
95
85
100
100
100
100
100
100
100
100
--
93:7
96:4
90:10
95:5
93:7
90:10
85:15
93:7
--
10
11
12
13
14
15 [e]
16 [f]
17 [g]
18 [h]
19 [i]
Pd(OAc)2
p-TsOH
Pd(OAc)2
--
--
--
Pd(OAc)2
Pd(OAc)2
Dppb
94
Pd(OAc)2
--
5
73
Dppp
Dppp
Dppp
Dppp
Dppp
91
91
91
91
91
Pd(OAc)2
--
--
--
--
--
5
5
5
5
5
40
91
0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
trace
trace
--
--
Pd(OAc)2
--
--
[a] Reaction conditions: phenylacetylene 2.0 mmo, [Pd] 1.0 mol%, P/Pd=2:1, additive 0.3 mmol, NH4HCO3 4.0 mmol, CO 1.0 MPa,
CH3CN 5 ml, 120 ◦C, 2 h; [b] Nature bite angles βn were cited from ref. 11; [c] Determined by GC analysis with n-Dodecane as the
internal standard sample; [d] Determined by HPLC analysis calibrated with the authentic products; [e] Gaseous NH3 (0.4 MPa)
was used instead; [f] (NH4)2CO3 (2.0 mmol) was used instead; [g] NH4Cl (4.0 mmol) was used instead; [h] HCOONH4 (4.0 mmol)
was used instead; [i] NH4OAc (4.0 mmol) was used instead.
Interestingly, it was found that, even without the presence of
h to 5 h also resulted in the successful transformation of
the auxiliary acid of p-TsOH, the prolonged reaction time from 2
phenylacetylene towards the corresponding α,β-unsaturated
2
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[1]
amides with 95% yield (Table 1, Entry 12 vs 11). Under the
same conditions, Dppp still corresponded to the best
performance for this reaction in comparison to Dppe and Dppb
(Entries 12 vs 13 and 14). The latter gave the product yields of
85% and 73%. Moreover, the use of gaseous NH3 instead of the
solid NH4HCO3 under the same conditions just led to the poor
conversion of phenylacetylene to the amides with the dropped
yield of 40% (Entry 15). These results indicated that the
released H2CO3 could serve as a weak acid additive upon the
decomposition of NH4HCO3, which absolutely facilitated the
formation Pd-H (hydride) species responsible for the efficient
hydroaminocarbonylation. Then the influence of the different
ammonium salts with possibility to release NH3 and the acid
were explored in parallel (Entries 16-19). (NH4)2CO3 (2.0 mmol)
also proved able to be used as ammonia surrogate and
Brønsted acid like the behaviour of NH4HCO3 (4.0 mmol) (Entry
16 vs 12). However, when NH4Cl, HCOONH4 and NH4OAC were
applied respectively, the reaction completely stopped (Entries
17-19).
tentatively proposed in Scheme 2. The Pd-H species (A) was
initially formed with the aid of Dppp, OAc-, and the released
H2CO3 (CO2+H2O). Then the subsequent coordination of alkynes
to Pd-center generates the intermediate B, which allows for the
formation of vinylpalladium intermediates (C and C’) upon the
coordination of CO. Due to the formation of a stabilized 3-Pd
complex, the gem-vinylpalladium intermediate C is much more
favored than C’ as a result of the predominant production of the
branched product as observed in the experimental results in
Table 1. Accompanied by the simultaneous coordination of NH3
(released from NH4HCO3) to Pd-center, the insertion of the
activated CO to C and C’ gave the acylpalladium intermediates
D and D’, which irreversibly convert to the primary α,β-
unsaturated amide products upon aminolysis along with the
regeneration of A. Herein, the steric effect of Dppp with βn of 91o
also plays an important role in determining the formation and
stability of the formed intermediates in each step. Herein, the
steric effect of Dppp with βn of 91o also plays an important role in
determining the formation and stability of the formed
intermediates in each step.
According to the above facts, the plausible catalytic
mechanism of the present hydroaminocarbonylation was
Scheme 2. The proposed catalytic mechanism for hydroaminocarbonylation of alkynes using NH4HCO3 dually as ammonia surrogate and
Brønsted acid additive
Having identified the optimal reaction conditions, the scope of
the reaction was then explored with various alkyne derivatives
(Table 2). The electronic effects of the substituents of the
substrates indeed influenced the reaction rate dramatically.
Aromatic alkynes substituted by the groups with electron-
donating effect were all smoothly transformed into the
corresponding α,β-unsaturated amides in good yields under a
slightly prolonged reaction time (73-88%, entries 1-8). The
substituents such as alkyl (Entry 1-4), alkoxyl (Entry 5), chloro
(Entry 6), bromo (Entry 7) and fluoro (Entry 8) were all tolerated
under the applied reaction conditions. However, when the
aromatic alkynes possessing the strong electron groups like –
NO2 and –CN were applied, only trace amounts of the desired
products were detected (Entries 9-11). When 2 -ethynylpyridine
and 2-ethynylnaphthalene were used to repeat the reaction
respectively, the moderate to good yields of the branched
products were obtained (Entries 12 and13). Apart from the
terminal alkynes, the internal alkyne of 1,2-diphenylethyne was
also successfully adapted to the reaction, affording the
corresponding amide in good yield (Entry 14, 86%). And
aliphatic alkyne 1-octyne was employed to deliver the α,β-
unsaturated amide in 67% yield (Entry 15).
3
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Table 2 Substrate scope for the synthesis of the primary amides via
Conclusions
hydroaminocarbonylation of phenylacetylene derivatives with
[a]
NH4HCO3
In summary, we have successfully developed an efficient
strategy for the synthesis of α,β-unsaturated primary amides via
hydraminocarbonylation of various phenylacetylene derivatives
with NH4HCO3 as ammonia surrogate, which was catalyzed by a
Pd(OAc)2-Dppp system free of any auxiliary acid additive. The
use of the solid and inexpensive NH4HCO3 without presence of
stinky gaseous NH3 or liquids organic amines not only made the
reaction manipulations clean and easy-to-handle, but also
facilitated the formation of Pd-H catalytic active species via
serving as the acid additive upon decomposition to release
H2CO3. The selection of the diphosphine of Dppp was
prerequisite to warrant the success of this reaction. It was
Yield to major
Entry
1
Alkyne
Major amide
amide [%][b]
83
2
3
85
88
o
believed that the presence of Dppp with βn of 91 to Pd-center
played a crucial role in determining the formation and stability of
the Pd-intermediates in the proposed reaction mechanism.
4
5
6
7
8
75
Acknowledgement
91[c]
80[c]
80
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21473058 and 21273077),
and the Science and Technology Commission of Shanghai
Municipality (18JC1412100).
Keywords: Hydroaminocarbonylation; α, β-Unsaturated amides;
Ammonium hydrogen carbonate; Palladium catalyst
79
Notes and references
‡ CCDC 1842014 contains the supplementary crystallographic
data in this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
9
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COMMUNICATION
Dong-Liang Wang, Wendi Guo, Qing
Zhou, Lei Liu, Ye Liu*
Page No. – Page No.
Hydroaminocarbonylation of alkynes
to produce primary ,-unsaturated
amides using NH4HCO3 dually as
ammonia surrogate and Brønsted
acid additive
An efficient strategy for the synthesis of α,β-unsaturated primary amides
Hydraminocarbonylation of various phenylacetylene derivatives with
NH4HCO3 as ammonia surrogate was reported over a Pd(OAc)2-Dppp
system free of any auxiliary acid additive.
6
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