Ligand- and Additive-Controlled Pd-Catalyzed Aminocarbonylation of Alkynes with Aminophenols: Highly Chemo- and Regioselective Synthesis of α,β-Unsaturated Amides

Article abstract of DOI:10.1021/acscatal.7b00367

This work describes the chemo- and regioselective direct aminocarbonylation of alkynes and aminophenols to form hydroxy-substituted α,β-unsaturated amides in good to excellent yields. The latter are valuable compounds in pharmaceuticals and natural products. By a simple choice of different ligands and additives, branched or linear isomers could be selectively formed in excellent regioselectivity. Using a combination of boronic acid and 5-chlorosalicylic acid ( BCSA ) as the additives, linear amides were obtained in high yields and selectivities using 1,2-bis(di-tert-butylphosphinomethyl)benzene (DTBPMB) as the ligand. On the other hand, branched amides could be approached by introducing 1,3-bis(diphenylphosphino)propane as the ligand and p-TsOH·H₂O as the additive. In addition to the hydroxyl group, other functional substituents, such as carboxyl and vinyl groups, could also be tolerated using this method. As an application of this strategy, the natural product avenanthramide A could be synthesized directly in 84% yield and in 99% regioselectivity via the carbonylation of 2-amino-5-hydroxybenzoic acid and 4-ethynylphenol. Further studies show that the ligands and the additives are keys to good yields and selectivities.

Full text of DOI:10.1021/acscatal.7b00367

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Article
Ligand- and Additive-Controlled Pd-Catalyzed Aminocarbonylation
of Alkynes with Aminophenols: Highly Chemo- and
Regioselective Synthesis of #,#-Unsaturated Amides
Feng Sha, and Howard Alper
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b00367 • Publication Date (Web): 13 Feb 2017
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ACS Catalysis
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Ligand- and Additive-Controlled Pd-Catalyzed Aminocarbonylation
of Alkynes with Aminophenols: Highly Chemo- and Regioselective
Synthesis of α,β-Unsaturated Amides
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Feng Sha†,‡ and Howard Alper*,‡
† Key Lab for Advanced Materials and Institute of Fine Chemicals, School of Chemistry and Molecular Engineering,
East China University of Science and Technology, Meilong Road 130, Shanghai, China
‡ Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of
Ottawa, 10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada
ABSTRACT: This work describes the chemo- and regioselective direct aminocarbonylation of alkynes and aminophenols
to form hydroxy-substituted α,β-unsaturated amides in good-to-excellent yields. The latter are valuable compounds in
pharmaceuticals and natural products. By simply choosing different ligands and additives, branched or linear isomers
could be selectively formed in excellent regioselectivity. Using a combination of boronic acid and 5-chlorosalicylic acid
(‘BCSA’) as the additives, linear amides were obtained in high yields and selectivities using 1,2-
bis(ditertbutylphosphinomethyl)benzene (DTBPMB) as the ligand. On the other hand, branched amides could be ap-
proached by introducing 1,3-bis(diphenylphosphino)propane as the ligand and p-TsOH.H2O as the additive. In addition to
the hydroxyl group, other functional substituents, such as carboxyl and vinyl groups could also be tolerated using this
method. As the application of this strategy, the natural product avenanthramide A could be synthesized directly in 84%
yield and in 99% regioselectivity via the carbonylation of 2-amino-5-hydroxybenzoic acid and 4-ethynylphenol. Further
studies show that the ligands and the additives are key to good yields and selectivity.
INTRODUCTION
coupling reagent, and produce waste. Recently, new
methods have been developed to prepare amides, but
many of them suffer from multiple steps, complicated
substrates, or the need for activating reagents.6c,d,7 An
important objective is to construct α,β-unsaturated am-
ides directly and selectively with readily available reac-
tants in an atom-economic and environmentally benign
mannar.8
α,β-Unsaturated amides are important intermediates in
organic synthesis, functional subunits in materials, natu-
ral products and biological systems, and are of pharma-
ceutical interest as active structures.1-4 For instance (Fig. 1),
avenanthramides, a group of oat phenolics demonstrating
antiinflammatory and antioxidant capability, have been
widely used as nutrition additives and in clinical trials.2
The caffeic acid amides, which are abundant in nature,
are extremely versatile and have a number of biologically
active properties such as antitumor, antiviral, and MMP-
2/9 inhibitory activity.3 Moreover, the derivatives of gel-
danamycin KOSN1559 and macbecin II are highly efficient
Hsp90 inhibitors in the area of antitumor agents.4 How-
ever, only limited methods are known to directly synthe-
size α,β-unsaturated amides compared with their ester
counterparts. Conventional strategies to generate α,β-
unsaturated esters, such as aldol condensation,5a-c Wit-
tig,5d-f and Horner-Wadsworth-Emmons reactions,5f-i are
not transplantable, since the acidic hydrogen (N-H) is not
compatible under the basic conditions. α,β-Unsaturated
amides can be prepared via nucleophilic substitution of
activated carboxylic acid derivatives.1a,6 However, some
starting materials are not easy to access, and certain func-
tional groups, such as the OH and CO2H groups of sub-
strates, are not tolerated here. Furthermore, these meth-
ods usually use at least a stoichiometric amount of the
Figure 1. Examples of the Applications of Hydroxyl-α,β-
unsaturated Amides.
Carbonylation reactions can provide a facile approach
to amides through the assembly of unsaturated com-
pounds,9a-e halides,9a,b,f-h amines and CO in one step. By
choosing appropriate transition-metal catalysts and lig-
ands, high chemo-, regio- and stereoselectivity can be
realized.9-10 Since the pioneering work of Reppe,11 the tran-
sition-metal catalytic carbonylation of alkenes, alkynes,
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1,3-dienes or allenes has been developed and provides a
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1
promising strategy for the selective preparation of diverse
carbonyl compounds.9a-e,12-14 α,β-Unsaturated amides
could be obtained directly by using alkynes by this meth-
odology. However, in contrast to alkenes,13 there have
only been a few examples showing the selective synthesis
of amides via the aminocarbonylation of alkynes, and
most of these publications focused on the preparation of
branched α,β-unsaturated amides (2-substituted acryla-
mides).9a,14a-m For example, 2-substituted acrylamides
could be selectively obtained by the Pd-catalyzed ami-
nocarbonylation of alkynes in a strong acidic medium, in
an ionic liquid [bmin][Tf2N] or in the presence of organic
iodides, H2 or sulfonic acids (MsOH, p-TsOH).14a-l
Through the tin-radical-catalyzed carbonylation pathway,
acrylamides were formed by the coupling of alkynes, alkyl
amines and CO.14m Thus far, few examples demonstrate
the preference for the linear α,β-unsaturated amides.14g,h,n
In 2002, EI Ali and co-workers attempted to prepare
branched or linear amides selectively, but the linear selec-
tivity was not high, and only aliphatic alkynes were
used.14g,h Recently, Beller and co-workers investigated the
synthesis of N-alkyl linear amides with Fe3(CO)12 catalysis,
yet the application scope was quite limited using alkyl
amines.14n To our knowledge, there is no example of suc-
cessful research leading to the synthesis of both the linear
and branched α,β-unsaturated amides with broad sub-
strate scope and high regioselectivity.
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RESULTS AND DISCUSSION
Initially, phenylacetylene (1a) and 4-aminophenol (2a)
were chosen as model substrates to optimize the reaction
conditions (Table 1). In the presence of 5 mol% of PdCl2
o
and 20 mol% of PPh3 in THF at 120 C under a CO atmos-
phere (450 psi), the carbonylation of 1a and 2a afforded
the branched amide 3a, linear amide 4a and dicarbonyla-
tion imide 5a in 90% total yield in a 52/41/7 ratio, and no
esters were detected (entry 1). Encouraged by this result,
we tried other conditions to further optimize the regiose-
lectivity of the reaction. When MeCN was employed as
the solvent, the total yield of amides 3-5a decreased
slightly to 85%, but a better b/l ratio was observed (entry
2, b/l = 71/26). Other solvents, such as DMF, DCE, toluene,
etc., and reactions at different temperatures were studied.
The yields and the branched selectivities were lower than
that in the case of MeCN at 120 oC (for details, see Table S1,
SI). Different palladium precursors were investigated. As
shown in Table 1, although the total yield of amides 3-4a
was lower than that in the case of PdCl2, the branched
selectivity was significantly increased to 94% by the use of
Pd(OAc)2, and no imide 5a was formed (compare entry 3
with entries 1-2). Several other selected Pd precursors
were employed, but none was superior to Pd(OAc)2 (en-
tries 4-6). The effect of ligand was then investigated in the
presence of Pd(OAc)2 in MeCN. Only a small amount of
amides 3-5a was isolated in the absence of PPh3 (entry 7,
14% total yield). Considering that bidentate ligands were
often used for carbonylation processes, a variety of biden-
tate ligands were screened for the reaction. These ligands
demonstrated good branched selectivity but the yields of
amides ranged widely (entries 8-12). With DPPE as the
ligand, the yield of amides increased to 88% (entry 8).
Utilization of ligand DPPP increased the yield to 91%,
though accompanied by 7% of 6aa (entry 9). 6aa is an
ester which arose by the further carbonylation of amide
3a. Further investigation showed that the yields of amides
decreased with the increase of the length of the carbon
chain of the ligands (entries 9-11). Another bidentate lig-
and, BIPHEP, also worked well but the yield was a little
lower than DPPP (compare entry 12 with entry 9). When
the reaction was carried out using the tridentate ligand
Recently, we successfully introduced aminophenols as
nucleophiles for the Pd-catalyzed aminocarbonylation of
alkenes, and the OH group was retained in the final
products. With the employment of different ligands,
branched or linear amides were isolated in good yields
and in high selectivity (Scheme 1, a).13u Considering that
OH substituted α,β-unsaturated amides are useful com-
pounds for pharmaceuticals, natural products as well as
biological systems, etc. (see Fig. 1),2-4 we assumed that the
alkynes can be applied instead of alkenes to construct OH
substituted α,β-unsaturated amides. Compared with al-
kenes, however, alkynes exhibit different reactivity and
electronic properties, and this can result in complications
when aminophenols react to form esters and amides. On
the basis of our previous studies on carbonylations12c,f,13g-
i,u,14j,k,15 and given the interest to explore the selectivity, we
herein report the Pd-based ligand- and additive-
controlled aminocarbonylation reactions of alkynes and
aminophenols, which exhibit excellent chemo- and regi-
oselectivities to form both branched and linear OH sub-
stituted α,β-unsaturated amides in good-to-excellent
yields.
Scheme 1. Proposed Processes for the Pd-Catalyzed
Selective Carbonylation of Aminophenols
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mixed solvent MeCN/THF (v/v = 1:4) was used. TsOH: p-
TsOH.H2O. DPPE = 1,2-bis(diphenylphosphino)ethane. DPPP =
Triphos, the yield and the branched selectivity both de-
1
2
3
4
5
6
7
8
creased (entry 13). In addition, the effect of additives was
investigated using the catalytic system with DPPP as the
ligand. The yield of amides, and the branched selectivity,
both increased when 1.0 mol% of p-TsOH.H2O was added,
affording the amides 3a and 4a in 92% total yield, and the
branched selectivity increased to 98% (entry 14). However,
product 6aa was also isolated in 4% yield under these
conditions. Thereafter, use of a different amount of p-
TsOH.H2O was evaluated. Although the ratio of l/b was as
high as 58/10 with 100 mol% of acid used, the yield of am-
ides 3-5a decreased to 51%, accompanied by 16% of imide
5a (entries 15-16). Given that no 6aa was detected using
THF as the solvent, we chose THF instead of MeCN in the
presence of Pd(OAc)2/DPPP and p-TsOH.H2O for the re-
action, affording amides 3a and 4a in 97% yield (entry 17).
By using the mixed solvent MeCN/THF, amides 3a and 4a
were isolated in 96% yield and in 98% branched selectivi-
ty (entry 18).
1,3-bis(diphenylphosphino)propane.
bis(diphenylphosphino)butane.
bis(diphenylphosphino)pentane.
bis(diphenylphosphanyl)-1,1'-biphenyl.
DPPB
DPPPen
BIPHEP
=
=
=
1,4-
1,5-
2,2'-
(2-
Triphos
=
((diphenylphosphanyl)methyl)-2-methylpropane-1,3-
diyl)bis(diphenylphosphane).
9
The question arose whether the dicarbonylated imide
5a was generated from 3a or 4a or both. To determine
whether or not this is the case, 3a and 4a were isolated
and reacted with CO under conditions i-iii, respectively.
The results demonstrated that 3a could be transformed to
5a in 31-76% yields. However, there was none or only a
trace amount of 5a furnished from 4a (Scheme 2).
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Scheme 2. The Possible Production Path for Imide 5a
Table 1. Optimization of the Reaction Conditions for
the Branched Amide 3aa
Since the PdCl2/Ligand catalytic system in THF showed
high activity (Table 1, entries 1 and 17), we then intro-
duced a series of ligands under these conditions. As ex-
pected, when bidentate phosphine ligands were used, the
branched amide 3a was formed as the predominant prod-
uct (Table 2, entries 1-4). Up to 95% branched selectivity
was observed by using BIPHEP (entry 4). Monodentate
phosphine ligands also showed good activity. As demon-
strated in Table 2, employment of electron-donating lig-
ands L1 and L2 afforded higher yields, while the less elec-
tron-donating ligand L3 resulted in relatively lower prod-
uct yield (entries 5-7). For ligands L2 and L4 with similar
electron-donating property, L4 has a substantial steric
effect, resulting in lower product yield (entry 8). Similarly,
the utilization of L5 inhibited the reaction (entry 9). Sur-
prisingly, when ligand L6 was employed, the regioselectiv-
ity was reversed with the linear isomer 4a obtained as the
major product (entry 10). In addition, ligands L7-9 with
strong electron-donating capabilities and bulky structures,
were introduced, to selectively afford the linear amide 4a
as the major isomer in excellent yields (entries 11-13).
additive
(mol%)
yield
(%)b
3a/4a/5ac,
entry
PdX2/L
6aad
1e,f
2
PdCl2/PPh3
90
85
71
52/41/7, 0
71/26/3, 0
94/6/0, 0
78/20/2, 0
PdCl2/PPh3
3
Pd(OAc)2/PPh3
Pd(TFA)2/PPh3
4
82
Pd(MeCN)4(BF4)2/
PPh3
5e
80
64/35/1, 0
6e
Pd2(dba)3/PPh3
Pd(OAc)2/-
29
14
61/33/6, 0
37/56/7, 0
95/5/0, 2
95/5/0, 7
94/6/0, 0
94/6/0, 0
95/5/0, 2
70/29/1, 0
98/2/0, 4
71/25/4, 0
10/58/31, 0
97/3/0, 0
98/2/0, <2
7
8
Pd(OAc)2/DPPE
Pd(OAc)2/DPPP
Pd(OAc)2/DPPB
Pd(OAc)2/DPPPen
Pd(OAc)2/BIPHEP
Pd(OAc)2/Triphos
Pd(OAc)2/DPPP
Pd(OAc)2/DPPP
Pd(OAc)2/DPPP
Pd(OAc)2/DPPP
Pd(OAc)2/DPPP
88
91
9
10g
11g
12h
13h
14h
15e
16e
17g,f
18g,i
77
58
84
64
92
83
51
Table 2. Effect of Ligands on the Aminocarbonylation
Reactiona
TsOH/1
TsOH/10
TsOH/100
TsOH/1
97
TsOH/1
96
aConditions: 0.5 mmol of 1a, 0.5 mmol of 2a, 5 mol % of Pd, Pd/P
o
b
= 1/4, 5 mL of MeCN, CO (450 psi), 120 C, 24 h. total isolated
yield of 3a, 4a and 5a. cdetermined by 1H NMR. disolated yield. e48
f
g
h
i
h. 5 mL of THF was used as the solvent. 72 h. 30 h. 5 mL of
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equiv
and
decreasing
the
proportion
of
entry
ligand
DPPE
DPPP
DPPB
BIPHEP
L1
yield (%) b
3a/4a/5ac
92/8/0
93/7/0
81/17/2
95/5/0
65/34/1
68/29/3
66/30/4
41/52/7
-
1
2
3
4
5
6
7
8
Pd(OAc)2/DTBPMB and BCSA to 2.5 mol%/5 mol% and
0.075 equiv, the linear selectivity was 97%, and the yield
increased to 94% (entry 9). Further reduction of the
amount of catalyst led to the decrease of the yield of am-
ides (entry 10).
1
72
2
96
44
90
99
92
82
3
4
5
Table 3. Optimization of the Reaction Conditions for
the Linear Amide 4aa
6
7
L2
9
L3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
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49
50
51
52
53
54
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57
58
59
60
8
9
10
11
12
13
L4
27
L5
trace
96
91
L6
33/66/2
21/72/7
36/63/1
44/56/0
L7
L8
94
yield
entry
ligand
additive
4a/3a/5ac
(%)b
L9
96
aConditions: 0.5 mmol of 1a, 0.5 mmol of 2a, 5
mol % of PdCl2, Pd/P = 1/4, 5 mL of THF, CO (450
1d
2
DPPB
DPPB
DPPB
DPPB
DPPB
DPPB
77
6/94/0
69/2/29
24/76/0
17/12/71
89/6/5
BCSA/-
B(OH)3/-
Cl-SA/-
85
o
b
psi), 120 C, 48 h. total isolated yield of 3a, 4a
1
and 5a. cdetermined by H NMR. Condition C:
3
81
BIPHEP was used as the ligand. Condition D: L6
was used as the ligand.
4
78
5
BCSA/MeOH 83
BSA/MeOH 85
6
84/3/13
99.7/0.3/0
97/3/0
Considering that linear amides (e.g., cinnamamides) are
more desirable due to their utilization in many research
fields, we focused our effort to optimize the reaction con-
ditions to achieve better linear selectivity. However, as
alluded to earlier, the linear isomer is significantly more
difficult to generate relative to the branched isomer. As
illustrated in Table 3, by using Pd(OAc)2/DPPB as the
catalyst in MeCN at 120 oC, the reaction still gave
branched 3a as the major product (entry 1). However, we
were pleased to observe that the regioselectivity was re-
versed by the addition of ‘BCSA’16 (compare entry 1 with 2).
Employment of B(OH)3 or 5-chlorosalicylic acid alone
gave increased branched selectivity (5a was formed from
3a, see Scheme 2), demonstrating that the intermediate
BCSA, generated from B(OH)3 and 5-chlorosalicylic acid
in situ, was the key to promote linear isomer formation
and reverse the overall selectivity. The above results indi-
cate that 5-chlorosalicylic acid and p-TsOH.H2O could
promote the second carbonylation process (Table 3, entry
4 and Table 1, entry 16). Unexpectedly, the addition of
another additive, MeOH,17 led to a further increase in lin-
ear selectivity to 89%, albeit with a small amount of ester
(entry 5). MeOH may act as another proton-donor, to
improve the generation of the key intermediate Pd-H spe-
cies (see Scheme 3). Other palladium precursors and lig-
7
DTBPMB BCSA/MeOH 87
8
DTBPMB BCSA/-
DTBPMB BCSA/-
DTBPMB BCSA/-
90
94
67
9e,f
10e,g
97/3/0
96/4/0
aConditions: 0.5 mmol of 1a, 0.5 mmol of 2a, 5 mol% of
Pd(OAc)2, 10 mol% of ligand, 5 mL of MeCN, CO (350
o
b
psi), 110 C, 48 h. total isolated yield of 3a, 4a and 5a.
cdetermined by H NMR. d120 oC. e1.2 equiv of 1a was
1
f
used based on 2a. 2.5 mol% of Pd(OAc)2, 5 mol% of
DTBPMB and 7.5 mol% of BCSA were used. g1.5 mol% of
Pd(OAc)2, 3 mol% of DTBPMB and 4.5 mol% of BCSA
were used. BCSA: mixture of 1.0 equiv of B(OH)3 and 2.0
equiv of 5-chlorosalicylic acid. BSA: mixture of 1 equiv of
B(OH)3 and 2 equiv of salicylic acid. DTBPMB = 1,2-
bis(ditertbutylphosphinomethyl)benzene.
With the above optimized conditions (defined as condi-
tion A (Table 1, entry 18) and B (Table 3, entry 9)) in hand,
a series of phenylacetylenes 1 and 4-aminophenols 2 were
employed to determine the scope and regioselectivities of
these aminocarbonylation reactions (Table 4). Both elec-
tron-withdrawing and electron-donating substituted
phenylacetylenes 1 reacted with 4-aminophenol (2a)
smoothly, controllably affording branched or linear am-
ides in high regioselectivity (entries 1-8). When 4-Me, 4-
MeO, 4-HO and 4-Cl group substituted phenylacetylenes
(1b-e) were employed under condition A, the branched
selectivity was over 99%, and the corresponding products
3ba-ea were isolated in excellent yield (91-95% yields,
entries 2-5). Under condition B, the corresponding linear
products 4ba-ea could be generated in 86-91% yields, and
with up to 96-98% regioselectivities (entries 2-5). The
ands
were
investigated,
demonstrating
that
Pd(OAc)2/DPPB was a better choice (for details, see Table
S2, SI). Furthermore, when DPPB was replaced by
DTBPMB12a,j,13m,s,18, there was almost 100% linear selectivity
in the presence of BCSA and MeOH (entry 7). To avoid
the generation of ester, trials were conducted without
MeOH. Fortunately, the regioselectivity was still as high
as 97%, and the amides were isolated in 90% yield (entry
8). In addition, increasing the amount of alkyne 1a to 1.2
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above results demonstrated the OH substituted phenyla-
4a/90
97/3
1
1a 2a 3a/92
1b 2a 3ba/91
98/2
(88)d
(>99/1)d
1
2
3
4
5
6
7
8
cetylene could also be tolerated in these reactions (entry
4). Notably, the Br substituent of 4-bromophenylethyne 1f
remained intact under both conditions (entry 6). Howev-
er, when 1f and 4-cyanophenylethyne (1g) were reacted
under condition A, the yields of branched amides 3fa and
3ga decreased to 46% and 41%, respectively. Gratifyingly,
3fa and 3ga were isolated in 74% and 80% yields with
good selectivity using condition C (entries 6-7). In con-
trast, the reactions of 1f and 1g under condition B afford-
ed linear amides 4fa and 4ga in good yields and in 98%
and 92% regioselectivity, respectively (entries 6-7). It was
not yet clear why the selectivity of the linear isomer 4ga
was a little lower, but it is possible that the cyano group
acted as a co-ligand. Interestingly, with the utilization of
MeOH in the reaction of 1g, the linear selectivity could be
increased to 99% with the yield of 4ga not affected (entry
7, condition B). Substrate 2-methylphenylethyne 1h hav-
ing a methyl group near the ethynyl substituent, was ex-
periencing steric hindrance, but could still react with 2a
smoothly, affording amides 3ha and 4ha in good yields
and in 97% and 99% regioselectivity (entry 8). On the
other hand, differently substituted 4-aminophenols were
also successfully applied to the reaction. As shown in Ta-
ble 4, the methyl group or electron-withdrawing group
such as F, Cl or CO2Me (2b-f) could all be tolerated, af-
fording the corresponding branched or linear amides in
good-to-excellent yields and in high regioselectivity (en-
tries 9-13). Substrate 2b with a methyl substituted ortho
to the amino group, gave amide 3ab in 94% yield, and 98%
regioselectivity. The linear product 4ab was isolated in 75%
yield and 98% selectivity under condition B (entry 9). 4-
Aminophenols with a fluorine substituent at a different
position led to similar excellent selectivity under both
conditions A and B. Amides 3ac/3ad and 4ac/4ad were
generated smoothly and in good yields (entries 10 and 11).
The yield of linear amide 4ae decreased slightly in the
case of chlorine substituted 4-aminophenol 2e under
condition B (entry 12). In contrast, the substrate with a
CO2Me group (2f) afforded 4af in excellent yield (96%,
condition B, entry 13). When 4-aminonaphthalenol 2g
reacted with 1a, high selectivity for the branched or linear
amide was achieved, although the yield was lower (entry
14).
4ba/86
97/3
2
>99/1
(89)d
(>99/1)d
3
4
5
1c
2a 3ca/94
>99/1
>99/1
>99/1
4ca/91
4da/89
4ea/90
97/3
98/2
96/4
1d 2a 3da/91
1e 2a 3ea/95
3fa/46
>99/1
9
6
7
1f
2a
4fa/82
98/2
(74)c
(98/2)c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3ga/41
95/5
4ga/87
92/8
1g 2a
(80)c
(94/6)c
(85)d
(99/1)d
8
1h 2a 3ha/86
1a 2b 3ab/94
1a 2c 3ac/88
1a 2d 3ad/90
1a 2e 3ae/87
97/3
4ha/77
4ab/75
4ac/83
4ad/80
4ae/72
4af/96
4ag/53
>99/1
98/2
99/1
97/3
99/1
98/2
97/3
9
98/2
10
11
>99/1
>99/1
>99/1
>99/1
98/2
12
13
14
1a 2f
3af/83
1a 2g 3ag/78
Condition A: 0.5 mmol of 1, 0.5 mmol of 2, 5 mol % of
Pd(OAc)2, 10 mol% of DPPP, 1.0 mol% of p-TsOH.H2O. 1 mL
o
of MeCN and 4 mL of THF, CO (450 psi), 120 C, 72 h. Con-
dition B: 0.6 mmol of 1, 0.5 mmol of 2, 2.5 mol % of
Pd(OAc)2, 5 mmol of DTBPMB, 7.5 mol% of B(OH)3, 15
mol% of 5-chlorosalicylic acid and 5 mL of MeCN, CO (350
b
1
psi), 110 oC, 48 h. aisolated yield of 3 or 4. determined by H
NMR. cCondition C: 0.5 mmol of 1, 0.5 mmol of 2, 5 mol% of
PdCl2, 10 mol% of BIPHEP, 5 mL of THF, CO (450 psi), 120
oC, 48 h. d160 μL (8.0 equiv) of MeOH was added.
We next examined a reactant with both terminal car-
bon-carbon double and triple bonds in one substrate (1i),
to assess the degree of selectivity between the vinyl and
the ethynyl groups. The vinyl group still remained intact
under both conditions, and the corresponding branched
and linear amides 3ia and 4ia were obtained in good
yields and in high selectivities (eq 1). This result might be
due to the different reactivity between these two kinds of
unsaturated bonds under the reaction conditions.
Table 4. Selective Carbonylation of Phenylacetylene
with 4-Aminophenols
3-Aminophenols with a variety of substituents (2h-l)
were explored under reaction conditions A and B (Table
5). High selectivity for both branched and linear amides
was observed (entries 1-5). The yield of 3ah could be fur-
ther improved by using 1.1 equiv of 2h, and the corre-
sponding dicarbonylation product 6 could be suppressed
successfully (entry 1). The electronic property of substitu-
ents on 3-aminophenols also affected the yield and regi-
oselectivity. As indicated by the result, under both condi-
tions A and B, the electron-donating group on 3-
aminophenols could increase the yields of amides as
compared with an electron-withdrawing group (compare
entries 4-5 with 2-3). By employing methoxyl substituted
condition A
3/yield
condition B
4/yield
entry
1
2
3/4b
4/3b
(%)a
(%)a
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3-aminophenol 2l, the corresponding branched and linear MeOH was added to the reaction under condition B, 4am
1
2
3
4
5
6
7
8
amides 3al and 4al were generated in 98% and 96% yield,
respectively (entry 5). When 2j with a CO2Me group at the
ortho position of the hydroxyl substituent was used, the
branched amide 3aj, and linear amide 4aj, were isolated
in 67% and 92% yields (entry 3). Alternatively, the yield of
3aj could be improved to 83% under condition C (entry 3).
By choosing an electron-withdrawing group (Cl) and an
electron-donating group (Me) substituted phenylacety-
lenes 1e and 1h, the carbonylation afforded the corre-
sponding amides in good yields and in high regioselectivi-
ty (entries 6-7). It is noteworthy that the selectivity was
not affected greatly by steric hindrance when using 1h as
the substrate.
was formed in 98% regioselectivity (entry 1). In addition,
the carbonylation of substituted phenylacetylenes 1e and
1h with 2-aminophenol (2m) afforded the corresponding
amides in good yields and high regioselectivity, similar to
using 3-aminophenol (2h) (compare table 6, entries 6-7
with table 5, entries 6-7). As indicated by these results,
the hydroxyl group close to the reaction center does not
interfere in the reaction.
9
Table 6. Selective Carbonylation of Phenylacetylene
with 2-Aminophenols
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Selective Carbonylation of Phenylacetylene
with 3-Aminophenols
Condition A
3/yield
Condition B
4/yield
entry
1
1
2
b/lb
l/bb
(%)a
(%)a
3am/91
4am/94 96/4
1a 2m
>99/1
(83)c
(90)d
(98/2)d
Condition A
3/yield
Condition B
4/yield
2
3
4
5
6
7
1a 2n
1a 2o
1a 2p
1a 2q
1e 2m
1h 2m
3an/87
3ao/84
3ap/96
3aq/82
3em/81
94/6
98/1
>99/1
97/3
99/1
4an/92
4ao/91
4ap/97
4aq/96
97/3
95/5
98/2
98/2
entry
1
2
b/lb
l/bb
(%)a
(%)a
3ah/87
4ah/95
98/2
1
1a 2h
1a 2i
1a 2j
96/4
95/5
(81)c
2
3
3ai/85
4ai/93
4aj/92
98/2
97/3
4em/90 97/3
4hm/93 99/1
3aj/67
>99/1
3hm/85 95/5
(83)d
(96/4)d
Condition A: 0.5 mmol of 1, 0.55 mmol of 2, 5 mol % of
Pd(OAc)2, 10 mol% of DPPP, 1 mol% of p-TsOH.H2O. 1 mL of
MeCN and 4 mL of THF, CO (450 psi), 110 C, 72 h. Condi-
tion B: 0.6 mmol of 1, 0.5 mmol of 2, 2.5 mol % of Pd(OAc)2,
5 mmol of DTBPMB, 7.5 mol% of B(OH)3, 15 mol% of 5-
chlorosalicylic acid and 5 mL of MeCN, CO (350 psi), 80 C,
48 h. isolated yield of 3 or 4. determined by H NMR. 0.5
mmol of 2 was used. 160 μL (8.0 equiv) of MeOH was add-
ed.
4
5
6
7
1a 2k 3ak/92
1a 2l 3al/98
98/2
4ak/95
4al/96
4eh/94
99/1
97/3
97/3
o
>99/1
>99/1
96/4
1e 2h 3eh/88
1h 2h 3hh/79
o
4hh/96 98/2
a
b
1
c
Condition A: 0.5 mmol of 1, 0.55 mmol of 2, 5 mol % of
Pd(OAc)2, 10 mol% of DPPP, 1 mol% of p-TsOH.H2O. 1 mL
of MeCN and 4 mL of THF, CO (450 psi), 120 oC, 72 h.
Condition B: 0.6 mmol of 1, 0.5 mmol of 2, 2.5 mol % of
Pd(OAc)2, 5 mmol of DTBPMB, 7.5 mol% of B(OH)3, 15
mol% of 5-chlorosalicylic acid and 5 mL of MeCN, CO (350
d
Considering that the CO2H group could be tolerated
under condition B (additive: 5-chlorosalicylic acid), we
were then interested to introduce 5-amino-2-
hydroxybenzoic acid (2r), bearing a CO2H moiety at the
ortho position of the OH substituent, to react with phe-
nylacetylene (1a) in the presence of B(OH)3 without addi-
tional 5-chlorosalicylic acid (Fig. 2). To our surprise, the
carbonylation of 2r could give the corresponding amide
4ar in 89% yield and in over 99% regioselectivity, demon-
strating that substrate 2r and B(OH)3 also served as the
additive simultaneously. Similarly, the substrate 4-amino-
2-hydroxybenzoic acid (2s), could also be employed in the
reaction smoothly, affording 4as in 78% yield and 98%
selectivity. Furthermore, 3-amino-4-hydroxybenzoic acid
(2t), with the CO2H group not at the ortho position of OH,
was also examined and the chelation compound could not
o
a
b
psi), 110 C, 48 h. isolated yield of 3 or 4. determined by
1H NMR. 0.5 mmol of 2 was used. Condition C: 0.5 mmol
of 1, 0.5 mmol of 2, 5 mol% of PdCl2, 10 mol% of BIPHEP, 5
mL of THF, CO (450 psi), 120 oC, 48 h.
c
d
The selective carbonylation was also applied to 2-
aminophenols, affording amides in good-to-excellent
yields and in high regioselectivity (Table 6). With the in-
troduction of electron-withdrawing (such as F and Cl)
t
and electron-donating (such as Bu and MeO) groups on
2-aminophenols, the reactions showed a similar trend
with 3-aminophenols (entries 2-5). By utilizing 4-chloro-
2-aminophenol (2n) under condition A, the regioselectivi-
ty decreased slightly to 94% (entry 2). When 8.0 equiv of
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ACS Catalysis
be formed with B(OH)3 like salicylic acid. With the aid of
additive BCSA (7.5 mol%), the carbonylation of 2t with 1a
1
2
3
4
5
6
7
8
could react smoothly, the corresponding amide 4at was
isolated in 93% yield with over 99% selectivity. When
using the CO2H substituted phenylacetylene 1j as the sub-
strate under condition B, the corresponding amide 4ja
was successfully isolated in 88% yield with 99% regiose-
lectivity. Interestingly, the natural product avenan-
thramide A (4du) could be constructed directly through
this method by using 4-ethynylphenol (1d) and 5-
hydroxyanthranilic acid (2u), affording 4du in 84% yield
and over 99% selectivity.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Synthesis of OH and CO2H Substituted Cinnama-
mides
Other than aryl and alkyl alkynes, we were further in-
terested in exploring other types of alkynes for this car-
bonylation reaction. For example, substrate N-methyl-N-
phenylpropiolamide (8), bearing
a strong electron-
deficient carbon-carbon triple bond, could also react with
2a smoothly under condition B. The reaction afforded the
linear amide 9 in 84% isolated yield and in over 99% se-
lectivity (eq 5). However, no desired amide was detected
under condition A. On the contrary, ethynyltriiso-
propylsilane (10a), substituted with a strong electron do-
nor moiety (Si(iPr)3), could also react with 4-aminophenol
(2a), and only the linear isomer 11a was isolated under
conditions A and D (eq 6). The branched isomer was not
formed, which may largely be due to the steric effect of
the Si(iPr)3 group. When ethynyltrimethylsilane (10b) was
employed as the reactant, the branched amide was ob-
served, while the linear isomer 11b resulted as the major
product under condition A.
In addition, alkyl acetylenes were then utilized to fur-
ther determine the scope of this carbonylation reaction.
As demonstrated in eq. 2, n-1-hexyne (1k) could be ap-
plied smoothly, giving the corresponding amide 3ka and
4ka in 79% and 76% yields, and in good selectivity under
conditions A and B, demonstrating that aliphatic alkynes
could be well tolerated using this method. Another kind
of alkyl acetylene, 3-phenyl-1-propyne (1l), was then ex-
amined (eq 3), and the branched amide 3laa was generat-
ed in 84% yield and good selectivity under condition A.
However, under condition B, three amide products 3lab,
4laa and 4lab were detected, with the rearrangement
amide 4lab isolated as the major product (78% yield). The
linear selectivity was up to 98%, although the ratio of
4lab and 4laa was 87:11. Furthermore, internal alkynes 1m
and 1n were also applied and found compatible in these
reactions, to afford the corresponding amides 7ma and
7na in good yields (eq 4). The configuration of 7ma was
established by the NOESY study (see SI).
In addition, substrate 12, having a sterically encum-
bered group, was tested (compare with 10) and afforded
the linear amide 13 as the sole product in 41% and 89%
yields under conditions A and B (eq 7). It was interesting
that the OAc group was eliminated to form 1,3-diene 13,
which provided a readily accessible strategy to 1,3-diene
amides.
To verify the chemo- and regioselectivity of the reaction,
controlled reactions were conducted by employing phe-
nylacetylene (1a) with a mixture of 4-methylaniline (14)
and 4-methylphenol (15) (eq 8). In the presence of phenol
15, the reaction selectively afforded the branched amide
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Page 8 of 12
16 in 82% yield (condition A) and the linear amide 17 in nol, eq 8). On the basis of these results, two mechanistic
1
89% (condition B) yield, with no ester observed. Fur-
thermore, N-methylaniline (18a) and N-methyl 3-
aminophenol (18b), with a methyl group on the nitrogen
atom which may cause steric hindrance, were also inves-
tigated (eqs 9-10). Under condition B, the linear amides
20a and 20b were isolated in 91% and 94% yields with 98%
and over 99% regioselectivity, respectively. Interestingly,
the branched amide 19a could also be readily obtained
when using 18a as the substrate under condition A (eq 9).
However, when 18b was used under condition A, 19b and
20b were isolated in 75% yield, and in a 60/40 ratio (eq
10). These results demonstrated that the N-methyl group
did not affect the chemoselectivity under both conditions
A and B, but reduced the activity of the reactions to form
branched amides 19a and 19b under condition A. When
4-methylphenol (15, eq 8) or the phenolic hydroxyl moie-
ty (18b, eq 10) were present, the linear selectivity in-
creased more or less under condition A, which indicates
that the branched or the linear amide may be formed via
different Pd intermediates. The phenolic hydroxyl group
may act as the proton-donor to promote the generation of
Pd-H species, which was the key intermediate leading to
the formation of linear amides (see Scheme 3). Moreover,
the reactions of phenyl acetylene-d (d-1a, 92% D) with 4-
aminophenol (2a) under conditions A and B were carried
out to determine the position of deuterium in the final
product (eq 11). Under condition A, the corresponding
branched amide d-3a was isolated in 93% yield with 98%
branched selectivity, and content of deuterium in d-3a
pathways are proposed for the aminocarbonylation reac-
tions.19 As indicted in Scheme 3, the arylcarbamoyl group
(Path A) and the hydride (Path B) can serve as the carri-
ers. In the arylcarbamoyl mechanism (Path A), the sub-
strate reacts with the arylcarbamoylpalladium species II
(formed via the reaction of the arylaminopalladium spe-
cies I) to generate the intermediates III and IV. The latter
intermediates subsequently react to produce the final
branched and linear products by protonation with p-
TsOH.H2O, hydroxyl and/or amino groups. On the other
hand, in the hydride mechanism (Path B), the Pd(II) is
reduced to Pd(0) first, which could generate palladium
hydride V in the presence of acid (BCSA).20 The next step
involves migration of V to the substrate forming species
VI and VII, which produce the final products 4 and 3 via
CO insertion and amination of aminophenol. The C-C
bond forming reaction is significantly different between
these two pathways. As a result of steric effects, the mi-
gration reactions would be expected to favor products in
which the palladium atom and the phenyl group (R) end
up attached to different carbon atoms (intermediates III
and VI). This promotes the carbamoyl mechanism to give
the branched product 3 via intermediate III, whilst the
hydride mechanism should favor the linear product 4
through intermediate VI. In both cases cis addition (of Pd
and CONHAr or of Pd and H) during the migratory inser-
tion step should lead to the corresponding isomer. When
the reactions were conducted in the absence of alkyne 1,
the hydroformation product of aminophenol were ob-
served. N-(4-Hydroxyphenyl)formamide (21) was isolated
in 13% yield in the presence of BCSA. However, only a
trace amount of 21 was yield without acid (BCSA).21
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(78%) was confirmed through H NMR analysis. On the
other hand, the linear isomer d-4a was generated in 88%
yield with 97% linear selectivity, and the content of deu-
terium in d-4a was 71%.
Scheme 3. Proposed mechanism
As shown in Scheme 3, the pivotal catalyst species may
be LnPd(CO)NHAr I and LnPd(CO)-H V in the two possi-
ble mechanistic pathways. The generation amount and
speed by which the intermediate LnPd(CO)-H reacts, may
determine the reaction pathways and the regioselectivity
of the reaction, as well as the yield. Besides the effect of
the structure and electronic properties of the ligands, the
proton-donor (e.g., p-TsOH.H2O or BCSA) is another key
factor to control the generation of LnPd(CO)-H. As
demonstrated in Figure 3, when DPPP was employed as
The above experimental results showed that the
branched amides could be generated without adding any
additives (Tables 1 and 2). On the contrary, the linear se-
lectivity was increased in the presence of additives (p-
TsOH.H2O, Table 1, entries 15 and 16; BCSA, Table 3; phe-
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ACS Catalysis
howard.alper@uottawa.ca
the ligand, BCSA afforded better linear selectivity than p-
TsOH.H2O (compare p-TsOH.H2O line with BCSA line).
1
2
3
4
5
6
7
8
9
Notes
Furthermore, when the reactions were carried out using
DPPB instead of DPPP, increased linear selectivity were
observed. Superb linear selectivity resulted using
DTBPMB as the ligand. However, only 7% of desired am-
ides were isolated with 45% linear selectivity in the ab-
sence of BCSA (for details, see Table S3, SI). These results
indicate that BCSA serves as a proton-donor to promote
the generation of the LnPd-H species, which is key to im-
proving the hydride based catalytic cycle (Scheme 3, Path
B), and afford the linear amides.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful to the Natural Sciences and Engineering Re-
search Council of Canada for support of this research.
REFERENCES
10
11
12
13
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Figure 3. Effect of the Ligands as well as Amount and the
Nature of the Acid (for the original data of this Figure, see
Table S3, SI)
CONCLUSION
In summary, the ligand- and additive-controlled palla-
dium catalyzed aminocarbonylation reaction of alkynes
and aminophenols provide direct OH substituted α,β-
unsaturated amides. By simply changing the ligand and
the additives, branched or linear amides were formed in
excellent chemo- and regioselectivities, and in good-to-
excellent yields. Mechanistic studies were conducted to
gain some insight into these two catalytic reactions which
may proceed via different reaction pathways. Other than
the property and the structure of ligand, the additive
(proton-donor) can also act in a constructive manner to
promote the generation of LnPd-H intermediates, which
are critical to the regioselectivity and to form the linear
products in high selectivity. With the high chemo- and
regioselectivity, wide substrate scope, high atom-
economy property and excellent product yield, this strat-
egy provides an economical and facile synthetic approach
to α,β-unsaturated amides.
ASSOCIATED CONTENT
Supporting Information.
Additional experimental results, experimental procedures
and spectral data. This material is available free of charge via
the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
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tive ligation of hydrogen to Pd(0). To verify this point, the reac-
tion of 1a and 2a was conducted using the Pd(0) precursor
(Pd(DPPB)2), instead of Pd(OAc)2, under condition B, and the
corresponding product 4a was isolated in 95% yield and in 95%
linear selectivity. The reaction result indicated that Pd(0) could
smoothly catalyze the reaction. (a) Hu, Y.; Shen, Z.; Huang, H.
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(21) The reactions of 4-aminophenol (2a) and CO with or
without BCSA under Pd(OAc)2/DTBPMB or DPPP were carried
out. In the presence of BCSA, and the product N-(4-
hydroxyphenyl)formamide (21) was observed and isolated in 13%
yield. However, only a trace amount of 21 was observed without
BCSA. These results demonstrated that the acid may act as the
key component to form the Pd-H intermediate which could gen-
erate 21 via CO insertion and amination of 4-aminophenol, or
protonation of the arylcarbamoylpalladium intermediate II
through Path A.
(16) 'BCSA', a combination (or a mixture) of 1 equiv of
B(OH)3 and 2 equiv of 5-chlorosalicylic acid, was used as the
additive in the alkoxycarbonylation of alkynes, or in the car-
bonylation of alkenes. For details, see ref. 12i and ref. 13u.
(17) As reported by EI Ali and co-workers, the regioselectivity
of the carbonylation of alkynes could be affected by the nucleo-
philes. While using MeOH as the nucleophile, the selectivity
were changed with preference to afford the linear esters. For
details, see ref. 14l.
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(19) Similar mechanistic pathways were proposed for the
methoxycarbonylation of alkynes. For details, see ref. 12j.
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TOC graphic specifications.
1
2
3
4
5
H
H
R1
[Pd]/DTBPMB
BCSA
[Pd]/DPPP
N
N
CO
NH2
R1
R1
+
HO
HO
p-TsOH.H2O
O
O
R2
R2
For aryl alkynes:
94-99% selectivity
HO
For aryl/alkyl alkynes:
95-99% selectivity
R2
6
7
8
9
HO
O
OH
* Excellent yields and selectivities
* Broad functionalities tolerance
* Wide substrate scope
* Readily accessible starting materials
* High step- and atom-economy properties
H
N
O
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HO
avenanthramide A
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