Room temperature palladium-catalyzed hydroarylation of ynamides in water

Article abstract of DOI:10.1016/j.tetlet.2020.151725

Pd-catalyzed hydroarylation reactions of ynamides were studied in pure water in the presence of the water-soluble industrial TPPTS ligand in comparison with the use of PCy₃ or P(o-Tol)₃. Pd(OAc)₂/TPPTS (3,3′,3″-phosphanetriyltris(benzenesulfonic acid) trisodium salt) system exhibited high activity for the conversion of various aryl- and alkyl-ynamides in the presence of arylboronic acids bearing either electron-donating and electron-withdrawing groups. The hydroarylation reactions allowed the formation of (Z)-α,β-disubstituted enamides as major compounds in the case of arylynamides and as unique isomer in the case of alkylynamides. The reaction conditions were optimized and the presence of a base was necessary for the efficient preparation of enamides at room temperature. Conversely, α,β-disubstituted or β,β′-disubstituted enamides were isolated as major single stereoisomers and at room temperature in water in the absence of any additive by using PCy₃ or P(o-Tol)₃, respectively. The best activity was observed for oxazolidin-2-one, whereas other a tosylynamide was non-reactive.

Full text of DOI:10.1016/j.tetlet.2020.151725

Journal Pre-proofs
Room temperature palladium-catalyzed hydroarylation of ynamides in water
Antonella Di Nicola, Vincenzo Marsicano, Antonio Arcadi, Véronique Michelet
PII:
S0040-4039(20)30148-9
DOI:
https://doi.org/10.1016/j.tetlet.2020.151725
TETL 151725
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 November 2019
3 February 2020
7 February 2020
Please cite this article as: Di Nicola, A., Marsicano, V., Arcadi, A., Michelet, V., Room temperature palladium-
catalyzed hydroarylation of ynamides in water, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.151725
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Room temperature palladium-catalyzed
hydroarylation of ynamides in water
Antonella Di Nicola, Vincenzo Marsicano, Antonio Arcadi* and Véronique Michelet*
X
Pd(OAc)2
Pd(OAc)2
or
O
TPPTS
P(o-tolyl)3
H
Na2CO3
N
B(OH)2
O
R
X
R
O
Z:E from 60:40
to 100:0
N
O
Pd(OAc)2
P(Cy)3
H
O
X
N
O
R
Z:E 0:100
R = Ph, 4-Me-C6H4, 4-Cl-C6H4, 4-MeO-C6H4, n-Bu, Bn, cyclopropyl
X = H, 4-MeO, 3-Cl, 3-NO2, 3-F

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Room temperature palladium-catalyzed hydroarylation of ynamides in water
Antonella Di Nicolaa,b, Vincenzo Marsicanoa,c, Antonio Arcadia* and Véronique Micheletc *
a Dipartimento di Scienze Fisiche e Chimiche, Università dell’Aquila, Via Vetoio, 67010 Coppito (AQ), Italy
b Institut de Recherche de Chimie Paris PSL Research University, Chimie ParisTech-CNRS, 11 rue P. et M. Curie, 75005, Paris, France
c University Côte d’Azur, Institut de Chimie de Nice, UMR 7272 CNRS, Parc Valrose, Faculté des Sciences, 06100 Nice, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Pd-catalyzed hydroarylation reactions of ynamides were studied in pure water in the presence of
the water-soluble industrial TPPTS ligand in comparison with the use of PCy3 or P(o-Tol)3.
Pd(OAc)2 / TPPTS (3,3′,3″-phosphanetriyltris(benzenesulfonic acid) trisodium salt) system
exhibited high activity for the conversion of various aryl- and alkyl-ynamides in the presence of
arylboronic acids bearing either electron-donating and electron-withdrawing groups. The
hydroarylation reactions allowed the formation of (Z)-α,β-disubstituted enamides as major
compounds in the case of arylynamides and as unique isomer in the case of alkylynamides. The
reaction conditions were optimized and the presence of a base was necessary for the efficient
preparation of enamides at room temperature. Conversely, α,β-disubstituted or ,β’-disubstituted
enamides were isolated as major single stereoisomers and at room temperature in water in the
absence of any additive by using PCy3 or P(o-Tol)3, respectively. The best activity was observed
for oxazolidin-2-one, whereas other a tosylynamide was non-reactive.
Available online
Keywords:
Ynamides
Palladium
Boronic acids
Hydroarylation
Enamides
2009 Elsevier Ltd. All rights reserved.
Ynamides have become important building blocks for the synthetic chemist and have been recognized as modern functional groups
towards complex molecular derivatives.1 Although the first synthesis of ynamides was reported in 1972,2 the reactions implemented were
often not very effective, and giving access to a rather small panel of compounds. Thanks to the development of organometallic cross-
couplings, ynamides have become more accessible, in particular with a very large possible diversity in the substrates. Over the past 20
years, the preparation of ynamides has therefore been efficiently described and pioneered by Evano,3 Hsung4 and Stahl,5 giving great
opportunities for the study of the reactivity of this activated carbon-carbon triple bonds, with both electrophilic and nucleophilic
properties. Various synthetic transformations have therefore been described highlighting the exponential interest of ynamides.6 In this
context, many transformations implying hydrometalation and C-C bond formations have offered an array of novel structural enamides7
starting from ynamides. For example, Lam and co-workers8 successfully described the Rh-catalyzed addition of boronic acids to ynamides
that produced β,β′-disubstituted enamides in good regioselectivity (scheme 1, Eq. 1). The group of Zhu proposed two methods, based on
a Pd-catalyzed addition of boronic acids to N-sulfonyl ynamides, giving either (E)- or (Z)-α,β-disubstituted enamides depending on the
reaction conditions (scheme 1, Eq. 2).9 Following our continuous research programs dedicated to the development of green catalytic
systems10 such as catalysts in water,11 we wondered if the reactivity of ynamides would be possible in organoaqueous systems. Water
generally appears as an eco-friendly solvent12,13 and we and others have been involved in several C-C bond transformations in water in
the presence of the industrial commercially available TPPTS (3,3′,3″-phosphanetriyltris(benzenesulfonic acid) trisodium salt) ligand14 as
well as in the presence of other water-soluble ligands.15 We and others have also proposed new water-soluble ligands for the Rh-catalyzed
hydroarylation of alkynes16 as well as efficient conditions for Pd- and Rh-catalyzed hydroarylation of propargylic alcohols.17

2
O
O
H
RhLn
X
R2
+
R2B(OH)2
N
R1
Eq. 1
Eq. 2
N
X
R1
X = C, O
Pd(OAc)2
P(3-tol)3
O
O
R2
X
H
+
R2B(OH)2
N
R1
N
X
70°C
EtOH
R1
X = C, O
(E)
Na2CO3, dioxane (Z)
Figure 1. Rh- and Pd-catalyzed hydroarylation of ynamides.
As far as palladium-catalyzed hydroarylation in water is concerned, to the best of our knowledge, no examples were previously
disclosed with ynamides.18 We wish to report herein our results toward the discovery of water-soluble palladium system allowing
hydroarylation of ynamides under mild conditions. We initiated this study by investigating the reaction between the known ynamide 1a
and (4-methoxyphenyl)boronic acid in the presence of Pd(OAc)2 / water-soluble ligand combinations in water (Figure 2).
OMe
Pd(OAc)2
OMe
(x mol%)
L (y mol%)
O
O
O
H
OMe
+
O
H
N
+
N
N
O
O
Na2CO3
(z equiv.)
water
B(OH)2
(Z or E)
1a
2A
3B
Figure 2. Model reaction used for the optimization of Pd(OAc)2 / water soluble ligand catalyzed reaction conditions in pure water.
The results are summarized in Table 1. Based on our previous Pd- and Rh-catalyzed reactions in water, we anticipated that the use of
Na2CO3 would be beneficial. Pleasingly, we observed that the addition of arylboronic acid to ynamide 1a, in the presence of TPPTS
ligand, was possible in water at 80°C within one hour and at 50°C and room temperature under prolonged stirring (Table 1, entries 1-3).
The corresponding trisubstituted enamide 3B was obtained as the expected major product considering the reaction conditions, and as a
major Z stereochemistry. Increasing the molar percentage of ligand at room temperature led to a higher ratio of 3B and a Z/E ratio of 7/3
(Table 1, entries 4-6). The efficiency and selectivity of TPPTS ligand was further demonstrated as the use of the carboxylated analogue
m-TPPTC11a allowed a 40:60 regioisomer mixture and a poor selectivity was observed without ligand (Table 1, entries 7-11). The influence
of the quantity of base was investigated showing that 1.5 equivalents was the best ratio for regio- and stereoselectivities (Table 1, entries
12-15). Lowering the amount of palladium catalyst or switching to Pd(PPh3)4 gave lower yields (Table 1, entries 16-18).
Table 1. Optimization of the reaction conditions in pure water.
Ratio b A:B
Ratiob Z:E (B)
Yielda %
Entry [Pd] mol%
L (mol%)
TPPTS (9)
TPPTS (9)
TPPTS (9)
TPPTS (15)
TPPTS (15)
TPPTS (15)
m-TPPTC (9)
m-TPPTC (9)
/
Na2CO3 (equiv)
T (°C)
t (h)
1:1
72
72
89
88
95
1:1
2:3
7:3
11:0
72
89
88
95
1
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
/
89
2:3
2
88
7:3
3
95
11:0
4
5
50
rt
24
24
4
18:72
10:90
40:60
40:60
55:45
50:50
58:42
50:50
30:70
35:65
10:90
55:45
6:4
7:3
nd
74
98
55
57
75
81
60
77
88
92
90
67
6
7
50
50
80
50
rt
8
4
nd
9
1.5
1.5
1.5
0.5
/
2
nd
10
11
12
13
14
15
16
/
24
24
1
nd
/
nd
/
80
50
50
50
80
nd
TPPTS (9)
TPPTS (9)
TPPTS (9)
/
24
6
1:1
7:3
1:1
nd
1
0.5
1.5
6
24

3
17
18
1.5
3c
TPPTS (6)
/
1.5
1.5
80
rt
2
40:60
6:4
/
62
/
48
a Isolated yield. b Determined by 1HNMR. c Pd(PPh3)4 instead of Pd(OAc)2.
nd = not determined.
We then prepared various functionalized ynamides 1b-h according to the method described by the group of Stahl5 (Supporting
information) and explored the scope of the transformation. Under optimized reaction conditions (Table 1, entry 6, [Procedure A]),
we studied the influence of the arylethynyl ynamides 1 on the regio- and stereochemistry of the process (Figures 3, 4). In the case
of chloro-, methoxy- and non-substituted arylethynyl ynamides (1b-d), the B isomers were always obtained as major regioisomers
(Figure 4). The stereoselectivity was also determined as being Z for the major isomer, which is generally the case for Rh-catalyzed
hydroarylation19 of alkynes and which is in accordance with literature for Pd-catalyzed process.20 The overall yields for the
hydroarylation reactions were generally modest to good (from 46% to 93%), but the (Z/E) stereoisomers could unfortunately not be
separated.
R2
R2
R2
Pd(OAc)2 (3 mol%)
TPPTS (15 mol%)
O
O
O
H
R1
O
H
N
N
O
N
+
O
+
Na2CO3 (1.5 equiv.)
water, rt, 24 h
B(OH)2
(Z or E)
R1
R1
1b-1d
4-7A
8-11B
OMe
H
OMe
OMe
O
O
O
H
H
O
O
O
H
O
Ar
N
O
N
Ar
H
O
+
N
H
O
N
H
+
N
N
O
O
N
O
O
+
5
MeO
MeO
7
Cl
8, 46%
(Z):(E) = 6:4
6
9
9:5
85:15, 62%
10
(Z):(E) = 7:3
10:6
80:20, 93%
11
11:7
85:15, 72%
(Z):(E) = 7:3
(Z):(E) = 7:3
Ar = 4-MeOC6H4
Figure 3. Scope of the Pd/TPPTS-catalyzed hydroarylation reaction in water.
We therefore decided to study the hydroarylation on alky-substituted alkynes, expecting a higher difference of polarizability of
the C-C triple bond and thus a better regioselectivity. Indeed, in the case of the alkylethynyl ynamides, we were pleased to see that
the (Z)-α,β-disubstituted enamides were the only obtained isomers. The hydroarylation was efficiently conducted in the presence
arylboronic acids bearing electron-donating and electron-withdrawing groups, leading to enamides 12-17 within 42% to 86%. The
presence of the oxazolidin-2-one was found to be crucial for this process as an inseparable mixture of 18 and 19 was obtained with
a low yield of 38%.
R2
O
Pd(OAc)2 (3 mol%)
TPPTS (15 mol%)
R2
O
O
N
R1
+
(1)
H
N
O
Na2CO3 (1.5 equiv.)
water, rt, 24 h
R1
1e-g
B(OH)2
(Z)-12-17
OMe
OMe
NHCOMe
O
O
O
H
H
H
N
O
N
N
O
O
Bn
n-Bu
n-Bu
(Z)-12, 83%
(Z)-13, 42%
(Z)-14, 81%
F
NO2
Cl
O
O
O
H
H
N
O
N
O
H
N
O
Bn
(Z)-15, 86%
(Z)-16, 54%
(Z)-17, 76%
Pd(OAc)2 (3 mol%)
TPPTS (15 mol%)
Ts
N
H
n-Bu +
(2)
H
+
Na2CO3 (1.5 equiv.)
water, rt, 24 h
38%
Ts
N
Ts
N
n-Bu
1h
n-Bu
2 : 1
B(OH)2
18
19
Figure 4. Scope of the Pd/TPPTS-catalyzed hydroarylation reaction in water.
On the basis of previous results on rhodium- and palladium-catalyzed hydroarylation of propargylic amines with aryl boronic
acids, we envisaged that a suitable choice of the palladium ligand and additives should provide a straightforward entry into the ’-
disubstituted enamides by determining an inversion of the regiochemistry.21 By contrast with the expected results and the literature’s
data,22 it was found that by using tricyclohexylphosphine23 as ligand instead of TPPTS, the addition of AcOH was not necessary to
obtain the hydroarylated products but influenced the regio- and the stereo-selective outcome of the reaction in comparison with the
results observed with the procedure A (entry 2 vs. entry 3 of Table 2). Surprisingly, the temperature of the reaction seemed to play
a key role on directing the reaction toward the prevalent formation of the ’-disubstituted (E) enamide 6 when the

4
tricyclohexylphosphine was used as the ligand in the absence of any additive at room temperature [Procedure B] (Table 2, entry 4).
Moreover, the use of the P(o-Tol)3 as the ligand [Procedure C] achieved the prevalent formation of ,-disubstituted enamide 6 as
only (Z) isomer. In all cases of Table 2, the ’-disubstituted enamide 10 was isolated as only the (E) stereoisomer. The structure
of enamides 6 and 10 were assigned on the basis of the chemical shift of the vinylic proton and was confirmed unambiguously by
NOE experiments (See supporting Information).
Table 2. Role of additives, ligands and temperature in the Pd-catalyzed hydroarylation reaction in water
OMe
Pd(OAc)2
OMe
(3 mol%)
L (15 mol%)
O
O
O
H
OMe
O
H
N
N
O
+
N
O
+
Additive
(z equiv.)
water
B(OH)2
(Z) 10
(E) 6
1b
Entrya
L
Additive
Time (h)/
Temp
(Z) 10
% yieldb
(E) 6
% yieldb
-
CH3COOH
(1.3 equiv)
CH3COOH
(1.3 equiv)
-
1
2
TPPTS
PCy3
24 / 50
-
0.7/ 50
55
29
3
4
4
PCy3
PCy3
PCy3
1/50
1 / rt
50
22
43
49
69
30
-
Na2CO3
(1.5 equiv)
24 / rt
5
P(o-Tol)3
-
6 / rt
66
17
a Reaction Conditions: 1b (0.6 mmoles), 4-methoxyphenylboronic acid (1.8 mmoles), L (0.045 mmol), Pd(OAc)2 (0.018 mmoles) in 1 mL water, rt. b Isolated
yield.
The extension of the procedures B and C to various ynamides 1 confirmed the pivotal role of the ligand on the regioselective
outcome of the hydroarylation carried in water at room temperature (Table 3). The trans- addition of boronic acids to ynamides 1
was never observed by applying procedures B-C.
Table 3. Scope of the Pd/PCy3- vs. Pd/P(o-Tol)3-catalyzed hydroarylation reaction in water.
Entry Procedure
1
Time (h)
,
,
Regioisomer
% yieldb
Regioisomer
% yieldb
7 (56)
1b
1b
1c
1c
1d
1
2
3
4
5
6
7
8
B
C
B
C
B
C
B
C
3
5
(Z) 11 (19)
(Z) 11 (77)
(Z) 9 (11)
(Z) 9 (68)
(Z) 8 (9)
7 (13)
5 (64)
9
7
5 (17)
24
16
7
(Z) 4 (60)
(Z) 4 (13)
(E) 20 (44)
(E) 20 (18)
1d
1g
1g
(Z) 8 (63)
(Z) 14 (18)c
(Z) 14 (46)c
5
a Reaction Conditions: 1 (0.6 mmoles), boronic acid (1.8 mmoles), L (0.045 mmol), Pd(OAc)2 (0.018 mmoles) in 1 mL water, rt. b Isolated yield.c NMR
yield of the unseparated regioisomers.
O
H
OMe
N
O
Bn
(E)-20
In conclusion, we have studied Pd-catalyzed hydroarylation reactions of ynamides in pure water in the presence of the water-
soluble industrial TPPTS ligand in comparison with the employment of PCy3 or P(o-Tol)3 as an alternative ligand. The optimization
of the reaction conditions showed that this process could nicely be conducted at room temperature and allowed a green access to
enamides. The efficiency of the catalytic system Pd(OAc)2 / TPPTS (3,3′,3″-phosphanetriyltris(benzenesulfonic acid) trisodium
salt) was evaluated for various aryl- and alkylynamides in the presence of arylboronic acids bearing either electron-donating and
electron-withdrawing groups. The regio- and stereoselectivity of the hydroarylation reaction in water was in favor of the (Z)-α,β-
disubstituted enamides and unique isomer in the case of alkylynamides. Conversely, the alternative employment of PCy3 or P(o-

5
Tol)3 as the ligand achieved the prevalent formation of the ’-diaryl enamide or the α,β-disubstituted enamide as a single
stereoisomer in all examined cases, respectively. The best activity was observed for oxazolidin-2-one. Further studies are currently
dedicated to test the efficiency and selectivity other reactivities of aryl- and alkylynamides.
Funding Information
This work was financed by the Ministère des Affaires Etrangères et du Développement International and the Università Italo
Francese (Galileo Program G15-69) as well as Erasmus programmes. This work was also supported by the Centre National de la
Recherche Scientifique (CNRS) and the University Côte d’Azur.
Acknowledgments
This work was supported by the Università dell'Aquila, the Centre National de la Recherche Scientifique (CNRS) and the
University Côte d’Azur. This study was partly supported by research funding from the Canceropôle PACA, Institut National du
Cancer and Région Sud. We gratefully acknowledge the Università dell'Aquila for grants to AdN and VM.
Supplementary Material
References and notes
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Highlights
1. Pd-catalyzed hydroarylations of ynamides in water with the water-soluble TPPTS ligand
2. Regio- and stereoselectivity in favor of the (Z)-α,β-disubstituted enamides
3. ’- or α,β-disubstituted enamides in the presence of PCy3 or P(o-Tol)3 ligands

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