Palladium-catalyzed aminocarbonylation of aryl iodides using aqueous ammonia

Article abstract of DOI:10.1016/j.tetlet.2013.07.143

Aminocarbonylation of aromatic iodides using aqueous ammonia in toluene has been developed. Various primary aromatic amides have been efficiently synthesized in good to excellent yields in the presence of catalytic quantities of Pd(OAc)₂/CYTOP292. The usage of aqueous ammonia avoids the handling of two gases in the reaction.

Full text of DOI:10.1016/j.tetlet.2013.07.143

Tetrahedron Letters 54 (2013) 5496–5499
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed aminocarbonylation of aryl iodides using
aqueous ammonia
⇑
Tongyu Xu, Howard Alper
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Aminocarbonylation of aromatic iodides using aqueous ammonia in toluene has been developed. Various
primary aromatic amides have been efficiently synthesized in good to excellent yields in the presence of
catalytic quantities of Pd(OAc)2/CYTOPÒ292. The usage of aqueous ammonia avoids the handling of two
gases in the reaction.
Received 4 July 2013
Revised 25 July 2013
Accepted 27 July 2013
Available online 3 August 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Aminocarbonylation
Aqueous ammonia
Aryl iodide
Transition metal-catalyzed carbonylation reactions have be-
come a powerful tool in organic synthesis.1 As an inexpensive
and readily available C1 source, carbon monoxide can be used to
synthesize various carbonyl products, such as aldehydes, ketones,
carboxylic acids, esters, and amides.2 And a broad scope of sub-
strates has been used for carbonylation reactions, including aro-
matic halides,3 alkenes,4 alkynes,4 etc. Among the different types
of carbonylation reactions, palladium-catalyzed coupling carbonyl-
ation reaction of aromatic halides with different nucleophiles, has
been one of the most important methodologies for the synthesis of
valuable carbonyl containing compounds both from academic and
industrial perspectives.5
The amide is an important motif in natural products, agro-
chemicals, materials, and pharmaceutical molecules.6 Coupling
reagents (e.g., EDC, HOBt, CDI) or activated carboxylic acids
(e.g., acid chlorides, esters, anhydrides) are usually used for the
synthesis of amides.7 Although efforts have been devoted to
the efficient synthesis of amides, this methodology can produce
stoichiometric amounts of waste, which increases the cost of
commercial applications. In this respect, the atom-efficient palla-
dium-catalyzed aminocarbonylation of aromatic halides has
emerged as an alternative and promising strategy. Since the first
work of Heck and co-workers in 1974,8 an impressive amount of
development of the palladium-catalyzed aminocarbonylation of
aromatic halides has been devoted to the synthesis of aromatic
secondary and tertiary amide.9 There are only a few examples
of the preparation of aromatic primary amides via the palla-
dium-catalyzed aminocarbonylation. Some ammonia equiva-
lents10 have been developed to prepare primary amides, such
as hexamethyldisilazane (HMDS), formamide, N-tert-butylamine,
hydroxylamine, and
a titanium–nitrogen complex. However
ammonia, which is one of the most important chemical feed-
stocks for the chemical industry available at low cost, is the
most desirable source of nitrogen to synthesize primary amides.
Recently, Beller and Wu developed palladium catalysts based on
BuPAd2 or dppf as ligands for the synthesis of primary amides
using gaseous ammonia as reagent and base. Although important
progress has been accomplished,11 the required handling of two
gases still restricts the application of the method. Herein we re-
ported a palladium-catalyzed aminocarbonylation of aromatic io-
dides to synthesize primary amides using aqueous ammonia as
the nitrogen source.
In our initial studies, the aminocarbonylation of p-iodotoluene
1a was chosen as the reactant for the optimization of the
reaction conditions (Table 1). In the presence of 5 mol %
Pd(OAc)2 and 5 mol % dppf in 1,4-dioxane/aqueous ammonia
(v/v = 15:1), amide 2a was obtained in 31% isolated yield (entry
1). PPh3 afforded 2a in 35% yield while a phenyl-substituted
phospha-adamantane ligand, CYTOPÒ29212 (1,3,5,7-tetramethyl-
2,4,8-trioxa-6-phenyl-6-phosphaadamantane) gave amide 2a in
40% yield (entries 2 and 3). Additional base such as Cs2CO3 or
NaHCO3 did not improve the yield (entries 4 and 5). When the
⇑
Corresponding author. Tel.: +1 613 562 5189; fax: +1 613 562 5871.
E-mail address: howard.alper@uottawa.ca (H. Alper).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.143

T. Xu, H. Alper / Tetrahedron Letters 54 (2013) 5496–5499
5497
Table 1
Screening of the reaction conditionsa
I
CONH2
Pd/L
solvent, temp
CO
+ NH3 (aq)
+
CH3
CH3
2a
1a
Entry
Cat. (mol %)
Ligand
Solvent
Temp. (°C)/PCO (psi)
2ab (%)
1
2
5
5
5
5
5
5
5
5
5
5
5
5
2
0.5
2
2
2
dppf
PPh3
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
THF
100/200
100/200
100/200
100/200
100/200
100/200
100/200
100/200
100/200
100/200
100/200
80/200
100/200
100/200
100/100
100/100
100/50
100/100
130/100
130/100
130/100
130/100
130/100
130/100
31
35
40
35
25
65
35
86
93
70
19
30
93
50
93
88
<5
47
95
98
<5
93
96
94
3
CYTOPÒ292
CYTOPÒ292
CYTOPÒ292
CYTOPÒ292
CYTOPÒ292
CYTOPÒ292
CYTOPÒ292
CYTOPÒ292
CYTOPÒ292
CYTOPÒ292
CYTOPÒ292
CYTOPÒ292
CYTOPÒ292
PPh3
4c
5d
6
7e
8
9
Toluene
DCE
H2O
10
11f
12
13
14
15
16
17
18g
19h
20h
21h
22h
23h
24h
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CYTOPÒ292
CYTOPÒ292
CYTOPÒ292
CYTOPÒ292
CYTOPÒ292
DavePhos
JohnPhos
2
2
0.5
0.25
0.5
0.5
0.5
XPhos
a
b
c
Reagents and conditions: 0.5 mmol 1a, 0.2 mL aqueous ammonia, Pd(OAc)2/P = 1/2, entries 1–5, 3 mL solvent (0.17 M 1a); entries 6–24, 10 mL solvent (0.05 M 1a); 20 h.
Isolated yield.
2 equiv Cs2CO3.
2 equiv NaHCO3.
0.1 mL NH3.
10 mol % TBAI was added.
8 h.
d
e
f
g
h
3 h.
reaction concentration of 1a was reduced to 0.05 M, the yield in-
creased to 65% (entry 6). The yield decreased when the amount
of aqueous ammonia was reduced to 0.1 mL (entry 7).
CYTOPÒ292; and condition B, where the reaction was carried out
at 130 °C but with shorter reaction times, in the presence of
0.5 mol % Pd(OAc)2/1 mol % CYTOPÒ292. Amides with ortho-,
meta-, or para-alkyl-substituents were isolated in high yields
(85–98%, 2a–d). Both electron-rich and electron-deficient aryl io-
dides gave good yields of the primary amide (2e–i). The aryl io-
dides were selectively transformed to the corresponding amides
in the presence of other halogen substituents (F, Cl, Br) (2e–g). In
the case of 1-bromo-3-iodobenzene, the aminocarbonylation
should be effected at 120 °C under condition A. 1-Iodonaphthalene
and 3-iodothiophene were also converted to the primary amides in
high yield (2j and 2k).
A one gram scale reaction of 1a was carried out under condition
B. After heating at 130 °C for 6 h, the reaction mixture was cooled,
washed with water and then the organic phase was concentrated,
affording the amide 2a in 94% yield. This result indicates the poten-
tial application of the methodology.
Different solvents were tested for this reaction (entries 8–11).
When the reaction was carried out in THF and DCE, 2a was ob-
tained in 86% and 70% yields. Toluene was the best solvent and
afforded 2a in 93% yield. Water was also tried in the presence of
10 mol % tetrabutylammonium iodide (TBAI), only affording 2a in
19% yield. The yield decreased dramatically at a lower reaction
temperature such as at 80 °C (entry 12), indicating that tempera-
ture plays an important role in the reaction. The loading of the cat-
alyst could be reduced to 2 mol % without decreasing the yield
under lower pressure (100 psi) of carbon monoxide, while PPh3
afforded 88% yield (entries 13–17). When we carried out the reac-
tion at 130 °C with 0.5 mol % Pd(OAc)2 and 1 mol % CYTOPÒ292, the
aminocarbonylation could be completed in 3 h and afforded 2a in
98% yield (entries 18–21). Other ligands such as DavePhos, John-
Phos, and XPhos were studied under these conditions, affording
2a in slightly lower yields (93–96%, entries 22–24).
In summary, the palladium-catalyzed aminocarbonylation of
aromatic iodides using aqueous ammonia in toluene has been
developed. The usage of aqueous ammonia avoided the handling
of two gases and could be easily scaled up. Various primary aro-
matic amides have been efficiently synthesized in good to excel-
lent yields in the presence of Pd(OAc)2/CYTOPÒ292.
A variety of different aryl iodides were transformed to the cor-
responding primary amides using two types of reaction conditions
(Scheme 1): Condition A, where the reaction was carried out for
20 h at 100 °C in the presence of 2 mol % Pd(OAc)2/4 mol %

5498
T. Xu, H. Alper / Tetrahedron Letters 54 (2013) 5496–5499
CONH2
I
®
Pd(OAc)2/CYTOP 292
+
NH3 (aq)
+
CO (100 psi)
R
R
toluene (0.05 M)
1
2
CONH2
CONH2
CONH2
CONH2
Me
Me
2c
2d
2a
2b
A: 90%
B: 97%
A: 90%
B: 93%
A: 93%
A: 85%
B: 94%
B: 98%
CONH2
CONH2
CONH2
CONH2
Br
F
Cl
OMe
2h
2g
2e
2f
A: 88%
B: 95%
A: 95%
B: 92%
A: 94%
B: 97%
A: 90% (120 °C)
CONH2
CONH2
CONH2
S
O
Br
CONH2
Me
2i
2j
2k
2a (one gram scale)
A: 96%
B: 95%
A: 95%
B: 96%
A: 92%
B: 90%
B: 94%
Scheme 1. Palladium-catalyzed aminocarbonylation of aryl iodides using aqueous ammonia. Reagents and conditions A: 0.5 mmol 1, 0.2 mL aqueous ammonia, 2 mol %
Pd(OAc)2, 4 mol % CYTOPÒ292, 10 mL toluene, PCO = 100 psi, 100 °C, 20 h. Conditions B: 0.5 mmol 1, 0.2 mL aqueous ammonia, 0.5 mol % Pd(OAc)2, 1 mol % CYTOPÒ292, 10 mL
toluene, PCO = 100 psi, 130 °C, 3–8 h.
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Acknowledgments
We are grateful to Cytec Industries, Inc., and to the Natural Sci-
ences and Engineering Research Council of Canada for supporting
this research.
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Supplementary data (experimental procedures, 1H and 13C NMR
data) associated with this article can be found in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2013.07.143.
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