A novel Pd-catalyzed N-dealkylative carbonylation of tertiary amines for the preparation of amides

Article abstract of DOI:10.1039/c4cc07378a

A novel and convenient protocol for the formation of amides via palladium-catalyzed N-dealkylative carbonylation of alkyl tertiary amines has been developed. In the presence of PdCl₂(PhCN)₂, CuO, PhCN and CO, a range of substituents on both aryl iodides and alkyl tertiary amines were compatible with the reaction to afford a series of N,N-disubstituted amides in moderate to excellent yields. This journal is

Full text of DOI:10.1039/c4cc07378a

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A novel Pd-catalyzed N-dealkylative carbonylation
of tertiary amines for the preparation of amides†
Cite this: Chem. Commun., 2014,
50, 14775
Tao Fang, Xu-Hong Gao, Ri-Yuan Tang, Xing-Guo Zhang and Chen-Liang Deng*
Received 18th September 2014,
Accepted 6th October 2014
DOI: 10.1039/c4cc07378a
www.rsc.org/chemcomm
A novel and convenient protocol for the formation of amides via
palladium-catalyzed N-dealkylative carbonylation of alkyl tertiary
amines has been developed. In the presence of PdCl2(PhCN)2, CuO,
PhCN and CO, a range of substituents on both aryl iodides and alkyl
tertiary amines were compatible with the reaction to afford a series
of N,N-disubstituted amides in moderate to excellent yields.
Scheme 1 Transition metal-catalyzed carbonylation of amines for the
synthesis of amides.
The amides are very important functional groups with a variety
of biological activities.1 Amide moieties are found in many
biologically active compounds and natural products and in
numerous agrochemicals and pharmaceuticals.2 Transition metal- gave the highest yield of 3a. Various solvents were also screened
catalyzed carbonylation3 was first reported by Heck et al. in 1974 as (DMF, DMAc, MeCN, toluene, PhCN and dioxane) with PhCN
a powerful synthetic tool for amide formation.4
giving the best results (Table 1, entries 5–10). Notably, when the
The palladium-catalyzed carbonylation of aryl halides and reaction was carried out in a solvent with a high boiling point,
amines in the presence of carbon monoxide has undergone a enhanced reaction activity was observed. Various oxidants were
great deal of development recently5 (Scheme 1, eqn (1)). This also screened (such as ZnO, TBHP, Cu(OAc)2 and CuCl2), how-
reaction is generally limited to primary and secondary amines ever, CuO was found to be the most effective (Table 1, entries 9
because cleavage of the highly stable C–N bond of a tertiary and 11–14). Interestingly, TBHP, a non-metal oxidant, furnished
amine is challenging. Activation of this bond has attracted much 3a in 69% yield. The optimum conditions were found to be three
attention6,7 and a few catalytic systems have been developed for equivalents of CuO at 100 1C (Table 1, entries 15–19). The use of
the Pd-catalyzed carbonylation of tertiary amines.8 These methods O2 and CuO (20 mol%) instead of CuO (3 equiv.) as an oxidant
have some limitations, such as harsh conditions, long reaction lowered the yield of 3a (Table 1, entry 20).
times and low yields. Herein, we report a novel and convenient
The scope of substrates 1 and 2 was then explored (Table 2).
Pd-catalyzed carbonylation of aryl iodides with tertiary amines Substrates 1b–1e, which contain electron donating or electron
and carbon monoxide via C–N bond cleavage for the formation of withdrawing groups, were well tolerated under the optimal
N,N-disubstituted amides (Scheme 1, eqn (2)). Importantly, the conditions to give moderate to excellent yields of the target
protocol can be applied in synthesizing a-keto amide derivatives. products. Treatment of iodobenzene 1b with amine 2a in the
Treatment of 4-iodoanisole (1a) with tributylamine (2a) in presence of Pd(PhCN)2Cl2, CuO and benzonitrile gave 3b in 62%
the presence of Pd(OAc)2 (5 mol%) and CuO (1.3 equiv.) in yield (Table 2, entry 1). The reaction of substrate 1c, bearing a
DMSO at 100 1C for 16 h under a CO atmosphere (1 atm, 25 mL) p-CH3 group, gave an excellent yield of product 3c (Table 2,
gave N,N-dibutyl-4-methoxybenzamide (3a) in 43% yield (Table 1, entry 2). Iodides 1d–1e, which contain electron deficient groups,
entry 1). And then, Pd(MeCN)2Cl2, Pd(PhCN)2Cl2 and Pd(PPh3)4 such as p-CN and p-Br, provided the corresponding products in
were also investigated (Table 1, entries 2–4) and Pd(PhCN)2Cl2 moderate yields (Table 2, entries 3 and 4). Bulky substrates 1f
and 1g also reacted with tributylamine 2a to give target products
3f and 3g in 62% and 68% yield, respectively (Table 2, entries 5
and 6). A moderate yield was also observed when m-CH3 iodo-
College of Chemistry and Materials Engineering, Wenzhou University,
Wenzhou 325035, China. E-mail: dcl78@wzu.edu.cn
benzene 1h reacted with amine 2a under standard conditions
† Electronic supplementary information (ESI) available: Detailed synthetic pro-
cedures and characterization of new compounds. See DOI: 10.1039/c4cc07378a
(Table 2, entry 7). Gratifyingly, double carbonylation products
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Table 1 Palladium-catalyzed carbonylation of 4-iodoanisole (1a) with
tributylamine (2a)a
Table 2 Palladium-catalyzed carbonylation reactions of aryl iodides (1)
with tertiary amines (2)a
Entry Ar–I
1
Amines
Products
Yieldb (%)
Entry
[Pd]
Oxidants
Solvents
T
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
ZnO
TBHP
Cu(OAc)2
CuCl2
CuO
CuO
CuO
CuO
CuO
CuO
DMSO
DMSO
DMSO
DMSO
DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
120
80
43
48
55
46
65
50
Trace
43
72
Trace
35
69
NR
40
78
91
68
64
68
Pd(MeCN)2Cl2
Pd(PhCN)2Cl2
Pd(PPh3)4
2a
62, 3b
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
DMAc
MeCN
Toluene
PhCN
Dioxane
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
2
2a
2a
92, 3c
50, 3d
9
10
11
12
13
14
15c
16d
17e
18
19
20 f
3c
4
5
2a
2a
50, 3e
62, 3f
100
68
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), [Pd] (5 mol%),
oxidant (1.3 equiv.), and solvent (2 mL) at 100 1C under a CO atmo-
6d
2a
68, 3g
b
c
sphere (1 atm, 25 mL) for 16 h. Isolated yields. CuO (2 equiv.).
d
e
f
CuO (3 equiv.). CuO (4 equiv.). CuO (20 mol%) and O2 instead of
CuO (3 equiv.).
7
8
2a
2a
67, 3h
40, 3i
a-keto amide 3i and amide 3j were formed from 1,2-diiodo-
benzene 1i and 1,4-diiodobenzene 1j in 40% and 55% yield,
respectively (Table 2, entries 8 and 9).
The scope of tertiary amines was also examined and the
standard conditions were compatible with tertiary amines 2b–2j
(Table 2, entries 10–18). Alkyl tertiary amines 2b–2f performed
well with 1a, furnishing the corresponding amides 3k–3o in
68–91% yield (Table 2, entries 10–14). Surprisingly, N-ethyl-N-
isopropylpropan-2-amine 2g was compatible with the optimal
conditions forming target product 3p in 37% yield together
with another carbonylation product 3q in 7% yield (Table 2,
entry 15). The reaction of substrate 1a with 2h gave desired
product 3r in 61% yield (Table 2, entry 16). Target products 3s
and 3t were isolated from the reaction between bioactive 2i and
2j with iodide 1a in 76% and 25% yield, respectively (Table 2,
entries 17 and 18). Interestingly, primary amine 2k and secondary
amine 2l are confirmed suitable substrates for the reaction, to
produce carbonylation product 3u and 3a in 62% and 95% yield
respectively (Table 2, entries 19 and 20).
9d
2a
55, 3j
10
11
12
13
14
1a
1a
1a
1a
1a
Net3 2b
NPr3 2c
Nhex3 2d
Noct3 2e
NBn3 2f
70, 3k
70, 3l
90, 3m
91, 3n
68, 3o
37, 3p
Based on previous reports,5h,6c,7d,9 as well as our results, a
possible mechanism was proposed as outlined in Scheme 2.
Initially, the PdLn species inserts into ArI and combines with
aryl iodide and CO to form intermediate A, which then reacts
with secondary amines to give Pd complex C (iminium-type
intermediate B generated with the aid of CuO, which can be
hydrolyzed to produce secondary amines and by-products).
Finally, C then undergoes reductive elimination to afford the
target molecule and the PdLn catalyst is regenerated with CuO.
15d,e 1a
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Zhejiang Province (No. LY14B020011), and Faculty of Chemistry &
Material Engineering, Wenzhou University for their financial
support.
Table 2 (continued)
Notes and references
Entry Ar–I
Amines
Products
Yieldb (%)
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a
Reaction conditions: Pd(PhCN)2Cl2 (5 mol%), CuO (3 equiv.), and
PhCN (2 mL) at 100 1C under a CO atmosphere (1 atm, 25 mL) for 16 h.
b
c
d
e
Isolated yields. 30 h. 24 h. Another carbonylation product N,N-
diisopropyl-4-methoxybenzamide (3q) was isolated in 7% yield.
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Scheme 2 Proposed mechanism for the reaction.
In summary, a protocol for the preparation of amides via the
palladium-catalyzed carbonylation of aryl iodides and tertiary
amines has been described. Pd(PhCN)2Cl2, CuO, CO and benzo-
nitrile were found to be the optimum conditions for this
reaction and a number of aryl iodides and tertiary amines are
tolerated to furnish amides in moderate to excellent yields.
Importantly, the protocol uses commercially available tertiary
amines as the coupling partner. Work to extend the scope and
application of this reaction is currently underway.
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We thank the National Natural Science Foundation of China
(No. 21102104 and 21272177), the Natural Science Foundation of
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Chem. Commun., 2014, 50, 14775--14777 | 14777