Palladium-catalyzed amidation-hydrolysis reaction of gem-dihaloolefins: Efficient synthesis of homologated carboxamides from ketones

Article abstract of DOI:10.1039/b904991f

A simple and efficient palladium-catalyzed amidation-hydrolysis reaction has been developed to afford N-aryl monosubstituted carboxamides in good to excellent yields from easily accessible ketone-derived gem-dihaloolefins and aryl amines.

Full text of DOI:10.1039/b904991f

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Palladium-catalyzed amidation–hydrolysis reaction of gem-dihaloolefins:
efficient synthesis of homologated carboxamides from ketonesw
Wenchao Ye, Jun Mo, Tiankun Zhao and Bin Xu*
Received (in Cambridge, UK) 11th March 2009, Accepted 16th April 2009
First published as an Advance Article on the web 8th May 2009
DOI: 10.1039/b904991f
A simple and efficient palladium-catalyzed amidation–hydrolysis
reaction has been developed to afford N-aryl monosubstituted
carboxamides in good to excellent yields from easily accessible
ketone-derived gem-dihaloolefins and aryl amines.
aqueous dioxane using Cs2CO3 as a base. However, this reaction
gave monosubstituted carboxamide 3aa in only 29% yield
(Table 1, entry 1). When Pd(OAc)2/PPh3 was used, the yield
could be improved to 44% (entry 2). Other ligands in combina-
tion with Pd(OAc)2 led to good yields of 3aa (entries 3 and 4),
while Xantphos afforded the best result in 91% yield (entry 5,
Condition A). In comparison with Cs2CO3, other bases such as
K2CO3, K3PO4, NaOH and t-BuOK failed to give better yields
(entries 6–9). When the solvent was switched to DMF, toluene or
CH3CN, the yield of 3aa decreased (entries 10–12). Lower
reaction temperature led to lower yield (entry 13) and no product
was detected in the absence of palladium and ligand (entry 14).
No di-amidation side-product was detected in the reaction.
Encouraged by the results above, we then extended the
reaction to a range of commercially available arylamines. As
illustrated in Table 2, 1a was readily reacted with functionalized
arylamines bearing ortho, meta and para substitutions on the
aryl ring to give the carboxamides 3 in moderate to good yields
(entries 1–11). The homologation reaction worked better with
arylamines containing electron-donating groups (entries 1 and
2 vs. entry 7; entry 8 vs. entry 9) and with those that are less
Amides are playing critical roles as building blocks, functional
linkages, and pharmacophores in chemistry, biochemistry,
and materials science.1,2 The prevalence of monosubstituted
carboxamides as scaffolds for biologically active molecules3 has
promoted the development of many useful methods for their
preparation, including amidation of amines with carboxylic acids,4
carboxylic anhydrides,5 or carboxyl chlorides,6 carbene catalyzed
amide bond formation of a-reducible aldehydes and amines,7
nickel-catalyzed arylation of a-halocarbonyl compounds,8
palladium-catalyzed aminocarbonylation reaction,9 and one-
carbon homologation of aldehydes.10 Some of these methods,
however, either have limited substrate scope, use additives,4c,d,g,5,7
or are inapplicable for aryl amines10a,b or ketones.10a,d
gem-Dihaloolefins have been extensively studied in recent
years as important and versatile building blocks in synthetic
chemistry.11 Recently, Lautens12 and Urabe13 have developed
several novel and elegant methods allowing the conversion
of gem-dihaloolefins to nitrogen-containing heterocycles via
palladium- or copper-catalyzed reactions. In a program
aimed at developing gem-dihaloolefins as useful synthons,14,15
we found that 2,2-disubstituted-1,1-dihaloalkenes could be
efficiently converted into the target carboxamides in combination
with aryl amines as a successful extension based on Shen’s
work.10a In this study, we report a palladium-catalyzed
amidation–hydrolysis reaction for the efficient synthesis of
N-aryl monosubstituted carboxamides from easily accessible
gem-dihaloolefins and aryl amines (Scheme 1). To the best of
our knowledge, the given approach provides the shortest
and most convenient route to prepare homologated N-aryl
monosubstituted carboxamides from ketones.
Table 1 Optimization for synthesis of monosubstituted carboxamidesab
yieldc
(%)
entry
ligand
solvent
base
T/1C
t/h
d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Pd(PPh3)4
PPh3
DPPP
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
120
7
7
12
12
7
12
12
4
7
4
12
7
12
12
29
44
61
83
91
54
58
85
63
43
54
57
78
0
s-BINAP
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
—
Initial study was performed by examining the reaction of 1a
with p-toluidine in the presence of Pd(PPh3)4 (5 mol%) in
NaOH
t-BuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Toluene
CH3CN
Dioxane
Dioxane
Reflux
Reflux
80
Reflux
a
Reaction conditions: under nitrogen atmosphere, 1a (0.5 mmol), 2a
(1.0 mmol), Pd(OAc)2 (5 mol%), ligand (10 mol%), base (1.0 mmol), and
solvent : H2O = 7 : 1 (1.2 mL); BINAP = 2,20-bis(diphenylphosphino)-
Scheme 1 Formation of amides via homologation of ketones.
Department of Chemistry, Shanghai University, Shanghai 200444,
China. E-mail: xubin@shu.edu.cn; Fax: +86-21-66132065;
Tel: +86-21-66132065
w Electronic Supplementary Information (ESI) available: General
experimental procedures, spectral data for all compounds, 1H and
13C NMR spectra for all compounds.
1,10-binaphthalene, DPPP
=
Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. For
1,3-bis(diphenylphosphino)propane,
b
=
c
d
effect of amount of water, see ESI.w Isolated yield. Pd(PPh3)4 used
alone instead of Pd(OAc)2/ligand combination
ꢀc
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Table 2 Palladium-catalyzed reaction of 1a with aryl aminesa
Table 3 Reaction of gem-dihaloolefins with arylaminesa
a
All reactions were performed under N2 on a 0.5 mmol scale, using
arylamine (2 equiv), Pd(OAc)2 (5 mol%), Xantphos (10 mol%) and
Cs2CO3 (2 equiv) in 1.2 mL of dioxane–H2O (7 : 1) under reflux.
b Isolated yield. c 3 equiv. of 4-bromoaniline was used.
sterically demanding (entry 1 vs. entry 10; entry 2 vs. entry 11).
This reaction was not limited to simple benzene-containing
aromatics, the naphthalene- and pyrimidine-containing
substrates 2l and 2m also afforded 3al and 3am in good yields,
respectively (entries 12–13). However, aliphatic amines such as
butylamine, benzylamine and diisopropylamine failed to react
under the same conditions.
a
All reactions were performed under N2 on a 0.5 mmol scale, using
aniline (2 equiv), Pd(OAc)2 (5 mol%), Xantphos (10 mol%) and
Cs2CO3 (2 equiv.) in 1.2 mL of dioxane–H2O (7 : 1) under
To further explore the scope of this reaction, a variety of
gem-dibromoolefins 1b–l15 were investigated. As shown in
Table 3, this method was compatible with different types of
vinyl dibromides, which were attached with methyl and aryl
groups (entries 1–6), cycloalkyl groups (entries 7–8), diphenyl
groups (entry 9), and alkyl and heteroaryl groups (entry 10).
gem-Dibromoolefins containing electron-donating groups
afforded products in good yields (entries 1 and 2), whereas
the substrates with electron-withdrawing groups such as nitro
group gave slightly lower yields (entry 3). For substrates
having bromo substituents, the yields turned out to be lower
(entries 5 and 6), possibly due to the competitive reactions at
the different reactive bromines. Cycloalkyl substrates 1h and 1i
showed better reactivities and yields toward carboxamides
than the aryl ones (entries 7 and 8). Diphenyl substituted 1j
showed lower reactivity and afforded 3jd in 54% yield (entry 9),
while the replacement from aryl ring to furan gave 3kd in 51%
yield (entry 10). It is noteworthy that under the employed
conditions the styrenyl derivative 1l could be easily converted
to (E)-2-methyl-N,4-diphenylbut-3-enamide 3ld, an analogue
of alkene dipeptide isosteres, which are usually difficult to
access (entry 11).16 In particular, the employment of gem-
dichloroolefin 1m17 could also afford 3aa and 3ab in moderate
yields when reacted with 2a and 2b, respectively (entries 12 and
13). Benzaldehyde derived gem-dibromoolefin gave no desired
carboxamide.
reflux. b Isolated yield. c 2a was used. d 2b was used.
It was well reported that gem-dihaloolefins could be exploited
as substrates for the preparation of carbonyl derivatives.18 Li
and Alper found that 2-phenylpropanoic acid 4a could be
obtained in 23% yield when a mixture of 1a, KOH, Pd(OAc)2
and DPPE was heated to 65 1C for 17 h.19 For comparison, 4a
was produced in 70% NMR yield from 1a after reaction for 20 h
under Condition A (Table 1, entry 5) in the absence of arylamine
(Scheme 2). However, only a trace amount of 3aa could be
observed from NMR when a mixture of 4a4d and 2a was heated
for 10 h under Condition A (Scheme 2), indicating that the
carboxamide 3aa might not be achieved through carboxylic acid
4, which could be generated via intermediate II (Scheme 3, right
circle).19 From the results in Scheme 2, the formation of a C–N
bond appears to be faster than that of the C–O bond in the
presence of arylamine under palladium catalysis.
A
dibromoolefin to carboxamide is demonstrated in
possible mechanism for the conversion of gem-
1
3
Scheme 3. The palladium complex I is obtained when one
of two C–Br bonds in 1 is oxidatively added to the
Pd(0) complex14b and the palladium(II) arylamide III20 was
formed subsequently to afford the target carboxamide 3 by
direct hydrolysis of IV. Currently, we cannot rule out the
ꢀc
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In summary, we have developed a general and efficient method
for the one-pot synthesis of carboxamides from easily available
gem-dihaloolefins by using Pd(OAc)2/Xantphos in aqueous
dioxane. The given approach provides the most convenient
pathway for accessing N-aryl monosubstituted carboxamides
from ketones by one-carbon homologation. The scope and
limitations of the reaction itself and the synthetic applications
for bioactive compounds are under investigation.
We thank the National Natural Science Foundation of
China (No. 20672071), Shanghai Pujiang Program (No.
07pj14043), Shanghai Municipal Education Commission and
SRF for ROCS, SEM for financial support. We also thank
Prof. Hongmei Deng for spectral support.
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ꢀc
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3248 | Chem. Commun., 2009, 3246–3248