Synthesis of amides via palladium-catalyzed amidation of aryl halides

Article abstract of DOI:10.1021/ol103081y

A new and efficient method for the synthesis of amides via palladium-catalyzed C-C coupling of aryl halides with isocyanides is reported, by which a series of amides were formed from readily available starting materials under mild conditions. This transformation could extend its use to the synthesis of natural products and significant pharmaceuticals.(Figure Presented)

Full text of DOI:10.1021/ol103081y

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1028–1031
Synthesis of Amides via Palladium-
Catalyzed Amidation of Aryl Halides
Huanfeng Jiang,* Bifu Liu, Yibiao Li, Azhong Wang, and Huawen Huang
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, P. R. China
jianghf@scut.edu.cn
Received December 20, 2010
ABSTRACT
A new and efficient method for the synthesis of amides via palladium-catalyzed C-C coupling of aryl halides with isocyanides is reported, by
which a series of amides were formed from readily available starting materials under mild conditions. This transformation could extend its use to
the synthesis of natural products and significant pharmaceuticals.
Amides are an important class of N-containing com-
pounds in organic chemistry and also potential precursors
for the synthesis of numerous natural products, potent
pharmaceuticals, and bioactive polymers.1 The most pre-
valent strategy for preparation of amides relies heavily on
activated carboxylic acid derivatives2 or rearrangement
reactions3 induced by a base or acid, which generally
involves tedious procedures or needs anhydrous condi-
tions. Transition-metal-catalyzed reactions have emerged
as an effective tool for the formation of carbon-carbon
and carbon-heteroatom bonds and, hence, have attracted
intensive synthetic attention.4 Recent significant develop-
ments among them are direct amide synthesis from alco-
hols and amines using Ag-,5 Ru-,6 and Rh-based7 catalytic
systems by liberating H2. Based on our research interest in
palladium catalysis, we found a few reported examples
concerning palladium-catalyzed aminocarbonylation for
the synthesis of amides from aryl halides.8 However, the
use of toxic carbon monoxide limited the scope of this kind
of reaction (Scheme 1a).9 Thus, the palladium-catalyzed
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York, 1999. (d) Shendage, D. M.; Froehlich, R.; Haufe, G. Org. Lett. 2004,
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Chem. 2009, 74, 2207.
(3) Yadav, L. D. S.; Garima, V. P. S Tetrahedron Lett. 2010, 51, 739
and references therein.
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M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318. (d) Buchwald, S. L.;
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Am. Chem. Soc. 2002, 124, 6043. (g) Huang, X.; Anderson, K. W.; Zim,
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r
10.1021/ol103081y
Published on Web 02/04/2011
2011 American Chemical Society

Table 1. Optimization of Reaction Conditionsa
Scheme 1. (a) Reported Methods for the Aminocarbonylation
of Aryl Halides and (b) the Method Presented Herein
entry
Pd source/ligand
base
solvent
DMSO
yieldb (%)
1
PdCl2
-
-
n.r
2
PdCl2/PPh3
PdCl2/PPh3
PdCl2/PPh3
PdCl2/PPh3
PdCl2/PPh3
PdCl2/PPh3
PdCl2/PPh3
PdCl2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
n.r
3
KOH
K2CO3
t-BuOK
NEt3
Cs2CO3
CsF
36
4
70
direct amidation of aryl halides under mild conditions and
without toxic chemical waste in tedious procedures re-
mains a challenging goal. Isocyanides, a kind of unsatu-
rated molecule similar to carbon monoxide, would be the
most acceptable to substitute carbon monoxide for the
synthesis of amides, which will not only represent a new
path for palladium-catalyzed synthesis of amides but also
simplify the original strategies (Scheme 1b). To the best
of our knowledge, no examples of utilizing isocyanides as
a source of both a carboxy and amino group have been
described.10,11 Herein, we report this novel and practical
synthesisof amides via palladium-catalyzed C-C coupling
of aryl halides with isocyanides.
5
trace
trace
80
6
7
8
94 (90)
71
9
CsF
10
11
12
13c
14d
15
16
17
18e
PdBr2/PPh3
Pd(OAc)2/PPh3
Pd/C (10%)
PdCl2/PPh3
PdCl2/PPh3
PdCl2/PPh3
PdCl2/PPh3
PdCl2/PPh3
PdCl2/PPh3
CsF
64
CsF
70
CsF
10
CsF
trace
trace
61
CsF
CsF
CsF
CH3CN
1,4-dioxane
DMSO
n.r
CsF
40
CsF
60
In an initial attempt, bromobenzene (1a) was used as a
model compound for the reaction with tert-butyl-isocya-
nide (2a) to screen the reaction conditions (Table 1). In the
presence of the PdCl2 catalyst (5 mol %), no desired
product 3aa was detected without any base (entries 1, 2).
The screening of various bases revealed that the identity of
the base was proven critical to the success of the amino-
carbonylation reaction (entries 3-8). Only trace amounts
of 3aa were detected when t-BuOK and NEt3 were used
(entries 5, 6). The best result was obtained when CsF was
utilized as the base, affording 3aa in 90% yield (entry 8).
Other bases such as KOH and K2CO3 were not very good
for this transformation (entries 3, 4), but Cs2CO3 was also
found to be effective for this reaction system (entry 7).
Further optimization revealed that PPh3 was essential
in this reaction as well. Without PPh3, the yield decreased
to 71% (entry 9). And a lower yield of 3aa was obtained
when PdCl2 was replaced by other palladium catalysts so
far tested (entries 10-12). We next tested the aminocar-
bonylation reaction in the presence of different solvents.
DMSO/H2O (10:1) was superior to any other solvents
a Reactions conditions: All reactions were performed with 1a (1.0
mmol), 2a (1.2 mmol), PdX2 (5 mol %), PPh3 (10 mol %), base (1.0
equiv), and 0.1 mL of H2O in 1.0 mL of solvent at 90 °C for 12 h unless
otherwise noted. n.r. = noreaction. b Yieldsand conversions are based on
1a, detected by GC-MS. Number in parentheses is isolated yield. c 1.0 mL
of H2O was added to the DMSO. d The reactions was carried out under a
nitrogen atmosphere in extra-dried DMSO. e Reaction at 70 °C for 15 h.
(entries 13-17). Notably, the reaction was sluggish when
extra-dried DMSO was employed (entry 14). Lower tem-
perature disfavored the reaction, and the reaction gave a
60% yield after 15 h (entry 18).
With the optimized conditions in hand, we next focused
on the generality of the reaction with regard to both
coupling partners (Scheme 2). Upon repeating the reac-
tion with tert-butyl-isocyanide (2a), it was found that
both electron-poor and -rich phenyl bromides (1b-1p)
can be successfully converted to the corresponding pro-
ducts (3ba-3pa) in good to excellent yields. Generally,
the phenyl bromides with electron-withdrawing groups
(1h-1p) afforded higher yields of the products than that
of electron-donating groups (1b-1e, 1g), and the former
needed much less reaction time. We also found that the
reaction of polycyclic aryl bromides as well as heteroaryl
bromides (1s-1u) proceeded very well to afford the corre-
sponding amides in good yields. Various alkyl, cycloalkyl,
and aryl isocyanides (2a-2f) were also employed to probe
the scope of the reaction substrates. All the isocyanides
were found suitable for this transformation, affording the
corresponding amides in good yields. Even if sterically
bulky isocyanides such as 2e and 2f were used, the reac-
tion gave the corresponding products in acceptable yields,
indicating this transformation can tolerate various sub-
strates with steric bulk and a different electronic nature.
(9) For references on CO surrogates in the palladium-catalyzed
aminocarbonylation, see: (a) Lagerlund, O.; Larhed, M. J. Comb. Chem.
2006, 8, 4. (b) Ren, W.; Yamane, M. J. Org. Chem. 2009, 74, 8332. (c)
Ren, W.; Yamane, M. J. Org. Chem. 2010, 75, 3017. (d) Wannberg, J.;
Larhed, M. J. Org. Chem. 2003, 68, 5750. (e) Wu, X.; Larhed, M. Org.
Lett. 2005, 7, 3327. (f) Wu, X.; Ekegren, J. K.; Larhed, M. Organome-
tallics 2006, 25, 1434. (g) Kaiser, N. F. K.; Hallberg, A.; Larhed, M.
J. Comb. Chem. 2002, 4, 109.
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Chem. Soc. 2010, 132, 17045. (b) Rao, Y.; Li, X.; Danishefsky, S. J. J.
Am. Chem. Soc. 2009, 131, 12924. (c) Manabe, S.; Sugioka, T.; Ito, Y.
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Org. Lett., Vol. 13, No. 5, 2011
1029

Scheme 2. Palladium-Catalyzed Synthesis of Aryl Amides from
Aryl Halide and Isocyanidesa
Scheme 3. Synthesis of Amides from Alkenyl Bromides and
Benzyl Bromidesa
a All reactions were carried out using alkenyl or benzyl bromides
(1.0 mmol), isocyanides (1.2 mmol), PdCl2 (5 mol %), PPh3 (10 mol %),
CsF (1.0 equiv), and 0.1 mL of H2O in 1.0 mL of DMSO at 90 °C for
8-12 h unless otherwise noted. Isolated yield was given.
Scheme 4. Investigation of the Reaction Mechanisma
a Both (a) and (b) were carried using bromobenzene (1.0 mmol),
isocyanides (1.2 mmol), PdCl2 (5 mol %), PPh3 (10 mol %), and CsF
(1.0 equiv) in 1.0 mL of extra-dried DMSO at 90 °C for 8 h.
strong contrast with high reactivity of aryl iodides, the
reaction of aryl chlorides (1a, 1b, 1d, 1i, 1p) could not occur
under the same conditions unless the reaction temperature
was elevated from 90 to 110 °C. The aminocarbonylation
products were obtained only in moderate yields at 110 °C.
Unfortunately, when 2-chlorotoluene and 2-chloroanisole
were used in the reaction, no corresponding products were
detected.
Importantly, alkenyl and benzyl bromides were well
tolerated for this transformation (Scheme 3). When 1-((E)-
2-bromovinyl) benzene (1v) and 1-((Z)-4-bromo-3-propyl-
hept-3-en-1-ynyl) benzene12 (1w) were employed, the reac-
tion carried out effectively, affording the corresponding
products 3va and 3wa in 88% and 81% isolated yields,
respectively. Similarly, benzyl bromides (1x, 1y) can also
couple with isocyanides under our conditions.
To obtain a better understanding of the mechanism of
the present catalytic process, several reactions were per-
formed as shown in Scheme 4. When bromobenzene (1a)
was treated in extra-dried DMSO in the presence of H218O,
a All reactions were carried out using aryl bromides (1.0 mmol),
isocyanides (1.2 mmol), PdCl2 (5 mol %), PPh3 (10 mol %), CsF (1.0
equiv), and 0.1 mL of H2O in 1.0 mL DMSO at 90 o C for 8-12 h unless
otherwise noted. All the aryl chlorides were carried out at 110 °C for 15 h.
Isolated yield was given.
Additionally, the reaction can also be conducted with aryl
chlorides and iodides. As expected, the reaction time
of aryl iodides (1a, 1d) was shortened and the desired
products were furnished in satisfactory yields. Making a
(12) Li, Y.; Liu, X.; Jiang, H.; Feng, Z. Angew. Chem., Int. Ed. 2010,
49, 3338.
1030
Org. Lett., Vol. 13, No. 5, 2011

of isocyanide (2) into A.13 With the aid of the base, -X was
replaced by -OH and the intermediate C formed. A
subsequent reductiveeliminationof intermediateC formed
an unstable product (D), and the active catalyst species
Pd(0) regenerated. Immediately, the unstable product (D)
isomerized to give the final product (3).
Scheme 5. Proposed Mechanistic Possibility
In summary, we have demonstrated an efficient method
for the synthesis of amides via palladium-catalyzed C-C
coupling of aryl halides with isocyanides for the first time,
which is clearly different from the conventional proce-
dures. The reactions are operationally simple and avoid
using toxic carbon monoxide and acid chloride, which
must be used in an anhydrous system. Most importantly,
this transformation may be used to discover new nature
products and significant pharmaceuticals. Studies aimed at
developing related transformations are underway.
Acknowledgment. We thank the National Natural
Science Foundation of China (Nos. 20625205, 20772034,
and 20932002), National Basic ResearchProgramof China
(973 Program) (No. 2011CB808600), the Doctoral Fund of
the Ministryof Education of China (No. 20090172110014),
and Guangdong Natural Science Foundation (No.
10351064101000000) for financial support.
18O-labeled N-tert-butylbenzamide (3aa0) was observed
(Scheme 4a). It was rather interesting that once upon
replacing H2O by CH3OH (4a) as the nucleophile
under our reaction system, a ketimine intermediate
(5aaa) was detected by GC-MS. The methyl benzoate
(6aaa) was obtained after hydrolysis of ketimine (5aaa)
with 2 M aqueous hydrochloric acid at room tempera-
ture (Scheme 4b).
According to these results, we were tempted to assume
the mechanism of the reaction as follows (Scheme 5).
Initial oxidative addition of aryl halide (1) to a zerovalent
Pd species afforded aryl palladium intermediate A. Then
the intermediate B was formed by the migratory insertion
Supporting Information Available. Typical experimen-
tal procedure and characterization for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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Saura-Llamas, I.; Garcıa-Lopez, J. A. Organometallics 2009, 28, 448.
Org. Lett., Vol. 13, No. 5, 2011
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