Cu-catalyzed oxidative amidation of propiolic acids under air via decarboxylative coupling

Article abstract of DOI:10.1021/ol1004615

Figure presented A Cu-catalyzed aerobic oxidative amidation of propiolic acids via decarboxylation under air has been developed. Only carbon dioxide is produced as byproduct in this approach. The use of air as oxidant makes this method more useful and easy to handle.

Full text of DOI:10.1021/ol1004615

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2000-2003
Cu-Catalyzed Oxidative Amidation of
Propiolic Acids Under Air via
Decarboxylative Coupling
Wei Jia† and Ning Jiao*,†,‡
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking UniVersity, Xue Yuan Rd. 38, Beijing 100083, China, and Shanghai
Key Laboratory of Green Chemistry and Chemical Processes, Department of
Chemistry, East China Normal UniVersity, Shanghai 200062, China
jiaoning@bjmu.edu.cn
Received February 24, 2010
ABSTRACT
A Cu-catalyzed aerobic oxidative amidation of propiolic acids via decarboxylation under air has been developed. Only carbon dioxide is
produced as byproduct in this approach. The use of air as oxidant makes this method more useful and easy to handle.
Transition metal-catalyzed C-N bond formation presents
one of the most useful processes in syntheses of natural
products, pharmaceuticals, and materials.1 In particular,
efficient and novel catalysis for the C(sp)-N bond has
attracted much attention in the synthesis of ynamides due to
their great importance in chemistry and biology.2 Moreover,
they are also versatile substrates for organic transformations.3
Over the past decades, the use of hypervalent alkynyliodo-
nium salts as alkynylating agent4 and the transition metal-
catalyzed coupling of amides with alkynyl halides (eq 1)5
or 1,1-dihalo-1-alkenes (eq 2)6 as two general strategies have
mainly been developed. However, halogenated substrates
were required and halide byproducts were produced in these
methods. Recent advances have been achieved by Stahl and
co-workers7 through the direct amidation of terminal alkynes
using O2 (1 atm) as oxidant (eq 3). In this approach, the
catalyst loading was a little high, and dropwise addition of
alkyne partners (over 4 h) and a large excess of amides were
required to prevent the dimerization of alkynes (eq 3).8
(3) For some recent examples, see: (a) Gourdet, B.; Lam, H. W. J. Am.
Chem. Soc. 2009, 131, 3802. (b) Dooleweerdt, K.; Ruhland, T.; Skrydstrup,
T. Org. Lett. 2009, 11, 221. (c) Zhang, Y.; DeKorver, K. A.; Lohse, A. G.;
Zhang, Y.-S.; Huang, J.; Hsung, R. P. Org. Lett. 2009, 11, 899. (d) Alayrac,
C.; Schollmeyer, D.; Witulski, B. Chem. Commun. 2009, 1464. (e) Garcia,
P.; Moulin, S.; Miclo, Y.; Leboeuf, D.; Gandon, V.; Aubert, C.; Malacria,
M. Chem.sEur. J. 2009, 15, 2129. (f) Sato, A.; Yorimitsu, H.; Oshima, K.
Synlett 2009, 28. (g) Zhang, X.; Hsung, R. P.; Li, H.; Zhang, Y.; Johnson,
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Chang, S. Tetrahedron Lett. 2008, 49, 1745. (i) Oppenheimer, J.; Johnson,
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Lett. 2007, 9, 2361. (j) Oppilliart, S.; Mousseau, G.; Zhang, L.; Jia, G.;
Thue´ry, P.; Rousseau, B.; Cintrat, J.-C. Tetrahedron 2007, 63, 8094. (k)
Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006, 128, 4586.
(l) Couty, S.; Meyer, C.; Cossy, J. Angew. Chem., Int. Ed. 2006, 45, 6726.
(m) Das, J. P.; Chechik, H.; Marek, I. Nat. Chem. 2009, 1, 128.
† Peking University.
‡ East China Normal University.
(1) For some reviews, see: (a) Metal-Catalyzed Cross-Coupling Reac-
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Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461. (d) Beletskaya, I. P.;
Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337. (e) Kunz, K.; Scholz,
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2007, 107, 874.
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Thieme: Stuttgart, Germany, 2005; Vol. 21, p 387. (b) Witulski, B.; Alayrac,
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10.1021/ol1004615  2010 American Chemical Society
Published on Web 04/02/2010

Hence, the development of environmentally benign and
efficient methods for C(sp)-N bond formation is still
important for continued advancements in this area.
could be efficiently inhibited, and the amides loading could
be reduced. Herein, we demonstrate a novel copper-catalyzed
oxidative decarboxylative amidation of propiolic acids lead-
ing to ynamides under air (eq 4).
We initially paid attention to the decarboxylative cross-
coupling of phenyl propiolic acid 1a with 2-oxazolidinone
2a catalyzed by inexpensive CuCl2·2H2O in toluene under
air (Table 1). Interestingly, the expected oxidative decar-
Table 1. Cu-Catalyzed Oxidative Coupling of 1a with 2a via
Decarboxylative Amidationa
The importance of transition metal-catalyzed decarboxyl-
ative cross-coupling chemistry has grown rapidly in recent
years.9,10 We envisioned that decarboxylative cross-coupling
perhaps can provide a novel and attractive approach for
ynamides from amides and propiolic acids because (1) the
carboxylic acids are readily available, easy to store, and
simple to handle, (2) as opposed to organic halides, only
carbon dioxide is produced as byproduct, and (3) the
Glaser-Hay oxidative dimerization product diynes8 (eq 3)
temp time yield of
solvent (°C)
entry
Cu
base
(h) 3aa (%)b
1
2
3
4
5
6c
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
K2CO3
toluene 100
16
5
NaHCO3 toluene 100
pyridine toluene 100
Cs2CO3 toluene 100
Na2CO3 toluene 100
Na2CO3 toluene 100
Na2CO3 toluene 100
Na2CO3 toluene 100
Na2CO3 toluene 100
2.5
9
19
28
0
0
12
12
16.5
13
12
12
12
12
12
83
47
69
trace
70
68
66
56
trace
38
87
48
7d CuCl2·2H2O
8e
9
CuCl2·2H2O
CuBr2
(5) (a) Yao, B.; Liang, Z.; Niu, T.; Zhang, Y. J. Org. Chem. 2009, 74,
4630. (b) Dooleweerdt, K.; Birkedal, H.; Ruhland, T.; Skrydstrup, T. J.
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5, 4011.
10 Cu(OAc)2·H2O Na2CO3 toluene 100
11 CuSO4·5H2O Na2CO3 toluene 100
12 Cu2O
Na2CO3 toluene 100
Na2CO3 xylene 90
Na2CO3 CH3CN reflux 12
Na2CO3 benzene reflux 12
Na2CO3 toluene reflux 12
13 CuCl2·2H2O
14 CuCl2·2H2O
15 CuCl2·2H2O
16 CuCl2·2H2O
a General conditions: 1a (0.2 mmol), 2a (0.4 mmol), Cu (10 mol %),
base (2.0 equiv), solvent (2 mL), under air. b Isolated yield. Homocoupled
dimer product was observed in some reactions. c 5 mol % of CuCl2·2H2O
was employed. d The reaction was carried out in the presence of pyridine
(20 mol %) as additive. e The reaction was carried out under N2.
(6) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem.,
Int. Ed. 2009, 48, 4381.
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boxylative amidation product 3aa was obtained in 5% yield
in the presence of K2CO3 (Table 1, entry 1). When pyridine
or Cs2CO3 was used in this reaction, the expected product
3aa was not produced (Table 1, entries 3 and 4). Gratifyingly,
83% of 3aa was achieved when Na2CO3 was employed as
base (Table 1, entry 5). It is noteworthy that air participated
as an ideal oxidant11 to complete the catalytic cycle, which
makes this approach more economical, readily handled, and
practical. On the contrary, only a trace of 3aa was produced
when the reaction was carried out under N2 (Table 1, entry
8). Attempts of using other copper catalysts such as CuBr2,
1715
.
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Chem. Soc. 2008, 130, 15248. (n) Wang, C.; Tunge, J. A. J. Am. Chem.
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Org. Lett., Vol. 12, No. 9, 2010
2001

Cu(OAc)2·H2O, CuSO4·5H2O, or Cu2O gave lower yields
(Table 1, entries 9-12). After a great deal of screening on
different parameters (see the Supporting Information), we
found that the oxidative decarboxylative amidation catalyzed
by CuCl2·2H2O (10 mol %) with Na2CO3 as base refluxed
in benzene led to the highest efficiency (87% yield, Table
1, entry 15). As we expected, 2.0 equiv of amide 2a loading
efficiently completed this transformation, and the homo-
coupled dimer product was obviously inhibited (9%) (Table
1, entry 15). However, when the reaction was refluxed in
toluene instead of benzene, 3aa was obtained in only 48%
yield, which is lower than that at 100 °C in toluene or
refluxed in benzene (cf. entries 5, 15, and 16).
Table 3. Cu-Catalyzed Oxidative Decarboxylative Amidation of
1a with Different Amides 2a
The scope of the transformation was further expanded to
a variety of propiolic acids (Table 2). It is observed that aryl-
Table 2. Cu-Catalyzed Oxidative Decarboxylative Amidation of
1 with 2a
entry
R1 (1)
2
time (h) yield of 3 (%)b
1
2
3
4-MeO-C6H4- (1b)
4-Me-C6H4- (1c)
3-Me-C6H4- (1d)
3,4-(MeO)2-C6H3- (1e)
(E)-PhCHd CH (1f)
n-Hep (1g)
c-Hex (1h)
2-furyl- (1i)
4-MeO-C6H4- (1b)
4-Me-C6H4- (1c)
3-Me-C6H4- (1d)
2a
28
28
26
46
24
12
20
26
48
31
26
48
60
26
27
48
36
84 (3ba)
76 (3ca)
75 (3da)
86 (3ea)
42 (3fa)
65 (3ga)
65 (3ha)
22 (3ia)
70 (3bb)
61 (3cb)
66 (3db)
65 (3eb)
34 (3fb)
75 (3gb)
79 (3hb)
22 (3ib)
44 (3jb)
4c
5c
6
7
8c
9d
10d
11d
2b
12c,d 3,4-(MeO)2-C6H3- (1e)
13c d (E)-PhCH-CH- (1f)
,
a General conditions: 1a (0.2 mmol), 2 (0.4 mmol), CuCl2·2H2O (10
mol %), Na2CO3 (2.0 equiv), toluene (2 mL), 100 °C, under air. b Isolated
yield. Homocoupled dimer product was observed in some reactions but in
low yield. c The reaction was carried out in the presence of pyridine (2.0
equiv) as additive. d The reaction was refluxed in benzene.
14d
n-Hep (1g)
15c d c-Hex (1h)
,
16c d 2-furyl- (1i)
,
17d
i-Pr (1j)
a General conditions: 1 (0.2 mmol), 2 (0.4 mmol), CuCl2·2H2O (10 mol
%), Na2CO3 (2.0 equiv), toluene (2 mL), 100 °C, under air. b Isolated yield.
Homocoupled dimer product was observed in some reactions but in low
yield. c The reaction was refluxed in benzene. d The reaction was carried
out in the presence of pyridine (2.0 equiv) as additive.
Imidazolidinones were tolerated in this transformation. When
2c was used as nitrogen nucleophile, the expected 3ac was
obtained in 48% yield (Table 3, entry 3). Moreover, an
acyclic nitrogen nucleophile such as N-methyl benzensul-
fonamide 2d could successfully be transformed into 3ad, but
with lower yield (Table 3, entry 4).
A plausible mechanism for the transformation of 1 with
amide 2 is illustrated in Scheme 1. The copper(II) intermedi-
ates A are initially formed, which undergo decarboxylation
to produce the alkynyl copper(II) intermediates B. Nucleo-
philic attack by amide 2 affords the CuII(alkynyl)(amidate)
intermediates C, followed by C-N reductive elimination
leading to the expected products 3. Cu catalyst was then
reoxidized by dioxygen to fulfill the catalytic cycle.
We hypothesize that the reason for the reduction of diynes
formation is probably due to the absence of abundant alkynes
in this catalytic system in which propiolic acids were
and alkyl-substituted propiolic acids are good precoupling
partners for this transformation (22-86% yield). Aryl
propiolic acids with electron-donating substituents proceeded
efficiently in good yields (Table 2, entries 1-4 and 9-12).
Markedly, alkenyl-substituted propiolic acids such as (E)-
5-phenylpent-4-en-2-ynoic acid 1f underwent this transfor-
mation with 2a and 2b leading to 3fa and 3fb, respectively
(Table 2, entries 5 and 13).
Under the optimal reaction conditions, different amides
such as nitrogen nucleophiles were investigated (Table 3).
Oxazolidinones and indoles with electron-withdrawing groups
at the 2- or 3-position converted to the desired ynamides
efficiently in good yields (Table 3, entries 1-2 and 5-6).
2002
Org. Lett., Vol. 12, No. 9, 2010

tives, which are readily available, easy to store, and simple
to handle, as the coupling partner efficiently inhibits the
formation of dimerization product diynes, as well as reduces
the loading of the catalyst and the amide nucleophiles.
Moreover, as opposed to organic halides, only carbon dioxide
is produced as byproduct in this approach. The use of air as
oxidant makes this method more attractive not only for
academic research, but also for industrial application. Further
studies on the reaction scope and synthetic applications are
ongoing in our group.
Scheme 1
.
A Proposed Mechanism for the Direct
Transformation
Acknowledgment. This paper is dedicated to the memory
of Professor Xian Huang. Financial support from Peking
University, National Science Foundation of China (Nos.
20702002 and 20872003) and National Basic Research
Program of China (973 Program) (Grant No. 2009CB825300)
is greatly appreciated. We thank Si Li in this group for
reproducing the results of entries 2 and 5 in Table 2.
employed as precoupling partners. Hence, the bis-alkynyl-
Cu(II) intermediate E,7 which would result in the undesired
diyne byproduct, could not be efficiently formed (Scheme
1).
In summary, we have developed a novel Cu-catalyzed
aerobic oxidative amidation of propiolic acids via decar-
boxylation under air. To the best of our knowledge, this is
the first intermolecular sp-carbon-heteroatom bond forma-
tion via decarboxylation. The use of propiolic acid deriva-
Supporting Information Available: Experimental details
and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL1004615
Org. Lett., Vol. 12, No. 9, 2010
2003