Copper catalyzed decarboxylative alkynylation of quaternary α-cyano acetate salts

Article abstract of DOI:10.1021/ol400197y

Cu-catalyzed decarboxylative alkynylation of quaternary α-cyano acetate salts with alkynyl bromides and alkynyl chlorides is described. This new reaction can be used for preparing functionalized butynenitrile derivatives.

Full text of DOI:10.1021/ol400197y

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper Catalyzed Decarboxylative
Alkynylation of Quaternary r‑Cyano
Acetate Salts
Yi-Si Feng,† Zhong-Qiu Xu,† Long Mao,† Feng-Feng Zhang,† and Hua-Jian Xu*,†,‡
School of Chemical Engineering, School of Medical Engineering, Hefei University of
Technology, and Key Laboratory of Advanced Functional Materials and Devices,
Anhui Province, Hefei 230009, P. R. China.
hjxu@hfut.edu.cn
Received January 22, 2013
ABSTRACT
Cu-catalyzed decarboxylative alkynylation of quaternary R-cyano acetate salts with alkynyl bromides and alkynyl chlorides is described. This new
reaction can be used for preparing functionalized butynenitrile derivatives.
Transition-metal-catalyzed decarboxylative cross-coupling
reactions are widely studied in organic synthesis as a
novel method.1 These reactions can be used to construct
carbonꢀcarbon2 and carbonꢀheteroatom3 bonds to synthe-
size a variety of organic molecules. A number of studies
on the decarboxylative coupling reactions of aromatic,2aꢀl,4
alkenyl,2m,5 and alkynyl2n,o,6 carboxylic acids have been
† Hefei University of Technology.
‡ Key Laboratory of Advanced Functional Materials and Devices.
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Chem.;Eur. J. 2009, 15, 3666. (b) Ranjit, S.; Duan, Z.; Zhang, P.; Liu,
X. Org. Lett. 2010, 12, 4134. (c) Grainger, R.; Nikmal, A.; Cornella, J.;
Larrosa, I. Org. Biomol. Chem. 2012, 10, 3172. (d) Jia, W.; Jiao, N. Org.
Lett. 2010, 12, 2000. (e) Bhadra, S.; Dzik, W. I.; Gooßen, L. J. J. Am.
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Science 2006, 313, 662. (b) Goossen, L. J.; Rodrıguez, N.; Lange, P. P.;
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€
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4680.
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10.1021/ol400197y
XXXX American Chemical Society

coupling involving the breaking of a Csp3ꢀCOOH bond is
still a challenge.11
Scheme 1. Decarboxylative Coupling Reactions of Aliphatic
Carboxylic Acids
According to the previous studies, the decarboxylative
coupling reactions of R-cyano acetate salts need Pd as the
catalyst. For instance, Liu et al. developed a method to
synthesize R-aryl nitriles through the palladium-catalyzed
decarboxylative coupling of cyanoacetate salts with aryl
halides [Scheme 1, eq 1].7b More recently, they found that a
similar catalytic reaction can be achieved with benzyl
halides [Scheme 1, eq 2].7d Moreover, Li et al. reported
the silver-catalyzed decarboxylative alkynylation of ali-
phatic carboxylic acids with ethynylbenziodoxolones
[Scheme 1, eq 3].8c Herein, we reported the first case a
Cu-catalyzed decarboxylative alkynylation of quaternary
R-cyano acetate salts to synthesize butynenitrile deriva-
tives [Scheme 1, eq 4] that represent interesting organic
intermediates.12
Our study began by examining the cross-coupling of
(bromoethynyl)benzene with potassium cyanoacetate.
Unfortunately, the desired product was not observed
despite many attempts, as we only obtained the rapid
homocoupling product of the alkynylbromide. When we
used potassium 2-cyano-2-methylpropanoate instead of
potassium cyanoacetate with CuI as the catalyst and
DMAc (N,N-dimethylacetamide) as the solvent, the target
reported. More recently, Liu,7 Li,8 and others9 including
our group10 examined transition-metal-catalyzed decar-
boxylative coupling reactions involving the breaking of
Csp3ꢀCOOH bonds. Such reactions are synthetically
useful for making aliphatic compounds but have been
less studied. In particular, a Cu-catalyzed decarboxylative
Table 1. Optimization of the Reaction Conditionsa
yield
entry
CuX
ligand
solvent
DMAc
additive
(%)
1
CuI
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
13
2
CuBr
CuCl
Cu2O
CuBr
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
ꢀ
34
33
15
40
26
24
36
20
27
36
21
60
43
36
59
40
39
50
84(81c)
76
60
48
8
3
ꢀ
4
ꢀ
5
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2O
6
Cu(OAc)2
Cu(CH3CN)4PF6
CuBr2
CuBr
7
8
9
1,10-phen
10
11
12
13
14
15
16
17
18
19
20b
21b
22b
23b
24b
CuBr
TMEDA
CuBr
L-proline
CuBr
1-napthol
CuBr
8-hydroxyquinoline
pyridine
CuBr
CuBr
Ph3P
CuBr
8-hydroxyquinoline
8-hydroxyquinoline
8-hydroxyquinoline
8-hydroxyquinoline
8-hydroxyquinoline
8-hydroxyquinoline
8-hydroxyquinoline
8-hydroxyquinoline
8-hydroxyquinoline
CuBr
mesitylene
diglyme
NMP
CuBr
CuBr
CuBr
DMAc
DMAc
DMAc
DMAc
DMAc
CuBr
CuBr
AgNO3
ꢀ
CuBr
ꢀ
Ag2CO3
a Yield determined by GC methods using benzophenone. All reactions were performed by using potassium 2-cyano-2-methylpropanoate (0.5 mmol)
and (bromoethynyl)benzene (0.75 mmol), under an argon atmosphere for 16 h. b (Bromoethynyl)benzene (1.5 mmol). c Isolated yield.
B
Org. Lett., Vol. XX, No. XX, XXXX

product was detected, although the yield was only 13%
(Table 1, entry 1). To improve the reaction, we examined
the effects of different Cu salts and silver carbonate (entries
2ꢀ8). We found that CuBr was optimal, and Ag2CO3
could promote the reaction. However, common N-ligands,
such as 1,10-phenanthroline, TMEDA (N,N,N0,N0-tetra-
methylethylenediamine), and L-proline, all failed to pro-
mote the reaction (entries 9ꢀ11). We also tried other
types of ligands, such as 1-naphthol, 8-hydroxyquinoline,
pyridine, and Ph3P (entries 12ꢀ15), and found that 8-hy-
droxyquinoline can increase the yield to 60% (entry 13).
Next, weexaminedthe effects ofdifferent solvents. Mostof
the solvents that we investigated gave poor results (entries
16ꢀ19). To improve the yield, we increased the loading of
(bromoethynyl)benzene to 3 equiv and obtained a good
yield of 84% (entry 20). A brief survey of additives was
undertaken in which the optimal result was achieved using
Ag2CO3 (entries 21ꢀ22). We found that the yield dropped
to 48% in the absence of Ag2CO3 (entry 23) and the yield
was only 8% without CuBr (entry 24).
With the above optimized conditions in hand, we ex-
plored the scope of this reaction with various alkynyl
halides (Figure 1). To our satisfaction, the reaction took
place easily to give a good yield and was applicable to a
broad range of alkynyl bromides and chlorides. For
phenylethynyl bromide substrates, electron-donating
groups alkyl (2a, 2c) and ether (2d, 2i, 2j) can all react with
good yields of 79ꢀ82%. Phenylethynyl bromides carrying
electron-withdrawing groups including fluoro (2e), chloro
(2f), bromo (2g), and trifluoromethyl (2h) are all amenable
substrates. An ortho-substituted substrate (2i, 2j) can be
well tolerated. Naphthyl-1-ethynyl bromide (2k), pyridine-
3-ethynyl bromide (2l), and (4-bromobut-1-en-3-ynyl)-
benzene (2m) can also react with good yields. However,
an alkyl-substituted product (2n) was obtained in low yield
(35%).
Figure 2. Decarboxylative alkynylation of R-cyano acetate salts.
All reactions were performed by using R-cyano acetate salts
(0.5 mmol) and alkynyl halides (1.5 mmol), under a argon
atmosphere for 16 h. Yields are isolated.
Figure 1. Decarboxylative alkynylation of potassium 2-cyano-2-
methylpropanoate. All reactions were performed by using
R-cyano acetate salts (0.5 mmol) and alkynyl halides (1.5 mmol),
under an argon atmosphere for 16 h. Yields are isolated.
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Tetrahedron 2012, 68, 2113. (b) Li, Y.; Chen, H.-H.; Wang, C.-F.; Xu,
X.-L.; Feng, Y.-S. Tetrahedron Lett. 2012, 53, 5796.
(11) He, Z.-B.; Hu, M.-Y.; Luo, T.; Li, L.-C.; Hu, J.-B. Angew.
Chem., Int. Ed. 2012, 51, 11545.
(6) Recent examples: (a) Park, A.; Park, K.; Kim, Y.; Lee, S. Org.
Lett. 2011, 13, 944. (b) Chen, Z.-S.; Duan, X.-H.; Zhou, P.-X.; Ali, S.;
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8735.
Org. Lett., Vol. XX, No. XX, XXXX
C

We next explored the scope of the quaternary R-cyano
acetate salts (Figure 2). Potassium 2-cyano-2-methylbu-
tanoate (3a, 3g, 3i), potassium 2-cyano-2-methylpentano-
ate (3l, 3m), and potassium 2-cyano-2-ethylbutanoate (3o)
can react with moderate to good yields ranging from 35 to
75%. Potassium 1-cyanocyclohexanecarboxylate (3b, 3f,
3h), potassium 1-cyanocyclopentanecarboxylate (3c), and
potassium 1-cyanocyclobutanecarboxylate (3d) were all
amenable to decarboxylative alkynylation. Potassium
2-cyano-2-methyl-3-phenylpropanoate (3n) can react with
a moderate yield of 64%. Potassium 2-cyano-2-methyl-
pent-4-enoate (3p) gave a low yield of 30%. However,
R-cyano acetate containing active H failed to give any desired
product (3q) under the above experimental conditions.
The obtained butynenitrile derivatives were subjected to
a series of applications (Scheme 2). We chose R-cyano
alkynes for selective hydrogenation. The R-cyano alkyne
2a was successfully reduced to an alkyl nitrile (I) at room
temperature. R-Cyano alkyne 3m was also selectively
reduced to a β-amine alkyne (II) by LiAlH4. Next, 3,3-
dimethyl-5-phenyl-2(3H)-furanone (IV) was obtained by
hydrolysis of R-cyano alkyne 2a and further reaction of
R-carboxyl alkyne III with silver nitrate. Thus, our method
provides an efficient protocol for the preparation of a
furanone derivative.
Scheme 2. Further Synthetic Transformation of Some Products
R-cyano acetate salts. This new reaction was applicable not
only for alkynyl bromides but also for alkynyl chlorides.
With this new and simple method, we can synthesize a
series of butynenitrile derivatives. Through further trans-
formations, butynenitrile derivatives can be converted to
alkyl nitriles, β-amine alkynes, R-carboxyl alkynes, and
even furanone derivatives.
Acknowledgment. We gratefully acknowledge financial
support from the National Natural Science Foundation of
China (Nos. 21272050, 21072040, 21071040) and the
Program for New Century Excellent Talents in University
of the Chinese Ministry of Education (NCET-11-0627).
Finally, we performed experiments to study the mecha-
nism of this reaction. When this reaction was carried out
under the standard conditions in the presence of 1 equiv of
TEMPO, a radicaltrap, weonlydetecteda trace amount of
product (see Supporting Information). We suspect that the
process of free radicals may be present in the mechanism of
this reaction. Clarification of the detailed mechanism is a
goal in our future research.
Supporting Information Available. Standard experi-
mental procedure and characterization data of products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have successfully developed a
Cu-catalyzed decarboxylative alkynylation of quaternary
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX