Synthesis of 2-alkyl-2-arylcyanoacetates via CuI/sodium picolinate-catalyzed direct arylation of α-substituted cyanoacetates

Article abstract of DOI:10.1016/j.tetlet.2013.05.057

CuI/sodium picolinate-catalyzed direct arylation of α-substituted cyanoacetates takes place at 60 C in the presence of Cs₂CO ₃ and 4 A? molecular sieve, affording 2-alkyl-2- arylcyanoacetates in good to excellent yields. Both electro

Full text of DOI:10.1016/j.tetlet.2013.05.057

Tetrahedron Letters 54 (2013) 3889–3891
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2-alkyl-2-arylcyanoacetates via CuI/sodium
picolinate-catalyzed direct arylation of a-substituted cyanoacetates
b
b,
Siwei Xie a, Peng Qin a, Meng Li a, Xiaojing Zhang a, , Yongwen Jiang , Dawei Ma
⇑
⇑
a Shenyang Pharmaceutical University, 103 Wenhua Lu, Shenyang 110016, PR China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032,
PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 March 2013
Revised 2 May 2013
Accepted 13 May 2013
Available online 21 May 2013
CuI/sodium picolinate-catalyzed direct arylation of
the presence of Cs2CO3 and 4 Å molecular sieve, affording 2-alkyl-2-arylcyanoacetates in good to
excellent yields. Both electron-rich and electronic-deficient aryl iodides, and some functionalized
a-substituted cyanoacetates takes place at 60 °C in
a-substituted cyanoacetates are compatible with the reaction conditions, thereby allowing diverse
synthesis of 2-alkyl-2-arylcyanoacetates.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cross coupling
Catalysis
Arylation
Copper-mediated arylation of malonates, namely Hurtley reac-
tion,1 is an attractive approach for assembling
-arylated malonate
the possibility of ligand-promoted copper-catalyzed arylation of a-
a
substituted cyanoacetates. We found this coupling reaction
worked well under the catalysis of CuI and some special ligands,
thereby providing a valuable approach for synthesizing 2-alkyl-2-
arylcyanoacetates. Herein, we wish to disclose our results.
derivatives that are useful precursors to nonsteroidal anti-inflam-
matory drugs like Ibuprofen and Naproxen.2 The traditional reac-
tion conditions for this transformation normally require
a
stoichiometric amount of copper salts as the catalysts and rela-
tively high reaction temperatures.3 Under these conditions, sub-
strate scope is quite narrow and poor to moderate yields were
often observed. However, the situation has been dramatically
changed in recent years.3 This is because some special ligands such
In 1996, Miura et al.15 reported that copper-catalyzed coupling
of aryl iodides with ethyl 2-cyanopropanoate took place at 80 °C to
afford ethyl 2-cyano-2-phenylpropionate. However, only 69% con-
version could be reached even using 1.3 equiv of CuI. We envi-
sioned that this reaction could be improved by using suitable
ligands, and therefore a coupling reaction of 4-iodoanisole with
ethyl 2-cyanopropanoate was conducted. It was found that under
as 2-phenylphenol,4 -prolines,5 2-picolinic acid,6 and chelating
L
Schiff bases7 were found to be able to accelerate Hurtley-type cou-
pling reactions. Under the assistance of these ligands, mild condi-
tions for copper-catalyzed arylation of malonates,4–7 ethyl
cyanoacetate,5b,7 acetylacetone,5b and b-keto esters5a have been
discovered. Based on these investigations, some conceptually novel
methods for heterocycle synthesis have been developed. These
heterocycles include carbazoles,8 indoles,9 benzofurans,10 isoquin-
olines,11 3-acyloxindoles,12 as well as isoquinolin-1(2H)-ones.13
Although the progress in this field is remarkable, creation of a
quaternary carbon center through a copper-catalyzed direct cou-
pling reaction of aryl halides with suitable nucleophiles is still
the catalysis of 10 mol % CuI and 20 mol % trans-hydroxy-L-proline,
the reaction completed at 60 °C, affording the desired coupling
product 3a in 65% yield, together with 2-(4-methoxyphenyl)pro-
panenitrile 4a in 16% yield (Table 1, entry 1). Changing ligand to
trans-hydroxy-L-proline sodium salt gave an improved result (en-
try 2). Considering that 4a should be a decarboxylation product
of 3a, we decided to add 4 Å molecular sieve to inhibit the hydro-
lysis of 3a. To our delight, in this case no 4a was determined and
yield of 3a could be increased to 77% (entry 3). The best result
was observed when ligand was switched to sodium picolinate (en-
try 4). Changing ligand to sodium piperidine-2-carboxylate gave a
decreased yield (entry 5), while using other ligands like
N,N0-dimethylethane-1,2-diamine, 1,10-phenanthroline, BINOL,
and 8-hydroxy-quinoline did not give any coupling products (en-
tries 6–9). Further investigations revealed that the coupling reac-
tion is quite sensitive to both temperatures and bases, as evident
from that no conversion was found at 40 °C (entry 10), and de-
creased yields were observed when K2CO3 and K3PO4 were
challenging. We have reported that CuI/trans-4-hydroxy-L-proline
catalyzed arylation of 2-methyl-acetoacetates could take place by
using highly reactive 2-halotrifluoroacetanilides as the coupling
partners.14 As an extension of this work, in this Letter, we explore
⇑
Corresponding authors.
E-mail address: madw@mail.sioc.ac.cn (D. Ma).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.057

3890
S. Xie et al. / Tetrahedron Letters 54 (2013) 3889–3891
Table 1
Table 3
CuI/ligand-catalyzed coupling reaction of 4-iodoanisole with ethyl 2-
CuI/sodium picolinate-catalyzed arylation of a
-substituted 2-cyanopropanoatesa
cyanopropanoatea
O
CN
10 mol% CuI
CN
CO2Et
Me
CO2Me Me
+
CN
I
NC
R
20 mol % sodium picolinate
OEt
10 mol% CuI
ArI
+
O
Cs2CO3, DMSO, 60 o
4Å MS, 24 h
C
20 mol % ligand
R
2
Ar
3
NC
1
+
OEt
base, solvent
Me
2a
OMe
1a
OMe
4a
OMe
3a
HO
HO
Entry
Product yieldb (%)
Entry
Product yieldb (%)
CN
CN
CO2H
CO2Na
N
CO2Et
CO2Et
N
H
N
H
N
H
CO2Na
CO2Na
L1
L2
L3
L4
1
7
H
N
OMe
3t (71%)
OMe
3n (82%)
OH
OH
N
N
H
N
N
OH
CN
CN
L5
L6
-C H
CO2Et
n
CO2Et
5
11
L8
L7
2
8
Entry
Ligand
Base
Solvent
Yieldb (%)
F
OMe
1
2
L1
L2
L2
L3
L4
L5
L6
L7
L8
L3
L3
L3
L3
L3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
65c
70d
77
89
34
0
0
0
0
0
3u (79%)
3o (80%)
CN
3e
4e
5e
6
CN
CO2Et
n-C6H13
CO2Et
3
9
7
8
9
OMe
3v (78%)
Cl
10e,f
11e
12e
13e
14e
3p (84%)
CN
65
67
80
0
CN
K3PO4
Cs2CO3
Cs2CO3
-C H
CO2Et
n
CO2Et
4
9
1,4-Dixoane
4
5
10
a
Reaction conditions: 4-iodoanisole (0.5 mmol), ethyl 2-cyanopropanoate
(1.5 mmol), CuI (0.05 mmol), ligand (0.1 mmol), Cs2CO3 (1.5 mmol), DMSO (1.5 mL),
60 °C, 24 h.
Me
3w (80%)
OMe
(81%)
3q
CN
b
Isolated yield.
4a was isolated in 16% yield.
4a was isolated in 10% yield.
0.3 g of 4 Å MS was added.
CN
CO2Et
MeO
MeO
CO2Et
c
d
e
11
12
f
Reaction was carried out at 40 °C.
F
Me
3x
3r (86%)
CN
(84%)
Table 2
CuI/sodium picolinate-catalyzed arylation of ethyl 2-cyanopropanoatea
CN
n-C4H9
CO2Et
CO2Et
O
10 mol% CuI
CN
OMe
NC
Me
CO2Et
20 mol % sodium picolinate
OEt
6
ArI
+
Cs2CO3, DMSO, 60 oC
4Å MS, 24 h
Me
2a
Ar
3a-3m
1
OMe
3s
Cl
3y (77%)
(84%)
Reaction conditions: aryl iodide (0.5 mmol), ethyl 2-cyanopropanoate
Entry
Ar
Product
Yieldb (%)
a
1
2
3
4-MeC6H4
4-FC6H4
4-ClC6H4
3b
3c
3d
3e
3f
3g
3h
3i
85
89
83
73
90
88
85
86
76
39
87
80
(1.5 mmol), CuI (0.05 mmol), sodium picolinate (0.1 mmol), Cs2CO3 (1.5 mmol), 4 Å
MS (0.3 g), DMSO (1.5 mL), 60 °C, 24 h.
b
Isolated yield.
4
4-AcNHC6H4
4-NO2C6H4
3-MeC6H4
3-MeOC6H4
3-FC6H4
3,5-Me2C6H3
2-MeOC6H4
2-Pyridinyl
2-Naphthyl
5c
6
7
8
9
employed as the bases (entries 11 and 12). Solvent is another
important factor to influence the reaction course because a de-
creased yield was obtained in DMF (entry 13) and no conversion
was observed in dioxane (entry 14).
3j
3k
3l
10d
11
12
3m
Since enantiopure ligands such as L1 and L2 were used and a
chiral quaternary carbon center was generated in the present cou-
pling reaction, we wondered if some enantioselectivity could be
achieved and therefore the enantiopurity of 3a was measured. Dis-
appointingly, ee value of 3a was close to zero, which meant that
there was no asymmetric induction during the reaction course.
a
Reaction conditions: aryl iodide (0.5 mmol), ethyl 2-cyanopropanoate
(1.5 mmol), CuI (0.05 mmol), sodium picolinate (0.1 mmol), Cs2CO3 (1.5 mmol), 4 Å
MS (0.3 g), DMSO (1.5 mL), 60 °C, 24 h.
b
Isolated yield.
Reaction was carried out at 40 °C.
Reaction time was 36 h.
c
d

S. Xie et al. / Tetrahedron Letters 54 (2013) 3889–3891
3891
More explorations are required to reach good enantioselectivity by
using other enantiopure ligands.
and National Natural Science Foundation of China (Grant Nos.
20632050 and 20921091) for their financial support.
Having the optimized reaction conditions in hand, we examined
a number of substituted aryl iodides to explore the reaction scope
and limitations. As summarized in Table 2, coupling reactions of
ethyl 2-cyanopropanoate with both electron-rich and electron-
deficient aryl iodides completed smoothly under these conditions,
providing the corresponding arylation products in 73–90% yields.
The coupling reaction of 4-nitroiodobenzene even took place at
40 °C (entry 5). The only exception came from one ortho-substi-
tuted aryl iodide, which led to poor conversion even after prolong-
ing reaction time (entry 10). This result indicated that steric
hindrance of aryl iodides could greatly decrease the coupling rate.
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2013.05.057.
References and notes
1. Hurtley, W. R. H. J. Chem. Soc. 1929, 1870.
2. (a) Giordano, C.; Castaldi, G.; Uggeri, F. Angew. Chem., Int. Ed. Engl. 1984, 23,
413; (b) Harrington, P. J.; Lodewijk, E. Org. Process Res. Dev. 1997, 1, 72; (c)
Brunner, H.; Schmidt, P. Eur. J. Org. Chem. 2000, 2119.
We next examined the reaction scope by varying a-substituted
3. For reviews, see: (a) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108,
3054; (b) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450; (c) Monnier, F.; Taillefer,
M. Angew. Chem., Int. Ed. 2009, 48, 6954; (d) Surry, D. S.; Buchwald, S. L. Chem.
Sci. 2010, 13; (e) Sperotto, E.; Klink, G. P. M.; Koten, G.; Vries, J. G. J. Chem. Soc.,
Dalton Trans. 2010, 39, 10338.
4. Buchwald, S. L.; Hennessy, E. J. Org. Lett. 2002, 4, 269.
5. (a) Xie, X.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 4693; (b) Jiang, Y.; Wu, N.; Wu, H.;
He, M. Synlett 2005, 18, 2731.
ethyl 2-cyanoacetates. Gratifyingly, coupling reaction of ethyl 2-
cyanopent-4-enoate with several aryl iodides proceeded well un-
der the optimized conditions to deliver 3n–r in good yields (Ta-
ble 3, entries 1–5). Elongation of the side chain of
a-substituted
ethyl 2-cyanoacetates has little influence on the reaction, as evi-
dent from that 3s–w were obtained in similar reaction yields (en-
tries 6–10). Additionally, two functionalized a-substituted ethyl 2-
cyanoacetates were compatible with these conditions, leading to
formation of 3x and 3y.
In summary, we have demonstrated that combination of CuI
and sodium picolinate is a powerful catalytic system for promoting
6. Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9, 3469.
7. Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M. Chem. Eur. J. 2004, 10,
5607.
8. Yan, S.; Wu, H.; Wu, N.; Jiang, Y. Synthesis 2007, 17, 2699.
9. (a) Chen, Y.; Xie, X.; Ma, D. J. Org. Chem. 2007, 72, 9329; (b) Chen, Y.; Wang, Y.;
Sun, Z.; Ma, D. Org. Lett. 2008, 10, 625; (c) Tanimori, S.; Ura, H.; Kirihata, M. Eur.
J. Org. Chem. 2007, 3977.
10. (a) Chen, C.; Dormer, P. G. J. Org. Chem. 2005, 70, 6964; (b) Fang, Y.; Li, C. J. Org.
Chem. 2006, 71, 6427; (c) Carril, M.; SanMartin, R.; Tellitu, I.; Esther, D. Org. Lett.
2006, 8, 1467; (d) Lu, B.; Wang, B.; Zhang, Y.; Ma, D. J. Org. Chem. 2007, 72,
5337.
11. Wang, B.; Lu, B.; Jiang, Y.; Zhang, Y.; Ma, D. Org. Lett. 2008, 10, 2761.
12. Lu, B.; Ma, D. Org. Lett. 2006, 8, 6115.
direct arylation of a-substituted cyanoacetates. Our result not only
extends the scope of ligand-promoted Ullmann-type coupling
reactions, but also provides a reliable method for preparing syn-
thetically important 2-alkyl-2-arylcyanacetates.
13. Wang, F.; Liu, H.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2009, 11, 2469.
14. Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050.
15. Pivsa-Art, S.; Fukui, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1996, 69,
2039.
Acknowledgments
The authors are grateful to the Ministry of Science and Technol-
ogy (Grant No. 2009ZX09501-00), Chinese Academy of Sciences