Novel Synthesis of 2-Oxo-3-butynoates by Copper-Catalyzed Cross-Coupling Reaction of Terminal Alkynes and Monooxalyl Chloride

Article abstract of DOI:10.1021/jo0353076

A general and efficient Cu(I)-catalyzed cross-coupling reaction of terminal alkynes and monooxalyl chloride for the synthesis of 2-oxo-3-butynoates and 2-oxo-3-butynoamides was developed. Readily available starting materials, the mild reaction conditions, wide functional group tolerance, and the obviation of stoichiometric organolithium or magnesium reagents combine to highlight this reaction.

Full text of DOI:10.1021/jo0353076

Novel Syn th esis of 2-Oxo-3-bu tyn oa tes by
Cop p er -Ca ta lyzed Cr oss-Cou p lin g Rea ction
of Ter m in a l Alk yn es a n d Mon ooxa lyl
Ch lor id e
Minjie Guo, Dao Li, and Zhaoguo Zhang*
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Lu,
Shanghai 200032, People’s Republic of China
F IGURE 1. Possible intermediates for 2-oxo-3-butynoic esters.
zhaoguo@mail.sioc.ac.cn
Received September 5, 2003
TABLE 1. Cu (I)-Ca ta lyzed Cr oss-Cou p lin g Rea ction of
P h en yla cetylen e a n d Isop r op yl Oxa lyl Ch lor id ea
Abstr a ct: A general and efficient Cu(I)-catalyzed cross-
coupling reaction of terminal alkynes and monooxalyl chlo-
ride for the synthesis of 2-oxo-3-butynoates and 2-oxo-3-
butynoamides was developed. Readily available starting
materials, the mild reaction conditions, wide functional
group tolerance, and the obviation of stoichiometric orga-
nolithium or magnesium reagents combine to highlight this
reaction.
entry
catalyst
solvent
ligand
yield (%)b
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuOTf
CuBr
CuCl
CuI
Et3N
DMF
Toluene
CH3CN
CH2Cl2
THF
THF
THF
THF
THF
no
no
no
no
no
no
no
no
27
0
30
32
43
77
0
67
71
53
58
69
57
2-Oxo-3-butynoic esters 1 constitute an important class
of organic compounds due to their unique structure with
multiple functional groups and potential use as irrevers-
ible inhibitors of brewer’s yeast pyruvate decarboxylase.1a
Several methods have been reported for the synthesis of
2-oxo-3-butynoates.1 Of all of the reported methods, the
direct coupling between acetylenic compounds and oxalic
ester derivatives was most straightforward. However, due
to the high reactivity of the oxalate substrate and the
product in the presence of the acetylenic lithiums or
Grignard reagents, neither acetylenic lithiums nor Grig-
nard reagents can be used as nucleophile to react with
readily available oxalic ester derivatives 2a -c.2 Activated
oxalic ester derivatives, such as 2d 1a and 2e,1c were used
for a limited scope. However, they are expensive; they
ultimately are derived from oxalate. We are interested
in the synthesis of 2-oxo-3-butynoate using oxalate or
oxalic acid chloride.
9
no
10
11
12
13
dppe
dppb
bpy
Phenc
CuI
CuI
CuI
THF
THF
THF
a
All of the reactions were carried out with phenylacetylene (1
mmol), isopropyl oxalyl chloride (1.2 mmol), Et3N (2 mmol), and
Cu(I) salt (5 mol %) in a specified solvent with or without ligand
at room temperature for 12 h. Isolated yield. c Phen ) 1,10-
b
phenanthroline.
acyl chlorides has been reported as a general method for
the construction of ketones.5 The catalytic version of this
reaction has also been realized in the acylation of
terminal alkynes. However, the catalytic reaction has
been sporadically studied and is highly substrate-de-
pendent compared with the stoichiometric one.6
Cuprous iodide is a cheap and readily available but
versatile transition metal reagent. Besides its role as
cocatalyst in some palladium-catalyzed reactions, copper-
(I)-mediated reactions have also been explored in recent
years.3,4 The stoichiometric reaction of organocoppers and
(4) A stoichiometric amount of copper used in the arylations of
terminal alkynes has been reported and is known as the Castro
reaction: (a) Stephens, R. D.; Castro, C. E. J . Org. Chem. 1963, 28,
2163. (b) Stephens, R. D.; Castro, C. E. J . Org. Chem. 1963, 28, 3313.
(c) Castro, C. E.; Gaughan, E. J .; Owsley, D. C. J . Org. Chem. 1966,
31, 4071. (d) Ogawa, T.; Kusume, K.; Tanaka, M.; Hayami, K.; Suzuki,
H. Synth. Commun. 1989, 19, 2199. (e) Castro, C. E.; Havlin, R.;
Honwad, V. K.; Malte, A.; Moje´, S. J . Am. Chem. Soc. 1969, 91, 6464.
(5) Miller, M. J .; Lyttle, M. H.; Streitwieser, A., J r. J . Org. Chem.
1981, 46, 1977. (b) Robin. R. C. R. Hebd. Seances Acad. Sci. Ser. C
1976, 282, 281; Chem. Abstr. 1976, 85, 32378a. (c) Normant, J .-F.;
Bourgain, M. Tetrahedron Lett. 1970, 2659. (d) Kraus, G. A.; Frazier,
K. Tetrahedron Lett. 1978, 3195. (e) Coutrot, P.; Grison, C.; Lachgar,
M.; Ghribi, A. Bull. Soc. Chim. Fr. 1995, 925. (f) Normant, J .-F.;
Piechucki, C. Bull. Chim. Soc. Fr. 1972, 2402. (g) Normant, J .-F.;
Bourgain, M. Bull. Chim. Soc. Fr. 1973, 2137.
(6) Chowdhury, C.; Kundu, N. G. Tetrahedron Lett. 1996, 37, 7323.
(b) Chowdhury, C.; Kundu, N. G. Tetrahedron 1999, 55, 7011. (c) Wang,
J .-X.; Wei, B.; Hu, Y.; Liu, Z.; Fu, Y. Synth. Commun. 2001, 31, 3527.
(d) Zanina, A. S.; Shergina, S. I.; Sokolov, I. E.; Kotlyarevskii, I. L.
Izv. Akad. Nauk SSSR, Ser. Khim. 1990, 2551. (e) Shergina, S. I.;
Sokolov, I. E.; Zanina, A. S. Izv. Akad. Nauk SSSR, Ser. Khim. 1992,
158.
(1) Chiu, C. C.; J ordan, F. J . Org. Chem. 1994, 59, 5763. (b)
Katritzky, A. R.; Lang, H. J . Org. Chem. 1995, 60, 7612. (c) Heras, M.
A.; Vaquero, J . J .; Garc´ıa-Navio, J . L.; Alvarez-Builla, J . J . Org. Chem.
1996, 61, 9009.
(2) Hauptmann, H.; Mader, M. Synthesis 1978, 307.
(3) Copper-catalyzed coupling reaction of aryl halides: (a) Klapars,
A.; Antilla, J . C.; Huang, X.; Buchwald, S. L. J . Am. Chem. Soc. 2001,
123, 7727. (b) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001,
3, 3803. (c) Hennessy, E. J .; Buchwald, S. L. Org. Lett. 2002, 4, 269.
(d) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581.
(e) Wolter, M.; Nordmann, G.; J ob, G. E.; Buchwald, S. L. Org. Lett.
2002, 4, 973. (f) Klapars, A.; Huang, X.; Buchwald, S. L. J . Am. Chem.
Soc. 2002, 124, 7421. (g) Ma, D.; Zhang, Y.; Yao, J .; Wu, S.; Tao, F. J .
Am. Chem. Soc. 1998, 120, 12459. (h) J effery, T. Tetrahedron Lett.
1989, 30, 2225. (i) Okuro, K.; Furuune, M.; Miura, M.; Nomura, M.
Tetrahedron Lett. 1992, 33, 5363. (j) Okuro, K.; Furuune, M.; Enna,
M.; Miura, M.; Nomura, M. J . Org. Chem. 1993, 58, 4716.
10.1021/jo0353076 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/20/2003
10172
J . Org. Chem. 2003, 68, 10172-10174

TABLE 2. Cu (I)-Ca ta lyzed Cr oss-Cou p lin g Rea ction of
Ar yla cetylen e a n d Isop r op yl Oxa lyl Ch lor id ea
TABLE 3. Cu (I)-Ca ta lyzed Cr oss-Cou p lin g Rea ction of
Ter m in a l Alk yn es a n d Isop r op yl Oxa lyl Ch lor id e or
Dieth yla m in ooxa lyl Ch lor id ea
a
All of the reactions were carried out with aryl acetylene (1
mmol), isopropyl oxalyl chloride (1.2 mmol), CuI (5 mol %), and
b
Et3N (2 mmol) in THF at room temperature for 12 h. Isolated
yield.
Within our recently initiated program on asymmetric
transfer hydrogenation, 2-oxo-3-butynoate and its deriva-
tives are needed as substrates. There is no report of
transition metal-catalyzed coupling reaction to synthesize
this type of compound in the literature. Initially, we
applied the literature reaction conditions for the coupling
of alkyne and acyl chloride6 to the reaction between
phenyl acetylene and isopropyl oxalyl chloride 2f in the
presence of 5 mol % of CuI in Et3N; the desired product,
2-oxo-4-phenyl-3-butynoic acid isopropyl ester (1a ), was
isolated in 27% yield (entry 1, Table 1). This enlightening
result prompted us to optimize the reaction conditions
for this coupling reaction. Herein, we report our prelimi-
nary results on this copper-mediated coupling reaction.
For the coupling of alkyne and acyl chloride6 reported
in the literature, triethylamine is required as reaction
solvent to obtain the best results; this limits the practical
use of this reaction. To reduce the use of triethylamine,
a variety of solvents were screened, and THF was found
to be the best solvent as shown in Table 1. In the presence
of 2 equiv of triethylamine, the reaction proceeded
smoothly in THF at room temperature to give the desired
product in 77% yield (entry 6, Table 1). To further
improve the reaction efficiency, several ligands were used
in the copper-catalyzed reaction; however, when 1 or 2
equiv of ligands (relative to Cu) was employed, no
a
All of the reactions were carried out with terminal alkynes (1
mmol), isopropyl oxalyl chloride, diethylaminooxalyl chloride, or
ethyl oxalyl chloride (1.2 mmol), CuI (5 mol %), and Et3N (2 mmol)
in THF at room temperature for 12 h. Isolated yield.
b
improvement was found under these conditions (entries
10-13, Table 1). Different copper(I) sources have also
been examined; CuCl, CuBr, and CuI showed similar
reactivity, while CuOTf was totally inert. Therefore, the
optimized condition for the coupling reaction between
terminal alkynes (1 mmol) and isopropyl oxalyl chloride
(1.2 mmol) is using 5 mol % of CuI as catalyst in THF in
the presence of 200 mol % of Et3N.
J . Org. Chem, Vol. 68, No. 26, 2003 10173

SCHEME 1. P ossible Mech a n ism for th e Cou p lin g
Rea ction
alkynes and monooxalyl chlorides for the synthesis of
2-oxo-3-butynoates and 2-oxo-3-butynoamides. This is the
first report employing a transition metal catalyst to make
this type of compound. The readily available, cheap
starting materials, mild reaction conditions, good sub-
strate generality, wide functional group tolerance, and
the obviation of stoichiometric lithium or magnesium
reagents combine to make this method a most competi-
tive alternative.
A series of aryl acetylenes were subjected to the
optimized reaction conditions to react with isopropyl
oxalyl chloride, and the results are summarized in Table
2. Moderate to good yields were achieved with a variety
of alkyne substrates. Electron-rich substrates (entries 4,
5, Table 2) gave better yields than those of electron-
deficient ones (entries 2, 3, Table 2). It is noteworthy that
substrate with a nitro group, which is intolerable to
organolithium or organomagnesium reagents, is also
compatible under these conditions to give a moderate
yield.
Besides terminal aryl alkynes, this coupling reaction
could also be successfully applied to many other types of
alkynes (entries 1-5, Table 3), and good yields were
achieved in most cases. However, 1-hexyne, methyl
propargyl ether, and ethyl propiolate did not undergo this
reaction under the same conditions. When diethylami-
nooxalyl chloride (2g) was used instead of isopropyl oxalyl
chloride, alkynyl R-keto amides were obtained in good
yields.7 Therefore, this reaction is an efficient synthetic
method for the synthesis of 2-oxo-3-butynoamides, which
are difficult to make from the corresponding esters by
transfer amidation or from the acids and amines due to
the competitive Michael addition reaction.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Cr oss-Cou p lin g Rea ction . An
oven-dried Schlenk reaction tube equipped with a magnetic
stirrer bar and a Teflon stopcock was evacuated while hot and
allowed to cool under argon. The tube was charged in sequence
with CuI (10.1 mg, 0.05 mmol), triethylamine (0.28 mL, 2 mmol),
and THF (5 mL). Once a colorless clear solution formed, the
alkyne (1 mmol) and monooxalyl chloride (2 mmol) were added
and the reaction was allowed to proceed at room temperature.
When the reaction was completed, saturated aqueous NaHCO3
(5 mL) and diethyl ether (20 mL) were added. The reaction
system was allowed to partition, and the organic phase was dried
with Na2SO4, filtered, and concentrated on a rotary evaporator.
The residue was purified by silica gel chromatography to give
the cross-coupling product.
1a : 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J ) 6.3 Hz, 2 H),
7.53 (t, J ) 7.5 Hz, 1 H), 7.42 (t, J ) 7.5 Hz, 2 H), 5.21 (hept, J
) 6.3 Hz, 1 H), 1.41 (d, J ) 6.3 Hz, 6 H); 13C NMR (75.4 MHz,
CDCl3) δ 169.9, 158.7, 133.7, 131.7, 128.7, 119.0, 97.7, 87.1, 71.6,
21.4; MS m/z 216 (M+), 130 (13), 129 (100), 101 (8), 75 (16); IR
(neat) 2202, 1753, 1737 cm-1; HRMS calcd for C13H12O3 216.0786,
found 216.0778.
Ack n ow led gm en t. We thank the National Natural
Science Foundation of China, Chinese Academy of
Sciences, and the Science and Technology Commission
of Shanghai Municipality for financial support. We also
thank Prof. X. Lu in our institute for his continuous
encouragement and helpful discussions.
A possible mechanism for this reaction is described in
Scheme 1. The terminal alkyne reacts with cuprous
iodide to give the alkynyl copper, which further reacts
with isopropyl oxalyl chloride to give the 2-oxo-3-butynoic
ester and regenerate the catalyst: cuprous chloride.
In conclusion, we have developed a general and ef-
ficient Cu(I)-catalyzed cross-coupling reaction of terminal
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and analytical data for 1. This material is available free
of charge via the Internet at http://pubs.acs.org.
(7) Only two reports have been published about its synthesis:
Chauvelier, J . Bull. Soc. Chim. Fr. 1966, 1721, and ref 1b.
J O0353076
10174 J . Org. Chem., Vol. 68, No. 26, 2003