A copper-based catalytic system for carboxylation of terminal alkynes: Synthesis of alkyl 2-alkynoates

Article abstract of DOI:10.1039/c2ob06884b

An efficient coupling of terminal alkynes and CO₂ in the presence of alkyl halides can be achieved under ambient conditions using a copper/phosphine catalyst system, providing facile access to a variety of functionalised alkyl 2-alkynoates.

Full text of DOI:10.1039/c2ob06884b

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Chemistry
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COMMUNICATION
A copper-based catalytic system for carboxylation of terminal alkynes:
synthesis of alkyl 2-alkynoates†
Kiyofumi Inamoto,* Narumi Asano, Koji Kobayashi, Misato Yonemoto and Yoshinori Kondo*
Received 9th November 2011, Accepted 7th December 2011
DOI: 10.1039/c2ob06884b
been developed making use of the copper/N-heterocyclic
carbene (NHC) catalyst system.7 During the course of this work,
two other copper-based catalytic systems, one is copper/diamine8
and another is copper/NHC,9 have been introduced, which suc-
cessfully effect the carboxylative coupling of terminal alkynes
with CO2 to give alkynyl carboxylic acids under mild conditions
(rt–50 °C, 1–5 atm CO2). Herein, we present our independent
finding that the copper/phosphine system is also an active cata-
lyst for the reaction of terminal alkynes and CO2 in the presence
of alkyl halides, producing alkyl 2-alkynoates generally in good
to high yields under ambient conditions.10,11
Our investigation began by examination of the coupling reac-
tion of phenylacetylene (1a) with CO2 (1 atm) in the presence of
butyl iodide (2a) in DMA to obtain the optimal reaction con-
ditions (Table 1). The effect of base on the process was initially
evaluated using 8 mol% of CuI as a catalyst. Although DBU and
tBuONa turned out to be ineffective (entries 1 and 2), the use of
carbonate bases such as K2CO3 and Cs2CO3 provided the
desired 2-alkynoate 3aa in good yields (entries 3–6).
An efficient coupling of terminal alkynes and CO2 in the
presence of alkyl halides can be achieved under ambient con-
ditions using a copper/phosphine catalyst system, providing
facile access to a variety of functionalised alkyl 2-alkynoates.
Transformation involving the fixation of carbon dioxide (CO2)
into certain molecules, generally resulting in the formation of
carboxylic acids and their derivatives, constitutes a highly attrac-
tive synthetic method since CO2 is inexpensive, easily-available,
non-toxic and thus can be considered as an ideal C1 unit in
organic synthesis. A number of procedures, therefore, have so
far been developed for the process, including recently reported
transition metal-catalysed approaches.1
Alkynyl carboxylic acids and their derivatives are an impor-
tant class of compounds due to their existence in a number of
biologically active molecules2a as well as their utility as versatile
intermediates in organic synthesis.2b–f The most widely reported
approaches for synthesizing alkynyl carboxylic acids involve the
lithiation or magnesiation of terminal alkynes followed by react-
ing with solid or gaseous CO2.3 A major drawback of the
process, however, involves the poor functional group compatibil-
ity, limiting their efficiency and applicability. The palladium-
catalysed oxidative carbonylation of terminal alkynes in alcoholic
solvents under an atmosphere of CO, giving rise to alkynyl car-
boxylic acids, was first reported by Tsuji et al.4a and later studied
in detail by others.5 Although the reactions proceed under rela-
tively mild conditions, the use of toxic CO gas seems less prefer-
able. The copper catalyst has been reported to participate in the
coupling of alkynes with gaseous CO2, providing more efficient,
applicable routes to alkynyl carboxylic acids. Inoue et al. pre-
viously showed that the copper-catalysed carboxylative coupling
of terminal alkynes with CO2 in the presence of alkyl bromides
afforded alkyl 2-alkynoates at an elevated temperature (100 °C)
in a polar, aprotic solvent.6 Recently, synthesis of allylic
2-alkynoates via the coupling of terminal alkynes and allylic
chlorides under an atmosphere of 1.5 MPa (ca. 15 atm) CO2 has
Table 1 Effect of reaction parametersa
Entry
Base
Ligand
Temp. (°C)
Yield (%)b
1
2
3
4
5
6
7
8
DBU
none
none
none
none
none
none
IMes·HCl
IPr·HCl
2,2′-bipyridine
dppb
80
80
80
rt
80
rt
rt
rt
rt
rt
rt
rt
rt
rt
trace
trace
70
trace
77
tBuONa
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
65
24c
20c
61c
0
9
10
11
12
13
14d
PPh3
74c
72c
90
PtBu3
PEt3
Graduate School of Pharmaceutical Sciences, Tohoku University,
6-3Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. E-mail: inamoto@
mail.pharm.tohoku.ac.jp, ykondo@mail.pharm.tohoku.ac.jp; Fax:
+81-22-795-3921; Tel: +81-22-795-6804
†Electronic supplementary information (ESI) available: Experimental
procedures and spectral/analytical data. See DOI: 10.1039/c2ob06884b
none
0
a Reactions were carried out on a 0.50 mmol scale. b Isolated yield.
c Determined by 1H-NMR using 1,1,2-trichloroethane as an internal
standard. d Run in the absence of CuI.
1514 | Org. Biomol. Chem., 2012, 10, 1514–1516
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Table 2 Substrate scope of the process (alkynes)a,b
Table 3 Substrate scope of the process (alkyl halides)a
Entry
1
R–X
2
Product
Yield (%)b
2a
3aa
90
80
0
2
3
4
5
2b
2c
2d
2e
3aa
3aa
3aa
3ae
0
81
6
7
2f
3af
91
67
a Reactions were carried out on a 0.50 mmol scale. b Isolated yield.
d 48 h. d 2,2′-Bipyridine was used instead of PEt3. e 50 °C.
2g
3ag
8
9d
2h
2h
4
(94)c
65
Interestingly, the reaction proceeded even at room temperature
when Cs2CO3 was employed (entry 4 vs. 6). Subsequent screen-
ing of a number of ligands, including N-heterocyclic carbenes
(entries 7 and 8), diamine (entry 9) and phosphines (entries
10–13), revealed that Et3P was the best; in this case, 3aa was
obtained in excellent yield (entry 13). It is particularly note-
worthy that the process can be performed under ambient con-
ditions (room temperature, 1 atm CO2). On the other hand, no
product was obtained from the reaction in the absence of a
copper catalyst (entry 14).
3ah
10
5
81
a Reactions were carried out on a 0.50 mmol scale. b Isolated yield.
c Yield of 4. d Allyl bromide (2h) was added after 24 h and 36 h
(0.25 mmol each).
The coupling process was next performed using a variety of
alkyl halides (Table 3). In addition to alkyl iodide 2a (entry 1),
alkyl bromide 2b was found to be a suitable substrate for the
process (entry 2). On the other hand, alkyl chloride 2c and
triflate 2d were completely unreactive (entries 3 and 4).13 The
reaction using 1-bromo-4-chlorobutane 2e occurred selectively at
the bromine site to give 3ae in high yield (entry 5). Alkyl
bromide 2f, possessing an ethoxycarbonyl group, also partici-
pated in the process, providing the corresponding coupling
product 3af in high yield (entry 6). Moreover, the reaction
efficiently proceeded in the presence of benzyl bromide 2g,
affording benzyl 2-alkynoate 3ag in good yield (entry 7). We did
not obtain the desired product 3ah at all when allyl bromide 2h
was employed: in this case, byproduct 4 which resulted from
the direct coupling of 1a with 2h was isolated in 94% yield
(entry 8). On the contrary, it was found that the coupling product
3ah can indeed be obtained if the reaction was first carried out in
the absence of 2h and then 2h was added into the reaction
mixture (entry 9). Furthermore, the reaction of 1a with CO2
without adding any alkyl halides 2 provided the carboxylic acid
5 in high yield (entry 10).
The catalytic activity of the system was next evaluated in the
coupling reaction of an array of alkyne compounds 1b–l
(Table 2). Reactions of phenylacetylenes possessing an electron-
donating group on the benzene ring (1b and 1c) smoothly pro-
ceeded, producing the corresponding coupling products (3ba
and 3ca) in high yields. For some substrates that have an
electron-withdrawing group on the benzene ring, it was found
that the use of 2,2′-bipyridine as a ligand provided results
superior to PEt3.12 For example, the coupling reactions of phenyl-
acetylenes substituted with 4-cyano, 4-bromo or 2-chloro (1d–f)
underwent smooth coupling at 50 °C in the presence of the
CuI/2,2′-bipyridine catalyst system, resulting in the efficient for-
mation of the corresponding 2-alkynoates (3da–fa). On the other
hand, 4-ethoxycarbonylphenylacetylene (1g) and 4-nitrophenyl-
acetylene (1h) have turned out less reactive and the coupling
products (3ga and 3ha) were obtained only in lower yields. Sub-
strates bearing a heteroaromatic ring system were also employed
for the process. While 3-ethynylthiophene (1i) efficiently partici-
pated in the coupling process to give 3ia in quantitative yield,
the reaction of 2-pyridylacetylene (1j) was rather sluggish and
only a trace amount of 3ja was detected from the reaction
mixture. In addition, (cyclo)alkylacetylenes (1k and 1l) proved
suitable for the coupling and high yields were obtained,
especially when a copper/2,2′-bipyridine system was employed.
Influence of the added H2O in the coupling process was also
examined (Scheme 1). It was found that an increased amount of
H2O shuts down the reaction, suggesting that the removal of
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(d) L. Ackermann, Angew. Chem., Int. Ed., 2011, 50, 3842;
(d) S. N. Riduan and Y. Zhang, Dalton Trans., 2010, 39, 3347;
(e) A. Correa and R. Martín, Angew. Chem., Int. Ed., 2009, 48, 6201;
(f) D. J. Darensboug, Chem. Rev., 2007, 107, 2388; (g) T. Sakakura,
J.-C. Choi and H. Yasuda, Chem. Rev., 2007, 107, 2365; (h) J. Louie,
Curr. Org. Chem., 2005, 9, 605.
2 For a selected recent example, see: (a) S. L. Mooberry, D. A. Randall-
Hlubek, R. M. Leal, S. G. Hegde, R. D. Hubbard, L. Zhang and
P. A. Wender, Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 8803; For a
recent review, see: (b) T. Kitamura, Eur. J. Org. Chem., 2009, 1111;
(c) M. J. Jacobsen, E. D. Funder, J. R. Cramer and K. V. Gothelf, Org.
Lett., 2011, 13, 3418; (d) L.-G. Meng, N.-L. Ge, M.-M. Yang and
L. Wang, Eur. J. Org. Chem., 2011, 3403; (e) M. Bararjanian, S. Balalaie,
F. Rominger, B. Movassagh and H. R. Bijanzadeh, J. Org. Chem., 2010,
75, 2806; (f) B. M. Trost, F. D. Toste and K. Greenma, J. Am. Chem.
Soc., 2003, 125, 4518.
3 For selected recent examples, see: (a) A. Polyzos, M. O’Brien,
T. P. Petersen, I. R. Basendale and S. V. Ley, Angew. Chem., Int. Ed.,
2011, 50, 1190; (b) R. Knorr, C. Pires, C. Behringer, T. Menke,
J. Freudenreich, E. C. Rossmann and P. Bohrer, J. Am. Chem. Soc., 2006,
128, 14845; (c) S. Tajanmal and A. E. Tipping, J. Fluorine Chem., 1990,
47, 45.
4 J. Tsuji, M. Takahashi and T. Takahashi, Tetrahedron Lett., 1980, 21, 849.
5 (a) J. S. Prasad and L. S. Liebeskind, Tetrahedron Lett., 1988, 28, 1857;
(b) Y. Sakurai, S. Sakaguchi and Y. Ishii, Tetrahedron Lett., 1999, 40,
1701; (c) Y. Izawa, I. Shimizu and A. Yamamoto, Bull. Chem. Soc. Jpn.,
2004, 77, 2033.
6 Y. Fukue, S. Oi and Y. Inoue, J. Chem. Soc., Chem. Commun., 1994,
2091.
7 W.-Z. Zhang, W.-J. Li, X. Zhang, H. Zhou and X.-B. Lu, Org. Lett.,
2010, 12, 4748.
Scheme 1 Influence of added H2O.
H2O from the reaction system, especially from a relatively hygro-
scopic inorganic base, is crucial for successful coupling.
In summary, we have described new copper-based catalyst
systems that successfully achieved the coupling reactions of
terminal alkynes and CO2 in the presence of alkyl halides to
afford various alkyl 2-alkynoates. The method allows the reac-
tions to proceed under ambient conditions (room temperature to
50 °C, 1 atm of CO2), which compares favourably with the
recently reported, similar Cu-catalysed methods6–8 in which an
elevated temperature or a high pressure of CO2 is necessary for
efficient coupling. The choice of the ligand turned out to be con-
siderably important for the efficient conversion. Further studies
to broaden the substrate scope of the process are underway in
our laboratory.
8 L. J. Gooßen, N. Rodríguez, F. Manjolinho and P. P. Lange, Adv. Synth.
Catal., 2010, 352, 2913.
Acknowledgements
9 D. Yu and Y. Zhang, Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 20184.
10 Very recently, silver-catalysed carboxylation of terminal alkynes was
reported, see: X. Zhang, W.-Z. Zhang, X. Ren, L.-L. Zhang and
X.-B. Lu, Org. Lett., 2011, 13, 2402.
11 For related copper-catalysed carboxylation of (hetero)aryl compounds
using CO2, see: (a) L. Zhang, J. Cheng, T. Ohishi and Z. Hou, Angew.
Chem., Int. Ed., 2010, 49, 8670; (b) I. I. F. Boogaerts, G. C. Fortman,
M. R. L. Furst, C. S. J. Cazin and S. P. Nolan, Angew. Chem., Int. Ed.,
2010, 49, 8674.
This work was partly supported by a Grant-in-Aid for Scientific
Research (B) (No. 23390002), a Grant-in-Aid for Challenging
Exploratory Research (No. 23659001) and a Grant-in-Aid for
Young Scientists (B) (No. 23790002) from Japan Society for the
Promotion of Science.
12 Lower reactivity of electron-withdrawing group-substituted phenylacety-
lenes in a similar process has previously been observed, see reference 9.
13 Reactions of 2° alkyl halides such as isopropyl iodide, cyclohexyl iodide
and cyclohexyl bromide also resulted in no formation of the desired coup-
ling products.
Notes and references
1 For selected recent reviews on the use of CO2 in organic synthesis, see:
(a) I. I. F. Boogaerts and S. P. Nolan, Chem. Commun., 2011, 47, 3021;
(b) Y. Zhang and S. N. Riduan, Angew. Chem., Int. Ed., 2011, 50, 6210;
1516 | Org. Biomol. Chem., 2012, 10, 1514–1516
This journal is © The Royal Society of Chemistry 2012