Palladium-catalyzed coupling of alkynes with chloroformates to form alkynecarboxylic acid esters

Article abstract of DOI:10.1039/a908458d

The preparation of alkynecarboxylic acid esters, which are versatile building blocks for the synthesis of heterocyclic compounds, is described by means of the, palladium-catalyzed coupling of alkynes with chloroformates for the first time. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a908458d

View Online / Journal Homepage / Table of Contents for this issue
Palladium-catalyzed coupling of alkynes with chloroformates to
form alkynecarboxylic acid esters
Arnd Böttcher,a Heike Becker,a Melanie Brunner,a Thomas Preiss,a Jochem Henkelmann,*a
Christel De Bakkerb and Rolf Gleiterb
a BASF AG, Ammonia Laboratory, ZAR/C, 67056 Ludwigshafen, Germany,
Fax: ϩ621/6045044; E-mail: jochem.henkelmann@basf-ag.de
b Organisch-Chemisches Institut der Universität (Organic Chemistry Institute of the
University), Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Received (in Cambridge, UK) 25th October 1999, Accepted 5th November 1999
The preparation of alkynecarboxylic acid esters, which are
versatile building blocks for the synthesis of heterocyclic
compounds, is described by means of the palladium-
catalyzed coupling of alkynes with chloroformates for the
first time.
Alkynecarboxylic acid esters can be employed as building
blocks for diverse purposes, e.g. for the synthesis of hetero-
cyclic compounds.1 The methods used most frequently for the
preparation of alkynecarboxylic acid esters proceed via the
deprotonation of terminal alkynes using a Grignard reagent
or organolithium compounds. The lithium acetylides are
scavenged by chloroformates to form the desired alkynecarb-
Fig. 1
oxylic acid esters.2 Another possibility for their preparation is
the Pd-catalyzed alkoxycarbonylation of alkynes with carbon
monoxide in alcohols.3,4
The coupling of alkynes with chloroformates catalyzed by a
transition metal has so far not been described although the
field of catalyzed alkyne coupling reactions has undergone
enormous growth.5–8 For example suitable methods have been
developed for the preparation of many alkynyl-substituted
aromatics which would not have been possible without metal
catalysis. The reaction of alkynes with acid chlorides and carb-
amoyl chlorides for the preparation of alkynyl ketones using
transition metal catalysis has also been described.9–11
Fig. 2
A transition-metal catalyzed variant for the coupling of
alkynes with chloroformates (Scheme 1) could on the one hand
The first successful results were obtained by using [PdCl2-
(PPh3)2]–PPh3 and a stoichiometric quantity of the sterically
hindered base 1,2,2,6,6-pentamethylpiperidine. The coupling of
phenylacetylene with n-butyl chloroformate to form butyl
phenylpropiolate succeeded with a 14% yield using this system.
In combination with catalytic quantities of dimethylamino-
pyridine it was possible to raise this yield to 28%. On the other
hand with the Pd() complex [Pd(Ph2P(CH2)2PPh2)Cl2] no
reaction to form the desired alkynecarboxylic acid ester was
observed. With palladium() acetate–triphenylphosphine a
conversion level as high as 79% with good selectivity was found.
It was possible to achieve a marked improvement by the direct
use of Pd(0) complexes. Particularly good yields were obtained
with tetrakis(triphenylphosphine)palladium, the combination
Pd2(dba)3–tri-o-tolylphosphine and the cyclometallized com-
plex 4 (Fig. 1; see Table 1).12
With the chelate Pd(0) complex [Pd(Ph2P(CH2)2PPh2)2]
incomplete reaction was found although selectivity was good.
It was also possible to couple ethyl chloroformate with
phenylacetylene in good yield. However, the reaction is
restricted so far to alkyl chloroformates, there being no reaction
with aryl chloroformates. Phenylacetylene, hexyne, propyne
and 2-methylbut-3-yn-2-ol have been successfully used as
alkynes. In the case of the methylbutynol the reaction pro-
ceeded with better yields in acetonitrile. Byproducts are the
carbonates 5 and 6.
Scheme 1
yield significant cost advantages in industrial use and on the
other hand allow the reaction of labile molecules which in the
presence of a Grignard reagent or organolithium compounds
undergo different secondary reactions. In initial trials the con-
ditions used for the coupling of acid chlorides with alkynes10
were chosen. These did not result in product formation.
Problems arose in particular from the sensitivity of the chloro-
formates which readily decompose at elevated temperatures.
Chloroformates also impose limits on the choice of solvent. In
solvents such as DMF or DMSO they are not stable and they
react rapidly by decarboxylation to form alkyl chlorides. Suit-
able solvents, however, include dichloromethane or acetonitrile
for example. A third limitation is in the choice of base. In the
presence of nucleophilic bases, such as triethylamine for
example, chloroformates were likewise found to decompose
rapidly.
As a first step, therefore, it was important to find a sterically
hindered base in the presence of which chloroformates do not
decompose.
The mechanism of the reaction is not yet known. Presum-
J. Chem. Soc., Perkin Trans. 1, 1999, 3555–3556
This journal is © The Royal Society of Chemistry 1999
3555

View Online
Table 1 Reaction of alkynes with chloroformates to form alkynecarboxylic acid estersa
No.
R1
R2
Catalyst
Conversion (%)
Selectivity (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Et
Bu
Bu
Bu
Pd(OAc)2–PPh3 (1:4)
Pd2(dba)3–P(o-tolyl)3 (1:4)
Pd(PPh3)4
79
100
100
93
62
0
100
79
92
89
98
94
97
100
0
97
100
77
79
Binucleate Pd cycleb (4)
[Pd(Ph2P(CH2)2PPh2)2]
[Pd(Ph2P(CH2)2PPh2)Cl2]
Pd2(dba)3–P(o-tolyl)3 (1:4)
Pd2(dba)3–P(o-tolyl)3 (1:4)
Pd(PPh3)4
9
Me
C(CH3)2OH
10c
Pd2(dba)3–P(o-tolyl)3
93
a Conditions: catalyst concentration 2.2 mol%; T = 40 ЊC; solvent: dichloromethane; 1,2,2,6,6-pentamethylpiperidine–4-dimethylaminopyridine as
base. b Palladium complex as described by Herrmann and Beller.12 c Solvent: acetonitrile, 70 ЊC, 2.3 mol% catalyst.
ably the chloroformate first of all adds by oxidation to the
palladium(0) (corresponding (alkoxycarbonyl)chlorobis(phos-
phine)palladium() complexes have been described).13,14 The
alkynecarboxylic acid ester would have to be eliminated by
reduction from an alkynyl complex formed subsequently. In
those cases in which the reaction proceeded only moderately or
not at all when Pd() complexes were used it is probable that
insufficient amounts of palladium(0) were formed.
room temperature. 2.13 g (13.7 mmol) of 1,2,2,6,6-penta-
methylpiperidine, 0.015 g (0.12 mmol) of dimethylaminopyrid-
ine and 1.04 g (12.4 mmol) of methylbutynol were then added
and the mixture heated to 70 ЊC. 1.73 g (12.7 mmol) of butyl
chloroformate were metered in slowly over 90 minutes. The
reaction was monitored by GC. After 16.5 h 93% of the phenyl-
acetylene had reacted. The yield of butyl 3-hydroxy-3-
methylpent-2-ynoate was 79%.
To summarize, alkyl chloroformates can be coupled to
alkynes in very good yields in the presence of stoichiometric
quantities of the sterically hindered base 1,2,2,6,6-penta-
methylpiperidine and small amounts of dimethylaminopyrid-
ine. In this way a new and efficient route to the valuable class of
compounds represented by the alkynecarboxylic acid esters has
been found.
References
1 M. V. George, S. K. Khetan and R. K. Gupta, Adv. Heterocycl.
Chem., 1976, 19, 279.
2 C. Dimitriadis, M. F. Harte and M. Gill, Tetrahedron: Asymmetry,
1997, 8, 2153.
3 J. Tsuji, M. Takahashi and T. Takahashi, Tetrahedron Lett., 1980,
21, 849.
4 T. T. Zung, L. G. Bruk and O. N. Temkin, Mendeleev Commun.,
1994, 2.
Experimental
5 B. Cornils and W. A. Herrmann, Applied Homogeneous Catalysis
with Organometallic Compounds, 1st edition, VCH Weinheim, 1996.
6 K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett., 1975,
4467.
7 K. Sonogashira, in Comprehensive Organic Synthesis, Vol. 3,
ed. B. M. Trost and I. Fleming, Pergamon Press, New York, 1991,
521.
8 F. Diederich and P. J. Stang, in Metal-catalyzed Cross-coupling
Reactions, Wiley-VCH, Weinheim, 1998.
9 C. Chowdhury and N. G. Kundu, Tetrahedron Lett., 1996, 37, 7323.
10 Y. Tohda, H. Sonogashira and N. Hagihara, Synthesis, 1977, 777.
11 H. Ito, K. Arimoto, H. Sensui and A. Hosomi, Tetrahedron Lett.,
1997, 38, 3977.
Representative preparation of butyl phenylpropiolate
0.64 g (0.55 mmol) of tetrakis(triphenylphosphine)palladium in
50 ml of dichloromethane were stirred under an atmosphere of
argon for 1 h. 0.03 g (0.25 mmol) of dimethylaminopyridine, 4.3
g (27.5 mmol) of 1,2,2,6,6-pentamethylpiperidine and 2.6 g (25
mmol) of phenylacetylene were then added and heated under
slow reflux. Over a period of 25 minutes 7.5 g (55 mmol) of
butyl chloroformate were then added dropwise. The reaction
was monitored by GC. After 26 h 100% of the phenylacetylene
had reacted. The yield of butyl phenylpropiolate was 98%.
12 W. A. Herrmann, C. Brossmer, C.-P. Reisinger, T. H. Riermeier,
K. Öfele and M. Beller, Chem. Eur. J., 1997, 3, 1357.
13 T. Murray and J. R. Norton, J. Am. Chem. Soc., 1979, 101, 4107.
14 E. G. Samsel and J. R. Norton, J. Am. Chem. Soc., 1984, 106, 5505.
Representative preparation of butyl 3-hydroxy-3-methylpent-2-
ynoate
0.255
g (0.28 mmol) of tris(dibenzylidene acetone)di-
palladium(0) and 0.644 g (2.12 mmol) of tri-o-tolylphosphine
were dissolved in 25 ml of acetonitrile and stirred for 1 h at
Communication 9/08458D
3556
J. Chem. Soc., Perkin Trans. 1, 1999, 3555–3556