A straightforward synthesis of Ynones by reaction of dimethylalkynylaluminum reagents with acid chlorides

Article abstract of DOI:10.1021/jo050760y

Alkynyldimethylaluminum reagents react with various aromatic and aliphatic acid chlorides in a fast and efficient way. This reaction provides a simple entry to numerous ynones, using readily available, inexpensive, and nontoxic metalating agent, and does not require any transition metal as a catalyst.

Full text of DOI:10.1021/jo050760y

1 equiv of a Brønsted base (generally a tertiary amine4)
is, however, required to trap the acidic acetylenic proton,
and the presence of this amine can lead to serious side
reactions with some aliphatic acid chlorides or base-
sensitive substrates.5 This problem can be overcome
using preformed metallic acetylides, but the presence of
a palladium catalyst is still required to achieve clean and
selective transformations.6
As a part of our work on the use of mixed dialkylalky-
nylaluminum reagents in stereoselective transforma-
tions,7 we recently reported a straightforward access to
these species by a base-catalyzed alumination of terminal
alkynes (Figure 1)8 and their palladium-catalyzed cross-
coupling with aromatic halides.9 We report here the
reaction of such species with acid chlorides.
A Straightforward Synthesis of Ynones by
Reaction of Dimethylalkynylaluminum
Reagents with Acid Chlorides
Baomin Wang, Martine Bonin, and Laurent Micouin*
Laboratoire de Chimie The´rapeutique, UMR 8638 associe´e
au CNRS et a` l’Universite´ Rene´ Descartes, Faculte´ des
Sciences Pharmaceutiques et Biologiques 4, av de
l’Observatoire, 75270 Paris Cedex 06, France
laurent.micouin@univ-paris5.fr
Received April 15, 2005
Although the coupling of aluminum acetylides with
acid chlorides had been reported some years ago to
require a catalytic amount of palladium,10 the acylation
of vinylalanes has been described to proceed without any
catalyst.11 Furthermore, ynones can classically be pre-
pared starting from a silylated alkyne under Friedel-
Crafts conditions in the presence of aluminum trichlo-
ride.12 These results prompted us to reinvestigate the
reaction of mixed dimethylalkynylalanes with acid chlo-
rides.
First, experiments were conducted using heptynyldim-
ethylaluminum and benzoyl chloride in THF. As ex-
pected, no ynone could be detected after 24 h, confirming
that palladium catalysis is needed in this solvent. The
use of DME led to the same results, whereas a complex
mixture was obtained in toluene after 2 h at room
temperature. However, we were pleased to find that a
very fast reaction occurred in 1,2-dichloroethane, leading
to the desired acylated compound (Table 1, entry 1). Best
results were obtained when conducting the reaction at
Alkynyldimethylaluminum reagents react with various aro-
matic and aliphatic acid chlorides in a fast and efficient way.
This reaction provides a simple entry to numerous ynones,
using readily available, inexpensive, and nontoxic metalat-
ing agent, and does not require any transition metal as a
catalyst.
Ynones are extremely versatile substrates for further
synthetic elaboration. R,â-Acetylenic carbonyl compounds
can, for example, undergo sequential nucleophilic addi-
tions and cyclizations, leading in a simple and general
manner to a full range of heterocyclic derivatives.1 They
can also serve as intermediates for the synthesis of
natural products,2 heterocyclic ligands, or precursors for
materials with interesting properties.
As recently highlighted by Na´jera and co-workers, a
wide variety of synthetic approaches to conjugated acety-
lenic carbonyl compounds have been reported.3 Among
them, the palladium and/or copper-catalyzed cross-
couplings of terminal acetylenic derivatives with acid
chlorides are usually considered to be the methods of
choice. Both approaches require the formation of the
corresponding acetylides, either catalytically or stoichi-
ometrically. In the case of the catalytic version, at least
(4) For a recent interesting example of the use of an inorganic base
in the coupling of undeprotonable acid chlorides with aromatic acety-
lenic compounds in water in the presence of surfactants, see: Chen,
L.; Li, C.-J. Org. Lett. 2004, 6, 3151.
(5) The competitive formation of ketenes from aliphatic acid chlo-
rides has been recently discussed: Cox, R. J.; Ritson, D. J.; Dane, T.
A.; Berge, J.; Charmant, J. P. H.; Kantacha, A. Chem. Commun. 2005,
1037.
(6) Direct acylations of acetylides have been reported: the use of
alkali or alkaline-earth metals generally leads to complex reactions.
The use of organocadmium reagents is hampered by the toxicity of
Cd. Good results can be obtained with Cu or Mn acetylides, but the
preparation of such reactive species generally requires transmetalation
steps. For a general overview, see: (a) Dieter, R. K. Tetrahedron 1999,
55, 4177. See also: (b) Oh, C. H.; Reddy, V. R. Tetrahedron Lett. 2004,
45, 8545 and references cited in ref 3.
(7) (a) Blanchet, J.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche, C.;
Husson, H.-P. Tetrahedron Lett. 1999, 40, 2935. (b) Blanchet, J.; Bonin,
M.; Micouin, L.; Husson, H.-P. J. Org. Chem. 2000, 65, 6423. (c)
Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H.-P. Tetrahedron Lett.
2001, 42, 3171. (d) Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H.-P.
Eur. J. Org. Chem. 2002, 2598.
(8) Feuvrie, C.; Blanchet, J.; Bonin, M.; Micouin, L. Org. Lett. 2004,
6, 2333.
(9) Wang, B.; Bonin, M.; Micouin, L. Org. Lett. 2004, 6, 3481.
(10) Wakamatsu, K.; Okuda, Y.; Oshima, K.; Nozaki, H. Bull. Chem.
Soc. Jpn. 1985, 58, 2425.
(1) Pyrroles: (a) Utimoto, K.; Miwa, H.; Nozaki, H. Tetrahedron Lett.
1981, 22, 4277. (b) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am.
Chem. Soc. 2001, 123, 2074. Furans: (c) Wills, M. S. B.; Danheiser, R.
L. J. Am. Chem. Soc. 1998, 120, 9378. (d) Jeevanadam, A.; Narkunan,
K.; Ling, Y.-C. J. Org. Chem. 2001, 66, 6014. (e) Kel’in, A. V.;
Gevorgyan, V. J. Org. Chem. 2002, 67, 95. Pyrazoles: (f) Wang, X.;
Tan, J.; Zhang, L. Org. Lett. 2000, 2, 3107. (g) Grotjahn, D. B.; Van,
S.; Combs, D.; Lev, D. A.; Schneider, C.; Rideout, M.; Meyer, C.;
Hernandez, G.; Mejorado, L. J. Org. Chem. 2002, 67, 9200. Pyrim-
idines: (h) Karpov, A. S.; Muller, T. J. J. Org. Lett. 2003, 5, 3451.
(2) (a) Wender, P. A.; Bi, F. C.; Brodney, M. A.; Gosselin, F. Org.
Lett. 2001, 3, 2105. (b) Sneddon, H. F.; Gaunt, M. J.; Ley, S. V. Org.
Lett. 2003, 5, 1147.
(11) Neigishi, E.-I.; Bagheri, V.; Chatterjee, S.; Luo, F.-T.; Miller,
J. A.; Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181. In this case, the
direct reaction performed in CH2Cl2 occurred with stereoisomerization,
whereas the Pd-catalyzed coupling led to retention of configuration.
(12) Shi, A. L. K.; Shun, S.; Tykwinski, R. R. J. Org. Chem. 2003,
68, 6810.
(3) Alonso, D. A.; Na´jera, C.; Pacheco, Ma. C. J. Org. Chem. 2004,
69, 1615 and references cited.
10.1021/jo050760y CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/22/2005
6126
J. Org. Chem. 2005, 70, 6126-6128

TABLE 2. Reaction of Alkynyldimethylalanes with Acid
Chlorides
FIGURE 1. Triethylamine-catalyzed alumination of terminal
alkynes.
entrya
R1
R2
time (min) yield (%)b
TABLE 1. Reaction of Heptynyldimethylaluminum with
Acid Chlorides
1
2
Ph
Ph
Ph
Ph
10
5
88
97
91
88
98
90
42
53c
60c
44
cyclopropyl
i-Bu
3
5
4
Ph
ClCH2(CH2)2
ClCH2(CH2)2
ClCH2(CH2)2
HC≡C(CH2)6
10
5
5
cyclopropyl
i-Bu
6
5
7
Ph
10
10
5
entrya
R
time (min)
yield (%)b
8
p-MeOC6H4- HC≡C(CH2)6
9
cyclopropyl
HC≡C(CH2)6
1
Ph
15
10
10
40
20
120
5
87
10
n-Pr
HC≡C(CH2)6
5
2
p-MeOC6H4-
o-MeOC6H4-
p-ClC6H4-
thiophen-2-yl
Furyl-2-yl
PhCH2
87
3
94
a Reaction conditions: R1COCl (1 equiv), R2-≡AlMe2 (1 equiv).
b Isolated yield. c Bis-acylation was the main side product (20%
of bis-acylation for entry 8 and 19% for entry 9).
4
30c
5
86
6
no reactiond
7
72
85
82
91
88
98
86
SCHEME 1. Synthesis of Symmetrical Diynone
8
n-Pr
CH3(CH2)13CH2
i-Bu
i-Pr
cyclopropyl
t-Bu
5
9
5
10
11
12
13
5
5
10
10
a Reaction conditions: RCOCl (1 equiv), Pent-≡AlMe2 (1 equiv).
b Isolated yield. c A second addition of acetylide is observed as a
side reaction. d A complex mixture is obtained after 24 h.
process, typical for the behavior of oxalylchoride under
Friedel-Crafts conditions,14 enables a straightforward
preparation of this useful intermediate.15
0 °C. At this temperature, methylene chloride and, to a
lesser extent, toluene also proved to be suitable solvents
for this reaction.
In conclusion, the preparation of reactive acetylides
using inexpensive, widely available, and nontoxic trim-
ethylaluminum as a metal source via a triethylamine-
catalyzed terminal metalation can provide a valuable
alternative route to reactive acetylides in acylation
reactions. This coupling reaction does not require any
transition metal catalyst and occurs generally in less
than 15 min at 0 °C, provided that the reaction is
conducted in an appropriate solvent. This protocol en-
ables the use of base-sensitive aliphatic acid chlorides,
providing a general access to a wide range of ynones.
Various acid chlorides reacted in a very fast manner
under these reaction conditions (Table 1). The reactivity
of substituted benzoyl chlorides was generally good
(entries 2 and 3) although the para-chloro derivative
proved to be less reactive and led to a large amount of
the corresponding alcohol as a result of longer reaction
time and bis-alkynylation. A dramatic difference of
reactivity could also be observed between thiophene-
(entry 5) and furan- (entry 6) 2-carbonyl chlorides. More
interestingly, acylation with aliphatic acid chlorides,
bearing linear or branched, short or long alkyl chains,
occurred in a very fast and clean manner, leading to the
corresponding ynones in 72-98% yields (entries 7-13).
The coupling reaction was then investigated with
various alkynes (Table 2). Phenylacetylene proved to be
as reactive as heptyne in this acylation reaction, leading
to ynones in less than 10 min and with yields between
88 and 97% (entries 1-3). Similar results could be
obtained with a chlorinated acetylide (entries 4-6).
Monoacylation of a monometalated terminal diyne could
also be achieved, albeit in lower yields (entries 7-10).
Although the palladium-catalyzed mono-cross-coupling
with aromatic halides of such species has been reported
to occur in a selective manner,9 some bis-acylated prod-
ucts could be isolated from the crude reaction mixture.
The reaction of mixed alkynylalanes with oxalyl chlo-
ride is of particular interest. Although this reagent has
been described to react with copper acetylides to deliver
the corresponding acetylenic diketo derivatives,13 the use
of organoaluminum reagents led to the symmetrical
diynone in 69% yield (Scheme 1). This decarbonylative
Experimental Section
The preparation of 1-phenyl-oct-2-yn-1-one (Table 1, entry 1)
is representative. The alane solution was prepared according to
the procedure described in ref 9. An argon-flushed Schlenk tube
charged with acid chloride (0.5 mmol, 58 µL) and DCE (2 mL)
was cooled to 0 °C with ice water, and the dimethylalkynylalu-
minum solution (1.0 equiv, 1.4 M in heptane, 0.36 mL) was then
added dropwise. After the acid chloride disappeared (checked
by TLC), an aqueous solution of Rochelle’s salts16 (2.0 M, 2 mL)
(13) (a) Faust, R.; Weber, C.; Fiandanese, V.; Marchese, G.; Punzi,
A. Tetrahedron 1997, 53, 14655. (b) Mitzel, F.; FitzGerald, S.; Beeby,
A.; Faust, R. Chem.-Eur. J. 2003, 9, 1233.
(14) (a) Neubert, M. E.; Fishel, D. L. Org. Synth. 1983, 61, 8. (b)
Kakushima, M.; Hamel, P.; Frenette, R.; Rokach, J. J. Org. Chem.
1983, 48, 3214.
(15) (a) Chauvelier, J. C. R. Hebd. Seances Acad. Sci. 1948, 226,
927. (b) Migliorese, K. G.; Miller, S. I. J. Org. Chem. 1974, 39, 843. (c)
Detty, M. R.; Luss, H. R. Organometallics 1992, 11, 2157. (d) Leonard,
K.; Nelen, M.; Raghu, M.; Detty, M. R. J. Heterocycl. Chem. 1999, 36,
707. (e) Leonard, K.; Nelen, M. I.; Anderson, L. T.; Gibson, S. L.; Hilf,
R.; Detty, M. R. J. Med. Chem. 1999, 42, 3942.
J. Org. Chem, Vol. 70, No. 15, 2005 6127

was added to the vigorously stirred reaction mixture (caution:
gas evolvement). Ether (5 mL) was added, and the organic phase
was separated and washed with water and brine and dried over
anhydrous Mg2SO4. Chromatographic purification on silica gel
(eluent: cyclohexane/ethyl acetate 10/1) afforded 1-phenyl-oct-
2-yn-1-one (87 mg, 87%).17
Acknowledgment. B.W. thanks Paris 5 University
and the MRT for a postdoctoral grant. We thank the
CNRS for financial support and Prof. H.-P. Husson for
fruitful discussions and encouragement.
Supporting Information Available: Analytical data for
all new compounds and NMR spectra of every synthesized
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) Encyclopedia of Reagents for Organic Synthesis; Paquette, L.
A., Ed.; Wiley: New York, 1995; Vol. 6, p 4286.
(17) Bourgain, M.; Normand, J. F. Bull. Soc. Chim. Fr. 1973, 6, 2137.
JO050760Y
6128 J. Org. Chem., Vol. 70, No. 15, 2005