Rhodium-catalyzed anti-Markovnikov intermolecular hydroalkoxylation of terminal acetylenes

Article abstract of DOI:10.1021/ja1097385

We report here the first transition-metal-catalyzed anti-Markovnikov intermolecular hydroalkoxylation of terminal acetylenes to give enol ethers in high yields without using bases. Arylacetylenes as well as alkenyl- and alkylacetylenes were coupled with aliphatic alcohols, and the products were obtained with high Z selectivity in most cases. Effective catalysts were 8-quinolinolato rhodium complexes, which are structurally simple but have been relatively unexplored as catalysts.

Full text of DOI:10.1021/ja1097385

Published on Web 12/13/2010
Rhodium-Catalyzed Anti-Markovnikov Intermolecular Hydroalkoxylation of
Terminal Acetylenes
Masataka Kondo, Takuya Kochi, and Fumitoshi Kakiuchi*
Department of Chemistry, Faculty of Science and Technology, Keio UniVersity, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama, Kanagawa 223-8522, Japan
Received October 29, 2010; E-mail: kakiuchi@chem.keio.ac.jp
Table 1. anti-Markovnikov Addition of 2a to 1aa
Abstract: We report here the first transition-metal-catalyzed anti-
Markovnikov intermolecular hydroalkoxylation of terminal acety-
lenes to give enol ethers in high yields without using bases.
Arylacetylenes as well as alkenyl- and alkylacetylenes were
coupled with aliphatic alcohols, and the products were obtained
with high Z selectivity in most cases. Effective catalysts were
8-quinolinolato rhodium complexes, which are structurally simple
but have been relatively unexplored as catalysts.
Enol ethers are useful intermediates in organic synthesis.1
Addition of alcohols to acetylenes should be one of the most
straightforward strategies to access enol ethers, but the addition
under mild conditions is still rare. Herein we describe a simple
rhodium catalyst for the anti-Markovnikov addition of alcohols to
terminal acetylenes, giving Z-enol ethers selectively.
Traditionally, the addition of alcohols to acetylenes needs strong
bases under harsh conditions,2 and arylacetylenes were hydroalkox-
ylated in an anti-Markovnikov fashion to give ꢀ-arylvinyl ethers.3
Synthesis of enol ethers was also conducted by other methods such
as cross-coupling of alkenyl halides with alcohols,4 elimination of
alcohols from acetals,5 trans-alkenylation,6 Horner-Wittig and
a Reaction conditions: 1 mmol of 1a, 1 mL of 2a, catalyst, solvent,
Tebbe olefinations,7 and catalytic substitution of R,ꢀ-unsaturated
24 h. b GC yield of the mixture of Z- and E-isomers. c Used 2.5 mol %
acetals with Grignard reagents.8 But the simplicity and the high
of the dimer. d nd ) not detected. e 48 h. f 60% isolated yield. g Z/E
atom economy of the hydroalkoxylation is desirable, and the use
of transition metal catalysts has been examined. While various
intramolecular cyclizations have been reported,9 the intermolecular
reaction, particularly of terminal acetylenes, for the selective
synthesis of enol ethers is difficult to achieve.10 A PdMo3 cubane-
type cluster and AgOTf catalyze the anti-Markovnikov hydroalkox-
ylation only for acetylenes activated by esters.11 Addition of allyl
alcohol to phenylacetylene was also reported using a ruthenium
catalyst but suffers low product selectivity.12 Therefore, we
examined the simple catalytic addition of alcohols to terminal
acetylenes to obtain enol ethers with high product selectivity.
ratio of 4aa.
Solvents were then investigated for the hydroalkoxylation.13 Most
of the co-solvents screened, including toluene (entry 5) and THF
(entry 6), did not increase the yield significantly. But the use of
amides led to the improvement of the yield (entries 7 and 8), and
the reaction in a 1:1 ratio of 2a and DMA afforded the product in
59% yield (entry 8). To examine the effect of the slightly basic
nature of amide solvent on the yield, stronger bases, Et3N and
pyridine, were used but only decreased the yield (entries 9 and
10).
Further optimization of the conditions revealed that a slight
increase of the temperature to 70 °C (entry 11) and reduction of
the catalyst loading to 2 mol % (entry 12) were effective for the
reaction, and the product was obtained in 80% yield.13
The hydroalkoxylation described here is catalyzed specifically
by dicarbonyl(8-quinolinolato)rhodium complexes among the cata-
lysts screened (Scheme 1). Under the optimized conditions (Table
1, entry 12), several rhodium complexes bearing N-O anionic
bidentate ligands were employed as catalysts. While a catalyst with
unsubstituted 8-quinolinolato ligand provided 67% yield of 4aa,
use of carboxylate ligands was unsuccessful (e7% yield). Substitu-
tion of a CO ligand with PPh3 or both with COD ligand essentially
stopped the desired reaction. It is noteworthy that 8-quinolinolato
rhodium complexes have rarely been reported as catalysts, even
When the reaction of phenylacetylene (1a) and excess MeOH
(2a) was performed with 5 mol % of dicarbonyl(2-methyl-8-
quinolinolato)rhodium 3 at 65 °C for 24 h, anti-Markovnikov
addition of 2a proceeded to give ꢀ-methoxystyrene (4aa) in 22%
GC yield (Table 1, entry 1). The C-O bond formation took place
regioselectively at terminal carbon of 1a, and no product formed
via Markovnikov addition was observed.
Examination of various rhodium, iridium, and ruthenium com-
plexes was carried out but resulted in <5% yield or no observation
of 4aa. The selected results are listed in Table 1 (entries 2-4).13
The reaction using [RhCl(CO)2]2 as a catalyst gave acetophenone
and phenylacetaldehyde dimethyl acetal in addition to the small
amount of 4aa (entry 2).
9
32 J. AM. CHEM. SOC. 2011, 133, 32–34
10.1021/ja1097385  2011 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Effect of Ligands for Hydromethoxylation of 1a
Internal acetylenes such as 1-phenyl-1-propyne were also
investigated as substrates, but the reactions did not give hy-
droalkoxylation products. In the case of 1-phenyl-2-(trimethylsi-
lyl)acetylene, desilylated enol ether 4aa was obtained in 59% yield,
instead of the simple hydroalkoxylation product.17
The hydroalkoxylation was also examined with several alcohols.
When EtOH (2b) was used instead of 2a, product 4ab was obtained
in 54% yield, and addition of 5 mol % of 2a increased the yield to
64%. Extension of the reaction time to 72 h led to full conversion,
and a 72% yield of 4ab was achieved (eq 1). When more sterically
i
demanding PrOH (2c) was used, much longer reaction time was
required to complete the reaction, but the corresponding product
4ac was obtained in 62% yield with high Z selectivity (Z/E ) 93/
7).18
for well-known reactions,14 and have never been described as a
suitable catalyst for novel reactions.
A variety of aryl- and heteroarylacetylenes were hydroalkoxylated
by catalyst 3 to form enol ethers with high Z selectivity (Table
2).15 Arylacetylenes having electron-withdrawing groups at their
Table 2. Hydromethoxylation of Terminal Acetylenesa
entry
1
R
4
yield of 4b
Z/Ec
1
2
3
4
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
p-CF3C6H4
p-NCC6H4
p-MeO2CC6H4
p-AcC6H4
p-O2NC6H4
p-MeC6H4
o-MeC6H4
p-MeOC6H4
2-naphthyl
3-thienyl
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
4ja
4ka
4la
4ma
4na
4oa
4pa
92% (48%)
85% (54%)
82% (64%)
78% (55%)
73%c (57%)
64% (53%)
65% (58%)
64% (55%)
55% (45%)
64% (52%)
32%c (25%)
66% (39%)
29%c (28%)
27%c (17%)
69% (66%)
94/6
95/5
94/6
94/6
The addition of phenols was unsuccessful under similar reaction
conditions, but in this case, use of a catalytic amount of a weak
base, 2,6-lutidine, improved the product yields. When p-methox-
yphenol (2d) was reacted with 1a in the presence of 5 mol % of
2,6-lutidine in PhCl, aryl ether product 4ad was obtained in 32%
yield (eq 2).
5
94/6
6d
7d
8e
9
88/12
70/30
87/13
91/9
88/12
96/4
80/20
90/10
50/50
100/0
10
11
12
13
14f
15
The mechanism of the anti-Markovnikov addition of alcohols
to terminal acetylenes is unclear at this point.19 However, based
on the results that the C-O bond is formed only at the terminal
carbon and no hydroalkoxylation of internal acetylenes was
observed, the reaction may proceed via a vinylidene-rhodium
intermediate, followed by addition of alcohol,20 similar to other
additions of O-nucleophiles to terminal acetylenes.21
We reported here the first transition-metal-catalyzed anti-
Markovnikov intermolecular hydroalkoxylation of terminal acety-
lenes to give the enol ethers in high yields without using bases for
aliphatic alcohols. 8-Quinolinolato rhodium complexes were found
to be effective catalysts for this transformation, which are structur-
ally simple but relatively unexplored as catalysts. Further optimiza-
tion of the reaction conditions and elucidation of the reaction
mechanism are now underway
2-thienyl
N-methyl-2-indolyl
2-benzofuryl
1-cyclohexenyl
Ph3C
a Reaction conditions: 1 mmol of 1, 1 mL of 2a, 0.02 mmol of 3, 1
mL of DMA, 70 °C, 48 h. b GC yield of the mixture of Z- and
c
1
E-isomers. Isolated yields are in parentheses. Determined by H NMR.
d 6 days. e 7 days. f 3 days.
para position, such as CF3, CN, CO2Me, Ac, and NO2 groups,
reacted with 2a smoothly to give ꢀ-methoxystyrenes 4ba-4fa in
high yields with high stereo- and regioselectivities (entries 1-5).
The electron-rich arylacetylenes 1g-1i required longer reaction
times, and their Z selectivity slightly decreased (entries 6-8). The
reaction of sterically hindered o-tolylacetylene (1h) provided the
corresponding product 4ha in a yield similar to that of 4ga obtained
from p-tolylacetylene (1g). 2-Ethynylnaphthalene was also con-
verted to the enol ether product by 3 (entry 9). 3- and 2-thieny-
lacetylenes (1k, 1l) were coupled with 2a to give enol ethers 4ka
and 4la, and the higher yield was obtained for 4ka (entries 10 and
11). The addition of 2a to terminal acetylenes having N-methyl-
2-indolyl (1m) and benzofuryl (1n) groups also proceeded in the
presence of 3 (entries 12 and 13).
The hydroalkoxylation of alkenyl- and alkylacetylenes was also
examined. When the reaction was performed with (1-cyclohexenyl)-
acetylene 1o, methoxydiene product 4oa was obtained with 1:1 Z/E
selectivity (entry 14). The reaction was also found to be applicable
to sp3 carbon-substituted terminal acetylenes.16 The reaction of
tritylacetylene (1p) gave the corresponding anti-Markovnikov
addition product 4pa in 69% yield with complete Z selectivity (entry
15), and the structure of 4pa was confirmed by X-ray crystal-
lography.13
Acknowledgment. This work was supported, in part, by a
Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan, and by
The Science Research Promotion Fund. We are also grateful to
Prof. Kyoko Nozaki (the University of Tokyo) for X-ray crystal-
lographic analysis.
Supporting Information Available: Experimental procedures,
spectroscopic data for new compounds, and X-ray crystallographic data
for 4pa (CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
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