Palladium/benzoic acid-catalyzed hydroalkoxylation of alkynes

Article abstract of DOI:10.1016/S0040-4039(01)01207-2

The reaction of the internal alkyne 1 with alcohols 2 in the presence of a catalytic amount of Pd(PPh₃)₄ and benzoic acid in dioxane at 100°C gave the allylic ethers 3 in good to high yields. The reaction proceeds via the palladium/benzoic acid-catalyzed isomerization of the alkyne 1 to allene 6, followed by the addition of alcohols 2 to the π-allylpalladium intermediate 7 formed by the hydropalladation of the resulting allene 6. Furthermore, the intramolecular reaction of alkynes having a hydroxy group at the terminus of the carbon chain gave five- and six-membered cyclic ethers in good yields.

Full text of DOI:10.1016/S0040-4039(01)01207-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6207–6210
Palladium/benzoic acid-catalyzed hydroalkoxylation of alkynes
a
b
b
b,
Isao Kadota, Leopold Mpaka Lutete, Akinori Shibuya and Yoshinori Yamamoto *
a
Research Center for Sustainable Materials Engineering, Institute of Multidisciplinary Research for Advanced Materials,
Tohoku University, Sendai 980-8578, Japan
b
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 11 June 2001; revised 23 June 2001; accepted 6 July 2001
Abstract—The reaction of the internal alkyne 1 with alcohols 2 in the presence of a catalytic amount of Pd(PPh ) and benzoic
3
4
acid in dioxane at 100°C gave the allylic ethers 3 in good to high yields. The reaction proceeds via the palladium/benzoic
acid-catalyzed isomerization of the alkyne 1 to allene 6, followed by the addition of alcohols 2 to the p-allylpalladium intermediate
7
formed by the hydropalladation of the resulting allene 6. Furthermore, the intramolecular reaction of alkynes having a hydroxy
group at the terminus of the carbon chain gave five- and six-membered cyclic ethers in good yields. © 2001 Elsevier Science Ltd.
All rights reserved.
The addition of pronucleophiles to CꢀC multiple
bonds has been considered as one of the most
efficient methods for the synthesis of organic com-
pounds, because the addition process does not pro-
duce any waste elements in contrast to nucleophilic
substitution or addition reactions which inevitably
afford useless by-products such as organic or inor-
In an initial experiment, 1-phenyl-1-propyne 1 was
treated with 1.2 equiv. of benzyl alcohol 2a,
Pd(PPh ) (10 mol%), and benzoic acid (10 mol%) in
3
4
dioxane at 100°C for 3 days. As expected, benzyl
cinnamyl ether 3a was obtained as the sole product in
5
9
6% yield (Table 1, entry 1). Similarly, the reaction
of 1 with the primary alcohols 2b–e (entries 2–5) and
secondary alcohols 2f–i (entries 6–9) gave the corre-
sponding cinnamyl ethers 3b–i, respectively, in good
to high yields. In all cases, no regio- or stereoisomers
were obtained.
1
ganic salts. Recently, we reported that certain alky-
nes react with carbon and nitrogen pronucleophiles in
the presence of palladium/carboxylic acid catalyst to
give the corresponding allylation products (Eqs. (1)
2
and (2)). We now report the palladium/benzoic acid-
3,4
catalyzed hydroalkoxylation of alkynes (Eq. (3)).
The mechanism of this reaction is presumably similar
to those of the hydrocarbonation and hydroamination
Hydrocarbonation of Alkynes2a
5
5
mol% Pd(PPh3)4
0 mol% CH3CO2H
C
2
of alkynes (Scheme 1). The initial step could be the
R
+
H C
R
R
R
hydropalladation of 1 with the hydridopalladium spe-
R
dioxane, 100 °C
0
cies 4 generated from Pd and benzoic acid (catalytic
6
(
1)
cycle I). The resulting vinylpalladium species 5 would
Hydroamination of Alkynes2b
produce phenyl allene 6 and the active catalyst 4 via
5
mol% Pd(PPh3)4
7
b-elimination. Hydropalladation of 6 with 4 would
10 mol% PhCO2H
N
R
give the p-allylpalladium species 7 which would react
with an alcohol 2 to give the product 3 along with
the hydridopalladium 4 (cycle II).
+
H N
R
R
dioxane, 100 °C
(
2)
1
1
0 mol% Pd(PPh3)4
0 mol% PhCO2H
The intramolecular version of the present reaction
was investigated using substrates 8 and 10, which
were easily prepared from phenylacetylene (Table 2).
The reaction of 8a and 8b gave the corresponding
tetrahydrofuran derivatives 9a and 9b in 82 and 75%
yields, respectively (entries 1 and 2). Although the
Ph
CH3
+
H OR
Ph
OR
dioxane, 100 °C
3
1
2
(
3)
*
0
Corresponding author.
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01207-2

6
208
I. Kadota et al. / Tetrahedron Letters 42 (2001) 6207–6210
a
Table 1. Palladium/benzoic acid-catalyzed hydroalkoxylation of 1-phenyl-1-propyne 1
entry
1
alcohol
BnOH
product
yield (%)b
96
Ph
OBn
3a
2a
2
3
4
95
83
85
HO
Ph
Ph
O
O
2
b
3b
HO
2c
3c
Ph
Ph
HO
Ph
Ph
O
O
2
d
3d
HO
5
6
91
82
3e
2e
HO
2f
Ph
Ph
O
O
3f
7
8
82
HO
2g
3g
83
85
HO
Ph
Ph
O
O
2
h
3
h
Ph
Ph
9
HO
Ph
Ph 3i
2
i
a
All reactions were carried out with 0.5 mmol of 1, 0.6 mmol of 2, 10 mol% of Pd(PPh ) , and
3
4
1
0 mol% of benzoic acid in 5 mL of dioxane at 100 °C for 3 days. bIsolated yield.
Ph
OR
Ph
Me
resulted in lower yields. The reaction of 10a and 10b
gave the corresponding tetrahydropyran derivatives 11a
and 11b in 33 and 50% yields, respectively (entries 3
and 4). No diastereoselectivities were observed in the
reactions of 8b and 10b; the disubstituted cyclic ethers
3
1
ROH
2
X
H
Pd-X
H
9
b and 11b were obtained as a 1:1 mixture of
Pd
H-Pd-X
II
I
Ph
diastereoisomers.
H
4
H
Ph
5
7
We next examined the reaction of polyols. Treatment of
1
2
,4-butanediol 12 with 2.4 equiv. of 1 in the presence of
0 mol% of the catalysts gave the corresponding 2:1
•
adduct 13 in 85% yield (Eq. (4)). Although the reason is
not clear, the reaction of triol 14 was slower than those
described above and required excess amounts of the
alkyne 1. Thus, the reaction of 14 with 12 equiv. of 1
for 4 days gave the 3:1 adduct 15 in 95% yield (Eq. (5)).
The reaction using 3.6 equiv. of 1 gave 15 in only 35%
yield after 5 days.
Ph
X = PhCO2
6
Scheme 1.
formation of the five-membered cyclic ethers proceeded
in good yields, that of six-membered cyclic ethers

I. Kadota et al. / Tetrahedron Letters 42 (2001) 6207–6210
Table 2. Intramolecular hydroalkoxylation
6209
entry
1
substrate
product
yield (%)a
82
OH
Ph
Ph
O
O
8a
Ph
Ph
Ph
Ph
9a
9b
75b
33
2
3
4
OH
8b
HO
Ph
Ph
O
10a
10b
11a
50b
HO
O
11b
aIsolated yield. bA 1:1 mixture of diastereoisomers.
1
(2.4 eq)
OH
O
Ph
HO
Ph
O
Pd(PPh ) (20 mol%)
3
4
benzoic acid (20 mol%)
dioxane, 100 °C
13
1
2
(4)
(5)
overnight
85%
HO
OH
1 (12 eq)
Pd(PPh ) (30 mol%)
Ph
O
O
Ph
3
4
benzoic acid (30 mol%)
dioxane, 100 °C
HO
Ph
O
15
14
4
days
95%
The above results prompted us to investigate the syn-
thesis of dendritic molecules based on the present
methodology. Treatment of 14 with 6 equiv. of 16,
which has two protected hydroxy groups, under the
standard conditions (conditions A, see Ref. 5) used for
the above reactions gave the corresponding
hydroalkoxylation product 17, a hexa-TBS ether, the
first generation of a dendrimer, in 95% yield (Eq. (6)).
Although the yield of 17 was quite satisfactory, a
prolonged reaction time (6 days) was required for com-
pletion of the reaction. It was imagined that the synthe-
sis of the next generation of dendrimer would need an
extremely long reaction time. To solve this problem, we
searched for optimum reaction conditions and finally
found that premixing of the catalysts is extremely effec-
tive for acceleration of the reaction (conditions B). A
solution of Pd(PPh ) and benzoic acid in dioxane was
stirred for 30 min at 100°C. To the resulting mixture
was added a solution of 14 and 16, and the mixture was
stirred overnight at 100°C to give the product 17 in
96% yield. Accordingly, the reaction time was reduced
dramatically under the conditions B.
3
4
OTBS
TBSO
O
O
OTBS
16 (6 eq)
OTBS
14
TBSO
O
OTBS
(6)
Pd(PPh ) (30 mol%)
3
4
benzoic acid (30 mol%)
dioxane, 100 °C
.
TBSO
conditions A: 6 days, 95%
conditions B: overnight, 96%
17
TBSO

6
210
I. Kadota et al. / Tetrahedron Letters 42 (2001) 6207–6210
In conclusion, we have developed a simple and efficient
method for the synthesis of various allylic ethers from
alcohols and alkynes using a palladium/benzoic acid
catalyst. The use of easily available pronucleophiles and
the avoidance of the production of metal salts make
this methodology an atom economical and environmen-
tally benign process.
M.; Brieden, W.; Baringhaus, K. H. Angew. Chem., Int.
Ed. Engl. 1992, 31, 1335–1336.
4. For palladium-catalyzed hydroalkoxylations of CꢀC dou-
ble bonds, see: (a) Smutny, E. J. J. Am. Chem. Soc. 1967,
89, 6793–6794; (b) Yagi, H.; Tanaka, E.; Ishiwatari, H.;
Hidai, M.; Uchida, Y. Synthesis 1977, 334–335; (c) Inoue,
Y.; Ohtsuka, Y.; Hashimoto, H. Bull. Chem. Soc. Jpn.
1
984, 57, 3345–3346; (d) Camacho, D. H.; Nakamura, I.;
Saito, S.; Yamamoto, Y. Angew. Chem., Int. Ed. 1999, 38,
365–3367; (e) Camacho, D. H.; Nakamura, I.; Saito, S.;
Acknowledgements
3
Yamamoto, Y. J. Org. Chem. 2001, 66, 270–275.
5.
Typical procedure: To a mixture of Pd(PPh3)4 (58 mg,
This work was financially supported by the Grant-in-
Aid for Scientific Research from the Ministry of Educa-
tion, Science and Culture of Japan.
0
.05 mmol) and benzoic acid (6 mg, 0.05 mmol) in dry
dioxane (5 mL) were added 1-phenyl-1-propyne 1 (75 mL,
.6 mmol) and benzyl alcohol 2a (52 mL, 0.5 mmol), and
0
the resulting mixture was stirred for 3 days at 100°C
under Ar. The reaction mixture was then filtered through
a short silica gel column using diethyl ether as an eluent.
The filtrate was concentrated, and the residue was
purified by silica gel column chromatography (hexane/
EtOAc, 40:1) to give 3a (108 mg, 96%).
References
1
.
For reviews of palladium-catalyzed pronucleophile addi-
tion to CꢀC multiple bonds, see: (a) Trost, B. M. Science
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hakrishnan, U. Chem. Soc. Rev. 1999, 28, 199–207.
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Trost, B. M.; Rise, F. J. Am. Chem. Soc. 1987, 109,
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For palladium-catalyzed isomerization of alkynes to
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2
.
.
3
For related hydrocarboxylation of alkynes, see: Trost, B.
.