Gold-catalyzed intermolecular hydroalkoxylation of allenes; difference in mechanism between hydroalkoxylation and hydroamination

Article abstract of DOI:10.1016/j.tetlet.2008.05.152

A wide range of alcohols 2 react with various allenes 1 in the presence of ClAuPPh₃/AgOTf catalyst at ambient temperature without solvent to produce allylic ethers 3. Contrary to the hydroamination, which proceeds through high chiral-face selec

Full text of DOI:10.1016/j.tetlet.2008.05.152

Tetrahedron Letters 49 (2008) 4908–4911
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gold-catalyzed intermolecular hydroalkoxylation of allenes; difference
in mechanism between hydroalkoxylation and hydroamination
*
Naoko Nishina, Yoshinori Yamamoto
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide range of alcohols 2 react with various allenes 1 in the presence of ClAuPPh3/AgOTf catalyst at
ambient temperature without solvent to produce allylic ethers 3. Contrary to the hydroamination, which
proceeds through high chiral-face selectivity for chiral allenes to give the corresponding chiral allylic
amines, transfer of chirality is not observed in the hydroalkoxylation, suggesting that the mechanism
of the gold-catalyzed hydroalkoxylation is different from that of hydroamination.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 28 April 2008
Revised 30 May 2008
Accepted 30 May 2008
Available online 5 June 2008
Keywords:
Alcohol
Allene
Chirality transfer
Gold catalysis
Hydroalkoxylation
Allylic ether
Silver triflate
Gold chloride
Inter- or intramolecular hydroalkoxylation, the formal addition
of alcohols to carbon–carbon multiple bonds, is a direct and effi-
cient procedure for the synthesis of various ethers and oxygen-
containing heterocycles.1 The nucleophilic addition of alcohols
under basic conditions has been studied widely2 but the use of
transition metal catalysts is more favorable for the hydroalkoxyla-
tion than the use of bases, primarily due to their effectiveness and
the milder conditions.3 In general, the intermolecular addition of
alcohols is more difficult than the intramolecular process.4 Accord-
ingly, it has been considered that the use of strong Lewis acidic
transition metal catalysts is needed for intermolecular
hydroalkoxylation.3
of these additions could not be stopped at the stage of the first
addition, that is, during formation of the dialkyl acetals. For the
addition to the cumulated double bond of allenes, only one exam-
ple was reported; the gold-catalyzed reaction of gaseous allene
(CH2@C@CH2) with MeOH gave the corresponding dimethyl acetal,
(MeO)2C(CH3)2.10a
MeO OMe
2 mol% NaAuCl4
neat, reflux
ð1Þ
+
MeOH
R
R
R2
5 mol% ClAuPPh3
5 mol% AgOTf
neat, 30 °C
R2 R3
+
R4OH
R1
R3
ð2Þ
R1
OR4
2
3
1
The gold-catalyzed hydration reaction was reported in 1976.5–7
Later, a synthetically useful protocol appeared for hydration of al-
kynes with NaAuCl4 and cationic phosphine–gold as catalyst under
almost neutral conditions to give carbonyl compounds.8 The gold-
catalyzed hydroalkoxylation, the addition of alcohols, was first re-
ported in 1991 by Utimoto and co-workers (Eq. 1).9 They reported
the direct transformation of alkynes into dimethyl acetal by the
addition of two equivalents of MeOH. In 1997, Teles et al. used
MeAuPPh3 and MeSO3H, as precursors for the in situ generated
Au cationic catalyst, in the addition of alcohols to differently
substituted alkynes under acidic conditions.8c,10 However, most
Herein, we report that the intermolecular hydroalkoxylation of
allenes 1 with various alcohols 2 takes place readily without solvent
using cationic gold(I) as the catalyst to give the corresponding
allylic ethers 3 in high yields (Eq. 2). It should be noted that
mono-addition takes place at the terminal carbon of the allenes,
which is different from the addition at the central carbon observed
previously,10a and dialkyl acetals are not produced at all. Although
the gold-catalyzed intermolecular hydroamination of chiral allenes
with aromatic amines took place with high chiral-face selectivity,
and complete chirality transfer from chiral allenes to allylamines
was realized with very high efficiency (Eq. 3),11a the corresponding
hydroalkoxylation with alcohols proceeded without chirality trans-
fer, resulting in the formation of racemic allylic ethers (Eq. 4). This
dramatic change depending on the nucleophiles suggests that the
* Corresponding author. Tel.: +81 22 795 6581; fax: +81 22 795 6784.
E-mail address: yoshi@mail.tains.tohoku.ac.jp (Y. Yamamoto).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.152

N. Nishina, Y. Yamamoto / Tetrahedron Letters 49 (2008) 4908–4911
4909
Table 2
mechanism of the gold-catalyzed hydroalkoxylation is different
Gold-catalyzed intermolecular hydroalkoxylation of allene 1a with alcohols 2a
from that of hydroamination.
5 mol% ClAuPPh3
5 mol% AgOTf
neat , 30 °C
NHPh
Me
H
10 mol% AuBr3
THF, 30 °C
H
+
ROH
+
PhNH2
p
-tolyl
p
-tolyl
OR
Ph
Ph
Me
ð3Þ
Ph
(
1a
2
3
R
)-1i
(S)-4
Entry
R
Time (h)
3
Yieldb (%)
94% ee
88% ee
2
5 mol% ClAuPPh3
5 mol% AgOTf
30 °C
Me
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
i-Pr
Me
n-Bu
Cy
t-Bu
Bn
PhCH(Me)–
Allyl
2
0.5
1
1.25
5
0.3
1
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k/3k0
98
98
98
98
84
69
86
H
H
+
OH
O
Me
Ph
ð4Þ
(
R
)-1i
2a
3I
neat : 0% ee
0.25 M in toluene : 0% ee
94% ee
1
71
Initially, the catalytic activity of Lewis acidic transition metals
was investigated in the reaction of p-tolylallene (1a) with isopropyl
alcohol (2a) (Table 1). In the absence of a catalyst, no reaction oc-
curred at 30 °C or even at 50 °C (entry 1). The use of gold catalysts,
such as AuCl, AuI, AuCl(CO), AuBr3, and ClAuPPh3 was not effective
at all (entries 2–4, 6, and 8). Gold(III) salts such as AuCl3 and
NaAuCl4ꢀ2H2O, produced 3a in low yields (entries 5 and 7). Other
catalysts, such as Ag(I), Cu(I), Cu(II), and H+, did not promote the
hydroalkoxylation at all (entries 10–13). Although very reactive
gold catalysts were needed for hydroamination,11b the hydroalk-
oxylation proceeded with a very high yield using commercially
available ClAuPPh3 in the presence of AgOTf (entry 9). The reaction
at higher temperatures gave lower yields of 3a; 84% yield at 50 °C
and 45% yield at 80 °C.
The scope and limitations of the hydroalkoxylation with various
alcohols under the optimized conditions are summarized in Table
2. Primary, secondary, and tertiary alcohols proved to be good sub-
strates for the hydroalkoxylation (entries 1–5). Benzyl alcohol 2f
and its derivative 2g showed high reactivity affording the corre-
sponding allylic ethers in good to high yields (entries 6 and 7). Allyl
alcohol 2h gave the corresponding product in a good yield (entry
8), however, propargyl alcohol 2i gave a complex mixture of prod-
ucts (entry 9).12 Phenol 2j also produced a complex mixture of
products (entry 10).12,13 In the case of the diol, ethylene glycol
2k, the reaction proceeded well to give nearly a 1:1 mixture of
the products 3k and 3k0. Mono-hydroalkoxylation gave 3k and fur-
ther hydroalkoxylation of 3k produced 3k0 (double-hydroalkoxyl-
ation, entry 11).
Propargyl
Ph
–CH2CH2OH
0.5
0.5
7
0c
10
11
2j
2k
0c
28d/27e
OH
p
-tolyl
O
O
3k : 28%
p
-tolyl
2
3k' : 27%
a
To a mixture of 2 (0.75 mmol) and catalyst (5 mol %) was added 1a (0.50 mmol)
and the mixture was stirred at 30 °C.
b
Isolated yield.
c
A complex mixture of products was formed.
d
Monohydroalkoxylation product.
Dihydroalkoxylation product.
e
Table 3
Gold-catalyzed intermolecular hydroalkoxylation of allenes 1 with i-PrOH (2a)a
R2
R2 R3
5 mol% ClAuPPh3
5 mol% AgOTf
neat , 30 °C
R1
R3
R1
O
+
OH
1
2a
3
Entry
1
R1
R2
R3
Time (h)
3
Yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
p-Tolyl
Ph
p-Anisyl
p-F–C6H4
Bn
H
H
H
H
H
H
H
H
H
2
3A
3B
3C
3D
3E
3F
3G
3H
3I
98
96
0c
H
H
H
2.5
0.1
5
99
57
62
42
38d
93
65
97
13
The scope and limitations of the reaction with respect to various
allenes are summarized in Table 3. Aryl allenes proved to be good
H
1
n-Oct
Cy
t-Bu
Ph
Ph
H
H
2.5
2
H
12
H
Me
H
Me
H
2
6
Table 1
Effect of catalysta
10
11
12
1j
1k
1l
3J
3K
3L
n-Pent
n-Pent
n-Pent
H
2.5
6
5 mol% catalyst
neat , 30 °C, 2 h
n-Pent
+
OH
2a
p
-tolyl
Ph
O
a
To a mixture of 2a (0.75 mmol) and catalyst (5 mol %) was added 1 (0.50 mmol)
and the mixture was stirred at 30 °C.
1a
3a
Yieldb (%)
b
Entry
Catalyst
Isolated yield.
c
A complex mixture of products was formed.
1
2
3
none
AuCl
0
0
0
Yields were determined by 1H NMR with dibromomethane as an internal
d
standard.
AuI
4
5
6
ClAu(CO)
AuCl3
AuBr3
0
20
0
substrates for the hydroalkoxylation, except for the highly reactive
p-anisyl allene,12 which gave a complex mixture of products (en-
tries 1–4 and 9–10). Aliphatic allenes gave the corresponding prod-
ucts in moderate yields (entries 5–8). We also investigated the
reactivities of disubstituted allenes. The 1,3-disubstituted allene
1i showed reactivity comparable with the monosubstituted allene
1b (entry 9) without producing a regioisomer. The aliphatic 1,3-
disubstituted allene 1k gave the corresponding product in a high
yield unlike monosubstituted aliphatic allenes (entry 11 vs entries
5–7). The 1,1-disubstituted allene 1j gave the corresponding
7
8
9
10
11
12
13
NaAuCl4ꢀ2H2O
11
0
97
0
0
0
ClAuPPh3
ClAuPPh3/AgOTf
AgOTf
2[CuOTf]ꢀtoluene
Cu(OTf)2
TfOH
0
a
To
a mixture of 2a (0.75 mmol) and catalyst (5 mol %) was added 1a
(0.50 mmol) and the mixture was stirred at 30 °C for 2 h.
b
Yields were determined by 1H NMR with dibromomethane as an internal
standard.

4910
N. Nishina, Y. Yamamoto / Tetrahedron Letters 49 (2008) 4908–4911
based on the hydroamination observations; attack of gold takes
place from the less hindered side of the allene double bond. One
explanation for the observation of the E-isomers 3 is that the isom-
erization may take place through the intermediate D.
In conclusion, we have developed a gold-catalyzed intermole-
cular hydroalkoxylation of allenes, which proceeds smoothly at
room temperature without solvent. Investigation of the chirality
transfer of the hydroalkoxylation led to the important finding that
an oxygen nucleophile reacts differently to a nitrogen nucleophile
in the gold-catalyzed addition to allenes.17
product as a single stereoisomer in moderate yield (entry 10). In
our previous work on hydroamination, this allene gave the product
as a stereoisomeric mixture. The structure of the product 3J was
determined as E by NOE experiments. The aliphatic 1,1-disubsti-
tuted allene 1l gave the corresponding product in extremely low
yield (entry 12). It should be noted that all four potential selectivity
problems of substituted allenes (positional selectivity, chemoselec-
tivity, regioselectivity, and stereoselectivity) have been solved in
the reactions of 1i–k, and selective formation of 3I–K was realized
(entries 9–11).14
General procedure for hydroalkoxylation of an allene. To a suspen-
sion of ClAuPPh3 (12.4 mg, 0.025 mmol) and AgOTf (6.4 mg,
0.025 mmol) in i-PrOH (2a, 57 ll, 0.75 mmol; neat conditions)
was added p-tolylallene (1a, 64.9 mg, 0.50 mmol) and the mixture
was stirred at 30 °C under an Ar atmosphere. After the reaction was
complete (2 h), the reaction mixture was filtered through a short
silica gel pad with ether as the eluent. The product was purified
by column chromatography (silica gel, pentane) to give 3a in 98%
yield (93.4 mg).
The chirality transfer was also examined using the chiral allene
1i (Eq. 4). Surprisingly, the allene chirality was not transferred onto
the product at all. The experiment was also examined in dilute tol-
uene, however, only a racemic product was obtained. No chirality
transfer suggests that the mechanism of the hydroalkoxylation is
different from that of hydroamination. In the hydroamination, a
highly nucleophilic amine reacts first with a gold complex, result-
ing in the formation of an amine–gold complex which then reacts
with the allenes.11a Formation of the amine–gold complex was
strongly supported from the fact that, in the absence of an amine,
rapid racemization of the allene occurred (Eq. 5);11c,15 however, in
the presence of an amine, highly efficient chirality transfer was
accomplished. In the case of hydroalkoxylation, alcohols are in
general less nucleophilic than amines and thus a gold complex
must react first with the allene (R)-1i prior to the addition of alco-
hols. The fact that no chirality transfer took place also suggested
the formation of a gold–allene complex.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.152.
References and notes
H
H
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10 mol% [Au]
H
H
30 °C
Me
Me
Ph
(
Ph
ð5Þ
R
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94% ee
a) AuBr3 in THF : 1% ee (5 min)
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b) ClAuPPh3/AgOTf in toluene : 0% ee (30 s)
A plausible mechanism, though speculative, is shown in Scheme 1
The cationic gold species was generated in situ from ClAuPPh3 by
halogen precipitation as the silver salt. The catalytic cycle is initi-
ated most probably by coordination of the allene to gold to afford
the intermediate A. The addition of an alcohol takes place through
B to give the gold–vinyl intermediate C, which produces allylic
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tion.10b,16 The stereochemistry of the intermediates B is speculated
R
1
A
5. Norman, R. O. C.; Parr, W. J. E.; Thomas, C. B. J. Chem. Soc., Perkin Trans. 1 1976,
1983–1987.
Au-L
Ph3PAu
R
R
OR'
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3
R'OH 2
H
L
Au-L
OR'
Au-L
OR'
Au
R
R
R
R'
O
H
D
C / C'
B
L = PPh3
H
Scheme 1. Proposed mechanism for the gold-catalyzed intermolecular hydroalk-
oxylation of allenes 1 with alcohols 2.

N. Nishina, Y. Yamamoto / Tetrahedron Letters 49 (2008) 4908–4911
4911
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12. The reaction was very exothermic, and resulted in the formation of a complex
mixture of products. The corresponding allylic ether was not detected by GC–
MS and NMR. To make the reaction conditions milder, the hydroalkoxylation in
dilute toluene was carried out, but the corresponding product was not
detected.
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with alcohols, which is very similar with the present paper, has been
published; Zhang, Z.; Widenhoefer, R. A. Org. Lett. 2008, 10, 2079–2081.