Regioselective reductive hydration of alkynes to form branched or linear alcohols

Article abstract of DOI:10.1021/ja307145e

The regioselective reductive hydration of terminal alkynes using two complementary dual catalytic systems is described. Branched or linear alcohols are obtained in 75-96% yield with ?25:1 regioselectivity from the same starting materials. The method is compatible with terminal, di-, and trisubstituted alkenes. This reductive hydration constitutes a strategic surrogate to alkene oxyfunctionalization and may be of utility in multistep settings.

Full text of DOI:10.1021/ja307145e

Communication
pubs.acs.org/JACS
Regioselective Reductive Hydration of Alkynes To Form Branched or
Linear Alcohols
Le Li and Seth B. Herzon*
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
S
* Supporting Information
Scheme 1. Metal-Catalyzed and Stoichiometric Methods for
the Formation of Alcohols from Unsaturated Hydrocarbons
ABSTRACT: The regioselective reductive hydration of
terminal alkynes using two complementary dual catalytic
systems is described. Branched or linear alcohols are
obtained in 75−96% yield with ≥25:1 regioselectivity from
the same starting materials. The method is compatible
with terminal, di-, and trisubstituted alkenes. This
reductive hydration constitutes a strategic surrogate to
alkene oxyfunctionalization and may be of utility in
multistep settings.
he production of alcohols from hydrocarbon feedstocks is
Tamong the most important processes in the chemical
industry.1 Classical methods based on alkene oxyfunctionaliza-
tion employ Brønsted acid catalysts1 and generally provide the
branched (Markovnikov) addition product for terminal alkenes.
Recently, several powerful metal-catalyzed methods have been
developed to prepare alcohols from alkenes (Scheme 1). These
include tandem hydroformylation−reduction processes by
Breit,2 Nozaki,3 and co-workers, a highly enantio- and
diastereoselective hydrohydroxyalkylation of 1,3-dienes by
Krische and co-workers,4 an allylic oxidation−reduction
sequence by Stahl and co-workers,5 an oxidative hydration−
reduction by Grubbs and co-workers,6 and a chemoenzymatic
method by Groger and co-workers.7 Despite these significant
̈
advances, stoichiometric approaches, such as hydroboration−
oxidation or oxymercuration−reduction,8 are often the
methods of choice for complex substrates even though these
processes require two steps and are not always highly
regioselective.9 Consequently, the development of additional
regioselective, catalytic oxyfunctionalization reactions with
broad functional group compatibility is desirable.
Figure 1. Selected precatalysts used in these studies.
number of challenges need to be addressed. For instance, most
alkyne hydration processes are conducted under acidic
conditions13 while many transfer hydrogenation catalysts
require basic activating agents.10 Additionally, it has been
reported that transfer hydrogenation catalysts may undergo
irreversible deactivation in the presence of terminal alkynes.14
Finally, competitive reduction of the alkyne could compromise
the yield and/or selectivity.
Recent advances in transfer hydrogenation10 led us to
consider the conversion of alkynes to alcohols under reducing
conditions. Although alkynes retain many of the characteristics
of alkenes, including reactivity orthogonal to that of
heteroatom-based functional groups, alkyne-specific reaction
pathways are known, potentially providing a handle for
selectivity in polyunsaturated systems. Moreover, alkynes are
readily introduced by a number of methods, including
nucleophilic attack of metal acetylides to carbogenic electro-
philes, metal-catalyzed cross-coupling reactions,11 and carbonyl
homologation reactions.12
Our studies began with an evaluation of the ability of alkyne
hydration and transfer hydrogenation catalysts to effect the
conversion of phenylacetylene (4) to sec-phenethanol (5)
(Table 1). In addition to 5, acetophenone (6), and isopropyl α-
methylbenzyl ether (7) were formed. When Nolan’s catalyst
16
17
(1)15 (Figure 1) and either Ru(PPh3)3Cl2 or (Cp*IrCl2)2
were employed (in the presence of potassium carbonate), <5%
conversion of phenylacetylene (4) was observed, suggesting
The simplest method to effect reductive hydration would
seem to involve the transformation of an alkyne to an aldehyde
or ketone followed by in situ reduction. Although several
catalysts are known to affect each individual step (see below), a
Received: July 20, 2012
Published: October 16, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a
Table 1. Optimization of the Markovnikov Reductive
Hydration
Table 3. Scope of the Reductive Hydration Reaction
a
b
yield (%)
entry
1
deviation from standard conditions
5
6
7
1 mol% Ru(PPh3)3Cl2 + 10 mol% K2CO3
instead of 3
0
0
0
2
1 mol% (Cp*IrCl2)2 + 10 mol% K2CO3
instead of 3
0
0
0
3
4
5
6
7
8
9
standard conditions
44
13
3
7
39
29
33
7
42
0
1 mol% [Pt(C2H4)Cl2]2 instead of 1
1 mol% Hg(OTf)2 instead of 1
1 mol% AgSbF6 instead of 1
4 equiv of H2O
0
3
0
83
81
81
4
8 equiv of H2O
6
9
17 equiv of H2O
9
4
c
10 17 equiv of H2O, 70 °C
85
6
1
a
b
1.0 mmol scale, [4] = 0.5 M (based on 2-propanol). As determined
by H NMR analysis using an internal standard. Isolated yield after
purification. 30:1 branched/linear (5:8), as determined by H NMR
c
1
1
analysis of the unpurified product mixture.
Table 2. Optimization of the Anti-Markovnikov Reductive
a
Hydration
b
yield (%)
entry
deviation from standard conditions
8
9
1
2
3
4
5
6
7
8
1 mol% CpRu(dppm)Cl instead of 2, 1 mol% 3
4 mol% CpRu(dppm)Cl instead of 2
4 mol% CpRu(dppm)Cl instead of 2, 100 °C
1 mol% 2, 1 mol% 3
5
5
15
66
8
11
<5
23
<5
<5
<5
standard conditions
90
c
2 mol% 3
90
62
45
2 mol% 2, 2 mol% 3
1 mol% 2, 2 mol% 3
20
a
b
0.25−1.0 mmol scale, [4] = 0.5 M (based on 2-propanol). As
c
1
determined by H NMR analysis using an internal standard. Isolated
yield after purification. sec-Phenethanol (5) was not detected in the
unpurified product mixture (1H NMR analysis).
that the two catalysts are incompatible under the reaction
conditions (entries 1 and 2). Application of 1 and Shvo’s
catalyst (3)18 led to a substantial increase in the yield of
product 5 (44%); however, isopropyl α-methylbenzyl ether (7)
was also formed in 42% yield (entry 3). Interestingly
[Pt(C2H4)Cl2]2,19 mercury triflate,20 and silver hexafluoroan-
timonate21 selectively promoted the addition of water, but the
yields of sec-phenethanol (5) were low (3−13%; entries 4−6).
We found that the formation of isopropyl α-methylbenzyl ether
(7) using 1 and 3 could be suppressed by increasing the
amount of water (entries 7−9). Under the optimized
conditions, the temperature could be reduced to 70 °C to
afford an 87% yield (1H NMR analysis; 85% isolated yield) of
sec-phenethanol (5, entry 10). The ratio of the branched
product sec-phenethanol (5) to the linear product phenethanol
(8) was 30:1 under these conditions.
a
0.5−1.0 mmol scale, [10a−l] = 0.5 M (based on 2-propanol).
b
Isolated yields after purification. Branched/linear ratios determined
1
by H NMR of unpurified product mixtures. For anti-Markovnikov
reductive hydration, branched products were not detected. 0.5 mmol
10c, g, or j, 34 equiv H2O, 2 mol% Au(IPr)Cl, 2 mol% AgO2CCF3,
and 2 mol% 3 (10c,g) or 4 mol% 3 (10j) in 2 mL 2-propanol. 0.2
mmol 10k, 35 equiv H2O, 5 mol% 2, 2.5 mol% 3, and 1.0 equiv PTSA
in 0.5 mL 2-propanol, 80 °C, 12 h. 0.1 mmol 10k, 170 equiv H2O, 10
mol% Au(IPr)Cl, 10 mol% AgO2CCF3, 10 mol% 3, and 1.0 equiv
PTSA in 2 mL 2-propanol. 80 °C, 3 h. 0.2 mmol 10l, 85 equiv H2O,
5 mol% Au(IPr)Cl, 5 mol% AgO2CCF3, and 5 mol% 3 in 2 mL 2-
propanol, 1:1 dr (13C NMR).
c
d
e
f
g
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Journal of the American Chemical Society
Communication
a
Our success with complex 3 led us to select this precatalyst
for the anti-Markovnikov reductive hydration of phenyl-
acetylene (4) (Table 2). Initial experiments employing
CpRu(dppm)Cl22 with 3 provided low to moderate yields of
phenethanol (8) and phenylacetaldehyde (9) (entries 1−3).
Using Grotjahn’s catalyst (2)23 (Figure 1) and 3 (1 mol% each)
led to a 23% yield of phenylacetaldehyde (9) and an 8% yield of
phenethanol (8) (entry 4). When the amounts of 2 and 3 were
increased to 4 mol% (entry 5), phenethanol (8) was formed in
90% yield, and the yield of phenylacetaldehyde (9) was <5%
(1H NMR analysis). Decreasing the amount of 3 to 2 mol% was
not detrimental to the yield (90% isolated yield of 8; entry 6).
However, further reducing the amount of either ruthenium
catalyst led to lower yields of phenethanol (8) (45−62%;
entries 7 and 8). Under the optimized conditions (entry 6), sec-
phenethanol (5) was not detected (1H NMR analysis).
Table 4. Site-Selective Reductive Hydration of Enynes
The scope of these reductive hydration reactions is shown in
Table 3. Both aromatic and aliphatic alkynes gave high isolated
yields of either branched or linear alcohol products (80−96%;
entries 1−5). In the case of the electron-rich arylalkyne 10c, use
of silver trifluoroacetate instead of silver hexafluoroantimonate
was necessary to suppress the formation of the secondary
isopropyl ether in the Markovnikov reductive hydration. The
current protocol is also compatible with common functional
groups, including alcohols, carboxylic acids, imides, amides, and
primary alkyl chlorides (80−93%; entries 6−10). Amines may
also be employed, provided that an equivalent of acid [p-
toluenesulfonic acid (PTSA)] is used to attenuate the basicity
of the substrate (75, 82%; entry 11). 1,7-Octadiyne (10l)
underwent double reductive hydration in 80 and 81% yield
(linear and branched, respectively). In all cases, the anti-
Markovnikov reductive hydration afforded a single regioisomer
(1H NMR analysis); the branched-to-linear selectivities in the
Markovnikov reductive hydration were ≥25:1.
Significant efforts have been devoted to the selective
oxyfunctionalization of polyolefins,24 and the selective
functionalization of an alkyne in the presence of one or more
alkenes could provide an alternative solution to this problem.
Toward this end, the reactivity of enynes was evaluated (Table
4). Alkynes incorporating terminal (entry 1), di- (entry 2), and
trisubstituted alkenes (entries 3−5) were competent substrates
for these transformations, forming the expected branched or
linear alcohol products in good to excellent yields. In the
Markovnikov hydration of enynes, the use of trifluoroacetate as
the counterion provided higher product yields, presumably by
attenuating acid-catalyzed decomposition pathways. For sub-
strate 10m bearing a monosubstituted alkene, careful
optimization of the reaction parameters (catalyst loading,
counterion, temperature, and concentration) was required to
suppress isomerization25 of the alkene.
a
0.25−1.0 mmol scale, [10m−q] = 0.25−0.50 M (based on 2-
b
propanol). Isolated yields after purification. Branched/linear ratios
were determined by 1H NMR analysis of the unpurified product
mixtures. For the anti-Markovnikov reductive hydration, branched
products were not detected. 9:1 mixture of 11m and internal olefin
isomers. 3:1 mixture of 12m and internal olefin isomers. 0.5 mmol of
10n or 10p, 28 equiv H2O, 4 mol% 2, and 2 mol% 3 in 1 mL 2-
propanol at 80 °C for 3 h. 0.5 mmol of 10p, 34 equiv H2O, 2 mol%
Au(IPr)Cl, 2 mol% AgO2CCF3, and 4 mol% 3 in 2 mL 2-propanol at
70 °C for 42 h. 0.25 mmol of 10q, 56 equiv H2O, 8 mol% 2, and 4
c
d
e
f
g
Limitations of these dual catalyst systems include applica-
tions to substrates containing alkyl ester substituents, as these
undergo transesterification with 2-propanol during the reaction,
and acid-sensitive protecting groups (e.g., dioxolanes), which
were found to be unstable toward hydrolysis. However, the
acidic nature of the catalytic system may be exploited to effect a
one-flask desilylation−hydration−reduction procedure
(Scheme 2). Thus, exposure of trimethyl(phenylethynyl)silane
(13) to the reductive hydration conditions formed the linear or
branched alcohol product 8 or 5 directly (82 or 85% yield,
respectively). As trimethylsilylacetylene is often used as a
surrogate for acetylene itself, the direct reductive hydration of
mol% 3 in 1 mL 2-propanol at 70 °C for 14 h.
Scheme 2. Direct Conversion of 13 to 8 or 5
substrates incorporating protected alkynes should simplify
multistep synthetic sequences.
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Journal of the American Chemical Society
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In summary, we have described the reductive hydration of
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the presence of alkenes, which may provide a strategy for site-
selective functionalization of polyunsaturated substrates.
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ASSOCIATED CONTENT
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■
1991, 1063.
S
* Supporting Information
Detailed experimental procedures and spectral data (1H, 13C,
IR, and HRMS) for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
seth.herzon@yale.edu
■
Backvall, J.-E. Top. Organomet. Chem. 2011, 37, 85.
̈
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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Financial support from the David and Lucile Packard
Foundation and Yale University is gratefully acknowledged.
S.B.H. is a fellow of the David and Lucile Packard and Alfred P.
Sloan Foundations, and is a Camille Dreyfus Teacher−Scholar.
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