Stereoselective gold(I)-catalyzed intermolecular hydroalkoxlation of alkynes

Article abstract of DOI:10.1021/cs501976s

(Chemical Equation Presented) We report the use of cationic gold complexes [Au(NHC)(CH₃CN)][BF₄] and [{Au(NHC)}₂(μ-OH)][BF₄] (NHC = N-heterocyclic carbene) as highly active catalysts in the solvent-free hydroalkoxylation of internal alkynes using primary and secondary alcohols. Using this simple protocol, a broad range of (Z)-vinyl ethers were obtained in excellent yields and high stereoselectivities. The methodology allows for the use of catalyst loadings as low as 200 ppm for the addition of primary alcohols to internal alkynes (TON = 35 000, TOF = 2188 h^-1).

Full text of DOI:10.1021/cs501976s

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Letter
Stereoselective Gold(I)-Catalyzed
Intermolecular Hydroalkoxy-lation of Alkynes
Richard Veenboer, Stephanie Dupuy, and Steven P. Nolan
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/cs501976s • Publication Date (Web): 21 Jan 2015
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ACS Catalysis
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Stereoselective Gold(I)-Catalyzed Intermolecular Hydroalkoxla-
tion of Alkynes
Richard M. P. Veenboer,† Stéphanie Dupuy† and Steven P. Nolan*
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EaStCHEM School of Chemistry, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, U.K.
ABSTRACT: We report the use of cationic gold complexes [Au(NHC)(CH3CN)][BF4] and [{Au(NHC)}2(μ-OH)][BF4]
(NHC = N-heterocyclic carbene) as highly active catalysts in the solvent-free hydroalkoxylation of internal alkynes using
primary and secondary alcohols. Using this simple protocol, a broad range of (Z)-vinyl ethers were obtained in excellent
yields and high stereoselectivities. The methodology allows for the use of catalyst loadings as low as 200 ppm for the
addition of primary alcohols to internal alkynes (TON = 35 000, TOF = 2 188 h-1).
KEYWORDS: gold, hydroalkoxylation, alkynes, vinyl ethers, solvent-free
The development of synthetic methods for the formation
of C-O bonds is of great interest in synthetic organic
chemistry. A very effective approach is the addition of
alcohol O-H bonds across unsaturated C-C bonds in
inter- or intramolecular fashion to provide ethers.1 To
avoid the use of harsh reaction conditions2 and/or the
need for strong bases,3 these hydroalkoxylation reac-
tions are usually performed employing metal-catalyzed
conditions. Numerous procedures have been developed
that make use of complexes of Cu,4 Zn,5 Hg,6 Ru,7 Rh,8
Ir,9 Pd,10 Pt,11 Au,12 or Th13 as catalysts. These catalytic
procedures are desirable over substitution reactions (that
would form the same products) because the method
avoids the generation of stoichiometric amounts of
waste.14
Scheme 1. Common side-products formed in hy-
droalkoxylation reactions.
R
R'
R
R
R"
O
H
[Au]
O
O
O
O
+
+
+
+
R"
R"
R"
R
R'
O
R'
R
R'
R'
R"
Regioisomers
Side-products
Cationic gold complexes [Au(NHC)(CH3CN)][BF4] and
[{Au(NHC)}2(ꢀ-OH)][BF4] (NHC = N-heterocyclic car-
bene) have been demonstrated to be highly active cata-
lysts in various silver- and acid-free gold-catalyzed trans-
formations.19 Herein, we showcase their efficiency to
achieve good chemo- and stereoselectivity in hydroal-
koxylation reactions of internal alkynes.
We first examined the addition of 1-phenylethanol (3a) to
diphenylacetylene (2a), catalyzed by
The rapid growth of the field of homogeneous gold catal-
ysis has resulted in the development of a vast number of
gold-catalyzed organic transformations, most of which
rely on the ability of cationic gold complexes to activate
unsaturated C-C bonds.15 While gold-catalyzed intramo-
lecular hydroalkoxylation reactions have been success-
fully employed in the synthesis of various heterocycles16
and natural products,17 reports on the more challenging
intermolecular hydroalkoxylation reactions remain
scarce.18 Teles and co-workers were the first to report
intermolecular hydroalkoxylation of terminal alkynes.18a
The groups of Corma and Sahoo later achieved the ad-
dition of secondary and tertiary alcohols as well as phe-
nols to internal alkynes.18b, 18c These reports have estab-
lished that internal alkynes are more challenging sub-
strates in hydroalkoxylation reactions compared to their
terminal congeners. While monoaddition to alkynes had
already been demonstrated to be difficult, other chal-
lenges remain in terms of chemoselectivity, stereoselec-
tivity, regioselectivity and substrate scope (Scheme 1).
1
mol%
[{Au(IPr)}2(ꢀ-OH)][BF4] (1a) in toluene at 80 °C (Table 1,
entry 1). After 18 hours, full conversion was observed
(as monitored by GC) with high chemoselectivity, 90% of
the desired vinyl ether 4a and only 10% of its corre-
sponding hydrolysis product 5,18c, 18d, 20 and stereoselec-
tivity of 98% (Z)-4a. To the best of our knowledge, hy-
droalkoxylation reactions have not been reported previ-
ously with secondary benzylic alcohols.18c Moreover, we
were delighted to see that the corresponding acetal, re-
sulting from the addition of two molecules of 3a to 2a,
was not detected. Interestingly, the use of Gagosz-type
monogold [Au(IPr)(NTf2)],21 resulted in poor reactivity
(Table 1, entry 2). Gratifyingly, better chemoselectivity
and faster reactions were obtained under solvent-free
conditions (Table 1, entry 3). Other NHC ligands were
then tested using lower catalyst loading (0.3 mol%, Ta-
ble 1, entries 4-6). Catalysts 1a and 1b bearing IPr and
SIPr ligands gave very similar chemoselectivities. The
catalyst bearing the least electron-donating NHC ligand,
IPrCl, [{Au(IPrCl)}2(ꢀ-OH)][BF4] (1c) enhanced the reactivi-
ty but reduced the chemoselectivity. The use of solvate
monogold complexes [Au(NHC)(CH3CN)][BF4] 1d and 1e
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Page 2 of 6
as catalysts led to a large decrease in chemoselectivity most likely because of competitive coordination of the
1
2
3
4
5
6
7
8
(Table 1, entries 7-8). We concluded that the hydroal-
koxylation reaction could be performed most effectively
using 0.3 mol% of [{Au(SIPr)}2(ꢀ-OH)][BF4] (1b) or
[{Au(IPrCl)}2(ꢀ-OH)][BF4] (1c) at 80 °C under solvent-free
conditions. Indeed, after carrying out these hydroalkoxy-
lation reactions for 2 hours (Table 1, entries 9-10), the
desired vinyl ether 4a was formed with high chemoselec-
tivity and stereoselectivity, 96% and 95% (Z)-4a, respec-
tively.
catalyst to the triple bond of the nitrile moiety. We also
tested benzhydrol (3j) and derivatives 3k-l under these
reaction conditions. Longer reaction times were required
to reach completion in these instances, as these pos-
sess increased steric bulk. Nonetheless, the correspond-
ing (Z)-vinyl ethers 4j-l were obtained in modest yields
with excellent stereoselectivities.
The reactivity of various symmetrical and unsymmetrical
internal alkynes 2b-j was evaluated next (Scheme 3).
Despite the need for longer reaction times,22 the hy-
droalkoxylation reactions of unsymmetrical diaryl-
substituted alkynes 2b-f proceeded well. The corre-
sponding vinyl ethers 4m-p were isolated in good yields
as mixtures of regioisomers with high stereoselectivity
favoring the (Z)-isomer. A preferential addition to the less
electron-rich center was observed when NO2 or MeO
substituents were present, (alkynes 2b-c, vinyl ethers
4m-n), while a 1:1 mixture of regioisomers was obtained
with 1-chloro-4-(phenylethynyl)benzene (alkyne 2d, vinyl
ether 4o) that lacks such a substituent. With both MeO
and Cl substituents at the para positions of the phenyl
rings (alkyne 2e, vinyl ether 4p), the preference of addi-
tion to the less electron-rich center was restored.
9
Table 1. Catalyst screening with NHC-gold(I) com-
plexes.a
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entry
catalyst
t
conversion
(%)b (4a/5)c
>99 (9/1)
7
(loading in mol%)
(h)
18
18
1
1d
2d
3
[{Au(IPr)}2(ꢀ-OH)][BF4] 1a (1)
[Au(IPr)(NTf2)] (2)
>99
[{Au(IPr)}2(ꢀ-OH)][BF4] 1a (1)
[{Au(IPr)}2(ꢀ-OH)][BF4] 1a (0.3)
4
0.5
0.5
51 (32/1)
63 (31/1)
Scheme 2. Hydroalkoxylation of alkynes using vari-
ous secondary benzylic alcohols.a
5
[{Au(SIPr)}2(ꢀ-OH)][BF4] 1b
(0.3)
[{Au(IPrCl)}2(ꢀ-OH)][BF4] 1c (0.3)
[Au(IPr)(CH3CN)][BF4] 1d (0.6)
[Au(IPrCl)(CH3CN)][BF4] 1e (0.6)
6
7
8
9
0.5
0.5
0.5
2
86 (17/1)
51 (2/1)
74 (1/1)
>99 (9/1)
[{Au(SIPr)}2(ꢀ-OH)][BF4] 1b
(0.3)
[{Au(IPrCl)}2(ꢀ-OH)][BF4] 1c (0.3)
10
2
>99 (8/1)
aReaction conditions: 2a (0.50 mmol), 3a (0.55 mmol, 1.1
equiv.), neat, 80 °C, in air. bDetermined by GC analysis,
c
1
with respect to 2a. Determined by H NMR spectroscopy.
dReaction in 1M PhCH3.
We evaluated the performance of both 1b and 1c in the
hydroalkoxylation reactions of diphenylacetylene (2a)
with various secondary benzylic alcohols 3a-l (Scheme
2). Substituents at the ortho, meta and para positions of
the aryl group of 1-phenylethanol derivatives were toler-
ated and the corresponding vinyl ethers 4a-e were ob-
tained in good yields. Interestingly, the electronic proper-
ties of the aryl group of the alcohol did not affect the ste-
reoselectivity of the reaction and the (Z)-isomer was ob-
tained predominantly in all cases. Importantly, the hy-
droalkoxylation reaction of (S)-1-phenylethanol was
found to produce one enantiomer of the vinyl ether with
1b or 1c as catalysts.
aReaction conditions: 2a (0.50 mmol), 3a–o (0.55 mmol,
1.1 equiv.), 1b or 1c (0.3 mol%), neat, 80 °C, in air. The
catalyst giving the best result, reaction time, yield of isolated
product and Z/E ratio of product are given in parentheses.
The results for the other catalyst are given in the ESI.
Changing the methyl moiety at the α’-position of the al-
cohol (3f-i) required longer reaction times for the trans-
formation to reach completion. Interestingly, substitution
of this methyl group with an isopropyl (3f) or trifluorome-
thyl (3g) group led to a reversal in selectivity and gave
instead (E)-vinyl ethers 4f and 4g as main products. We
hypothesized that this change in selectivity was linked to
the electronic nature of the substituent in the α’-position.
The addition of methyl mandelate 3h to 2a, however,
resulted again in the predominant formation of (Z)-vinyl
ether 4h. Mandelonitrile 3i did not undergo the reaction,
Next, hydroalkoxylation with symmetrical alkynes was
evaluated. The reaction of strongly activated dimethyla-
cetylene dicarboxylate (DMAD, 2f) with 3a afforded a 1:1
mixture of the desired vinyl ether 4q, with complete ste-
reoselectivity towards the (E)-vinyl ether, along with al-
cohol condensation side-product (oxybis(ethane-1,1-
diyl))dibenzene.23 In agreement with the report of Teles
and co-workers, the hydroalkoxylation reactions of 1,4-
bis(2-thiophene)butyne 2g, 4-octyne 2h and 1,4-
dichlorobutyne 2i to form vinyl ethers 4r-t were unsuc-
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ACS Catalysis
cessful under these reaction conditions.18a Replacing
tained in excellent yields and selectivities (Table 2). As
1
2
3
4
5
6
7
8
one phenyl group of diphenylacetylene 2a with a methyl
(2j) hampered the hydroalkoxylation reaction and led to
the formation of a complex mixture of products instead of
the vinyl ether 4u. The hydroalkoxylation reaction of
phenylacetylene 2k led to the formation of a complex
mixture of products. Digold hydroxide catalysts
[{Au(NHC)}2(ꢀ-OH)][BF4] are known to be able to disso-
ciate into a Lewis acidic [Au(NHC)][BF4] and a Brønsted
basic [Au(NHC)(OH)] components.24 Competitive depro-
tonation of the acetylenic proton of phenylacetylene by
the latter might explain the incompatibility with this sub-
strate.25 Attempts to form vinyl ether 4v by using non-
Brønsted basic catalysts 1d or 1e, however, were un-
reported previously, the reactivity increases from i-PrOH
to MeOH by one order of magnitude (Table 2, entries1
and 4).18a These results constitute a significant improve-
ment compared to previous catalyst systems with re-
gards to reaction conditions, catalyst loading and chemo-
and stereoselectivity.18c
We compared the performance of monogold catalyst 1e
to digold hydroxide catalyst 1c for the addition of MeOH
to diphenylacetylene (2a). We found that 1e was more
active in the addition of MeOH than digold hydroxide 1c,
but the selectivity towards the (Z)-vinyl ether decreased
to 85% (Table 2, entry 5). We found that monogold cata-
lyst 1e was much more active than digold 1c when the
catalyst loading was drastically decreased (Table 2, en-
tries 6-7). Indeed, while the formation of vinyl ether 6d
stopped after 50% conversion using 250 ppm of digold
1c, this product could be isolated in quantitative yield
and complete stereoselectivity after 16 h using only 200
ppm of monogold catalyst 1e. This catalyst loading ena-
bles a very high TON of 35 000 and a TOF of 2 188 h-1.
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successful and ketone
5
and (oxybis(ethane-1,1-
diyl))dibenzene formed as the sole products.
Scheme 3. Substrate scope for the hydroalkoxylation
of alkynes using various symmetrical/unsymmetrical
alkynes.a
Table 2. Addition of aliphatic alcohols to diphenyla-
cetylene 2a.a
entry
R-OH
catalyst
(mol%)
t (h)
prod-
uct
yield
(%)[b] (Z/E)[c]
1
2
3
4
5
6
7
i-PrOH
n-BuOH
BnOH
1c (0.3)
1c (0.1)
12
4
6a
6b
6c
6d
6d
6d
6d
>99 (100/0)
96 (100/0)
98 (100/0)
98 (100/0)
96 (85/15)
50 (100/0)
>99 (100/0)
1c (0.3)
3
MeOH
MeOH
MeOH
MeOH
1c (0.3)
2
1e (0.6)
1
aReaction conditions: 2b-2k (0.50 mmol), 3a (0.55 mmol,
1.1 equiv.), 1b (0.3 mol%), neat, 80 °C, in air. Reaction time
and yield are given. Z/E ratios are given in parentheses.
1c (0.025)
1e (0.020)
28
16
aReaction conditions: 2a (0.5 mmol), 3 (0.5 mmol, 1
bAlcohol condensation side-product (oxybis(ethane-1,1-
b
c
c
equiv.), neat, in air. Yield of isolated product. Determined
diyl))dibenzene was observed as the major product. 5 was
by 1H NMR spectroscopy.
observed as the major product. dA complex mixture formed.
We continued to examine the difference between cata-
lysts 1c and 1e at different loadings in the hydroalkoxyla-
tion reaction of MeOH and DMAD (2f) (Table 3). This
transformation proceeded rapidly at room temperature
and reached completion after 3 hours using either cata-
lysts (Table 3, entries 1-2). Interestingly, the correspond-
ing (E)-vinyl ether 6e was obtained selectively. At re-
duced catalyst loadings, however, we observed the for-
mation of (Z)-6e after 2 hours (Z/E = 15/85 at 55% con-
version for digold catalyst 1c and Z/E = 33/67 at 24%
conversion for monogold catalyst 1e), which was then
predominantly converted to (E)-6e after prolonged reac-
tion time (Table 3, entries 3-4). These results suggest
that the hydroalkoxylation reaction and the subsequent
isomerization are competitive processes.
To assess the efficiency of catalyst 1b, once the reaction
between alkyne 2a and alcohol 3a was complete, itera-
tive additions of both substrates (0.5 and 0.55 mmol,
respectively) were performed. As a result, 2.5 mmol of
2a was converted to 4a over 12 hours affording a high
turnover number (TON) of 840 and a modest turn over
frequency (TOF) of 70 h-1. In addition, the performance
of the new digold hydroxide catalyst (1c) was evaluated
by conducting the hydroalkoxylation reaction between 2a
(5.0 mmol) and 3a (5.5 mmol) on a gram scale using 0.3
mol% 1c. This reaction afforded vinyl ether 4a in excel-
lent yield (1.4 g, 94%) without loss of stereoselectivity
(Z/E = 98/2).
Previous studies examining gold-catalyzed hydroalkoxy-
lation reactions have used aliphatic alcohols such as
Corma and co-workers have proposed a mechanism to
account for the conversion of (Z)-vinyl ethers into (E)-
vinyl ethers.18c This mechanism involves a trans-addition
of a second molecule of alcohol to the (Z)-vinyl ether and
MeOH, i-PrOH, n-BuOH and BnOH as model sub-
18c
strates.18a,
Their addition to diphenylacetylene (2a)
proceeded smoothly at room temperature using 1c as
catalyst and the corresponding vinyl ethers were ob-
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Page 4 of 6
subsequent cis-elimination to form the (E)-vinyl ether
Table 4. Isomerization reactions of pure (Z)-4a and
(Z)-6d.a
1
2
3
4
5
6
(Scheme 4). Alternatively, a thermal process or rotation
around the C-C bond of the vinylgold intermediate could
be envisioned.26 This latter route would be particularly
fast for vinyl ethers from DMAD because of its ability to
be involved in keto-enol tautomerization.
Table 3. Addition of MeOH to DMAD 2f.a
7
8
9
entry
ether
3
Catalyst
(mol%)
t
Z/Eb
(equiv.)
(h)
10
11
12
13
14
15
16
17
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19
20
21
22
23
24
25
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1
2
3
4
5
6
(Z)-4a
(Z)-4a
(Z)-4a
(Z)-6b
(Z)-6b
(Z)-6b
3a (1.5)
3a (1.5)
3a (1.5)
none
none
24
24
24
1
100/0
96/4
entry
catalyst
(mol%)
t
conversion
1c (0.3)
1e (0.6)
none
b
(h)
89/11
93/7
(%)(Z/E)c
>99 (4/96)
>99 (4/96)
87 (7/93)
1
2
3
4
1c (0.3)
1e (0.6)
3
3
6
6
none
1c (0.3)
1e (0.6)
1
80/20
80/20
none
1
1c (500 ppm)
1e (0.1)
aReaction conditions: neat, in air. bDetermined by 1H
NMR spectroscopy.
34 (26/74)
aReaction conditions: 2f (0.5 mmol), MeOH (0.5 mmol, 1
b
c
We further probed whether the vinyl ether products could
be transformed into other vinyl ethers. To this end, we
subjected vinyl-ether 6d and CD3OD to catalytic condi-
tions (Scheme 5). Apart from the previously observed
Z/E isomerisation, no formation of acetal or incorporation
of CD3 was observed. The reverse experiment, the reac-
tion of d4-6d with MeOH, gave an analogous result. The
incorporation of small amounts of deuterium in the vinylic
position suggests the formation of a alkylgold species
(as in Scheme 4) that is subsequently deuterodeaurated
under these conditions.
equiv.), neat, in air. Conversion with respect to 2f. Deter-
mined by 1H NMR spectroscopy.
Scheme 4. Proposed isomerization of (Z)-vinyl ethers
to (E)-vinyl ethers.18c
Scheme 5. Reaction of 6b with CD3OD.a
To shed light on the isomerization process, the direct
isomerization reactions of pure vinyl ethers (Z)-4a and
(Z)-6d catalyzed by digold catalyst 1c and monogold
catalyst 1e were surveyed (Table 4). As expected from
the high stereoselectivity obtained in reactions (Schemes
2-3) involving 1-phenylethanol (3a), isomerization of vinyl
ether (Z)-4a was found to be slow (Table 4, entry 1).
aZ/E ratios are determined by H NMR analysis, deuteri-
1
1
um content was determined by H NMR analysis and
confirmed by 2D NMR analysis.
Appreciable isomerization was only observed in the
presence of 1-phenylethanol (3a) and monogold catalyst
1e (Table 4, entries 2-3). We found that isomerization of
(Z)-6d occurred spontaneously at 80 °C and was accel-
erated when catalytic amounts of either the mono- or
digold hydroxide catalyst was added (Table 4, entries 4-
6). No appreciable isomerization was observed at lower
temperatures and the proposed acetal intermediates
were never observed. These results suggest that the
isomerization process from (Z)-vinyl ethers to (E)-vinyl
ethers occurs spontaneously at elevated temperature
and is accelerated by cationic gold species, but does not
involve or require the addition of a second molecule of
alcohol.
In conclusion, we have demonstrated that both
[Au(NHC)(CH3CN)][BF4] and [{Au(NHC)}2(µ-OH)][BF4]
complexes are highly effective catalysts for the stereose-
lective intermolecular hydroalkoxylation of alkynes. Their
use under solvent-free conditions constitutes a practical,
operationally simple and scalable strategy for the as-
sembly of a range of new vinyl ethers in high yields. In
particular [Au(IPrCl)(CH3CN)][BF4] (1e) has been shown
to be highly active in the addition of aliphatic alcohols to
internal alkynes. Experiments have also revealed that
monogold and digold hydroxide catalysts display differ-
ent behavior in the isomerization of the two stereoiso-
mers of the vinyl ethers at different catalyst loadings.
Further synthetic and mechanistic studies focusing on
the catalytic uses of these complexes are ongoing in our
laboratories.
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9. Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H., Org. Lett.
2005, 7, 5437-5440.
AUTHOR INFORMATION
1
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8
Corresponding Author
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*E-mail: snolan@st-andrews.ac.uk.
Author Contributions
†These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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The EPSRC and ERC are gratefully acknowledged for sup-
port. Umicore AG is acknowledged for their generous gift of
materials. The EPSRC National Mass Spectrometry Service
Centre (NMSSC) is gratefully acknowledged for HRMS
analyses. S.P.N. is a Royal Society Wolfson Research Merit
Award holder.
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ASSOCIATED CONTENT
Supporting Information Available
Experimental procedures, optimization studies, mechanistic
studies and characterization data. This information is avail-
able free of charge via the internet at http://pubs.acs.org.
ABBREVIATIONS
NHC,
IPr,
N-heterocyclic carbene;
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene;
1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene;
4,5-dichloro-1,3-bis(2,6-diisopropylphenyl)imid-
azol-2-ylidene.
SIpr,
IPrCl,
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Gold-NHC complexes have been shown as highly efficient catalysts in the hydroalkoxylation of unactivated internal alkynes. The
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