Gold(III)-catalyzed nucleophilic substitution of propargylic alcohols

Article abstract of DOI:10.1021/ja0534147

Gold-catalyzed nucleophilic substitution on propargylic alcohols, with various C-, O-, and S-nucleophiles, is described under very mild conditions (room temperature, dichloromethane) in 0-97% yield. Copyright

Full text of DOI:10.1021/ja0534147

Published on Web 09/21/2005
Gold(III)-Catalyzed Nucleophilic Substitution of Propargylic Alcohols
Marie Georgy, Vale´rie Boucard, and Jean-Marc Campagne*
Institut de Chimie des Substances Naturelles, CNRS, AVenue de la Terrasse F-91190 Gif-sur-YVette, France
Received May 25, 2005; E-mail: campagne@icsn.cnrs-gif.fr
Scheme 1
The substitution of propargylic alcohols, compared to allylic sub-
stitution, is a relatively underscored reaction. These reactions have
been traditionally carried out using the Nicholas reaction, with, how-
ever, some limitations (several steps and a stoichiometric amount
of [Co2(CO)8] are necessary).1 More recently, Toste2 and Nishiba-
yashi/Uemura3 have described efficient rhenium (5% (dppm)Re-
(O)Cl3, MeNO2, 65 °C) and diruthenium (5% [Cp*RuCl(SR)]2,
Scheme 2. Gold-Catalyzed Allylation of 1a
ClCH2CH2Cl, 60 °C, R3dH) catalyzed reactions. In the past few
years, gold (Au(I) and Au(III)) homogeneous catalysis has emerged
as an efficient tool to activate triple bonds for the addition of various
nucleophiles.4,5 We anticipated that, through coordination to π-bond,
gold catalysts may also act as propargylic alcohol-activating agents
Table 1. Gold-Catalyzed Substitution of 1a with
Allyltrimethylsilane
in propargylic substitutions (Scheme 1).6
To test this hypothesis, the reactivity of 1-phenyloct-2-yn-1-ol
2a isolated
1a (R1 ) Ph, R2 ) H, R3 ) n-pentyl) with allyltrimethylsilane has
entry
gold cat. (%)
time (H)
yield (%)
been tested in the presence of various gold catalysts (Scheme 2,
Table 1) at room temperature. Gratifyingly, the reaction proved to
be efficient with various Au(III) catalysts (5%) (Table 1, entries
1-4). Best results were observed with NaAuCl4‚2H2O (Table 1,
entry 1) and allowed us to reduce the amount of catalyst to 1%,
leading to 2a in 2 h and 71% yield (Table 1, entry 9). In the presence
of Au(I) catalysts (Table 1, entries 5 and 6), more disappointing
results were obtained. Finally, no reaction occurred under the same
reaction conditions in the presence of PtCl2 and PdCl2(PhCN)2
catalysts. Toste has recently described the gold(I)-catalyzed isomer-
ization of 1,5-enynes to bicyclo[3,1,0]hexenes.5d Such post-
transformation of 1,5-enyne 2a to 3a was only observed with
HAuCl4‚3H2O (Table 1, entry 4), however, to a small extent (11%).
Starting from these initial experiments, we set out to define the
scope of the Au(III)-catalyzed propargylic substitution. Variations on
the substrate have then been first examined (Scheme 1, Table 2).
The reaction could be carried out with electron-rich (entries 1
and 2) and moderately electron-poor aromatic substrates (entry 3).
No reaction was, however, observed using a p-nitro substituent
(entry 4). Starting from a cinnamyl derivative (entry 5), an
inseparable 2:2:1 mixture of R/γE/γZ isomers was obtained.
Modifications on the alkynyl part are also allowed in these
reactions (entries 6-8) since silyl and aryl substituents are well
tolerated, whereas once again, no reaction occurred with an electron-
withdrawing group (entry 8). Finally, nonbenzylic and tertiary
propargylic alcohols (Table 2, entries 9 and 10) can also act as
efficient substrates in these reactions.
1
2
3
4
5
6
7
8
9
NaAuCl4‚2H2O (5)
AuBr3 (5)
AuCl3 (5)
HAuCl4‚3H2O (5)
AuCl
Ph3PAuCl
PdCl2(PhCN)2 (5)
PtCl2 (5)
12
12
12
12
12
12
12
12
2
82
68
65
60a
30
NR
NR
NR
71
NaAuCl4‚2H2O (1)
a Bicyclic 3a (11%) was isolated in this reaction.
Table 2. Gold-Catalyzed Substitution of Various Propargylic
Alcohols 1 with Allyltrimethylsilane NudAllyla
isolated
entry
R1; R2; R3
product
yield (%)
1
2
3
4
5
6
7
8
9
2-naphthyl; H; n-pentyl
(2,3-diOMe)C6H3; H; n-pentyl
3-Br-C6H4; H; n-pentyl
4-NO2-C6H4; H; n-pentyl
cinnamyl; H; n-pentyl
Ph; H; TMS
Ph; H; Ph
Ph; H; CO2Et
Ph; Me; n-pentyl
Me; Me; Ph
2b
2c
2d
2e
2f
2g
2h
2i
83
85
72
NR
66b
71
97
NR
33
2j
2k
10
59
a Reactions carried out at room temperature, in DCM, in the presence
of NaAuCl4‚2H2O (5%). b An inseparable 2:2:1 mixture of R:γ(E):γ(Z)
isomers is obtained.
yields (Table 3, entries 6-8). Finally, thiols (Table 3, entries 9-11)
could also act as efficient nucleophiles to give the corresponding
sulfides in modest to good yields. From a mechanistic point of view,
starting from an enantiomerically enriched propargylic alcohol 1h
(96% ee),8 the corresponding allylated compound 2h was obtained
in a racemic form. Such an experiment, consistent with previously
observed pitfalls (Table 2, entries 4 and 8), suggests a mechanism
through the formation of a carbonium intermediate.9,10
The Au(III)-catalyzed reaction was next tested for a diverse
collection of nucleophiles, as illustrated in Table 3. Using alcohols
(Table 3, entries 1-3), the corresponding propargylic ethers were
obtained in good yields. In the presence of ethanol (Scheme 3 and
Table 3, entries 4 and 5) and 5% of NaAuCl4‚2H2O, the rearranged
unsaturated ketones7 are obtained in good yields. However, starting
from 1a with only 1% of catalyst, the reaction can be stopped at
the ether stage (2o) obtained in 60% yield.
In conclusion, we have developed an efficient gold-catalyzed
propargylic substitution with various C-, O-, and S-nucleophiles,
where gold simultaneously acts as a Lewis acid and as a transition
In the presence of electron-rich aromatic compounds, Friedel-
Crafts arylation occurs to give the arylated compounds in good
9
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J. AM. CHEM. SOC. 2005, 127, 14180-14181
10.1021/ja0534147 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Gold-Catalyzed Substitution of Propargylic Alcohols 1
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isolated
entry
R1; R2; R3
Nu
−
H
product
yield (%)
1
2
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Ph; H; n-pentyl
Ph; H; TMS
Me; Me; Ph
butanol
2l
2m
2n
88
75
79
see text
Scheme 3
72
3-buten-1-ol
HO(CH2)3Cl
ethanol
Ph; H; n-pentyl
2o/4
5
6
7
8
9
Me; Me; Ph
Ph; H; TMS
Ph; H; TMS
Ph; H; Ph
Ph; H; n-pentyl
Ph; H; Ph
ethanol
5
b
(1,3-diOMe)C6H4
methoxybenzenec
furan
HSCH2COOEt
PhSH
2p
2q
2r
2s
2t
2u
75
65d
46
66
10
11
50
Ph; H; Ph
Boc(L)-CysOEt
35e
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Scheme 3
Scheme 4
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metal.6c The reaction proceeds under very mild conditions (dichlo-
romethane, room temperature) with a commercially available
catalyst, with water as the only byproduct. Further developments
on this methodology are currently going on in our laboratories.
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(9) (a) However, no Ritter reaction could be observed in the presence of
acetonitrile. (b) In the presence of electron-rich aromatic nucleophiles
(Table 3, entries 6-8), an alternative mechanism first involving the direct
metalation of the arene (and H+ release) can be envisioned (see ref 5u).
(10) One referee has suggested that HCl (from the reaction of water with the
gold complex) might be the actual catalyst. Although such a mechanism
cannot totally be excluded in some particular cases, no reaction occurred
in a model reaction with 1a and butanol (see Table 3, entry 1) in the
presence of 10% (and up to a stoichiometric amount) of HCl.
Acknowledgment. We are grateful to the CNRS for financial
support, and MENRT-France (M.G.) for a grant.
Supporting Information Available: Experimental details and
characterization for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA0534147
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