COMMUNICATION
We observed that substrate 4a was unreactive, whereas
4b reacted very slowly (more than 40 h). However, 4c and
4d in dichloromethane gave the desired products in less
than 24 h. The alcohol 4c was not reactive at 08C. For both
substrates the diastereomeric ratio (d.r.) was quite low when
the MacMillan catalysts 6a–d were employed in the reac-
tion. Catalyst 6e gave an acceptable d.r. with alcohol 4d but
the enantiomeric excesses recorded were quite low. We
found an increased stereoselectivity when undergoing the
propargylation in the presence of water.[16] However, under
these conditions only substrate 4d had shown reactivity.[17]
In general, the reaction was promoted in the presence of In-
Scheme 2. Favorable combination of cooperative catalysts for the alkyla-
tion of internal alkynes.
AHCTUNGRTEG(NUNN OTf)3, whereas other indium salts gave slightly inferior re-
tions prompted us to explore other stabilized carbocations
in the alkylation of internal propargylic alcohols. The alco-
hols 4a–d were selected as model substrates and the reac-
tion was performed in the presence of indium salts with the
MacMillan catalysts 6a–e. No reaction occurred if the Mac-
Millan catalysts were used with alcohols and octanal in the
absence of indium salts. Even the propargylic alcohol 4d,
which is able to form a stabilized carbocation, was com-
pletely unreactive in the absence of indium salts under the
reaction conditions employed (Table 1).
sults in terms of diastereoselectivity. Although the MacMil-
lan catalyst 6e gave a poor stereoselectivity in the reaction,
the use of the catalysts 6c[18] in the presence of water gave a
good d.r. and excellent enantiocontrol with alcohol 4d. It is
noteworthy that the use of water as the reaction medium is
well-explored in organocatalysis.[19] Although we have not
observed a dramatic acceleration of the reaction typical of
“on water” conditions,[20] it is quite remarkable that the SN1
reaction is not hampered by water and that the reaction is
working only in the presence of indium salts.
The subtle role played by water in organocatalytic pro-
cesses was recently highlighted by Wennemers[21] and Flow-
ers,[22] whereas the compatibility of Lewis acid with water in
terms of their kinetic stability and water exchange processes
was reported by Kobayashi.[23] Indium salts have the desira-
ble characteristic of stability and compatibility to promote
acidic processes in the presence of water. Furthermore, the
SN1 type reaction of a propargylic cation in water is dictated
by the stability of the carbocation relative to the nucleophi-
licity of water.[24] Based on the Mayr table[10] we have select-
ed the substrates 4e–s for exploring the scope of our reac-
tion and the results are illustrated in Tables 2 and 3.
Table 1. Organocatalytic a-alkylation of octanal with propargylic alco-
hols in the presence of indiumACTHNUGRTENUNG(III) salts.
Different substrates (4e–s) were obtained from the corre-
sponding aldehydes (see the Supporting Information for de-
tails). Aryl, indole, or naphthyl groups attached to the prop-
argylic alcohols did not significantly affect the reactivity or
selectivity of the reaction.
Alcohol
Cat.
Solvent
Yield [%]
d.r.[b]
ee [%][c]
4c[d,e]
4c[d]
4c[f]
4d
4d
4d
4d
4d
4d
4d
6e
6e
6c
6a
6b
6c
6d
6e
6c
6c
6a
CH2Cl2
CH2Cl2
H2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
H2O
>95
>95
–
75
70
56
<10
90
90
95
1:1
1.1:1
–
1.1:1
1.2:1
1.3:1
1:1
40/20
63/47
–
Quite remarkably, the reaction tolerates a range of func-
tional groups including thio, amides, silyl ether, and even
acetals in the alkyne moiety. The presence of groups that
are able to stabilize the carbenium ion is mandatory for the
reaction. When other functionalized aldehydes were used
with 4d, the corresponding products were isolated in good
yields as a mixture of two diastereoisomers, each one with
high stereoselectivity, showing that the reaction has also
broad scope with respect to the aldehyde (Table 3). The rel-
ative configurations of the syn and anti products were as-
signed by comparison with products obtained by Nishibaya-
shi,[9] whereas the absolute configuration was assigned by
chemical correlation to a known product (see the Support-
ing Information for details).[25] The absolute and relative
configurations of the products obtained in the reaction are
in general agreement with the model that we have suggested
98/94
97/97
95/90
n.d.[g]
69/41
95/84
98/88
98/94
3:1
1.3:1
3.3:1
1.1:1
4d
CH2Cl2
75
[a] Reaction conditions: alcohols 4a–d (0.1 mmol), octanal 5a
(0.3 mmol), 20% of the catalyst 6a–e, solvent (0.5 mL), and 20 mol% of
the corresponding indium salt (0.33m solution in CH3CN) at 08C for 16–
24 h. [b] For all the reactions the d.r. ratio was determined by 1H NMR
spectroscopic analysis. The ratio is indicated as anti versus syn. [c] Deter-
mined by chiral HPLC analysis of the isolated products or of the corre-
sponding alcohols. See the Supporting Information for details. [d] Re-
action time: 4 h at RT. No reaction occurred in 24 h at 08C. [e] InBr3
(20 mol%) was used as Lewis acid. [f] No reaction occurred. [g] n.d.=
not determined.
Chem. Eur. J. 2011, 17, 7404 – 7408
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7405