Synthesis of functionalized THF and THP through Au-catalyzed cyclization of acetylenic alcohols

Article abstract of DOI:10.1016/j.tetlet.2006.12.100

ω-Acetylenic alcohols are regio- and stereo-selectively converted to the corresponding α-alkylidene oxygenated heterocycles in the presence of catalytic amounts of AuCl and K₂CO₃.

Full text of DOI:10.1016/j.tetlet.2006.12.100

Tetrahedron Letters 48 (2007) 1439–1442
Synthesis of functionalized THF and THP through
Au-catalyzed cyclization of acetylenic alcohols
Hassina Harkat, Jean-Marc Weibel and Patrick Pale*
`
´ ´ ´ ´
Laboratoire de synthese et reactivite organique, associe au CNRS, Institut Le Bel, Universite L. Pasteur, 67000 Strasbourg, France
Received 9 November 2006; revised 14 December 2006; accepted 15 December 2006
Available online 20 December 2006
Abstract—x-Acetylenic alcohols are regio- and stereo-selectively converted to the corresponding a-alkylidene oxygenated hetero-
cycles in the presence of catalytic amounts of AuCl and K2CO3.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
cyclizations. Chromium, tungsten, and molybdenum
catalysts led in the presence of base to endocyclic enol
ethers,6 while iridium(I) in methanol led to adducts
derived from exocyclic products.7
Tetrahydrofurans and pyrans (oxolanes and oxanes) are
common motifs in a wide variety of natural products.1
Since such compounds often exhibit interesting biologi-
cal activities, numerous routes have been developed for
their synthesis.2 Among these methods, the cyclization
of acetylenic alcohols is one of the most rapid and con-
venient. Such cyclizations are usually performed
through metal catalysis and can yield to products result-
ing either from an exo-dig or an endo-dig process or
from both (Scheme 1). Earlier versions were based on
intramolecular oxymercuration starting from acetylenic
alcohols, usually leading to the corresponding exocyclic
enol ether.3 Later, palladium(II) catalyzed version was
pioneered by Utimoto et al., but mixture or exo- and
endo-dig products could be obtained.4 Silver carbonate
catalyzed the exclusive and very effective formation of
exocyclic enol ethers.5 More recently, other transition
metals also proved to be useful catalysts for such hetero-
In the last few years, gold salts or complexes also proved
to be efficient catalysts in some heterocyclization reac-
tions.8–11 However, only a few cyclizations of acetylenic
alcohols were reported. Hashmi, in one of his seminal
papers, mentioned the AuCl3-catalyzed cyclization of
2-methylpent-2-en-4-yn-1-ol to 2,4-dimethylfuran, via
probable intermediate 4-methyl-2-methyleneoxolene.10
The same reaction was reported by Liu et al. with the
corresponding aryl substituted penten-yn-ols.11 Krause
et al.9d and De Brabander et al.9i independently reported
the cyclisation–alkoxylation of respectively homopro-
pargylic alcohols to 1-alkoxyoxolanes and some acetyl-
enic diols to spiroketals.
Our investigations in related silver-catalyzed cycliza-
tions showed us that electronic effects play a significant
role in such cyclizations.5b We thus wondered if gold-
catalyzed cyclization of acetylenic alcohols could be a
general process or if it is restricted to activated sub-
strates. We reported here the preliminary results in this
area, showing that gold chloride and potassium carbon-
ate catalyzed a highly regio- and stereoselective cycliza-
tion of acetylenic alcohols (Scheme 2).
AgI
IrI
O
R1
R1
R2
HO
n
HgII, PdII
and/or
R1
n
O
Cr or W0
NR3
R2
R2
n
Scheme 1. Formation of di- or tetrahydrofuranes and pyranes through
2. Results and discussion
metal-catalyzed cyclization of acetylenic alcohols.
*
Simple terminal acetylenic alcohols of different chain
Corresponding author. Tel./fax: +33 390 241 517; e-mail: ppale@
chimie.u-strasbg.fr
lengths 1a, 3 were submitted to various gold catalysts
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.100

1440
H. Harkat et al. / Tetrahedron Letters 48 (2007) 1439–1442
Interestingly, no evolution was observed without gold
R1
R1
HO
O
species (entry 1). Moreover, a reaction performed in
deuterated acetonitrile with 1a and AuCl in the presence
of potassium carbonate revealed through 1H NMR
monitoring the formation, after 1.5 h, of a cyclization
product among side-products, while the major com-
pound in the mixture remained the starting alcohol (en-
try 6). The detected compound 2a exhibited the typical
NMR pattern of 2-methylene oxolanes.5,12
AuCl 10%
K2CO3 10%
MeCN, rt
60-90%
n
n
R2
R2
Scheme 2. Formation of a-alkylidene oxolanes and oxanes catalyzed
by gold chloride and base.
in various conditions, but although the starting materi-
als were mostly consumed, several unidentified degrada-
tion products were produced (Table 1, entries 2–5, 7).
Knowing the high sensitivity of such a-methylene he-
terocycles,5c,12 we next turned to non-terminal acetylenic
Table 1. Synthesis of a-alkylidene oxolanes and oxanes from the corresponding acetylenic alcohols
Entry
Acetylenic alcohol
Catalysta
Solvent
Time
Temperature (°C)
À30 to 50
Yieldsb
0
Heterocycle
SM recovered
1
1a
1a
None
CH2Cl2
THF
MeCN
CH2Cl2
THF
20 h
1a
OH
2
AuCl
20 h
À30 to 50
dec
—
OH
MeCN
MeCN
3
4
5
6
1a
1a
1a
1a
AuCl3
20 h
20 h
20 h
2 h
À30 to 50
À30 to 50
25
dec
—
—
—
OH
OH
OH
OH
AuCl(PPh3)
AuCl, K2CO3
AuCl, K2CO3
MeCN
MeCN
CD3CN
dec
dec
O
25
10–20
2ac
7
8
3
AuCl, K2CO3
AuCl, K2CO3
MeCN
MeCN
20 h
20 h
25
25
dec
0
—
OH
Me3Si
Ph
1b
SM recovered
1b
OH
Ph
O
9
1c
AuCl, K2CO3
MeCN
4 h
25
82
2cc
OH
O
OH
OH
10
11
4a
4b
AuCl, K2CO3
AuCl, K2CO3
MeCN
MeCN
1 h
2 h
25
25
90
80
5a
5b
OBn
BnO
O
OSiPh2tBu
OSiPh2tBu
Ph
O
Ph
Br
OH
OH
12
13
4c
AuCl, K2CO3
MeCN
24 h
3 h
25
50
30
70
5c
OBn
BnO
Br
O
14
4d
6
AuCl, K2CO3
AuCl, K2CO3
MeCN
MeCN
1 h
25
25
84
76
5d
7
OBn
BnO
O
OMOM
OH
15
15 min
MOMO
O
O
a 0.1 equiv.
b Yield of isolated pure product.
c The product is extremely sensitive.

H. Harkat et al. / Tetrahedron Letters 48 (2007) 1439–1442
1441
alcohols which could give relatively stable cyclized prod-
OH
OH
n
ucts. The trimethylsilylated pent-4-yn-1-ol 1b remained
mostly untouched in the same conditions (e.g., entry
8). However, 5-phenylpent-4-yn-1-ol 1c was readily con-
verted to the corresponding 2-(phenylmethylene) oxo-
lane 2c in the presence of catalytic amounts of gold
chloride and potassium carbonate in acetonitrile (entry
9). Other conditions did not give rise to any characteriz-
able product. Therefore, gold chloride in acetonitrile
seems to exclusively promote the exo-dig cyclization in
the presence of potassium carbonate. Moreover, a single
stereoisomer was detected, the Z stereochemistry of
which was assigned from NMR data and by comparison
with related compounds.5,9a
n
R
R
Au+
A
H
R
O
_
B
Au+
n
Cl
Au
K2CO3
KHCO3 + KCl
R
O
R
O
n
C
n
Au
Scheme 3. Proposed mechanism for the gold catalyzed cyclization of
x-acetylenic alcohols.
We then investigated the cyclization of acetylenic alco-
hols bearing an activating group at the propargylic posi-
tion. 3-Benzyloxypent-4-yn-1-ol 4a was thus prepared
and submitted to these conditions. In contrast to the
unsubstituted analog 1a, 4a gave the exo-dig product
5a in as high yield at room temperature (entry 10 vs 5,
6). No other product could be isolated. The correspond-
ing O-silylated derivative 4b behave in the same way,
giving 5b with a slightly lower yield, probably due to
the longer reaction time (entry 11 vs 10).
cess.9h This cyclization would lead to a protonated
alkoxyorganogold intermediate B. Potassium carbonate
probably deprotonated this intermediate leading to a
neutral organogold species C. Hydrolysis of the
carbon–gold bond would then liberate the a-alkylidene
heterocycle and regenerate the gold catalyst. The fact
that only catalytic amount of potassium carbonate is
necessary suggests that the deprotonation as well as
the carbon–gold bond hydrolysis are linked in the later
step (Scheme 3).
The phenyl substituted acetylenic alcohol 4c also gave
the expected exo-dig product 5c, but this cyclization sur-
prisingly proceeded more slowly than the corresponding
terminal alkyne 1c at room temperature (entry 12 vs 9).
Raising the temperature to 50 °C speeded up the reac-
tion without increasing too much the decomposition of
the formed product (entry 13 vs 12). Interestingly, a
single compound was again formed, the spectroscopic
data of which corresponded to the Z stereoisomer.
The cyclization was effective without or with an oxygen-
ated propargylic substituent (entry 9 vs 10). Moreover,
when the oxygen atom of this substituent carried a bulky
and electron-withdrawing group, there is only a slight
decrease in yield and an increased reaction time. There-
fore, such oxygenated propargylic substituent may not
have a role as important as in the corresponding silver
catalyzed cyclization.5b
In order to have a flexible entry toward substituted
alkylidene heterocycles, we prepared the corresponding
brominated derivative 4d. In the same conditions, this
compounds readily cyclized, giving again a single Z
stereoisomer 5d in good yields (entry 14). This bromo-
methylene oxolane could be a useful starting point
toward polyenyne derivatives through cross-coupling
reactions.
It is worth noting that only exo-dig cyclization products
were observed here, in contrast with the recently de-
scribed cyclization–alkoxylation of some acetylenic
alcohols9d and diols.9i
3. Conclusion
To check if larger cycles can be produced, 2,3-epoxyhex-
5-yn-1,4-diol, protected at its secondary alcohol, 6, was
prepared and submitted to the above mentioned condi-
tions. This substrate proved to be very reactive since,
after only a few minutes, the corresponding cyclized
product 7 was formed (entry 15). Here again, only the
compound resulting from an exo-dig process was
observed.
In conclusion, we have developed a simple and efficient
method for the synthesis of a-alkylidene oxolanes and
oxanes by intramolecular cyclization of x-acetylenic
alcohols catalyzed by AuCl and K2CO3. Moreover,
besides being highly regioselective, this cyclization is
also highly stereoselective since a single Z stereoisomer
was formed.
From a mechanistic point of view, the results summa-
rized here suggest a cyclization based on electrophilic
activation of the acetylenic moiety by gold ion. Surpris-
ingly, only AuI is an effective catalyst, indicating that
disproportionation is not involved in this reaction. The
observed regio- and stereoselectivity suggest an activa-
tion of the acetylenic moiety through AuI-coordination
(A in Scheme 3), which would induce a nucleophilic
addition of the alcohol group in an anti auration pro-
The Au-catalyzed cyclization of acetylenic alcohols
is thus a general process, since terminal as well as non-
terminal alkynes, functionalized or not, could be
cyclized. Nevertheless, the role of a propargylic substituent
appeared to be a key factor.
Further works are now underway to expand the scope of
this reaction, as well as to develop its applications in
organic synthesis.

1442
H. Harkat et al. / Tetrahedron Letters 48 (2007) 1439–1442
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To a solution of x-acetylenic alcohol (1 equiv) in aceto-
nitrile (3 ml/mmol) at room temperature, was added
gold chloride (0.1 equiv) and then K2CO3 (0.1 equiv).
The reaction mixture, rapidly turned to a dark brown
solution. After disappearance of the starting material
(TLC monitoring, see Table 1), a filtration over a short
path silica gel column and solvent evaporation provided
the product, which was repurified by flash chromato-
graphy when necessary. It is worth noting that these
compounds are extremely sensitive.12
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Acknowledgements
H.H. thanks the Algerian government for a PhD fellow-
ship. P.P. and J.M.W. thank the ‘CNRS’ and the French
Ministry of Research for financial support.
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