Rapid SnCl2 catalyzed phenylselenoetherification of (Z)- and (E)-hex-4-en-1-ols

Article abstract of DOI:10.1007/s00706-008-0936-y

A fast and efficient method for intramolecular heterocyclization of (Z)- and (E)-hex-4-en-1-ols was developed. The method does not cause side reactions of the substrates and provides the cyclic phenylselenoethers in high yields after only few minutes. A c

Full text of DOI:10.1007/s00706-008-0936-y

Monatsh Chem 139, 1373–1376 (2008)
DOI 10.1007/s00706-008-0936-y
Printed in The Netherlands
Rapid SnCl2 catalyzed phenylselenoetherification
of (Z)- and (E)-hex-4-en-1-ols
´ ˇ ´
Vera M. Divac, Marina D. Rvovic, Zorica M. Bugarcic
Department of Chemistry, Faculty of Science, University of Kragujevac, Kragujevac, Serbia
Received 13 March 2008; Accepted 18 March 2008; Published online 2 June 2008
# Springer-Verlag 2008
Abstract A fast and efficient method for intramolec-
ular heterocyclization of (Z)- and (E)-hex-4-en-1-ols
was developed. The method does not cause side reac-
tions of the substrates and provides the cyclic phenyl-
selenoethers in high yields after only few minutes. A
catalytic amount of SnCl2 increased the yield, but in
the presence of an equimolar amount of SnCl2, for-
mation of corresponding cyclic ethers were almost
quantitative and reaction occurred instantaneously un-
der extremely mild experimental conditions.
clization reaction can directly build complicated
molecules from readily accessible starting materials
under mild conditions. Cyclic ethers are present in
the skeletons of several groups of natural compounds
exhibiting important biological activities [8]. These
units can be found in monocyclic or polycyclic
compounds, fused with other cyclic ethers or form-
ing spiro systems [9]. The presence of molecules
with oxygenated heterocycles in nature is receiving
considerable attention considering their capacity of
modification of the transport of the Naþ, Kþ, and
Ca2þ cations through lipid membranes [10–13].
This activity is responsible for their antibiotic [10],
neurotoxic [14, 15], antiviral [16], and cytotoxic ac-
tion [17, 18] and as growth regulators [10, 19, 20] or
inhibitors of the level of cholesterol in blood [21].
In many respects selenocyclofunctionalization of
unsaturated alcohols has the advantage that the in-
troduction of the heteroatom, the manipulation of the
obtained product, and the removal of the function are
facilitated by simple and mild condition required [5,
6, 22]. This methodology has been extended to more
complex systems having alcohol and double bond
functions.
Keywords Alcohol; Cyclization; Phenylselenoetherification;
SnCl2.
Introduction
Practical syntheses of cyclic ethers have attracted
considerable attention in organic, pharmaceutical, or
medical chemistry, since this basic skeleton occurs
broadly in natural products and biologically active
substances. Cyclofunctionalization of unsaturated
alcohols is a very popular reaction providing easy
access to cyclic ethers [1–6]. These cyclizations
are well documented in literature as convenient path-
ways in the synthesis of natural products and related
compounds [7]. During the last years, cyclic ether
synthesis has become of common use because a cy-
For some time we have been involved in the
development and exploration of new methods for
cyclofuncionalization of substituted unsaturated al-
cohols [23–26]. We have investigated the regiose-
lectivity of this cyclofunctionalization reaction by
means of PhSeCl and PhSeBr as a function of alkyl
substitution at the unsaturated carbon atoms and at
ˇ ´
Correspondence: Zorica M. Bugarcic, Department of Chem-
istry, Faculty of Science, University of Kragujevac, Radoja
´
Domanovica 12, P.O.Box 60, YU-34000 Kragujevac, Serbia.
E-mails: zoricab@kg.ac.yu; Zoricab@knez.uis.kg.ac.yu

1374
Vera M. Divac et al.
the carbinol carbon atom [23]. In the past few years
attention has been focused on the synthesis of the
substituted tetrahydropyranes and tetrahydrofuranes
as key starting materials for the preparation of
numerous heterocyclic compounds including physi-
ologically active products. Substituents at the olefin-
ic double bond decreases the yield of the cyclic ether
products, but substituents at the carbinol carbon
atom show a stronger influence on the decreasing
of the yields. Thus, secondary alkenols cyclize to a
considerably lower extent, while tertiary alkenols are
not converted into cyclic products at all by PhSeBr
and in a small extent with PhSeCl. The steric influ-
ence of substituents is clearly demonstrated in that
case. Hence, of particular importance is discovering
of the appropriate experimental conditions under
which phenylselenocyclization of tertiary alkenols
would readily be accomplished in synthetically use-
ful yields, regardless of the reagent used. Thus we
found that in the presence of pyridine tertiary al-
kenols cyclized in quantitative yields [24]. We ex-
plored this method on the primary and secondary
alcohols and found the same effect [27].
zation of (Z)- and (E)-hex-4-en-1-ols in the presence
of SnCl2.
Results and discussion
In connection to expanding the generality of catalyt-
ic ring-closing reactions, (Z)- and (E)-hex-4-en-1-ols
(1 and 2, Schemes 1 and 2) in the presence of SnCl2
were subjected to phenylselenyl halides (PhSeX,
X ¼ Cl, Br). In the presence of a catalytic amount
of SnCl2 yields of cyclic ethers products increase rap-
idly. When the reactions were carried out in the pres-
ence of equimolar amount of SnCl2 an instantaneous
cyclization occurred and almost quantitative yields
of cyclic ether products were obtained (Scheme 1
and Table 1). This seems to be due to the participa-
tion of SnCl2, which can stabilize the episelenonium
ion intermediate (1c and 2c, Scheme 2), but the de-
tails are not yet clear.
We describe herein the details of this new proce-
dure. The procedure employs phenylselenyl chloride
and bromide, and a catalytic or equimolar amount of
SnCl2 to generate an episelenonium ion intermediate
(1c, 2c, Scheme 2) from which the cyclic ether prod-
uct tetrahydropyran (1a, 1b) or tetrahydrofuran (2a,
Next, we turned our attention to the other catalyst.
The present study considers the phenylselenocycli-
Scheme 1
Table 1 SnCl2 catalyzed phenylselenoetherification of (Z)- and (E)-hex-4-en-1-ols
Substrates
Products
Yields and ratio (a:b) of cyclic products=%
PhSeBr
PhSeCl
A
B
C
A
B
C
1
2
1a, 1b
2a, 2b
81 (69:31)
72 (70:30)
98 (96:4)
99 (87:13)
96 (97:3)
100 (97:3)
65 (65:35)
75 (30:70)
99 (96:4)
98 (82:18)
100 (97:3)
99 (84:16)
A – without addtitive; B – with catalytic amount of SnCl2; C – with equimolar amount of SnCl2

Rapid SnCl2 catalyzed phenylselenoetherification
1375
Scheme 2
2b) type arise by internal nucleophilic displacement.
The results of our investigation are shown in Table 1
and in the Schemes 1 and 2.
The possible role of SnCl2 as an additive is to re-
move halide ions from reagent (PhSeCl and PhSeBr).
In this way the electrophilicity of the reagent is
increased and the halide ions are removed from re-
action, so the side products of halide attack as a nu-
cleophile on an episelenonium ion (which results as
addition reaction on the double bond) are minimal.
As it can be seen from the results obtained the
presence of SnCl2 plays an important role in chemo-
selection of the reaction and in regio- and stereo-
selection of the produced oxacyclic compounds.
Therefore, the reaction seems to proceed as follows:
PhSeX approaches the double bond moiety of the
alkenols (1 and 2, Scheme 2). Intramolecular capture
of the selenonium species (1c and 2c) by an internal
hydroxyl nucleophile, which is facilitated by the
presence of SnCl2, results in the formation of a rings
1a and 1b or 2a and 2b depending on the structure of
starting alkenol.
Á4-Alkenol (hex-4-en-1-ol) 1 with (E)-configura-
tion in contrast to 2 ((Z)-configuration) affords six-
membered cyclic ethers 1a and 1b as unique pro-
ducts (Table 1, Scheme 1). (Z)-Hex-4-en-1-ol (2)
affords only five-membered cyclic ethers 2a and
2b. The ratio of trans-=cis-tetrahydropyranyl ethers
1a and 1b depends on experimental conditions. In all
reactions the trans product predominates, especially
in the case of an equimolar amount of SnCl2.
Tetrahydrofuranyl ethers 2a and 2b are the only
products in the reactions with (Z)-hex-4-1-ol. Ratio
of threo- (2a) and erythro- (2b) isomers in the reac-
tion without additive depends of the reagent used. In
the reaction with PhSeCl erythro-isomer predomi-
nates (70:30) but with PhSeBr threo-isomer is the
main product. Presence of SnCl2 changes the distri-
bution of threo-=erythro-isomers. In all cases threo-
isomer generates in higher yields. This is due to the
presence of SnCl2.
Experimental
GM analysis were obtained with a Agilent Technologies in-
strument, model 6890 N with HP-5NS columns (5% phenyl
95% methylpolysyloxane). 1H and 13C NMR spectra were run
in CDCl3 on Varian Gemini 200 MHz NMR spectrometer. IR
spectra were obtained with Perkin-Elmer Model 137B and
Nicolet 7000 FT spectrophotometers. Microanalyses were
performed by ‘‘Dornis and Colbe’’ and found to be in good
agreement with the calculated values. Thin layer chromatog-
raphy (TLC) was carried out on 0.25 mm E. Merck precoated
silica gel plates (60F-254) using UV light for visualization.
For column chromatography E. Merck silica gel (60, par-
ticle size 0.063–0.200mm) was used. Olefinic alcohols
used as substrates are commercially available. Reagents
(PhSeCl and PhSeBr) were used as supplied by Aldrich.
Dichloromethane was distilled from calcium hydride.
General procedure
All reactions were carried out on a 1 mmol scale. To a mag-
netically stirred solution of 0.1 g alkenol (1mmol) and 0.019g
or 0.19 g SnCl2 (0,1mmol or 1 mmol) in 5 cm3 dry dichlo-
methane was added 0.212 g solid PhSeCl (1.1mmol) or
0.260 g PhSeBr (1.1mmol) at room temperature until the solid
dissolved. The reaction went to completion virtually instan-
taneously. Pale yellow solution was washed with saturated
NaHCO3 aqueous solution and brine. Organic layer was dried
(Na2SO4), concentrated, and chromatographed. TLC and GM
analysis as well as NMR spectra showed complete conversion
of starting alkenol to cyclic ether product. The product was

1376
Vera M. Divac et al.
obtained after the eluation of the traces of diphenyl diselenide
on a silica gel-dichloromethane column. All the products were
characterized and identified on the basis of their spectral data.
Cyclic ether products were known compounds and their spec-
tral data have been presented previously [23].
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This work was funded by the Ministry of Science, Technology
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