Phenylselenoetherification of some Δ4-alkenols facilitated by pyridine and some Lewis acids

Article abstract of DOI:10.1002/jhet.487

Studies on the phenylselenoetherification of some Δ⁴- alkenols in the presence of pyridine and some Lewis acids are described. All alkenols underwent intramolecular cyclization yielding corresponding tetrahydrofuran or tetrahydropyran derivativ

Full text of DOI:10.1002/jhet.487

November 2010
Phenylselenoetherification of Some D4-Alkenols Facilitated by
Pyridine and Some Lewis Acids
1443
ˇ
ˇ ´
Biljana M. Smit* and Zorica M. Bugarcic
Department of Chemistry, Faculty of Science, University of Kragujevac, 34000 Kragujevac, Serbia
*E-mail: biljam@kg.ac.rs
Received February 4, 2010
DOI 10.1002/jhet.487
Published online 25 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
Studies on the phenylselenoetherification of some D4-alkenols in the presence of pyridine and some
Lewis acids are described. All alkenols underwent intramolecular cyclization yielding corresponding tet-
rahydrofuran or tetrahydropyran derivatives. Yield and diastereomeric ratio of the cyclic products
depend on counterion of selenylating reagent used. We found that external additives, such as pyridine
and some Lewis acids coordinating to the electrophilic and/or nucleophilic species are used to control
the course of cyclizations with high degrees of efficiency and improve the level of stereoinduction.
J. Heterocyclic Chem., 47, 1443 (2010).
INTRODUCTION
Different electrophilic selenium reagents and a variety of
reaction conditions have been used and recent reviews
are highlighting the broad scope of this general process
[14]. Scheme 1 illustrates the possible modes of cycliza-
tion depending on the relative position of hydroxyl group
and the double bond in the starting alkene.
Cyclization of unsaturated alcohols leading to cyclic
ethers is well documented in a literature as convenient
pathways in the synthesis of natural products and related
compounds [1].
Substituted tetrahydrofuran and tetrahydropyran rings
are common in many natural products and play impor-
tant role as building blocks for the synthesis of various
biologically active organic target molecules [2]. Stereo-
selective synthesis [3] of substituted cyclic ethers is im-
portant since cyclic ether units are frequently found in
polyether antibiotics [4], C-glycosides [5], and polyene
mycotoxins [6]. A number of these compounds exhibit
remarkable antibiotic [4], neurotoxic [7], antiviral [8],
and cytotoxic [9] effects, which have opened perspective
for selected clinical applications [10]. This circumstance
has brought about a growing demand for cyclic ethers in
general. Since their supply cannot be covered from natu-
ral sources alone, the invention of methods for stereose-
lectively constructing the tetrahydrofuran and tetrahy-
dropyran nucleus from unsaturated alcohols has received
considerable attention [11].
Outcome of this reaction is influenced by the nature
of selenium reagent used, and the reactivity of the sele-
nium electrophile also depends on the nature of counter-
ion. Although standard conditions can be used for these
cyclizations, the interactions between the selenium elec-
trophile, counterion, the solvent, and the substrate are
not fully understood, and we describe herein our recent
investigations toward these cyclizations.
Lewis acids are widely used as catalysts and media-
tors in many organic reactions [15] and stereoselective
synthesis [16]. However, PhSeCl in combination with
equimolar amount of ZnCl2 is known as strong chloro-
phenilselenilating reagent for olefins [17]. These find-
ings prompt us to extend the use of Lewis acids to phe-
nylselenoetherification of some D4-alkenols. Now, we
are interested in the behavior toward additives such as
Lewis acids and pyridine in the reaction conditions to
study reactivity and regiochemical and stereochemical
outcome of the cyclization.
Among the various kinds of ring-forming reactions,
those based on the reaction of an electrophilic reagent
with an alkene holding a suitably positioned hydroxyl
group are certainly very useful. The term of cycloetherifi-
cation is generally used to describe this kind of process
which can be promoted by several electrophilic reagents
[12]. The increasing popularity gained in recent years by
selenium reagents induced ring closure reactions [13].
RESULTS AND DISSCUSION
In recent years, we have studied intramolecular cycliza-
tion of some D4- and D5-alkenols by means of phenylselenyl
C
V
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B. M. Smit and Z. M. Bugarcic
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Scheme 1
seleno moiety. The results of our investigation are
shown in Scheme 2 and Table 1.
Primary 1a and secondary 1c alkenols gave expected
tetrahydropyran-type cyclic ether products, while tertiary
alkenols 1d–f gave anti-Markovnikoff tetrahydrofuran-type
products predominantly due to stereoelectronic effects.
Cyclization is facilitated by the presence of pyridine
and Lewis acids. It became clear that phenylselenyl hal-
ides in combination with these additives usually gave
rise to cleaner reactions and improved yields compared
with phenylselenyl halides alone. Also, the additives
increased the reaction rate dramatically. In the case of
tertiary alkenols with larger substituents 1d,f, the yields
of products decreased regarding to the effects of steric
hindrance. Depending on mechanism, this can indeed be
expected. As it can be seen from Table 1, pyridine gave
the best results, conversion to cyclic products was quan-
titative in all cases. It appears that the presence of pyri-
dine is beneficial to the cyclizations process due to its
basic properties. Function of external base was to neu-
tralize hydrohalogenic acid generated on cyclizations. In
the absence of external base, the halide counterion must
fulfill this role and an undesired acid-promoted reaction
was competitive. All additives could enhance the nucle-
ophilicity of the hydroxyl group of the alkenol and also
mediate the stabilization of oxonium ion intermediates.
Although phenylselenoetherification with nonhiral se-
lenium reagents is generally known to give low stereo-
selectivity [20], very good results were obtained in the
cyclizations of D3-alkenols [21]. However, in all cases,
stereoselectivity of the ring closure reaction was
strongly influenced by the presence and the nature of al-
lylic substituent in the starting alkenol.
halides, PhSeX (X ¼ Cl, Br) [18]. Intramolecular heter-
ocyclization is the main reaction in the case of all inves-
tigated primary and secondary alkenols, while tertiary
alkenols, under the same experimental conditions, are
not converted into cyclic products at all by PhSeBr and
in a small amount with PhSeCl. Although the additional
products are expected, we have found that all investi-
gated tertiary alkenols in the reaction with PhSeBr
afforded c- and d-bromoalkanols in high yields [19].
Recently, we found that cyclizations of D5-alkenols
can be facilitated in the presence of pyridine, Ag2O, and
some Lewis acids as catalysts [18d]. In this article, we
wish to present the extension of the method to D4-alke-
nols. These alkenols envisage to the 5-exo and/or
6-endo cyclizations. Prompted by this fact, we consid-
ered it synthetically interested to study the influence of
additives, pyridine, and some Lewis acids (ZnCl2 and
FeCl3) on reactivity and regioselectivity and stereoselec-
tivity in selenocyclization reaction.
In this context, we initiated our study of phenylsele-
noetherification of (Z)- and (E)-hex-4-en-1-ols 1b under
kinetic conditions using both selenium reagents and pyr-
idine, in dichloromethane at temperature ranging from
ꢀ78ꢁC to room temperature. cis-Alcohol is envisage to
facilitate the 5-exo-favored cyclization, while trans-iso-
mer facilitate the 6-endo-unfavored cyclizations by the
The reactions are performed with two selenylating
reagents, PhSeCl and PhSeBr, and equimolar amount of
additives, in dichloromethane as solvent, at room tem-
perature. All reactions proceeded to form five- and/or
six-membered oxygen heterocycles bearing the phenyl-
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Phenylselenoetherification of Some D4-Alkenols Facilitated by
Pyridine and Some Lewis Acids
1445
Table 1
Phenylselenoetherification of D4-Alkenols in the presence of pyridine, ZnCl2, and FeCl3.
Yields (%) PhSeCl
Yields (%) PhSeBr
Alkenol
No additives
Py
FeCl3
ZnCl2
No additives
Py
FeCl3
ZnCl2
1a
69
81
72
56
37
46
23
100
100
100
100
100
100
100
96
90
98
78
71
58
53
92
92
96
81
75
62
58
63
65
75
18
0
100
100
100
100
100
100
100
100
96
99
74
60
52
48
98
95
98
76
62
55
52
1b (E)
1b (Z)
1c
1d
1e
1f
0
0
Baldwin’s rules, yielded regioselectively tetrahydrofur-
ans 2b (threo and erythro) and tetrahydropyrans 3b
(trans and cis), respectively (Scheme 3).
mer predominantly. In the presence of Lewis acids,
reactivity of selenium electrophile is independent of nature
of counterion.
The experimental results, summarized in Table 2,
show that more electrophilic PhSeCl was used to drive
reaction more completely and maintain better stereose-
lectivity but the poorer electrophile, PhSeBr, gave rever-
sal stereoselectivity. The results reveal the effect of
reaction temperature, which drove the reaction further
toward completion and better stereoselectivity. Superior
results are obtained with pyridine. Conversion to cyclic
ethers was quantitative with increased and reversal ste-
reoselectivity regardless to reagent used. (E)-Hex-4-en-
1-ol affords six-membered cis-izomer predominantly,
while (Z)-hex-4-en-1-ol affords five-membered erythro-
isomer as unique product.
All used additives can bound counter ion from rea-
gent, increase electrophilicity of PhSe group, and elimi-
nate Xꢀ as a concurrent of hydroxyl group in cycliza-
tion step. They could also enhance the nucleophilicity of
hydroxyl group of the alkenol and also mediate the sta-
bilization of the oxonium ion intermediates.
In summary, we found that external additives, such as
pyridine and Lewis acids coordinating to the electro-
philic species are used to control the course of cycliza-
tions with high degrees of efficiency and improve the
level of stereoinduction. The course of cyclization can
be directed as desired by the choice of the electrophile
and the additives used in the reaction.
We also studied the reactivity and stereoselectivity of
these reactions in the presence of equimolar amount of
some Lewis acids, which were considered as the per-
spective candidates. ZnCl2, FeCl3, and AlCl3 were tested
at room temperature. As it can be seen from the results
obtained, Lewis acids also promoted cyclization process
(Table 3). In all cases, reactions were high yielded. Dia-
stereomeric ratio was improved and reversal stereoselec-
tivity in the reactions with PhSeBr was not noticed. (Z)-
Hex-4-en-1-ol affords five-membered threo-isomer,
while (E)-hex-4-en-1-ol affords six-membered trans-iso-
EXPERIMENTAL
Gas chromatography/mass spectrometry analyses were
obtained with an Agilent Technologies instrument, model 6890
N with HP-5NS columns. 1H and 13C NMR spectra were run
in CDCl3 on Varian Gemini 200-MHz NMR spectrometer. IR
spectra were obtained with Perkin-Elmer FTIR spectrophotom-
eter model Spectrum one. Microanalyses were performed by
‘‘Dornis and Colbe’’ and found to be in good agreement with
the calculated values. Thin layer chromatography was carried out
on 0.25-mm E. Merck precoated silica gel plates (60F-254)
Scheme 3
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B. M. Smit and Z. M. Bugarcic
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REFERENCES AND NOTES
Table 2
Phenylselenoetherification of (Z)- and (E)-hex-4-en-ols at different
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Aldrich. Dichloromethane was distilled from calcium hydride.
General procedure. All reactions were carried out on a 1
mmol scale. To a magnetically stirred solution of 1 mmol of
alkenol and 1 mmol of additive (0.162 g FeCl3, 0.136 g
ZnCl2, or 0.134 g AlCl3) in 5-mL dry dichloromethane was
added 0.212 g solid PhSeCl (1.1 mmol) or 0.260 g PhSeBr
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reaction went to completion virtually instantaneously. Solution
was washed with saturated NaHCO3 aqueous solution and
brine. Organic layer was dried over Na2SO4, concentrated, and
chromatographed. The products were obtained after the elua-
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dichloromethane column. All the products were characterized
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Acknowledgment. This work was funded by Ministry of Sci-
ence, Technology and Development of the Republic of Serbia
(Grant: 142008).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet