Pyridine-facilitated phenylselenoetherification of some tertiary alkenols

Article abstract of DOI:10.1002/hc.1072

An improved procedure for intramolecular cyclization of tertiary alkenols using benzeneselenyl halides has been developed. We found that cyclization can be facilitated by pyridine. Thus, in the presence of an equimolar amount of pyridine, a chemospecific

Full text of DOI:10.1002/hc.1072

Heteroatom Chemistry
Volume 12, Number 6, 2001
Pyridine-Facilitated Phenylselenoetherification
of Some Tertiary Alkenols
Biljana M. Mojsilovic and Zorica M. Bugarcic
University of Kragujevac, Faculty of Science, Department of Chemistry, Radoja Domanovica 12,
P.O. Box 60, YU-34 000 Kragujevac, Yugoslavia
Received 13 November 2000; revised 31 January 2001
Intramolecular cyclization of unsaturated alco-
hols to cyclic phenylselenoethers (termed phenyse-
lenoetherification) by means of organoselenium re-
agents has become an important tool for the
synthesis of oxacyclic compounds [11]. In continu-
ation of our studies on the electrophile-assisted in-
tramolecular cyclization of alkenols [12–14], we
have investigated the regioselectivity of this cyclo-
ABSTRACT: An improved procedure for intramolec-
ular cyclization of tertiary alkenols using benzenese-
lenyl halides has been developed. We found that cycli-
zation can be facilitated by pyridine. Thus, in the
presence of an equimolar amount of pyridine, a che-
mospecific reaction could be observed that resulted in
formation of corresponding cyclic ethers, and quanti-
tative yields were achieved instantaneously under ex-
tremely mild experimental conditions. The effect of the
halide ion of the selenylating reagent is not significant,
functionalization reaction by means of PhSeCl and
PhSeBr as a function of alkyl substitution at the un-
saturated carbon atoms and at the carbinol carbon
C
both halides generally giving equal results.
2001
atom [15]. Intramolecular heterocyclization is the
main reaction in the case of all investigated primary
and secondary 14- and 15-alkenols, PhSeCl has been
more efficient than PhSeBr in terms of yield and re-
gioselectivity. Also, the influence of the reaction tem-
perature and structure of the substrate is more sig-
nificant in the reaction with PhSeBr. Substituents at
the olefinic double bond decreases the yield of the
cyclic ether products, but substituents at the carbi-
nol 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 to a small extent with PhSeCl. The
steric influence of substituents is clearly demon-
strated in that case. Substituted tetrahydrofuran and
tetrahydropyran rings are common in many natural
products and thus play an important role as building
blocks for the synthesis of various biologically active
organic target molecules [16,17]. Hence, of particu-
lar importance is the discovery of the appropriate
experimental conditions under which phenylselen-
ocyclization of tertiary alkenols would readily be
John Wiley & Sons, Inc. Heteroatom Chem 12:475–479,
2001
INTRODUCTION
Unsaturated substrates carrying internal nucleo-
philes (COOH, OH, SH, SAc, NHCOOEt, CH2 SnMe3,
etc.) were found to react smoothly with certain or-
ganoselenium reagents to afford cyclic systems [1–
4]. Among the various types of cyclic systems to be
synthesized according to this general methodology
are lactones [3], ethers [5], thioethers [6], nitrogen
heterocycles [7], and carbocycles [8]. The syntheses
of these classes of compounds play an important role
in the construction of biologically active prostacyc-
lines [9] and other naturally occurring products [10].
Correspondence to: Zorica M. Bugarcic. E-mail: Zoricab@knez.
uis.kg.ac.yu
Contract Grant Sponsor: Ministry of Science and Technology
of Serbia.
c
2001 John Wiley & Sons, Inc.
475

476 Mojsilovic and Bugarcic
accomplished in synthetically useful yields, regard-
less of the reagent used.
(7b), nerolidol (7c), and ␣-terpineol (10) with ben-
zeneselenyl halide, cyclization by the oxygen atom
proceeded to form oxygen heterocycles bearing the
phenylseleno moiety (3 and/or 4) (Figure 1). As it can
be seen from the results obtained, the presence of
pyridine play an important role in chemoselection of
the reaction and in regioselection and stereoselec-
tion of the produced oxacyclic compounds.
RESULTS
In order to have synthetic utility, we studied the in-
tramolecular cyclization of some tertiary alkenols by
means of benzeneselenyl halides (PhSeX, X Cl,
Br) under a variety of conditions, including the al-
tering of reaction temperature (from 78 C to room
temperature), solvents, reaction time, and concen-
tration of the reactants, but all the attempts to im-
prove yield of the cyclized products were unsuccess-
ful. However, it turned out that cyclization could be
facilitated by pyridine. In the presence of pyridine,
a chemospecific reaction was observed that resulted
in formation of corresponding cyclic ethers, and
quantitative yields were achieved instantaneously
under extremely mild experimental conditions. We
describe herein the details of this new procedure.
We were interested in exploring how PhSeX be-
haves in the presence of some additives and have
therefore undertaken a study of the reaction of ter-
tiary alkenols with PhSeX in the presence of base.
As it seemed essential to remove HX, the reactions
were performed in the presence of NaHCO3 and tri-
ethylamine, but there was not any significant effect
on the yield. Finally, when the reactions were carried
out in the presence of an equimolar amount of pyr-
idine, an instantaneous cyclization occurred, and
quantitative yields of cyclic ether products were
obtained.
DISCUSSION
Cyclization of the simplest alkenol in this series, 2,6-
dimethyl-hept-6-en-2-ol (5), with PhSeX occurs in-
stantaneously producing essentially a sole tetrahy-
dropyran product (6) in quantitative yield (Figure 2).
It is in accordance with the ionic mechanism of this
reaction and may be ascribed to the thermodynamic
stability of the cyclized product.
In the case of alkenols with a terminally disub-
stituted double bond (7), although the Markovnikov
rule requires that the PhSe group be added at the
less substituted carbon to afford the more stable car-
benium ion, the reaction is mostly dominated by
stereoelectronic effects that favor attack of the oxy-
gen at the less substituted carbon, producing as the
major products tetrahydrofuran derivatives (8) (Fig-
ure 3). This fact might play an important role in the
preparation of tetrahydrofurans because of the wide-
spread occurrence among natural products of struc-
tures with
oxygen.
a five-membered ring-incorporated
2,6-Dimethyl-hept-5-en-2-ol (7a) cyclizes quan-
titatively, affording five- and six-membered cyclic
ethers in a ratio of 88:12 at room temperature. Re-
gioselectivity could be improved by performing the
reaction at the lower temperature. In comparison
with previous results [15], the regioselectivity at
78 C is the same, but at room temperature is much
better (Table 1).
Here we report on the results of pyridine-facili-
tated phenylselenoetherification of some tertiary 14-
and 15-alkenols by PhSeX (X Cl, Br) to afford the
corresponding cyclic ethers. The results of our in-
vestigation are shown in Tables 1 and 2 and in Fig-
ures 1–4. By the reaction of 2,6-dimethyl-hept-6-
en-2-ol (5), 2,6-dimethyl-hept-5-en-2-ol (7a), linalool
Table 1 reveals that quantitative yields and
high regioselectivity are achieved even at room
temperature.
Linalool (7b) cyclizes in the same way, and simi-
lar regioselectivity is obtained. It seems that pyridine
plays an important role in stereoselection of the
FIGURE 1
FIGURE 2

Pyridine-Facilitated Phenylselenoetherification of Some Tertiary Alkenols 477
FIGURE 3
TABLE 1 Phenylselenoetherification of 2,6-Dimethyl-hept-
5-en-2-ol
Yield (%) (Ratio of Products 8a and 9a)
Reagent
78 C
0 C
Room Temperature
PhSeCl
PhSeCl/Py
75 (95:5) 43 (66:34)
100 (95:5) 100 (87:13)
37 (55:45)
100 (88:12)
TABLE 2 Phenylselenoetherification of Some Tertiary Al-
kenols at Room Temperature
Yields of Cyclic Ether Products (%)
Sub-
strate Products PhSeCl a PhSeBr a PhSeCl/py b PhSeBr/py b
c
5
6
31
37
46
23
34
n.c.p.
n.c.p.
n.c.p.
n.c.p.
n.c.p.
100
100
c
c
c
c
d
d
d
d
7a
7b
5
8a + 9a
8b + 9b
6
100 (88:12) 100 (87:13)
100 (86:14) 100 (84:16)
100 (92:8)
100 (3:97)
FIGURE 4
d
d
100 (90:10)
100 (1.5:98.5)
d
d
7a
8a + 9a
aIsolated yields.
produced cyclic ethers. The major product in this re-
action, a tetrahydrofuran derivative (8b), is formed
in a trans:cis ratio of 34:66. In such a reaction, the
stereochemistry of the product is the opposite of that
obtained previously [15] (trans:cis ratio 70:30). The
high cis selectivity among the stereomers of (8b)
may be due to the participation of pyridine. Pyridine
allows the reaction to be carried out under kinetic
conditions, probably explaining the reversal of stere-
oselectivity.
Nerolidol (7c) behaves like linalool in the reac-
tion with PhSeX, affording predominantly tetrahy-
drofuran derivative (8c) in a trans:cis ratio of 32:68.
As indicated in Table 2, in this case, regioselectivity
is the highest regarding to the effects of steric
hindrance.
bThese are absolute yields determined by GLC relative to an internal
standard. Isolated yields did not differ significantly from chromato-
graphically determined yields.
cn.c.p., no cyclized product. Diphenyl diselenide was recovered al-
most quantitatively, but unreacted starting alkenol was not recovered.
Products were polar and could not be analyzed by TLC. In another
experiment we monitored the reactions of these alkenols with PhSeBr
by 1H NMR spectroscopy. The signals corresponding to starting al-
kenol disappeared and new signals appeared assignable to the cor-
responding bromide of the alcohol. However, the attempted isolation
of these products resulted in the isolation of only diphenyl diselenide
due to the polimerization of the bromides on the column.
dRelative distribution of the THF- and THP-type phenylseleno ether
products (given in parentheses) was evaluated by capillary GLC and
1H NMR analysis.
strain energy may be accomplished by forming the
product 12 rather than the originally expected 11
(Figure 4).
In conclusion, the aforementioned results
clearly indicate that there is no difference in reactiv-
ity between PhSeCl and PhSeBr (Table 2). As far as
we know, it is the first example where these two
In the case of a constitutionally similar case to
the aforementioned alkenols (7), but with cyclic, ␣-
terpineol (10), the same behavior was expected. By
contrast, the tetrahydropyran derivative predomi-
nates presumably because of electronic and confor-
mational factors. In this case, the release of much

478 Mojsilovic and Bugarcic
reagents have the same behavior. PhSeBr is known
to be a superior reagent only for effecting intramolec-
ular amidoseleniations of N-alkenylamides [18]. Pre-
vious results obtained in the reactions of alkenols
with PhSeX indicate that PhSeCl is a more efficient
reagent for cyclization than PhSeBr [15]. This ob-
servation may be ascribed to the role of the pyridine.
It appears that the presence of pyridine is beneficial
to the cyclization process and more likely due to its
basic properties. In addition, pyridine could enhance
the nucleophilicity of the hydroxyl group of the al-
kenol and also mediate the stabilization of the ox-
onium ion intermediates by abstracting the proton.
It seems that pyridine could play several roles. On
the whole, its presence serves to increase the effi-
ciency of the cyclization process. This reaction not
only has enormous potential for the regioselective
synthesis of substituted tetrahydrofuran and tetra-
hydropyran derivatives, but also opens a new area
involving the use of pyridine as an additive in cycli-
zation reactions.
This improved procedure for phenylselenoeth-
erification should often prove the simplest and su-
perior to those currently available. As for the yields
of cyclic ethers, the procedure described in this ar-
ticle gave better results than reported procedures.
Accompanied by other merits, such as the mildness
of the reaction conditions and the simplicity of the
experimental procedure, our procedure is the most
attractive one for the conversion of alkenols into ox-
acyclic compounds. Moreover, we are confident pyr-
idine-facilitated seleniation will be of general use for
a facile synthesis of various heterocycles.
mercially available, while the other ones (5 and 7a)
were synthesized from 2,6-dimethyl-hept-5-en-2-one
and 2,6-dimethyl-hept-6-en-2-one respectively (com-
mercially available), according to the known proce-
dure. Reagents (PhSeCl and PhSeBr) were used as
supplied by Aldrich. Methylene chloride was dis-
tilled from calcium hydride.
General Procedure
All reactions were carried out on a 1 mmol scale. To
a magnetically stirred solution of alkenol (1 mmol)
and pyridine (0.087 g, 1.1 mmol) in dry methylene
chloride (5 mL) was added solid PhSeCl (0.212 g, 1.1
mmol) or PhSeBr (0.260 g, 1.1 mmol) at room tem-
perature until the solid dissolved. The reaction went
to completion virtually instantaneously. PhSeCl and
PhSeBr worked equally well. The pale yellow solu-
tion was washed with 1 M HCl aqueous solution (5
mL), saturated NaHCO3 aqueous solution, and then
brine. The organic layer was dried over Na2 SO4 and
concentrated, and chromatography was performed.
The TLC and GLC analyses and NMR spectra
showed complete conversion of the starting alkenol
to the cyclic ether product. The product was ob-
tained after the elution of the traces of diphenyl di-
selenide from a silica gel-methylene chloride col-
umn. All the products were characterized and
identified on the basis of their spectral data. The cy-
clic ether products were known compounds, and
their spectral data had been given previously [15,19].
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