Zirconocene-promoted synthesis of substituted tetrahydropyrans

Article abstract of DOI:10.1007/s11243-012-9669-1

Zirconocene reagents derived from zirconocene dichloride and two equivalents of butyllithium react with allylic, homoallylic diene ethers. Hydrolysis of the reaction products yields substituted tetrahydropyrans. The reaction is postulated to occur via cyclization of the diene to form a zirconacyclopentane. This cyclization occurs without allylic rearrangement.

Full text of DOI:10.1007/s11243-012-9669-1

Transition Met Chem (2013) 38:129–131
DOI 10.1007/s11243-012-9669-1
Zirconocene-promoted synthesis of substituted tetrahydropyrans
•
Bradley A. McKeown Shanelle L. Newton
•
Kyle S. Knight
Received: 21 September 2012 / Accepted: 29 October 2012 / Published online: 17 November 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract Zirconocene reagents derived from zirconocene
dichloride and two equivalents of butyllithium react with
allylic, homoallylic diene ethers. Hydrolysis of the reaction
products yields substituted tetrahydropyrans. The reaction
is postulated to occur via cyclization of the diene to form a
zirconacyclopentane. This cyclization occurs without
allylic rearrangement.
successfully undergo cyclization without rearrangement.
The zirconocene reagent would bind preferentially to the
unsubstituted homoallylic side, which would not undergo
ether cleavage. It could then bind to the allylic side and
undergo cyclization without rearrangement, giving rise to
the bicyclic zirconacyclopenetane (Scheme 1).
Results and discussion
Introduction
Several allylic, homoallylic ethers were synthesized and
cyclized in the presence of reagents derived from zirco-
nocene dichloride and two equivalents of butyllithium. The
products of these reactions were hydrolyzed and charac-
terized. The results are listed in Table 1. These results
show that appropriately substituted diene ethers can
undergo cyclization without rearrangement.
The use of zirconocene reagents to promote reactions in
which 1,5- or 1,6-dienes undergo cyclization to form
bicyclic zirconacyclopentanes is well precedented [1, 2].
Zirconocenes have also been used to synthesize nitrogen
containing heterocycles [3–9]. Analogous reactions in
which ether-containing dienes are cyclized to yield oxygen
containing heterocycles have been unsuccessful. Cleavage
of the allylic ether linkage occurs instead of the cyclization
[10–13]. Indeed, zirconocene has been employed as a
reagent to deprotect allyl-protected alcohols [14].
It is well established that zirconocene cyclizations in
which the zirconocene intermediate is generated by alkyl-
ating zirconocene dichloride occur by complexation of the
Cp2Zr-butene adduct with one of the reactant alkenes,
followed by displacement of butane by the second alkene
[1, 2]. The resultant zirconocene-diene complex can
undergo cyclization to a zirconacyclopentane.
As part of our efforts to expand the utility of transition
metal complexes in the transformation of organic mole-
cules [15–18], we sought to develop reactions in which
zirconium reagents could promote the cyclization of diene
ethers to zirconacyclopentanes. It was postulated that a
diene ether that contained both allylic and homoallylic,
with a methyl substituent on the allylic side, could
The presence of a methyl group at the 2-position on the
allylic side makes complexation of the unsubstituted
homoallylic side faster. It can then complex to the more
substituted allylic side. The zirconocene-diene complex
can then cyclize to form a zirconacyclopentane. This
zirconacycle can be protonated to liberate the cyclized
organic product. Deuterolysis of the zirconacycle yields a
di-deuteriated organic product (Scheme 2).
B. A. McKeown Á S. L. Newton Á K. S. Knight (&)
Department of Chemistry, The University of Tennessee at
Chattanooga, 615 McCallie Ave., Chattanooga, TN 37403, USA
e-mail: kyle-knight@utc.edu
Diene substrates were synthesized by addition of allyl-
magnesium chloride to a carbonyl compound, followed by
alkylation with 1-chloro-2-methyl-2-propene (Scheme 3).
123

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Transition Met Chem (2013) 38:129–131
were used without further purification. Starting reagents
were purchased from Acros Organics and used without
further purification. NMR studies were conducted on a Jeol
ECX 400 MHz spectrometer.
Scheme 1 Zirconocene-promoted cyclization
2-propyl-4,5,5-trimethyltetrahydropyran (2): 1-Heptene-
(2-methyl-2-propen-1-yloxy) (1) (1.003 g, 5.978 mmoL)
and zirconocene dichloride (1.922 g, 6.576 mmoL) were
dissolved in dry THF (15 mL) and cooled to -78 °C. BuLi
(8.22 mL) was slowly added, causing the mixture to turn
yellow and become cloudy with precipitate. The mixture
was allowed to stir for 18 h as it was warmed to 0 °C and
then slowly to room temperature. The reaction was quen-
ched with H2O (15 mL). The mixture was dissolved in
Et2O and washed with 2 M HCl and saturated brine. The
aqueous layer was back-extracted into Et2O. The organic
layers were collected, dried over magnesium sulfate, and
concentrated on a rotary evaporator. The concentrate was
dissolved in ethyl acetate, filtered through silica gel, and
then concentrated on a rotary evaporator. The concentrate
was purified by column chromatography, using a 90 %
hexanes/10 % ethyl acetate solution as the eluent to yield
the product as a pale oil (0.87 g, 72 %). 1H NMR
(400 MHz, CDCl3) d 0.76 (s, 3H), 0.90 (t, J = 7.3, 3H),
0.95, (d, J = 6.7, 3H), 1.01 (s, 3H), 1.2-1.6 (m, 8H), 3.22
(d, J = 11.4, 1H), 3.34 (d, J = 11.4, 1H), 3.5-3.6 (m, 1H).
13C NMR (100 MHz, CDCl3) d 14.22, 15.63, 15.85, 17.88,
18.85, 19.03, 22.36, 24.24, 26.41, 32.71, 33.34, 35.10,
35.22, 36.74, 37.20, 38.53, 38.97, 72.12, 72.58, 78.37,
79.88. Anal. Calcd for C11H22O: C, 77.6; H, 13.0. Found:
C, 77.6; H, 13.0.
Table 1 Zirconocene-promoted cyclization of allylic, homoallylic
dienes
Diene
R
Quench
Product
Yield
(%)
1
3
5
5
CH3CH2CH2CH2–
–CH2CH2CH2CH2–
C6H5–
H?/H2O
H?/H2O
H?/H2O
D?/D2O
2
4
6
7
72
41
62
72
C6H5–
Conclusions
Zirconocene reagents derived from zirconocene dichloride
and two equivalents of butyllithium have been used to syn-
thesize substituted tetrahydropyrans from allylic, homoal-
lylic diene ethers. The reaction is postulated to occur via
cyclization of the diene to form a zirconacyclopentane,
which, upon hydrolysis, yields the organic product.
Experimental
6-Oxaspiro[4.5]decane, 9,10,10-trimethyl- (4): 1-(2-pro-
pene-1-yl)-1-(2-methyl-2-propen-1-yloxy)-cyclopentane (3)
(1.000 g, 5.547 mmoL) and zirconocene dichloride (1.784 g,
6.102 mmoL) were dissolved in dry THF (15 mL) and cooled
All reactions were carried out under nitrogen gas using
standard Schlenk techniques. Tetrahydrofuran (THF) was
distilled from sodium/benzophenone. All other solvents
Scheme 2 Cyclization and
quench of the resultant
zirconacycle
Scheme 3 Cyclization and
allylic rearrangement pathways
123

Transition Met Chem (2013) 38:129–131
131
to -78 °C. BuLi (8.0 mL) was slowly added, causing the
mixture to turn yellow and become cloudy with precipitate.
The mixture was allowed to stir for 24 h as it was warmed to
0 °C and then slowly to room temperature. The reaction was
quenched with H2O (15 mL). The mixture was dissolved in
Et2O and washed three times with 2 M HCl and once with
saturated brine. The aqueous layer was back-extracted into
Et2O. The organic layers were collected, dried over magne-
sium sulfate, and concentrated on a rotary evaporator. The
concentrate was dissolved in ethyl acetate, filtered through
silica gel, and then concentrated on a rotary evaporator. The
concentrate was purified by column chromatography, using a
90 % hexanes/10 % ethyl acetate solution as the eluent to
reaction was warmed to room temperature slowly and stirred
for 24 h. The mixture became dark red in color. The reaction
was quenched with the addition of deuterium oxide (15 mL)
and stirred for 2 h. The product was extracted into Et2O and
washed with 2.0 M HCl (150 mL) and brine (150 mL). The
aqueous phase was back-extracted with Et2O. The collected
aqueous phases were dried over magnesium sulfate and
condensed via rotary evaporation. The concentrate was dis-
solved in Et2O, filtered to remove LiCl salts, and then con-
centrated again. The crude concentrate was purified by
column chromatography to yield a pale yellow oil (1.84 g,
72 %) 1H NMR (400 MHz, CDCl3) d ppm : 7.375 (m, 5H),
4.621 (dd, J = 3.21, 10.07 Hz, 1H), 3.54 (d, J = 11.45 Hz,
1H), 3.35 (d, J = 11.45 Hz, 1H), 2.12 (m, J = 4.58, 7.10,
14.2 1H), 1.75 (m, 1H), 1.55 (m, J = 3.6, 7.7, 14.2 Hz, 1H),
1.12 (s, 3H), 1.09 (m, J = 1.83, 6.87 Hz, 2H), 0.854 (m,
J = 1.83 Hz, 2H). 13C NMR (100 MHz, CDCl3) d ppm:
142.906, 128.394, 127.212, 126.897, 126.182, 74.381, 73.055,
36.509, 35.785, 32.467, 26.479, 22.551, 22.360, 22.169,
15.419, 15.228, 15.037.
1
yield the product as a pale oil (0.413 g, 41 %). H NMR
(400 MHz, CDCl3) d 0.76 (s, 3H), 0.81 (d, J = 5.6, 3H), 0.86
(s, 3H), 1.22 (d, J = 10.1, 1H), 1.37-1.57 (m, 6H), 1.66-1.77,
4H), 1.89-1.97 (m, 1H), 3.16 (d, J = 11.5, 1H), 3.24 (d,
J = 11.5, 1H). 13C NMR (100 MHz, CDCl3) d 15.87, 17.31,
23.33, 24.57, 32.73, 33.16, 36.27, 40.25, 41.47, 74.2, 84.4.
Anal. Calcd for C12H22O: C, 79.1; H, 12.2. Found: 79.1; H,
12.2.
Acknowledgments This work was supported by the University of
Tennessee at Chattanooga Grote Chemistry Fund.
2H-Pyran, tetrahydro-4,5,5-trimethyl-2-phenyl- (6):
1-(2-methylpropenoxy)-1-phenyl-3-butene (5) (2.50 g,
12.36 mmoL) and zirconocene dichloride (3.974 g,
13.59 mmoL) were dissolved in THF (15 mL) and cooled
to -78 °C. Butyllithium (1.6 M, 17.0 mL) was added
slowly as the reaction warmed to 0 °C. The mixture
immediately became cloudy with precipitate and yellow in
color. The reaction was warmed to room temperature
slowly and stirred for 24 h. The mixture became dark red
in color. The reaction was quenched with the addition of
2.0 M HCl (15 mL). The product was extracted into Et2O
and washed with 2.0 M HCl (150 mL) and brine (150 mL).
The aqueous phase was back-extracted with Et2O. The
collected aqueous phases were dried over magnesium sul-
fate and concentrated via rotary evaporation. The crude
concentrate was purified by column chromatography to
yield a pale yellow oil (1.565 g, 62 % 1H NMR (400 MHz,
CDCl3) d 0.85 (s, 3 H), 1.09 (d, J = 7.3 Hz, 3H), 1.12 (s,
3H), 1.55 (m, 1H), 1.68 (m, 1H), 2.12 (m, 1H), 3.35 (d,
J = 11.4 Hz, 1H), 3.54 (d, J = 11.4 Hz, 1H), 4.63 (dd,
J = 3.2, 9.6 Hz, 1H), 7.38 (m, 5H). 13C NMR (400 MHz,
CDCl3) d 15.51, 22.65, 26.48, 32.55, 35.79, 36.52, 73.06,
74.38, 126.18, 126.90, 127.21, 128.39, 142.91. Anal. Calcd
for C14H20O: C, 82.3; H, 9.9. Found: C, 82.3; H, 9.9.
2H-Pyran, tetrahydro-4-methyl-d1-5-methyl-d1-5-methyl-
2-phenyl- (7): 1-(2-methylpropenoxy)-1-phenyl-3-butene (5)
(2.50 g, 12.36 mmoL) and zirconocene dichloride (3.974 g,
13.59 mmoL) were dissolved in THF (15 mL) and cooled to
–78 °C. Butyl lithium (1.6 M, 17.0 mL) was added slowly as
the reaction warmed to 0 °C. The mixture immediately
became cloudy with precipitate and yellow in color. The
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