Synthesis of the 3-methylene-2-vinyltetrahydropyran unit; the hallmark of the sesquiterpene, hodgsonox

Article abstract of DOI:10.1021/jo047998r

(Chemical Equation Presented) The synthesis of some simple compounds containing the previously unreported 3-methylene-2-vinyltetrahydropyran system, a unique feature of the liverwort metabolite, hodgsonoxis reported. Key features are the creation of an ac

Full text of DOI:10.1021/jo047998r

Synthesis of the 3-Methylene-2-vinyltetrahydropyran Unit; the
Hallmark of the Sesquiterpene, Hodgsonox
Anna J. Barlow, Benjamin J. Compton, and Rex T. Weavers*
Department of Chemistry, University of Otago, Box 56, Dunedin, New Zealand
rweavers@alkali.otago.ac.nz
Received November 11, 2004
The synthesis of some simple compounds containing the previously unreported 3-methylene-2-
vinyltetrahydropyran system, a unique feature of the liverwort metabolite, hodgsonox is reported.
Key features are the creation of an acrolein substituted in the R-position with a three-carbon chain
bearing a terminal electrophilic site, addition of a vinyl group, and cyclization.
Introduction
chain bearing a terminal cation equivalent. Addition of
a vinyl anion equivalent to the aldehyde, followed by
cyclization, would then lead to the desired framework.
Alternative access to the central doubly allylic alcohol
might be available by reaction of a pent-1-en-2-yl anion
equivalent with acrolein (Scheme 1).
Hodgsonox (1),1 isolated from the New Zealand liver-
wort Lepidolaena hodgsoniae Grolle, is the only liverwort
sesquiterpene known to arise via the methyl erithritol
phosphate biosynthetic pathway.2 Its structurally dis-
tinguishing feature is that it contains a tetrahydropyran
ring with the oxygen in a unique, doubly allylic environ-
ment, positioned between 1,1-disubstituted and mono-
substituted double bonds as in 2. This combination of
functionality does not appear to have been encountered
previously, whether in a natural product or in a synthetic
compound. Hodgsonox proved to inhibit the larval de-
velopment of an agricultural pest, the Australian green-
bottle blowfly, Lucilla cuprina,3 but this activity was lost
upon epoxidation of the disubstituted double bond. This
prompted our interest in synthesizing the basic 3-meth-
ylene-2-vinyltetrahydropyran 2 or some simple deriva-
tives to explore the possible role of the doubly allylic ether
system in the insecticidal activity.
Results and Discussion
One approach to the realization of our synthetic
strategy (Scheme 1, Path A) centered on the use of a
halide leaving group as the cation equivalent. The known
chlorohydrin 3 offered all the desired features. This
masked acrolein derivative was accessible by bromination
of acrolein and acetal protection,4 followed by lithiation
and reaction of the resulting vinyllithium with epichlo-
rohydrin which had been pretreated with boron trifluo-
ride etherate (Scheme 2).5 We found this latter reaction
to be very sensitive to the quality of the boron trifluoride
etherate and prior distillation resulted in highly im-
proved yields.
Base treatment of chlorohydrin 3 generated epoxide 4
which was hydrolyzed to form aldehyde 5. Reaction with
vinylmagnesium bromide created the key doubly allylic
Our synthetic strategy focused on the synthesis of an
acrolein derivative substituted at C-2 with a three-carbon
(3) Gerard, P. J.; Ruf, L. D.; Lorimer, S. D.; Heath, A. G. C. N. Z. J.
Agric. Res. 1997, 40, 261-267.
(1) Ainge, G. A.; Gerrard, P. J.; Hinkley, S. F.; Lorimer, S. D.;
Weavers, R. T. J. Org. Chem. 2001, 66, 2818-2821.
(2) Barlow, A. J.; Lorimer, S. D.; Morgan, E. R.; Weavers, R. T.
Phytochemistry 2003, 63, 25-29.
(4) Smith, A. B., III; Levenberg, P. A.; Jerris, P. J.; Scarborough, R.
M.; Wovkulich, P. M. J. Am. Chem. Soc. 1981, 103, 1501-1513.
(5) Takahashi, T.; Takehira, Y. In U.S. Patent 5180844, Daiso Co.,
Ltd., Osaka, Japan, 1993.
10.1021/jo047998r CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/09/2005
2470
J. Org. Chem. 2005, 70, 2470-2475

Synthesis of 3-Methylene-2-vinyltetrahydropyran
SCHEME 1. Strategy to Attain the
3-Methylene-2-vinyltetrahydropyran System 2
SCHEME 4. Synthesis of Tetrahydropyran
Derivative 12a
SCHEME 2. Preparation of Chlorohydrin 3 from
Acroleina
a (a) t-BuPh2SiCl/imidazole (96%); (b) SiO2/(COOH)2 (84%); (c)
CH2dCHMgBr (65%); (d) NaH (33%).
SCHEME 5. Synthesis of Benz-Fused
2-Vinyl-3-methylenetetrahydropyran 19a
a (a) Br2 (36%); (b) (EtO)3CH/NH4NO3 (63%); (c) n-BuLi then
epichlorohydrin/BF3.Et2O (88%).
SCHEME 3. Synthesis of Tetrahydrofuran
Derivatives 7 and 8a
a (a) NaOH/(CH2OH)2 (48%); (b) SiO2/(COOH)2 (99%); (c)
CH2dCHMgBr (23%); (d) NaH then (e) PhCOCl (11%).
alcohol (Scheme 3). As vinyl addition was accompanied
by epoxide opening, the product was the bromo diol 6,
which was isolated as a 1.2:1 mixture of diastereomers.
Treatment of 6 with sodium hydride yielded the
tetrahydrofuran derivative 7 as a cis/trans mixture,
presumably via rapid epoxide formation followed by
kinetically favored 5-exo cyclization. Compound 7 was
characterized as its benzoate ester 8. 2-Vinyl-3-methyl-
enetetrahydrofuran derivatives have only been reported
once before.6
To control the ring size upon cyclization, compound 3
was transformed into the racemic tert-butyldiphenylsilyl
ether 9, previously reported as the (S)-isomer.5 Acetal
hydrolysis formed the target R-substituted acrolein 10,
and addition of a vinyl group was achieved with vinyl-
magnesium bromide to produce the doubly allylic alcohol
11 as a 1.2:1 mixture of diastereomers. Cyclization with
NaH yielded the desired tetrahydropyran 12 (Scheme 4).
The goal of synthesizing a 2-vinyl-3-methylenetetrahy-
dropyran had been achieved, with a functionalized site
at C-5 available for further modification. However, the
formation of the product was complicated by the fact that
a (a) (CH2OH)2/PTSA (83%); (b) PdCl2(PPh3)2/CuI/Et3N/(CH3)2-
COHCtCH (88%); (c) NaH (75%); (d) PdCl2(PPh3)2/Bu3SnH (99%);
(e) n-BuLi then DMF (59%); (f) CH2dCHMgBr (81%); (g) n-BuLi
then CH2dCH-CHO (79%); (h) MeOH/PTSA; (95%) (i) Et3SiH/
CF3COOH (95%).
both cis and trans isomers were produced and the yield
for the cyclization step was low.
An alternative implementation of Scheme 1, Path A
led to a benz-fused derivative of 2 in significantly higher
yield (Scheme 5). The appropriately substituted acrolein
was derived from o-bromobenzaldehyde. Acetal protec-
tion7 was followed by palladium-catalyzed fusion with
2-methyl-3-butyn-2-ol by a procedure based on the method
of Hiyama et al.8 This yielded the hydroxy alkyne 13
(7) Flower, K. R.; Howard, V. J.; Naguthney, S.; Pritchard, R. G.;
Warren, J. E.; McGown, A. T. Inorg. Chem. 2002, 41, 1907-1912.
(8) Hiyama, T.; Wakasa, N.; Ueda, T.; Kusumoto, T. Bull. Chem.
Soc. Jpn. 1990, 63, 640-642.
(6) Dulcere, J.-P.; Baret, N.; Rodriguez, J. Synlett 1995, 923-924.
Baret, N.; Dulcere, J.-P.; Rodriguez, J.; Pons, J.-M.; Fayre, R. Eur. J.
Org. Chem. 2000, 1507-1516.
J. Org. Chem, Vol. 70, No. 7, 2005 2471

Barlow et al.
SCHEME 6. Synthesis of 2-Vinyl-3-methylene-
which was transformed into the terminal alkyne 14 by
treatment with NaH followed by slow distillation to
remove acetone.9 Palladium-catalyzed hydrostannation
of 14 was achieved in high yield by reaction with PdCl2-
(PPh3)2 followed by treatment with tributyltin hydride.
The addition of a tin adduct at either the terminal (â) or
nonterminal (R) end of an alkyne has been reported, and
best yields and excellent selectivity for production of the
R-isomer have been reported for Wilkinson’s catalyst,
RhCl(PPh3)3.10 However, a palladium catalyst11 was
chosen in this study because a sample was readily
available and it proved remarkably effective, yielding
only the R-adduct. The resulting vinyl tin derivative 15
was lithiated with butyllithium and then reacted with
dimethylformamide to give the desired acrolein derivative
16, the precursor to the critical cyclization event.
tetrahydropyan 2 and Derivativesa
Transformation to the doubly allylic alcohol 17 was
achieved either by reaction of aldehyde 16 with vinyl-
magnesium bromide (implementing Scheme 1, Path A)
or from the vinyl tin derivative 15 by lithiation followed
by reaction with acrolein (Scheme 1, Path B). Compound
17 proved difficult to handle and appeared to undergo
cyclization to yield mixtures of products upon short-term
storage. Internal acetal formation is favored in 17 as a
result of the low degree of conformational freedom
induced by the rigidity of the benzene ring. Spectra of
17 were obtained, but it was fully characterized by the
microanalysis of its acetate. Methanolysis of 17 gave
methoxy acetal 18, which was separated into its cis and
trans isomers in a 1:5.8 ratio. Reduction of the isomeric
mixture by treatment with triethylsilane in the presence
of trifluoroacetic acid12 produced the benz-fused 2-vinyl-
3-methylenepyran 19 (Scheme 5).
a (a) Cyclohexylamine (82%); (b) Et2NLi/HMPA then CH2dCBr-
CH2Br then hydrolysis (92%); (c) (CH2OH)2/PTSA (92%); (d) t-BuLi
then DMF (86%); (e) CH2dCHMgBr (75%); (f) t-BuLi then
CH2dCH-CHO (92%) (g) HCl(aq) (44%); (h) PhCOCl/C5H5N (38%)
or Dess-Martin (23%); (i) Ag2CO3/Celite (64%); (j) Et3Si/CF3COOH
(63%).
By a similar sequence, we achieved the synthesis of
the parent structure 2 (Scheme 6). Published work by
Kozmin13 provided an efficient route via vinyl bromide
20 to the key substituted acrolein, 4-(1,3-dioxolan-2-yl)-
2-methylenebutanal (21). The vinyl group was introduced
as before, by addition of vinyl Grignard reagent (Scheme
1, Path A), but compound 22 could be formed more
directly by lithiation of vinyl bromide 20, followed by
reaction with acrolein (Scheme 1, Path B). Acetal hy-
drolysis was accompanied by cyclization, forming hemi-
acetal 23. This new 2-vinyl-3-methylenetetrahydropyran
was also produced as a pair of geometric isomers. We did
not attempt to separate these hemiacetals, but benzoyl-
ation followed by chromatography of the ensuing mixture
on a silica gel yielded the pure cis and trans isomers of
24 in a 1:1.2 ratio. NOESY experiments identified the
cis isomer by showing a correlation between H-2 and H-6.
Only the cis isomer can occupy a conformation with both
these two hydrogens axial and in reasonable proximity.
In an attempt to remove the complication of dealing
with diastereoisomeric mixtures, oxidation of 23 was
attempted using the Dess-Martin reagent. Preparative
TLC of the crude product yielded both the cis and trans
isomers of acetate 25 but no significant quantity of
lactone 26. We could find no precedent for acetylation
under these conditions. The stereochemistry of the
acetates was determined by comparison of chemical shifts
and coupling constants with those of the benzoate esters
24. Oxidation of 23 was achieved by using Fetizon’s
reagent14 which gave 26 in good yield. More significantly,
the unembellished 2-vinyl-3-methylenetetrahydropyran
2 was successfully synthesized by treating hemiacetal 23
with triethylsilane in the presence of trifluoroacetic acid.
Conclusions
We have not had the opportunity to explore the
potential of our synthetic tetrahydropyrans against L.
cuprina as this assay is no longer available. Nonetheless,
we have succeeded in developing a synthetic protocol for
the 2-vinyl-3-methylene tetrahydropyran system found
only in hodgsonox and, most notably, have created the
basic unit 2. The natural product, hodgsonox (1), remains
to be synthesized.
(9) Havens, S. J.; Hergenrother, P. M. J. Org. Chem. 1985, 50, 1763-
1765.
Experimental Section
(10) Smith, N. D.; Mancuso, J.; Lautens, M. Chem. Rev. 2000, 100,
3257-3282.
2-(2-Diethoxymethylallyl)-oxirane (4). On the basis of
Imai et al.,15 crushed NaOH was added to 1-chloro-4-(di-
ethoxymethyl)-4-penten-2-ol (3) (0.673 g, 3 mmol) in ethylene
(11) Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55,
1857-1867.
(12) Kraus, G. A.; Molina, M. T.; Walling, J. A. J. Chem. Soc., Chem.
Commun. 1986, 1568-1569.
(14) Morgenlie, S. Acta Chem. Scand. 1971, 1154-1155.
(15) Imai, T.; Nishida, S. J. Org. Chem. 1990, 55, 4849-4852.
(13) Kozmin, S. A. Org. Lett. 2001, 3, 755-758.
2472 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis of 3-Methylene-2-vinyltetrahydropyran
glycol (3.5 mL) and the mixture was stirred at room temper-
ature for 1 h. H2O (15 mL) was added and the mixture was
extracted into pentane and washed with H2O. The organic
layer was dried (Na2SO4) and evaporated to yield 4 as a volatile
colorless oil (0.267 g, 48%): IR (film) νmax 2976, 2930, 2875,
A small-scale reaction on 6 (0.015 g), adding H2O instead
of benzoyl chloride, yielded a sample (0.005 g) of a 1.1:1
mixture (1H and 13C NMR) of two isomers of the underivatized
alcohol 7, of suitable purity for NMR experiments; 1H and 13
C
NMR see Supporting Information.
1443, 1328, 1117, 1060, 1010, 920, 829, 665 cm-1 1H NMR
;
1-Chloro-2-t-butyldiphenylsiloxy-4-methylenehept-6-
en-5-ol (11). Vinylmagnesium bromide (4.5 mL, 1 M in THF)
was added dropwise with stirring over 15 min to a stirred
solution of aldehyde 10 (0.50 g, 1.3 mmol) in anhyd THF (10
mL) at -30 °C under an Ar atmosphere. The mixture was
warmed to room temperature (12 h) before being quenched by
dropwise addition to saturated aq NH4Cl at 0 °C. The mixture
was extracted with Et2O (2 × 50 mL) and the combined organic
extracts were washed with saturated aq NaCl (2 × 50 mL),
dried (MgSO4), and evaporated to yield diastereoisomers of 11
in a 1.1:1 ratio (1H and 13C NMR) as a pale yellow oil (0.467 g,
∼65%), contaminated with ca. 20% of tert-butyldiphenylsilyl
impurities (1H NMR): IR (film) νmax 3415, 3071, 2957, 2931,
(500 MHz, CDCl3) δ 1.20 (t, J ) 7 Hz, 6H, -OCH2CH3), 2.29
(dd, J ) 4 Hz, 2H, H-1′) 2.49 (dd, J ) 1.5, 3 Hz, 1H, H-3), 2.77
(m, 1H, H-3), 3.08 (m, 1H, H-2), 3.42-3.61 (m, 4H, -OCH2-
CH3), 4.74 (s, 1H, CH(OEt)2), 5.16 (s, 1H, H-3′), 5.25 (s, 1H,
H-3′); 13C NMR (125 MHz, CDCl3) δ 15.1 (q, O-CH2CH3), 34.1
(t, C-1′), 47.1 (t, C-3), 51.1 (d, C-2), 61.8 (2 × t, O-CH2CH3),
103.5 (d, CH(OEt)2), 114.9 (t, C-3′), 142.5 (s, C-2′); HRMS (EI)
calcd for C10H18O3 M.+ ) 186.1256, found 186.1250.
2-Oxiranylmethylpropenal (5). On the basis of Huet et
al.,16 a slurry of Si-gel (0.855 g), 2-methylene-3,3-diethoxypro-
pyloxirane (4) (0.285 g, 1.53 mmol), 10% aq oxalic acid (0.3 g),
and CH2Cl2 (1.14 mL) was stirred at room temperature for 1
h. Saturated NaHCO3 (200 µL) was added and the mixture
was filtered. The Si-gel was rinsed with Et2O (2×). Evapora-
tion yielded (5) as a colorless oil (0.170 g, 99%): IR (film) νmax
3450, 2927, 1689, 1438, 1092, 1060, 1011, 861 cm-1; 1H NMR
(300 MHz, CDCl3) δ 2.31 (br dd, J ) 7, 15 Hz, 1H, H-1′), 2.43
(dd, J ) 2.5, 5 Hz, 2H, H-3′′), 2.54 (ddd, J ) 1, 4, 15 Hz, 1H,
H-1′), 2.70 (dd, J ) 4, 5 Hz, 1H, H-3′′), 3.06 (m, 1H, H-2′′),
6.10 (s, 1H, H-3), 6.42 (s, 1H, H-3), 9.55 (s, 1H, H-1); 13C NMR
(125 MHz, CDCl3) δ 31.0 (t, C-1′), 46.8 (t, C-3′′), 50.1 (d, C2′′),
136.0 (t, C-3), 145.7 (s, C-2), 194.0 (s, C-1); HRMS (EI) calcd
for C6H8O2 M.+ ) 112.0524, found 112.0525.
1-Bromo-4-methylenehept-6-ene-2,5-diol (6). On the
basis of Sinha et al.,17 vinylmagnesium bromide (1.9 mL, 1.9
mmol, 1.0 M in THF) was added dropwise with stirring over
a period of 15 min to a stirred solution of aldehyde (5) (0.216
g, 1.9 mmol) in anhyd THF (5 mL) at -30 °C under an Ar
atmosphere. The mixture was allowed to warm to room
temperature overnight. The reaction was quenched by adding
the mixture dropwise to an aq solution of ice-cold saturated
NH4Cl. The products were then extracted into Et2O (3 × 30
mL). The organic layer was washed with saturated aq NH4Cl
(2 × 100 mL) and saturated aq NaCl (2 × 100 mL) before being
dried (MgSO4). Evaporation gave a crude product (0.253 g) that
was separated by flash-column chromatography on Si-gel (8
g), eluted with a gradient of pentane:Et2O 9:1-1:1.5. Cmpd 6
(0.095 g, 23%) was obtained as a pair of diastereomers in a
1.2:1 ratio (1H and 13C NMR): IR (film) νmax 3382, 2930, 1719,
1664, 1640, 1422, 1329, 1296, 1043, 924 cm-1; 1H and 13C NMR
see Supporting Information; MS (EI) m/z 220/222 (M.+), 123
(M.+-H2O-Br).
5-Ethenyl-4-methylenetetrahydro-2-furanmethanyl
benzoate (8). On the basis of Brown et al.,18 cmpd 6 (0.100 g,
0.45 mmol) in anhyd THF (4 mL) was added dropwise with
stirring over 5 min to NaH (60% in oil, 0.010 g, 0.14 mol,
prewashed with anhyd THF (3 × 1 mL)) in THF (1 mL) at
-20 °C. The mixture was stirred for 3 h as it warmed to room
temperature, then benzoyl chloride (0.11 mL, 0.90 mmol) was
added, and the mixture was stirred for a further 30 min. The
mixture was poured into Et2O, washed with H2O, and dried
(MgSO4). Evaporation was followed by separation on Si-gel (2
g) with elution with a pentane:Et2O 9:1-1:1 gradient. Frac-
tions containing impure 8 (pentane:Et2O 4:1) (0.048 g) were
further purified by a short Si-gel column in a Pasteur pipet,
eluted with benzene. Fractions (0.5 mL) were collected and
combined, on the basis of TLC, to yield 8 (0.013 g, 11%), a
1.1:1 mixture of two isomers (1H and 13C NMR), as a pale
yellow oil: IR (film) νmax 3423, 1719, 1638, 1272, 1068, 1026,
710 cm-1; 1H and 13C NMR see Supporting Information; HRMS
(EI) calcd for C15H16O2 M.+ ) 244.1099, found 244.1110.
2858, 1427, 1111, 703, 505 cm-1 1H and 13C NMR see
;
Supporting Information; HRMS (EI) calcd for C20H2235/37ClO2Si
M
.+-Bu ) 357.1073, 359.1043, found 357.1071, 359.1057.
cis- and trans-tert-Butyldiphenyl(tetrahydro-5-meth-
ylene-6-vinyl-2H-pyran-3-yloxy)silane (12). To a stirred
suspension of NaH (0.60 g, 60% in oil, 0.01 mol, prewashed
with dry pentane) in THF (10 mL) was added the unpurified
chloro alcohol (11) (0.89 g, ∼1.7 mmol) in THF (30 mL) at -30
°C under Ar. The mixture was allowed to warm to room
temperature and stirred for 24 h before addition of Et2O (30
mL). The organic layer was washed with water (3 × 50 mL).
The solvent was evaporated and the residue was purified by
vacuum liquid chromatography on silica gel (30 g). Elution
with a gradient of hexanes:CH2Cl2 1:0-0:1 afforded a 3.5:1
ratio (13C NMR) of cis and trans 12 as a colorless oil (0.210 g,
33%): IR (film) νmax 3071, 3047, 2957, 2928, 2855, 1785, 1727,
1
1638, 1589, 1471, 1111, 923, 822, 702, 614, 506 cm-1; H and
13C NMR see Supporting Information; HRMS (EI) calcd for
C24H30O2Si M.+ ) 378.2015, found 378.2009.
4-(2-(1,3-Dioxolan-2-yl)phenyl)-2-methylbut-3-yne-2-
ol (13). On the basis of Hiyama et al.,8 a mixture of 2-(2-
bromophenyl)-1,3-dioxolane (10.0 g, 43 mmol), 2-methyl-3-
butyn-2-ol (5.0 g, 59 mmol), Et3N (100 mL), and PdCl2(PPh3)2
(0.90 g) in a 500-mL Schlenck tube was stirred under Ar for
10 min. CuI (0.10 g) was added and the solution was heated
under reflux for 18 h. Once cooled, the ammonium salt was
filtered off and the solvent evaporated. The resulting black
oil was purified by vacuum-liquid chromatography on silica
gel (20 g) eluted with a gradient of cyclohexane:EtOAc 7:1-
1:1 to give 13 (8.82 g, 88%) as a yellow oil: IR (film) νmax 3408,
1
2981, 2890, 1484, 1450, 1394, 1165, 1074, 964, 762 cm-1; H
NMR (300 MHz, CDCl3) δ 1.62 (s, 6H, 2 × CH3), 2.39 (br s,
1H, OH), 4.05, 4.17 (m, 2 × 2H, H-4′′, H-5′′), 6.16 (s, 1H, H-2′′),
7.29 (ddd, J ) 2, 8, 8 Hz, 1H, H-4′), 7.34 (ddd, J ) 2, 8, 8 Hz,
1H, H-5′), 7.43 (dd, J ) 2, 8 Hz, 1H, H-6′), 7.55 (dd, J ) 2, 8
Hz, 1H, H-3′); 13C NMR (75 MHz, CDCl3) δ 31.4 (2 × q, CH3),
63.6 (s, C-2), 65.5 (t, C-4′′,C-5′′), 79.3 (s, C-4), 98.9 (s, C-3),
101.9 (d, C-2′′), 122.0 (s, C-1′), 126.0 (d, C-3′), 128.4 (d, C-4′),
128.9 (d, C-5′), 132.4 (d, C-6′), 138.9 (s, C-2′). An analytical
sample was prepared by microdistillation at 98 °C/0.2 mm.
Anal. calcd for C14H16O3: C, 72.4; H, 6.9. Found: C, 72.1, H,
7.0.
2-(2-Ethynylphenyl)-1,3-dioxolane (14). On the basis of
Smith et al.,10 to NaH (0.10 g, 60% in oil, prewashed with
pentane (3 × 1 mL)) was added a solution of the acetylenic
alcohol 13 (2.11 g, 9.17 mmol) in anhyd toluene (30 mL). The
stirred suspension was slowly distilled until the boiling point
of the distillate reached 110 °C (ca.. 17 mL of distillate
collected). The residue was cooled and the filtrate was evapo-
rated under reduced pressure. The brown oil was dissolved in
CH2Cl2 and the solution was washed with 5% NaHCO3 (50
mL) and H2O (50 mL). The organic layer was dried (MgSO4),
filtered, and the solvent evaporated to give 14 (1.21 g, 75.4%)
as a yellow oil: IR (film) νmax 3280, 2887, 2360, 2341, 1394,
(16) Huet, F.; Lechevallier, A.; Pellet, M.; Conia, J. M. Synthesis
1978, 1, 63-65.
(17) Sinha, S. C.; Sinha, S. C.; Keinan, E. J. Org. Chem. 1999, 64,
7067-7073.
(18) Brown, R. C.; Phadke, A. S. Synlett 1993, 927-928.
J. Org. Chem, Vol. 70, No. 7, 2005 2473

Barlow et al.
1
1217, 1115, 1072, 943, 762 cm-1; H NMR (300 MHz, CDCl3)
H-6′), 7.13 (ddd, J ) 2, 8, 8 Hz, 1H, H-5′), 7.14 (ddd, J ) 2, 8,
8 Hz, 1H, H-4′), 7.76 (dd, J ) 2, 8 Hz, 1H, H-3′); 13C NMR (75
MHz, CDCl3) 65.4 (2 × t, C-4′′, C-5′′), 76.4 (d, C-3), 101.8 (d,
C-2′′), 115.6 (t, C-1), 115.9 (t, C-5), 126.3 (d, C-6′), 127.6 (d,
C-4′), 128.7 (d, C-5′), 129.4 (d, C-3′), 135.0 (s, C-2′), 138.6 (d,
C-4), 139.7 (s, C-1′), 148.9 (s, C-2). Cmpd 17 was further
characterized as its acetate. Acetic anhydride (0.3 mL) was
added to a stirred solution of 17 (0.100 g, 0.43 mmol) in
pyridine (2 mL) cooled to 0 °C. The reaction mixture was
allowed to warm to room temperature over 2 h. The solvents
were removed by rotary evaporation under high vacuum to
give (28) (0.111 g, 95%) as a yellow oil. Microdistillation at
110 °C/0.2 mm gave the acetate as a colorless oil. Anal. calcd
for C16H18O4: C, 70.1; H, 6.6. Found: C, 70.3; H, 6.8.
Method 2. To a solution of vinyl stannane 15 (3.00 g, 6.45
mmol) in anhyd THF (50 mL), cooled to -78 °C under Ar, was
added n-BuLi (4.2 mL, 1.6 M in hexanes, 6.7 mmol) dropwise
over 20 min (color change from pale yellow to dark red). The
reaction mixture was stirred for a further 20 min before the
dropwise addition of acrolein (0.90 g, 15.0 mmol) in anhyd THF
(10 mL). The reaction mixture was warmed to 0 °C (color
change from dark red to yellow) before being poured into
saturated aq NH4Cl (200 mL) at 0 °C. The aq solution was
extracted with Et2O (2 × 70 mL) and the combined organic
fractions were dried (MgSO4) and evaporated to give a biphasic
yellow oil. The separation of organotin residues from the
desired product was achieved by partitioning the residue
between pentane and acetonitrile (1:1, 100 mL). Rotary
evaporation of the acetonitrile extract yielded a yellow oil (1.90
g) which was purified by vacuum-liquid chromatography on
basic Al2O3 (30 g, Activity I) eluted with a gradient of hexanes:
EtOAc 1:0-1:4 to give 17 (1.18 g, 79%).
3,4-Dihydro-1-methoxy-4-methylene-3-vinyl-1H-iso-
chromene (18). p-TsOH (0.2 g) was added to hydroxy acetal
17 (0.70 g, 3.1 mmol) in MeOH (20 mL) and the mixture was
heated under reflux under Ar for 3 h. The yellow solution was
filtered through powdered Ca(OH)2, washed with MeOH, and
evaporated to give 18 (0.574 g, 95%) as a yellow oil: IR (film)
νmax 2929, 2889, 1694, 1485, 1368, 1208, 1083, 1047, 1031, 747
cm-1. Preparative TLC (hexanes:Et2O 1.3:1) gave the trans
isomer as the major product (0.023 g), along with the cis isomer
(0.004 g). Trans 18: 1H and 13C NMR see Supporting Informa-
tion; Anal. calcd for C13H14O2: C, 77.2; H, 7.0. Found C, 77.0;
H, 7.0. Cis 18: 1H and 13C NMR see Supporting Information;
HRMS (EI) calcd for C13H14O2 M.+ ) 202.0994, found 202.0987.
δ 3.32 (s, 1H,), 4.07, 4.17 (m, 2 × 2H, H-4, H-5), 6.22 (s, 1H,
H-2), 7.32 (ddd, J ) 2, 8, 8 Hz, 1H, H-4′), 7.39 (ddd, J ) 2, 8,
8 Hz, 1H, H-5′), 7.52 (dd, J ) 2, 8 Hz, 1H, H-6′), 7.58 (dd, J )
2, 8 Hz, 1H, H-3′); 13C NMR (75 MHz, CDCl3) δ 65.6 (t, C-4,
C-5), 80.9 (s, C-1′′), 81.9 (d, C-2′′), 101.8 (d, C-2), 121.4 (s, C-2′),
126.1 (d, C-6′), 129.0 (d, C-4′, C-5′), 133.2 (d, C-3′), 139.7 (s,
C-1′). Anal. calcd for C11H10O2: C, 75.8; H, 5.8. Found: C, 76.0;
H, 6.0.
Tributyl-[1-(2-[1,3]dioxolan-2-ylphenyl)-vinyl]-stan-
nane (15). On the basis of Zhang et al.,11 to a stirred solution
of the acetylene 14 (1.0 g, 5.7 mmol) in anhyd THF (20 mL) at
0 °C under Ar was added PdCl2(PPh3)2 and the mixture was
stirred for 10 min. Bu3SnH (1.81 g, 6.0 mmol) was added
dropwise over a 5-min period and the resulting solution was
warmed to room temperature. Excess Bu3SnH was added
dropwise until a solution color change, from yellow to purple,
was observed. Filtration through Celite (15 g) gave a dark oil
(2.82 g). Vacuum-liquid chromatography on Al2O3 (15 g, basic,
Activity I) eluted with cyclohexane:Et2O 1:0-19:1 yielded 15
(2.67 g, 99%) as a yellow oil: IR (film) νmax 3063, 3029, 2955,
1599, 1521, 1461, 1376, 1216, 1067, 942, 754 cm-1; H NMR
1
(300 MHz, CDCl3) δ 0.86 (t, J ) 7 Hz, 9H, CH2-CH3), 0.87
(m, 6H, CH2-CH2-CH2), 1.26 (tq, J ) 7, 7 Hz, 6H, CH2-CH3),
1.42 (m, 6H, Sn-CH2), 3.95, 4.14 (m, 2 × 2H, H-4′′, H-5′′), 5.58
(d, J ) 3 Hz, 1H, dCH2), 5.82 (s, 1H, H-2′′), 5.83 (d, J ) 3 Hz,
1H, dCH2), 6.89 (dd, J ) 2, 8 Hz, 1H, H-6′), 7.21 (ddd, J ) 2,
8, 8 Hz, 1H, H-5′), 7.26 (ddd, J ) 2, 8, 8 Hz, 1H, H-4′), 7.55
(dd, J ) 2, 8 Hz, 1H, H-3′); 13C NMR (75 MHz, CDCl3) δ 10.3
(t, Sn-CH2), 13.7 (q, CH3), 27.3, 28.9 (2 × t, Sn-CH2-CH2), 65.4
(t, H-4′′, H-5′′), 101.4 (d, C-2′′), 125.6 (d, C-4′), 126.1 (d, C-3′),
127.0 (d, C-6′), 128.7 (d, C-5′), 129.3 (t, C-2), 132.4 (s,
C-2′), 147.4 (s, C-1′), 154.1 (s, C-1); HRMS (EI) calcd for
C19H29O2116/117/118/119/120/122/124Sn M.+-Bu ) 405.1178, 406.1190,
407.1177, 408.1194, 409.1183, 411.1195, 413.1213, found
405.1178, 406.1199, 407.1186, 408.1202, 409.1189, 411.1202,
413.1213.
2-(2-(1,3-Dioxolan-2-yl)phenyl)pent-1,4-dien-3-ol (17).
Method 1. To a solution of vinyl stannane 15 (1.6 g, 3.4 mmol)
in anhyd THF (40 mL), cooled to -78 °C under Ar, was added
n-BuLi (5 mL, 1.6 M in hexanes, 8.0 mmol) dropwise over 15
min (color change from yellow to purple). The solution was
stirred for 15 min before the addition of anhyd DMF (5 mL)
(color change from purple to yellow) and was warmed to room
temperature overnight. The reaction was quenched by the
addition of H2O (100 mL) and the aq layer was extracted with
Et2O (2 × 50 mL). Combined organic fractions were dried
(MgSO4) and evaporated to give a yellow oil (1.81 g). Purifica-
tion by column chromatography on silica gel (15 g) eluted with
a gradient of cyclohexane:Et2O 1:0-0:1 gave 2-(2-[1,3]dioxolan-
2-yl-phenyl)-propenal (16) (0.413 g, 59%) as a yellow oil, which
was used in the next step without purification: 1H NMR (300
MHz, CDCl3) δ 3.95, 4.04 (m, 2 × 2H, H-4′′, H-5′′), 5.69 (s,
1H, H-2′′), 6.38 (s, 1H, H-3), 6.48 (s, 1H, H-3), 7.13 (dd, J ) 2,
8 Hz, 1H, H-6′), 7.38 (ddd, J ) 2, 8, 8 Hz, 1H, H-5′), 7.41 (ddd,
J ) 2, 8, 8 Hz, 1H, H-4′), 7.65 (dd, J ) 2, 8 Hz, 1H, H-3′), 9.74
(s, 1H, H-1).
Vinylmagnesium bromide (5.1 mL, 1 M in THF) was added
dropwise over 15 min to a stirred solution of 16 (0.413 g, 2.0
mmol) in anhyd THF (15 mL) at -30 °C under Ar. The mixture
was warmed to room temperature over 12 h. The reaction
mixture was quenched by dropwise addition to saturated aq
NH4Cl (80 mL) at 0 °C and extracted with Et2O (3 × 30 mL).
The combined organic extracts were washed with saturated
aq NaCl (2 × 30 mL), dried (MgSO4), and evaporated to yield
17 (0.376 g, 81%) as a yellow oil: IR νmax 3444, 2926, 2873,
1695, 1457, 1368, 1210, 1047, 1038 cm-1; 1H NMR (500 MHz,
C6D6) δ 3.39, 3.58 (m, 2 × 2H, H-4′′, H-5′′), 4.92 (br d, J ) 5
Hz, 1H, H-3), 5.00 (ddd, J ) 1.5, 1.5, 10.5 Hz, 1H, cis H-5),
5.08 (br s, 1H, dCH2), 5.27 (ddd, J ) 1.5, 1.5, 17.5 Hz, 1H,
trans H-5), 5.49 (br s, 1H, dCH2), 5.89 (ddd, J ) 5, 10.5, 17.5
Hz, 1H, H-4), 6.00 (s, 1H, H-2′′), 7.10 (dd, J ) 2, 8 Hz, 1H,
3,4-Dihydro-4-methylene-3-vinyl-1H-isochromene (19).
To cis and trans methyl acetal 18 (0.080 g, 0.39 mmol) in CH2-
Cl2 cooled to 0 °C was added TFA (0.05 mL, 0.66 mmol) and
the solution was stirred for 15 min. Et3SiH (0.10 mL, 0.63
mmol) was added to the stirred solution which was slowly
warmed to room temperature (6 h) before being quenched with
H2O (15 mL). The product was extracted with CHCl3 (3 × 15
mL) and the combined organic extracts were dried (MgSO4)
and evaporated to give 19 (0.064 g, 95%) as a colorless oil: IR
(film) νmax 3019, 2928, 1694, 1455, 1216, 1083, 757, 666 cm-1
;
1H NMR (500 MHz, CDCl3) δ 4.79 (br d, J ) 6 Hz, 1H, H-3),
4.84 (d, J ) 12 Hz, 2H, H-1), 5.06 (br s, 1H, CdCH2), 5.35
(ddd, J ) 1.5, 1.5, 17.5 Hz, 1H, CHdCH2), 5.36 (ddd, J ) 1.5,
1.5, 9.5 Hz, 1H, CHdCH2), 5.72 (br s, 1H, CdCH2), 6.04 (ddd,
J ) 6, 9.5, 17.5 Hz, 1H, CH ) CH2), 7.03 (dm, J ) 8 Hz, 1H,
H-8), 7.23 (m, 1H, H-6), 7.25 (m, 1H, H-7), 7.69 (dm, J ) 8
Hz, 1H, H-5); 13C NMR δ 66.5 (t, C-1), 79.1 (d, C-3), 108.7 (t,
C ) CH2), 119.2 (t, CH ) CH2), 123.8 (d, C-5), 124.5 (d, C-8),
127.0 (d, C-6), 127.9 (d, C-7), 131.2 (s, C-4a), 134.3 (s, C-8a),
136.0 (d, CHdCH2), 140.1 (s, C-4); HRMS (EI) calcd for
C12H22O M.+ ) 172.0888, found 172.0883. Anal. calcd for
C12H12O: C, 83.7; H, 7.0. Found C, 83.6; H, 7.0.
6-(1,3-Dioxolan-2-yl)-4-methyenehex-1-en-3-ol
(22).
Method 1. Vinylmagnesium bromide (14.5 mL, 1 M in THF,
14.5 mmol) was added dropwise over 15 min to a stirred
solution of aldehyde 21 (2.21 g, 14.1 mmol) in anhyd THF (80
mL) at -30 °C under Ar. The mixture was warmed to room
2474 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis of 3-Methylene-2-vinyltetrahydropyran
temperature over 12 h. The reaction mixture was quenched
by dropwise addition to saturated aq NH4Cl (200 mL) at 0 °C
and extracted with Et2O (3 × 100 mL). The combined organic
extracts were washed with saturated aq NaCl (2 × 100 mL),
dried (MgSO4), and evaporated to yield 22 (1.956 g, 75%) as a
colorless oil: IR (film) νmax 3442, 2952, 2883, 1683, 1208, 1138,
min, the reaction mixture was quenched with Et2O, added to
NaOH (15 mL, 1.3 M), and stirred for 10 min. The organic
layer was separated and washed with NaOH (20 mL, 1.3 M)
and H2O (20 mL). The solvent was removed by distillation to
yield crude material (0.98 g). Silica gel column purification (3.5
g) eluted with a gradient of cyclohexane:Et2O 20:1-2.3:1
yielded a mixture of the diastereomeric acetates 25 (0.051 g,
23%) as a colorless oil: Anal. calcd for C10H14O3: C, 65.9; H,
7.7. Found: C, 65.9; H, 7.9. Preparative TLC (hexanes:Et2O
1:5) separated the trans isomer (0.021 g) from the cis isomer
(0.006 g). cis-25 had IR (film) νmax 2928, 2855, 2357, 1722, 1175,
1081, 1018, 910, 889, 750 cm-1; 1H and 13C NMR see Support-
ing Information. trans-25 had IR (film) νmax 2931, 2854, 2355,
1
1037, 967, 750, 576 cm-1; H NMR (500 MHz, CDCl3) δ 1.84
(m, 2H, H-5), 2.14 (m, 2H, H-6), 2.63 (br s, 1H, OH), 3.82, 3.93
(m, 2 × 2H, H-4′, H-5′), 4.54 (br d, J ) 6 Hz, 1H, H-3), 4.86 (t,
J ) 5 Hz, 1H, H-2′), 4.88 (d, J ) 1 Hz, 1H, dCH2), 5.09 (d, J
) 1 Hz, 1H, dCH2), 5.14 (ddd, J ) 1.5, 1.5, 10.5 Hz, 1H, H-1),
5.28 (ddd, J ) 1.5, 1.5, 17 Hz, 1H, H-1), 5.82 (ddd, J ) 6, 10.5,
17 Hz, 1H, H-2); 13C NMR (75 MHz, CDCl3) δ 25.9 (t, C-5),
32.1 (t, C-6), 64.9 (t, C-4′,C-5′), 76.2 (d, C-3), 104.2 (d, C-2′),
110.4 (t, ) CH2) 115.6 (t, C-1), 139.1 (d, C-2), 149.6 (s, C-4);
1
1723, 1451, 1272, 1175, 1081, 910, 889, 750 cm-1; H and 13C
NMR see Supporting Information.
HRMS (EI) calcd for C10H14O2
166.0992.
M
.+-H2O ) 166.0994, found
Tetrahydro-5-methylene-6-vinyl-2H-pyran-2-one (26).
Ag2CO3 on Celite14 was added to hemiacetal 23 (0.20 g, 1.4
mmol) in anhyd benzene (15 mL) and the mixture was heated
under reflux under Ar for 6 h. The mixture was filtered
through Celite and washed with EtOAc (100 mL). The solvent
was evaporated and the residue purified by column chroma-
tography on silica gel (13 g) eluted with a gradient of pentane:
Et2O 1:0-1:1.5 to yield 26 (0.124 g, 64%). IR (film) νmax 2924,
Method 2. To a stirred solution of vinyl bromide 20 (5.00
g, 24.2 mmol) in THF (30 mL) was added n-BuLi (20 mL, 1.6
M in hexanes, 32.0 mmol) over 30 min at -78 C, under Ar.
Acrolein (2.5 mL, 36.0 mmol) in THF (20 mL) was added and
the reaction mixture was allowed to warm to 0 °C before being
quenched by the addition of saturated NH4Cl (80 mL) at 0 °C.
The aq layer was extracted with Et2O (2 × 100 mL) and the
combined ethereal fractions were washed with NH4Cl (100
mL), dried (MgSO4), and evaporated to give 22 (4.12 g, 92%)
as a yellow oil.
Tetrahydro-5-methylene-6-vinyl-2H-pyran-2-ol (23). A
mixture of HCl (8 mL, 3 M) and hydroxy acetal 22 (1.95 g,
10.5 mmol) in THF (115 mL) was gently heated under reflux
under Ar for 10 h. The resulting mixture was partitioned
between aq 10% NaHCO3 (25 mL) and Et2O (150 mL). The
organic layer was dried (MgSO4) and evaporated to yield a
brown oil (1.67 g). Purification by flash-column chromatogra-
phy on silica gel (10 g) eluted with a gradient of pentane:Et2O
9:1-1:1 afforded diastereomeric 23 (0.654 g, 44%) as a colorless
oil: IR (film) νmax 3442, 2925, 1694, 1456, 1368, 1209, 1082,
1046, 992, 750 cm-1; 1H and 13C NMR see Supporting Informa-
tion. Anal. calcd for C8H12O2: C, 68.5; H, 8.6. Found: C, 68.3;
H, 8.7.
1
2854, 1724, 1455, 1359, 1141, 1034, 924 cm-1; H NMR (500
MHz, CDCl3) δ 2.63 (m, 4H, H-3, H-4), 5.09 (br s, 1H, dCH2),
5.13 (br s, 1H, dCH2), 5.30 (br d, J ) 6 Hz, 1H, H-6), 5.38
(ddd, J ) 1.5, 1.5, 11.5 Hz, 1H, CHdCH2), 5.39 (ddd, J ) 1.5,
1.5, 17.5 Hz, 1H, CHdCH2), 5.93 (ddd, J ) 6, 11.5, 17.5 Hz,
1H, CH ) CH2); 13C NMR (125 MHz, CDCl3) δ 25.7 (t, C-4),
30.3 (t, C-3), 82.3 (d, C-6), 113.2 (t, ) CH2), 118.4 (t, CH )
CH2), 134.6 (d, CHdCH2), 140.0 (s, C-5), 171.2 (s, C-2). HRMS
(EI) calcd for C8H10O2 M.+ ) 138.0679, found 138.0681.
Tetrahydro-3-methylene-2-vinyl-2H-pyran (2). To hemi-
acetal 23 (0.50 g, 3.57 mmol) in CH2Cl2 (10 mL) at 0 °C was
added TFA (0.30 mL, 3.96 mmol) and the solution was stirred
for 20 min. Et3SiH (0.60 mL, 3.78 mmol) was added to the
stirred solution which was slowly warmed to room temperature
over 6 h before being quenched with water H2O (15 mL). The
product was extracted with CHCl3 (3 × 25 mL) and the
combined organic extracts were dried (MgSO4) and evaporated.
Column chromatography on silica gel (15 g) eluted with a
gradient of pentane:Et2O 1:0-2:1 yielded 2 (0.28 g, 63%) as a
colorless oil: IR (film) νmax 2960, 1788, 1458, 1404, 1344, 1260,
cis- and trans-Tetrahydro-5-methylene-6-vinyl-2H-py-
ran-2-yl benzoate (24). Benzoyl chloride (0.25 mL, 2.1 mmol)
was added dropwise to a stirred solution of hemiacetal (23)
(0.10 g, 0.71 mmol) in anhyd pyridine (1.0 mL) at 0 °C under
Ar. The reaction mixture was warmed to room temperature.
After 16 h, a mixture of iced H2O (2.1 mL) was added and the
mixture was stirred for an additional 50 min. The reaction
mixture was extracted with CH2Cl2 (3 × 10 mL) and the
combined organic extracts were washed with ice-cold aq H2-
SO4 (3 × 20 mL, 3 M), H2O (3 × 20 mL), and saturated aq
NaHCO3 (3 × 20 mL). The combined organic fractions were
dried (NaSO4) and evaporated to give crude benzoate (0.111
g) as a brown oil. Column chromatography on silica gel (4 g)
eluted with a gradient of cyclohexane:Et2O 20:1-3:1 afforded
the trans isomer (0.036 g, 21%), a cis/trans mixture (0.019 g,
11%), followed by the cis isomer (0.029 g, 17%) as colorless
oils. cis-24: IR (film) νmax 3083, 2953, 2930, 2855, 1724, 1450,
1314, 1273, 1136, 1093, 1023, 910, 710 cm-1; 1H and 13C NMR
see Supporting Information. Anal. calcd for C15H16O3: C, 73.8;
H, 6.6. Found: C, 73.4; H, 6.8. trans-24: IR (film) νmax 3071,
2953, 2931, 2857, 1724, 1450, 1314, 1273, 1136, 1093, 1023,
1
1150, 1093, 1021, 801, 460 cm-1; H NMR (500 MHz, CDCl3)
δ 1.73 (m, 2H, H-5), 2.27 (m, 1H, H-4), 2.45 (ddd, J ) 5, 5,
13.5 Hz, 1H, H-4), 3.64 (ddd, J ) 1.5, 4, 11.5 Hz, 1H, H-6),
3.99 (ddd, J ) 1.5, 4, 11.5 Hz, 1H, H-6), 4.35 (d, J ) 6 Hz, 1H,
H-2), 4.78 (br s, 1H, CdCH2), 4.84 (br s, 1H, CdCH2), 5.29
(ddd, J ) 1.5, 1.5, 11.5 Hz, 1H, CHdCH2), 5.30 (ddd, J ) 1.5,
1.5, 16.5 Hz, 1H, CHdCH2), 5.96 (ddd, J ) 6, 11.5, 16.5 Hz,
1H, CH ) CH2; 13C NMR (125 MHz, CDCl3) δ 28.3 (t, C-5),
31.9 (t, C-4), 66.4 (t, C-6), 80.3 (d, C-2), 109.5 (t, C ) CH2),
117.7 (CH ) CH2), 136.4 (CHdCH2), 145.9 (C-3): HRMS (EI)
calcd for C8H12O M.+ ) 124.0888, found 124.0890.
Acknowledgment. We thank M. Thomas for as-
sistance with NMR experiments, B. Clark and D. Rowan
for MS analysis, and M. Dick for microanalysis.
Supporting Information Available: Experimental pro-
cedures and new data for previously reported compounds;
listings of 1H and 13C NMR data for pairs of diastereomers 6,
7, 8, 11, 12, 18, 23, 24, and 25; 13C NMR spectra of compounds
2, 4, 5, 6, 8, 11, 12, 13, 14, 15, 17, trans-18, 19, 22, cis- and
trans-24, trans-25, and 26. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
910, 710 cm-1; H and 13C NMR see Supporting Information.
Anal. calcd for C15H16O3: C, 73.8; H, 6.6. Found: C, 74.0; H,
6.7.
cis- and trans-Tetrahydro-5-methylene-6-vinyl-2H-py-
ran-2-yl acetate (25). Hemiacetal 23 (0.50 g, 1.2 mmol) in
CH2Cl2 (6 mL) was added to Dess-Martin periodinane (0.5 g,
1.2 mmol) in CH2Cl2 (8 mL) with stirring under Ar. After 20
JO047998R
J. Org. Chem, Vol. 70, No. 7, 2005 2475