Preparation and Properties of 2-Methyleneoxetanes

Article abstract of DOI:10.1021/jo9906072

The methylenation of β-lactones 5 with dimethyltitanocene provides a versatile, reliable, and highly chemoselective entry to 2-methyleneoxetanes 7. The conversion proceeds selectively in the presence of alkenes, unprotected alcohols, and a variety of other carbonyl moieties. A study of conditions for the optimization of this reaction is delineated. In addition, the first X-ray structure of a 2-methyleneoxetane, which shows its similarity to related β-lactones, is reported. Reactivity studies of 2-methyleneoxetanes are presented in which it is demonstrated that these compounds are attacked at C-4 with a nucleophile; then, subsequently, the resultant enolate reacted with an electrophile. An interesting dichotomy of reactivity was observed when methyleneoxetane 7c was treated with electrophiles. Reaction of 7c with acetic acid gave acetoxyoxetane 19. When 7c was exposed to bromine, dibromoketone 20 resulted.

Full text of DOI:10.1021/jo9906072

7074
J . Org. Chem. 1999, 64, 7074-7080
P r ep a r a tion a n d P r op er ties of 2-Meth ylen eoxeta n es
Lisa M. Dollinger, Albert J . Ndakala, Mehrnoosh Hashemzadeh, Gan Wang, Ying Wang,
Isamir Martinez, J oel T. Arcari, David J . Galluzzo, and Amy R. Howell*
Department of Chemistry, The University of Connecticut, Storrs, Connecticut 06269-3060
Arnold L. Rheingold and J oshua S. Figuero
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
Received April 8, 1999
The methylenation of â-lactones 5 with dimethyltitanocene provides a versatile, reliable, and highly
chemoselective entry to 2-methyleneoxetanes 7. The conversion proceeds selectively in the presence
of alkenes, unprotected alcohols, and a variety of other carbonyl moieties. A study of conditions for
the optimization of this reaction is delineated. In addition, the first X-ray structure of a
2-methyleneoxetane, which shows its similarity to related â-lactones, is reported. Reactivity studies
of 2-methyleneoxetanes are presented in which it is demonstrated that these compounds are attacked
at C-4 with a nucleophile; then, subsequently, the resultant enolate reacted with an electrophile.
An interesting dichotomy of reactivity was observed when methyleneoxetane 7c was treated with
electrophiles. Reaction of 7c with acetic acid gave acetoxyoxetane 19. When 7c was exposed to
bromine, dibromoketone 20 resulted.
In tr od u ction
Strained, saturated heterocyclic systems have been
widely employed as molecular templates in the construc-
tion of a host of organic compounds. One largely unex-
plored class of strained heterocycles that should provide
remarkable flexibility is the 2-alkylidene oxetanes 1.1-4
The unique combination of functionalitiessa reactive
oxetane, an enol cyclic ether, and an exocyclic double
bondsoffers intriguing possibilities for further manipula-
tion.
F igu r e 1. Paterno-Bu¨chi reaction with allenes.
Two approaches resulting in 2-alkylidene oxetanes5
have been previously described. The first, reported in the
late 1960s by Arnold1 and Hammond,2 utilized the
Paterno-Bu¨chi reaction with allenes (Figure 1). A very
limited range of mostly symmetrical allenes was used.
Moreover, although a large excess of allene was generally
employed, further photocycloaddition to give dioxaspiro-
heptanes 2 and 3 was common. We have reported
preliminary results of our own investigation of the
Paterno-Bu¨chi reaction between aldehydes and unsym-
metrical allenes.6 The other strategy, described by Hudrlik
et al.,7 utilized intramolecular O-alkylation of enolates
(e.g., 4). The authors found the requirement for geminal
R-disubstitution to be too limiting for their purposes and
did not further develop the methodology.8
We recently communicated a straightforward and
reliable preparation of 2-methyleneoxetanes 7 by the
reaction of â-lactones 5 with dimethyltitanocene 6.9
Further, we have demonstrated in preliminary publica-
tions that 2-methyleneoxetanes are biologically interest-
ing10 and that they are useful and promising synthetic
intermediates.11,12 In this paper, an investigation of the
scope and optimization of the Petasis reaction with
* To whom correspondence should be addressed. Tel: 860-486-3460.
Fax: 860-486-2981. E-mail: howell@nucleus.chem.uconn.edu.
(1) Arnold, D.; Glick, A. J . Chem. Soc., Chem. Commun. 1966, 813-
814.
(2) Gotthardt, H.; Steinmetz, R.; Hammond, G. S. J . Org. Chem.
1968, 33, 2774-2780.
(3) Gotthardt, H.; Hammond, G. S. Chem. Ber. 1974, 107, 3922-
3927.
(8) Hudrlik, P. F. Personal communication.
(4) Hudrlik, P. F.; Hudrlik, A. M.; Wan, C.-N. J . Org. Chem. 1975,
40, 1116-1120.
(9) Dollinger, L. M.; Howell, A. R. J . Org. Chem. 1996, 61, 7248-
7249.
(5) Two syntheses of 2-methyleneoxetane have been described. See
ref 30 and: Haslouin, J .; Rouessac, F. C. R. Acad. Sci., Ser. C 1973,
276, 1691-1693.
(10) Dollinger, L. M.; Howell, A. R. Bioorg. Med. Chem. Lett. 1998,
8, 977-978.
(11) Ndakala, A. J .; Howell, A. R. J . Org. Chem. 1998, 63, 6098-
(6) Howell, A. R.; Fan, R.; Truong, A. Tetrahedron Lett. 1996, 37,
8651-8654.
(7) Hudrlik, P. F.; Mohtady, M. J . Org. Chem. 1975, 40, 2692-2693.
6099.
(12) Dollinger, L. M.; Howell, A. R. J . Org. Chem. 1998, 63, 6782-
6783.
10.1021/jo9906072 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/21/1999

Preparation and Properties of 2-Methyleneoxetanes
J . Org. Chem., Vol. 64, No. 19, 1999 7075
Sch em e 1
Sch em e 2
â-lactones and of some of the properties of 2-methyl-
eneoxetanes is detailed.
Resu lts a n d Discu ssion
P r ep a r a tion of 2-Meth ylen eoxeta n es. In our previ-
ous paper,9 we reported that â-lactones are excellent
precursors for 2-methyleneoxetanes. â-Lactones them-
selves are readily accessible by a variety of straightfor-
ward and well-documented routes. Lactones 5b-e were
prepared as described in our previous paper.9 Lactones
5f and 5g were prepared from (()-tropic acid-derived
lactone 5b. Deprotonation of 5b13 with lithium diisopro-
pylamide (LDA), followed by treatment with benzalde-
hyde, resulted in an alcohol 5u that was either protected
with tert-butyldimethylsilyl chloride to give 5f or oxidized
with PCC to give 5g. Lactones 5h and 5i were synthe-
sized as described by Schick,14 lactone 5j as described by
Adam,15 lactone 5p as described by Romo,16 lactone 5q
as described by Danheiser,17 lactone 5r as described by
Vederas,18 and lactone 5s as described by Beaulieu.19
Lactone 5t, an intermediate in a published synthesis of
orlistat,20 was kindly provided by Hoffmann La Roche.
Lactones 5k and 5l were prepared in two steps from
carboxylic acids 8a 21 and 8b,22 respectively (Scheme 1).
Condensation of the dianions of 8a and 8b with acetone
resulted in â-hydroxy acids 9a and 9b, which were then
treated with benzenesulfonyl chloride in pyridine23 to give
lactones 5k and 5l.
Ta ble 1
isolated yield
reactant (5)
(%) of 7
a , R ) H; R′ ) Ha
57a
76
76
86
47
b, R ) Ph, H; R′ ) H
c, R ) Ph, CH3; R′ ) H
d , R ) Ph, CH2CHdCH2; R′ ) H
e, R ) Ph, CO(CH2)3CHdCH2; R′ ) H
f, R ) Ph, CH(OTBDMS)Ph; R′ ) H
g, R ) Ph, COPh; R′ ) H
h , R ) CH3; R′ ) C(CH3)3, H
i, R ) CH3; R′ ) (CH2)5
j, R ) CH3, H; R′ ) (CH2)5
k , R ) CH2CH2OTBDPS, H; R′ ) CH3
l, R ) (CH2)2CH2OTBDPS, H; R′ ) CH3
m , R ) (CH2)3CHdCH2, H; R′ ) CH3,
n , R ) (CH2)4CHdCH2, H; R′ ) CH3, H
o, R ) (CH2)2CH2OTBDMS, H; R′ ) CH3,
H (trans)
74
20
50b
67b
60b
62
60
70b
80b
71
H
Lactones 5m -o were prepared from ethyl acetoacetate
(10) as shown in Scheme 2. Alkylation with the appropri-
ate alkyl iodides led to substituted â-ketoesters 11a -c.24
Sodium borohydride reduction resulted in mixtures of
diastereomers 12a -c,25 which were subjected to alkaline
hydrolysis, followed by cyclization, providing lactones
5m -o. The lactone mixtures of 5m and 5n were meth-
ylenated. Lactone diastereomers 5o were separated, and
the trans isomer was methylenated.
p , R ) CH3, H; R′ ) CH2CH2OTBDMS,
75
H (trans)
q, R ) CH3, H; R′ ) CH2CH2Ph, H (trans)
r , R ) NHBoc, H (S); R′ ) H
s, R ) N(Boc)CH2CHdCH2, H (S); R′ ) H
t, see below
74
40
56
69
a
Distilled directly from the reaction mixture; contains toluene.
Yield based on 1H NMR. b These compounds are somewhat volatile
and require care when handling.
(13) Mulzer, J .; Kerkmann, T. J . Am. Chem. Soc. 1980, 102, 3620-
3622.
(14) Wedler, C.; Kunath, A.; Schick, H. J . Org. Chem. 1995, 60, 758-
760.
(15) Adam, W.; Baeza, J .; Liu, J .-C. J . Am. Chem. Soc. 1972, 94,
2000-2006.
The results for the methylenations of the â-lactones
are shown in Table 1. There are a number of facets of
this reaction that merit discussion. One noteworthy
feature, as stated in our prior paper,9 is the chemoselec-
tivity. The preference for reaction with the lactone
carbonyl over alkene (see 5d ,e,m ,n ,s) parallels the
observation of Petasis.26 The selectivity over other car-
bonyl functionalities, including ester,10 carbamate, and
particularly, ketones, is remarkable (see 5e,g,r ,s). The
yields of these reactions vary, but it is important to note
that there is no evidence for methylenation of other
carbonyl functionalities present. Each of these reactions
has been monitored by 1H NMR. The normal observation
has been that the only apparent lactone-related materials
(16) Romo, D.; Yang, H. W.; Zhao, C. Tetrahedron 1997, 53, 16471-
16488.
(17) Danheiser, R. L.; Nowick, J . S. J . Org. Chem. 1991, 56, 1176-
1185.
(18) Arnold, L. D.; Kalantar, T. H.; Vederas, J . C. J . Am. Chem.
Soc. 1985, 107, 7105-7109.
(19) Beaulieu, P.; Soucy, F.; Wernic, D. J . Chem. Soc., Perkin Trans.
1 1991, 2885-2887.
(20) Barbier, P.; Schneider, F.; Widmer, U. Helv. Chim. Acta 1987,
70, 1412-1418.
(21) J acobi, P. A.; Murphree, S.; Rupprecht, F.; Zheng, W. J . Org.
Chem. 1996, 61, 2413-2427.
(22) Barrett, A. G. M.; Bezuidenhoudt, B. C. B.; Dhanak, D.;
Gasiecki, A. F.; Howell, A. R.; Lee, A. C.; Russell, M. A. J . Org. Chem.
1989, 54, 3321-3324.
(23) Hanessian, S.; Tehim, A.; Chen, P. J . Org. Chem. 1993, 58,
7768-7781.
(24) Brandstrom, A.; J unggren, U. Tetrahedron Lett. 1972, 13, 473-
474.
(25) Brown, H. C.; Ichikawa, K. J . Am. Chem. Soc. 1962, 84, 373-
376.
(26) Petasis, N. A.; Bzowej, E. I. J . Am. Chem. Soc. 1990, 112, 6392-
6394.

7076 J . Org. Chem., Vol. 64, No. 19, 1999
Dollinger et al.
Ta ble 2
expt
5
1
2
3
4
6
7
8
9
T (°C)
time (h)
equiv of Cp2TiMe2
yield of 7ba (%)
remaining 5ba (%)
80
5
1.75
35
0
50
2
0.75
<5
95
50
2
3.0
<5
90
50
24
0.75
8
50
24
3.0
25
65
110
2
0.75
21
0
110
2
3.0
34
0
110
24
0.75
0
110
24
3.0
0
90
0
0
a
Yields based on tri-tert-butylbenzene as internal standard.
(with no observable undissolved material) were the
starting lactone and the product. The reactions were
worked up once the starting material had disappeared
(the issue of mass balance will be discussed separately).
Also of interest is the fact that an unprotected hydroxyl
group does not interfere with the outcome of the reaction
(see 5t). It should be pointed out, however, that a
proximal hydroxyl is not tolerated. Thus, to date, the only
â-lactone that we have been unable to methylenate is
compound 5u . However, when the hydroxyl was protected
(see 5f), the methylenation proceeded smoothly.
1
As stated above, on the basis of the H NMR spectra
of the crude reaction mixtures, these reactions appeared
to be remarkably clean. For this reason, it was of some
concern to us that, although the yields were generally
good, they were not closer to quantitative. One potential
explanation considered was the method of purification.
Although reproducible yields were obtained using tri-
ethylamine-deactivated flash silica, we were concerned
about loss of material, since the 2-methyleneoxetanes
were sensitive under a variety of purification conditions.
We ruled out purification problems when either doubling
the amount of silica or recolumning the product resulted
in substantially the same yield as the usual column
conditions.
When the reaction of lactone 5b with dimethylti-
tanocene was monitored with an internal standard (0.11
equiv of tri-tert-butylbenzene), we found that the isolated
yield was reproducibly reflective of the calculated yield,
based on the internal standard, just prior to workup.
Further, earlier in the course of the reaction, when both
starting material and product were present, the internal
standard showed that the material balance was good.
Although this would suggest that for optimum yields the
reactions should be monitored to a point where product
yields begins to deteriorate, based on the internal stan-
dard, rather than until the starting materials have
disappeared, our own practical experience suggests that
gains in yield would be negligible compared to the added
difficulty of closely monitoring the reaction.
F igu r e 2. ORTEP drawing of 7r .
reactions were good. Therefore, a series of methylenation
reactions with 5b was conducted at 50, 60, and 70 °C
with 3 equiv of dimethyltitanocene (data not shown).
1
These reactions were monitored by H NMR for disap-
pearance of the reactant lactone. Indeed, the material
balances for the these reactions were favorable over long
periods of time. However, once the starting material had
disappeared, there were no significant differences in
yields of product in comparison to reactions run under
standard conditions. We also saw no substantial in-
creases in yields by either increasing (1.0 M) or decreas-
ing (0.25 or 0.1 M) the concentration of dimethylti-
tanocene. The one exception was that in preparing
2-methyleneoxetane (7a ), which was distilled directly
from the reaction mixture, optimum yields were obtained
with 1.0 M solutions of dimethyltitanocene. Reactions
conducted in THF proceeded more slowly with no en-
hancement in yields.
St r u ct u r e of 2-Met h ylen eoxet a n es. 2-Methylene-
oxetane 7r was isolated as a solid, and a single X-ray
study represents, to our knowledge, the first example of
a crystal structure (Figure 2)27 of a 2-methyleneoxetane.
The bond lengths and angles in the oxetane ring are
similar to related â-lactones.28 Thus, the O(1)-C(2) bond
length is 1.35 Å, and the O(1)-C(3) bond length is 1.45
Å, the latter also corresponding closely to the C-O bond
lengths in oxetane.29 The trend in bond angles in the
endocylic bonds also corresponds with those observed in
â-lactones. The observed bond angles are as follows:
C(4)-C(2)-O(1), 94.7°; C(2)-O(1)-C(3), 91.3°; O(1)-
C(3)-C(4), 90.0°; C(3)-C(4)-C(2), 83.3°. The observed
methylene exocyclic bond angles are as follows: O(1)-
Because no lactone-related byproducts were apparent
1
by H NMR, even when the reactions were completely
homogeneous, the task of yield optimization was rendered
more difficult. We decided to systematically alter the
reaction variables that we deemed most likely to affect
the reaction outcome. The parameters altered were
temperature, the number of equivalents of dimethylti-
tanocene, and reaction time. Because variables can
sometimes act in a synergistic fashion, a matrix of
reactions was conducted as shown in Table 2. Experiment
1 represents what we considered to be typical conditions.
All of the yields were based on an internal standard.
Values chosen for temperature, time, and equivalents of
dimethyltitanocene were above and below the standard
conditions. The most interesting trend observed was that
at the lower temperature the material balances in the
(27) For 7r : C9H15NO3, monoclinic, P21, a ) 10.7776(5) Å, b )
9.3265(3) Å, c ) 11.1862(5) Å, â ) 115.069(2)°, V ) 1018.48(7)Å3, Z )
4, T ) 198 K, Dcalc ) 1.208 g cm-3, R ) 7.25% for 2728 observed
independent reflections (4° e 2θ e 50°). µ ) 0.9 cm-1. The asymmetric
unit contains two chemically equivalent molecules. Each of these
molecules is hydrogen bonded to itself and forms a one-dimensional
chain. The absolute configuration has not been confirmed.
(28) Tymiak, A. A.; Culver, C. A.; Malley, M. F.; Gougoutas, J . Z. J .
Org. Chem. 1985, 50, 5491-5495.
(29) Luger, P.; Buschmann, J . J . Am. Chem. Soc. 1984, 106, 7118-
7121.

Preparation and Properties of 2-Methyleneoxetanes
J . Org. Chem., Vol. 64, No. 19, 1999 7077
F igu r e 3. Potential reactivity of 2-mMethyleneoxetanes.
C(2)-C(1), 127.7°; C(4)-C(2)-C(1), 137.6°. These also
correspond closely to related â-lactones, as do the ring
torsional angles (alternating +6°). Taken together, these
structural studies suggest that the postulation in our
original paper of structural isosterism between â-lactones
and 2-methyleneoxetanes is logical. Further confirmation
of the potential of 2-methyleneoxetanes serving as â-lac-
tone isosteres was the level of inhibition we reported10
for the 2-methyleneoxetane analogue of orlistat, a potent
pancreatic lipase inhibitor, currently marketed as an
antiobesity drug.
F igu r e 4.
homopargylic alcohol dianion 16 to give 17 under the
conditions shown in Figure 4, a byproduct, subsequently
identified as 18, was also isolated in 29% yield. Once we
recognized that the trimethylaluminum was used as a
solution in toluene, we realized that, under the reaction
conditions, benzyllithium was being generated. The ben-
zyllithium acted as a nucleophile, rather than a base,
leading to an enolate that reacted with the large excess
of iodomethane. Further, in the presence of excess tert-
butyllithium, deprotonation of the resultant ketone led
to incorporation of an additional methyl group. Thus, it
is apparent that tandem reactions of nucleophiles, fol-
lowed by electrophiles, are possible, and we are exploring
this currently.
With 3-methyl-3-phenyl-2-methyleneoxetane (7c) we
have also confirmed that in the presence of acetic acid
addition to the enol ether gave oxetane 19, a 4:1 mixture
of diastereomers, as the sole product by 1H NMR.
However, when 7c was treated with bromine, dibromoke-
tone 20 was isolated in 87% yield. The divergence in
outcome is noteworthy and might be explained by greater
steric hindrance in the bromonium ion or bromooxonium
ion, leading to preferential attack at C-4 to give 20. The
synthetic implications are interesting, especially if al-
ternative electrophiles (e.g., Hg(II)) or nucleophiles could
be utilized.
Rea ctivity of 2-Meth ylen eoxeta n es. In considering
the structure of 2-methyleneoxetanes there were two
modes of reactivity that we thought would be of particu-
lar interest. On one hand, the 2-methyleneoxetane could
be viewed as a latent enolate, regiocomplementary to
those generated in Michael additions (Figure 3, path a),
where reaction with a nucleophile at C-4 would expose
enolate 14, which could subsequently react with an
electrophile, in either an inter- or intramolecular process.
A multitude of applications could be envisaged utilizing
this tandem process. Alternatively, the electron-rich
double bond could be exploited advantageously. Reaction
of an electrophile, followed by a nucleophile (Figure 3,
path b), could lead to a variety of systems, either with
the oxetane ring intact or not. Reported precedent for
either pathway is limited. In the preparation of the
parent 2-methyleneoxetane reported by Hudrlik and co-
workers,30 structural identity was in part confirmed by
the reaction of 2-methyleneoxetane with phenyllithium
to give 4-phenyl-2-butanone (path a, Nuc ) Ph; E ) H+).
1
An example of path b is reported in which an H NMR-
monitored reaction between 2-methyleneoxetane and
acetic acid in carbon tetrachloride provided 2-acetoxy-2-
methyloxetane in over 90% yield, based on an internal
standard.31
Con clu sion s
We have demonstrated that the methylenation of
â-lactones with dimethyltitanocene provides a versatile,
reliable and highly chemoselective entry to 2-methyl-
eneoxetanes. It is also apparent that the 2-methylene-
oxetanes display a useful range of reactivity. It is possible
to exploit both the ring strain and the exocylic enol ether,
sometimes in a one-pot process. Further, in this and other
publications we have seen some unexpected reactivities
that suggest that there is much fertile ground for the
exploration of this, now, readily available, but little
investigated, class of strained heterocycles.
Although we were able to repeat the reaction between
2-methyleneoxetane and phenyllithium, we found that
phenyllithium did not react with the more sterically
encumbered 3-methyl-3-phenyl-2-methyleneoxetane (7c).
However, in the presence of trimethylaluminum 7c was
converted to homopropargyl alcohol 15 in over 60% yield.
Presumably, in this case deprotonation proceeds more
rapidly than the corresponding ring opening. This result
led to our investigation of 2-methyleneoxetanes as novel
and versatile precursors of homopropargylic alcohols.12
Interestingly, while we were investigating capture of
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Tetrahydrofuran
was distilled from dark blue solutions of sodium/benzophenone.
Toluene was distilled from sodium. Methylene chloride was
(30) Hudrlik, P. F.; Hudrlik, A. M. Tetrahedron Lett. 1971, 12, 1361-
1364.
(31) Wan, C.-N. Ph.D. Thesis, Rutgers University, 1977.

7078 J . Org. Chem., Vol. 64, No. 19, 1999
Dollinger et al.
distilled from CaH2. Pyridine was dried over KOH and
distilled. Acetone was dried over calcium sulfate and distilled.
Petroleum ether was purchased from Baker and distilled.
Carbon tetrachloride was washed with aqueous KOH and
water, distilled, and then stored over molecular sieves (4 Å)
for 3 days. The concentrations of solutions of methyllithium
and n-butyllithium were determined by titrations with sec-
butyl alcohol using 1,10-phenanthroline as the indicator. With
the exceptions noted, all starting reagents were purchased
from Aldrich and used without further purification. 5-Hexenal
was obtained by PCC mediated oxidation of 5-hexenol. Cyclo-
hexanone was purchased from Aldrich and distilled. â-Propi-
olactone (5a ) was purchased from Acros. Lactone 5t was kindly
provided by Hoffmann La Roche.
Literature procedures were followed for the preparation of
4-tert-butyl-3,3-dimethyloxetan-2-one (5h ),14 3,3-dimethyloxe-
tan-2-on-4-spirocyclohexane (5i),1 3-methyl-4-spirocyclohexyl-
oxetan-2-one (5j),15 trans-4-(2-tert-butyldimethylsilyloxyethyl)-
3-methyloxetan-2-one (5p ),16 trans-3-methyl-4-phenylethyloxe-
tan-2-one (5q),17 (S)-N-(t-butoxycarbonyl)-3-amino-2-oxetanone
(5r ),18 and (S)-N-allyl-N-(t-butoxycarbonyl)-3-amino-2-oxe-
tanone (5s).19 3-Phenyloxetan-2-one (5b), 3-methyl-3-phenyl-
oxetan-2-one (5c), 3-allyl-3-phenyloxetan-2-one (5d ), and 3-(1-
oxo-5-hexenyl)-3-phenyloxetan-2-one (5e) were prepared as
described in our previous paper,9 and experimental procedures
can be found in the Supporting Information.
filtered, and concentrated under reduced pressure. Flash
chromatography of the crude product on silica gel (petroleum
ether/EtOAc/triethylamine 92:7:1) gave 5k (0.76 g, 76%) as a
colorless oil: IR (film) 3073, 2931, 1816, 1113, 1072 cm-1
;
1HNMR (400 MHz, CDCl3) δ 7.65 (m, 4H), 7.41 (m, 6H), 3.65-
3.80 (m, 2H), 3.50 (dd, J ) 8.5, 6.9 Hz, 1H), 2.00 (m, 1H), 1.89
(m, 1H), 1.58 (s, 3H), 1.45 (s, 3H), 1.06 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 171.3, 135.5, 133.3, 129.8, 127.8, 80.1, 61.2,
55.0, 27.8, 27.8, 26.8, 22.2, 19.2; MS (FAB) m/z 338 (M+ - CO2),
281 (338 - t-Bu), 199 (100), 135, 105, 83, 55; Anal. Calcd for
C
23H30O3Si: C, 72.21; H, 7.90. Found: C, 72.35; H, 8.30.
3-[Hydr oxy(ph en yl)m eth yl]-3-ph en yloxetan -2-on e (5u ).
n-Butyllithium (1.6 M in hexane, 16.8 mL, 26.8 mmol) was
added dropwise to a stirred solution of diisopropylamine (2.98
g, 29.5 mmol) in dry THF (55 mL) at 0 °C under N2, stirred
for 15 min, then cooled to -78 °C. A solution of 3-phenyloxetan-
2-one (5b) (3.96 g, 26.8 mmol) in THF (55 mL) was added
dropwise, and the solution was stirred for 15 min. Benzalde-
hyde (8.50 g, 80.4 mmol) in dry THF (27 mL) was then added
dropwise. After 1.5 h at -78 °C, the reaction mixture was
poured into saturated aqueous NH4Cl (100 mL). The organic
layer was removed, and the aqueous layer was further
extracted with Et2O (4 × 250 mL). The combined organic
extracts were dried (MgSO4), and the solvents were removed
in vacuo. The residue was first purified by flash chromatog-
raphy on silica gel (petroleum ether/EtOAc 85:15) to remove
the benzaldehyde. This gave the product (4.66 g, 70%), a
mixture of two diastereomers, as a white solid. The diastere-
omers could be separated by careful chromatography (petro-
leum ether/EtOAc 92.5:7.5) in a 15:85 ratio: 5u (less polar,
minor diastereomer) 1H NMR (CDCl3) δ 7.27 (m, 6H), 7.05 (d,
J ) 6.9 Hz, 2H), 6.91 (d, J ) 6.9 Hz, 2H), 5.16 (s, 1H), 5.04 (d,
J ) 5.2 Hz, 1H), 4.48 (d, J ) 5.2 Hz, 1H), 2.51 (s, 1H); 13C
NMR (CDCl3) δ 171.3, 138.0, 134.4, 128.5, 128.4, 128.2, 128.1,
127.4, 126.7, 75.9, 71.6, 66.3. 5u (more polar, major diastere-
3-[ter t-Bu tyld im eth ylsilyloxy(p h en yl)m eth yl]-3-p h en -
yloxeta n -2-on e (5f). Compound 5u (0.21 g, 0.83 mmol) was
dissolved in dry CH2Cl2 (5 mL) and treated with 2,6-lutidine
(0.18 g, 1.66 mmol). The solution was cooled to -10 °C, and
tert-butyldimethylsilyltriflate (0.33 g, 1.25 mmol) was added.
After 45 min, water (5 mL) and EtOAc (10 mL) were added.
The aqueous layer was removed and was further extracted
with EtOAc (2 × 10 mL). The combined organic extracts were
washed with H2O (10 mL) and brine (10 mL) and dried
(MgSO4). The solvent was removed in vacuo, and the crude
product was purified by flash chromatography on silica gel
(petroleum ether/EtOAc 85:15) to give a white solid (0.25 g,
82%): mp 96-98 °C; IR (KBr) 3028, 2954, 2856, 1813, 1128,
omer): mp 104-106 °C; IR (KBr) 3537, 3060, 1826, 1111 cm-1
;
1H NMR (CDCl3) δ 7.29 (m, 6H), 7.20 (m, 4H), 5.07 (s, 1H),
4.86 (d, J ) 4.8 Hz, 1H), 4.85 (d, J ) 4.8 Hz, 1H), 2.40 (s, 1H);
13C NMR (CDCl3) δ 170.1, 137.9, 134.8, 128.6, 128.5, 128.2,
1
1093, 1070 cm-1; H NMR (400 MHz, CDCl3) δ 7.25 (m, 6H),
128.1, 127.3, 127.2, 76.7, 71.0, 68.1; MS (EI) m/z 224 (M+
-
7.17 (m, 4H), 4.92 (s, 1H), 4.76 (d, J ) 4.7 Hz, 1H), 4.51 (d, J
) 4.7 Hz, 1H), 0.87 (s, 9H), -0.15 (s, 3H), -0.35 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 169.9, 138.6, 135.4, 128.3, 128.2,
127.9, 127.8, 127.6, 127.5, 77.8, 72.0, 67.9, 25.7, 18.1, -4.9,
-5.7; MS (EI) m/z 353 (M+ - CH3), 311, 221, 91, 73 (100). Anal.
Calcd for C22H28O3Si: C, 71.74; H, 7.60. Found: C, 71.60: H,
7.83.
CH2O), 148 (100), 103, 77, 51. Anal. Calcd for C16H14O3: C,
75.57; H, 5.55. Found: C, 75.39; H, 5.43.
P r ep a r a tion of Dim eth yltita n ocen e (6). Dimethylti-
tanocene was prepared with some modification of a previously
described procedure.32 Methyllithium (1.4 M in Et2O, 132 mL,
185 mmol) was added dropwise under N2 to a stirred slurry of
titanocene dichloride (20.0 g, 80.3 mmol) in dry toluene (160
mL) at -5 °C. The mixture was stirred at -5 °C for 1 h and
then allowed to warm to rt over 1 h. The mixture was cooled
to 0 °C and then quenched carefully with ice-cold 6% aqueous
NH4Cl (50 mL). After separation, the organic layer was washed
with water (50 mL) and brine (50 mL), dried (MgSO4), and
filtered to provide a red solution. The solution was concen-
3-Ben zoyl-3-p h en yloxeta n -2-on e (5g). Sodium acetate
(0.047 g, 0.67 mmol) and PCC (1.07 g, 4.95 mmol) were added
to compound 5u (0.21 g, 0.83 mmol) in dry CH2Cl2 (20 mL) at
rt. The reaction mixture was stirred for 5 h. Et2O (40 mL) was
then added, and stirring was continued for 30 min. The
reaction mixture was filtered through silica gel/Florisil (1:1),
and the filtrate was concentrated to 50 mL, washed with 2 M
NaOH (10 mL) and brine (10 mL), and dried (MgSO4).
Purification by flash chromatography on silica gel (dry loaded,
CH2Cl2) (petroleum ether/EtOAc 95:5) afforded lactone 5g (0.17
g, 81%) as a white solid: mp 72-74 °C; IR (CH2Cl2) 1820, 1690,
1
trated to one-third the volume. H NMR assay indicated 15.2
g (91%) of dimethyltitanocene: 1H NMR (400 MHz, CDCl3) δ
6.09 (s, 5H), 6.08 (s, 5H), -0.11 (s, 3H), -0.12 (s, 3H). The
dimethyltitanocene was generally stored in the freezer as a
0.5 M solution in toluene.
1
1285 cm-1; H NMR (400 MHz, CDCl3) δ 8.08 (d, J ) 8.5 Hz,
Gen er a l P r oced u r e for Meth ylen a tion . 3-Allyl-2-m eth -
ylen e-3-p h en yloxeta n e (7d ). Dimethyltitanocene (0.5 M in
toluene, 10.8 mL, 5.4 mmol) and 3-allyl-3-phenyloxetan-2-one
(0.50 g, 2.7 mmol) were stirred at 80 °C under N2 in the dark.
2H), 7.49 (t, J ) 8.5 Hz, 1H), 7.3 (m, 7H), 5.34 (d, J ) 5.0 Hz,
1H), 4.32 (d, J ) 5.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
190.3, 166.5, 134.7, 133.9, 133.6, 130.7, 129.8, 128.8, 128.5,
125.9, 77.7, 70.3; MS (EI) m/z 224 (M+ - CH2O), 196, 165, 115,
105 (100), 77. Anal. Calcd for C16H12O3: C, 76.17; H, 4.80.
Found: C, 76.06; H, 4.84.
1
The reaction was monitored by TLC and/or H NMR, and after
the disappearance of the starting material (2-15 h) the
solution was allowed to cool. An equal volume of petroleum
ether was then added, at which point a yellow precipitate
formed. The mixture was stirred for 30 min and then passed
through Celite with petroleum ether until the filtrate was
colorless. After concentration, if large amounts of solid were
still present, the mixture was diluted with petroleum ether
and filtered through Celite a second time. The residue was
then purified by flash chromatography on silica gel (petroleum
Gen er a l P r oced u r e for th e P r ep a r a tion of La cton es
5k -o. 3-(2-ter t-Bu tyld ip h en ylsilyloxy)eth yl-4,4-d im eth yl-
oxeta n -2-on e (5k ). A solution of 9a (1.05 g, 3.37 mmol) in
anhydrous pyridine (35 mL) was cooled to 0-5 °C, and
benzenesulfonyl chloride (1.49 g, 8.43 mmol) was added
dropwise with stirring. After being stirred overnight at 0-5
°C, the reaction mixture was poured onto crushed ice (150 mL),
stirred, and extracted with of Et2O (5 × 60 mL). The combined
organic extracts were washed with saturated aqueous sodium
bicarbonate (3 × 60 mL) and water (200 mL), dried (MgSO4),
(32) Claus, K.; Bestian, H. J ustus Liebigs Ann. Chem. 1962, 654, 8.

Preparation and Properties of 2-Methyleneoxetanes
J . Org. Chem., Vol. 64, No. 19, 1999 7079
1
ether/EtOAc/triethylamine 98.5:0.5:1), which afforded meth-
yleneoxetane 7d (0.33 g, 76%) as a pale yellow oil: IR (film)
3150, 3000, 2900, 1650, 1500, 1490, 1190, 980 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.35 (m, 5H), 5.76 (m, 1 H), 5.15 (m, 1 H),
5.12 (m, 1H), 4.76 (d, J ) 5.0 Hz, 1H), 4.72 (d, J ) 5.0 Hz,
1H), 4.32 (d, J ) 4.0 Hz, 1 H), 4.03 (d, J ) 4.0 Hz, 1 H), 2.74
(m, 2 H); 13C NMR (100 MHz, CDCl3) δ 170.3, 141.9, 133.2,
128.5, 126.9, 126.2, 118.8, 80.4, 79.1, 54.0, 44.0; MS (EI) m/z
(film) 3500 (br), 3050, 2950, 1710, 1620, 1490, 1400 cm-1; H
NMR (400 MHz, CDCl3) δ 5.76 (m, 1H), 5.01 (m, 1H), 4.97 (m,
1H), 4.20 (q, J ) 9.5 Hz, 0.6H), 4.19 (q, J ) 9.5 Hz, 0.4H),
4.00 (m, 0.4H), 3.90 (ddq, J ) 8.5, 8.5, 8.5 Hz, 0.6H), 2.50 (m,
2H), 2.12 (m, 2H), 1.81-1.32 (m, 4H), 1.29 (t, J ) 9.5 Hz, 3H),
1.23 (d, J ) 8.5 Hz, 1.6H), 1.20 (d, J ) 8.5 Hz, 1.4H); 13C NMR
(100 MHz, CDCl3) δ 175.4, 175.2, 138.3, 138.2, 114.9, 114.8,
68.4, 68.2, 60.5, 52.5, 52.1, 35.8, 33.6, 33.5, 28.9, 26.9, 26.7,
21.6, 20.3, 14.3; MS (EI) m/z 201 (M+ + H), 185, 156, 132, 109,
101, 73 (100), 67, 55. Anal. Calcd for C11H20O3: C, 65.97; H,
10.07. Found: C, 65.60; H, 9.94.
186 (M+), 158, 115, 103 (100), 77; HRMS (EI) calcd for C13H14
O
(M+) 186.1045, found 186.1044.
Gen er a l P r oced u r e for th e P r ep a r a tion of Acid s 9a
a n d 9b. 2-(2-ter t-Bu tyld ip h en ylsilyloxy)eth yl-3-h yd r oxy-
3-m eth ylbu ta n oic Acid (9a ). n-Butyllithium (2.6 mmol, 1.6
M in hexane) was added dropwise to a stirred solution of
diisopropylamine (0.27 g, 2.6 mmol) in dry THF (1.3 mL) at 0
°C under N2. The solution was maintained at 0 °C for 10 min
and then warmed to rt. 4-(tert-Butyldiphenylsilyloxy)butanoic
acid21 (0.45 g, 1.30 mmol) in dry THF (1.3 mL) was then added
to the resulting solution, and the reaction was maintained at
rt for 1.5 h. Anhydrous acetone (0.080 g, 1.3 mmol) in THF
(0.52 mL) was added, and the mixture was stirred for 16 h.
The mixture was cooled to 0 °C and acidified to pH 2 with 2 N
HCl. The resulting mixture was extracted with Et2O (5 × 20
mL), and the combined organic extracts were dried (MgSO4)
and concentrated in vacuo. Purification by flash chromatog-
raphy on silica gel (petroleum ether/EtOAc 9:1; then petroleum
ether/EtOAc/acetic acid 75:25:0.3) gave 9a (0.43 g, 81%) as a
white solid: mp 94-94.5 °C; IR (diffuse reflectance FTIR)
3425, 3073, 2966, 1710, 1590 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.68 (m, 4H) 7.38 (m, 6H), 3.75 (m, 1H), 3.69 (m, 1H), 2.68
(dd, J ) 9.7, 3.3 Hz, 1H), 2.00 (m, 1H), 1.93 (m, 1H) 1.32 (s,
3H), 1.27 (s, 3H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
179.9, 135.5, 133.3, 129.7, 127.7, 71.4, 62.4, 52.8, 30.7, 28.7,
26.8, 26.6, 19.1; MS (FAB) m/z 384 (M+ + H - OH), 366, 282,
201, 135 (100), 105, 83. Anal. Calcd for C23H32O4Si: C, 68.96;
H, 8.05. Found: C, 68.87; H, 8.12.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ester s 11a -
c. Eth yl 2-Acetyl-6-h ep ten oa te (11a ). A solution of ethyl
acetoacetate (4.69 g, 36.1 mmol) and 5-iodopent-1-ene (5.90 g,
30.1 mmol) in CH2Cl2 (100 mL) was added to a vigorously
stirred solution of tetra-n-butylammonium hydrogen sulfate
(10.2 g, 30.1 mmol) and sodium hydroxide (2.41 g, 60.1 mmol)
in H2O (100 mL). The mixture was heated at reflux for 2.5 h.
The mixture was then cooled to rt, and the layers were
separated. The aqueous layer was further extracted with CH2-
Cl2 (3 × 30 mL). The combined organic extracts were concen-
trated in vacuo, and the residue was taken up in Et2O (50 mL).
The insoluble material was removed by filtration and washed
with Et2O. The filtrate was washed with H2O (15 mL) and
brine (15 mL) and dried (Na2SO4), and the solvent was
removed in vacuo. The residue was purified by flash chroma-
tography on silica gel (petroleum ether/EtOAc 93:7), and 11a
was isolated as a colorless oil (3.1 g, 52%): IR (film) 3050, 2990,
1750, 1720, 1630, 1490, 1480 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.74 (m, 1H), 4.99 (m, 1H), 4.94 (m, 1H), 4.18 (q, J ) 7.1 Hz,
2H), 3.38 (dd, J ) 7.4, 7.4 Hz, 1H), 2.20 (s, 3H), 2.04 (m, 2H),
1.83 (m, 2H), 1.35 (m, 2H), 1.25 (t, J ) 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 203.1, 169.8, 137.9, 115.0, 61.3, 59.7, 33.3,
28.7, 27.5, 26.6, 14.1; MS (EI) m/z 199 (M+ + H), 156, 143,
130, 109, 101, 73, 68, 55 (100). Anal. Calcd for C11H18O3: C,
66.44; H, 9.15. Found: C, 66.07; H, 9.38.
Gen er a l P r oced u r e for th e P r ep a r a tion of Acid s 13a -
c. 2-(1-Hyd r oxyeth yl)-6-h ep ten oic Acid (13a ). A solution
of 2 N KOH (30.3 mL, 60.6 mmol) and ethyl 2-(1-hydroxyethyl)-
6-heptenoate (12a ) (2.16 g, 10.8 mmol) in MeOH (70 mL) was
stirred at rt for 20 h. The reaction mixture was acidified (pH
2-3) by dropwise addition of phosphoric acid. The MeOH was
evaporated under reduced pressure, and the resulting slurry
was dissolved in H2O (60 mL) and extracted with Et2O (3 ×
30 mL). The combined organic extracts were dried (MgSO4),
and the solvent was removed in vacuo. Purification by flash
chromatography on silica gel (petroleum ether/EtOAc/acetic
acid 90:10:0.3) afforded a 1:1 mixture of diastereomers as a
viscous, colorless oil (1.6 g, 86%): IR (film) 3500-3100 (br),
2950, 1720, 1640, 1490, 1420 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.77 (m, 1H), 5.00 (m, 1H), 4.97 (m, 1H), 4.05 (dq, J ) 6.4,
6.4 Hz, 0.5H), 3.95 (dq, J ) 6.4, 6.4 Hz, 0.5H), 2.47 (m, 0.5H),
2.40 (m, 0.5H), 2.07 (m, 2H), 1.69 (m, 1H), 1.59 (m, 1H), 1.43
(m, 2H), 1.26 (d, J ) 6.4 Hz, 1.5H), 1.23 (d, J ) 6.4 Hz, 1.5H);
13C NMR (100 MHz, CDCl3) δ 180.1 170.9, 138.2, 138.0, 115.0,
114.9, 68.3, 68.2, 52.6, 51.7, 33.6, 33.5, 28.6, 26.9, 26.5, 26.4,
21.5, 20.1; MS (EI) m/z 154 (M+ - H2O), 132, 124, 96, 81, 73,
67, 55(100); HRMS (EI) calcd for C9H14O2 (M+ - H2O)
154.0994, found 154.0991.
2,4-Dim eth yl-4,6-d ip h en ylh exa n -3-on e (18). Trimethyl-
aluminum (2.0 M in toluene, 0.31 mL, 0.62 mmol) was added
dropwise to a solution of 3-methyl-3-phenyl-2-methyleneoxe-
tane (7c) (0.10 g, 0.62 mmol) in THF (2 mL) at 0 °C under N2,
and the solution was maintained at 0 °C for 10 min. tert-
Butyllithium (1.6 M in heptane, 2.36 mL, 3.6 mmol) was then
added dropwise, and the resulting yellow solution was main-
tained at 0 °C for 5 min. Iodomethane (0.88 g, 6.2 mmol) was
then added. The solution was slowly warmed to rt and
maintained overnight. NaF (0.11 g, 2.5 mmol) and H2O (1 drop,
ca. 25 mg) were added. The mixture was stirred for 20 min,
and the resulting yellow solid was filtered and washed with
Et2O (10 mL). The filtrate was washed with H2O (10 mL). The
aqueous layer was then further extracted with Et2O (3 × 5
mL), and the combined organic extracts were dried (Na2SO4)
and concentrated in vacuo. Purification by flash chromatog-
raphy on silica gel (petroleum ether/EtOAc 98:2) afforded (1-
methoxymethyl-1-methylbut-2-ynyl)benzene (17)12 (0.052 g,
45%) as a colorless oil: IR (film) 3150, 3100, 3000, 2950, 2850,
1650, 1540, 1510, 1480, 1180, 1100 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.57 (m, 2H), 7.31 (m, 2H), 7.25 (m, 1H), 3.55 (d, J )
9.0 Hz, 1H), 3.48 (d, J ) 9.0 Hz, 1H), 3.35 (s, 3H), 1.92 (s,
3H), 1.59 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.8, 128.1,
126.6, 126.5, 83.0, 81.8, 78.8, 59.6, 41.2, 26.0, 3.8; MS (EI) m/z
173 (M+ - CH3) 158, 143 (100), 120, 115, 65; HRMS (EI) calcd
for C12H13O (M+ - CH3) 173.0966, found 173.0969. (1-Meth-
oxymethyl-1-methylprop-2-ynyl)benzene was also isolated as
a colorless oil (0.014 g, 14%): 1H NMR (400 MHz, CDCl3) δ
7.57 (m, 2H), 7.31 (m, 2H), 7.25 (m, 1H), 3.59 (d, J ) 9.0 Hz,
1H), 3.52 (d, J ) 9.0 Hz, 1H), 3.37 (s, 3H), 2.43 (s, 1H), 1.64
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.5, 128.2, 126.9,
126.4, 88.1, 81.3, 71.3, 59.6, 41.2, 25.7; MS (EI) m/z 159 (M+
- CH3), 144, 129 (100), 115, 77, 51; HRMS (EI) calcd for
C11H11O (M+ - CH3) 159.0810, found 159.0814. 1,3-Dimethyl-
3,6-diphenylhexane-2-one (18) (0.052 g, 29%) was isolated as
a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 3H),
7.28 (m, 5H), 7.14 (m, 2H), 2.68 (m, 1H), 2.43 (m, 1H), 2.28
(m, 1H), 2.21 (m, 2H), 1.63 (s, 3H), 0.93 (d, J ) 6.7 Hz, 3H),
0.83 (d, J ) 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 216.9,
142.5, 141.6, 128.6, 128.3, 128.2, 127.0, 126.9, 125.7, 56.2, 39.4,
Gen er a l P r oced u r e for th e P r ep a r a tion of â-Hyd r oxy-
est er s 12a -c. E t h yl 2-(1-H yd r oxyet h yl)-6-h ep t en oa t e
(12a ). A solution of ethyl 2-acetyl-6-heptenoate (11a ) (3.16 g,
16.0 mmol) in 95% ethanol (20 mL) was added dropwise over
0.5 h to a stirred suspension of NaBH4 (0.60 g, 16.0 mmol) in
95% ethanol (35 mL) at 0 °C. The mixture was stirred for 2.5
h at 0 °C and then acidified (pH 3-4) by dropwise addition of
2 N HCl. The ethanol was evaporated under reduced pressure.
The resulting slurry was dissolved in H2O (35 mL) and
extracted with Et2O (3 × 20 mL). The combined organic
extracts were dried (MgSO4), and the solvent was removed
under reduced pressure. Purification by flash chromatography
on silica gel (petroleum ether/EtOAc 88:12) afforded a 3:2
mixture of diastereomers (2.6 g, 81%) as a colorless oil: IR

7080 J . Org. Chem., Vol. 64, No. 19, 1999
Dollinger et al.
35.7, 30.8, 21.1, 20.2, 20.3; MS (EI) m/z 237 (M+ - 43) 209,
170, 131, 105, 91 (100).
14 Hz, 1H), 3.72 (d, J ) 11 Hz, 1H), 1.80 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 201.3, 138.7, 129.7, 128.8, 126.7, 56.5,
40.8, 32.4, 21.3; MS (EI) 199, 197, 118 (100), 91, 77; HRMS
(EI) calcd for C11H12Br2O (M+) 317.9255, found 317.9244.
2-Acetoxy-2,3-d im eth yl-3-p h en yloxeta n e (19). Acetic
acid (11 µL, 0.18 mmol) was added to 3-methyl-2-methylene-
3-phenyloxetane (7c) (25 mg, 0.16 mmol) in CCl4 (2 mL) in an
NMR tube at room temerature. The reaction was monitored
by 1H NMR, and after 23 days the reaction reached equilib-
rium. Integration indicated that 2-acetoxy-2,3-dimethyl-3-
phenyloxetane (19) was formed in 84% yield, as a mixture (6:
1) of diastereomers (16% remaining 7c): 1H NMR (400 MHz,
CCl4) (major diastereomer) δ 7.20-7.49 (m, 5H), 4.76 (d, J )
5.3 Hz, 1H), 4.18 (d, J ) 5.3 Hz, 1H), 2.00 (s, 3H), 1.60 (s,
3H), 1.51 (s, 3H).
Ack n ow led gm en t. We thank Pfizer, Inc. for support
of J .T.A. through the PREPARE program for under-
graduates. Support by donors of the Petroleum Research
Fund, administered by the American Chemical Society,
and by the University of Connecticut Research Founda-
tion is gratefully acknowledged. A.R.H. thanks the NSF
for a CAREER Award.
1,4-Dibr om o-2-m eth yl-2-p h en yl-3-bu ta n on e (20). Bro-
mine (77 µL, 0.63 mmol) in CCl4 (2 mL) was added dropwise,
via syringe, to a stirred solution of 3-methyl-3-phenyl-2-
methyleneoxetane (7c) (0.10 g, 0.63 mmol) in CCl4 (2 mL) at
0 °C. The rate of addition was such as to maintain the reaction
temperature at 0 °C. After 20 min, the reaction mixture was
washed with NaHSO3 (5 mL), NaOH 10% (5 mL), and brine
(5 mL) and dried (MgSO4). The solvent was removed in vacuo,
and the crude product was purified by flash chromatography
on silica gel (dry loaded, CH2Cl2) (petroleum ether/EtOAc 99:
1) to give 20 as a colorless oil (0.16 g, 81%): IR (CH2Cl2) 1710
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.38 (m, 3H), 7.24 (m, 2H),
3.98 (d, J ) 14 Hz, 1H), 3.97 (d, J ) 11 Hz, 1H), 3.84 (d, J )
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds 5b-e.
Characterization data for compounds 5l-o, 7a -c,e-t, 9b,
11b,c, 12b,c, and 13b,c. Copies of high-resolution 1H NMR
spectra of those new compounds for which elemental analyses
are not reported. Tables giving crystallograpic details for
crystal data and structure refinement, atomic coordinates,
bond lengths and angles, anisotropic displacement coefficients,
and H-atom coordinates. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O9906072