An Unanticipated Ring-Opening of 2-Methyleneoxetanes: A Fundamentally New Approach to the Preparation of Homopropargylic Alcohols

Full text of DOI:10.1021/jo9816360

6782
J . Org. Chem. 1998, 63, 6782-6783
Ta ble 1. Attem p ted Nu cleop h ilic Rin g-Op en in g of
2-Meth ylen eoxeta n e (4)
An Un a n ticip a ted Rin g-Op en in g of
2-Meth ylen eoxeta n es: A F u n d a m en ta lly New
Ap p r oa ch to th e P r ep a r a tion of
Hom op r op a r gylic Alcoh ols
nucleophile Lewis acid
conditions
results
n-BuLi
n-BuLi
-95-0 °C, THF
4 consumed
no isolable product
Lisa M. Dollinger and Amy R. Howell*
Department of Chemistry, The University of Connecticut,
Storrs, Connecticut 06269-3060
BF3OEt2 -95 -10 °C, THF no isolable product
recovery of some 4
n-BuLi
PhLi
PhLi
PhLi
Al(CH3)3 -95-0 °C, THF
-78 °C-RT, THF
BF3OEt2 -78 °C-RT, THF
Al(CH3)3 -78 °C-RT, THF
6
no reaction
no reaction
6
Received August 13, 1998
The alkyne functionality occupies a place of undisputed
importance in organic synthesis.1,2 The moiety is exception-
ally versatile, open to ready regio- and stereoselective func-
tionalization. In addition, numerous natural and synthetic
products of biological significance contain the acetylenic
unit.3,4 One class of acetylenic compounds that has received
wide attention because of its broad utility in organic synthe-
sis is the homopropargylic alcohols 1. Recently, in an on-
going investigation of the reactivity of 2-methyleneoxetanes
2, we discovered a novel preparation of 1. In this com-
munication we describe our initial study of the scope of this
procedure and delineate why it represents a fundamentally
different and useful approach to the preparation of homo-
propargylic alcohols.
Sch em e 1
oxacycles. An analogous ring-opening of a 2-alkylidene
tetrahydrofuran treated with LDA in the absence of trim-
ethylaluminum has been previously observed, but only as a
minor pathway.8,9
Intrigued by the conversion of 4 to 6 we decided to
investigate the scope of this reaction. A range of 2-meth-
yleneoxetanes 9 was prepared7 by the reaction of the cor-
responding â-lactones 7 with dimethyltitanocene 8.10 The
â-lactones were prepared either by the alkylation of 3-phen-
yl-2-oxetanone11 or by the cyclization of â-hydroxy acids with
benzenesulfonyl chloride. 2-Methyleneoxetanes 9 in THF
were then added to a solution of lithium diisopropylamide
(LDA) in THF at 0 °C. It is noteworthy that, when LDA
was employed as the base, rather than n-butyllithium or
phenyllithium, trimethylaluminum was not required for
successful ring opening. The terminal homopropargylic
alcohols 10a -d were isolated in 48-88% yield. Presuming
the intermediacy of 5, we also examined the outcome of the
addition of electrophiles other than water. As illustrated
in Table 2, the syntheses of (trimethylsilyl)alkyne 10e
(electrophile ) trimethylsilyl chloride) and internal alkyne
10f (electrophile ) iodomethane) were readily achieved.
Although the possibility of racemization at the propargylic
position cannot be ignored, if the postulated mechanism in
Scheme 1 is correct, the stereochemical integrity at this
position should remain intact. Consequently, homochiral
â-lactones should result in homochiral homopropargylic
alcohols. To confirm this, 2-methyleneoxetane 11b was
prepared from diastereomerically pure â-lactone 11a .12
2-Methyleneoxetanes 2 are a largely unexplored class of
heterocycles5-7 that we believe will prove to be highly useful
as synthetic intermediates. One attractive feature is that the
precedented5 ring opening of 2 affords an enolate 3, which,
potentially, could be captured by a variety of electrophiles.
Our investigation of this versatile tandem sequence
focused on ring-opening of 4 with carbanions. As shown in
Table 1, neither n-butyllithium nor phenyllithium alone ef-
fected significant ring-opening. An attempt to boost the re-
activity at C-4 by the addition of a Lewis acid produced an
unanticipated outcome. Although boron trifluoride diethyl
etherate did little to alter the course of the reactions, addi-
tion of trimethylaluminum to a solution of 4 in THF, fol-
lowed by the addition of either n-butyllithium or phenyl-
lithium, resulted in a single product 6, isolated in 60-70%
yield. Apparently, prior coordination of the oxygen with tri-
methylaluminum enhances the reactivity of the vinylic CH
bond (Scheme 1). This reaction is largely unprecedented and
should also be applicable to other methylene (or alkylidene)
* To whom correspondence should be addressed. Tel: 860-486-3460.
Fax: 860-486-2981. E-mail: howell@nucleus.chem.uconn.edu.
(1) Boyd, G. V. In The Chemistry of the Triple-Bonded Functional
Groups: Supplement C2; Patai, S., Rappoport, Z., Eds.; J ohn Wiley and
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(2) Siegel, S. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8, p 417.
(3) Chemistry and Biology of Naturally Occurring Acetylenes and Related
Compounds (NOARC); Lam, J ., Breteler, H., Arnason, T., Hansen, L., Eds.;
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Compound 11b was readily converted to homopropargylic
alcohol 12, as a single diastereoisomer, in 81% yield.
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S0022-3263(98)01636-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/11/1998

Communications
J . Org. Chem., Vol. 63, No. 20, 1998 6783
Ta ble 2. P r ep a r a tion of Hom op r op a r gylic Alcoh ols (10a -f) fr om 2-Meth ylen eoxeta n es
entry
lactone 7
isolated yield 9, %
R4
isolated yield 10, %
a
R, R1 ) H; R2, R3 ) Ph, CH2CHCH2
74
60
60
76
H
H
H
H
85
48
86
88
87
74
b
c
d
e
f
R, R1 ) CH3; R2 ) H; R3)(CH2)3OSit-BuPh2
R, R1 ) (CH2)5; R2,R3 ) H,CH3
R, R1 ) H; R2, R3 ) Ph,CH3
7d
(CH3)3Sia
b
7d
CH3
a
b
Electrophile ) (CH3)3SiCl. Electrophile ) CH3I.
F igu r e 1. Common approaches to homopropargylic alcohols 1.
F igu r e 2.
The conversion of 7 to 10 represents a novel protocol for
the preparation of homopropargylic alcohols. The two most
widely used approaches to 1 are illustrated in Figure 1. One
strategy exploits propargylic anion equivalents 13 in reac-
tions with carbonyl compounds. Historically, this approach
has been hampered by problems of regioselection with many
propargyl anion equivalents giving mixtures of 1 and allenyl
alcohols.13 However, some of the more recent methodologies
centered on 13 are regiospecific and high yielding, although
their syntheses are not always trivial.14-26 With substituted
propargyl anions (13 R2 and/or R3 * H) that produce
diastereomeric alcohols (1 R4 * R5),18-26 a major drawback
is that, with one exception,24 diastereoselectivities tend to
be quite variable. More importantly, of these examples only
Marshall et al. examine the issue of the enantioselectivity
of the addition when the propargyl anion equivalent is
chiral.25,26 It should be noted that efficient asymmetric
syntheses of 1 from unsubstituted 13 (R1, R2, R3 ) H) are
available.27-30 The other widely used approach to 1 involves
the reaction of acetylenic anions 14 with epoxides.31-34 The
regioselectivity of the ring-opening reaction can be problem-
atic, but the variety of asymmetric epoxidation procedures
available35-37 makes this an attractive protocol. Obviously,
the versatility of any synthetic methodology must be evalu-
ated by the accessibility of key intermediates.
In evaluating the utility of 2-methyleneoxetanes as pre-
cursors for 1, it is important to recognize that â-hydroxy
acids are common precursors for â-lactones. When combined
with the many approaches,38,39 both racemic and enantiose-
lective, to â-hydroxy acids, the protocol outlined in this
communication represents a fundamentally different way of
considering the retrosynthesis of homopropargylic alcohols,
as shown in Figure 2. The retrons are an alkyl halide 15, a
"C2-" synthon 16 and a â-hydroxy acid 17.40
In conclusion, the one-step conversion of 2-methyleneoxe-
tanes to homopropargylic alcohols is an unusual, useful, and
largely unprecedented reaction. Further, the conversion
represents a fundamentally new approach to the preparation
of homopropargylic alcohols.
Ack n ow led gm en t. Support by donors of the Petroleum
Research Fund, administered by the American Chemical
Society, and by the University of Connecticut Research
Foundation is gratefully acknowledged. A.R.H. thanks the
NSF for a CAREER Award. We thank David Galluzzo for
the preparation of 2-methyleneoxetane 9c.
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