Unusual, strained heterocycles: 3-Alkylidene-2-methyleneoxetanes from Morita-Baylis-Hillman-type adducts

Article abstract of DOI:10.1021/ol020202v

(Matrix presented) 3-Alkylidene-2-methyleneoxetanes have been prepared by treating α-alkylidene-β-lactones, derived from Morita-Baylis-Hillman-type adducts, with dimethyltitanocene. Preliminary studies of the reactivity of these little known, strained het

Full text of DOI:10.1021/ol020202v

ORGANIC
LETTERS
2003
Vol. 5, No. 4
399-402
Unusual, Strained Heterocycles:
3-Alkylidene-2-methyleneoxetanes from
Morita−Baylis−Hillman-type Adducts†
Isamir Mart´ınez, Alexander E. Andrews, Joseph D. Emch, Albert J. Ndakala,
Jun Wang, and Amy R. Howell*
Department of Chemistry, The UniVersity of Connecticut,
Storrs, Connecticut 06269-3060
amy.howell@uconn.edu
Received October 8, 2002
ABSTRACT
3-Alkylidene-2-methyleneoxetanes have been prepared by treating r-alkylidene-â-lactones, derived from Morita−Baylis−Hillman-type adducts,
with dimethyltitanocene. Preliminary studies of the reactivity of these little known, strained heterocycles are also described.
The high reactivity and tremendous potential for acting as
chiral templates have made strained heterocyclic systems
attractive targets for synthetic development. Our interest in
such systems has centered on the exploitation of the little
investigated 2-methyleneoxetanes. We developed a straight-
forward entry into this class of compounds by the methyl-
enation of â-lactones with dimethyltitanocene.1 Our antici-
pation of the flexibility of 2-methyleneoxetanes has been
confirmed by their conversion to homopropargylic alcohols,2
functionalized ketones,3,4 and 1,5-dioxaspiro[3.2]hexanes,5
the latter representing useful strained heterocyclic systems.6,7
In studying these transformations, it occurred to us that the
presence of unsaturation at the 3-position of the 2-methyl-
eneoxetane (cf. 11) would provide additional flexibility and
utility. In this communication, we describe our approach to
3-alkylidene-2-methyleneoxetanes and preliminary studies of
their reactivity. Also highlighted is an unexpected formation
of electron-rich aryl allenes.
To our knowledge, there are two examples (compounds 1
and 2)8,9 of 2,3-dialkylidene oxetanes in the literature.10
Compound 1 was a byproduct isolated in 17% yield from
the reaction between 1,3-dimethylallene and bis(trifluoro-
methyl)ketene.8 Compound 2, isolated in 25% yield, ulti-
mately resulted from a partial decomposition of 4-hydroxy-
4-methylpentynenitrile in the presence of sodium azide.9
Neither approach is broadly applicable, and we sought a more
general entry to 2,3-dialkylidene oxetanes. Because of our
success with methylenating â-lactones, our targeted entry
into 2,3-dimethyleneoxetanes (or the related 3-alkylidene-
† Dedicated to the memory of Joseph D. Emch, a NSF REU student
from The Ohio State University who died suddenly on January 6, 2001.
(1) Dollinger, L. M.; Ndakala, A. J.; Hashemzadeh, M.; Wang, G.; Wang,
Y.; Martinez, I.; Arcari, J. T.; Galluzzo, D. J.; Howell, A. R.; Rheingold,
A. L.; Figuero, J. S. J. Org. Chem. 1999, 64, 7074-7080.
(2) Dollinger, L. M.; Howell, A. R. J. Org. Chem. 1998, 63, 6782-
6783.
(3) Wang, Y.; Bekolo, H.; Howell, A. R. Tetrahedron 2002, 58, 7101-
7107.
(4) Hashemzadeh, M.; Howell, A. R. Tetrahedron Lett. 2000, 41, 1855-
1858.
(8) England, D. C.; Krespan, C. G. J. Org. Chem. 1970, 35, 3322-3327.
(9) Trofimov, B. A.; Mal’kina, A. G.; Kudyakova, R. N. Russ. J. Org.
Chem. 1993, 30, 1616-1619.
(10) There are a number of reports in the literature of 3,4-dialkylide-
neoxetan-2-ones, which do contain a 2,3-dialkylideneoxetane substructure.
However, these compounds will have a fundamentally different reactivity
than the targeted dialkylideneoxetanes. For examples of the structurally
related oxetanones, see: (a) Masters, A. P.; Sorensen, T. S. Tetrahedron
Lett. 1989, 30, 5869-5872. (b) Zhidkova, T. A.; Vakulova, L. A.;
Yanotovskii, M. T.; Svetlaeva, V. M.; Filippova, T. M. Pharm. Chem. J.
(Engl. Transl.) 1983, 17, 344-346. (c) Baxter, G. J.; Brown, R. F. C.;
Eastwood, F. W.; Gatehouse, B. M.; Nesbit, M. C. Aust. J. Chem. 1978,
31, 1757-1767. (d) Payne, G. B. J. Org. Chem. 1966, 31, 718-721.
(5) Ndakala, A. J.; Howell, A. R. J. Org. Chem. 1998, 63, 6098-6099.
(6) Ndakala, A. J.; Hashemzadeh, M.; So, R. C.; Howell, A. R. Org.
Lett. 2002, 4, 1719-1722.
(7) Howell, A. R.; Ndakala, A. J. Org. Lett. 1999, 1, 825-827.
10.1021/ol020202v CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/22/2003

2-methyleneoxetanes) was via methylenation of R-methyl-
ene(or R-alkylidene)-â-lactones 3.
Table 1.a,b
entry
R
R′ % yield of 7 % yield of 8 % yield of 9
a
b
c
d
e
f
PhCH2CH2
Ph2CH
isopropyl
tert-butyl
methyl
H
H
I
I
Ph
Ph
74c
88
77
51
55c
68c
51d
35d
84
66
96
A number of approaches to R-alkylidene-â-lactones have
been reported.11-19 The most straightforward and general
strategies for R-methylene-â-lactones are a phenyselenation/
oxidation/elimination of R-methyl-â-lactones 4, utilized by
Danheiser and co-workers,14 and a cyclization of R-meth-
ylene-â-hydroxy acids 5 (Figure 1). From 4, the late-stage
isopropyl
a See Supporting Information for experimental procedures. b All yields
are isolated, purified yields. c Yield over two steps. d Yield over three steps.
Acids 8a,b,g-i were prepared by the traditional Morita-
Baylis-Hillman reaction, followed by hydrolysis with KOH
in methanol. Optimization of lactonization conditions was
examined with 8a. Benzenesulfonyl chloride, a common
promoter of lactonization of â-hydroxy acids, did not produce
9a. Both p-toluenesulfonyl chloride and methanesulfonyl
chloride gave 9a in 20-30% yield. However, o-nitroben-
zenesulfonyl chloride provided 9a in good yield and was
used in the preparation of all of the lactones except 9c and
9d.
The syntheses of lactones 9c and 9d have been previously
described.17 Iodozirconation of methyl propiolate and in situ
condensation with isobutyraldehyde and pivaldehyde, re-
spectively, provided esters 7c and 7d. Hydrolysis with LiOH,
followed by methanesulfonyl chloride-promoted cyclization,
provided the lactones.
Morita-Baylis-Hillman adducts 7e and 7f were prepared
by a one-pot hydroalumination-condensation procedure
described by Ramachandran et al.21 Hydrolysis and cycliza-
tion provided 9e and 9f. It is noteworthy that these lactones
were prepared without purification of the intermediates. We
are confident that these overall yields can be improved.
An unexpected outcome resulted when the preparation of
simple 4-aryl-substituted â-lactones was attempted. Upon
exposure to o-nitrobenzenesulfonyl chloride, the Morita-
Baylis-Hillman-derived acid 8g was converted directly to
aryl allene 10g, rather than to the desired R-methylene-â-
lactone 9g (Table 2). Although the isolated yield was low
(28%), the allene was the only product observed in 1H NMR
spectra of the reaction mixture. A similar outcome was
observed for the Morita-Baylis-Hillman-derived acid 8h.
The thermal decarboxylations of 4-alkyl-substituted 3-alkyl-
idene-2-oxetanones have been previously reported, with
decarboxylations occurring at temperatures above 110 °C
to produce allenes.14,23 In contrast, these aryl allenes were
formed at room temperature. No attempts were made to
optimize the yields of 10g and 10h; moreover, the yields
may reflect the volatility of the allenes. We were interested
Figure 1. Potential strategies for R-methylene-â-lactones
introduction of the double bond utilizing a strong base and
oxidative conditions represented a potential problem of
intolerance of some functional groups.
The lactonization of R-alkylidene-â-hydroxy acids 5 is
precedented.11,15-17 Although these cyclizations are not
specifically related to Morita-Baylis-Hillman reaction
adducts, we recognized that this reaction20 represented an
ideal entry into R-methylene-â-hydroxy acids. Morita-
Baylis-Hillman reactions are generally limited to R-meth-
ylene, rather than R-alkylidene-â-hydroxy esters; however,
similarly efficient procedures for the synthesis of R-alkyl-
idene-â-hydroxy esters have been recently described.17,21,22
Our results for the preparation of R-alkylidene-â-lactones
via Morita-Baylis-Hillman-type adducts 7 are shown in
Table 1.
(11) Bartels, A.; Jones, P. G.; Liebscher, J. Synthesis 1998, 1645-1654.
(12) Adam, W.; Groer, P.; Saha-Moeller, C. R. Tetrahedron: Asymmetry
1997, 8, 833-836.
(13) Roso-Levi, G.; Amer, I. J. Mol. Catal. A: Chem. 1996, 106, 51-
56.
(14) Danheiser, R. L.; Choi, Y. M.; Menichincheri, M.; Stoner, E. J. J.
Org. Chem. 1993, 58, 322-327.
(15) Adam, W.; Albert, R.; Dachs Grau, N.; Hasemann, L.; Nestler, B.;
Peters, E.-M.; Peters, K.; Prechtl, F.; von Schnering, H. G. J. Org. Chem.
1991, 56, 5778-5781.
(16) Campi, E. M.; Dyall, K.; Fallon, G.; Jackson, W. R.; Perlmutter,
P.; Smallridge, A. J. Synthesis 1990, 855-856.
(17) Zhang, C.; Lu, X. Synthesis 1996, 586-589.
(18) Matsuda, I.; Ogiso, A.; Sato, S. J. Am. Chem. Soc. 1990, 112, 6120-
6121.
(19) Gabriele, B.; Salerno, G.; DePascali, F.; Costa, M.; Chiusoli, G. P.
J. Chem. Soc., Perkin Trans. 1 1997, 147-153.
(20) For reviews of the Baylis-Hillman reaction, see: (a) Ciganek, E.
Org. React. 1997, 51, 201-350. (b) Basavaiah, D.; Rao, P. D.; Hyma, R.
S. Tetrahedron 1996, 52, 8001-8062.
(21) Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T. J. Chem. Soc.,
Chem. Commun. 1999, 1979-1980.
(22) Wei, H.-X.; Willis, S.; Li, G. Tetrahedron Lett. 1998, 39, 8203-
8206.
(23) Adam, W.; Albert, R.; Hasemann, L.; Nava Salgado, V. O.; Nestler,
B.; Peters, E.-M.; Peters, K.; Prechtl, F.; von Schnering, H. G. J. Org. Chem.
1991, 56, 5782-5785.
400
Org. Lett., Vol. 5, No. 4, 2003

of the Petasis reagent and decreasing the concentration and
temperature increased the rates of reaction and improved the
yields for most of these substrates. Neither sonication nor
microwave methods enhanced the yields. As with 2-meth-
yleneoxetanes, the Tebbe reagent provided products, but in
lower isolated yields.
Table 2.a
Initial methylenation studies were conducted with hydro-
cinnamaldehyde-derived lactone 9a. Disappointingly, no
matter how the reaction conditions were modified, the yield
of 11a never exceeded 35%. Careful monitoring of the
reaction never revealed any lactone-related material other
than the reactant and the product. Running the reaction in
the presence of an internal standard (1,3,5-tri-tert-butylben-
zene) demonstrated that the isolated yield was consistent with
the yield based on the internal standard. On the other hand,
lactone 9d, the next lactone prepared, gave high yields. Low
yields were also observed with lactone 9e. It appeared that
steric effects at C4 might be playing a role, with bulkier
substituents at C4 leading to higher yields. In support of this,
lactones 9b, 9c, and 9f all provided higher yields of the
corresponding 3-alkylidene-2-methyleneoxetanes. The reac-
tion of 9i with dimethyltitanocene was problematic. 1H NMR
spectra of reaction mixtures were messy, but showed some
11i; however, product isolation was not successful. We did
not see evidence of allene formation in the 1H NMR spectra.
Other 4-aryl-substituted 3-alkylidene-2-oxetanones would
need to be prepared before generalizations about the meth-
ylenations of these systems could be made.
The difference in stability between 2-methyleneoxetanes
and 3-alkylidene-2-methyleneoxetanes is noteworthy. The
former can be stored in the freezer for extended periods.
3-Alkylidene-2-methyleneoxetanes decompose within days.
Also, there is substantially more product loss with repeated
purification of 3-alkylidene-2-methyleneoxetanes in com-
parison to what was observed with 2-methyleneoxetanes.
We decided to compare the reactivity of 3-alkylidene-2-
methyleneoxetanes with that of 2-methyleneoxetanes. The
enol ether of 11a was oxidized chemoselectively with
DMDO to provide 1,5-dioxaspiro[3.2]hexane 12, as a ∼3:2
mixture of diastereomers, in excellent yield (Scheme 1).
entry
R
% yield of 9
% yield of 10
g
h
i
phenyl
28
34
p-tolyl
(o)-nitrophenyl
46
a See Supporting Information for experimental procedures.
in having 4-aryl-substituted R-methylene-â-lactones as sub-
strates for methylenation and wondered if decarboxylation
could be suppressed.
Cossio and co-workers had reported the results of com-
putational studies on structural and solvent effects on the
mechanism of the thermal decarboxylation of 2-oxetanones.24
Their calculations suggested that π donors at C4 decreased
the activation energy for decarboxylation. Consequently, an
electron-deficient aromatic aldehyde, o-nitrobenzaldehyde,
was employed to prepare acid 8i, which was successfully
converted to R-methylene-â-lactone 9i. Although the yield
of the lactonization was not high, no allene was observed in
1H NMR spectra of the reaction mixture.
Results for the preparation of 3-alkylidene-2-methylene-
oxetanes 11 via the methylenation of lactones 9 are presented
in Table 3. The lactones were dissolved in a solution of
Table 3.a
entry
R
R′
% yield of 11b
a
b
c
d
e
f
PhCH2CH2
Ph2CH
isopropyl
tert-butyl
methyl
H
H
I
35d
55c
70d
I
75b
Scheme 1
Ph
Ph
H
28d
isopropyl
(o)-nitrophenyl
60d
i
see text
a See Supporting Information for experimental procedures. b Isolated,
purified yields. c Petasis (1.5-2 equiv), 0.5 M, 80 °C. d Petasis (4 equiv),
0.25 M, 75 °C.
dimethyltitanocene in toluene and heated under N2 in the
dark until the starting material disappeared. At the beginning
of the investigation, conditions similar to those we employed
to prepare 2-methyleneoxetanes were used.1 However, ox-
etanes 11 are more sensitive and less stable than simple
2-methyleneoxetanes. Increasing the number of equivalents
(24) Morao, I.; Lecea, B.; Arrieta, A.; Cossio, F. J. Am. Chem. Soc. 1997,
119, 816-825.
Org. Lett., Vol. 5, No. 4, 2003
401

Compound 12 was far less stable than any of the 1,5-
dioxaspirohexanes that we previously prepared.3 In the
presence of LDA, 11a was converted to enynol 14 in 56%
yield. Further functionalization of the dianionic intermediate
13 should be possible, as we found for 2-methyleneoxetanes.2
Moreover, enynols are useful synthetic intermediates. For
example, they are direct precursors of highly substituted
furans.25-28
We were interested in the potential of 3-alkylidene-2-
methyleneoxetanes as electron-rich dienes in Diels-Alder
reactions. Experimental evidence and computational studies
suggest that, as the 1,4-distance in outer ring dienes increases,
the Diels-Alder reactivity drops.29,30 Nevertheless, 1,2-
dimethylenecyclobutanes undergo Diels-Alder reactions
with a wide range of dienophiles.31-37 An initial investigation
involved the reaction of 11a with methyl acrylate in the
presence of MgBr2. Allylic bromide 16, presumably arising
from a SN2′-like attack by bromide, was the sole product
observed and isolated. This result could be reproduced by
exposing 11a to magnesium bromide diethyl etherate in
dichloromethane (Scheme 1). The conversion of 11a to 16,
which presumably proceeded through magnesium enolate 15,
offers the potential for tandem reactions that should yield
highly functionalized products that are useful intermediates
for further transformation.
In summary, we have described a general method for the
synthesis of 3-alkylidene-2-methyleneoxetanes 11 by the
methylenation of 3-alkylidene-2-oxetanones 9; these lactones
have been readily prepared from Morita-Baylis-Hillman-
type adducts. Preliminary investigations of the reactivity of
these unusual, strained heterocyclic compounds using 11a
have demonstrated their potential as synthetic scaffolds. The
conversion of electron-rich 3-aryl-2-methylene-3-hydroxy
acids to give electron-rich aryl allenes at room-temperature
represents an unanticipated transformation that may have
synthetic utility.
Acknowledgment. Helpful discussions about the hy-
droalumination procedure with Israel Figueroa are gratefully
acknowledged, as are discussions on the potential Diels-
Alder reactivity of 11 with Prof. Jeff Winkler and Dr.
Sithamalli Chandramouli. We thank Daniel R. Clark for
preliminary studies. This material is based upon work
supported by the National Science Foundation (NSF) under
Grant CHE-0111522. We thank the NSF/REU (CHE-
9732366) Program at the University of Connecticut for
support of J. D. Emch, Bristol-Myers-Squibb for support of
A. E. Andrews via an undergraduate summer fellowship, and
the NIH for a predoctoral fellowship to I. Martinez.
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Supporting Information Available: Experimental details
and characterization data for all compounds reported. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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