Intramolecular [2 + 2] Cycloaddition reactions of alkynyl ether derived ketenes. a convenient synthesis of donor-acceptor cyclobutanes

Article abstract of DOI:10.1021/ol202989c

Mild thermolysis of tert-butyl alkynyl ethers furnishes aldoketenes, which undergo facile [2 + 2] cycloaddition reactions with pendant di- and trisubstituted alkenes. A wide variety of cis-fused cyclobutanones are produced in moderate to high diastereoselectivity and good to excellent yields by this method, and free hydroxyl groups are tolerated in the ene-ynol ether starting materials. Enol-ynol ethers also undergo efficient reaction to produce donor-acceptor cyclobutanes in high yields.

Full text of DOI:10.1021/ol202989c

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6588–6591
Intramolecular [2 þ 2] Cycloaddition
Reactions of Alkynyl Ether Derived
Ketenes. A Convenient Synthesis of
DonorꢀAcceptor Cyclobutanes
Vincent Tran and Thomas G. Minehan*
Department of Chemistry and Biochemistry, California State University,
Northridge 18111 Nordhoff Street, Northridge, California 91330, United States
thomas.minehan@csun.edu
Received November 6, 2011
ABSTRACT
Mild thermolysis of tert-butyl alkynyl ethers furnishes aldoketenes, which undergo facile [2 þ 2] cycloaddition reactions with pendant di- and
trisubstituted alkenes. A wide variety of cis-fused cyclobutanones are produced in moderate to high diastereoselectivity and good to excellent
yields by this method, and free hydroxyl groups are tolerated in the ene-ynol ether starting materials. Enol-ynol ethers also undergo efficient
reaction to produce donorꢀacceptor cyclobutanes in high yields.
Cyclobutanones are useful starting materials for organic
synthesis, since they are an excellent source of cyclopenta-
nones (by one-carbon ring expansion), γ-butyrolactones
(by peracid oxidation), and butyrolactams (by Beckmann
rearrangement), moieties that form the core of numerous
natural products.1 The efficient preparation of substituted
cyclobutanones is thus an important area of current
synthetic methods research.
gives rise to fused cyclobutanones, has been previously
studied by the groups of Marko,3 Snider,4 and Brady.5 The
ketene intermediates utilized for the [2 þ 2] cycloaddition
are most frequently generated from the corresponding acid
chlorides by treatment with NEt3 at elevated temperatures.
The use of moisture-sensitive and/or unstable acid chlo-
rides may constitute a drawback of this method, as well as
the necessity of employing triethylamine at high tempera-
tures for base-sensitive substrates.
Cyclobutanones have been most frequently prepared by
the cycloaddition of ketenes or ketiminium salts with
olefins.2 The intramolecular variant of this process, which
Ynol ethers possess significant potential in organic
chemistry for the formation of carbonꢀcarbon bonds.6,7
The pioneering studies of Ficini8 and Arens9 have shown
(1) (a) Namyslo, J. C.; Kaufman, D. E. Chem. Rev. 2003, 103, 1485.
(b) Fu, N. -Y.; Chan, S. -H. In The Chemistry of Cyclobutanes; Rappoport,
Z., Liebman, J. F., Eds.; J. Wiley & Sons: Chichester, NY, 2005; p 357. (c) For
an elegant application of cylobutanone ring expansion in natural product
synthesis, see: Corey, E. J.; Desai, M. C.; Engler, T. A. J. Am. Chem. Soc.
1985, 107, 4339.
(2) (a) Lee-Ruff, E. In The Chemistry of Cyclobutanes; Rappoport, Z.,
Liebman, J. F., Eds.; J. Wiley & Sons: Chichester, NY, 2005; p 281. (b)
Ghosez, L.; O’Donnell, M. J. Pericyclic Reactions; Marchand, A. P., Lehr,
R. E., Eds.; Academic Press: New York, 1977; Vol. II, p 79. (c) Ghosez, L.;
Marchand-Brynaert, J. Iminium Salts in Organic Chemistry Part 1;
Bohme, J., Viehe, H. G., Eds.; Wiley: New York, 1976; p 421. (d) Falmagne,
J. B.; Escudero, J.; Taleb-Sahraoui, S.; Ghosez, L. Angew. Chem., Int.
Ed. Engl. 1981, 20, 879. (e) Snider, B. B. Chem. Rev. 1988, 88, 793.
(3) Marko, I.; Ronsmans, B.; Hesbain-Frisque, A.-M.; Dumas, S.;
Ghosez, L. J. Am. Chem. Soc. 1985, 107, 2192.
(4) (a) Snider, B. B.; Hui, R. A. H. F.; Kulkarni, Y. S. J. Am. Chem.
Soc. 1985, 107, 2194. (b) Lee, S. Y.; Kulkarni, Y. S.; Burbaum, B. W.;
Johnston, M. I.; Snider, B. B. J. Org. Chem. 1988, 53, 1848.
(5) Brady, W. T.; Giang, Y. F. J. Org. Chem. 1985, 50, 5177.
(6) For reviews of the chemistry of ynol ethers and the methods for
the synthesis of ynol ethers, see: (a) Brandsma, L.; Bos, H. J.; Arens, J. F.
In The Chemistry of Acetylenes; Viehe, H. G., Ed.; Marcel Dekker:
New York, 1969; pp 751ꢀ860. (b) Stang, P. J.; Zhdankin, V. V. In The
Chemistry of Triple-Bonded Functional Groups; Patai, S., Ed.; John Wiley
& Sons: New York, 1994; Chapter 19.
r
10.1021/ol202989c
Published on Web 11/21/2011
2011 American Chemical Society

that ethoxyacetylenes extrude ethylene gas at temperatures
in excess of 100 °C, and the resulting ketenes undergo
dimerization reactions or can be trapped by nucleophiles
to form carboxylic acid derivatives. Significantly, tert-
butyl alkynyl ethers undergo the retro-ene reaction with
liberation of isobutylene gas at much lower temperatures
(>50 °C),6a and this process has been utilized recently
by MaGee,10 Magriotis,11 Funk,12 and Danheiser13 for the
preparation of lactones, lactams, amides, and cyclic im-
ides. We were interested in exploring the utility of tert-butyl
alkynyl ethers as ketene precursors for [2 þ 2] cycloaddi-
tion reactions with alkenes, and in this Letter we report
the successful application of this strategy to the synthesis
of diverse cyclobutanones.
Following the protocol of Danheiser et al.,13 treatment
of 1,2-dichlorovinyl tert-butyl ether 1 (Scheme 1) with 2.0
equiv of n-BuLi in THF at ꢀ78 °C, followed by addition of
hexanal and warming to room temperature, furnished
alkynyl ether 2a in 78% yield. Reaction of 2a with methal-
lyl mesylate in the presence of sodium hydride (THF,
0 °Cfrt) then provided enyne test substrate 3a in 95%
yield. Heating a 0.01 M toluene solution of 3a for 2 h at
90 °C under argon led to the production of cyclobutanone
4a in 85% yield as a 3:1 mixture of diastereomers. It should
benoted that attempting thisprocessusingthe correspond-
ing ethyl alkynyl ether (prepared from commercially avail-
able ethoxyacetylene), which required heating the substrate
in excess of 120 °C to achieve starting material conversion,
led to none of the desired cyclobutanones 4, furnishing
instead a complex mixture of UV-active products.
1ꢀ3 h. A variety of cyclobutanone-fused carbo- and
heterocyclic ring systems were formed in good to excellent
yields, and high diastereoselectivities were obtained for
substrates bearing sterically demanding X-substituents
(such as i-Pr and t-Bu, entries 3ꢀ5). Interestingly, the
lowest diastereoselectivities (∼1:1) were observed for sub-
strates possessing silyl ether groups at C.5 (entries 6 and 7).
Crosspeaks observed in the NOESY spectrum of cyclobu-
tanone 4b (Figure 1 and Supporting Information) indicate
that the major diastereomer formed in these reactions
possesses the 2,3-syn, 2,5-syn stereochemistry, in accord
with literature precedent for similar ketene-olefin cyclo-
additions.14 The observed stereochemistry likely arises
from a substrate conformer in which the C.5 substituent
adopts a pseudoequatorial position in the transition state
for [2 þ 2] cycloaddition.
Table 1. Scope of the Thermal Retro-ene/[2 þ 2] Cycloaddition
Reaction of Ene-Ynol Ethers 3a
% yieldb
entry
X
Y
Z
3
4
d.r.
3:1
1
2
3
4
5
6
7
CH3(CH2)4
CH2Ph
O
CH3
CH3
CH3
CH3
CH3
CH3
Ph
a
b
c
85
90
78
64
92
60
81
O
4:1
(CH3)2CH
(CH3)3C
(CH3)3C
OTIPS
O
>95:5
>95:5
>95:5c
1.2:1
1.2:1
O
d
e
f
NTs
CH2
CH2
Scheme 1. Synthesis of Ene-Ynol Ether 3a and Thermal Trans-
formation to Cyclobutanone 4a
OTBDPS
g
a Representative conditions for the transformation 3f4: toluene
(0.01 M), 2.5 h, 90 °C. b Isolated yield after chromatographic purification.
c NOESY data for 4e indicate that the major diastereomer possesses the 2,
3-syn, 2,5-anti stereochemistry (see Supporting Information).
To explore the scope of this process, substrates 3bꢀ3g
(Table 1) were prepared in a similar fashion (see Support-
ing Information) and subjected to heating in toluene for
(7) (a) Tudjarian, A. A.; Minehan, T. G. J. Org. Chem. 2011, 76, 3576.
(b) Sosa, J. R.; Tudjarian, A. A.; Minehan, T. G. Org. Lett. 2008, 10,
5091. (c) Christopher, A.; Brandes, D.; Kelly, S.; Minehan, T. G. Org.
Lett. 2006, 8, 451.
Figure 1. Proposed mechanistic model and stereochemical as-
signment of major diastereomer 4b based on correlations ob-
served in its NOESY spectrum.
(8) Ficini, J. Bull. Soc. Chim. Fr. 1954, 1367.
(9) (a) Nieuwenhuis, J.; Arens, J. F. Recl. Trav. Chim. Pays-Bas 1958,
77, 761. (b) van Daalen, J. J.; Kraak, A.; Arens, J. F. Recl. Trav. Chim.
Pays-Bas 1961, 80, 810.
(10) (a) Liang, L.; Ramaseshan, M.; MaGee, D. I. Tetrahedron 1993,
49, 2159. (b) MaGee, D. I.; Ramaseshan, M. Synlett 1994, 743. (c)
MaGee, D. I.; Ramaseshan, M.; Leach, J. D. Can. J. Chem. 1995, 73,
2111.
(11) Magriotis, P. A.; Vourloumis, D.; Scott, M. E.; Tarli, A. Tetra-
hedron Lett. 1993, 34, 2071.
(12) Funk, R. L.; Abelman, M. M.; Jellison, K. M. Synlett 1989, 36.
(13) Mak, X. Y.; Ciccolini, R. P.; Robinson, J. M.; Tester, J. W.;
Danheiser, R. L. J. Org. Chem. 2009, 74, 9381.
During our studies we discovered that employing aro-
matic aldehydes for the generation of enyne substrates in
the above protocol proved troublesome. While addition of
tert-butoxyethynyllithium to benzaldehyde proceeded un-
eventfully, all attempts to install the methallyl ether moiety
by base-promoted SN2 reaction led to extensive substrate
(14) Mori, K.; Masahiro, M. Tetrahedron 1987, 10, 2229.
Org. Lett., Vol. 13, No. 24, 2011
6589

decomposition (Scheme 2). Furthermore, silylation (TBS-
Cl, imid, DMF; TBS-Cl, Et3N, DMAP; TBS-Cl, Li2S,16
CH3CN) or acylation (Ac2O, Pyr) of such benzylic pro-
pargylic alcohols under mildly basic conditions led only to
low yields (<10%) of product; acid-catalyzed processes
(DHP, cat. PPTS) afforded R,β-unsaturated esters arising
from the well-known MeyerꢀSchuster rearrangement.15
Ultimately it was found that enyne alcohol 2h could be
protected as its ethoxymethyl acetal in high yield by
treatment with chloromethyl ethyl ether and excess DIEA
in CH2Cl2 at room temperature for 2 h. The obtained
acetal (3h) was a suitable substrate for the retro-ene/
cycloaddition reaction, giving rise to cyclobutanone 4h
(R = CH2OEt) in 70% yield and 2:1 diastereoselectivity
upon heating at 90 °C in toluene for 2 h. Interestingly, it
was also found that heating unprotected benzylic alcohol
2h under our standard conditions gave rise to cyclobuta-
none 4h (R = H) in 45% yield but with >20:1 diastereos-
electivity. The dramatically increased stereoselectivity for
this substrate relative to enynes bearing protected alcohols
(3h, 3f, and 3g) is perhaps indicative of the existence of an
interaction between the hydroxyl proton and the π-system
of either the ketene or alkene in the transition state for [2þ 2]
cycloaddition. The successful cyclization of a substrate
bearing an unprotected alcohol represents an advantage of
this method over other procedures for ketene generation
involving acid chlorides, since clearly unprotected alcohols
in such substrates would be highly prone to inter-/intra-
molecular esterification reactions under basic conditions.
Efforts to improve the yield of cyclobutanone formation
for enynes bearing unprotected alcohols are underway,
as well as an analysis of the scope and origins of the
high stereoselectivity of this process. In line with Marko’s
observation3 that increasing the tether length between alkene
and ketene suppresses cycloaddition, thermolysis of the
homologous ene-ynol ether 3i17 under our standard condi-
tions gave negligible amounts of cyclobutanone products.
To broaden the substrate scope of this process, alter-
native approaches to the enyne cyclization substrates were
next investigated. The nucleophilic substitution reaction of
appropriate alkyl halides with tert-butoxyethynyllithium
in THF/HMPA18 furnished enynes 3j and 3m. Reaction of
1 with n-BuLi, followed by treatment with excess paraf-
ormaldehyde, gives rise to 3-tert-butoxyprop-2-yn-1-ol,
which was not purified but rather directly combined with
appropriate allylic methanesulfonates under basic condi-
tions to give rise to enynes 3kꢀl and 3nꢀo (Scheme 3).
As can be seen in Table 2, whereas enyne substrate 3j
bearing a floppy carbon tether between the alkynyl ether
and alkene moieties gave negligible amounts of 4j under
standard reaction conditions (entry 1), substrates with
tethers containing an oxygen atom (3k, 3l, 3n, 3o, entries
2, 3, 5, 6) or unsaturated carbon atoms (3m, entry 4) gave
good yields of cyclobutanone products. The use of trisub-
Scheme 3. Methods for the Preparation of Enynes 3jꢀ3o
Table 2. Thermal Retro-ene/[2 þ 2] Cycloaddition Reaction of
Substrates 3jꢀ3oa
Scheme 2. Employing Protected and Unprotected Benzylic Al-
cohols in the Cyclization Process
a Representative conditions for the transformation 3f4: toluene
(0.01 M), 2.5 h, 90 °C. b Isolated yield after chromatographic purification.
c The low isolated yields are due to the high volatility of cyclobutanone 4k.
(15) For a recent review of the MeyerꢀSchuster rearrangement, see:
Engel, D. A.; Dudley, G. B. Org. Biomol. Chem. 2009, 7, 4149.
6590
Org. Lett., Vol. 13, No. 24, 2011

and 4t, which is likely due to the decreased steric require-
ments of the ether substituent in the transition state for [2 þ 2]
cycloaddition. Again, the NOESY spectrum of cycload-
duct 4p confirmed the 2,3-syn, 2,5-syn stereochemistry for
these substrates. Although cyclobutanones 4pꢀt proved
to be quite sensitive to Bronsted and Lewis acids,20 com-
pound 4q could be smoothly transformed into lactone 5q
in 92% yield by an MCPBA-mediated BaeyerꢀVilliger
reaction (Scheme 4).
Table 3. Thermal Retro-ene/[2 þ 2] Cycloaddition Reaction of
Ynol-Enol Ethers 3pꢀ3t
In summary, we have shown that ynol ether-alkenes and
enol-ynol ethers produce the corresponding cyclobuta-
nones under mild, neutral conditions in good to excellent
yields and diastereoselectivities. Notably, substrates bear-
ing unprotected hydroxyl groups are also tolerated in this
protocol. Investigation of the Lewis acid promoted cyclo-
addition and ring expansion reactions of the donorꢀacceptor
cyclobutanes available by this protocol is currently under-
way and will be reported in due course.
Scheme 4. BaeyerꢀVilliger Oxidation of 4q
a Representative conditions for the transformation 3f4: toluene
(0.01 M), 2.5 h, 90 °C. b Isolated yield after chromatographic puri-
fication.
stituted alkenes is also well tolerated, allowing the pre-
paration of fused tricyclic compounds 4n and 4o.
Acknowledgment. We thank the National Institutes of
Health (SC3 GM096899-01) and the Henry Dreyfus Teacher-
Scholar Award for their generous support of our research
program.
Finally, we wished to examine the feasibility of prepar-
ing donorꢀacceptor cyclobutanes utilizing this protocol.
Substrate ynol-enol ethers 3pꢀ3t were prepared19 by the
above-mentioned protocols (see Supporting Information)
and heated in toluene solution at 90 °C for 2 h to provide
cyclobutanones 4pꢀ4t cleanly and in high yields (Table 3).
In comparison to the methyl-substituted cyclobutanones
4b, 4d, and 4h, slightly diminished diastereoselectivities
were observed in the formation of cyclobutanones 4p, 4q,
Supporting Information Available. Experimentaldetails,
characterization data, 1H, 13C spectra of all products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(18) Moyano, A.; Charbonnier, F.; Greene, A. E. J. Org. Chem. 1987,
52, 2919.
(16) Olah, G. A.; Gupta, B. G. B.; Narang, S. C.; Malhotra, R. J.
Org. Chem. 1979, 44, 4272.
(19) The alkylating agent 3-bromo-2-(ethoxymethoxy)prop-1-ene used
for the preparation of 3pꢀr was synthesized from 1,3-dibromo-2-propanol.
See: Dhanjee, H.; Minehan, T. G. Tetrahedron Lett. 2010, 51, 5609.
(20) Matsuo has demonstrated Lewis acid promoted formal [4 þ 2]
cycloaddition reactions between 3-alkoxycyclobutanones and alde-
hydes, ketones, allylsilanes, and silylenol ethers: (a) Matsuo, J. -i.;
Sasaki, S.; Hoshikawa, T.; Ishibashi, H. Org. Lett. 2009, 11, 3822. (b)
Matsuo, J.-i.; Negishi, S.; Ishibashi, H. Tetrahedron. Lett. 2009, 50,
5831. (c) Matsuo, J.-i.; Sasaki, S.; Tanaka, H.; Ishibashi, H. J. Am.
Chem. Soc. 2008, 130, 11600.
(17) Compound 3i was prepared in four steps from commercially
available 2-bromobenzaldehyde diethyl acetal by copper-catalyzed al-
lylation of the corresponding Grignard reagent (Mg, THF; cat. CuI,
methallyl mesylate), hydrolysis of the diethyl acetal (acetone, cat.
TsOH), addition of tert-butoxyethynyllithium (THF, ꢀ78 °C), and
protection of the benzylic alcohol as its ethoxymethyl acetal (EtOCH2Cl,
DIEA, 2 h, rt). See: Lin, S.; Song, C.-X.; Cai, G. -X.; Wang, W. -H.; Shi,
Z. -J. J. Am. Chem. Soc. 2008, 130, 12901.
Org. Lett., Vol. 13, No. 24, 2011
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