Oxetan-3-ones from allenes via spirodiepoxides

Article abstract of DOI:10.1021/ol400749e

Two concise methods for generating oxetan-3-ones from allenes are reported. The first method employs allene epoxidation, opening of the spirodiepoxide by a halide nucleophile, and then intramolecular displacement of a halide by an alkoxide. The second method involves allene epoxidation and then thermal rearrangement of the corresponding spirodiepoxide to oxetan-3-one. The two methods are complementary and stereochemically divergent. Computational analysis of the thermal rearrangement is also described.

Full text of DOI:10.1021/ol400749e

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2202–2205
Oxetan-3-ones from Allenes via
Spirodiepoxides
Rojita Sharma and Lawrence J. Williams*
Department of Chemistry and Chemical Biology, Rutgers, The State University of
New Jersey, Piscataway, New Jersey 08854, United States
lawjw@rci.rutgers.edu
Received March 21, 2013
ABSTRACT
Two concise methods for generating oxetan-3-ones from allenes are reported. The first method employs allene epoxidation, opening of the
spirodiepoxide by a halide nucleophile, and then intramolecular displacement of a halide by an alkoxide. The second method involves allene
epoxidation and then thermal rearrangement of the corresponding spirodiepoxide to oxetan-3-one. The two methods are complementary and
stereochemically divergent. Computational analysis of the thermal rearrangement is also described.
Oxetane containing compounds have many uses in syn-
thetic and medicinal chemistry. Recently, Carreira and co-
workers have used the oxetane moiety as a gem-dimethyl
variant and to influence solubility, lipophilicity, metabolic
stability, and molecular conformation.1,2 Oxetan-3-ones are
also useful in synthesis and drug discovery and can serve as
precursors to oxetanes, as well as 3-aminooxetanes, oxeta-
nocins, and other oxetane derivatives.3 Steroids containing
oxetan-3-ones have demonstrated antiinflammatory and
antiglucocorticoid activities.4,5 Owing to the considerable
diversity of possible oxetan-3-one structural variants, new
methods for the synthesis of these heterocycles are highly
desirable. Routes to specific oxetanone targets and a limited
number of methods for oxetanone synthesis are known.3c,6
For example the recently described gold catalyzed oxidative
cyclization of propargyl alcohols developed by Zhang is a
marked advance over previous multistep routes.6n Never-
theless, tetra- and trisubstituted oxetan-3-ones that do not
bear electron-withdrawing groups adjacent to the hetero-
cycle are still difficult to access directly. We recognized that
oxetan-3-ones and spirodiepoxides are isomers and there is
the potential to use this precursor to access oxetan-3-ones.
Two new methods that complement existing synthetic
methods for this heterocycle are described below.
Allene double epoxidation gives spirodiepoxides. These
synthetically useful intermediates allow direct entry to
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r
10.1021/ol400749e
Published on Web 04/25/2013
2013 American Chemical Society

diverse motifs.7 Although only one instance of the thermal
rearrangement of this species to oxetan-3-ones has been
described (by flash vacuum pyrolysis), oxetan-3-ones are
commonly observed as byproducts of spirodiepoxide de-
composition in acid.7d,8 For example, we reported that
epoxidation of bisallene I followed by exposure to lithium
methylcyanocuprate gave oxetan-3-one III as a byproduct
(Scheme 1).7d
effective for other substrates and often favored the hydro-
xyketone product. The ready loss of iodide from R-iodo-
ketones is well-known.9 Consequently, we turned to bromide
and identified a simple, efficient, and reliable procedure for
oxetan-3-one synthesis under mild conditions. Dissolution of
the spirodiepoxide in tetrahydrofuran followed by addition
of lithium bromide, replacement of the solvent with methyl
sulfoxide, and then exposure to potassium hydroxide gave
the oxetan-3-one (2) in excellent yield (92%, Scheme 2,
condition B).
We have reported the synthesis of R-hydroxy-R0-haloke-
tones from spirodiepoxides.7a It seemed reasonable that
under similar reaction conditions the nascent alkoxide
Scheme 2. Iodide Induced Oxetan-3-one Synthesis
Scheme 1. Oxetan-3-one Formation from Spirodiepoxide
could be induced to displace the halide in situ and thereby
form the oxetan-3-one.
We initially evaluated iodide (Scheme 2). Allene 1 was
exposed to dimethyldioxirane (DMDO), and then the
crude spirodiepoxide was taken up in acetonitrile. Subse-
quent addition of sodium iodide gave three products: the
desired oxetan-3-one 2, the R-hydroxy-R0-iodoketone 3,
and the R-hydroxylketone 4. Lithium iodide gave iodohy-
droxylketone 3 as the sole product in good yield. The
addition of HMPA to the lithium iodide reaction mixture
gave the oxetan-3-one 2 (Scheme 2, condition A), as
desired; however, these conditions were not generally
We used this method to convert several allenes to oxetan-
3-ones as shown in Table 1. For simple trisubstituted allenes
the yields were excellent (Table 1, entries 1ꢀ4). However,
for more complex trisubstituted allenes the yields were
modest (Table1, entries 5ꢀ7). Importantly, the ratios of
spirodiepoxide precursors and oxetan-3-one products were
identical. The major byproduct was the simple hydroxyke-
tone. Evidently, debromination competes with cyclization
in some substrates.
(7) (a) Sharma, R.; Manpadi, M.; Zhang, Y.; Kim, H.; Ahkmedov,
N. G.; Williams, L. J. Org. Lett. 2011, 13, 3352–3355. (b) Joyasawal, S.;
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988–991. (c) Zhang, Y.; Cusick, J. R.; Shangguan, N.; Katukojvala, S.;
Inghrim, J.; Emge, T. J.; Williams, L. J. J. Org. Chem. 2009, 74, 7707–
7714. (d) Ghosh, P.; Zhang, Y.; Emge, T. J.; Williams, L. J. Org. Lett.
2009, 11, 4402–4405. (e) Ghosh, P.; Cusick, J. R.; Inghrim, J.; Williams,
L. J. Org. Lett. 2009, 11, 4672–4675. (f) Wang, Z. H.; Shangguan, N.;
Cusick, J. R.; Williams, L. J. Synlett 2008, 2, 213–216. (g) Ghosh, P.;
Lotesta, S. D.; Williams, L. J. J. Am. Chem. Soc. 2007, 129, 2438–2439.
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1096. (i) Lotesta, S. D.; Kiren, S. K.; Sauers, R. R.; Williams, L. J.
Angew. Chem., Int. Ed. 2007, 46, 7108–7111. (j) Lotesta, S. D.; Hou, Y.;
Williams, L. J. Org. Lett. 2007, 9, 869–872. (k) Katukojvala, S.; Barlett,
K. N.; Lotesta, S. D.; Williams, L. J. J. Am. Chem. Soc. 2004, 126,
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Table 1. Bromide Induced Oxetan-3-one Synthesisa
(8) (a) Crandall, J. K.; Machleder, W. H. Tetrahedron Lett. 1966, 7,
6037–6041. (b) Crandall, J. K.; Machleder, W. H.; Thomas, M. J. J. Am.
Chem. Soc. 1968, 90, 7292–7296. (c) Crandall, J. K.; Conover, W. W.;
Komin, J. B.; Machleder, W. H. J. Org. Chem. 1974, 39, 1723–1729. (d)
2-Methylocta-2,3-diene was converted to the oxetan-3-one after epox-
idation and then flash vacuumpyrolysis. See: Crandall, J. K.; Batal, D. J.
J. Org. Chem. 1988, 53, 1338–1340. (e) Crandall, J. K.; Batal, D. J.;
Sebesta, D. P.; Lin, F. J. Org. Chem. 1991, 56, 1153–1166. (f) Crandall,
J. K.; Batal, D. J.; Lin, F.; Reix, T.; Nadol, G. S.; Ng, R. A. Tetrahedron
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3651. (b) Townsend, J. M.; Spencer, T. A. Tetrahedron Lett. 1971, 2,
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406–407.
a Conditions: DMDO (2.5 equiv), CHCl3, ꢀ20 °C, 1ꢀ2 h; LiBr (1.1
equiv), THF, 0 °C to rt, 1ꢀ3 h; KOH (1.10 equiv), DMSO, 5ꢀ10 min.
Org. Lett., Vol. 15, No. 9, 2013
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We also recognized that thermal rearrangement of the
spirodiepoxide to the isomeric oxetanone represented an
alternative approach. Spirodiepoxides have good kinetic
stability in nonacidic conditions; they can be prepared in
multigram scale, manipulated, and used without purifi-
cation.7 The data in Tables 2 and 3 demonstrate that these
epoxides also have good stability to increased temperature.
Initially, hot toluene (∼100 °C) was used to effect rearran-
gement. For other substrates, higher temperatures were
required and refluxing p-xylene worked well.10 Further
investigations demonstrated that microwave heating of
spirodiepoxides at 200 °C effected their smooth and effi-
cient rearrangement tooxetan-3-ones. This transformation
was general for a range of allenes including tetrasubstituted
(Table 2, entry 1), trisubstituted (Table 2, entries 2ꢀ5 and 8),
and disubstituted (Table 2, entries 6 and 7) substrates. The
moderate yield reported in Table 2, entry 1 is due to the
high volatilities of the intermediate tetramethyl spirodiep-
oxide and the oxetan-3-one product. The diastereomeric
ratio ofallene epoxidation matchedthe ratio ofoxetanones
obtained (Table 2, entries 6 and 7). The stereochemical
fidelity of the transformation suggests that rearrangement
is concerted. A more complete mechanistic discussion is
put forth below. The stereochemical assignments for the
products in Table 2, entries 7 and 8 were based by analogy
on findings for Table 2, entry 6. The assignment of entry 6
the cis isomer as shown, with the products of reduction
corresponding to the cis and trans alcohols (3.5:1). The
minor oxetan-3-one must be the trans isomer; reduction of
this compound can give only a single alcohol, since the
hydroxyl-bearing carbon is not stereogenic.
Scheme 3. Proof of Stereochemical Assignment
Spirodiepoxides derived from terminal allenes are parti-
cularly sensitive to manipulation, presumably due to the
high accessibility of one of the reactive termini. Pleasingly,
thermal rearrangement of these substrates was efficient
(Table 3). Both acyclic and cyclic 1,1-disubstituted allene
substrates were smoothly transformed to the correspond-
ing terminal oxetan-3-ones (Table 3, entries 1 and 2), as
were monosubstituted allenes (Table 3, entries 3 and 4).
Indeed, the method summarized in Tables 2 and 3 provides
a simple, single-flask procedure for the conversion of
allenes to these functionalized heterocycles.
Table 2. Oxetan-3-one Synthesis by Thermal Rearrangementa
What are the stereochemical consequences of oxetan-3-
one formation for these two methods? We reasoned that in
the halide-induced method the spirodiepoxide is opened by
a halide at the least substituted terminus with inversion
at that substituted carbon (Scheme 4, top, IVfV). The
bromide is then displaced by the alkoxide, and this
same center is inverted again with overall retention (VfVI).
Based on the stereochemical fidelity, we suggest that the
thermal rearrangement method is a concerted, asynchronous
one-step process. This pathway is expected to proceed with
inversion of configuration on the carbon atom most able to
stabilize the anticipated partial positive charge developed in
Table 3. Terminal Oxetan-3-one Synthesis by Thermal
Rearrangementa
a Conditions: 2.50 equiv of DMDO, CHCl3, ꢀ20 °C, 1ꢀ2 h; concd,
PhMe, 200 °C, 1ꢀ1.5 h.
was determined unambiguously by reduction of the ketone
(Scheme 3). Exposure of the major oxetan-3-one, 5,tosodium
borohydride gave two isomeric alcohols, 6 and 7, whereas the
minor oxetan-3-one, 8, gave a single isomer 9. These results
are uniquely interpretable. The major oxetan-3-one must be
(10) In refluxing toluene, many spirodiepoxides failed to rearrange
and only slow decomposition was noted after extended reaction times.
See also ref 8f. High quality DMDO is especially important in the
thermal rearragement reaction; see Supporting Information in ref 7i for
DMDO preparation.
a Conditions: 2.50 equiv of DMDO, CHCl3, ꢀ20 °C, 1ꢀ2 h; concd,
PhMe, 200 °C, 1ꢀ1.5 h.
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Org. Lett., Vol. 15, No. 9, 2013

Scheme 4. Mechanistic Framework
Figure 1. Computed concerted, nonsynchronous thermal rear-
rangement of spirodiepoxides to oxetan-3-ones. (All distances given
˚
in A, differentials between starting material ground and transition
state atomic distances given as Δ, energies given in kcal/mol.)14
two methods are highly complementary, as either diastereo-
meric oxetan-3-one can be prepared as the major product.11
We evaluated the thermal rearrangement computation-
ally (Figure 1). Consistent with the experimental findings
thermal rearrangement was found to be concerted and
asynchronous. A single barrier separates the starting ma-
terial from product, and the reaction is highly exothermic.
Key bond lengths of the computed transition structure
(IX‡) are indicated.12 As the transition structure is ap-
proached, C1ꢀO1 elongates, O1ꢀC2 contracts, C2ꢀO2
elongates, and O2ꢀC1 contracts. Importantly, the C1ꢀO1
the contraction between O2 and C1, indicative of a sig-
nificant charge buildup on C1.13 This insight supports the
above rationale and is consistent with the stereochemical
data and mechanistic framework outlined in Scheme 4.
Insummary, we have reportedtwo methodsof oxetan-3-
one synthesis and have described key stereochemical and
mechanistic features of these new reactions. Oxetan-3-ones
can be accessed in one or two steps from allenes, which are
readily prepared from commercial reagents. The methods
allow access to structure types that are problematical for
other procedures and thus complement previous methods
of oxetanone synthesis.
the transition structure. Taken together, the first method
should engage the less substituted terminus of the epoxide,
the second method should engage the more substituted
terminus, and these methods should lead to divergent stereo-
chemical outcomes.
These predictions are consistent with experimental find-
ings (Scheme 4, bottom). Spirodiepoxides derived from
enantioenriched allene 10 gave oxetan-3-one 11 and di-
astereomeric oxetan-3-one 12 as the major and minor
products, respectively. In contrast, the major product of
thermal rearrangement was the antipode of 12, and the
minor rearrangement product was the antipode of 11. The
˚
bond distance increases by 0.649 A without compensating
(11) The first epoxidation of an allene effectively sets the absolute
configuration of the SDE, as it converts the chiral axis to center chirality.
The second epoxidation determines the diastereomeric ratio within that
enantiomeric series. In the halide-induced method, both configurations
are retained. In the thermal rearrangment the center that sets the
absolute configuration is inverted, reversing the enantiomeric series.
This is the only center that is inverted; consequently, the diastereotopi-
city is also reversed relative to the halide-based method.
(12) See Supporting Information for the full structural details of
these calculations.
(13) (a) The frequency calculation of the transition structure revealed
a vibrational mode similar to a vibrational mode in the SDE starting
material. This relationship suggests a vibrational pathway that enables
the concerted process. See: (b) Ess, D. H.; Houk, K. N. J. Am. Chem.
Soc. 2007, 129, 10646. (c) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc.
2008, 130, 10187. (d) Kolakowski, R. V.; Williams, L. J. Nat. Chemistry
2010, 2, 303 and references cited therein.
(14) (a) Electronic structure calculations were performed and opti-
mized using DFT (B3LYP) and the G631* basis set: (a) Gaussian 03
(revision B.02): Frisch, M. J.; et al. ; see the Supporting Information.
B3LYP functional: (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (c)
Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. 6-31g(d,p)
basis sets: (d) Clark, T.; Chandrasekhar, J.; Spitznagel, G. W.; Schleyer,
P. v. R. J. Comput. Chem. 1983, 4, 294. (e) McLean, A. D.; Chandler,
G. S. J. Chem. Phys. 1980, 72, 5639. (f) Krishnan, R.; Binkley, J. S.;
Seeger, R.; Pople, J. A. J. Chem. Phys. 1980, 72, 650. (g) Hariharan,
P. C.; Pople, J. A. Mol. Phys. 1974, 27, 209. (h) Ditchfield, R.; Hehre,
W. J.; Pople, J. A. J. Chem. Phys. 1971, 54, 721. CPCM: (i) Cossi, M.;
Barone, V. J. Phys. Chem. A 1998, 102, 1995.
Acknowledgment. Financial support from the NIH
(GM078145) and preliminary studies by Dr. Yue Zhang
(Rutgers University).
Supporting Information Available. Synthetic methods,
compound characterization data, energies and coordinates
for computed structures, and the full citation for ref 14a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 9, 2013
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