Origins of stereoselectivity in the oxido-alkylidenation of alkynes

Article abstract of DOI:10.1021/ol8019154

(Chemical Equation Presented) A mild, convenient oxido-alkylidenation of alkynes is described. The three-step sequence involves the 1,3-dipolar cycloaddition of a nitrone and an alkynoate, oxidation of the resulting isoxazoline, and stereoselective extrusion of nitrosomethane. Quantum mechanical calculations identified the interactions of R₃ with the oxidant and the preferred conformation of a diradical intermediate as major factors controlling the stereoselectivity of the oxidation and torquoselectivity of the extrusion.

Full text of DOI:10.1021/ol8019154

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4597-4600
Origins of Stereoselectivity in the
Oxido-Alkylidenation of Alkynes
Daniel P. Canterbury,† Alison J. Frontier,*,† Joann M. Um,‡ Paul H.-Y. Cheong,‡
Dahlia A. Goldfeld,‡ Richard A. Huhn,‡ and K. N. Houk*,‡
Department of Chemistry, UniVersity of Rochester, Rochester, New York, 14627-0216,
and Department of Chemistry and Biochemistry, UniVersity of California,
Los Angeles, California 90095-1569
frontier@chem.rochester.edu; houk@chem.ucla.edu
Received August 15, 2008
ABSTRACT
A mild, convenient oxido-alkylidenation of alkynes is described. The three-step sequence involves the 1,3-dipolar cycloaddition of a nitrone
and an alkynoate, oxidation of the resulting isoxazoline, and stereoselective extrusion of nitrosomethane. Quantum mechanical calculations
identified the interactions of R3 with the oxidant and the preferred conformation of a diradical intermediate as major factors controlling the
stereoselectivity of the oxidation and torquoselectivity of the extrusion.
We report the origins of selectivity in the oxido-alkylidenation
of alkynes involving a reaction sequence which exploits a
regioselective 1,3-dipolar cycloaddition, stereoselective N-
oxidation, and spontaneous torquoselective cheletropic extrusion
(Scheme 1). The sequence provides a facile entry to the
preparation of alkylidene ꢀ-ketoesters, which prove to be useful
precursors to the divinyl ketones of value in the Nazarov
cyclization.1 Padwa first reported examples of these reactions
but did not provide unequivocal evidence for the alkene
geometries or a rationale for the origins of selectivity.2
nitrones react with highly HOMO-LUMO-controlled regi-
oselectivity3 to give isoxazoline intermediate 1. Upon
treatment with m-CPBA, the ring nitrogen of 1 is thought to
undergo oxidation to give intermediate 2, which cannot be
isolated or even observed by NMR spectroscopy. Instead,
immediate cheletropic extrusion of nitrosomethane occurs
at low temperature to yield trisubstituted alkenes 3 and 4 in
high yield (Table 1). Assignment of E and Z isomers was
3
accomplished by analysis of JC,H coupling constants. For
most substrates, the extrusion was highly stereoselective,
favoring alkene diastereomer 3 (termed the “in” isomer
because the torquoselective rotation of R3 occurs in an
“inward” fashion, Scheme 2). In a few cases, alkene 4 (the
“out” isomer) dominated (entries 9-12). We and others have
shown that stereoelectronic effects control the torquoselec-
We have now found that a variety of propiolates and
† University of Rochester.
‡ University of California.
(1) (a) He, W.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2003, 125,
14278 Correction: J. Am. Chem. Soc. 2004, 126, 10493. (b) Malona, J. A.;
Colbourne, J. M.; Frontier, A. J. Org. Lett. 2006, 8, 5661. (c) He, W.;
Herrick, I. R.; Atesin, T. A.; Caruana, P. A.; Kellenberger, C. A.; Frontier,
A. J. J. Am. Chem. Soc. 2008, 130, 1003.
(3) (a) Houk, K. N.; Sims, J.; Duke, R. E.; Strozier, R. W.; George,
J. K. J. Am. Chem. Soc. 1973, 95, 7287. (b) Houk, K. N.; Sims, J.; Watts,
C. R.; Luskus, L. J. J. Am. Chem. Soc. 1973, 95, 7301. (c) Sims, J.; Houk,
K. N. J. Am. Chem. Soc. 1973, 95, 5798.
(2) (a) Padwa, A.; Kline, D. N.; Perumattam, J. Tetrahedron Lett. 1987,
28, 913. (b) Padwa, A.; Chiacchio, U.; Kline, D. N.; Perumattam, J. J. Org.
Chem. 1988, 58, 2238.
10.1021/ol8019154 CCC: $40.75
Published on Web 09/18/2008
2008 American Chemical Society

Scheme 1
Scheme 2. Extrusion of Diastereomeric Isoxazoline N-Oxides
saddle points by vibrational frequency analysis. All free
energies are reported in kcal·mol-1.
Table 1. Oxido-Alkylidenation Resultsa
Performic acid was used to model the oxidant and
isoxazoline 1a (Scheme 3) was used to model Table 1, entry
4 as a typical “in”-yielding isoxazoline. Although isoxazoline
conformation 1a-trans is more stable than 1a-cis, oxidation
of 1a is selective for N-oxide diastereomer 2a-cis due to an
unfavorable interaction between the oxidant and phenyl π
system in TS1a-trans.
The decomposition of intermediate 2 can occur via a
concerted or stepwise sequence (Scheme 4). The barrier for
the concerted pathway was calculated to be 6 kcal·mol-1
higher than that of the stepwise. Reactions that preferentially
(4) Electrocyclic reactions: (a) Rondan, N. G.; Houk, K. N. J. Am. Chem.
Soc. 1985, 107, 2099. (b) Evanseck, J. D.; Thomas, B. E., IV; Spellmeyer,
D. C.; Houk, K. N. J. Org. Chem. 1995, 60, 7134. (c) Dolbier, W. R., Jr.;
Koroniak, H.; Houk, K. N.; Sheu, C. Acc. Chem. Res. 1996, 29, 471. (d)
Luo, L.; Bartberger, M. D.; Dolbier, W. R., Jr. J. Am. Chem. Soc. 1997,
119, 12366. (e) Walker, M. J.; Hietbrink, B. N.; Thomas, B. E., IV;
Nakamura, K.; Kallel, E. A.; Houk, K. N. J. Org. Chem. 2001, 66, 6669.
(f) Ikeda, H.; Kato, T.; Inagaki, S. Chem. Lett. 2001, 3, 270. (g) Murakami,
M.; Miyamoto, Y.; Ito, Y. Angew. Chem., Int. Ed. 2001, 40, 189. (h) Lee,
P. S.; Zhang, X.; Houk, K. N. J. Am. Chem. Soc. 2003, 125, 5072.
(5) Nazarov-type cyclizations: (a) Dieker, J.; Froehlich, R.; Wuerthwein,
E.-U. Eur. J. Org. Chem. 2006, 23, 5339. (b) Cavalli, A.; Masetti, M.;
Recanatini, M.; Prandi, C.; Guarna, A.; Occhiato, E. G. Chem. Eur. J. 2006,
12, 2836. (c) Harmata, M.; Schreiner, P. R.; Lee, D. R.; Kirchhoefer, P. L.
J. Am. Chem. Soc. 2004, 126, 10954. (d) Faza, O. N.; Lopez, C. S.; Alvarez,
R.; de Lera, A. R. Chem. Eur. J. 2004, 10, 4324. (e) Lopez, C. S.; Faza,
O. N.; York, D. M.; de Lera, A. R. J. Org. Chem. 2004, 69, 3635.
(6) Sigmatropic shift: Faza, O. N.; Lopez, C. S.; de Lera, A. R. J. Org.
Chem. 2007, 72, 2617.
a R2 ) CO2Et for all entries. b Reaction conditions: alkyne (1.0 equiv),
nitrone (1.3 equiv), toluene, 50 °C, 12 h. c Reaction conditions: isoxazoline
(1.0 equiv), m-CPBA (1.5 equiv), CH2Cl2, 0 °C, 5 min.
(7) Cope rearrangement: Zhao, Y.-L.; Suhrada, C. P.; Jung, M. E.; Houk,
K. N. J. Am. Chem. Soc. 2006, 128, 11106.
tivity of numerous pericyclic reaction types,4-7 but only one
group of related torquoselective extrusions has been reported,
involving an achiral nitrogen center.8
(8) (a) Chiacchio, U.; Liguori, A.; Rescifina, A. Tetrahedron 1992, 48,
123. (b) Chiacchio, U.; Casuscelli, F.; Liguori, A.; Romeo, G.; Sindona,
G.; Uccella, N. Heterocycles 1993, 36, 585. (c) Casuscelli, F.; Chiacchio,
U.; Rescifina, A.; Romeo, R.; Romeo, G.; Tommasini, S.; Uccella, N.
Tetrahedron 1995, 51, 2979.
Quantum mechanical calculations were performed to
identify the factors controlling the stereoselectivity of the
oxidation and extrusion steps. All structures were computed
using UB3LYP9 density functional theory as implemented
in Gaussian 03.10 The structures and energies reported in
Schemes 5 and 6 were calculated with the 6-31+G(d)11 basis
set. Because calculations at the UB3LYP/6-31G(d)12 level
resulted in virtually no geometry or energy change, the
remaining structures are calculated at this level of theory.
All stationary points were verified as minima or first-order
(9) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5468. (b) Becke, A. D.
J. Chem. Phys. 1993, 98, 1372. (c) Lee, C.; Yang, W.; Parr, R. G. Phys.
ReV. B 1988, 98, 785.
(10) Frisch, M. J. et al. Gaussian 03, revision C.02; 2004. See the
Supporting Information for a full reference.
(11) (a) Clark, T.; Chandrasekhar, J.; Spitznagel, G. W.; Schleyer, P. v.
R. J. Comput. Chem. 1983, 4, 294. (b) Frisch, M. J.; Pople, J. A.; Binkley,
J. S. J. Chem. Phys. 1984, 80, 3265. (c) Latajka, Z.; Scheiner, S. Chem.
Phys. Lett. 1984, 105, 435.
(12) (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971,
54, 724. (b) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972,
56, 2257. (c) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28,
213.
4598
Org. Lett., Vol. 10, No. 20, 2008

kcal·mol-1 less stable than “in” diradical 5 due to repulsion
between the oxygen lone pairs in 5′. Diradical 5′ undergoes
a nearly barrierless rotation via TS4 to the more stable 5,
which then extrudes nitrosomethane to yield “in” alkene 3.
The rotational barrier for the C-N bond of 5′ (TS5, Scheme
5), which would give the more stable conformation 5-ent
and subsequently “out” alkene 4, is 2.6 kcal·mol-1 higher in
energy than TS4.
Scheme 3. Oxidation Stereoselectivity
Having established that the relative energies of TS3 and
TS3′ (C-N bond cleavage of 5 and 5′) determines the alkene
ratio, these transition structures were located for the “in”
and “out” diradicals resulting from decomposition of sub-
stituted N-oxide 2a-cis. Consistent with experimental results
the “in” alkene was calculated to be favored by 3.0
kcal·mol-1 (Figure 1).
To explain “out” product 4, entry 10 of Table 1 was
modeled by 1b (Figure 2). The oxidation selectivity was
calculated to be similar to that of “in”-yielding isoxazoline
1a, with a 3.6 kcal·mol-1 preference for TS1b-cis over TS1b-
trans. These results show that formation of 4 is not due to
a change in the oxidation selectivity.
The stereochemistry-determining C-N bond cleavage
transition state was next investigated (Figure 3). In agreement
with experimental results, decomposition to “out” alkene 4b
was calculated to be favored by 0.8 kcal·mol-1. The reversal
Scheme 4. Possible Decomposition Mechanisms of 2
Figure 1
.
Model MeNO extrusion TSs; Table 1, entry 4.
Scheme 5
proceed through low energy diradical NO intermediates such
as 5 are not uncommon.13
To explain the torquoselectivity, the “inward” and “out-
ward” decompositions of unsubstituted 2 (R1 ) R2 ) R3 )
H) were investigated (Scheme 6). The N-O bonds of 2,
bearing a pseudoaxial oxygen, and 2′, bearing a pseudoequa-
torial oxygen, readily cleave to form “in” and “out” diradicals
5 and 5′, respectively. While the N-oxide exhibits a modest
selectivity for outward ring-opening, the resulting 5′ is 3.9
(13) (a) Breton, G. W.; Nickerson, J. E.; Greene, A. M.; Oliver, L. H.
Org. Lett. 2007, 9, 3005. (b) Leach, A. G.; Houk, K. N. Org. Biomol. Chem.
2003, 1, 1389. (c) Leach, A. G.; Houk, K. N. Chem. Commun. 2002, 12,
1243. (d) Leach, A. G.; Houk, K. N. J. Am. Chem. Soc. 2002, 124, 14820.
Figure 2
.
Transition structures for oxidation of 1b.
Org. Lett., Vol. 10, No. 20, 2008
4599

Scheme 6
of torquoselectivity of 1b is attributed to steric clash between
an ortho ethyl group of R3 and the planar allyl radical in
TS3b.
In conclusion, stereoselective oxidation of 1 occurs to
minimize steric hindrance between the oxidizing agent and
substituent alpha to the isoxazoline nitrogen (R3). A stepwise
extrusion that maximizes the distance between the two radical
oxygens in the diradical intermediate (e.g., 5 vs 5′) explains
the general formation of “in” alkene 3. This selectivity is
reversed when large ortho substituents on R3 destabilize the
diradical intermediate of type 5.
Acknowledgment. We are grateful to the University of
Rochester and the National Institute of General Medical
Sciences, National Institutes of Health (GM 36700) for
support of this work. We thank Dr. Alice Bergmann
(SUNY-Buffalo) for the collection of high-resolution mass
spectra.
Figure 3. Model MeNO extrusion TSs; Table 1, entry 10 (relative
enthalpies in parentheses).
coordinates and energies of all reported structures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. Cartesian
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