Intramolecular oxyallyl-carbonyl (3 + 2) cycloadditions

Article abstract of DOI:10.1021/ja312459b

Cycloadditions involving oxyallyl intermediates typically require an electron-rich diene or alkene, but we have discovered the first examples of the cycloaddition of heteroatom-stabilized oxyallyls onto carbonyl groups. An oxazolidinone-substituted oxyallyl undergoes chemoselective (3 + 2) cycloaddition onto the carbonyl group of a tethered dienone in preference to formation of the expected (4 + 3) cycloadduct. Density functional theory calculations indicated that the (3 + 2) cycloaddition takes place through a concerted, highly asynchronous mechanism. The transition state features simultaneous interactions of the oxyallyl LUMO with the carbonyl π and lone-pair orbitals, making this reaction hemipseudopericyclic (halfway between purely pericyclic and purely pseudopericyclic). Further (3 + 2) cycloadditions involving tethered phenyl ketones and a tethered enone were predicted theoretically and verified experimentally.

Full text of DOI:10.1021/ja312459b

Communication
pubs.acs.org/JACS
Intramolecular Oxyallyl−Carbonyl (3 + 2) Cycloadditions
Elizabeth H. Krenske,*,†,‡,∥ Shuzhong He,§ Jian Huang,§ Yunfei Du,§ K. N. Houk,*,‡
and Richard P. Hsung*,§
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
∥School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia
†School of Chemistry, The University of Melbourne, and Australian Research Council Centre of Excellence for Free Radical
Chemistry and Biotechnology, VIC 3010, Australia
§Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin at Madison, Madison, Wisconsin 53705,
United States
S
* Supporting Information
features: a concerted intramolecular (3 + 2) cycloaddition of an
ABSTRACT: Cycloadditions involving oxyallyl inter-
mediates typically require an electron-rich diene or alkene,
but we have discovered the first examples of the
cycloaddition of heteroatom-stabilized oxyallyls onto
carbonyl groups. An oxazolidinone-substituted oxyallyl
undergoes chemoselective (3 + 2) cycloaddition onto the
carbonyl group of a tethered dienone in preference to
formation of the expected (4 + 3) cycloadduct. Density
functional theory calculations indicated that the (3 + 2)
cycloaddition takes place through a concerted, highly
asynchronous mechanism. The transition state features
simultaneous interactions of the oxyallyl LUMO with the
carbonyl π and lone-pair orbitals, making this reaction
“hemipseudopericyclic” (halfway between purely pericyclic
and purely pseudopericyclic). Further (3 + 2) cyclo-
additions involving tethered phenyl ketones and a tethered
enone were predicted theoretically and verified exper-
imentally.
oxazolidinone-substituted oxyallyl onto the carbonyl group of a
dienone, enone, or phenyl ketone. While (3 + 2) cycloadditions
have been reported for oxyallyls generated from α,α′-dibromo
ketones,4−6 to the best of our knowledge, such (3 + 2)
cycloadditions involving heteroatom-stabilized oxyallyls have
not been previously reported.
In recent years, we have explored (4 + 3) cycloadditions of
oxazolidinone-substituted oxyallyls (3) (Scheme 2) with
Scheme 2. Intermolecular and Intramolecular (4 + 3)
Cycloadditions of Allenamide-Derived Oxazolidinone-
Substituted Oxyallyls with Dienes7a,c
xyallyl cations (1) (Scheme 1) are valuable substrates for
cycloaddition reactions that provide access to a variety of
O
Scheme 1. Generalized (4 + 3) and (3 + 2) Cycloadditions of
Oxyallyl Cations
numerous classes of dienes.7 Oxyallyls 3 are readily generated
by oxidation of allenamides and can be trapped either
intermolecularly or intramolecularly by dienes. We had
intended to apply the allenamide oxidation/(4 + 3) cyclo-
addition sequence to access bicyclic species 4c (Figure 1) in a
planned synthesis of aromadendrane natural products.8
Unexpectedly, treatment of allenamide 2c with dimethyldiox-
irane (DMDO) under standard conditions led not to 4c but to
the oxabicyclic species 5c (85%), whose identity was confirmed
by X-ray crystallography. Adduct 5c is the product of
chemoselective (3 + 2) cycloaddition of the oxyallyl onto the
carbonyl group of the tethered dienone.
ring types.1 Both [4π + 2π] and [2π + 2π] modes of
cycloaddition are known under thermal conditions.2 Important
examples are the (4 + 3) cycloadditions with dienes leading to
cycloheptenones and the (3 + 2) cycloadditions with alkenes
leading to cyclopentanones, respectively. A frequent hallmark of
oxyallyl cycloaddition chemistry is a requirement for an
electron-rich partner (diene or alkene), since the oxyallyl
cation is electrophilic. These polar cycloadditions often have
stepwise mechanisms.3 We have now uncovered an unprece-
dented type of oxyallyl cycloaddition that displays the opposite
The formation of 5c is surprising given the fact that other
oxyallyls in which the diene is connected by a three-carbon
tether do undergo intramolecular (4 + 3) cycloadditions (e.g.,
Received: December 20, 2012
Published: April 1, 2013
© 2013 American Chemical Society
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Figure 1. Synthesis and X-ray crystal structure of (3 + 2) cycloadduct
5c.
Scheme 2b).7c We conducted density functional theory (DFT)
calculations to explore how 5c is formed.9 Transition states
(TSs) were computed for the (4 + 3) and (3 + 2)
cycloadditions of 3c leading to 4c and 5c, respectively, at the
B3LYP/6-31G(d) level of theory.10 Activation energies were
then obtained from M06-2X/6-311+G(d,p) single-point
calculations,11 and solvent effects (CH2Cl2) were modeled
through SMD calculations.12 The computational results are
shown in Figure 2. For comparison, we also computed TSs for
intermolecular cycloadditions of a model oxyallyl (3d) with
hexadienone (Figure 3).
Figure 3. Transition states for intermolecular (4 + 3) and (3 + 2)
cycloadditions of oxyallyl 3d with hexadienone.
modes of intramolecular cycloaddition are downhill by more
than 40 kcal/mol (ΔGsoln). The switch in chemoselectivity
displayed by 3c reflects a 4.6 kcal/mol lower activation enthalpy
and a 3.1 kcal/mol smaller entropic term (−TΔS⧧). While the
inter- and intramolecular (3 + 2) cycloaddition TSs are
geometrically very similar (except for the orientation of the
diene chain), the (4 + 3) TS occurs intramolecularly at a more
advanced stage of bond formation, and the carbonyl group is
twisted 21° out of the diene plane (compared with 7° in TSC).
The (3 + 2) cycloadditions are concerted but highly
asynchronous processes. C−O bond formation is much more
advanced at the TS (1.87 Å) than C−C bond formation (3.11−
3.15 Å). Addition is antarafacial with respect to 3c or 3d and
suprafacial with respect to the carbonyl, in agreement with the
orbital symmetry rules for a thermal [2π + 2π] cycloaddition.13
To explore the details of the mechanism, we calculated TSs for
alternative modes of (3 + 2) cycloaddition in the reaction of 3d
with formaldehyde (Figure 4). The preference for antarafacial
addition over suprafacial addition (TSE vs TSF) is 3 kcal/mol.
Figure 2. Transition states for the intramolecular (4 + 3) and (3 + 2)
cycloadditions of 3c leading to 4c and 5c, respectively (distances in Å,
ΔH⧧ and ΔG⧧ in kcal/mol; M06-2X//B3LYP, SMD solvation in
CH2Cl2).
The activation energies for the intermolecular cycloadditions
(Figure 3) show that the dienone has no innate preference for
the (3 + 2) mode of cycloaddition. The (3 + 2) TS (TSD) is
12.4 kcal/mol higher in energy than the (4 + 3) TS (TSC) in
the gas phase (ΔΔG⧧) and 6.4 kcal/mol higher in solution. By
contrast, the intramolecular (3 + 2) cycloaddition of 3c (Figure
2) is favored over the (4 + 3) cycloaddition by 7.7 kcal/mol in
the gas phase and 13.7 kcal/mol in solution. Both of these
Figure 4. Transition states for antarafacial and suprafacial (3 + 2)
cycloadditions of oxyallyl 3d with formaldehyde.
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The concerted antarafacial mechanism is favored over stepwise
mechanisms by at least 10 kcal/mol.
different from most other synthetically important oxyallyls,
which are cationic, electrophilic species. We had previously
reported that oxyallyls 3 are ambiphilic in (4 + 3) cyclo-
additions with furans.14b The cycloadditions onto carbonyls
represent an even more unusual pairing and suggest tantalizing
new synthetic prospects; pursuit of potential applications is
underway.
The highest occupied molecular orbital (HOMO) and lowest
unoccupied MO (LUMO) of oxyallyls 3 are depicted at the
bottom of Figure 4. The HOMO is enolate-like, while the
LUMO has both allyl π* and iminium π* character.14 To reach
the antarafacial TS, the iminium and enolate moieties rotate
into a roughly perpendicular arrangement that allows maximum
overlap with the π orbitals of the carbonyl. Orbital interactions
with π(CO) and π*(CO), which define the pericyclic [2π
+ 2π] cycloaddition, are accompanied by a simultaneous
interaction between the LUMO of 3 and a carbonyl oxygen
lone pair. The latter interaction endows the reaction with
pseudopericyclic15 character. The contributions of pericyclic
and pseudopericyclic character to TSE are approximately equal,
as shown by the geometry of approach of the aldehyde viewed
along the CO bond (Figure 4). The iminium terminus of 3d
approaches at an angle of 47° with respect to the CH2O
plane, halfway between the angles expected for purely pericyclic
(90°) and pseudopericyclic (0°) processes. We describe this
new type of reaction not as pericyclic or pseudopericyclic but as
“hemipseudopericyclic”.
We also explored the feasibility of intermolecular (3 + 2)
cycloadditions. Reactions of 3d with ketones, esters, and
aliphatic or aromatic aldehydes are predicted to have ΔH⧧ = 6−
9 kcal/mol and ΔG⧧soln = 20−23 kcal/mol (see the Supporting
Information).16 Unfortunately, experimental attempts to
perform intermolecular (3 + 2) cycloadditions with a number
of carbonyl systems, including aldehydes, ketones, esters, and
amides, were thwarted by competing oxidation of the carbonyl
substrates under the conditions used for generation of the
oxyallyl. Intramolecularity appears to be necessary for the
cycloaddition to compete with these unwanted oxidation
reactions.17 Consistent with this, analogous (3 + 2) cyclo-
additions were accomplished with tethered phenyl ketones 2e−
g and tethered enone 2h (Scheme 3). On the other hand,
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, compound characterizations, NMR
spectra, crystallographic data (CIF), computational method-
ology and data, and complete citations for ref 9. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
e.krenske@uq.edu.au; houk@chem.ucla.edu; rhsung@wisc.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIH (GM-66055 to R.P.H), NSF (CHE-
0548209 to K.N.H.), Australian Research Council
(FT120100632 and DP0985623 to E.H.K.), and ARC Centre
of Excellence for Free Radical Chemistry and Biotechnology
(funding to E.H.K.) for generous financial support and the
NCSA, UCLA ATS, UCLA IDRE, NCI NF (Australia),
University of Queensland Research Computing Centre, and
University of Melbourne for computer resources.
REFERENCES
■
(1) For general reviews of oxyallyl cycloadditions, see: (a) Rigby, J.
H.; Pigge, F. C. Org. React. 2004, 351. (b) Davies, H. M. L. Adv.
Cycloaddit. 1999, 5, 119. (c) Hartung, I. V.; Hoffmann, H. M. R.
Angew. Chem., Int. Ed. 2004, 43, 1934. (d) Battiste, M. A.; Pelphrey, P.
M.; Wright, D. L. Chem.Eur. J. 2006, 12, 3438. (e) Harmata, M. Adv.
Synth. Catal. 2006, 348, 2297. (f) Harmata, M. Chem. Commun. 2010,
46, 8886. (g) Harmata, M. Chem. Commun. 2010, 46, 8904. For a
recent review, see: (h) Lohse, A. G.; Hsung, R. P. Chem.Eur. J. 2011,
17, 3812. For (4 + 3) cycloadditions of donor-substituted oxyallyls,
see: (i) Beck, H.; Stark, C. B. W.; Hoffmann, H. M. R. Org. Lett. 2000,
2, 883. (j) Harmata, M.; Ghosh, S. K.; Hong, X.; Wacharasindhu, S.;
Kirchhoefer, P. J. Am. Chem. Soc. 2003, 125, 2058. (k) Chung, W. K.;
Lam, S. K.; Lo, B.; Liu, L. L.; Wong, W.-T.; Chiu, P. J. Am. Chem. Soc.
2009, 131, 4556. (l) Liu, L. L.; Chiu, P. Chem. Commun. 2011, 47,
3416. (m) MaGee, D. I.; Godineau, E.; Thornton, P. D.; Walters, M.
A.; Sponholtz, D. J. Eur. J. Org. Chem. 2006, 3667. (n) Lo, B.; Lam, S.;
Wong, W.-T.; Chiu, P. Angew. Chem., Int. Ed. 2012, 51, 12120.
(o) Han, X.; Li, H.; Hughes, R. P.; Wu, J. Angew. Chem., Int. Ed. 2012,
51, 10390.
Scheme 3. Experimental and Theoretical Investigations of
Other (3 + 2) Cycloadditions
(2) For a review of cycloadditions of photochemically generated
oxyallyls, see: West, F. G. In CRC Handbook of Organic Photochemistry
and Photobiology, 2nd ed.; Horspool, W., Lenci, F., Eds.; CRC Press:
Boca Raton, FL, 2004; Chapter 83.
methyl ketone 2i failed to react under the same conditions. It
appears that an electron-rich carbonyl substituent (R) is
necessary to stabilize the cationlike character at the carbonyl
carbon in the highly asynchronous TS. Calculations on 2e−i
agreed with experiment, predicting the methyl ketone to have a
barrier 2 kcal/mol higher than that of 2c, while the vinyl and
phenyl ketones have lower barriers that decrease as the ketone
becomes more electron-rich.
(3) (a) Cramer, C. J.; Barrows, S. E. J. Org. Chem. 1998, 63, 5523.
(b) Cramer, C. J.; Barrows, S. E. J. Phys. Org. Chem. 2000, 13, 176.
(4) For a leading review of oxyallyl reactivity including (3 + 2)
cycloaddition modes, see: (a) Noyori, R.; Hayakawa, Y. Org. React.
1983, 29, 163. For precedents of oxyallyl (3 + 2) cycloadditions
grouped by class, see: CC−C + amide CO: (b) Hayakawa, Y.;
Takaya, H.; Makino, S.; Hayakawa, N.; Noyori, R. Bull. Chem. Soc. Jpn.
1977, 50, 1990. (c) Noyori, R.; Hayakawa, Y.; Makino, S.; Hayakawa,
N.; Takaya, H. J. Am. Chem. Soc. 1973, 95, 4103. (d) Barrow, M.-A.;
Richards, A. C.; Smithers, R. H.; Hoffmann, H. M. R. Tetrahedron Lett.
The (3 + 2) cycloadditions of 3 with carbonyl compounds
are an unexpected addition to the repertoire of oxyallyl
reactivity.4−6 Oxyallyls 3 possess a reactivity profile quite
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1972, 13, 3101. CC−O + amide CO to give dioxolanes:
(e) Hoffmann, H. M. R.; Clemens, K. E.; Schmidt, E. A.; Smithers, R.
H. J. Am. Chem. Soc. 1972, 94, 3201. CC−O + ketone CO to
give dioxolanes: (f) Fry, A. J.; Ginsburg, G. S.; Parente, R. A. J. Chem.
Soc., Chem. Commun. 1978, 1040. CC−C + tetracyanoethylene
CC: (g) Cookson, R. C.; Nye, M. J. Proc. Chem. Soc. 1963, 129.
CC−C + DEAD NN: (h) Cookson, R. C.; Nye, M. J. J. Chem.
Soc. 1965, 2009.
(5) Nakamura and co-workers reported the only related (3 + 2)
cycloaddition, but their work involved nucleophilic allyl anion
equivalents generated by thermal ring opening of exo-methylenecy-
clopropane acetals. See: (a) Yamago, S.; Nakamura, E. J. Org. Chem.
1990, 55, 5553. (b) Yamago, S.; Nakamura, M.; Wang, X. Q.;
Yanagawa, M.; Tokumitsu, S.; Nakamura, E. J. Org. Chem. 1998, 63,
1694. (c) Yamago, S.; Yanagawa, M.; Nakamura, E. Chem. Lett. 1999,
879. For an account of this work, see: (d) Nakamura, E.; Yamago, S.
Acc. Chem. Res. 2002, 35, 867.
oxygen rather than to the oxyallyl carbon, leading to a 4-alkylidene-5-
oxazolidinyl-1,3-dioxolane. This TS is much lower in energy than TSE
(ΔG⧧ = 10.7 kcal/mol) and may represent an unwanted side reaction
in certain of our attempted intermolecular cycloadditions; however, its
importance depends on the carbonyl substituents. With hexadienone,
for example, addition across CCO is 0.2 kcal/mol higher in energy
than addition across CCC. At this stage, we have not observed any
products that could be assigned to cycloadditions of ketones across
CCO of oxyallyls. In all of our intramolecular examples, addition
across CCO is prevented by the geometrical constraints of the tether.
Analogous products from reactions of α,α′-dibromoketones with
ketones or amides under reductive conditions have been reported.4e,f
(6) For other examples of (3 + 2) cycloadditions of allyl
intermediates, see: (a) Danheiser, R. L.; Kwasigroch, C. A.; Tsai, Y.-
M. J. Am. Chem. Soc. 1985, 107, 7233. (b) Trost, B. M.; King, S. A. J.
Am. Chem. Soc. 1990, 112, 408. (c) Trost, B. M.; Bringley, D. A.;
Silverman, S. M. J. Am. Chem. Soc. 2011, 133, 7664.
(7) (a) Xiong, H.; Hsung, R. P.; Berry, C. R.; Rameshkumar, C. J.
Am. Chem. Soc. 2001, 123, 7174. (b) Xiong, H.; Huang, J.; Ghosh, S.
K.; Hsung, R. P. J. Am. Chem. Soc. 2003, 125, 12694. (c) Rameshkumar,
C.; Hsung, R. P. Angew. Chem., Int. Ed. 2004, 43, 615. (d) Huang, J.;
Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50. (e) Antoline, J. E.;
Hsung, R. P.; Huang, J.; Song, Z.; Li, G. Org. Lett. 2007, 9, 1275.
(f) Antoline, J. E.; Hsung, R. P. Synlett 2008, 739.
(8) For leading references, see: (a) Mayol, L.; Piccialli, V.; Sica, D.
Tetrahedron 1987, 43, 5381. (b) Braekman, J.-C.; Daloze, D.;
Moussiaux, B.; Stoller, C.; Deneubourg, F. Pure Appl. Chem. 1989,
61, 509.
(9) The DFT calculations were performed using Gaussian 03 and
Gaussian 09 (for the citations, see the Supporting Information).
(10) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
(b) Becke, A. D. J. Chem. Phys. 1993, 98, 1372. (c) Becke, A. D. J.
Chem. Phys. 1993, 98, 5648. (d) Stephens, P. J.; Devlin, F. J.;
Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623.
(11) (a) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215.
(b) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157.
(12) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
2009, 113, 6378.
(13) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital
Symmetry; Verlag Chemie: Weinheim, Germany, 1970.
(14) (a) Krenske, E. H.; Houk, K. N.; Lohse, A. G.; Antoline, J. E.;
Hsung, R. P. Chem. Sci 2010, 1, 387. (b) Lohse, A. G.; Krenske, E. H.;
Antoline, J. E.; Houk, K. N.; Hsung, R. P. Org. Lett. 2010, 12, 5506.
(c) Antoline, J. E.; Krenske, E. H.; Lohse, A. G.; Houk, K. N.; Hsung,
R. P. J. Am. Chem. Soc. 2011, 133, 14443. (d) Du, Y.; Krenske, E. H.;
Antoline, J. E.; Lohse, A. G.; Houk, K. N.; Hsung, R. P. J. Org. Chem.
2013, 78, 1753.
(15) (a) Ross, J. A.; Seiders, R. P.; Lemal, D. M. J. Am. Chem. Soc.
1976, 98, 4325. For computational studies of pseudopericyclic
reactions, see: (g) Birney, D. M.; Ham, S.; Unruh, G. R. J. Am. Chem.
Soc. 1997, 119, 4509. (b) Shumway, W. W.; Dalley, N. K.; Birney, D.
M. J. Org. Chem. 2001, 66, 5832. (c) Zhou, C.; Birney, D. M. J. Am.
Chem. Soc. 2002, 124, 5231. (d) Cabaleiro-Lago, E. M.; Rodríguez-
Otero, J.; Gonzal
J. Phys. Chem. A 2005, 109, 5636. (e) Cabaleiro-Lago, E. M.;
Rodríguez-Otero, J.; García-Lopez, R. M.; Pena-Gallego, A.; Hermida-
Ramon
, J. M. Chem.Eur. J. 2005, 11, 5966. (f) Gonzal
Souto, J. A.; Lop
́
ez-Lopez, I.; Pena-Gallego, A.; Hermida-Ramon, J. M.
́
́
̃
́
̃
́
́
ez Per
́
ez, A. B.;
́
́
ez, C. S.; de Lera, A. R. Eur. J. Org. Chem. 2011, 2933.
(16) Amides are predicted to be more reactive than these types of
carbonyl compounds. For example, cycloaddition of 3d with
dimethylacetamide is calculated to have ΔH⧧ = 1.0 kcal/mol and
ΔG⧧soln = 12.1 kcal/mol.
(17) We also located a TS for an alternative mode of (3 + 2)
cycloaddition in which the formaldehyde carbon binds to the oxyallyl
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