Cyclization reactions through DDQ-mediated vinyl oxazolidinone oxidation

Article abstract of DOI:10.1021/ol901188q

Vinyl oxazolidinones react with DDQ to form α,β-unsaturated acyliminium ions in a new method for forming electrophiles under oxidative conditions. Appended nucleophiles undergo 1,4-addition reactions with these intermediates to form cyclic vinyl oxazolidinones with good levels of diastereocontrol, highlighting a new approach to utilizing oxidative carbon-hydrogen bond functionalization to increase molecular complexity.

Full text of DOI:10.1021/ol901188q

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3152-3155
Cyclization Reactions through
DDQ-Mediated Vinyl Oxazolidinone
Oxidation
Lei Liu and Paul E. Floreancig*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
florean@pitt.edu
Received May 27, 2009
ABSTRACT
Vinyl oxazolidinones react with DDQ to form r,ꢀ-unsaturated acyliminium ions in a new method for forming electrophiles under oxidative
conditions. Appended nucleophiles undergo 1,4-addition reactions with these intermediates to form cyclic vinyl oxazolidinones with good
levels of diastereocontrol, highlighting a new approach to utilizing oxidative carbon-hydrogen bond functionalization to increase molecular
complexity.
Converting carbon-hydrogen bonds to functional groups
through oxidative transformations provides excellent op-
Scheme 1
.
Alternate Oxidative Pathways to Stabilized
Carbocations
portunities for increasing molecular complexity from readily
accessible substrates,1 and efforts toward expanding the scope
of these processes are well warranted. We recently reported2
that benzylic and allylic ethers are oxidized by DDQ (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone) to form oxocarbe-
nium ion intermediates that react with appended nucleophiles
in an efficient cyclization process. The oxidative cation
formation appears to proceed (Scheme 1) through a sequence
of radical cation formation followed by hydrogen atom
abstraction. On the basis of this hypothesis we proposed an
alternative entry to unsaturated carbocations that proceeds
from vinyl ethers or amides. This approach benefits from
improved access to radical cation intermediates because of
the lower oxidation potentials of heteroatom-substituted
alkenes relative to allylic ethers.3
Vinyl oxazolidinones have recently become an increasingly
well-studied structural family.4 These compounds are easily
prepared from oxazolidinones through direct condensation
(1) For representative examples, see: (a) Mukaiyama, T.; Hayashi, Y.;
Hashimoto, Y. Chem. Lett. 1986, 1627. (b) Hayashi, Y.; Mukaiyama, T.
Chem. Lett. 1987, 1811. (c) Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae,
T. J. Am. Chem. Soc. 2003, 125, 15312. (d) Ying, B.-P.; Trogden, B. G.;
Kohlman, D. T.; Liang, S. X.; Xu, Y.-C. Org. Lett. 2004, 6, 1523. (e) Zhang,
Y.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 4242. (f) Catino, A. J.; Nichols,
J. M.; Nettles, B. J.; Doyle, M. P. J. Am. Chem. Soc. 2006, 128, 5648. (g)
Chen, M. S.; White, M. C. Science 2007, 318, 783. (h) Niu, M.; Yin, Z.;
Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008, 73, 3961. (i) Cheng, D.;
Bao, W. AdV. Synth. Catal. 2008, 350, 1263. (j) Zhao, L.; Li, C.-J. Angew.
Chem., Int. Ed. 2008, 47, 7075. (k) Lin, S.; Song, C.-X.; Cai, G.-X.; Wang,
W.-H.; Shi, Z.-J. J. Am. Chem. Soc. 2008, 130, 12901.
(3) Rathore, R.; Kochi, J. K. Tetrahedron Lett. 1994, 35, 8577.
(4) Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455.
(5) Song, Z.; Lu, T.; Hsung, R. P.; Al-Rashid, Z. F.; Ko, C.; Tang, Y.
Angew. Chem., Int. Ed. 2007, 46, 4069.
(2) (a) Tu, W.; Liu, L.; Floreancig, P. E. Angew. Chem., Int. Ed. 2008,
47, 4184. (b) Tu, W.; Floreancig, P. E. Angew. Chem., Int. Ed. 2009, 48,
4567.
10.1021/ol901188q CCC: $40.75
Published on Web 06/24/2009
 2009 American Chemical Society

reactions with aldehydes,5 cross-coupling reactions,6 and
metal-mediated additions across alkynes.7 Vinyl oxazolidi-
nones are electron-rich alkenes and react readily with
electron-deficient reagents such as oxidants,8 dihalides,9
metallocarbenes,4,10 and dicarbonyl compounds.11 The facile
access and electron wealth of these compounds suggested
that they would be excellent precursors to R,ꢀ-unsaturated
acyliminium ions upon oxidative carbon-hydrogen bond
activation.12 In this manuscript we demonstrate that vinyl
oxazolidinones react readily with DDQ to form electrophiles
that undergo 1,4-addition reactions with appended nucleo-
philes to form cyclohexane structures. The reactions proceed
with good levels of diastereocontrol when tertiary carbons
are formed. 1,3-Diketones can be used directly as nucleo-
philes in this process, obviating the need to preform the
nucleophile.
could form the reaction between cyclization products and
DDQ. While exposing substrate 6 to DDQ resulted in
substantial amounts of overoxidation, adding LiClO4 (15 mol
%) to the reaction led to the formation of cyclohexanone 7
in 76% yield in 1 h (Scheme 3). Quaternary carbons can
Scheme 3. Carbon-Carbon Bond Formation
We chose to utilize the hydroxyl group as a nucleophile
in initial studies (Scheme 2). Branching was also incorporated
Scheme 2
.
Allylic Carbon-Hydrogen Bond Activation from
Vinyl Oxazolidinones
also be prepared through carbon-carbon bond formation,
as illustrated by the conversion of 8 to 9. This reaction
proceeded to completion within 1 h to provide the desired
product in 74% yield. In contrast allylic oxazolidinone 10,
which lacks heteroatom substitution on the alkene, was inert
under the reaction conditions, thereby demonstrating the
kinetic benefit of utilizing substrates with electron-rich
alkenes in these reactions.
We prepared several substrates to explore the scope of
the process, the capacity to effect diastereoselective cycliza-
tion reactions, and the potential for expanding the scope of
(6) (a) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett.
2003, 5, 3667. (b) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809. (c)
Brice, J. L.; Meerdink, J. E.; Stahl, S. S. Org. Lett. 2004, 6, 1845. (d)
Bolshan, Y.; Batey, R. A. Angew. Chem., Int. Ed. 2008, 47, 2109.
(7) Goossen, L. J.; Rauhaus, J. E.; Deng, G. Angew. Chem., Int. Ed.
2005, 44, 4042.
at the allylic position of the vinyl oxazolidinone to prevent
product oxidation. Exposing 1 to DDQ in 1,2-dichloroethane
(DCE) resulted in the formation of tetrahydropyran 3 in 98%
yield after 20 min. This process proceeded through the
formation of R,ꢀ-unsaturated acyliminium ion 2 followed
by an intramolecular 1,4-addition reaction. Secondary alcohol
4 cyclized to form tetrahydropyran 5 at -30 °C in 85% yield
with modest diastereocontrol as expected on the basis of the
steric similarity between methyl and vinyl groups. Diaste-
reocontrol was somewhat higher when this reaction was
conducted in toluene rather than dichloroethane.
(8) (a) Xiong, H.; Hsung, R. P.; Shen, L.; Hahn, J. M. Tetrahedron Lett.
2002, 43, 4449. (b) Adam, W.; Bosio, S. G.; Wolff, B. T. Org. Lett. 2003,
5, 819. (c) Sivaguru, J.; Saito, H.; Poon, T.; Omonuwa, T.; Franz, R.;
Jockusch, S.; Hooper, C.; Inoue, Y.; Adam, W.; Turro, N. J. Org. Lett.
2005, 7, 2089. (d) Aciro, C.; Davies, S. G.; Garner, A. C.; Ishii, Y.; Key,
M.-S.; Ling, K. B.; Prasad, R. S.; Roberts, P. M.; Rodriguez-Solla, H.;
O’Leary-Steele, C.; Russel, A. J.; Sanganee, H. J.; Savory, E. D.; Smith,
A. D.; Thomson, J. E. Tetrahedron 2008, 64, 9320.
(9) Ko, C.; Hsung, R. P.; Al-Rashid, Z. F.; Feltenberger, J. B.; Lu, T.;
Yang, J.-H.; Wei, Y.; Zificsak, C. A. Org. Lett. 2007, 9, 4459.
(10) Lu, T.; Song, Z.; Hsung, R. P. Org. Lett. 2008, 10, 541.
(11) Gohier, F.; Bouhadjera, K.; Faye, D.; Gaulon, C.; Maisonneuve,
V.; Dujardin, G.; Dhal, R. Org. Lett. 2007, 9, 211.
(12) For related examples, see: (a) Magnus, P.; Lacour, J. J. Am. Chem.
Soc. 1992, 114, 767. (b) Evans, P. A.; Longmire, J. M.; Modi, D. P.
Tetrahedron Lett. 1995, 36, 3985. (c) Magnus, P.; Lacour, J.; Evans, P. A.;
Rigollier, P.; Tobler, H. J. Am. Chem. Soc. 1998, 120, 12486.
(13) (a) Seiders, J. R.; Wang, L.; Floreancig, P. E. J. Am. Chem. Soc.
2003, 125, 2406. (b) Wang, L.; Seiders, J. R.; Floreancig, P. E. J. Am.
Chem. Soc. 2004, 126, 12596. (c) Jung, H. H.; Seiders, J. R.; Floreancig,
P. E. Angew. Chem., Int. Ed. 2007, 46, 8464. For the initial report of using
enol acetates as latent ketone enolates, see: (d) Mukaiyama, T.; Izawa, T.;
Saigo, K. Chem. Lett. 1974, 323.
Our initial studies in applying this approach for carbon-
carbon bond formation focused on the use of enol acetate
nucleophiles. These easily handled and readily accessible
moieties are excellent latent enolates in reactions that proceed
through oxidatively generated carbocations.13 We postulated
that the ketones that arise from these reactions would
suppress overoxidation by destabilizing carbocations that
Org. Lett., Vol. 11, No. 14, 2009
3153

nucleophiles and product ring sizes in the reaction. The
results of this study are shown in Table 1.
tional control elements that could preorganize it for cycliza-
tion. Incorporating such constraints in the design of a
cyclization substrate should improve cyclization efficiency.
Silylallenes, which have proven to be excellent surrogates
for propargylic anions14 in oxidative cyclization
reactions,13a,b are effective nucleophiles in the synthesis of
alkynylcyclohexanes (entry 6). These substrates show low
levels of diastereocontrol, as expected on the basis of the
minimal gauche and transannular interactions between
the linear allene and the forming ring. Entries 7 and 8 show
the results of our efforts at using ꢀ-dicarbonyl compounds
as nucleophiles. The use of these nucleophiles is advanta-
geous because no additional steps are required for the
preparation of a latent nucleophile, and the cyclization
products contain a high degree of substitution. The resulting
process is an example of a cross-dehydrogenative coupling
reaction15 in which carbon-carbon bond formation occurs
through a formal loss of H2. We observed that the enol
content of the substrate played a critical role in the success
of these reactions. ꢀ-Diketones exist largely in the enol form
in nonpolar solvents, as illustrated in compound 23, and are
suitable nucleophiles for the cyclization reaction. ꢀ-Keto
esters, however, exist largely in the dicarbonyl form and are
not effective nucleophiles.
Table 1. Oxidative Cyclizationsa
The stereochemical outcome of the cyclization of ether
substrate 15 illustrates the role that electrostatic effects can
play in conformational equilibria (Scheme 4). The lone pairs
Scheme 4. Conformational Control through Electrostatic Effects
a Representative procedure: substrate, DDQ (2 equiv), LiClO4 (0.15
equiv), 2,6-dichloropyridine (2 equiv), and 4 Å MS were added to 1,2-
dichloroethane at the appropriate temperature. See Supporting Information
for details. b Isolated yields of purified materials. Diastereomeric ratios were
determined on the basis of isolated products or NMR-derived signal ratios
of mixtures. c 75% yield based on recovered starting material. d 74% based
on recovered starting material.
In general the reactions proceeded with good efficiency
and diastereoselectivity. Notably, these are the first examples
that we have observed in which carbocyclic structures have
been prepared diastereoselectively through oxidative car-
bocation formation. The major products from substrates that
contain alkyl branches (entries 1, 2, and 4) are consistent
with chairlike transition states in which the alkyl groups and
the R,ꢀ-unsaturated acyliminium ions occupy pseudoequa-
torial orientations. Interestingly the stereochemical outcome
of the cyclization of methyl ether 15 (entry 3) is opposite
that of the cyclization of 13. This suggests that the stereo-
chemical outcomes of these reactions are controlled by
kinetics rather than thermodynamics. Cycloheptanones can
be formed through this method (entry 5), though this reaction
proceeds less efficiently than reactions that produce lower
homologues. Substrate 19, however, contains no conforma-
on the oxygen of the equatorial methoxy group are separated
from the electrophilic site by a greater distance in conforma-
tion 27 than the lone pairs of the axial methoxy group and
the electrophilic site in conformation 28. Since an axially
oriented methoxy group is only minimally disfavored relative
to an equatorially oriented methoxy group through steric
effects, this electrostatic stabilization is sufficient to promote
cyclization through conformation 28. As a comparison we
calculated (AM1) the distance between the oxygens of the
methoxy groups and the corresponding carbons of axial and
equatorial 3-methoxy cyclohexanone (O f C5). The axial
oxygen is 2.92 Å from C5 while the distance from the
equatorial oxygen is 3.75 Å. Similar explanations have been
(14) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293.
(15) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
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Org. Lett., Vol. 11, No. 14, 2009

proposed to describe the conformational preferences of cyclic
alkoxy-substituted oxocarbenium ions.16
aldol reaction to form the known17 bridged bicycle 30 in an
81% yield. The ketone can be reduced by NaBH4 to provide
the alcohol as a 5:1 mixture of diastereomers in 93% yield.
No reduction of the oxazolidinone was observed under these
conditions. Acidic hydrolysis of the vinyl oxazolidinone
followed by alcohol silylation yielded known18 aldehyde 31.
We have shown that vinyl oxazolidinones are excellent
substrates for DDQ-mediated oxidative R,ꢀ-unsaturated
acyliminium ion formation. The importance of alkene
electron density is apparent through the significantly higher
reactivity of vinyl oxazolidinones relative to allyl oxazoli-
dinones. Cyclization through carbon-oxygen or carbon-
carbon bond formation was demonstrated. Successful carbon-
carbon bond formation was observed with enol acetate,
silylallene, and ꢀ-diketone nucleophiles, with ꢀ-diketones
being partularly attractive because they can be used without
modification in cross-dehydrogenative coupling reactions.
Diastereocontrol in the cyclizations is good to excellent when
a chiral center is present in the substrate. The vinyl
oxazolidinone groups in the reaction products can engage
in a wide range of reactions to broaden the scope of products
that are available through this method.
Vinyl oxazolidinones can serve as substrates for a number
of transformations, providing significant flexibility to the
types of structures that can ultimately be prepared through
this sequence. Representative examples of these transforma-
tions are shown in Scheme 5. Ozonolytic cleavage of
Scheme 5. Vinyl Oxazolidinone Functionalization
Acknowledgment. We thank the National Institutes of
Health (GM062924) and the National Science Foundation
(CHE-139851) for generous support of this work.
Supporting Information Available: Schemes for sub-
strate preparations, cyclization protocols, and complete
characterization data for all substrates and products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
oxazolidinone 7 followed by reduction with Me2S provides
a 96% yield of aldehyde 29. Exposing 7 to aqueous HCl
results in vinyl oxazolidinone hydrolysis and subsequent
(16) (a) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc.
1992, 114, 859. (b) Miljkovic, M.; Yeagley, D.; Deslongchamps, P.; Dory,
Y. L. J. Org. Chem. 1997, 62, 7597. (c) Dudley, T. J.; Smoliakova, I. P.;
Hoffmann, M. R. J. Org. Chem. 1999, 64, 1247. (d) Ayala, L.; Lucero,
C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem.
Soc. 2003, 125, 15521.
OL901188Q
(17) Tzvetkov, N. T.; Schmoldt, P.; Neumann, B.; Stammler, H.-G.;
Mattay, J. Tetrahedron: Asymmetry 2006, 17, 993.
(18) Ren, L.; Crudden, C. M. J. Org. Chem. 2002, 67, 1746.
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