Novel Chemistry of R-Tosyloxy Ketones
A R T I C L E S
Scheme 1. One-Pot Entry to R-Tosyloxy Ketones from Olefinsa,b
of motifs found in a variety of biologically active molecules
(privileged structures). We had originally been attracted by a
number of potential candidates6 accessible through the use of
an R-halo ketone scaffold; however, this entity suffers due to a
lack of consistency because of the variety of positions and
modes of reaction that are available.7 Conversely, we felt the
reactions of R-sulfonyloxy ketones with nucleophiles, which
have been rather sporadically explored with the notable excep-
tion of the comprehensive work of R. V. Hoffman et al.7-8 in
the arena of R-nosyloxy ketones, may provide a more consistent
reaction manifold. In addition, several tantalizing observa-
tions7-10 persuaded us that this was potentially a fertile field to
embrace. Thus, by tapping into and elaborating upon the rich
chemistry of R-sulfonyloxy ketones, we were afforded an
attractive linker that met the stringent requirements of our initial
design criteria. Herein, we present a full account of our
investigations into the solution- and solid-phase chemistry of
R-tosyloxy ketones leading to an array of biologically relevant
heterocycles via a cascade “heterocyclic-release” strategy11 and
an approach toward the synthesis of enediynes.
a Reagents and conditions: (a) DMDO (1.3 equiv, ca. 0.1 M solution in
acetone), CH2Cl2, 1 h, 25 °C; then p-TsOH (5.0 equiv), 12 h, 25 °C; then
NaHCO3 (6.0 equiv), DMP (2.0 equiv), 25 °C, 65%; (b) benzene (0.05 M),
Hanovia (450 W, medium-pressure Hg lamp), 25 °C, 8 h, 65%; (c) IBX
(4.0 equiv every 5 h), p-TsOH (cat.), DMSO:fluorobenzene (10:1), 85 °C,
15 h, 72%; (d) K2CO3 (5.0 equiv), MeOH, 25 °C, 1 h, 83%; (e) 2-amino-
thiophenol (10 equiv), PPTS (cat.), benzene, reflux (Dean-Stark), 24 h,
82%; DMDO ) dimethyldioxirane, p-TsOH ) p-toluenesulfonic acid,
DMP ) Dess-Martin periodinane, PPTS ) pyridinium p-toluenesulfonate,
IBX ) o-iodoxybenzoic acid, DMSO ) dimethyl sulfoxide. b Yields refer
to chromatographically and spectroscopically homogeneous material.
Results and Discussion
1. Solution-Phase Chemistry of r-Tosyloxy Ketones and
Loading onto Solid Support. Because of the widespread
availability of olefins, we focused our attention on the develop-
ment of a mild, one-pot protocol for their conversion to
R-tosyloxy ketones. Two methods are known for the synthesis
of R-sulfonyloxy ketones: (a) treatment of ketones and enol
ethers with hypervalent iodine reagents;12 and (b) oxidation of
enol esters, enol ethers, and enamines with arylsulfonyl per-
oxides.13 To develop a mild route to R-sulfonyloxy ketones
from olefins, we considered the opening of epoxides with
p-toluenesulfonic acid (p-TsOH). Predictably, we found that if
excess water was present during the epoxide opening with
p-TsOH, a 1,2-diol was formed. If, however, there was only
very little or no water available, then epoxide opening with
p-TsOH led smoothly to an R-tosyloxy alcohol which could
easily be oxidized to the coveted R-sulfonyloxy ketone. Thus,
cyclooctene (1) could be easily converted to the R-sulfonyloxy
ketone 4 in 65% yield upon sequential treatment with DMDO,14
p-TsOH, and DMP15 (Scheme 1) (for abbreviations of reagents
and protecting groups, see legends in schemes). In contrast to
the corresponding R-halo ketone which is known to exhibit
lability, 4 was a remarkably stable crystalline solid which could
be stored at room temperature unprotected from light.
Our initial studies using R-tosyloxy ketone 4 to access novel
molecular diversity, as depicted in Scheme 1, gave us a glimpse
of the rich chemistry of these species. Application of Schaffner’s
R-sulfonated ketone fragmentation16 led to the R,â-unsaturated
ketone 5 in 65% yield upon irradiation of 4 in benzene for 8 h.
Our recently reported IBX-based protocol for oxidation adjacent
to carbonyl groups17 proceeded regioselectively in 72% yield
furnishing the unsaturated R-tosyloxy ketone 6. Upon treatment
of 4 with K2CO3 in MeOH, the R-methoxy ketone 7 was
obtained in 83% yield.
Encouraged by reactions of o-thioaniline with R-halo ketones,6c
we proceeded to attempt this heterocyclic annulation reaction
with our R-tosyloxy ketone (4). In the event, treatment of this
scaffold (Scheme 1) with o-thioaniline in refluxing benzene in
the presence of catalytic amounts of PPTS, and azeotropic
removal of water led to thiazine 8 in 82% yield. We reasoned
that in a matter similar to the reactions reported for several
primary R-mesyloxy ketones,9 the thiol might initiate reaction
by directly displacing the tosylate followed by intramolecular
condensation of the amine with the ketone under acid catalysis.
Finally, imine to enamine tautomerization would account for
the observed product.
(6) (a) Doorenbos, N. J.; Dorn, C. P. J. Pharm. Sci. 1965, 54, 1219. (b) Steiner,
B.; Koos, M.; Matulova, M.; Proksa, B. Monatsh. Chem. 1993, 124, 425.
(c) Watanabe, S.; Nakazumi, H.; Kitao, T. J. Chem. Soc., Perkin Trans. 1
1988, 1829.
(7) (a) Verhe, R.; De Kimpe, N. In The Chemistry of Functional Groups,
Supplement D; Patai, S., Rappoport, Z., Eds.; John Wiley and Sons:
London, 1983; p 813. (b) Hoffman, R. V.; Jankowski, B. C.; Carr, C. S.;
Duesler, E. N. J. Org. Chem. 1986, 51, 130.
In light of these promising results, we decided to seek
applications of this chemistry on solid-phase paradigms and,
therefore, set out to develop a linker which suitably emulated
the tosyloxy group. This end was accomplished by synthesizing
the immobilized variant to p-TsOH as shown in Scheme 2.18
Thus, to obtain a resin with the physical properties required
for application in SPOS (solid-phase organic synthesis), we
(8) Hoffman, R. V. Tetrahedron 1991, 47, 1109.
(9) Simons, S. S., Jr.; Pons, M.; Johnson, D. F. J. Org. Chem. 1980, 45, 3084.
(10) For investigation of R-keto cations obtained by solvolysis of R-mesyloxy
ketones, see: (a) Creary, X. Acc. Chem. Res. 1985, 18, 3. (b) Creary, X.
J. Am. Chem. Soc. 1984, 106, 5568. (c) Conia, J. M.; Salaun, J. R. Acc.
Chem. Res. 1972, 5, 33.
(11) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2000, 122,
10246.
(12) (a) From ketones: Tuncay, A.; Dustman, J. A.; Fisher, G.; Tuncay, C. I.;
Suslick, K. S. Tetrahedron Lett. 1992, 33, 7647. Lodaya, J. S.; Koser, G.
F. J. Org. Chem. 1988, 53, 210. (b) From enol ethers: Moriary, R. M.;
Epa, W. R.; Penmasta, R.; Awasthi, A. K. Tetrahedron Lett. 1989, 30,
667.
(13) Hoffman, R. V.; Carr, S. C.; Jankowski, B. C. J. Org. Chem. 1985, 50,
5148.
(14) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847.
(15) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Dess, D.
B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (c) Meyer, S. D.;
Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(16) Iwasaki, S.; Schaffner, K. HelV. Chim. Acta 1968, 51, 557.
(17) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122,
7596. (b) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J.
Am. Chem. Soc. 2002, 124, 2245-2258.
(18) Hunt, J. A.; Roush, W. R. J. Am. Chem. Soc. 1996, 118, 9998. Reuter, J.
K.; Nortey, S. O.; Baxter, E. W.; Leo, G. C.; Reitz, A. B. Tetrahedron
Lett. 1998, 39, 975. Baxter, E. W.; Reuter, J. K.; Nortey, S. O.; Reitz, A.
B. Tetrahedron Lett. 1998, 39, 979.
9
J. AM. CHEM. SOC. VOL. 124, NO. 20, 2002 5719