Interestingly, the reaction of alkynyl alcohol 3b (R = Ph, R9 =
Et) with 3.0 equiv. of IBX in DMSO at room temperature failed to
give traces of allenyl ketone 5b, providing instead Z-enedione 6b as
main product in 65% yield after 24 h (entry 2). Increasing the
reaction temperature to 60 uC led to the anticipated increase in
reaction rate affording 6b in 49% yield within 1 h, along with a
significant amount of unidentified byproducts. In both cases,
diketo compound 4b was formed as major byproduct in 28%
and 32% yield, respectively. Treatment of allenyl ketone 5b with
IBX under these conditions did not lead to the formation of
Z-enedione 6b, indicating that allenes are unlikely intermediates in
the IBX-mediated transformation 3 A 6. Since IBX is itself a mild
acid, we probed the effect of added base or acid. Addition of
substoichiometric amounts of p-TsOH (0.5 equiv.) tended to favor
the formation of diketone 4b as well as the formation of the
E-isomer of enedione 6, while the reaction was slowed markedly
when pyridine (1.0 equiv.) was added (55% yield of 6b after 52 h in
the presence of 2 + 3 equiv. of IBX).
As summarized in Table 1,{ the conversion of 3 to 6 can be
accomplished in satisfactory yields under notably practical
conditions: substrate concentration of 0.5 M, 3.0 equiv. of IBX,
23 uC, reaction times 12–24 h (entries 2–14).10 Although not
extensively examined at this point, the formation of Z-enediones 6
took place with R9 being alkyl and phenyl substituents (entries
2–6). A broad variety of 2-alkynyl alcohols 3 with different aryl
and heteroaryl substituents R were effectively converted into the
enediones (entries 7–12). The reaction of alkenyl substituted
substrates 3m and 3n (R = alkenyl) with IBX also took place in
moderate yield (entries 13–14). The assignment of Z stereo-
chemistry for all compounds 6 was based on the JCHLCH coupling
constant of # 12 Hz and was confirmed by NOE studies with 6b.
Under acidic conditions, rapid isomerization to the more stable E
isomer (JCHLCH # 16 Hz) occurred.
The method described above provides an easy and flexible entry
to Z-enediones which are classically prepared by oxidative ring
opening of 2,5-disubstituted furans.11 The synthetic utility of
this route is somewhat depreciated by the difficulty in obtaining
the furan precursors. Alternatively, approaches using diazo
compounds12 have been suggested to obtain the desired
Z-enediones.
Fig. 2 Possible mechanism for the formation of Z-enediones by IBX.
being studied. Possible applications in synthesis will be reported in
due course.{
This project was supported by the ‘‘Bundesministerium fu¨r
Bildung und Forschung’’ and the ‘‘Fonds der Chemischen
Industrie’’. We thank A. Duschek, F. Benisch and A.
Obenhuber for excellent assistance.
Notes and references
{ General Procedure: IBX (0.66 mmol, 184 mg) was added to a solution of
alcohol 3 (0.66 mmol) in DMSO (1.3 mL) and the reaction vial was sealed,
protected from light and stirred at room temperature. After 30 min,
additional IBX (0.66 mmol, 184 mg) was added. After stirring for 1 h at
room temperature, a third equivalent of IBX (0.66 mmol, 184 mg) was
added. The reaction mixture was then stirred at room temperature for 10–
22 h (until TLC analysis indicated complete consumption of starting
material and of intermediary occurring ketone 7), diluted with CH2Cl2
(20 mL), and stirring was continued for 30 min to precipitate the insoluble
byproduct, which was removed by filtration. The precipitate was washed
with CH2Cl2 (2 6 5 mL), and the combined filtrate was subsequently
diluted with water (20 mL). The phases were separated and the aqueous
phase was extracted with CH2Cl2 (2 6 5 mL). The combined organic
phases were washed with brine (30 mL), dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by flash chromatography
on silica to afford the corresponding Z-enediones 6 in 33–65% yield.
A plausible mechanism for the IBX-mediated formation of
Z-enediones reported herein is shown in Fig. 2. Oxidation of
alcohol 3 with IBX produces ketone 7. In the case of R = alkyl, 7
undergoes isomerization to allenyl ketone 5 in the presence of IBX
(path A). Since the direct oxygenation at C4 is unlikely, we suggest
the formation of intermediate 8, which undergoes intramolecular
oxygen transfer when R is aryl or alkenyl using the oxide ligand of
IBX as a nucleophile (path B). Expulsion of iodosobenzoic acid
(IBA) and subsequent IBX oxidation then gives diketo compound
4 as a byproduct. As the major pathway, formal [3,3]-sigmatropic
rearrangement of intermediate 9 produces allene species 10, which
after proton transfer and loss of IBA gives enedione 6. This
process involves, at some stage, the delivery of a proton to the
central carbon of the allene p-system from the sterically less
hindered face giving the thermodynamically less stable Z alkene
with high stereoselectivity.13
1 For the synthesis of IBX, see: C. Hartmann and V. Meyer, Chem. Ber.,
1893, 26, 1727; M. Frigerio, M. Santagostino and S. Sputore, J. Org.
Chem., 1999, 64, 4537.
2 For reviews, see: T. Wirth, Angew. Chem., Int. Ed., 2001, 40, 2812;
V. V. Zhdankin and P. J. Stang, Chem. Rev., 2002, 102, 2523; I. Kumar,
Synlett, 2005, 1488; T. Wirth, Angew. Chem., Int. Ed., 2005, 44, 3656.
3 M. Frigerio and M. Santagostino, Tetrahedron Lett., 1994, 35, 8019;
S. De Munari, M. Frigerio and M. Santagostino, J. Org. Chem., 1996,
61, 9272; J. D. More and N. S. Finney, Org. Lett., 2002, 4, 3001;
Currently, the experiments are being extended to the synthesis of
more complex enediones. As the Z-configured enediones should be
excellent dienophiles, their cycloaddition chemistry is currently
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 764–766 | 765
Crone, Benedikt
