Oxidation of silyl enol ethers by using IBX and IBX·N-oxide complexes: A mild and selective reaction for the synthesis of enones

Article abstract of DOI:10.1002/1521-3773(20020315)41:6<996::AID-ANIE996>3.0.CO;2-I

α,β-Unsaturated carbonyl compounds can be prepared by the oxidation of trimethylsilyl enol ethers with IBX (1) or IBX·MPO (2). A diverse set of carbonyl compounds can be dehydrogenated with ease by using this method. Trimethylsilyl enol ethers such as 4, which are formed in situ by the addition of an organometallic species to an enone, can be dehydrogenated with 1 or 2 to give a functionalized enone (e. g. 3 → 5). IBX = iodoxybenzoic acid; MPO = 4-methoxypyridine-N-oxide.

Full text of DOI:10.1002/1521-3773(20020315)41:6<996::AID-ANIE996>3.0.CO;2-I

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Table 2. Effect of concentration and solvent composition on the outcome
of the IBX ¥ MPO-mediated dehydrogenation reaction.[a]
[7] K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, S. Barluenga, K. W. Hunt, R.
Kranich, J. A. Vega, J. Am. Chem. Soc., in press.
[8] a) K. C. Nicolaou, P. S. Baran, R. Kranich, Y.-L. Zhong, K. Sugita, N.
Zou, Angew. Chem. 2001, 113, 208; Angew. Chem. Int. Ed. 2001, 40,
202; b) K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, J. A. Vega, Angew.
Chem. Int. Ed. 2000, 112, 2625; Angew. Chem. Int. Ed. 2000, 39, 2525;
c) K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, J. Am. Chem. Soc. 2001,
123, 3183.
[9] a) S. D. Meyer, S. L. Schreiber, J. Org. Chem. 1994, 59, 7 549; b) S. De
Munari, M. Frigerio, M. Santagostino, J. Org. Chem. 1996, 61, 9272.
[10] a) A. R. Katritszky, B. L. Duell, H. D. Durst, B. L. Knier, J. Org.
Chem. 1988, 53, 3972; b) V. T. Zhdankin, R. M. Arbit, B. L. Lynch, P.
Kiprof, J. Org. Chem. 1998, 63, 6590.
Entry Substrate (m) Solvent
IBX ¥ MPO Time Yield
[equiv]
[h]
[%][b]
1
2
3
4
5
6
7
8
9
35 (0.20)
35 (0.20)
35 (0.20)
35 (0.20)
14 (0.40)
14 (0.50)
14 (0.75)
16 (0.36)
16 (0.48)
16 (0.55)
16 (0.55)
DMSO
DMSO/THF (1:1)
DMSO/CH2Cl2 (2:1) 1.5
DMSO/CH2Cl2 (1:1) 1.5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1.5
1.5
15
15
6
0
< 40
92
15
40
40
40
22
22
22
22
91
68
72
87
82
76
73
86
2.0
2.0
2.0
2.2
2.2
2.2
ˆ
[11] In addition to the ligands shown in Figure 1, nBu3P O, tBuOH,
2-picoline-N-oxide, and 4-phenylpyridine-N-oxide were examined,
but the rate of reaction for these complexes was lower than that of
uncomplexed IBX under the same conditions.
10
11
DMSO/CH2Cl2 (2:1) 2.2
[a] Reactions were carried out on a 1.0 mmol scale. [b] Yield of isolated
chromatographically pure compound.
[12] The commercially available hydrate of MPO, which is considerably
less hygroscopic than NMO, was used. The IBX ¥ NMO complex is
prepared in the same manner and can also be successfully employed at
ambient temperature, although the reaction times are longer and the
yields show greater variation with this reagent.
[13] When CH2Cl2 is used as cosolvent the reaction rate is retarded;
however, its addition was frequently necessary to obtain complete
solubility of the substrate (see Table 2, entries 1 4).
dehydrogenation reaction is the subject of continuing re-
search. Elucidation of these features should facilitate further
rational designs toward expanding this new area of chemistry
whose applications in organic synthesis are expected to be
widespread. These results introduce a new paradigm for
modifying the iodine(v) nucleus and, hence, controlling its
reactivity profile.
[14] M. Frigerio, M. Santagostino, S. Sputore, J. Org. Chem. 1999, 64, 4537.
[15] We thank Professor Giannis and Dr. Mazitschek for helpful
discussions regarding the experimental conditions for this reaction.
Experimental Section
IBX (1.2 mmol) and MPO[12] (1.2 mmol) were added to DMSO (see Table 2
for concentration effect) and stirred at ambient temperature until complete
dissolution (15 60 min). The carbonyl compound (0.5 mmol) was added,
and the mixture was stirred vigorously at the same temperature. The
reaction progress was monitored by thin-layer chromatography. The
reaction mixture was diluted with an equal volume of aqueous NaHCO3
(5%) solution and extracted with diethyl ether (3 Â ). The combined
organic phase was filtered through a pad of celite and then washed with
saturated NaHCO3 solution, water, and brine. After drying (MgSO4), the
organic layer was concentrated to yield the crude product, which could be
further purified by column chromatography (silica gel).
Oxidation of Silyl Enol Ethers by Using IBX
and IBX ¥ N-Oxide Complexes: AMild and
Selective Reaction for the Synthesis of
Enones**
K. C. Nicolaou,* David L. F. Gray, Tamsyn Montagnon,
and Scott T. Harrison
Our recent explorations into the chemistry of iodine(v)
reagents have highlighted their remarkable synthetic utili-
ty.[1 8] In particular, IBX (o-iodoxybenzoic acid) has proved to
have a rather unique set of properties which can be
appropriately exploited to manipulate the course of a
reaction.[7, 9] In the preceding paper,[9] we delineated the
For optimal results in this reaction the following points should be noted:
a) in cases in which the substrate was not soluble in the DMSO solution of
IBX ¥ MPO, increasing amounts of CH2Cl2[13] were added as co-solvent until
dissolution, and/or the rate was optimized (see Table 2); b) a large excess of
IBX ¥ MPO complex is not recommended, as the rather insoluble IBA
formed under these conditions causes precipitation of IBX; in this respect it
is also important that the IBX quality is assured by preparation in strict
accordance to the method of Santagostino[14] and subsequent checking by
means of 1H NMR spectroscopy; c) commercial DMSO (Aldrich) was used
directly without prior drying; furthermore, it was noted that anhydrous
solvent (sequential drying over activated 4-ä molecular sieves) was
deleterious to the yield; d) IBX is light-sensitive, thus the reaction vessel
was covered with aluminum foil.[15]
[*] Prof. Dr. K. C. Nicolaou, D. L. F. Gray, Dr. T. Montagnon,
S. T. Harrison
Department of Chemistry and The Skaggs Institute for Chemical
Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037(USA)
Fax : (‡1)858-784-2469
Received: November 28, 2001 [Z18291]
E-mail: kcn@scripps.edu
and
[1] K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, J. Am. Chem. Soc. 2000, 122,
7596.
Department of Chemistry and Biochemistry
University of California San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[2] K. C. Nicolaou, T. Montagnon, Y.-L. Zhong, P. S. Baran, J. Am. Chem.
Soc., in press.
[**] We thank Dr. D. H. Huang and Dr. G. Suizdak for NMR spectroscopic
and mass spectrometric assistance, respectively. Financial support for
this work was provided by The Skaggs Institute for Chemical Biology,
a GlaxoWellcome fellowship (T.M.), a Louis R. Jabinson fellowship
(D.L.F.G.), and grants from Amgen, Array Biopharma, Boehringer-
Ingelheim, Glaxo, Hoffmann-LaRoche, DuPont, Merck, Novartis,
Pfizer, and Schering Plough.
[3] T. Wirth, U. H. Hirt, Synthesis 1999, 1271.
[4] K. C. Nicolaou, P. S. Baran ,Y.-L. Zhong, K. Sugita, J. Am. Chem. Soc.,
in press.
[5] K. C. Nicolaou, K. Sugita, P. S. Baran, Y.-L. Zhong, J. Am. Chem. Soc.,
in press.
[6] K. C. Nicolaou, K. Sugita, P. S. Baran, Y.-L. Zhong, Angew. Chem.
2001, 40, 213; Angew. Chem. Int. Ed. 2001, 40, 207.
996
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discovery and evolution of IBX ¥ N-oxide complexes and their
use in the dehydrogenation of ketones and aldehydes at
ambient temperature.[9] We have postulated that these IBX-
mediated dehydrogenation reactions[4,7,9] proceed through
enolization (facilitated by the reagent) with concomitant
capture of the enolate moiety, followed by single electron
transfer (SET) to IBX and rearrangement of the resulting
radical cation to give the a,b-unsaturated carbonyl com-
pound.[7] This assessment led us to speculate that silyl enol
ethers might undergo a similar oxidation with IBX, which
would be a new, complimentary oxidation method for
the synthesis of the much coveted enone functionality
(Scheme 1A). Herein we report the successful implementation
Figure 1. Graph of the rate of conversion of the TMS enol ether derived
from cyclooctanone (31), to cyclooctenone (32) by using IBX (1) or IBX ¥
MPO complex (2).[29] X ˆ Conversion of TMS enol ether into cyclo-
octenone (32).
16]
for its implementation.[10 Amongst the known procedures
for this transformation, the palladium-catalyzed proto-
col,[15, 16] originally introduced by Saegusa and co-workers,[15]
stands out by virtue of its relative efficiency and mild nature.
However, even within this preferred method, a great variation
is seen in the reaction conditions, in the catalyst employed
and, ultimately, in the yields of product. These disadvantages,
when added to the expense associated with the use of
palladium and its incompatibility with various functional
groups, allow considerable room for improvement in this area.
As our investigations with hypervalent iodine(v) reagents
evolved, it was gratifying to discover the remarkable ease with
which IBX-based reagents, particularly the IBX ¥ MPO com-
plex (2, Figure 1), converted TMS enol ethers into a,b-
unsaturated carbonyl compounds.
As shown in Table 1, a wide variety of sensitive function-
alities can be tolerated under the employed conditions; the
reaction times are short, and the yields are often very high.
Thus, substrates that contain reactive functionalities, for
example, amines, sulfides, mesylates, TBS ethers, dithianes,
or primary iodides (Table 1, entries 2, 3, 6, 9, 12, and 13) all
furnished the desired enones in high yield. Significantly, the
protocol works well in a number of situations which caused
problems with known methods. For example, generation of
allylic epoxide 30 proceeds in high yield (Table 1, entry 10)
and a proximal, but unconjugated olefin in the product 26
(Table 1, entry 8) remains unaffected under these conditions.
Furthermore, a survey of the literature[17 19] revealed that the
oxidation of indanones to form indenones is frequently
cumbersome or can be plagued by low yields or multiple by-
products. In contrast, the current method performs admirably
well in this challenging situation (Table 1, entries 4 and 5), and
furnishes the corresponding enones in yields that significantly
exceed those obtained by the best published procedure
(<75%), which involves the use of a stoichiometric amount
of Pd(OAc)2 to oxidize the silyl enol ether.[19] Although the
oxidation of cyclooctanone (31; Table 1, entry 11) may appear
trivial, this specific ring size, and hence strain, leads to a lack
Scheme 1. Proposed mechanism for A) dehydrogenation, or B) ketone
formation, from enol ethers with the IBX ¥ MPO complex.
of this strategy in the conversion of a diverse set of ketones
into their a,b-unsaturated counterparts by the fast oxidation
of the corresponding TMS enol ethers (for abbreviations, see
legends in schemes) induced by IBX (1) or the IBX ¥ MPO
complex (2, Figure 1).[9] We also describe the extension of this
powerful method to cascade sequences that involve tandem
conjugate additions of organometallic reagents to enones,
trapping of the resultant enolates, and regeneration of the
original enone motif, thereby increasing the molecular com-
plexity without sacrificing functionality.
The oxidation of silyl enol ethers to enones has frequently
been used in the construction of complex molecules, and the
multiplicity of protocols available attests not only to its
versatility but also to deficiencies in the known methodology
Angew. Chem. Int. Ed. 2002, 41, No. 6
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1433-7851/02/4106-0997 $ 17.50+.50/0
997

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Table 1. Facile room temperature dehydrogenation of ketones via the corresponding trimethylsilyl enol ethers by using IBX ¥ MPO complex.[a]
Entry Substrate
Product
TMS enol ether formation[b] IBX ¥ MPO [equiv] Time [min] Yield [%][c]
A
1.5
40
96
1
2
3
A
A
1.5
1.5
40
40
92
88
4
A
1.3
40
94
5
A
1.5
30
95
6
C
3.0
240
72[d]
7
8
9
B
A
C
1.5
1.5
1.5
60
40
60
94[e]
94
62[f]
10
11
12
C
A
C
1.5
1.1
4.0
40
20
93
96
360
43[g]
13
C
2.0
120
76
[a] Reactions were carried out on a 0.1 5.0 mmol scale in DMSO/CH2Cl2 (see main text for discussion). [b] A: ref. [20], B: ref. [21], C: ref. [22]. [c] Yield of
isolated chromatographically pure compound, except where stated. The starting ketone was frequently recovered as the product of enol ether hydrolysis but
is only noted when >10%. [d] Plus 23% inseparable ketone, ratio assigned by means of 1H NMR spectroscopy. [e] Product distribution assigned by means of
1H NMR spectroscopy. [f] Plus 33% ketone. [g] Plus 52% inseparable ketone, ratio assigned by means of 1H NMR spectroscopy. MPO ˆ 4-methoxypyridine-
N-oxide.
998
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of specificity in the alternate IBX methodologies,[7, 9] in
which the dienone is a major component of the product
mixture. However, the present method allows for the intro-
duction of just one double bond through the formation of the
silyl enol ether, followed by oxidation with 2.
Table 2. Dehydrogenation of trimethylsilyl enol ethers, formed in situ
from an enone.[a]
Entry
Substrate
Silyl enol ether
Product
Yield [%][b]
1
90[c]
The method is not without limitations, as substituents at the
a position of the ketone substrate lead to some complications,
including the regioselective generation of the silyl enol ether,
22]
an issue which is amply covered in the literature.[20 In the
2
3
97[d]
simplest case of a substitution that we examined (Table 1,
entry 7) the oxidation reaction is essentially nonselective
(exo/endo ca. 5:3). With compounds that bear a phenyl group
at the a position, the desired oxidation reaction was unfea-
sible as a result of the propensity of the highly stabilized
incipient radical cation (e.g. IIa, Scheme 1A) to dimerize. The
influence of steric hindrance around the carbonyl group could
not be easily evaluated owing to the difficulties in accessing a
range of a-substituted substrates (see above). However, an
adjacent tertiary center (Table 1, entry 9) and an iodine atom
(Table 2, entries 5 and 7) are both well tolerated. In a number
of examples (e.g. Table 1, entries 6, 9, and 12), the alternate
reaction pathway, that is, hydrolysis of the silyl enol ether back
to the original starting ketone (Scheme 1B), proved to be of
greater significance. There are generally two reasons for this
observed side reaction. First, the insolubility of the substrate
in DMSO, such as with a steroid-derived enol ether (Table 1,
entry 9), which required the addition of a large volume of
CH2Cl2, thus leading to a slower oxidation reaction and
competing hydrolysis.[23] In the enol ethers derived from
substrates 19, 33, and 35 (Table 1, entries 6, 12, and 13)
coordination to the oxidant through heteroatoms may be
responsible for the need to use excess IBX, thus leading to
the retardation of the desired reaction and varying degrees
of competing hydrolysis. The second reason relates to
the reactivity of the silyl enol ether (Table 2, entry 1).
Thus, when highly reactive species were utilized, hydrolysis
was rapid (even beginning upon isolation of the enol ether),
and oxidation was compromised. This result precluded
the inclusion of silyl ketene acetals as substrates for this
method.
Incorporation of the current oxidation method within a
cascade reaction could allow a rapid increase in molecular
complexity. Particularly attractive appeared to be a sequence
that involved conjugate addition to an enone, followed by in
situ silyl enol ether formation, and subsequent isolation and
oxidation of the resulting product to regenerate a new enone
functionality for further elaboration. Table 2 summarizes the
results of the implementation of this strategy. Thus, the
addition of cuprate reagents (RMgX, CuBr¥ SMe2) to enones
37, 40, 43, and 46 (Table 2, entries 1 4) followed by quenching
with TMSCl and oxidation of the resulting silyl enol ethers
with IBX (1) or IBX ¥ MPO (2) furnished the elaborated
enones 39, 42, 45, and 48, respectively, in high overall yields.
Some of these products were difficult to synthesize by means
of alternative protocols.[24] This is particularly true for the
sensitive enone product 48, which was difficult to obtain from
the corresponding saturated ketone. This protocol was
extended to the synthesis of enones substituted at the a-
position with iodine (Table 2, entries 5 and 7) and at the b
94
4
47[c,d]
5
6
7
98
98
82[c]
[a] Reactions were carried out on a 2.0 mmol scale. [b] Overall yield of
pure isolated compound, no chromatography required. [c] Chromatogra-
phy required to separate enone from hydrolysis product. [d] Oxidation
performed without complex, IBX (1.5 2.0 equiv) added as a solid to a
solution of enol ether in DMSO (see 2 below). Reagents and conditions:
Entries 1 5; 1) CuBr¥ SMe2 (2.0 equiv), THF, À788C add RMgX
(4.0 equiv), 30 min; then add TMEDA (4.0 equiv), TMSCl (5.0 equiv),
enone (1.0 equiv) in THF, À78 !258C, 30 min. Entries 6 and 7;
1) Et2AlCN (1.3 equiv), hexanes, À108C, add enone, 90 min; then pyridine
(4.0 equiv), TMSCl (3.7equiv), À10 !258C, 2 h. 2) Add preformed
solution of IBX ¥ MPO complex (1.5 2.0 equiv, 0.4m in DMSO) to
substrate, vigorous stirring, 30 60 min. TMS ˆ trimethylsilyl. TMEDA ˆ
N,N,N',N'-tetramethylethylenediamine.
position with cyanide (Table 2, entries 6 and 7) by the use of
Et2AlCN.[25]
IBX (1) and IBX ¥ MPO complex (2) were examined in
their reactions with a range of enol ethers derived from
cyclohexanone (Table 3). Only the TBS enol ether 58c was
inert to the reaction conditions, as all the remaining substrates
led to ketone 59 and/or enone 60 as products. The extent to
which the enone arose from the complex-mediated dehydro-
genation of the corresponding saturated ketone[9] was not
significant, although it was found to be dependent on the
substrate. The oxidation of the TES enol ether 58b was, as
predicted, slower than that of the TMS enol ether 58a. When
the TES enol ether was used in more sophisticated examples
Angew. Chem. Int. Ed. 2002, 41, No. 6
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Table 3. Reactions of various enol ether derivatives of cyclohexanone with
IBX ¥ MPO complex.
[1] K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, K. Sugita, J. Am. Chem. Soc.,
in press.
[2] K. C. Nicolaou, Y.-L. Zhong, P. B. Baran, Angew. Chem. 2000, 112,
636; Angew. Chem. Int. Ed. 2000, 39, 622; Corrigendum: K. C.
Nicolaou, Y.-L. Zhong, P. B. Baran, Angew. Chem. 2000, 112, 1592;
Angew. Chem. Int. Ed. 2000, 39, 1532.
[3] K. C. Nicolaou, K. Sugita, P. S. Baran, Y.-L. Zhong, J. Am. Chem. Soc.,
in press.
[4] K. C. Nicolaou, P. S. Baran, R. Kranich, Y.-L. Zhong, K. Sugita, N.
Zou, Angew. Chem. 2001, 113, 208; Angew. Chem. Int. Ed. 2001, 40,
202.
[5] K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, S. Barluenga, K. W. Hunt, R.
Kranich, J. A. Vega, J. Am. Chem. Soc., in press.
[6] a) K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, Angew. Chem. 2000, 112,
639; Angew. Chem. Int. Ed. 2000, 39, 625; b) K. C. Nicolaou, P. S.
Baran, Y.-L. Zhong, J. A. Vega, Angew. Chem. 2000, 112, 2625;
Angew. Chem. Int. Ed. 2000, 39, 2525.
Enol ether
Products[b]
Time [h]
58
X
58
59
60
a:
b:
c:
d:
e:
f:
TMS
TES
TBS
Ac
0
0
1
8
3
3
:
:
:
:
:
:
0
1
0
1
6
8
:
:
:
:
:
:
1
18
0
0
1
1
8
12
12
2
Me
ˆ
CH2CH CH2
1
1
[7] K. C. Nicolaou, T. Montagnon, Y.-L. Zhong, P. S. Baran, J. Am. Chem.
Soc., in press.
[8] K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, J. Am. Chem. Soc. 2000, 122,
7596.
[a] see main text for discussion. [b] Ratios determined by 1H NMR
spectroscopy.
[9] K. C. Nicolaou, T. Montagnon, P. S. Baran, Angew. Chem. 2002, 114,
1035; Angew. Chem. Int. Ed. 2002, 41, 993.
[10] E. Friedrich, W. Lutz, Angew. Chem. 1977, 89, 426; Angew. Chem. Int.
Ed. Engl. 1977, 16, 413.
[11] H. J. Reich, S. Wollowitz, J. E. Trend, F. Chow, D. F. Wendelborn, J.
Org. Chem. 1978, 43, 1697.
[12] P. Magnus, A. Evans, J. Lacour, Tetrahedron 1992, 33, 2933.
[13] I. Fleming, I. Paterson, Synthesis 1979, 736.
such as steroid 27 and amine 33 (Table 1, entries 9 and 12), no
significant dehydrogenation occurred, with hydrolysis being
the major pathway. The ease with which IBX effects
hydrolysis of the relatively stubborn 58e may be readily
rationalized by the mechanism shown in Scheme 1B, since
both the Lewis acidity and nucleophilicity of IBX are well
known.[26] We propose that the oxidation reaction of TMS
enol ethers is likely to proceed through a SET pathway by
analogy to the original IBX-based method (Scheme 1A).[7]
In conclusion, we have developed an extremely mild and
efficient procedure for the oxidation of silyl enol ethers to the
corresponding a,b-unsaturated carbonyl compounds through
the use of IBX (1) or its MPO complex 2, which is
complimentary to the method delineated in the preceding
paper.[9] By careful selection of one of these two protocols,
based on the substrate features, a diverse set of carbonyl
compounds can now be dehydrogenated with ease. This
method exhibits a broad scope, affords clean products in high
yields, and is expected to find wide-ranging applications in
organic synthesis.
[14] M. E. Jung, Y.-G. Pan, M. W. Rathke, D. F. Sullivan, R. P. Woodbury, J.
Org. Chem. 1977, 42, 3961.
[15] Y. Ito, T. Hirao, T. Saegusa, J. Org. Chem. 1978, 43, 1011.
[16] R. C. Larock, T. R. Hightower, G. A. Kraus, P Hahn, D. Zheng,
Tetrahedron Lett. 1995, 36, 2423, and references therein.
[17] F. D. Bellamy, J. B. Chazun, K. Ou, Tetrahedron 1983, 39, 2803.
[18] D. Mai, S. Ghorai, N. Hazra, Indian J. Chem. Sect. B 2001, 40, 994.
[19] F. M. Hauser, M. Zhou, Y. Sun, Synth. Commun. 2001, 1, 7 7 .
[20] Procedure A involved the generation of the silyl enol ether at 08C in
CH2Cl2 (0.2m solution) by treatment with Et3N (3.0 9.0 equiv)
followed by addition of TMSOTf (1.5 3.0 equiv); the workup was
the same as that described in ref. [21b]; OTf ˆ trifluoromethanesul-
fonate.
[21] a) P. Cazeau, F. Duboudin, F. Moulinnes, O. Babot, J. Dunogues,
Tetrahedron 1987, 43, 2075; b) R. Rathore, J. K. Kochi, J. Org. Chem.
1996, 61, 627.
[22] Procedure C involved the generation of the silyl enol ether by
deprotonation of the ketone at À408C in THF (NaHMDS, 1.0m
solution in THF, 1.2 equiv) followed by quenching with TMSCl
(1.5 equiv) at À408C and subsequent warming to 08C; the workup
was the same as that described in ref. [21b]; HMDS ˆ hexamethyldi-
silazane.
Experimental Section
Typical procedure: IBX[27] and MPO[28] (1.1 to 4.0 equiv) were dissolved in
DMSO (0.4m) in an equimolar ratio at ambient temperature. The solvent
used was not dried, and no precautions were taken to exclude moisture or
oxygen from the reaction vessel. The TMS enol ether was generated by
[23] J. H. Horner, M. Newcomb, J. Am. Chem. Soc. 2001, 123, 4364.
[24] The selenium-[11] and palladium-based[15] protocols delivered 48 in
yields of only 7and 24%, respectively.
[25] M. Samson, M. Vandewalle, Synth. Commun. 1978, 8, 231.
[26] R. A. Moss, S. Swarup, S. Ganguli, J. Chem. Soc. Chem. Commun.
1987, 860.
using one of a number of established procedures (depending on the
22]
substrate) from the carbonyl compound (1.0 equiv).[20
The crude TMS
enol ether was vacuum-dried wherever possible to minimize the amount of
(TMS)2O present, as this was detrimental to the desired reaction. The IBX ¥
MPO solution was added in one portion at ambient temperature to the
crude TMS enol ether dissolved in a minimum of DMSO. In cases in which
the substrate was not completely soluble in DMSO, CH2Cl2 was added
dropwise to the suspension (or emulsion) until clear. The CH2Cl2 content
was always minimized, as its use as a cosolvent retards the reaction.[4, 23] The
solution was stirred vigorously, and progress was monitored by means of
thin-layer chromatography. Upon completion, the reaction mixture was
diluted with aqueous NaHCO3 (5%) and extracted with diethyl ether (3 Â
). The combined organic phase was filtered through a pad of celite and
washed with saturated aqueous NaHCO3, water, and brine. After drying
(MgSO4), the solvent was removed in vacuo to yield the crude product,
which could be purified further by means of column chromatography.
[27] Complex 2 was found to be the fastest agent for effecting this
oxidation, as was the case for the ambient temperature dehydrogen-
ation of carbonyl compounds,[9] although IBX (1) itself could be used
without any detriment to the reaction in simpler cases.
[28] The commercially available hydrate of MPO was used.
[29] In this case, the reaction was carried out at higher dilution to give a
1
timescale appropriate for accurate monitoring by means of H NMR
spectroscopy.
Received: November 28, 2001 [Z18292]
1000
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1433-7851/02/4106-1000 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 6