Modulation of the reactivity profile of IBX by ligand complexation: Ambient temperature dehydrogenation of aldehydes and ketones to α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1002/1521-3773(20020315)41:6<993::AID-ANIE993>3.0.CO;2-U

The reactivity profile of IBX can be altered by complexation with various ligands (e. g. 1-4). A new complex, IBX·MPO, is a remarkably effective oxidant and allows the room-temperature dehydrogenation of carbonyl compounds, for example, the formation of cyclooctenones 6 and 7 from cyclooctanone 5. IBX = iodoxybenzoic acid; MPO = 4-methoxypyridine-N-oxide.

Full text of DOI:10.1002/1521-3773(20020315)41:6<993::AID-ANIE993>3.0.CO;2-U

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development of a room-temperature dehydrogenation reac-
tion of carbonyl compounds which tolerates a greater breadth
of functional groups than previously realized. This develop-
ment became possible through the introduction of a new class
of oxidants, the complexes of IBX with N-oxides (4,
Scheme 1), which often exhibit superior reactivity to that of
the parent reagent.
Extensive investigations[2] into the original IBX-mediated
dehydrogenation reaction demonstrated that at elevated
temperatures, IBX dissolved in DMSO acted as a single
electron transfer (SET) agent and as such effected oxidation
adjacent to carbonyl functionalities to furnish their a,b-
unsaturated counterparts (Scheme 2). On a number of
Modulation of the Reactivity Profile of IBX by
Ligand Complexation: Ambient Temperature
Dehydrogenation of Aldehydes and Ketones to
a,b-Unsaturated Carbonyl Compounds**
K. C. Nicolaou,* Tamsyn Montagnon, and Phil S. Baran
We have recently reported[1, 2] that the use of IBX (o-
iodoxybenzoic acid)[3] represents a highly adept method for
accessing the coveted, yet synthetically challenging, a,b-
unsaturated carbonyl motif by effecting the dehydrogenation
of ketones and aldehydes at elevated temperatures. Our
8]
interest[4 in this unique iodine(v) species has grown further
owing to the tantalizing discovery that its chemistry can be
modulated by complexation with a variety of ligands, thus
leading to dramatic changes in its reactivity profile.[2,8a, 10] The
ligand appended to IBX not only allows moderation of the
reagent×s reactivity, but also differentiation between reaction
pathways when a number of alternatives are available
(Scheme 1).[2] Herein, we report the discovery and elucidation
of this new and exciting concept and its application to the
Scheme 2. Postulated mechanism for the IBX-mediated dehydrogenation
of ketones and aldehydes to a,b-unsaturated carbonyl compounds.
occasions, however, when these reactions were performed in
deuterated DMSO and monitored by means of 1H NMR
spectroscopy, unexpected signals were observed which we
surmised could derive from a complex between DMSO and
IBX (3, Scheme 2). Because these observations were made
only in samples that had been subjected to heating at >508C,
and since our procedure to dehydrogenate carbonyl species
required elevated temperatures, we speculated that it might
be a complex of IBX and DMSO that was the active agent in
these oxidation reactions. We were, therefore, pleased to find
that heating IBX in DMSO at 758C for 30 min provided a
solution, which upon cooling to 258C could indeed effect
limited dehydrogenation of a test substrate, cyclooctanone (5,
see Figure 1, trace d). The conversion after this activation
process was greater than that observed in a parallel experi-
ment with IBX that had merely been dissolved in DMSO at
room temperature (Figure 1, trace e). With these promising
results in hand, the search for other IBX complexes with
improved reactivity was immediately initiated.
Scheme 1. Access to, and reactivity of novel iodine(v)-based reagents
formed by complexation of IBX with different ligands.
[*] Prof. Dr. K. C. Nicolaou, Dr. T. Montagnon, Dr. P. S. Baran
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
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
A number of well-characterized complexes of IBX with
hydroxy and 1,2-dihydroxy compounds and IBX analogues
have been reported in the literature,[9b] having been observed
during studies into the Dess-Martin periodinane (DMP)- and
IBX-mediated oxidation of alcohols. Furthermore, we were
mindful of the dramatic effect that a switch in reaction media
[**] 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,
fellowships from GlaxoWellcome (T.M.) and the National Science
Foundation (P.S.B.), and grants from Amgen, Array Biopharma,
Boehringer-Ingelheim, Glaxo, Hoffmann-LaRoche, DuPont, Merck,
Novartis, Pfizer, and Schering Plough.
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993

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produced during our forays into the IBX-mediated cyclization
or oxidation of multifunctionalized molecules and the im-
portance of solvent (THF) coordination in this instance.[2, 8a]
We surmised, however, that heteroatom oxide ligands (e.g.
DMSO), when appended to IBX, might provide a unique
electronic environment around the iodine center which could
enhance the propensity of these reagents to serve as electron
sinks. As such, we focused our first study on this category of
potential ligands; the results are illustrated in Figure 1.[11]
Figure 2. 1H NMR spectra (500 MHz, [D6]DMSO) of NMO (top), IBX
(center), and the observed NMO ¥ IBX complex (bottom).
Figure 1. Graph of the rate of conversion of cyclooctanone (5) into
dehydrogenated products (cis enone 6 and dienone 7) over time, for
different IBX ¥ ligand systems: a) IBX ¥ MPO; b) IBX ¥ NMO; c) IBX ¥ tri-
methylamine-N-oxide; d) IBX ¥ DMSO formed by dissolution at 758C for
30 min; e) IBX ¥ DMSO formed by dissolution at 258C; f) IBX ¥ DMSO
formed by dissolution at 908C for 20 min (leads to significant quantities of
IBA from the reduction of IBX by DMSO which inhibits the desired
reaction[2]). Reagents and conditions: IBX/ligand 1:1 (2.2 equiv),
[D6]DMSO, 258C, conversion monitored by means of 1H NMR spectros-
copy. x ˆ Total dehydrogenation.
respect to the quality of IBX, the concentration, and the
substrate solubility (see Table 2and Experimental Section).
Substrates that previously did not lead to products in
satisfactory yields for a variety of reasons, perform well under
the present conditions (Table 1, entries 8, 10, 12, and 17).
Thus, the advantages of this method are particularly apparent
with acid-labile substrates and in cases in which b-elimination
is possible. Furthermore, the first productive example of the
inclusion of an alkyl amine in a substrate subjected to IBX-
mediated dehydrogenation was observed (Table 1, entry 17).
The success of the reaction of this challenging substrate can be
attributed directly to the lower temperature employed, since
substrates with an amine functionality decompose readily
when exposed to IBX at elevated temperatures. The IBX ¥
MPO complex is the reagent of choice for the dehydrogen-
ation of reactive or volatile aldehydes, because the method is
particularly efficient and mild, and minimal purification is
required (Table 1, entries 5 8). Furthermore, other IBX-
induced SET reactions[2, 8a] such as benzylic oxidations[8c] do
not compete with carbonyl dehydrogenation (Table 1, en-
tries 15 and 16).
In conclusion, we have unearthed new details about the
nature of the oxidant in the IBX-mediated dehydrogenation
of carbonyl compounds originally discovered in these labo-
ratories[1, 2] which suggest that the active species in this
reaction is most likely a complex between IBX and DMSO.
By using insight gained in the rational design of new oxidants,
IBX ¥ MPO was developed as an effective dehydrogenation
reagent for carbonyl compounds and exhibits high selectivity
under remarkably mild conditions. The precise origins of the
accelerating effect induced by the N-oxide complexes 4 in this
The formation of a distinct complex was most easily
detected in the case of N-methylmorpholine-N-oxide
(NMO). Thus, when NMO and IBX (1:1) were dissolved in
deuterated DMSO at room temperature, 100% conversion
into a complex was clearly observed (1H and 13C NMR
spectroscopy, see Figure 2).
The most gratifying result to emerge from this initial survey
of potential ligands was observed with 4-methoxypyridine-N-
oxide (MPO), which resulted in the clean and effective
conversion of cyclooctanone (5) into the dehydrogenated
products (6 and 7, Figure 1, trace a). The success of this ligand
relative to other N-oxides[11] can be rationalized as resulting
from two key features of MPO: mesomeric stabilization of the
positive charge by the methoxy substituent, and the inclusion
of the N-oxide moiety on the aromatic nucleus, thus prevent-
ing oxidative degradation of the ligand under the reaction
conditions. Subsequent experimentation demonstrated that
this complex, when employed in the dehydrogenation reac-
tion of carbonyl substrates, is not only general but also mild
and highly efficient (see Table 1). However, for optimal
results, certain conditions must be fulfilled, particularly with
994
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1433-7851/02/4106-0994 $ 17.50+.50/0
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Table 1. Facile room temperature dehydrogenation of ketones and aldehydes using IBX ¥ MPO.[a]
Entry
Substrate
Product(s)
Conditions
IBX ¥ MPO [equiv]
Yield [%][b]
t [h]
1
2
3.5
1.8
18
96
78
24
32
3
2.5
79
4
5
6
1.8
2.2
4.0
36
22
48
86
84
78[c]
7
8
2.5
1.4
30
88
4272
9
1.8
2.5
20
24
77
74
10
11
2.2
32
92
12
13
1.8
2.2
40
48
81
78
14
15
1.5
1.5
15
15
91
88
16
17
3.0
2.2
45
48
43[e]
62[f]
[a] Reactions were carried out on a 0.1 1.0 mmol scale in DMSO. [b] Yield of isolated chromatographically pure compound. Some starting material was
always recovered; however, the quantity is only specified when it exceeds 20%. [c] Plus 11% enone. [d] Plus 21% recovered starting material. [e] Plus 37%
recovered starting material. [f] Plus 34% recovered starting material. MPO ˆ 4-methoxypyridine-N-oxide; SEM ˆ 2-(trimethylsilyl)ethoxymethyl; Bn ˆ
benzyl; TBS ˆ tert-butyldimethylsilyl.
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1433-7851/02/4106-0995 $ 17.50+.50/0
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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, 2 62 5A; ngew. Chem. Int. Ed. 2000, 39, 2 52 5;
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, 7549; 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 (1.2mmol) and MPO [12] (1.2mmol) 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
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4106-0996 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 6