o-Iodoxybenzoic Acid as a Viable Reagent
A R T I C L E S
Table 1. Discovery and Optimization of the Iodine(V)-Mediated
Oxidation of Aminesa
successful deprotection of dithioacetals and dithioketals to yield
their parent carbonyl species, (3) the oxidative dimerization of
hydrazines and hydrazones, via organized iodine coordination
complexes, and (4) the synthesis of substituted imidazoles,
pyridines, and pyrroles through the facile aromatization of
N-heterocyclic precursors.
entry
reagent
conditions
yieldb
1
2
3
4
5
6
IBX (1.1 equiv)
IBX (1.1 equiv)
IBX‚MPO (1.1 equiv)
DMP (1.1 equiv)
I2O5 (1.1 equiv)
IBA (1.1 equiv)
DMSO, 45 °C, 30 min
DMSO, 25 °C, 10 min
DMSO, 25 °C, 10 min
CH2Cl2, 25 °C, 10 min
DMSO/H2O (9:1), 25 °C, 1.5 h
DMSO (0.1 M), 25 °C, 2 h
83
83
44c
64
1c
The pertinence of this methodology stems from the fact that
all the aforementioned transformations are quite fundamental
in nature and can be easily applied to a multitude of synthetic
strategies. Aromatic nitrogen heterocycles have long been of
widespread interest by virtue of their ubiquitous presence in
multifarious natural products and other biologically active
compounds. Furthermore, imines and dithianes have found, and
will continue to find, extensive use in a myriad of synthetic
contexts. With these applications in mind, the mild and
chemoselective nature of IBX, coupled with the high reaction
yields that frequently accompany its employment, has rendered
this reagent as a unique and powerful tool in chemical synthesis.
3c
a Reactions were conducted on 0.2-0.3 mmol scale at a concentration
of 0.3 M except where noted. b Isolated yield. In percent. c Unreacted starting
material was also recovered (entry 3: 44%, entry 5: 98%, entry 6: 94%).
IBX ) o-iodoxybenzoic acid, MPO ) 4-methoxypyridine N-oxide, IBA )
o-iodosobenzoic acid, DMSO ) dimethyl sulfoxide.
and diphenylselenium bis(trifluoroacetate)21 are restricted to
tetrahydroisoquinoline systems, and yet other procedures em-
ploying Swern conditions,22 di-tert-butyliminoxyl radical,23
iodosobenzene,18 and alkylperoxy-λ3-iodane24 have similarly
only been accomplished on a handful of simple substrates. In
general, each method fails to present a broad scope by asserting
its compatibility with a wide variety of systems. Thus, as we
proceeded with our investigations into the chemistry of hyper-
valent iodine(V), it was gratifying to observe that an abundance
of amine substrates were readily oxidized with IBX in excellent
yield, under particularly mild conditions and with short reaction
times.
As shown in Table 1, entry 2, the oxidation of dibenzylamine
(1) to its benzylidene counterpart (2) was performed smoothly
upon treatment with IBX at room temperature for 10 min. These
conditions were instituted following the communication of our
initial results in this area,26 as a result of the discovery that
many amine oxidations conducted with IBX do not need the
elevated temperatures and longer reaction times previously
employed for this transformation (entry 1, Table 1). In the
process of developing this hypervalent iodine-mediated reaction,
a number of additional iodine(V) reagents were also examined.
Like IBX, DMP was discovered to be a viable amine oxidant
(entry 4, Table 1), although the yield of imine 2 was consider-
ably lower, presumably due to the acidic nature of the reaction
media. Dehydrogenation of 1 proved to be somewhat sluggish
when subjected to IBX‚MPO complex (entry 3, Table 1), first
employed in the context of aldehyde and ketone dehydrogena-
tion,12 and virtually nonexistent when diiodine pentoxide (I2O5)
was utilized (entry 5, Table 1). The iodine(III) compound
o-iodosobenzoic acid (IBA) was also examined (entry 6, Table
1) to assert that the observed conversion of 1 to 2 in entries 1
and 2 was occurring as a result of the action of IBX, without
contribution from its byproduct IBA.
Results and Discussion
1. Dehydrogenation of Amines Using IBX. Many protocols
affecting the oxidation of amines to imines have been reported
in the literature, with the multiplicity of these reports serving
to emphasize the versatility of this transformation, but also
concomitantly accentuating the shortcomings that accompany
each of these methods.14-24 The lack of a mild and general
procedure for the oxidation of amines reflects a severe deficiency
in the synthetic utility of such processes. This state of affairs is
rather odd given the fact that such a method would present a
facile route to common synthetic building blocks such as imines
and oximes, thus providing a direct entryway into various
heterocycles as well as to a plethora of transformations,
including alkylations, aza-Diels-Alder cycloadditions, and
condensation reactions.25 Among the known procedures for this
transformation, amine oxidation conducted with catalytic tetra-
N-propylammonium perruthenate (TPAP) and N-methylmor-
pholine N-oxide (NMO) as a stoichiometric co-oxidant, is
notably uncomplicated and usually undertaken at room tem-
perature. However, only a small number of benzylamines were
examined under these conditions, and optimum yields were only
obtained after up to 72 h of reaction time and increased
equivalents of NMO.14 Ruthenium catalysis was also utilized
in a more recent procedure where oxygen serves as the
stoichiometric co-oxidant in refluxing triflurotoluene.15 Other
transition-metal-based methods rely on copper(II) bromide-
lithium tert-butoxide,16 expensive cobalt Schiff base com-
plexes,17 manganese(III)/iron(III) porphyrins or manganese(III)
salen,18 or manganese dioxide (8 equiv) in refluxing benzene.19
Reports of dehydrogenation accomplished with Fremy’s salt20
(14) Goti, A.; Romani, M. Tetrahedron Lett. 1994, 35, 6567.
(15) Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2003, 42, 1480.
(16) Yamaguchi, J.; Takeda, T. Chem. Lett. 1992, 1933.
(17) (a) Maruyama, K.; Kusukawa, T.; Higuchi, Y.; Nishinaga, A. Chem. Lett.
1991, 1093. (b) Nishinaga, A.; Yamazaki, S.; Matsuura, T. Tetrahedron
Lett. 1988, 29, 4115.
(18) Larsen, J.; Jorgensen, K. A. J. Chem. Soc., Perkin Trans. 2 1992, 1213.
(19) Pratt, E. F.; McGovern, T. P. J. Org. Chem. 1964, 29, 1540.
(20) Wehrli, P. A.; Schaer, B. Synthesis 1974, 288.
(21) Marino, J. P.; Larsen, R. D. J. Am. Chem. Soc. 1981, 103, 4642.
(22) Keirs, D.; Overton, K. J. Chem. Soc., Chem. Commun. 1987, 1660.
(23) Cornejo, J. J.; Larson, K. D.; Mendenhall, G. D. J. Org. Chem. 1985, 50,
5382.
(24) (a) Sueda, T.; Kajishima, D.; Goto, S. J. Org. Chem. 2003, 68, 3307. (b)
Ochiai, M.; Kajishima, D.; Sueda, T. Heterocycles 1997, 46, 71.
(25) Bailey, P. D.; Morgan, K. M. Organonitrogen Chemistry; Oxford University
Press: New York, 1996.
As shown in Table 2, the IBX dehydrogenation protocol
tolerates a wide range of substrate functionality, and furthermore,
has shown to affect the oxidation of secondary amines rapidly
and frequently in excellent yield. In particular, substrates with
nitrogen-containing components, aside from a secondary amine,
all furnished the desired imines in high yield (entries 6, 7, and
12, Table 2). Likewise, a halide, benzyl ether, and even a
primary hydroxy group were subjected to the established
reaction conditions and found to be unaffected, further signifying
(26) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew. Chem., Int.
Ed. 2003, 42, 4077.
9
J. AM. CHEM. SOC. VOL. 126, NO. 16, 2004 5193