IBX amides: A new family of hypervalent iodine reagents

Article abstract of DOI:10.1002/anie.200351018

Amides of 2-iodoxybenzoic acid (IBX amides, 1) are a new class of pentavalent iodine compounds with a pseudo-benziodoxole structure. These 2-iodoxybenzamides are useful reagents for the oxidation of alcohols, with a reactivity pattern similar to IBX (R=CH(CH₃)CO₂CH₃ or CH(CH₂Ph)CO₂CH₃ (in crystal structure shown)).

Full text of DOI:10.1002/anie.200351018

Communications
benziodoxol-3-(1H)-one-1-oxide (2a), have emerged as the
reagents of choice for the oxidation of alcohols to carbonyl
compounds and for other synthetically useful oxidative
[
1,2]
transformations.
Reagent 2a is commonly referred to as
2
-iodoxybenzoic acid (IBX, 2b), although the tautomeric
form 2a is the best representation of the actual structure of
this compound. This has been confirmed by X-ray crystallo-
graphic analysis, which also indicated that IBX has a
polymeric structure formed through an extended linkage of
intermolecular secondary I···O bonding interactions.[ The
polymeric structure of IBX renders it essentially insoluble in
all nonreactive media. Its low solubility and potentially
explosive nature restrict the practical application of this
reagent. Herein we report the preparation and structure of
novel derivatives of 2-iodoxybenzoic acid, namely 2-iodoxy-
benzamides 4, which are stable, soluble reagents with oxidiz-
ing properties similar to IBX and DMP. These synthetically
valuable characteristics of compounds 4 are best explained by
their pseudocyclic structure in which intramolecular secon-
dary I···O bonds partially replace the intermolecular I···O
secondary bonds that give rise to the polymeric structures of
other reported iodylarenes.
3]
Oxidation of Alcohols
IBX Amides: A New Family of Hypervalent
Iodine Reagents**
The new 2-iodoxybenzamides 4a–g were prepared by
dioxirane oxidation of the readily available 2-iodobenzamides
Viktor V. Zhdankin,* Alexey Y. Koposov,
Brian C. Netzel, Nikolai V. Yashin, Brian P. Rempel,
Michael J. Ferguson, and Rik R. Tykwinski*
3
(Scheme 1) and isolated in the form of stable, white,
microcrystalline solids. This procedure allows the preparation
of compounds 4 derived from numerous types of amino
Organic derivatives of pentavalent iodine have found wide
application as oxidizing reagents in the synthesis of bio-
logically important complex organic molecules.[1] The most
important representatives of this class of compounds, Dess–
Martin periodinane (DMP, 1) and its precursor 1-hydroxy-1,2-
O
O
O
I
O
O
I
H
N
R
acetone, RT
O
HN
R
3a-g
4a-g (45-73%)
OAc
O
OH
O
O
O
AcO
OAc
I
I
a: R = (S)-CH(CH3)CO2CH3
b: R = (R)-CH(CH3)CO2CH3
c: R = (S)-CH(CH2Ph)CO2CH3
d: R = (S)-CH(i-Bu)CO2CH3
e: R = CH2CH2CO2H
f: R = CH(CH3)CH2CO2H
g: R = (R)-CH(Ph)CH3
I
O
OH
O
O
O
1
2a
2b
Scheme 1. Preparation of 2-iodoxybenzamides 4a–g.
[
*] Prof. Dr. V. V. Zhdankin, A. Y. Koposov, B. C. Netzel, N. V. Yashin
Department of Chemistry, University of Minnesota Duluth
Duluth, Minnesota 55812 (USA)
compounds, such as esters of natural a-amino acids (4a, 4c,
and 4d) and non-natural amino acids (4b), b-amino acids (4e
and 4 f), and (R)-1-phenylethylamine (4g). Optical rotation
measurements showed substantially greater [a]D values for
the chiral products 4 relative to the respective amino acids,
and, as expected, the values for oxidants 4a and 4b, derived
from l- and d-alanine, respectively, were opposite in sign and
Fax: (+1)218-726-7394
E-mail: vzhdanki@d.umn.edu
Prof. Dr. R. R. Tykwinski, B. P. Rempel
Department of Chemistry, University of Alberta
Edmonton, Alberta, T6G 2G2 (Canada)
Fax: (+1)780-492-8231
E-mail: rik.tykwinski@ualberta.ca
Dr. M. J. Ferguson
[4]
nearly equal in magnitude. It is interesting to note that the
X-Ray Crystallography Laboratory
Department of Chemistry, University of Alberta
Edmonton, Alberta, T6G 2G2 (Canada)
dioxirane oxidation of ester derivatives 3a–d does not result
in the formation of cyclic benziodazoles, as has been observed
in the oxidation of 2-iodobenzamides derived from a-amino
[
**] This work was supported by a research grant from the National
Institutes of Health (R15 GM065148-01), the National Science and
Engineering Research Council of Canada, and the University of
Alberta.
[
5a]
[5b–d]
acids and some other precursors.
Products 4 were characterized by elemental and spectro-
scopic analysis, as well as single-crystal X-ray analysis in the
[
6,7]
case of 4c.
IR spectra of all compounds showed an N-H
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
ꢀ1
absorption at about n˜ = 3300 cm , a carbonyl stretch at n˜ =
2
194
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200351018
Angew. Chem. Int. Ed. 2003, 42, 2194 – 2196

Angewandte
Chemie
ꢀ
1
ꢀ1
1
610–1620 cm , and an I¼O absorption at n˜ = 780–740 cm .
The solid-state structure suggests that the partial replace-
ment of intermolecular I···O bonds with intramolecular I···O
1
The signals of the N-H protons in the H NMR spectra of
compounds 4 were observed as a characteristic doublet
bonds through the introduction of an ortho substituent is
[
9,10]
(
broad singlet for 4e) centered at about d = 9.6 ppm. The
crucial for stabilization and improved solubility.
Further-
1
3
most characteristic signals in the C NMR spectra of
compounds 4 were those of the carbon atom of the amide
carbonyl group at d = 165–166 ppm and C-IO2 at d =
ca. 149 ppm. All products 4 have moderate solubility in
common organic solvents, such as chloroform, dichloro-
methane, and acetonitrile.
more, intermolecular I···O interactions in other iodyl benzene
derivatives afford structures best described as polymeric,
which accounts for their more limited solubility in comparison
to 4c, with its discrete tetrameric structure. The significance
of secondary I···O bonding interactions in previously reported
[
9]
iodylbenzene derivatives, including a 2-sulfonyl-substituted
iodylbenzene, has recently been discussed by Protasiewicz
A single crystal of 4c suitable for X-ray crystallographic
analysis was obtained through the slow evaporation of an
acetonitrile solution and was analyzed as the respective
solvate. The unit cell consists of four crystallographically
independent molecules that are pseudocentrosymmetrically
arranged in a tetrameric structure (Figure 1). Strong second-
[
10a]
and co-workers.
Preliminary experiments demonstrate that 2-iodoxybenz-
amides show aspects of reactivity similar to both IBX and
DMP, but consistent with neither. As outlined in Table 1, a
range of alcohols were oxidized to the respective carbonyl
compounds under mild conditions. For example, the reaction
of benzyl alcohol with 4c gave benzaldehyde cleanly, as the
1
only product detected by H NMR spectroscopy (Table 1,
entry 1). A variety of secondary alcohols were converted into
the corresponding ketones in good yields with 4a–c (Table 1,
entries 2, 3, and 5), although reaction times varied as a
function of the reagent used. The oxidative kinetic resolution
of racemic sec-phenethyl alcohol was also investigated with
reagents 4a–c. The reaction mixture containing 0.5 equiva-
lents of the respective oxidant was analyzed by gas chroma-
tography (GC) on a chiral stationary phase. Whereas analysis
of the reactions with 4a and 4b indicated no enantiomeric
enrichment of the alcohol remaining in the product mixture
(
Table 1, entries 5 and 6), in the reaction with 4c the alcohol
starting material was enriched to a very modest 9% ee
Table 1, entry 7). Reagent 4b, in contrast with DMP, effected
(
Table 1: Reaction of IBX amides 4a–c with alcohols.[a]
Entry
Alcohol
Reagent (equiv)
t [h]
Yield [%]
100
1
4c (1.02)
2
2
3
4c (1.04)
4c (1.03)
18
18
98
89
Figure 1. Perspective view of the four crystallographically independent
molecules of 4c·CH CN (shown in black, CH CN removed for clarity)
3
3
4
5
6
4b (0.50)
4b (0.50)
4a (0.51)
24
72
72
26[b,c]
and extended lattice (shown in gray). Selected distances [Š] and angles
8]: I1–O11 1.823(5), I1–O12 1.807(5), I1–O13 2.571(6), I1–O32
.594(5), I1–O42 2.690(5), I1–C1 2.114(8); O11–I1–C1 92.4(3), O12–
[
2
94[b,c]
I1–C1 98.4(3), O13–I1–C1 71.0(3).
ary I···O bonding interactions between neighboring molecules
of this tetramer (e.g., I1–O42 2.690(5) Š, I1–O32(5) 2.594 Š,
shown as dashed lines) enforce this arrangement. Hydrogen
bonding (shown as dotted lines) between the amide proton of
molecules 1 and 3 and an oxygen atom of molecules 2 and 4
link adjacent tetramers together. An additional intramolec-
ular close contact of the hypervalent iodine center with the
oxygen atom of the amide group (e.g., I1–O13 2.571(6) Š)
within each molecule enforces a planar geometry on the
resulting five-membered ring, a geometry that is analogous to
that observed for IBX and other benziodoxoles.[
100[b,c]
7
8
4c (0.46)
4c (1.00)
18
48
96[b,d]
309[e]
[a] Reactions were carried out in CDCl at room temperature. [b] Yield of
3
ketone based on oxidant. [c] Remaining alcohol is racemic, as deter-
mined by GC. [d] Remaining alcohol shows 9% ee, as determined by GC.
[e] Yield of 1,6-hexanedial.
3,8]
Angew. Chem. Int. Ed. 2003, 42, 2194 – 2196
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2195

Communications
oxidative cleavage of cis-1,2-cyclohexanediol to give hexane-
[6] Representative procedure: A freshly prepared solution of
dimethyldioxirane in acetone (0.1m, 90 mL, 9 mmol) was
added to a stirred mixture of 3c (1.23 g, 3.0 mmol) in dry
dichloromethane (15 mL) at 08C, upon which the solution
immediately turned light yellow. The reaction mixture was
stirred at room temperature for an additional 8 h, then filtered,
and the precipitate collected was washed with diethyl ether and
dichloromethane, and dried under vacuum to afford 4c (0.86 g,
65%) as a white microcrystalline solid. M.p. 1568C (decomp);
dial in 30% yield (Table 1, entry 8). It should be emphasized
that, according to literature data,[1] iodylbenzene (PhIO ) and
2
other noncyclic iodylarenes do not react with alcohols in the
absence of acid catalysis. In agreement with their structural
features, the oxidizing reactivity of 2-iodoxybenzamides 4 is
closer to that of the benziodoxole-based pentavalent iodine
reagents.
In conclusion, we have reported the preparation and
structure of novel 2-iodoxybenzamides 4, which are stable and
soluble compounds with unique and synthetically valuable
oxidizing properties. X-Ray data on 4c reveals a pseudo-
benziodoxole structure in which intramolecular I···O second-
ary bonds partially replace the intermolecular I···O secondary
bonds, thus disrupting the polymeric structure characteristic
RT
1
[a]D = ꢀ34 (c = 0.0023, CH
CN);
H NMR (300 MHz,
3
3
[
D ]DMSO, 258C): d = 9.66 (d, J(H,H) = 7.8 Hz, 1H; NH),
6
3
8
.27 (m, 2H; Ar), 7.95 (t, J(H,H) = 7.6 Hz, 1H; Ar), 7.76 (t,
3
J(H,H) = 7.6 Hz, 1H; Ar), 7.27 (m, 5H; Ph), 4.74 (m, 1H; CH),
1
3
3
.67 (s, 3H; OCH ), 3.21 ppm (m, 2H; CH ); C NMR
3
2
(
75.5 MHz, [D ]DMSO, 258C): d = 171.2, 166.1, 149.1, 137.1,
6
1
3
33.1, 131.3, 128.9, 128.3, 127.9, 127.2, 126.6, 123.1, 54.7, 52.1,
5.8 ppm; IR (KBr): n˜ = 3220 (NH), 1744 (C O), 1620 (C O),
¼
¼
ꢀ
1
of PhIO and other previously reported iodylarenes. This
760 cm (I¼O); elemental analysis: calcd for C H INO : C
2
17 16
5
structural characteristic substantially increases the solubility
and stability of these reagents relative to other IV reagents.
46.28, H 3.66, N 3.17, I 28.76; found: C 46.07, H 3.69, N 3.17, I
(78). See
+
28.47; MS(CI): m/z (%): 410.0 [MꢀMeOHþH]
Supporting Information for additional synthetic and character-
ization details.
Received: January 24, 2003 [Z51018]
[
7] X-ray diffraction data were collected on a Bruker PLATFORM/
SMART 1000 CCDdiffractometer with graphite monochrom-
ated MoKa radiation (0.71073 Š). Crystal data for 4c
C H I N O ·C H10.50N3.50: M = 1908.52, colorless, 0.46 ” 0.22 ”
Keywords: alcohols · hypervalent compounds · iodine ·
.
oxidation · synthetic methods
6
8
64
4
4
20
7
r
3
0
.07 mm , monoclinic, P2 (No. 4), a = 11.1810(8), b = 30.221(2),
1
3
c = 12.0210(9) Š, b = 100.468(2)8, V= 3994.2(5) Š , Z = 2,
[
1] a) A. Varvoglis, Hypervalent Iodine in Organic Synthesis,
Academic Press, London, 1997; b) V. V. Zhdankin, P. J. Stang,
Chem. Rev. 2002, 102, 2523; c) T. Wirth, Angew. Chem. 2001, 113,
ꢀ3
ꢀ1
1calcd = 1.587 gcm , m = 1.634 mm . Data collection and refine-
ment: w scans (0.28; 20 s exposures), T= ꢀ808C, 2q max =
5
2.808, total data collected = 25445, independent reflections =
5852 (Rint = 0.0366). The data were corrected for absorption
2889; Angew. Chem. Int. Ed. 2001, 40, 2812; d) H. Tohma, Y.
1
Kita, Top. Curr. Chem. 2003, 224, 209.
with a multiscan model by using SADABS (transmission factors:
[
2] a) R. Mazitschek, M. Mulbaier, A. Giannis, Angew. Chem. 2002,
0
.8942–0.5203). The structure was solved by direct methods
1
14, 4216; Angew. Chem. Int. Ed. 2002, 41, 4059; b) K. C.
Nicolaou, T. Montagnon, P. S. Baran, Angew. Chem. 2002, 114,
035; Angew. Chem. Int. Ed. 2002, 41, 993; K. C. Nicolaou,
D. L. F. Gray, T. Montagnon, S. T. Harrison, Angew. Chem. 2002,
14, 1038; Angew. Chem. Int. Ed. 2002, 41, 996; K. C. Nicolaou,
T. Montagnon, P. S. Baran, Y.-L. Zhong, J. Am. Chem. Soc. 2002,
24, 2245; K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, S. Bar-
luenga, K. W. Hunt, R. Kranich, J. A. Vega, J. Am. Chem. Soc.
002, 124, 2233; e) K. C. Nicolaou, K. Sugita, P. S. Baran, Y.-L.
2
(SHELXS-86) and full-matrix least-squares refinement on F of
9
1
1
04 variables (SHELXL-93) converged to R = 0.0451 (for
1
1
2
2
3250 observed data with F ꢁ 2s(F )), wR = 0.1093, and S =
o
o
2
2
o
2
o
.036 (all data, F ꢁ ꢀ3s(F )); Flack parameter= 0.01(2). Non-
1
hydrogen atoms were refined anisotropically; hydrogen atoms
were included in calculated positions using a riding model.
1
ꢀ3
Residual electron density = 1.413 and ꢀ0.696 eŠ . CCDC-
200547 (4c) contains the supplementary crystallographic data
2
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
Zhong, J. Am. Chem. Soc. 2002, 124, 2221; K. C. Nicolaou, P. S.
Baran, Y.-L. Zhong, K. Sugita, J. Am. Chem. Soc. 2002, 124,
2212.
[
[
3] P. J. Stevenson, A. B. Treacy, M. Nieuwenhuyzen, J. Chem. Soc.
Perkin Trans. 2 1997, 589.
[
[
8] V. V. Zhdankin, Rev. Heteroat. Chem. 1997, 17, 133.
9] a) N. W. Alcock, J. F. Sawyer, J. Chem. Soc. Dalton Trans. 1980,
4] In addition to the chirality of the amino acid derived moiety, the
iodine is also a potential stereogenic center, as is seen in the solid
state. As the preferred conformation/configuration about the
iodonium center in solution is not known, the enantiomeric/
diastereomeric relationship between 4a and 4b can not be
established.
115; b) A. R. Katritzky, G. P. Savage, G. J. Palenik, K. Qian, Z.
Zhang, H. D. Durst, J. Chem. Soc. Perkin Trans. 2 1990, 1657;
c) D. G. Naae, J. Z. Gougoutas, J. Org. Chem. 1975, 40, 2129.
[10] a) D. Macikenas, E. Skrzypczak-Jankun, J. D. Protasiewicz,
Angew. Chem. 2000, 112, 2063; Angew. Chem. Int. Ed. 2000,
39, 2007; b) D. Macikenas, E. Skrzypczak-Jankun, J. D. Prota-
siewicz, J. Am. Chem. Soc. 1999, 121, 7164; c) U. H. Hirt,
M. F. H. Schuster, A. N. French, O. G. Wiest, T. Wirth, Eur. J.
Org. Chem. 2001, 1569; d) U. H. Hirt, B. Spingler, T. Wirth, J.
Org. Chem. 1998, 63, 7674.
[
5] a) V. V. Zhdankin, A. E. Koposov, J. T. Smart, R. R. Tykwinski,
R. McDonald, A. Morales-Izquierdo, J. Am. Chem. Soc. 2001,
123, 4095; b) V. V. Zhdankin, R. M. Arbit, B. J. Lynch, P. Kiprof,
V. G. Young, J. Org. Chem. 1998, 63, 6590; c) H. J. Barber, M. A.
Henderson, J. Chem. Soc. C 1970, 862; d) T. M. Balthazar, D. E.
Godaz, B. R. Stults, J. Org. Chem. 1979, 44, 1447.
2
196
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 2194 – 2196