Asymmetric oxidation of o-alkylphenols with chiral 2-(o-lodoxyphenyl)- oxazolines

Article abstract of DOI:10.1021/ol8029092

A new class of chiral iodine(V) derivatives has been prepared. These compounds have been found to transform ortho-alkylphenols into ortho-quinol Diels-Alder dimers with significant levels of asymmetric induction.

Full text of DOI:10.1021/ol8029092

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1221-1223
Asymmetric Oxidation of o-Alkylphenols
with Chiral
2-(o-Iodoxyphenyl)-oxazolines
Jagadish K. Boppisetti and Vladimir B. Birman*
Department of Chemistry, Washington UniVersity, Campus Box 1134,
One Brookings DriVe, St. Louis, Missouri 63130
birman@wustl.edu
Received December 17, 2008
ABSTRACT
A new class of chiral iodine(V) derivatives has been prepared. These compounds have been found to transform ortho-alkylphenols into
ortho-quinol Diels-Alder dimers with significant levels of asymmetric induction.
A reaction of o-alkylphenols 1 with achiral oxidants, such
as sodium periodate 4,1 benzeneseleninic anhydride 5,2 and
Scheme 1
.
Transformation of o-Alkylphenols into o-Quinol
o-iodoxybenzoic acid (IBX) 6,3 produces o-quinols 2, which
dimerize spontaneously via a regio- and stereoselective
intermolecular Diels-Alder reaction to give tricyclic prod-
ucts 3 (Scheme 1, Figure 1). The overall process is
remarkable for the rapid increase in molecular complexity
achieved in a single preparative step. Until a few years ago,
enantioselective oxidative dearomatization of phenols re-
mained unknown. In 2005, Porco et al. published a highly
enantioselective oxidation of resorcinols with stoichiometric
amounts of copper-spartein-dioxygen complex 7.4a In
2008, they extended this process to o-alkylphenols producing
o-quinol dimers with 99% ee’s.4b The same year, Kita et al.
Dimers
Prompted by these reports, we disclose the results of our
recent studies in this area.
In connection with a total synthesis project, we sought to
find new types of chiral oxidants capable of converting
o-alkylphenols into o-quinol dimers in an enantioselective
fashion. Inspired by the success of IBX in the racemic variant
of this reaction,3 we decided to explore the potential of chiral
organoiodine(V) compounds. Although ortho-substituted
iodoxybenzene derivatives, such as IBX 66 and Dess-Martin
periodinane,7 are widely used in organic synthesis,8 the utility
of their chiral analogues remains relatively little explored.
Chiral derivatives of IBX amide (9)9 and iodoxybenzene
developed
a
related processsasymmetric ortho-
acetoxylationsusing spirocyclic iodine(III) derivative 8.5
(1) Adler, E.; Holmberg, K. Acta Chem. Scand. 1971, 25, 2775.
(2) Barton, D. H. R.; Ley, S. V.; Magnus, P. D.; Rosenfeld, M. N.
J. Chem. Soc., Perkin Trans. 1 1977, 567.
(3) (a) Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.; Pettus,
T. R. R. Org. Lett. 2002, 4, 285. (b) Gagnepain, J.; Castet, F.; Quideau, S.
Angew. Chem., Int. Ed. 2007, 46, 1533. (c) Lebrasseur, N.; Gagnepain, J.;
Ozanne-Beaudenon, A.; Le´ger, J. M.; Quideau, S. J. Org. Chem. 2007, 72,
6280.
10.1021/ol8029092 CCC: $40.75
Published on Web 02/20/2009
2009 American Chemical Society

chiral ligands for Lewis acids,12 we decided to investigate
the preparation and properties of chiral 2-(o-iodoxyphenyl)-
oxazolines, abbreviated as CIPOs (cf. 17, Scheme 2).
Scheme 2. Synthesis of Chiral 2-(o-Iodoxyphenyl)-oxazolines
Figure 1. Reagents for oxidative dearomatization of o-alkylphenols.
(10)10 (Figure 2) were synthesized and investigated by
Zhdankin et al. The latter showed moderate levels of
enantioselectivity in the oxidation of benzylic alcohols and
thioanisole.
Several 2-(o-iodophenyl)-oxazolines 16a-e were prepared
starting from chiral 2-amino alcohols 14a-e following
known general protocols.13 Their oxidation with
dimethyldioxirane11a,14 yielded the desired CIPOs in moder-
ate to good yields after chromatographic purification. The
new compounds were obtained as white microcrystalline
powders soluble in most organic solvents. The presence of
the iodoxy group was evidenced by the diagnostic IdO
stretches in IR (700-775 cm-1 region) and the chemical
shifts of the ipso-carbon (149 ppm) and the ortho-proton (8.3
ppm) in NMR.11 All attempts to grow X-ray quality crystals
of CIPOs have so far proved unsuccessful. Thus, the
existence of a captodative bond between the oxazoline
nitrogen and the iodoxy group cannot be ascertained at this
point.
Figure 2. o-Substituted iodoxybenzene derivatives.
To our delight, reaction of 0.6 equiv of i-Pr-CIPO 17a
with 1 equiv of 2,6-dimethylphenol 1a in chloroform
produced the desired o-quinol dimer 3a with an encouraging
level of enantioselectivity (Table 1, entry 1). Notably, Porco’s
enantioselective oxidation method was reported to be unsuc-
cessful in the case of this substrate.4b
However, the reaction stopped at low conversions. Mindful
of Barton’s report on activation of the unsubstituted iodoxy-
benzene by trichloroacetic acid,15 we investigated the effect
of acid promoters (entries 2-5). Stoichiometric amounts of
acetic acid were found to improve the reaction rate, whereas
trifluoroacetic acid led to decomposition. Several solvents
were screened next (entries 6-10). DME (1,2-dimethoxy-
ethane) proved to be optimal giving 3a in 51% yield and
55% ee (entry 10). Again, addition of acetic acid was
confirmed to be beneficial in this solvent (entries 10-12).
At this point, all other available CIPOs were examined
Iodoxybenzene derivatives ortho-substituted with a car-
bonyl, sulfonyl, or phosphonyl group, e.g., 10-13, are known
to form pseudocyclic structures in which the iodine forms a
captodative bond with the adjacent oxygen atom.11 Surpris-
ingly, there have been no reports of the analogous iodoxy-
benzene derivatives with a neutral nitrogen ligand at the
ortho-position. Given the ubiquitous use of oxazolines as
(4) (a) Zhu, J.; Grigoriadis, N. P.; Lee, J. P.; Porco, J. A., Jr. J. Am.
Chem. Soc. 2005, 127, 9342. (b) Dong, S.; Zhu, J.; Porco, J. A., Jr. J. Am.
Chem. Soc. 2008, 130, 2738.
(5) Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.; Minamitsuji,
Y.; Fujioka, H.; Caemmerer, S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008,
47, 3787.
(6) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
(7) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(8) For recent reviews on hypervalent organoiodine compounds, see:
(a) Wirth, T. Top. Curr. Chem. 2003, 224, 1–248. (b) Zhdankin, V. V.
Curr. Org. Synth. 2005, 2, 121. (c) Ladziata, U.; Zhdankin, V. V. ArkiVoc
2006, 9, 26. (d) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2008, 108, 5299.
(9) Zhdankin, V. V.; Smart, J. T.; Zhao, P.; Kiprof, P. Tetrahedron Lett.
2000, 41, 5299.
(12) For reviews, see: (a) Gomez, M.; Muller, G.; Rocamora, M. Coord.
Chem. ReV. 1999, 193-195, 769. (b) Desimoni, G.; Faita, G.; Jørgensen,
K. A. Chem. ReV. 2006, 106, 3561.
(10) Ladziata, U.; Carlson, J.; Zhdankin, V. V. Tetrahedron Lett. 2006,
47, 6301.
(11) (a) Zhdankin, V. V.; Koposov, A. Y.; Litvinov, D. N.; Ferguson,
M. J.; McDonald, R.; Luu, T.; Tykwinski, R. R. J. Org. Chem. 2005, 70,
6484. (b) Macikenas, D.; Skrzypczak-Jankun, E.; Protasiewicz, J. D. Angew.
Chem., Int. Ed. 2000, 39, 2007. (c) Meprathu, B. V.; Justik, M. W.;
Protasiewicz, J. D. Tetrahedron Lett. 2005, 46, 5187.
(13) Crosignani, S.; Young, A. C.; Linclau, B. Tetrahedron Lett. 2004,
45, 9611.
(14) Murray, R. W. Chem. ReV. 1989, 89, 1187
.
(15) Barton, D. H. R.; Godfrey, C. R. A.; Morzycki, J. W.; Motherwell,
W. B.; Stobie, A. Tetrahedron Lett. 1982, 23, 957.
1222
Org. Lett., Vol. 11, No. 6, 2009

Table 1. Oxidation of 2,6-Dimethylphenol 1a with CIPOsa
Scheme 3
.
Asymmetric Oxidation of Isomeric Dimethylphenols
with t-Bu-CIPO 17b
entry oxidant
solvent
additive (equiv) % yieldb % ee
1
2
3
4
5
6
7
8
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17b
17c
17d
17e
17b
17b
CHCl3
none
29
40
47
14
dec
43
51
58
36
51
29
43
43
36
36
36
30
33
36
38
ND
53
43
17
56
55
55
56
65
46
24
32
62
63
CHCl3
CHCl3
CHCl3
CHCl3
PhMe
MeCN
AcOH (0.25)
AcOH (1.0)
AcOH (3.0)
TFA (1.0)
AcOH (1.0)
AcOH (1.0)
CF3CH2OH AcOH (1.0)
THF
9
AcOH (1.0)
AcOH (1.0)
none
AcOH (0.25)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
10
11
12
13
14
15
16
17
18
DME
DME
DME
DME
DME
DME
DME
DME
DME
26(64)c
65d
a Conditions: 0.10 mmol 2,6-dimethylphenol 1a, 0.060 mmol CIPO
17a-e, 0.2 mL of solvent, rt, 12 h, unless noted otherwise. b Yields are
based on 1a, unless noted otherwise. c 0.10 mmol 1a and 0.040 mmol 17b
were used. The yield shown in parentheses is based on 17b. d 0.10 mmol
1a and 0.11 mmol 17b were used.
(entries 13-16). Only t-Bu-CIPO 17b displayed enhanced
enantioselectivity compared to i-Pr-CIPO 17a and was
therefore selected for further experimentation. The stoichi-
ometry of the reaction with respect to the oxidant was initially
uncertain, since in principle either one or both of the oxygen
atoms of the iodoxy group could be utilized. An experiment
with 2.5 equiv of the substrate with respect to the oxidant
confirmed that only one oxygen atom is utilized in the desired
oxidation (entry 17). Accordingly, increasing the amount of
the oxidant from 0.6 to 1.1 equiv improved the yield of the
dimer based on the substrate to 65% (entry 18). The rest of
the starting material was mostly consumed by unidentified
side reactions. The fate of the second oxygen atom of the
iodoxy group remains unclear at this point. Only the fully
reduced compounds, oxazoline 16b (54%) and amide 15b
(19%), could be isolated after the reaction in entry 13.
Application of the optimized set of conditions to other
dimethylphenols was investigated next. 2,5-Isomer 1b pro-
duced the dimer (3b) with almost the same yield and
enantioselectivity as 3a (Scheme 3). Oxidation of 2,4-
dimethylphenol 1c attained 77% eesthe highest value
observed in this studysalbeit in a more modest yield. No
dimer could be isolated from the reaction of 2,3-dimeth-
ylphenol 1d, which is consistent with previous reports.3c,4b
The absolute configurations of 3b and 3c were deduced from
their signs of optical rotation.4b The configuration of 3a was
assigned by analogy.
In conclusion, we have synthesized the first examples of
iodoxybenzene derivatives with chiral oxazoline groups at
the ortho-position and applied them to the enantioselective
oxidation of phenols. Although the ee values remain moder-
ate at this point, our results demonstrate the potential of the
new class of chiral hypervalent iodine compounds in asym-
metric synthesis. Further studies in this direction will be
reported in due course.
Acknowledgment. The authors thank Dr. V. V. Zhdankin
and Dr. V. N. Nemykin (University of Minnesota-Duluth)
for helpful discussions and suggestions. Financial support
for this study was provided in part by NIGMS (R01
GM072682).
Note Added after ASAP Publication. Scheme 3 con-
tained errors in the version published ASAP February 20,
2009; the corrected version published February 25, 2009.
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL8029092
Org. Lett., Vol. 11, No. 6, 2009
1223