Chemoselective C-H oxidation of alcohols to carbonyl compounds with iodosobenzene catalyzed by (Salen)chromium complex

Article abstract of DOI:10.1021/jo9913457

Primary and secondary alcohols with benzylically and allylically activated C-H bonds are chemoselectively oxidized to the corresponding carbonyl compounds by the (salen)Cr(III) complex I as the catalyst and iodosobenzene as the oxygen source; the oxidizing species is the Cr(V) oxo complex. Allylic alcohols with fully substituted double bonds give appreciable amounts of epoxides besides the C-H oxidation products enones, while saturated alcohols are less readily oxidized.

Full text of DOI:10.1021/jo9913457

J . Org. Chem. 2000, 65, 1915-1918
1915
Ch em oselective C-H Oxid a tion of Alcoh ols to Ca r bon yl
Com p ou n d s w ith Iod osoben zen e Ca ta lyzed by (Sa len )ch r om iu m
Com p lex
Waldemar Adam,* Feyissa Gadissa Gelalcha, Chantu R. Saha-Mo¨ller, and Veit R. Stegmann
Institute of Organic Chemistry, University of Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany
Received August 24, 1999
Primary and secondary alcohols with benzylically and allylically activated C-H bonds are
chemoselectively oxidized to the corresponding carbonyl compounds by the (salen)Cr(III) complex
I as the catalyst and iodosobenzene as the oxygen source; the oxidizing species is the Cr(V) oxo
complex. Allylic alcohols with fully substituted double bonds give appreciable amounts of epoxides
besides the C-H oxidation products enones, while saturated alcohols are less readily oxidized.
Sch em e 1. Ca ta lytic Cycle for th e Oxid a tion of
Alcoh ols to Ca r bon yl Com p ou n d s by
(Sa len )Cr (III)/P h IO
In tr od u ction
The chemo-, regio-, and stereoselective oxidation of
alcohols to carbonyl compounds is one of the fundamental
organic transformations not only from the synthetic point
of view, but it also enjoys significant biological and
mechanistic interest. Thus, there has been much research
on this oxidation, especially the search for versatile and
selective reagents. Among the most widely used are
chromium compounds; in fact, chromic acid is one of the
most powerful and universal oxidants.1 The J ones re-
agent (chromiumtrioxide/H2SO4), the Collins reagent
(chromiumtrioxide/pyridine complex), pyridinium chloro-
chromate (PCC), poly(vinylpyridinium) chlorochromate
(PVPCC), and pyridinium dichromate (PDC) are some of
the more popular commercially available chromium-
based oxidants used for such transformations.
Presently, we report on the selective (salen)chromium-
(III)-catalyzed oxidation of a series of alcohols to the
corresponding carbonyl compounds with iodosobenzene
(PhIO) as the oxygen source (Scheme 1). The in-situ-
generated (salen)oxochromium(V) complex is proposed as
the actual oxidant, which shows a great preference for
allylic oxidation versus epoxidation in allylic alcohols as
substrates. Such (salen)oxochromium(V) complexes have
been previously isolated and subsequently used in the
epoxidation of olefins by Kochi’s group;5 the asymmetric
version was recently established.6
The main drawback of these reagents is that in
addition to their lack of generality, they have to be
applied in stoichiometric amounts or even in large excess
to effect complete conversion of the substrate. However,
in view of the carcinogenicity of chromium compounds,
health and environmental concerns limit their use for
large-scale and industrial applications. Although much
effort has been made in the development of methods for
chromium-based catalytic oxidations in recent years,2
there is still need for catalytic oxidations of alcohols with
a wide scope of applicability. Indeed, ongoing research
has been directed toward the development of such
methods, especially for selective oxidations.3 For example,
oxochromium(V) heteropolytungstate complexes were
reported to effect the catalytic allylic oxidation of
cyclohexenol.3c Very recently, the chromium(VI)-catalyzed
oxidation of allylic alcohols by tert-butyl hydroperoxide
to carbonyl products has been developed.4
Resu lts a n d Discu ssion
To assess the general scope of the catalytic oxidation
mediated by the (salen)oxochromium(III) complex I,7 the
saturated and benzylic primary and secondary alcohols
1 were chosen as substrates and PhIO as oxygen source.
4-Phenylpyridine N-oxide (PPNO) was used as additive,
because it has been reported5a that this donor ligand
enhances the reaction rates in the Cr(salen)-catalyzed
oxidations. Unusually mild conditions (ca. 20 °C, in CH2-
Cl2, and a 0.15:0.30:1.00:1.50 ratio of catalyst I/PPNO/
substrate/PhIO) afforded the corresponding carbonyl
products 2 (eq 1).
* To whom correspondence should be addressed. Fax: +49(0)931/
8884756. E-mail: adam@chemie.uni-wuerzburg.de. Internet: http://
www-organik.chemie.uni-wuerzburg.de.
(1) (a) Hudlicky, M. Oxidations in Organic Chemistry; ACS Mono-
graph 186; American Chemical Society: Washington DC, 1990. (b)
Cainelli, G.; Cardillo, G. Chromium Oxidations in Organic Chemistry;
Springer-Verlag: Berlin, Heidelberg, 1984; Chapter 4.
(2) Muzart, J . Chem. Rev. 1992, 92, 113-140.
(3) (a) Muzart, J .; N’Ait Ajjou, A. Synthesis 1993, 785-787. (b)
Bouquillon, S.; A¨ıt-Mohand, S.; Muzart, J . Eur. J . Org. Chem. 1998,
2599-2602. (c) Khenkin, A. M.; Hill, C. L. J . Am. Chem. Soc. 1993,
115, 8178-8186.
(4) Riahi, A.; He´nin, F.; Muzart, J . Tetrahedron Lett. 1999, 40,
2303-2306.
(5) (a) Samsel, E. G.; Srinivasan, K.; Kochi, J . K. J . Am. Chem. Soc.
1985, 107, 7606-7617. (b) Srinivasan, K.; Kochi, J . K. Inorg. Chem.
1985, 24, 4671-4679.
(6) (a) Bousquet, C.; Gilheany, D. G. Tetrahedron Lett. 1995, 36,
7739-7742. (b) Ryan, K. M.; Bousquet, C.; Gilheany, D. G. Tetrahedron
Lett. 1999, 40, 3613-3616. (c) Daly, A. M.; Dalton, C. T.; Renehan, M.
F.; Gilheany, D. G. Tetrahedron Lett. 1999, 40, 3617-3620.
(7) Coggon, P.; McPhail, A. T.; Mabbs, F. E.; Richards, A.; Thornley,
A. S. J . Chem. Soc. A 1970, 3296-3303.
10.1021/jo9913457 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/18/2000

1916 J . Org. Chem., Vol. 65, No. 7, 2000
Adam et al.
Ta ble 2. Oxid a tion of Allylic Alcoh ols w ith
Ta ble 1. Oxid a tion of Sa tu r a ted a n d Ben zylic Alcoh ols
w ith Iod osoben zen e Ca ta lyzed by th e Ch r om iu m (III)
Sa len Com p lex Ia
Iod osoben zen e Ca ta lyzed by th e Ch r om iu m (III) Sa len
Com p lex Ia
a
Reaction conditions: 0.3 equiv of 4-phenylpyridine N-oxide
(PPNO), 0.15 equiv of catalyst I, 1.5 equiv of PhIO, CH2Cl2, 20
b
°C. Determined by 1H NMR analysis of the crude reaction
products with an internal standard (1,3,5-trioxane); error ( 5%
of the stated values; the mass balances were g80% in every case
except for entry 3 (64%). c Yields of the respective carbonyl
products 2 based on 100% conversion of the alcohol; all products
are known and have been identified by 1H and 13C NMR spec-
d
troscopy. Cyclopropyl. e Used as mixture of diastereomers.
The results in Table 1 demonstrate that the oxidation
is relatively sluggish for the saturated, unactivated
substrates (entries 1 and 2) n-decanol (1a ) and menthol
(1b), since only ca. 20% conversion to the corresponding
carbonyl compounds 2a and 2b was achieved, even on
prolonged (72 h) reaction time. In contrast, the primary
benzyl alcohol (1c) was oxidized to 2c (entry 3) in 93%
conversion in only 14 h. As to the oxidation of the
secondary benzylic alcohols 1d -g (entries 4-7), the
significantly lower conversion (26%, entry 7) of the
sterically hindered tert-butyl-substituted substrate 1g
compared to that of the other secondary alcohols 1d -f
(50-89%, entries 4-6) implies that the CH insertion is
sensitive to steric effects. The cyclopropyl-substituted
derivatives 1e and 1f (entries 5 and 6) were oxidized
smoothly to the corresponding ketones without any ring-
opening products, as established by careful 1H NMR
analysis (eq 2). For this purpose, substrate 1f was
a
Reaction conditions: As in Table 1, except entry 7, 0.5 equiv
b
of PhIO. Determined as in Table 1; mass balances were g80%
in most cases except for the substrates 3c (entry 3) and 3h (entry
8) due to high volatility. c Ratio of R,â-enone 4 to epoxy alcohol 5,
the threo/erythro diastereomeric ratios of epoxy alcohols are given
1
in parentheses; determined by H NMR spectroscopy of the crude
d
product; error ( 5% of the stated values. Observed as cis,trans
mixture of 61:39 for the enones 4c/4d . e Yield of 4 + 5. f Observed
as cis,trans mixture of 70:30 for the enones 4i/4j. g Epoxy alcohols
observed as a mixture of all threo/erythro stereoisomers; the
stereoisomeric ratios were not determined because of severe signal
overlap in the 1H NMR spectrum. Determined by GLC analysis
h
with n-decanol as the internal standard; error ( 2% of the stated
values.
°C (no rate data are available for the hydroxy-substituted
radical derived from the carbinol 1f), the cyclopropyl-
carbinyl radical, if formed, persists and does not re-
arrange.
Since this catalytic oxidation is promoted by benzyl
substitution, it was anticipated that allylic alcohols
should react readily under these conditions; however, in
these bifunctional substrates also epoxidation of the
double bond is possible, besides allylic CH insertion (eq
3). As the results for a series of structurally varied cyclic
and acyclic allylic alcohols 3 convey (Table 2), with few
exceptions (entries 5 and 9-11), the allylic oxidation
products 4 were formed nearly exclusively. Even for the
obtained as a 67:33 mixture of diastereomers by NaBH4
reduction of the ketone 2f in ethanol8 and subsequently
used as such in the Cr-catalyzed oxidation. In view of
Hill’s radical mechanism,3c the cyclopropylcarbinyl radi-
cal is expected to intervene. However, since the reported9
rate constant for the ring opening of the (2-phenylcyclo-
8
propyl)phenylmethyl radical is only 3.6 × 10 s-1 at 40
(9) (a) Hollis, R.; Hughes, L.; Bowry, V. W.; Ingold, K. U. J . Org.
Chem. 1992, 57, 4284-4287. (b) Newcomb, M. Tetrahedron 1993, 49,
1151-1176.
(8) Patro, B.; Ila, H.; J unjappa, H. Tetrahedron Lett. 1992, 33, 809-
812.

C-H Oxidation of Alcohols to Carbonyl Compounds
J . Org. Chem., Vol. 65, No. 7, 2000 1917
alcohols with allylically and benzylically activated CH
bonds. The corresponding carbonyl compounds have been
obtained in good yield on the semipreparative scale. With
the exception of the tetrasubstituted derivative 3k , allylic
alcohols are chemoselectively oxidized to enones by CH
insertion rather than epoxidation of the double bond.
exceptions, at best equal amounts of epoxidation and CH
insertion had occurred, as displayed by the tetrasubsti-
tuted allylic alcohol 3k (entry 11). Evidently, increased
methyl substitution promotes epoxidation sufficiently to
compete with the usually preferred CH insertion. Of note
is the high threo diastereoselectivity in the epoxidation
of the chiral allylic alcohols 3e and 3k (entries 5 and 11),
but not for 3j (entry 10). For the former two derivatives,
1,3-allylic strain operates, which conformationally aligns
the allylic hydroxy group for favored threo attack through
hydrogen bonding with the (salen)oxochromium(V) com-
plex. Such hydroxy group directivity has been reported
for the related epoxidation by the (salen)oxomanganese-
(V) complex10 and for the diperoxo complex of methyltri-
oxorhenium,11 which implies similar hydrogen-bonded
transition structures also for the (salen)oxochromium-
(V) oxidant.
Exp er im en ta l Section
1
Gen er a l Asp ects. H and 13C NMR spectra were recorded
in CDCl3 on a Bruker AC 200 (1H, 200 MHz; 13C, 50 MHz), a
Bruker AC 250 (1H, 250 MHz; 13C, 63 MHz), or a Bruker DMX
600 (1H, 600 MHz) spectrometer against CDCl3 or tetrameth-
ylsilane (TMS) as reference standard on the δ scale (ppm).
Perkin-Elmer 1600 series FTIR-spectrophotometer was used
for IR spectra. TLC analysis was conducted on precoated silica
gel foils 60 F254 (20 × 20 cm) from Merck, Darmstadt. Spots
were visualized either by UV irradiation (254 nm), by a 5%
polymolybdic acid in ethanol, or by a solution of 0.5 g of 2,4-
dinitrophenylhydrazine in 2.5 mL of concentrated H2SO4,
which was diluted with 100 mL of absolute ethanol. Silica gel
(63-200 and 32-63 µm) from Woelm, Erlangen, was used for
column and flash chromatography. Solvents were dried by
standard methods and purified by distillation before use. GLC
analysis was performed on a Carlo Erba instrument HRGC
5160 gas chromatograph, equipped with a 30 m × 0.25 mm
HP-5 capillary column and an FID detector. Melting points
In the oxidation of the Z-configured allylic alcohols 3c
and 3i, cis-trans isomerization of the resulting enones
was observed, as displayed by Z/E ratios of 61:39 (4c/
4d ) and 70:30 (4i/4j) (entries 3 and 9). In contrast, no
such isomerization was noted in the catalytic oxidation
of the E-configured substrates 3d and 3j since the
corresponding E-configured ketones 4d and 4j are ther-
modynamically favored and persist. Geraniol (3f) was
oxidized under similar conditions to geranial (4f) in a
(uncorrected) were determined on
a Reichert Thermovar
apparatus. All commercial reagents were used without further
purification.
Sta r tin g Ma ter ia ls. Iodosobenzene (98% by iodometry13
)
was prepared by hydrolysis of the corresponding diacetate
according to the literature method14 and was stored at -20
°C.
The alcohols 1a -e,g and the allylic alcohols 3b,f,n were
1
commercially (Fluka, Aldrich) available. The benzylic alcohol
good yield (entry 6); however, H NMR analysis of the
15
1f and the allylic alcohols 3c,16 3d ,17 3e,18 3g,19 3h ,20 3i,21
crude product showed that ca. 5% isomerization at the
enone double bond had occurred and traces (<5%) of the
epoxidation at the C-7 position of geranial (4f) were
detected. The methyl derivative 3g (entry 7) was oxidized
with only 0.5 equiv of PhIO to its enone 4g in 30%
conversion without side products.
The hydroxy-protected derivatives of substrate 3e,
namely OMe (6a ),12 OSiMe2t-Bu (6b), and OAc (6c), were
not oxidized (no CH insertion nor epoxidation) under the
same reaction conditions (data not shown). This empha-
sizes the importance of hydrogen bonding between the
substrate and the (salen)oxochromium(V) complex for
both the CH insertion and epoxidation.
To assess whether the salen ligand sphere is necessary
for the Cr(III)-catalyzed selective oxidation of alcohols,
CrCl3‚3THF instead of catalyst I was tested as catalyst
for the oxidation of 3e. Although the reaction was
accelerated (complete substrate conversion within <30
min), a complex mixture was obtained, with the enone
4e as the major oxidation product; no conversion was
observed for this case without PPNO. These results
demonstrate that the Cr(salen) complex is superior to
CrCl3‚3THF in the catalytic oxidation of allylic alcohols.
3j,19 3l,22 3m ,23 3o,24 6a ,25 6b,26 and 6c27 were synthesized
analogously to known methods.
N ,N ′-E t h yle n e b is(sa licylid e n e im in a t o)ch r om iu m -
(III) Ch lor id e (I). To a suspension of 2.59 g (9.96 mmol) of
bis(salicyliden)ethylenediamine in 50 mL of absolute ethanol
was added a suspension of 1.31 g (10.7 mmol) of anhydrous
chromous chloride in ethanol (20 mL) within 15 min with
vigorous stirring under an Ar-gas atmosphere at room tem-
perature (ca. 20 °C) for 1 h. The dark-brown solution was
allowed to reflux in the presence of air for 2 h. The solvent
was removed (ca. 20 °C, ca. 20 Torr), and the residue was
suspended in water (50 mL) and allowed to stir for 2 h in the
(13) Lucas, J .; Kennedy, E. R.; Formo, M. W. Org. Synth. 1955, 3,
483-485.
(14) Saltzman, H.; Sharefkin, J . G. Org. Synth. 1973, 5, 658-659.
(15) Patro, B.; Ila, H.; J unjappa, H. Tetrahedron Lett. 1992, 33, 809-
812.
(16) Schalley, C. A.; Schro¨der, D.; Schwarz, H. J . Am. Chem. Soc.
1994, 116, 11089-11097.
(17) Morgan, B.; Oehlschlager, A. C.; Stokes, T. M. J . Org. Chem.
1992, 57, 3231-3236.
(18) House, H. O.; Wilkins, J . M. J . Org. Chem. 1978, 43, 2443-
2454.
(19) Adam, W.; Mitchell, C. M.; Paredes, R.; Smerz, A. K.; Veloza,
L. A. Liebigs Ann./ Recueil 1997, 1365-1369.
(20) Ho, N.-H.; le Noble, W. J . J . Org. Chem. 1989, 54, 2018-2021.
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2433.
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5459.
Con clu sion
(23) Mousseron, M.; J acquier, R.; Mousseron-Canet, M.; Zagdoun,
R. Bull. Soc. Chim. Fr. 1952, 1042-1053.
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723.
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3353-3361.
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White, C. T.; Van Derveer, D. J . Org. Chem. 1980, 45, 3846-3856.
(27) Bonazza, B. R.; Lillya, C. P.; Magyar, E. S.; Scholes, G. J . Am.
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We have developed a convenient catalytic oxidation
(PhIO/cat I, CH2Cl2, ca. 20 °C) of primary and secondary
(10) Adam, W.; Stegmann, V. R.; Saha-Mo¨ller, C. R. J . Am. Chem.
Soc. 1999, 121, 1879-1882.
(11) Adam, W.; Mitchell, C. M.; Saha-Mo¨ller, C. R. J . Org. Chem.
1999, 64, 3699-3707.
(12) A small amount (ca. 5%) of enone 4e was detected by 1H NMR
spectroscopy.

1918 J . Org. Chem., Vol. 65, No. 7, 2000
Adam et al.
presence of air at ca. 20 °C. The undissolved, yellowish-brown
material was collected by filtration on a G4 sintered-glass
funnel and was washed with water (3 × 10 mL). The material
was extracted with water (2 × 500 mL) by heating in an open
glass beaker, with vigorous stirring for 2 h. After filtration
and concentration of the filtrate at normal pressure by
evaporation, a reddish brown material precipitated; more
material precipitated on cooling overnight, which was collected
and dried under reduced pressure (120 °C, ca. 10-2 Torr, P2O5,
12 h) to afford 1.2 g (31%, yield not given in ref 6) dark-brown,
hygroscopic product, mp (dec) 338-340 °C. IR (KBr): 3026,
1800, 1496, 1027, 893 cm-1. EIMS m/z (relative intensity): 318
(M+ - Cl, 100). Anal. Calcd for C16H14ClCrN2O2: C, 54.32; H,
3.99; N, 7.92. Found: C, 53.64; H, 4.12; N, 7.93.
2f,28 4c,29 4d ,30 4g,31 4i,32 4k ,33 and 4o34 and the epoxy alcohols
threo/ erythro-5e,i-k 35 were identified by comparison with the
literature known NMR data.
Oxid a tion of (E)-4,8-Dim eth yl-3,7-n on a d ien -2-ol (3g).
The substrate (1.00 mmol) was processed as above, except that
0.5 mmol of iodosobenzene was used.
2-Cyclohexen-1-ol (3m ) was oxidized according to the gen-
eral procedure. Analysis was performed by GLC after filtration
of the reaction mixture over silica gel and addition of the
internal standard n-decanol. 2-Cyclohexen-1-one (4m ) was
identified as the sole oxidation product by comparison of its
retention time (tR) of the authentic material. Temperature
program: 40 °C (5 min) f 20 °C/ min f 200 °C (5 min); tR
(min): 6.86 (3m ), 7.76 (4m ), 11.17 (1a ).
Ca ta lytic Oxid a tion s. Gen er a l P r oced u r e for th e Oxi-
d a tion of th e Sa tu r a ted Alcoh ols 1a ,b, Ben zylic Alcoh ols
1c-g, a n d Allylic Alcoh ols 3a -o Ca ta lyzed by th e Ch r o-
m iu m Com p lex I. To a solution of the substrate (0.50-1.00
mmol) in 5-10 mL of dichloromethane were added 0.3 equiv
of 4-phenylpyridine N-oxide (PPNO) and 0.15 equiv of catalyst
I with stirring, followed by 1.5 equiv of iodosobenzene under
an Ar-gas atmosphere. A color change of brown to dark green
and then back to brown was observed. TLC monitoring showed
a positive hydrazone test (yellow spots characteristic of the
carbonyl products). After the mixture was stirred for the times
specified in the Tables 1 and 2, the solvent was evaporated
carefully (25 °C, 400-600 Torr) and the brown residue was
prepurified by passing through a short silica gel (5-8 g)
column. Elution employed first petroleum ether (50-70 mL)
to separate the iodobenzene and then ether (70-100 mL) to
obtain the carbonyl products, epoxy alcohols, and unreacted
alcohols as mixtures. This treatment was necessary to remove
the paramagnetic chromium species, which causes severe line
broadening in the NMR spectrum and prevents a quantitative
product analysis. The solvent was removed as above, and the
products were identified by TLC and 1H and 13C NMR
spectroscopy. Conversions, mass balances, chemo- and stereo-
Ack n ow led gm en t. This work was supported by the
Deutsche Forschungsgemeinschaft (SFB-347, “Selektive
Reaktionen Metall-aktivierter Moleku¨le”) and the Fonds
der Chemischen Industrie. We thank Prof. M. Newcomb
(Wayne State University) for helpful discussions on the
cyclopropylcarbinyl radical probe.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O9913457
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1
selectivities (threo/erythro), and yields were quantified by H
NMR analysis by calibration against an internal standard (see
Tables 1 and 2).
P r od u ct Id en tifica tion . The carbonyl compounds 2a -e,g
and 4a ,b,e,f,h ,j,l-n are commercially available and were
identified by comparison with authentic samples. The ketones
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