NaIO4-mediated selective oxidation of alkylarenes and benzylic bromides/alcohols to carbonyl derivatives using water as solvent

Article abstract of DOI:10.1021/jo0606305

A new transition-metal-free, sodium metaperiodate (NaIO₄)- mediated direct oxidation of methylarenes and benzylic bromides to the corresponding aromatic carboxylic acids is described. Under the same reaction conditions, benzylic alcohols are selectively oxidized to afford the corresponding aldehydes in good yields without undergoing overoxidation. Unprecedentedly, oxidation of benzyl bromide, toluene, or benzyl alcohol with NaIO₄ underwent nuclear bromination followed by oxidation to give 4-bromobenzoic acid in 60-79% yields.

Full text of DOI:10.1021/jo0606305

SCHEME 1. Oxidation of an Alkylarene by NaIO4/LiBr
NaIO4-Mediated Selective Oxidation of
Alkylarenes and Benzylic Bromides/Alcohols to
Carbonyl Derivatives Using Water as Solvent
Tanveer Mahammad Ali Shaikh,
Lourdusamy Emmanuvel, and Arumugam Sudalai*
Chemical Engineering & Process DeVelopment DiVision,
National Chemical Laboratory, Pashan Road,
Pune, India 411008
amounts have been employed in such oxidative processes.
Among nonoxometal oxidants, HNO3 is commonly used. In
a.sudalai@ncl.res.in
6
particular, RuO4-catalyzed oxidations of methylarenes to oxy-
genated derivatives are achieved only for deactivated systems;
for activated systems, ring halogenation is often the competitive
reaction. Also, oxidations of alkylarenes with HNO3 have often
led to electrophilic ring nitrations. In continuation of our work7
on NaIO4-mediated reactions, we report herein a novel transi-
tion-metal-free method for the oxidation of methylarenes to the
corresponding carboxylic acids using NaIO4/LiBr/H+ combina-
tions.
ReceiVed March 22, 2006
Recently, we reported that direct oxidation7b of alkylarenes
produced the corresponding benzylic acetates mediated by
NaIO4/LiBr. During our mechanistic investigations, we found
that the reaction proceeded through benzylic bromide intermedi-
ates, which were subsequently oxidized by NaIO4 to liberate
bromine and benzyl cations; solvolysis of the latter gave benzylic
acetates 2. With this information, we believed that solvolysis
from the benzyl cation with water, instead of AcOH, should
give benzylic alcohol. Surprisingly, when 4-bromotoluene (1)
was heated with NaIO4 (1 equiv) and LiBr (1 equiv) in 2% aq
H2SO4, the reaction took a different course to furnish 4-bro-
mobenzoic acid (3) in 71% yield (Scheme 1).
Encouraged by this result, we subjected a variety of methyl-
arenes having both electron-donating and -withdrawing groups
to oxidation with NaIO4 (1 equiv) and LiBr (1 equiv) in 2% aq
H2SO4 (15 mL) at 95 °C and successfully obtained carboxylic
acids 4 in good yields (Table 1). The use of excess NaIO4
(1.2 equiv) did not improve the yield considerably. The yields
were found to be higher in the case of methylarenes with
electron-withdrawing groups (NO2, Cl). When highly activating
substituents (NH2, OH) are present, electrophilic ring bromi-
nation took place preferentially. Attempts to improve the yields
further by using a combination of solvents (t-BuOH/H2O, THF/
H2O, CH3CN/H2O, etc.) were not fruitful. When LiBr was
replaced by other halogen sources such as NaCl or KI, no
reaction took place. Another interesting feature is that, although
methyl groups were selectively oxidized to the corresponding
carboxylic acids, benzylic methylene groups were oxidized to
ketones; the overoxidation of benzylic methylenes to carboxylic
acids with carbon C-C bond cleavage,8 a common feature
noticed in the case of transition-metal oxides, was not observed
here (entries m and n, Table 1).
A new transition-metal-free, sodium metaperiodate (NaIO4)-
mediated direct oxidation of methylarenes and benzylic
bromides to the corresponding aromatic carboxylic acids is
described. Under the same reaction conditions, benzylic
alcohols are selectively oxidized to afford the corresponding
aldehydes in good yields without undergoing overoxidation.
Unprecedentedly, oxidation of benzyl bromide, toluene, or
benzyl alcohol with NaIO4 underwent nuclear bromination
followed by oxidation to give 4-bromobenzoic acid in
60-79% yields.
The oxidation of methylarenes to the corresponding carboxy-
lic acids is of industrial importance because such carbonyl
derivatives constitute versatile building blocks in pharmaceutical
and polymer industries.1 A variety of oxometal oxidants2 such
as KMnO4, Na2Cr2O7, or CrO3 in stoichiometric amounts and
RuO4,3 Co(OAc)2,4 and more recently Bi5 salts in catalytic
(1) (a) Sheldon, R. A.; Kochi, J. K. Metal Catalyzed Oxidations of
Organic Compounds; Academic press: New York, 1981. (b) Cainelli, G.;
Cardillo, G. Chromium Oxidations in organic Chemistry; Springer: Berlin,
1984. (c) Hudlicky, M. Oxidations in Organic Chemistry; American
Chemical Society: Washington, DC, 1990.
(2) (a)Wiberg, K. B. In Oxidation in Organic Chemistry; Wiberg, K.
B., Ed; Academic: New York, 1965; Part A, p 69. (b) March, J. AdVanced
Organic Chemistry; Reactions, Mechanisms and structure, 4th ed.; John
Wiley & sons: New York, 1992. (c) For KMnO4 oxidation, see: Sam, D.
J.; Simmons, H. E. J. Am. Chem. Soc. 1972, 94, 4024. (d) For Na2Cr2O7
oxidation, see: Friedman, L.; Fishel, D. L.; Shechter, H. J. Org. Chem.
1965, 30, 1453. (e) For CrO3 oxidation, see: (i) Muzart, J. Tetrahedron
Lett. 1986, 27, 3139. (ii) Muzart, J. Tetrahedron Lett. 1987, 28, 2131. (iii)
Yamazaki, S. Org. Lett. 1999, 1, 2129.
An unprecedented transformation occurred when toluene was
subjected to oxidation under the same reaction conditions
(3) Sasson, Y.; Zappi, G. D.; Neumann, R. J. Org. Chem. 1986, 51, 2880.
(4) Saha, B.; Espenson, J. H. J. Mol. Catal. A: Chem. 2005, 241, 33
and the references therein.
(5) Bonvin, Y.; Callens, E.; Larrosa, I.; Henderson, D. A.; Oldham, J.;
Burton, A. J.; Barrett, A. G. M. Org. Lett. 2005, 7, 4549.
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(7) (a) Dewkar, G. K.; Narina, S. V.; Sudalai, A. Org. Lett. 2003, 5,
4501. (b) Shaikh, T. M.; Sudalai, A. Tetrahedron Lett. 2005, 46, 5589. (c)
Emmanuvel, L.; Shaikh, T. M.; Sudalai, A. Org. Lett. 2005, 7, 5071.
10.1021/jo0606305 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/25/2006
J. Org. Chem. 2006, 71, 5043-5046
5043

TABLE 1. NaIO4/LiBr-Mediated Oxidation of Alkylarenes and
Benzylic Bromides in Acidic Mediuma
SCHEME 2. Unprecedented Oxidation with Nuclear
Bromination Mediated by NaIO4
(NaIO4/LiBr/H+) giving 4-bromobenzoic acid in 60% isolated
yield instead of the expected unsubstituted benzoic acid. We
also found a similar observation when either benzyl bromide
or benzyl alcohol was subjected to oxidation, although other
methylarenes gave only the expected unsubstituted benzoic
acids. Additional 2-methoxybenzyl bromide under the same
reaction conditions gave 5-bromo-2-methoxybenzaldehyde in
18% yield. It may be explained that the intermediate benzyl
alcohol, formed by solvolysis, probably underwent nuclear
bromination at the para position with Br2 before, itself, being
oxidized to carboxylic acids (Scheme 2). To explain this
observation, the following experiments have been carried out:
(1) when 2-nitrotoluene was subjected to oxidation under this
reaction condition, 2-nitrobenzoic acid (54%) was obtained, as
a side-chain oxidized product; (2) o-xylene under the same
experimental condition gave only 4-bromo-1 and 2-dimethyl-
benzene, a ring-brominated product; (3) a simple competitive
experiment was carried out with a mixture of toluene and
2-chlorotoluene where we obtained only 4-bromo- and 2-chlo-
robenzoic acid, respectively. Notably, we observed that the
electrophilic ring bromination was observed only in electron-
rich methylarenes with an unblocked, sterically favorable para
position. However, the presence of electron-withdrawing groups
such as Br, Cl, NO2, etc. probably deactivates the ring and also
facilitates the oxidation of the intermediate species thereby
shortening their lifetime thus resulting in no ring bromination.
Ortho bromination was not observed possibly because of the
steric nature of the bromonium ion.
To study its scope, we subjected several benzylic bromides
to oxidation with NaIO4/H+ conditions. Indeed, such oxidations
of benzylic bromides with NaIO4 produced the corresponding
carboxylic acids in high yields (71-89%). Although a variety
of reagents are known9 to oxidize organic halides to aldehydes,
no practical method10 exists, to the best of our knowledge, for
the direct one-step conversion of benzylic bromides to the
corresponding carboxylic acids. As can be seen from Table 1,
several benzylic bromides with both electron-withdrawing and
-donating groups underwent oxidation with NaIO4/H+ conditions
to give the corresponding carboxylic acids in excellent yields.
Secondary benzylic bromides were also oxidized to give the
(8) (a) Moriarty, R. M.; Prakash, I.; Penmasta, R. J. Chem. Soc., Chem.
Commun. 1987, 202. (b) Zevaco, T.; Duriach, E.; Postel, M. Tetrahedron
Lett. 1993, 34, 2601. (c) Gurunath, S.; Sudalai, A. Synlett 1999, 5, 559. (d)
Kameda, K.; Morimoto, K.; Imanaka, T. Chem. Lett. 1988, 1295. (e)
Santaniello, E.; Manzocchi, A.; Farachi, C. Synthesis 1980, 563. (f) Ayres,
D. C. J. Chem. Soc., Chem. Commun. 1975, 440.
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Group Preparations; Larock, R. C., Ed.; Wiley-VCH: New York, 1989.
(b) Fisher, C. H. J. Am. Chem. Soc. 1934, 56, 2056. (c) Kornblum, N.;
Jones, W. J.; Anderson, G. J. J. Am. Chem. Soc. 1959, 81, 4113. (d) Suzuki,
S.; Onishi, T.; Fujita, Y.; Misawa, H.; Otetra, J. Bull. Chem. Soc. Jpn. 1986,
59, 3287. (e) Das, S.; Panigrahi, A. K.; Maikap, G. C. Tetrahedron Lett.
2003, 44, 1375.
a See Experimental Section for procedure. b Isolated yield. c 50 mol %
of NaIO4 and LiBr were employed. d KIO3 (1.2 equiv) was employed as
the oxidant. e Terephthalic acid was obtained in 4% yield. f Methyl ester is
hydrolyzed to form terephthalic acid. g Reactions were not done. h Yield
was 83% with 50 mol % of NaIO4. i Corresponding ketones were obtained.
(10) Itoh, A.; Kodama, T.; Inagaki, S.; Masaki, Y. Org. Lett. 2000, 2,
2455.
5044 J. Org. Chem., Vol. 71, No. 13, 2006

TABLE 2. Oxidation of Benzylic Alcohols to Benzaldehydes by
NaIO4 in Acidic Mediuma
corresponding ketones in 87% yield (entries m and n, Table 1).
The use of a substoichiometric amount of NaIO4 (50 mol %)
generally gave poor yields of carboxylic acids except in the
case of bromodiphenylmethane (entry n), which gave a com-
parable yield of benzophenone (83%) due to the easy oxidiz-
ability of the C-Br bond. However, benzyl chloride was
resistant to undergo oxidation under the reaction conditions,
probably because of the higher bond strength of the C-Cl bond.
KIO3 was also found to oxidize benzylic bromide to give
benzoic acid in high yields (entry d, Table 1). The prolonged
oxidation of 4-methylbenzyl bromide led to successive oxidation
of benzyl bromide as well as methyl to give 4% terephthalic
acid (entry f, Table 1).
We also observed that when benzyl alcohol was subjected to
oxidation with NaIO4 (1 equiv) in the presence of acidic medium
without LiBr benzaldehyde was exclusively obtained in 79%
yield with no formation of benzoic acid. To study the generality
of the reaction, a variety of primary benzylic alcohols were
subjected to oxidation with NaIO4/H+ conditions, and the results
are presented in Table 2. Among the various solvents screened,
H2O was found to give the best results. However, secondary
benzylic alcohols as well as aliphatic alcohols were resistant to
oxidation under the reaction conditions. The present protocol
is mild and selective as compared to the reported literature
procedures, which involve transition metals,11 hypervalent iodine
compounds,12 and other halogen-related systems.13
We observed that the oxidation of methylarenes to carboxylic
acids proceeds through intermediates such as benzyl bromide,
benzyl alcohol, and benzaldehyde in that order, confirmed by
GC-MS analysis, during the oxidation process of toluene with
NaIO4/LiBr/H+ combinations. Following the concept of side-
chain bromination of alkylarenes using metal halide in the
presence of an oxidizing agent14 (H2O2, TeO2, etc.) as reported
by others and us,7b we believe that NaIO4 oxidizes LiBr in the
presence of acid to liberate molecular bromine that brominates
the side chain of alkylarenes to give the corresponding benzylic
bromides (eqs 1-3). Similar to inorganic halides (LiBr),
benzylic bromides are solvolyzed with water in the presence of
(11) Backvall, J.-E.; Chowdhury, R. L.; Karlsson, U. J. Chem. Soc.,
Chem. Commun. 1991, 473. (b) Almeida, M. L. S.; Beller, M.; Wang, G.-
Z.; Backvall, J.-E. Chem.-Eur. J. 1996, 2, 1533. (c) Marko, I. E.; Giles, P.
R.; Tsukazaki, M.; Brown, S. M.; Urch, C. J. Science 1996, 274, 2044. (d)
Arterburn, J. B.; Perry, M. C.; Nelson, S. L.; Dible, B. R.; Holguin, M. S.
J. Am. Chem. Soc. 1997, 119, 9309. (e) Yamaguchi, K.; Mori, K.; Mizugaki,
T.; Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2000, 122, 7144. (f)
Yamaguchi, K.; Mizuno, N. New. J. Chem. 2002, 26, 972. (g) Muldoon, J.;
Brown, S. N. Org. Lett. 2002, 4, 1043. (h) Steinhoff, B. A.; Fix, S. R.;
Stahl, S. S. J. Am. Chem. Soc. 2002, 124, 766. (i) Zhan, B.-Z.; White, M.
A.; Sham, T.-K.; Pincock, J. A.; Doucet, R. J.; Rao, K. V. R.; Robertson,
K. N.; Cameron, T. S. J. Am. Chem. Soc. 2003, 125, 2195. (j) Velusamy,
S.; Punniyamurthy, T. Org. Lett. 2004, 6, 217. (k) Jiang, N.; Ragauskas,
A. J. Org. Lett. 2005, 7, 3689.
a Reaction conditions: alcohol (3 mmol), NaIO4 (3 mmol), 2% aq H2SO4
in water (15 mL), 95 °C, 8 h. b Isolated yields after column chromato-
graphic purification. c Yield by GC. d 2-Pyridinemethanol was employed
for oxidation.
NaIO4 in acidic medium at elevated temperature (95 °C) to give
benzylic alcohols (eq 4).
8Br- + NaIO4 + 8H+ f 4Br2 + 4H2O + I- + Na+ (1)
(12) (a) Varvolgis, A. HyperValent Iodine in Organic Synthesis; Aca-
demic Press: London, 1997. (b) Dess, D. B.; Martin, J. C. J. Org. Chem.
1983, 48, 4155. (c) Marx, M.; Tidwell, T. T. J. Org. Chem. 1984, 49, 788.
(d) Tidwell, T. T. Synthesis 1990, 857. (e) Nicolao, K. C.; Baran, P. S.;
Zhong, Y.-L. J. Am. Chem. Soc. 2001, 123, 3183. (f) Surendra, K.;
Krishnaveni, N. S.; Reddy, M. A.; Nageswar, Y. V. D.; Rao, K. R. J. Org.
Chem. 2003, 68, 2058. (g) De Luca, L.; Giacomelli, G.; Porcheddu, A. J.
Org. Chem. 2001, 66, 7907. (h) More, J. D.; Finney, N. S. Org. Lett. 2002,
4, 3001. (i) Kuhakarn, C.; Kittigowittana, K.; Pohmakotr, M.; Reutrakul,
V. Tetrahedron 2005, 61, 8995.
(13) (a) Blair, L. K.; Baldwin, J.; Smith, W. C., Jr. J. Org. Chem. 1977,
42, 1816. (b) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org.
Chem. 1996, 61, 7452. (c) Gogoi, P.; Sarmah, G. K.; Konwar, D. J. Org.
Chem. 2004, 69, 5153.
4ArCH3 + 4Br2 f 4ArCH2Br + 4HBr
ArCH3 + 2Br- + (1/4)NaIO4 + 2H+ f
(2)
ArCH2Br + (1/4)I- + H2O + HBr + (1/4)Na+ (3)
8ArCH2Br + NaIO4 + 8H+ + 8H2O f
8ArCH2OH + 4Br2 + I- + 4H2O + Na+ (4)
The fact that the reagent NaIO4/H+ alone did not oxidize
secondary alcohols, whereas the NaIO4/LiBr/H+ combination
did, led to our belief that benzylic alcohols were directly
(14) (a) Bergman, J.; Engman, L. J. Org. Chem. 1982, 47, 5191. (b)
Mestres, R.; Palenzuela, J. Green Chem. 2002, 4, 314.
J. Org. Chem, Vol. 71, No. 13, 2006 5045

SCHEME 3. Oxidation of Alcohols to Aldehydes
95 °C (using an oil bath) for 18 h. The reaction mixture was then
cooled to room temperature and extracted with ethyl acetate (40
mL × 3), and the combined organic phase was washed with
saturated sodium thiosulfate solution and water, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure to give
crude product; it was washed with cold n-hexane and recrystallized
from suitable solvents to afford pure product.
Procedure for the Oxidation of Benzylic Halide. Benzylic
halides were subjected to the reaction conditions as given above
but without LiBr.
Procedure for the Oxidation of Primary Benzylic Alcohols.
To a mixture of benzylic alcohols (3 mmol) and NaIO4 (3 mmol)
was added 2% aq H2SO4 (15 mL). The reaction mixture was heated
at 95 °C (using an oil bath) for 12 h. Progress of the reaction was
monitored by TLC. The reaction mixture was then cooled to room
temperature and extracted with ethyl acetate (40 mL × 3), and the
combined organic phase was washed with saturated sodium
thiosulfate solution and water, dried over anhydrous Na2SO4, and
concentrated under reduced pressure to give crude product, which
was purified by column chromatography packed with silica gel
using n-hexane and ethyl acetate (9:1) as eluent to afford pure
aldehydes.
oxidized to the corresponding carboxylic acids with Br2 via a
free radical pathway15 (eqs 5-10).
Br2 f 2Br3
(5)
(6)
(7)
ArCH2OH + Br3 f ArC4 HOH + HBr
ArC4 HOH + Br2 f ArCHO + Br3 + HBr
ArCHO + Br3 f ArC4 O + HBr
ArC4 O + Br2 f ArCOBr + Br3
(8)
(9)
ArCOBr + H2O f ArCO2H + HBr
(10)
The probable pathway for the oxidation of primary benzylic
alcohol to aldehyde in the absence of LiBr is shown in Scheme
3. The species A formed by reaction of benzyl alcohol with
NaIO4 undergoes oxidation to give benzaldehyde. As the further
oxidation of aldehydes to acids was not observed, we conclude
that NaIO4 was not capable of oxidizing aldehydes to carboxylic
acids.
We have developed a mild procedure for the direct conversion
of methylarenes and benzyl bromides to the corresponding
carboxylic acids in high yields using NaIO4/LiBr/H2SO4 condi-
tions. In the absence of LiBr, NaIO4 oxidizes benzylic alcohols
to the corresponding benzaldehydes selectively under an acidic
medium. An unprecedented oxidation at the benzylic position
coupled with nuclear bromination had occurred when toluene,
benzyl bromide, or benzyl alcohol was subjected to oxidation
with NaIO4/LiBr/H+/95 °C conditions to give 4-bromobenzoic
acid in up to 79% yield.
Acknowledgment. Authors T.M.S. and L.E. thank CSIR for
the award of senior research fellowships, New Delhi, and DST,
New Delhi (Sanction No. SR/S1/OC-22/2002), respectively. The
authors are also thankful to Dr. B. D. Kulkarni, Head, CE-PD
Division, for his constant encouragement.
Supporting Information Available: Experimental procedures
as well as spectral data for the selected compounds are given.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental Section
JO0606305
Procedure for the Oxidation of Alkylarene. To a mixture of
alkylarene (3 mmol), NaIO4 (3 mmol), and LiBr (3.3 mmol) was
added 2% aq H2SO4 (15 mL). The reaction mixture was heated at
(15) Amati, A.; Dosualdo, G.; Zhao, L.; Bravo, A.; Fontana, F.; Minisci,
F.; Bjorsvik, H. R. Org. Process Res. DeV. 1998, 2, 261.
5046 J. Org. Chem., Vol. 71, No. 13, 2006