A Versatile and Highly Selective Hypervalent Iodine (III)/ 2,2,6,6-Tetraniethyl-1-piperidinyloxyl-Mediated Oxidation of Alcohols to Carbonyl Compounds

Article abstract of DOI:10.1021/jo971046m

Catalytic amounts of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) are used in combination with [bis(acetoxy)iodo]benzene (BAIB) as a stoichiometric oxidant in the conversion of primary and secondary alcohols to carbonyl compounds. This procedure works efficiently at room temperature in almost all common solvents and neat in some cases. This process exhibits a very high degree of selectivity for the oxidation of primary alcohols to aldehydes, without any noticeable overoxidation to carboxyl compounds, and a high chemoselectivity in the presence of either secondary alcohols or of other oxidizable moieties. This procedure allows an easy, convenient, high-yielding method for the oxidation of alcohols starting from commercially available compounds.

Full text of DOI:10.1021/jo971046m

6974
J . Org. Chem. 1997, 62, 6974-6977
A Ver sa tile a n d High ly Selective Hyp er va len t Iod in e (III)/
2,2,6,6-Tetr a m eth yl-1-p ip er id in yloxyl-Med ia ted Oxid a tion of
Alcoh ols to Ca r bon yl Com p ou n d s
Antonella De Mico,† Roberto Margarita,*,† Luca Parlanti,† Andrea Vescovi,† and
Giovanni Piancatelli*,‡
Centro CNR di Studio per la Chimica delle Sostanze Organiche Naturali, Istituto Nazionale di
Coordinamento “Chimica dei Sistemi Biologici”, and Dipartimento di Chimica, Universita` “La Sapienza”,
Piazzale Aldo Moro 5, 00185 Roma, Italy
Received J une 10, 1997X
Catalytic amounts of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) are used in combination with
[bis(acetoxy)iodo]benzene (BAIB) as a stoichiometric oxidant in the conversion of primary and
secondary alcohols to carbonyl compounds. This procedure works efficiently at room temperature
in almost all common solvents and neat in some cases. This process exhibits a very high degree of
selectivity for the oxidation of primary alcohols to aldehydes, without any noticeable overoxidation
to carboxyl compounds, and a high chemoselectivity in the presence of either secondary alcohols or
of other oxidizable moieties. This procedure allows an easy, convenient, high-yielding method for
the oxidation of alcohols starting from commercially available compounds.
In tr od u ction
They have been used stoichiometrically either in isolated
form6 or generated in situ via acid-catalyzed dismuta-
tion.7 A number of oxidants, including m-chloroperben-
zoic acid,8 high-valent metal salts,9 sodium bromite,10
sodium or calcium hypochlorite,11 N-chlorosuccinimide,12
and electrooxidation,13 have been used.
In the last decade there has been increasing interest
by organic chemists in the oxidizing properties of hyper-
valent iodine compounds.1 Various iodo(V)-based re-
agents, the 12-I-5 Dess-Martin periodane (DMP, 1,1,1-
triacetoxy-1,1-dihydro-1,2-benzodoxol-3H-one)2 and its
direct precursor the 10-I-4 iodinane oxide (IBX, 1-hy-
droxy-1,2- benzodoxol-3H-one 1-oxide, o-iodoxybenzoic
acid),3 have been utilized for the efficient oxidation of
alcohols to carbonyl compounds. Although the dehydro-
genating properties of the 10-I-3 derivatives (BTIB,
[bis(1,1,1-trifluoroacetoxy)iodo]benzene; BAIB, [bis(ac-
etoxy)iodo]benzene)1e,f have been demonstrated in a
number of cases, only a few selective examples describe
the oxidation of alcohols.4 Due to the permanent demand
of selective methods for synthetic chemists, protocols for
the oxidation of alcoholic moieties able to discriminate
between various functional groups remain a challenge.
Recently N-oxoammonium salts have been demonstrated
to be useful reagents for the transformation of alcohols.5
Resu lts a n d Discu ssion
In this paper we wish to describe a novel, high-selective
N-oxoammonium salt-based oxidation protocol, where
catalytic amounts of 2,2,6,6-tetramethyl-1-piperidinyloxyl
(TEMPO) are used in combination with BAIB as sto-
ichiometric oxidants (Scheme 1).14 This procedure works
(6) (a) Miyazawa, T.; Endo, T.; Shiihashi, S.; Okawara, M. J . Org.
Chem. 1985, 50, 1332. (b) Miyazawa, T.; Endo, T. J . Org. Chem. 1985,
50, 3930. (c) Bobbitt, J . M.; Flores, M. C. L. Heterocycles 1988, 27, 509.
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1977, 42, 2077.
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1984, 106, 3374.
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Chem. 1990, 55, 462.
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1987, 52, 2559. (b) Anelli, P. L.; Banfi, S.; Montanari, F.; Quici, S. J .
Org. Chem. 1989, 54, 2970. (c) Siedlecka, R.; Skarzewski, J .; Mlo-
chowski, J . Tetrahedron Lett. 1990, 31, 2177. (d) Leanna, M. R.; Sorvin,
T. J .; Morton, H. E. Tetrahedron Lett. 1992, 33, 5029. (e) Davies, N.
J .; Flitsch, S. L. Tetrahedron Lett. 1993, 34, 1181. (f) Rychnovsky, S.
D.; Mc Lernon, T. L.; Rajapakse, H. J . Org. Chem. 1996, 61, 1194.
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Chem. 1996, 61, 7452.
(13) (a) Semmelhack, M. F.; Chou, C. S.; Cortes, D. A. J . Am. Chem.
Soc. 1983, 105, 4492. (b) Inokuchi, T.; Matsumoto, S.; Torii, S. J . Org.
Chem. 1991, 56, 2416. (c) For a review, see: Yamaguchi, M.; Miyazawa,
T.; Takata, Y.; Endo, T. Pure Appl. Chem. 1990, 62, 217. (d) Kashiwagi,
Y.; Yanagisawa, Y.; Kurashima, F.; Anzai, J .; Osa, T.; Bobbit, J . M.
Chem. Commun. 1996, 2745.
† Istituto Nazionale di Coordinamento “Chimica dei Sistemi Bio-
logici”.
‡ Universita` “La Sapienza”.
X Abstract published in Advance ACS Abstracts, September 1, 1997.
(1) For general reviews, see: (a) Nguyen, T. T.; Martin, J . C. In
Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Eds.; Pergamon Press: Oxford, 1984; Vol. 1, pp 563-572. (b) Varvoglis,
A. The Organic Chemistry of Polycoordinated Iodine; VCH: New York,
1992; pp 379-405. (c) Koser, G. F. In The Chemistry of Functional
Groups, Supplement D; Patai, S., Rappoport, Z., Eds.; J ohn Wiley &
Sons: New York, 1983; Chapter 18. (d) Varvoglis, A. Synthesis 1984,
709. (e) Varvoglis, A. Hypervalent Iodine in Organic Chemistry;
Academic Press: London, 1997. (f) Varvoglis, A. Tetrahedron 1997,
53, 1179.
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Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277. (c)
Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899. (d) Meyer, S. D.
M.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549.
(3) (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35,
8019. (b) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J .
Org. Chem. 1995, 60, 7272. (c) Corey, E. J .; Palani, A. Tetrahedron
Lett. 1995, 36, 3485. (d) Corey, E. J .; Palani, A. Tetrahedron Lett. 1995,
36, 7945.
(4) (a) Spyroudis, S.; Varvoglis, A. Synthesis 1975, 445. (b) Muller,
P.; Godoy, J . Tetrahedron Lett. 1981, 25, 2361. (c) Muller, P.; Godoy,
J . Helv. Chim. Acta 1983, 66, 1791. (d) Narakasa, K.; Morikawa, A.;
Saigo, K.; Makuiyma, T. Bull. Chem. Soc. J pn. 1977, 50, 2773.
(5) For a recent review, see: de Nooy, A. E. J .; Besemer, A. C.;
VanBekkum, H. Synthesis 1996, 1153.
(14) For previous examples of TEMPO and hypervalent iodine
chemistry, see: (a) Togo, H.; Aoki, M.; Kuramochi, T.; Yakoyama, M.
J . Chem. Soc., Perkin Trans. 1 1993, 2417. (b) Magnus, P.; Lacour, J .;
Evans, P. A.; Roe, M. B.; Hulme, C. J . Am. Chem. Soc. 1996, 118, 3406.
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Lett. 1996, 37, 1889.
S0022-3263(97)01046-3 CCC: $14.00 © 1997 American Chemical Society

Iodine/TEMPO Oxidation of Alcohols to Carbonyls
J . Org. Chem., Vol. 62, No. 20, 1997 6975
Ta ble 1. Oxid a tion of Alcoh ols w ith BAIB/TEMP O
a
The reported yields refer to isolated, chromatographically pure or recrystallized compounds. All the structures have been confirmed
by IR, 1H-NMR, and 13C-NMR analysis. Solvent: CH3CN/aqueous buffer, pH 7 (1/1).
b
aldehydes;18 meanwhile the 1,3-diols (entries 13 and 14)
Sch em e 1. Oxid a tion of Alcoh ols w ith BAIB/
TEMP O
are converted to 1,3-hydroxycarbonyl compounds. Since
acetic acid is developed during the reaction, the oxidation
of alcohols with acid labile groups is an important target.
Homoallylic substrates (entries 15 and 16) are cleanly
oxidized to the corresponding carbonyl compounds with-
out transposition of the double bond to the conjugated
position. The optically pure 2S,3R epoxides (entries 17
and 18), prepared according to the Sharpless protocol,19
are rapidly oxidized to epoxy aldehydes in high yields,
without epimerization at the C2 carbon.20 Under the
standard reaction conditions, entry 7 undergoes a fu-
ranization process; however, performing the reaction in
a 1/1 CH3CN/aqueous buffer at pH 7 solvent mixture, the
corresponding aldehyde is recovered in excellent yield,
without E-Z isomerization.21 Selenium or sulfur func-
tional groups have been reported to be oxidized by both
iodine(III)4c,22 compounds and TEMPO/primary oxidant
systems.5 Our reactive system exhibits high chemose-
lectivity toward the alcoholic moiety even in the presence
of these heteroatoms (entries 19-20). We have already
efficiently at room temperature in CH2Cl2 (and also in
almost all common solvents and neat in some cases)15 at
high concentrations (>1 M) and can be performed in an
open flask without any particular precaution, e.g., inert
atmosphere or dry solvent. Under these conditions
primary alcohols (Table 1, entries 1-3) are oxidized in
less than 2 h to the corresponding aldehydes without any
noticeable overoxidation to the carboxylic acids, even with
an excess of BAIB. No oxidation process was observed
in the absence of the TEMPO. Primary allylic and
benzylic alcohols (entries 4-8) are rapidly oxidized to
aldehydes. It should be noticed that the easily isomer-
izable16 Z configuration of the nerol (entry 5) is recovered
unchanged from the reaction medium. Secondary alco-
hols (entries 9-12) are oxidized to the corresponding
ketones in longer reaction times. No isomerization to the
R,â-unsaturated aldehydes is noted for secondary allylic
alcohols.17 1,2-Diols are cleaved to the corresponding
(17) Dauben, W. G.; Michno, D. N. J . Org. Chem. 1977, 42, 682.
(18) Pausacker, K. H. J . Chem. Soc. 1953, 107.
(19) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 1987.
(20) Oxiranes undergo C-O cleavage with hypervalent iodine(III)
reagents: Spyroudis, S.; Varvoglis, A. J . Org. Chem. 1981, 46, 5231.
(21) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 2647.
(22) Castrillon, J . P. A.; Szmant, H. H. J . Org. Chem. 1967, 32, 976.
(15) When the alcohol is liquid the reaction can be performed
without any solvent under strong agitation at 0 °C. Benzyl alcohol,
1-phenylethanol, and geraniol were efficiently oxidized under this
condition.
(16) Santaniello, E.; Milani, F.; Casati, R. Synthesis 1983, 748.

6976 J . Org. Chem., Vol. 62, No. 20, 1997
De Mico et al.
Ta ble 3. Solven t In flu en ce on th e Rea ction a
Ta ble 2, Oxid a tion s of P r im a r y Alcoh ols in th e
P r esen ce of Secon d a r y Alcoh olsa
dielectric
constant
conversion
solvent
after 1 h (%)b
n-hexane
Et2O
1.9
3.8
50
50
AcOH
6.4
90
CH2Cl2
pyridine
CH3CN
DMSO
8.9
70
12.9
35.9
46.4
<1c
80
90
a
The reactions were performed on
a
1 mmol scale under
b
standard conditions. Conversions refer to 2-cyclohexylethanol
and were determined by GC analysis. c Less than 5% after 1 week.
a
The reactions were carried out on a 1:1 mixture of primary
b
and secondary alcohols, on a 1 mmol scale. The yields were
determined by H-NMR spectroscopy and confirmed by GC analy-
1
F igu r e 1. Catalyst efficiency. The reactions were performed
on a 1 mmol scale under standard conditions. Conversions
refer to benzyl alcohol and were determined by GC analysis.
sis.
reported that 1-(5-methyl-2-furyl)alcohols are smoothly
converted to pyranones with BAIB.23 Under these new
reaction conditions they are selectively transformed to
furyl ketones (entry 21).24
Sch em e 2. P r op osed Rea ction P a th w a y for th e
Oxid a tion of Alcoh ols w ith BAIB/TEMP O
The different reaction rates between primary and
secondary alcoholic functions suggest a possible chemose-
lectivity. In fact, the competing reaction of a 1:1 mixture
of 10-undecen-1-ol and 2-octanol using 1 equiv of BAIB
resulted in the complete conversion of the primary alcohol
into aldehyde, whereas no ketone could be detected (Table
2, entry 1). The competitive oxidation of allylic and
benzylic alcohols exhibits a similar degree of selectivity
(Table 2, entries 2 and 3). Entry 13 (Table 1) is an
example of regioselectivity between primary and second-
ary alcoholic functions, which is achieved in 70% yield.
Prompted by these results, we have analyzed some
aspects in order to elucidate the reaction pathway.
TEMPO is not directly oxidized by BAIB in CH2Cl2.25
However the corresponding hydroxylamine26 is converted
to the radical. The outcome of the reaction is influenced
by the dielectric constant of the medium (Table 3). The
results in acetic acid and pyridine are explained by the
acid-catalyzed dismutation of TEMPO,27 favored in the
former and inhibited in the latter. Analogous results are
obtained with stoichiometric quantities of other organic
bases. The reaction proceeds even faster when catalytic
amounts of acetic acid are added.
catalyzes the dismutation of TEMPO to hydroxylamine
and oxoammonium salt.5 This species is responsible for
the selective oxidation of alcohols while being reduced
to hydroxylamine. The role of BAIB is to regenerate the
TEMPO in order to close the catalytic cycle (Scheme 2).
ESR studies demonstrate a direct involvement of the
radical species whose signal intensity decreases during
the reaction and returns to the initial value at its end.29
In order to elucidate the efficiency of the catalyst, we
have performed the oxidation of benzyl alcohol at several
concentrations of TEMPO (Figure 1). The reaction
proceeds even at 10-2 mol equiv without any problem
except for longer reaction times. This result allowed the
scaling up to preparative oxidation reactions (0.1 mol).
As a result of these experimental observations and
according to preceding studies, we are able to propose a
possible reaction pathway. After a ligand exchange
around the iodine atom,28 the developed acetic acid
(23) De Mico, A.; Margarita, R.; Piancatelli, G. Tetrahedron Lett.
1995, 36, 3553.
(24) Piancatelli, G.; Scettri, A.; D’Auria, M. Tetrahedron Lett. 1979,
1507.
(25) ESR spectra support this evidence.
(28) (a) Seveno, A.; Morel, G.; Foucaud, A.; Marchand, E. Tetrahe-
dron Lett. 1977, 3349. (b) Schardt, B. C.; Hill, C. L. Inorg. Chem. 1983,
(26) Paleos, C.; Dais, P. J . Chem. Soc., Chem. Commun. 1977, 345.
(27) Golubev, V. A.; Sen, V. D.; Kulyk, I. V.; Aleksandrov, L. Izv.
Akad. Nauk. SSSR 1975, 2235.
22, 1563.
(29) Quantitative ESR studies will be published elsewhere in due
course.

Iodine/TEMPO Oxidation of Alcohols to Carbonyls
J . Org. Chem., Vol. 62, No. 20, 1997 6977
Gen er a l P r oced u r e for Alcoh ol Oxid a tion s. BAIB (354
mg, 1.1 mmol) was added to a solution of alcohol (1 mmol) and
TEMPO (15 mg, 0.1 mmol) in 1 mL of CH2Cl2. The reaction
mixture was stirred until the alcohol was no longer detectable
(TLC), and then it was diluted with CH2Cl2 (5 mL). The
mixture was washed with a saturated aqueous solution of
Na2S2O3 (5 mL) and extracted with CH2Cl2 (4 × 5 mL). The
combined organic extracts were washed with aqueous NaHCO3
(5 mL) and brine (5 mL), dried (Na2SO4), and concentrated
under reduced pressure. Flash column chromatography or
crystallization afforded pure products.
Con clu sion s
In conclusion we have demonstrated that the dehy-
drogenating properties of BAIB can be used for the
TEMPO-mediated oxidation of alcohols to carbonyl com-
pounds. This process exhibits a high degree of selectivity
for the oxidation of primary alcohols to aldehydes, without
any noticeable overoxidation to carboxyl compounds, and
a high chemoselectivity in the presence of either second-
ary alcohols or other oxidizable moieties. Furthermore,
the procedure reported here allows an easy, convenient,
high-yielding method for the transformation of alcohols
starting from commercially available compounds.
In ter m olecu la r Com p etition Exp er im en ts. The stan-
dard procedure was applied to an equimolecular mixture of
primary and secondary alcohols with a stoichiometric amount
of BAIB.
Oxid a tion P r od u cts. Aldehydes and ketones obtained by
oxidation were characterized by usual spectral data and
compared with the literature values.
ESR sp ectr a . ESR spectra were recorded every 15 min
on the reaction of benzyl alcohol performed on a 0.5 mmol scale
under standard conditions.
Exp er im en ta l Section
Gen er a l Exp er im en ta l. 1H (200 MHz) and 13C (50MHz)
nuclear magnetic resonance spectra were recorded at room
temperature in CDCl3 solutions. ESR spectra were recorded
at room temperature in CH2Cl2 solutions. Mass spectra were
obtained on a mass spectrometer using GC-MS coupling.
Flash chromatography was executed with Merck Kiesegel 60
(230-400 mesh) using a mixture of ethyl acetate or methylene
chloride and hexane as eluants. All commercially available
reagents were purchased from Aldrich and used as received.
Epoxy alcohols, 2-(phenylseleno)-2-butenal,30 4-(phenylthio)-
2-buten-1-ol,31 and 3â,4â-bis(benzyloxy)-5â-[(benzyloxy)methyl]-
2,5-anhydro-D-talitol32 were prepared according to cited lit-
erature procedures.
Ack n ow led gm en t. This work was financially sup-
ported by MURST. The authors express their gratitude
to Prof. D. Cordischi for his help in ESR spectroscopy.
J O971046M
(31) Ichinose, Y.; Oshima, K.; Utimoto, K. Chem. Lett. 1988, 8, 1437.
(32) Bettelli, E.; D’Andrea, P.; Mascanzoni, S.; Passacantilli, P.;
Piancatelli, G. Carbohydr. Res., in press.
(30) Renard, M.; Hevesi, L. Tetrahedron Lett. 1985, 41, 5939.