Catalytic synthesis of aldehydes and ketones under mild conditions using tempo/oxone

Article abstract of DOI:10.1021/ol005792g

A novel, metal-free oxidation system for the catalytic synthesis of aldehydes and ketones - TEMPO/Oxone - has been developed. An optimized reaction protocol proved especially successful for the synthesis of ketones. Additionally, the influence of quarternary ammonium salts on the catalysis was studied. The mild conditions of this novel procedure were shown to tolerate even sensitive silyl protective groups which can otherwise be cleaved in the presence of Oxone.

Full text of DOI:10.1021/ol005792g

ORGANIC
LETTERS
2
000
Vol. 2, No. 8
173-1175
Catalytic Synthesis of Aldehydes and
Ketones under Mild Conditions Using
TEMPO/Oxone
1
Carsten Bolm,* Angelika S. Magnus, and Jens P. Hildebrand
Institut f u¨ r Organische Chemie der RWTH Aachen, Professor-Pirlet-Strasse 1,
D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received March 11, 2000
ABSTRACT
A novel, metal-free oxidation system for the catalytic synthesis of aldehydes and ketonessTEMPO/Oxoneshas been developed. An optimized
reaction protocol proved especially successful for the synthesis of ketones. Additionally, the influence of quarternary ammonium salts on the
catalysis was studied. The mild conditions of this novel procedure were shown to tolerate even sensitive silyl protective groups which can
otherwise be cleaved in the presence of Oxone.
The development of selective oxidation processes constitutes
an active area of both academic and industrial research. The
recently developed a recoverable, metal-free TEMPO-based
catalyst on silica-support. In this system, aqueous bleach
1
9
growing number of attractive systems for alcohol oxidations
was used as terminal oxidant which is the most common
one for the catalytic synthesis of aldehydes.
2
3
includes examples such as TPAP- and copper-catalyses to
4
5
give aldehydes or ketones, and reactions with chromium
Within this context, we desired to replace bleach by a
6
10
or tungsten catalysts for the synthesis of carboxylic acids.
milder stoichiometric oxidant which would allow oxidations
In the area of metal-free catalytic alcohol oxidations TEMPO
in purely organic solvents using substrates otherwise prone
to hydrolysis under the standard biphasic conditions. We
therefore screened a number of different terminal oxidants
under homogeneous and heterogeneous conditions and found
(
2,2,6,6-tetramethylpiperidinyl-1-oxy) has emerged as the
catalyst of choice, and often very low catalyst loadings are
7
sufficient to achieve complete conversion within minutes.
8
11
During our program on selective oxidation reactions, we
Oxone to be suitable for the prerequesites mentioned above.
Its combination with TEMPO provides an efficient catalyst
(1) (a) Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations of
Organic Compounds; Academic Press: New York 1984. (b) Hudlicky, M.
Oxidations in Organic Chemistry; ACS Monograph 186; 1990.
(7) For overviews and leading early contributions, see: (a) de Nooy, A.
E. J.; Besemer, A. C.; Bekkum, H. V. Synthesis 1996, 1153-1174. (b)
Bobbit, J. M.; Flores, M. C. L. Heterocycles 1988, 27, 509-533. (c) Anelli,
P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559-
2562. (d) Miyazawa, T.; Endo, T.; Shiihashi, S.; Okawara, M. J. Org. Chem.
1985, 50, 1332-1334.
(2) (a) For an excellent overview, see: Ley, S. V.; Norman, J.; Griffith,
W. P.; Marsden, S. P. Synthesis 1994, 639-666. (b) See also: Mark o´ , I.
E.; Giles, P. R.; Tsukazaki, M.; Ch e´ lle-Regnaut, I.; Urch, C. J.; Brown, S.
M. J. Am. Chem. Soc. 1997, 119, 12661-12662 and references therein.
(3) (a) Mark o´ , I. E.; Gautier, A.; Giles, P. R.; Ch e´ lle-Regnaut, I.;
Tsukazaki, M.; Urch, C. J.; Brown, S. M. J. Org. Chem. 1998, 63, 7576-
577. (b) Mark o´ , I. E.; Giles, P. R.; Tsukazaki, M.; Ch e´ lle-Regnaut, I.;
Gautier, A.; Brown, S. M.; Urch, C. J. J. Org. Chem. 1999, 64, 2433-
439. (c) Semmelhack, M. F.; Schmidt, C. R.; Cort e´ s, D. A.; Chou, C. S.
J. Am. Chem. Soc. 1984, 106, 3374-3376.
4) For a palladium-based catalyst-system with molecular oxygen as
oxidant, see: Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem.
999, 64, 6750-6755 and references therein.
5) Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.; Grabowski,
E. J. J.; Reider, P. J. Tetrahedron Lett. 1998, 39, 5323-5326.
6) (a) Sato, K.; Aoki, M.; Takagi, J.; Noyori, R. J. Am. Chem. Soc.
(8) Selected references on various oxidations: (a) Bolm, C.; Schlingloff,
G.; Weickhardt, K. Angew. Chem., Int. Ed. Engl. 1994, 33, 1848-1849.
(b) Bolm, C.; Bienewald, F. Angew. Chem., Int. Ed. Engl. 1995, 34, 2640-
2642. (c) Bolm, C.; Kadereit, D.; Valacchi, M. Synlett 1997, 687-688. (d)
Bolm, C.; Maischak, A.; Gerlach, A. Chem. Commun. 1997, 2353-2354.
(e) Bolm, C. Med. Chem. Res. 1999, 19, 348-356.
(9) Bolm, C.; Fey, T. Chem. Commun. 1999, 1795-1796.
(10) In addition, the use of aqueous bleach often leads to chlorinated
byproducts which lower the yield and can make product isolation
problematic.
7
2
(
1
(
(
(11) Oxone or Caroat is commercially available from DuPont or Degussa-
H u¨ ls, respectively, and has the approximate empirical formula 2 KHSO5‚
KHSO4‚K2SO4.
1
997, 119, 12386-12387. (b) Sato, K.; Aoki, M.; Noyori, R. Science 1998,
81, 1646-1647.
2
1
0.1021/ol005792g CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/30/2000

system for the mild oxidation of primary and secondary
alcohols to the corresponding aldehydes and ketones.
Because preliminary experiments had shown that optimal
catalytic performances in the oxidations of primary and
secondary alcohols required different solvents, we began to
investigate the influence of the solvent on the catalysis with
the goal to optimize the reaction conditions for both kinds
of substrates. The most significant results are summarized
in Table 1.
higher ketone yield in toluene. Aliphatic substrates such as
1-nonanol (5) and 2-nonanol (6) showed the same trend but
performed somewhat less efficiently, giving the products in
up to 67% and 56% yield, respectively.
Rychnovsky and Vaidjanathan have demonstrated that a
combination of TEMPO and m-CPBA is very effective for
the oxidation of secondary alcohols, and they have also
studied the dependence of the catalysis on the presence of
1
5
various halide ions. They revealed that in their system
16
tetrabutylammonium bromide was the best additive for the
oxidation of 2-octanol to 2-octanone and proposed that this
effect was due to the formation of hypobromous acid and
subsequent oxidation of TEMPO to an N-oxoammonium
Table 1. Solvent Dependence in the TEMPO-Catalyzed
Oxidation with Oxonea
1
7
bromide.
entry
alcohol
solvent
yield (%)b
We therefore tested several quarternary ammonium salts
as additives in the TEMPO/Oxone oxidation and also found
a strong influence of the halide on the efficiency of the
1
2
3
4
5
6
7
8
9
1
1
1
1
3
3
3
3
5
5
6
6
CH2Cl2
toluene
THF
90
83
-
18
catalysis (Table 2). Interestingly, the effectiveness of the
MtBE
73
34
91
17
61
CH2Cl2
toluene
THF
Table 2. Influence of the Use of Quarternary Ammonium Salts
on the TEMPO-Catalyzed Oxidation with Oxone
MtBE
CH2Cl2
toluene
CH2Cl2
toluene
67c
35c
entry
alcohol
solvent
additivea
yield (%)b
1
1
1
0
1
2
9c
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
3
3
3
3
3
3
CH2Cl2
CH2Cl2
Bu4NF
Bu4NCl
-
92 (6)
90 (9)c
18
23
-
-
28 (<5)
91 (18)
91
13
-
56c
c
a
CH Cl2
Bu NBr
Reactions were carried out as a 0.2 M solution of alcohol in the
2
4
b
corresponding solvent using catalytic amounts of n-Bu4NBr. Yield referring
to isolated amount of product after column chromatography. c Yield
determined by GC.
CH2Cl2
Bu4NI
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
BnBu3NCl
Bu4NSCN
Bu4NF
Bu4NCl
Bu4NBr
Bu4NI
BnMe3NCl
Bu4NSCN
c
c
Interestingly, in some solvents such as toluene, secondary
alcohols reacted even more efficiently than their primary
counterparts, resulting in higher yields of the corresponding
1
1
0
1
12
12
carbonyl compound. This observation was quite unexpected
a
In each run 2 mol % of additive were used. b Yield referring to isolated
since it is known that TEMPO usually oxidizes primary
amount of product after column chromatography. c Yields in parentheses
refer to control experiments without TEMPO.
alcohols preferentially.13,14
In THF, benzyl alcohol (1) did not react at all, and
acetophenone (4) was formed from 1-phenylethanol (3) in
low yield (entries 3, 7). Experiments with methyl tert-butyl
ether (MtBE) showed that ethereal solvents are suitable for
TEMPO/Oxone oxidations though only moderate product
yields were obtained (entries 4, 8). Finally, it was found that
primary alcohols were best oxidized in dichloromethane
while the oxidation of secondary alcohols proceeds with
additive was highly substrate dependent. For example, iodide
and bromide had a pronounced beneficial effect on the
product yield in the oxidation of 3 (entries 9, 10), while
employing chloride led to low yields (entries 8, 11). Contrary,
the catalytic oxidation of 1 was most efficient when chloride
was present. Furthermore, only tetrabutylammonium chloride
was useful as halide source (entry 2), whereas addition of
benzyltributylammonium chloride led to a significant reduced
yield (entry 5). This was also true in oxidations of 3, which
showed a similar behavior. At present, the reason for this
dependence of the catalytic efficiency on the kind of
ammonium ion remains unclear, and it seems that benzyl-
(
12) This result is not due to overoxidation of the aldehydes to their
corresponding carboxylic acids.
13) See reference 7a. For a recent report on the oxidation of primary
(
alcohols to the corresponding carboxylic acids using TEMPO, see: Zhao,
M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. J. J.; Reider,
P. J. J. Org. Chem. 1999, 64, 2564-2566.
(14) For selected examples on oxidations of secondary alcohols to
ketones, see: (a) Cella, J. A.; Kelley; J. A.; Kenehan, E. F. J. Org. Chem.
1
975, 40, 1860-1862. (b) Cella, J. A.; McGrath, J. P.; Kelley, J. A.;
ElSoukkary, O.; Hilpert, L. J. Org. Chem. 1977, 42, 2077-2080. (c)
Inokuchi, T.; Matsumoto, S.; Nishiyama, T.; Torii, S. J. Org. Chem. 1990,
(15) Rychnovsky, S. D.; Vaidjanathan, R. J. Org. Chem. 1999, 64, 310-
312.
5
5, 462-466. (d) Banwell, M. G. Bridges, V. S.; Dupuche, J. R.; Richards,
(16) Chloride ion proved also successful probably due to the formation
of the corresponding hypochlorous acid.
(17) The presence of acids inhibited the catalysis.
(18) Control experiments revealed that in the absence of TEMPO
aldehydes and ketones were also formed though in low yield. Without
ammonium salt no oxidation was observed.
S. L., Walter, J. M. J. Org. Chem. 1994, 59, 6338-6343. (e) Drauz, K.;
Kottenhahn, M.; Stingel, K. US Patent 5631385. (f) De Mico, A.; Margarita,
R.; Parlanti, L.; Vescovi, A.; Pincatelli, G. J. Org. Chem. 1997, 62, 6974-
6
1
977. (g) Dijksman, A.; Arends, I. W. C. E.; Sheldon, R. A. Chem. Commun.
999, 1591-1592 and references therein.
1174
Org. Lett., Vol. 2, No. 8, 2000

tributylammonium chloride is generally not applicable in the
TEMPO/Oxone oxidation.
Scheme 1
As expected, fluoride and thiocyanate gave no detectable
oxidation product.
With these optimized conditions19 in hand, we tested the
scope of this process and a number of primary and secondary
alcohols were oxidized with TEMPO/Oxone and tetrabutyl-
ammonium bromide as additive. Table 3 summarizes the
results.
Table 3. TEMPO-Catalyzed Oxidation of Various Primary and
Secondary Alcohols Using Oxone as Terminal Oxidant
entry
alcohol
solvent
yield (%)b
bearing a phenolic TBDMS-ether moiety, and the TBDMS-
protected benzyl alcohols 9 and 10 to the TEMPO/Oxone
oxidation conditions (Scheme 2). In all three cases the ether
linkage remained intact, and only 7 was oxidized to the
corresponding aldehyde 8 in 81% yield.
1
2
3
4
5
6
7
8
1
3
5
6
CH2Cl2
toluene
CH2Cl2
toluene
toluene
toluene
toluene
CH2Cl2
90
91
67a
56a
96
93
71
37
1,2,3,4-tetrahydro-1-naphthol
1-phenylpropanol
1-cyclohexylethanol
4-methoxybenzyl alcohol
Scheme 2
a
The yield was determined by GC. b Yield referring to isolated amount
of product after column chromatography.
Benzylic secondary alcohols gave high yields of the
corresponding ketones. In addition, 1-cyclohexylethanol was
also oxidized in good yield (entry 7), while other aliphatic
alcohols regardless of the position of the hydroxyl function-
ality were oxidized with lower yield: for example, nonanal
was obtained from 1-nonanol (5) in 67% yield and oxidation
of 2-nonanol (6) provided the ketone in 56%. In contrast to
the high yielding synthesis of benzaldehyde (2) from benzyl
alcohol (1) (entry 1), oxidation of the more electron-rich
4
-methoxybenzyl alcohol afforded 4-methoxybenzaldehyde
In summary, we have demonstrated that the combination
of TEMPO and Oxone is an efficient system for the oxidation
of alcohols to aldehydes and ketones. The performance of
the catalyst is largely influenced by the presence of quar-
ternary ammonium salts, and the addition of tetrabutyl-
ammonium bromide proved useful for the oxidation of most
substrates. Furthermore, the reaction conditions of the
TEMPO/Oxone system are much milder than those with
previously reported stoichiometric oxidants which results in
an improved functional group tolerance avoiding over-
oxidation to the corresponding carboxylic acids.
in only 37% yield.
Recently, Sabitha and co-workers reported an Oxone-
mediated deprotection of phenolic and benzylic TBDMS-
ethers under mild conditions.20 They also found that silyl-
protected hydroxy groups in the benzylic position could be
cleaved in the presence of phenolic TBDMS-ethers.
To establish whether TBDMS-ethers were stable under the
novel oxidation procedure, we subjected benzyl alcohol 7
(19) Representative procedure: To a solution of the alcohol (1 mmol)
and Bu4NBr (4 mol %, 0.04 mmol) in 5 mL of the indicated solvent is
added TEMPO (1 mol %, 0.01 mmol, 0.1 M solution of the indicated
solvent) and Oxone (2.2 equiv, 2.2 mmol). The mixture is then stirred for
Acknowledgment. We thank Oliver Beckmann and
Thomas Fey for GC measurements, and we are grateful to
the Katalyseverbund NRW and the Fonds der Chemischen
Industrie for financial support of our work.
1
2 h at room temperature, and the reaction is monitored by TLC. After the
rection is complete, the solvent is removed under reduced pressure, and
the remaining solid is purified by column chromatography (silica gel,
hexanes/ethyl acetate: 10/1).
(20) Sabitha, G.; Syamala, M.; Jadav, J. S. Org. Lett. 1999, 1, 1701-
1
703.
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