A simple and highly practical oxidation of primary alcohols to acids mediated by 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)

Article abstract of DOI:10.1248/cpb.51.888

Primary alcohols were quantitatively oxidized in one-pot to acids via 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) mediated oxidation. The reported method is simple and suitable for large scale synthesis.

Full text of DOI:10.1248/cpb.51.888

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Chem. Pharm. Bull. 51(7) 888—889 (2003)
Vol. 51, No. 7
A Simple and Highly Practical Oxidation of Primary Alcohols to Acids
Mediated by 2,2,6,6-Tetramethyl-1-piperidinyloxy (TEMPO)
Atsuhiko ZANKA
Chemical Development Laboratories, Fujisawa Pharmaceutical Co. Ltd.; 2–1–6 Kashima, Yodogawa-ku, Osaka 532–
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514, Japan. Received March 3, 2003; accepted April 24, 2003
Primary alcohols were quantitatively oxidized in one-pot to acids via 2,2,6,6-tetramethyl-1-piperidinyloxy
(
TEMPO) mediated oxidation. The reported method is simple and suitable for large scale synthesis.
Key words 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO); oxidation; alcohol; acid; one-pot
Conversion of alcohols to the corresponding acids is an other, over 2 h is difficult to control on a large scale, (3) con-
important transformation in organic and pharmaceutical syn- version of alcohols to aldehydes proceeded sluggishly due to
thesis and a number of methods have been developed to date. the presence of the reduced amount of NaClO in the system.
These include the classical and most well known methods In addition, the mixture of NaClO and NaClO appears to be
2
1
,2)
using chromium(VI) oxides, represented by Jones reagent,
unstable under the reported condition (pHϭ6.7) as described
in the paper. In order to develop more practical methods
3
,4)
5,6)
11)
Collins reagent, and pyridinium chlorochromate (PCC).
Although these methods are commonly applied on a labora- we investigated conditions where NaClO selectively reacted
2
tory scale, and are efficient enough to give materials in gram with aldehydes to give the corresponding acids without react-
quantities, the highly toxic chromium salts produced in the ing with NaClO. Herein, we report an efficient procedure for
reaction, strict control of reaction temperature (ca. Ϫ20 °C) one-pot conversion of primary alcohols to the corresponding
or preparation of unstable reagent are problematic from the acids suitable for a large scale synthesis.
standpoint of large scale synthesis of pharmaceutical prod-
We initiated studies by evaluating reaction conditions that
ucts. The Parikh–Doering reaction was found to be useful to allow easy conversion of alcohols to the corresponding alde-
1
2,13)
solve these problems and has been applied to the large scale hydes. As pointed out in the previous paper,
the reactiv-
7
)
synthesis of pharmaceutical intermediate. However, this ity is critically dependent on the pH employed, and the reac-
method involves stench (dimethyl sulfide), and in addition, tion was dramatically accelerated under slight basic condi-
pyridine-sulphur trioxide complex is rather expensive and tions (pHϭ8—10) compared with neutral conditions (pHϭ
should be stored under low humidity conditions. As an alter- 6.7). Sodium carbonate contained in NaClO was smoothly
native reagent, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) neutralized by hydrogen chloride produced during the reac-
is especially attractive since this reagent is inexpensive and tion due to high reactivity, and sodium phosphate was not
readily available in large quantities from Koei Chemical needed in the system. Next, we investigated oxidation of
Co. and Degussa AG. A number of oxidative methods medi- aldehydes to the corresponding acids by NaClO . Whilst
2
ated by TEMPO have been reported to convert alcohols to the reaction proceeded sluggishly under basic conditions
8
,9)
the corresponding aldehydes and ketones. Recently Ley (pHϭ8—10), NaClO was unstable and easily led to decom-
2
and Yasuda reported one-pot conversion of primary alcohols position under acidic conditions (pHϭϽ4.0). Surprisingly
to the corresponding carboxylic acids using polymer-sup- though, the reactivity was dramatically increased at a pH of
1
0)
ported TEMPO. However there appears to be few practical 4.0—6.0, and neither decomposition of NaClO nor side re-
2
methods for direct conversion to acids amenable to a large action between NaClO and NaClO was detected to any sig-
2
scale synthesis. Conceptually, alcohols are converted to the nificant degree. Thus, this finding led us to realize a selective
corresponding aldehydes in the presence of catalytic amounts reaction of aldehydes to the corresponding acids by NaClO2
of TEMPO and sodium hypochlorite (NaClO) as cooxidant, in the presence of NaClO in significant amounts. As can be
followed by oxidation to acids by sodium chlorite (NaClO2). seen in Table 1, many alcohols were cleanly and quantita-
Both NaClO and NaClO are inexpensive and readily avail- tively converted to aldehydes by TEMPO mediated oxidation
2
able in large quantities. The problematic feature in the when NaClO was added dropwise to the mixture over 30 min
process is that NaClO easily reacts with NaClO . Zhao et al. at pH of 8—10. Next, to the mixture was added NaClO2
2
developed a one-pot conversion of primary alcohols to the dropwise over 30 min at pH of 5.0, giving the materials in
1
4)
corresponding acids in the presence of catalytic amount of quantitative yield. According to theses limited studies, ace-
TEMPO in a mixture of acetonitrile and sodium phosphate tonitrile and ethyl acetate are suitable for these conversions.
1
1)
buffer (pHϭ6.7). The success of this process was attrib- When toluene or methylenechloride was used as solvent, the
uted to the dilute conditions and reduced quantities of NaClO conversion of aldehydes to acids proceeded slightly slug-
(
10 mol%) to avoid the side reaction between NaClO and gishly, leading to aldehydes remained in traceable amounts.
NaClO . Whilst efficient enough to afford the materials in The result in entry 2 is noteworthy. In general, oxidation of
2
less than several hundreds grams quantities, the reported b-arylalcohols proceeded to give the corresponding aldehy-
methods involved several drawbacks from the viewpoints of des in low yields since the aldehydes are unstable under basic
1
5)
multi-kilogram scale manufacturing; (1) productivity is low conditions. On the other hand TEMPO mediated oxidation
due to diluted reaction conditions, (2) simultaneous addition of phenylethanol gave the product in quantitative yield pre-
of both NaClO and NaClO , which easily react with each sumably due to mild and nearly neutral reaction conditions.
2
e-mail: atsuhiko_zanka@po.fujisawa.co.jp
© 2003 Pharmaceutical Society of Japan

July 2003
889
Table 1. TEMPO-Catalyzed Oxidation of Primary Alcohols
TEMPO and stoichiometric NaClO, followed by one-pot
conversion to acids by NaClO . The described procedures
a)
2
Entry
1
Substrate
Product
Solvent
Yield (%)
using only inexpensive reagents are safe and practically and
environmentally advantageous over the reported methods es-
pecially from the standpoints of large scale manufacturabil-
ity.
CH CN
98
3
2
3
AcOEt
AcOEt
92
93
Acknowledgment I especially thank Dr. David Barrett, Medicinal
Chemistry Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., for his
interest and on-going advice in this work.
References and Notes
1
2
3
)
)
)
Bowden K., Heilbron I. M., Jones E. R. H., Weedon B. C. L., J. Chem.
Soc., 1946, 39—45 (1946).
Bowers A., Halsall T. G., Jones E. R. H., Lemin A. J., J. Chem. Soc.,
4
5
AcOEt
100
99
1
953, 2548—2560 (1953).
Collines J. C., Hess W. W., Frank F. J., Tetrahedron Lett., 1968, 3363—
366 (1968).
3
CH CN
3
4
5
6
)
)
)
Ratcliffe R., Rodehorst R., J. Org. Chem., 35, 4000—4002 (1970).
Corey E. J., Suggs J. W., Tetrahedron Lett., 1975, 2647—2650 (1975).
For a review, see: Piancatelli G., Scettri A., D’Auria M., Synthesis,
1982, 245—258 (1982).
6
7
CH CN
95
3
7
)
Zanka A., Itoh N., Kuroda S., Org. Process Res. Dev., 3, 394—399
(
1999).
b)
b)
AcOEt
16 (65)
17 (70)
8) For a review, see: de Nooy A. E. J., Besemer A. C., van Bekkum H.,
CH CN
Synthesis, 1996, 1153—1174 (1996).
3
9
)
Miyazawa T., Endo T., Shiihashi S., Okawara M., J. Org. Chem., 50,
332—1334 (1985).
0) Yasuda K., Ley S. V., J. Chem. Soc., Perkin Trans. 1, 2002, 1024—
025 (2002).
1) Zhao M., Li J., Mano E., Song Z., Tschaen D. M., Grabowski E. J. J.,
Reider P. J., J. Org. Chem., 64, 2564—2566 (1999).
1
1
1
c)
8
9
AcOEt
AcOEt
24 (55)
1
84
1
1
2) de Nooy A. E. J., Besemer A. C., Tetrahedron, 51, 8023—8032 (1995).
3) Anelli P. L., Biffi C., Montanari F., Quici S., J. Org. Chem., 52, 2559—
a) Isolated yield. b) Yields in parentheses refer to percent of aldehyde. c) Yield
2
562 (1987).
in parenthesis refers to percent of 2-chloro-5-methoxybenzoic acid.
1
4) General procedure for oxidation of alcohol: Ethyl acetate (750 ml) was
added to a mixture of phenylethanol (61.1 g, 0.5 mol) and KBr in
water (0.5 M, 100 ml), followed by addition of TEMPO (1.6 g,
Entries 7 and 8 show the limitation of this method. p-
Methoxybenzyl alcohol was quantitatively oxidized to the
corresponding aldehyde, however, the following conversion
to the acid proceeded sluggishly (entry 7). The hypochlorite
formed in the system may interfere with substrate at pH of
1
0 mmol). A solution of 12% NaClO in water (390 g, 625 mmol) was
added dropwise to the mixture over 30 min at 5 °C at pH of 8.0—10.0.
Stirring continued for 30 min at ambient temperature. Then, pH was
adjusted to 5.0 by addition of 35% hydrochloric acid, followed by ad-
dition of 25% NaClO in water (227 g, 625 mmol) over 30 min main-
2
taining the temperature of 27—33 °C. Stirring continued for 3 h at am-
bient temperature. The product was extracted with ethyl acetate,
washed with brine, followed by concentration to give 62.6 g of pheny-
lacetic acid (92 % yield).
1
6)
5
.0 in the absence of Cl scavenger. For example ring chlo-
rinated material was obtained as a main product in the oxida-
tion of m-methoxybenzyl alcohol (entry 8).
In summary, a new method for one-pot conversion of alco-
hols to acids has been revealed. Alcohols were efficiently ox-
idized to aldehydes in the presence of a catalytic amount of
1
1
5) Mancuso A. J., Swern D., Synthesis, 1981, 165—185 (1981).
6) Kraus G. A., Roth B., J. Org. Chem., 52, 4825—4830 (1980).