Halogens halt aromatic group migration in Baeyer-Villiger oxidation

Article abstract of DOI:10.1016/S0022-1139(00)00296-7

Oxidation of a dihalogenated benzaldehyde under Baeyer-Villiger conditions led to the aromatic carboxylic acid as opposed to the desired phenol. Fluorine was located at the para-position of the benzaldehyde, halting migration of the aryl group and thus resulting in the carboxylic acid product.

Full text of DOI:10.1016/S0022-1139(00)00296-7

Journal of Fluorine Chemistry 105 (2000) 107±109
Halogens halt aromatic group migration in Baeyer±Villiger oxidation
Adeboye Adejarea,*, Jun Shenb,1, Alaba M. Ogunbadeniyia
aDepartment of Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Pocatello, ID 83209, USA
bDivision of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64110, USA
Received 18 February 2000; accepted 12 April 2000
Abstract
Oxidation of a dihalogenated benzaldehyde under Baeyer±Villiger conditions led to the aromatic carboxylic acid as opposed to the
desired phenol. Fluorine was located at the para-position of the benzaldehyde, halting migration of the aryl group and thus resulting in the
carboxylic acid product. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Fluorobenzaldehyde; Fluorocarboxylic acid; Baeyer±Villiger oxidation mechanism
1. Introduction
faster, leading to the acid observed [7,8]. We are currently
examining other methods of obtaining the desired phenol.
Our group has been involved in studying syntheses of
several aromatic amines of biological interest, especially
those with ¯uorine on the aromatic ring [1±3]. As part of
these studies, we needed the novel bromo¯uorophenol (1) as
a reagent. We proposed synthesizing it by Baeyer±Villiger
oxidation [4±6] of 3-bromo-4-¯uorobenzaldehyde (2).
Several oxidizing agents such as meta-chloroperoxyben-
zoic acid (MCPBA), peroxyacetic acid and tri¯uoroperoxy-
acetic acid were examined in the reaction (Table 1). The
reactivities of those reagents decreased in the order of
peroxytri¯uoroacetic acid (synthesized from tri¯uoroacetic
anhydride and H2O2)>MCPBA>peroxyacetic acid (synthe-
sized from acetic anhydride and H2O2). Reaction of perox-
yacetic acid with the aldehyde required long time and was
not complete. Reaction of MCPBAwith it was carried out in
chloroform or methylene chloride and heated to different
temperatures. The reaction gave a high yield (62%). How-
ever, the product was 3-bromo-4-¯uorobenzoic acid (3) and
not the desired phenol (1). Using tri¯uoroperoxyacetic acid
gave the same compound but in shorter time. Reaction with
this oxidizing agent was complex and resulted in many side-
products. Some of these may involve oxidations of the
benzene ring to form phenols.
2. Experimental
Melting points were determined on a Mel temp II capil-
lary melting point apparatus. IR spectra were recorded on a
Perkin-Elmer 457 spectrometer. 1H NMR spectra were
recorded on Bruker AC250 (250 MHz) spectrometer. MS
spectra were obtained by electrospray method using the
Finnigan TSQ-700 mass spectrometer. Elemental analyses
were performed by Galbraith laboratories, Knoxville, TN,
and the observed values were within Æ0.4% of theoretical
values.
2.1. Oxidation by MCPBA
A solution of 3-bromo-4-¯uorobenzaldehyde (1.00 g,
5 mmol), and 60% MCPBA (3.0 g, 10 mmol) in CH2Cl2
(30 ml) was re¯uxed for 24 h. After the solvent was eva-
porated, saturated NaHCO3 solution (30 ml) was added to
the residue, and the mixture was extracted by AcOEt
(2Â30 ml). The organic extracts were combined, dried over
Na2SO4 and the solvent was evaporated to yield a white
powder (0.92 g, 84%). A solution of the solid in MeOH
(10 ml) and 10% KOH solution (3 ml) was stirred for 1 h at
room temperature. After the solvent was evaporated, and the
pH of the residue was adjusted to 2 with 2 N HCl solution.
The mixture was extracted with AcOEt (3Â30 ml). The
organic extracts were combined, dried over Na2SO4 and
the solvent was evaporated to yield 0.81 g (74%) of a white
solid 3-bromo-4-¯uorobenzoic acid (3). Further, character-
In the mechanism (Scheme 1), we propose that migration
of the aromatic group of oxazon ion (4) was hindered by the
electron withdrawing ¯uorine, with possible contribution by
the bromine. Hydride was therefore able to migrate much
* Corresponding author.
1 Present address: Berlex BioSciences, Richmond, CA 94804, USA.
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 2 9 6 - 7

108
A. Adejare et al. / Journal of Fluorine Chemistry 105 (2000) 107±109
Table 1
Oxidation of 3-bromo-4-fluorobenzaldehyde by different peroxyacids
Type of peroxyacids
Catalyst
Solvent
Time (h)
Yielda (%)
meta-chloroperoxybenzoic acid
Acetic anhydride/H2O2
No
CHCl3
12
48
4
62
48
36
36
H2SO4
H2SO4
No
CH2Cl2
CH2Cl2
CH2Cl2
Trifluoroacetic acid/H2O2
Trifluoroacetic anhydride/H2O2
0.5
a The yields refer to the amounts of the acid formed.
ization was consistent with the proposed acid, mpˆ136±
1408C; ([7], mpˆ1378C) IR (CHCl3) cm 1: 1695 (COOH);
1H NMR (CDCl3): 9.70±9.25 (s, 1H, COOH), 7.90±7.30 (m,
3H, 3ÂAr-H).
58C to generate the tri¯uoroperoxyacetic acid in situ. A
solution of 3-bromo-4-¯uorobenzaldehyde (1.02 g, 5 mmol)
in CH2Cl2 was added with vigorous stirring. The reaction
was complete in 15 min, and the mixture was ®ltered to yield
0.98 g (91.0%) of a white solid tri¯uoroacetate ester,
mpˆ106±1088C, 1H NMR (CDC13): 7.80±7.58 (d, 1H),
7.55±7.00 (m, 2H), 6.85 (s, 1H). A solution of this solid
in MeOH (20 ml) and 10% KOH (10 ml) was re¯uxed for
2 h, and then concentrated. The residue was acidi®ed with
2.2. Oxidation by trifluoroperoxyacetic acid
30% H2O2 (0.65 ml, 5.8 mmol) was slowly added to the
mixture of tri¯uoroacetic acid (10 ml) and H2SO4 (0.5 ml) at
Scheme 1. Possible mechanism to explain formation of phenol (1) and acid (3).

A. Adejare et al. / Journal of Fluorine Chemistry 105 (2000) 107±109
109
2 N HCl solution and extracted with AcOEt (2Â30 ml). The
organic extracts were combined, dried over Na2SO4 and the
solvent was evaporated to yield 0.38 g of a white solid
(40.0%) 3-bromo-4-¯uorobenzoic acid (3). Results of the
characterization were consistent with the compound pre-
pared by the MCPBA method, mpˆ138±1418C; IR
acknowledged. Assistance of Dr. Paul W. Brown in obtain-
ing MS spectra is also gratefully acknowledged.
References
[1] Taken in part from the MS Thesis of Jun Shen, University of
Missouri-Kansas City, Kansas City, MO, USA, 1995.
[2] A. Adejare, K.L. Kirk, F. Gusovsky, C.R. Creveling, J.W. Daly, J.
Med. Chem. 31 (1988) 1972.
1
(CHCl3) cm 1: 1710 (COOH); H NMR (CDCl3): 9.50±
9.20 (s, 1H, COOH), 7.70±7.10 (m, 3H, 3ÂAr-H). MS ESI:
‡
m/z 218 (M‡H , base), 217. Anal. Calc. for C7H4O2BrF: C,
[3] A. Adejare, J. Nie, D. Hebel, L.E. Brackett, O. Chol, F. Gusovsky, W.
Padgett, J.W. Daly, C.R. Creveling, K.L. Kirk, J. Med. Chem. 34
(1991) 1063.
38.39; H, 1.84; F, 8.67. Found: C, 38.79; H, 2.01; F, 8.27.
[4] B.P. Branchaud, C.T. Wash, J. Am. Chem. Soc. 107 (1985) 2153.
[5] S. Ege, Organic Chemistry, 2nd Edition, Heath, Leungton, MA, 1989,
pp. 605±608.
Acknowledgements
[6] C.H. Hassall, Baeyer±Villiger oxidation of aldehydes and ketones,
Organic Reactions, Vol. 9, Wiley, New York, NY, 1957, pp. 73±106.
[7] J.M.W. Scott, Can. J. Chem. 38 (1960) 2441.
Financial support by the UMKC FRG, Missouri Alzhei-
mer's Disease and Related Disorders Program, and NIH
(NINDS Grant no. 1 R15 NS36393±01A1) are gratefully
[8] E.E. Smissman, J.P. Li, Z.H. Israili, J. Org. Chem. 33 (1968) 4231.