Amidation of polyaromatic carboxylic acids in aqueous medium

Article abstract of DOI:10.1016/S0040-4039(00)00825-X

The amidation of polyaromatic carboxylic acids, such as 4- biphenylcarboxylic acid, 4-biphenylacetic acid, 4-carboxy-4'-hydroxybiphenyl, and N-phenylanthranilic acid, was satisfactorily carried out to give the corresponding amides using a wild-type bacter

Full text of DOI:10.1016/S0040-4039(00)00825-X

Tetrahedron Letters 41 (2000) 5229±5232
Amidation of polyaromatic carboxylic acids in
aqueous medium
Reiji Maruyama, Shin Ono and Masami Inoue*
Faculty of Engineering, Toyama University, Gofuku, Toyama 3190, Japan
Received 10 April 2000; revised 15 May 2000; accepted 19 May 2000
Abstract
The amidation of polyaromatic carboxylic acids, such as 4-biphenylcarboxylic acid, 4-biphenylacetic
acid, 4-carboxy-40-hydroxybiphenyl, and N-phenylanthranilic acid, was satisfactorily carried out to give
the corresponding amides using a wild-type bacterium, Bacillus cereus (w), in an aqueous medium. # 2000
Elsevier Science Ltd. All rights reserved.
Keywords: biotransformation; amidation; Bacillus cereus; polyaromatic carboxylic acid.
Amide compounds of polyaromatic carboxylic acids (PAA) are useful in ®ne chemical industries
as materials of liquid crystals1,2 and as intermediates for pharmaceuticals. Such amide com-
pounds are generally obtained by the ammonolysis of acid chlorides under anhydrous conditions or
by heating carboxylic acids in the presence of ammonia in an autoclave. Since undesired by-products
are often generated during these amidation reactions, a new method to prepare amide compounds
under milder reaction conditions is required.
Biotransformation technology has been developed as a new synthetic method that gives the
desired compounds with high enantioselectivity and high substrate speci®city under clean conditions
without the use of organic solvents. This technology has been applied to various transformations,
such as hydroxylation, oxidation and reduction, but there have been few reports on application to
amidation of PAA.3 Biotin has been transformed into biotinamide using Rhodotorula ¯ava in
30% yield by a ®ve day reaction at 30ꢀC.4 Cultivation of Bacillus cereus 50 with 12-hydroxy-
octadecanoic acid at 30ꢀC for ®ve days a€orded the corresponding 12-hydroxy-octadecanamide in
24% yield.5 It has been found that oleic acid decomposes to give a mixture of 9(z)-octadecenamide,
hexadecenamide, tetradecenamide, and tetradecanamide (5±7% yields) in the presence of Bacillus
megaterium B-3437.6 Thus, water-soluble natural products were used as the substrates in all of
these reactions because aqueous media are required for such biotransformation. Therefore,
although there have been a few reports on successful amidation by biotransformation, there have
been no reports on amidation of water-insoluble substrates such as PAA.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00825-X

5230
To prepare amide compounds corresponding to PPA, we focused on the biotransformation
ability of Bacillus cereus.7 Using Bacillus cereus (w) from soil, 4-biphenylcarboxylic acid (1) was
satisfactorily transformed to 4-phenylbenzamide (2) in excellent yield (95%) by 24 h reaction at
37ꢀC (Scheme 1).8
Scheme 1.
Through monitoring of the reaction by HPLC, several optimal reaction conditions, (substrate
concentration, temperature, reaction time, and atmosphere) were determined, as shown in Table 1.
Since the amount of 2 transformed from 1 increased with the growth of bacteria, the e€ect of cell
density in the reaction mixture was also investigated. As a result of these examinations, the
highest yield (95%) was obtained under the following conditions: cell density, 20 g/l; substrate
concentration, 1 mM; temperature, 37ꢀC; and reaction time, 24 h.
The supply of oxygen was found to be indispensable, since the reaction stopped under N2 or
CO2 atmosphere. Other Bacillus cereus strain IFO 3001 obtainable from the list of cultures9 also
gave 2 in 92% yield. On the other hand, no amidation of PAA occurred using either E. coli or
baker's yeast.
Table 1
Amidation of 4-biphenylcarboxylic acid in nutrient broth
Our amidation system was also applied to substrates other than 1. Interestingly, a simple
aromatic carboxylic acid having one benzene ring, such as benzoic acid, could not be amidated by
our system. Several PAAs, such as 4-carboxy-4-hydroxybiphenyl, N-phenylanthranilic acid, 9-
¯uorenone-2-carboxylic acid, and 4-biphenylacetic acid, were satisfactorily transformed to the
corresponding amide compounds using Bacillus cereus (w), as shown in Table 2.10
The di€erence between conversion rates and yields shows a loss of each product during
extraction with ethyl acetate. In the case of 9-¯uorenone-2-carboxylic acid, although monitoring

5231
Table 2
Amidation of polyaromatic carboxylic acids
by HPLC showed that the conversion of the carboxyl group to amide occurred in 75% yield, the
amide product was obtained in only 41% yield. The rates of these losses are thought to depend on
the solubility in ethyl acetate. Thus, our system is applicable to the amidation of PAA.
In summary, we have demonstrated that polyaromatic carboxylic acids can be speci®cally
transformed to the corresponding amide compounds using Bacillus cereus (w) in an aqueous
medium at 37ꢀC. On the other hand, biotransformation of several aliphatic11 and aromatic12
nitrile compounds with nitrile hydratases also a€ords the corresponding amide compounds and
this technology has been applied to acrylamide production.13 Therefore, our biocatalytic amidation
system can be used as a simple, direct and clean alternative to organochemical amidation methods.
References
1. Mettler, H.-P. Ger. O€en 19833409, 1998; Chem. Abstr. 1999, 130, 66276.
2. Saito, T.; Ikemoto, K. Jpn. Patent 08208578, 1995; Chem. Abstr. 1996, 125, 275426.
3. Biotransformation abstracts, 1997, 11, 1, Warwick biotransformation club ed. Chapman & Hall.
4. Sekijo, C.; Tsuboi, T.; Yoshimura, Y.; Shoji, O. Agric. Biol. Chem. 1968, 32, 1181.
5. Huang, J. K.; Kendell, K. C.; Klopfenstein, W. E.; Wen, L.; Bagby, M. O.; Vesonder, R. F.; Norton, R. A.;
Weisleder, D. J. Am. Oil Chem. Soc. 1997, 74, 5, 601.
6. Kaneshiro, T.; Vesonder, R. F.; Peterson, R. E.; Weisleder, D.; Bagby, M. O. J. Am. Oil Chem. Soc. 1994, 71, 5,
491.
7. Cerniglia, C. E.; Freeman, J. P.; Evans, F. E. Arch. Microbiol. 1984, 138, 283.
8. Into an L-shaped test tube were added PAA, seed bacteria and a sterilized culture solution composed of peptone
(1%), ®sh meat (bonito) extracts (1%), and NaCl (0.2%). The reaction was started by shaking the tube in a 37ꢀC
water bath. The decrease in the substrate and the increase in amide were analyzed for the extracts of ethyl acetate
by HPLC (Gilson Co. model 102, column YMC pac, ODS-A, 4 mm i.d.Â150 mm in length) with a gradient
system (MeOH:H2O=3:7 to 7:3) monitored by a UV detector at 270 nm. The evolution of ammonia from
nutrients increased the pH from 7.0 to 8.4 during the reaction.

5232
9. List of cultures; Inst. Fermentation: Osaka (IFO), 1996; p. 131.
10. The substrate (0.2 mmol), seed bacteria (4 wet-g) and medium (200 ml) in a 500 ml ¯ask was shaken reciprocally
(120/min) at 37ꢀC for 24 h. After the reaction the products were extracted with ethyl acetate and dried on
anhydrous sodium sulfate. Evaporation of the solvent left a white powder of amide. Further puri®cation was
carried out on a separate column (YMC-pac, ODS, 20 mm i.d.Â150 mm in length).
11. Asano, Y.; Fujishiro, K.; Tani, Y.; Yamada, H. Agric. Biol. Chem. 1982, 46, 5, 1165.
12. Mauger, J.; Nagasawa, T.; Yamada, H. Tetrahedron 1989, 45, 1347.
13. Asano, Y.; Yasuda, T.; Tani, Y.; Yamada, H. Agric. Biol. Chem. 1982, 46, 5, 1183.