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Brine-Mediated EfficientBenzoylation of PrimaryAmines and Amino AcidsGautam Chattopadhyay a , Suchandra Chakraborty b

& Chandan Saha ba Postgraduate Department of Chemistry, PresidencyCollege, Kolkata, Indiab Department of Clinical and ExperimentalPharmacology, School of Tropical Medicine, Kolkata,IndiaPublished online: 31 Oct 2008.

To cite this article: Gautam Chattopadhyay , Suchandra Chakraborty & Chandan Saha(2008): Brine-Mediated Efficient Benzoylation of Primary Amines and Amino Acids,Synthetic Communications: An International Journal for Rapid Communication ofSynthetic Organic Chemistry, 38:23, 4068-4075

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Brine-Mediated Efficient Benzoylationof Primary Amines and Amino Acids

Gautam Chattopadhyay,1 Suchandra Chakraborty,2 and

Chandan Saha2

1Postgraduate Department of Chemistry, Presidency College,Kolkata, India

2Department of Clinical and Experimental Pharmacology,School of Tropical Medicine, Kolkata, India

Abstract: Benzoylation of primary amines and amino acids is efficiently carriedout in a brine solution using a stoichiometric amount of benzoyl chloridefollowed by trituration with aqueous saturated bicarbonate solution.

Keyword: Amines, amino acids, benzoylation, brine

Benzoylation provides an efficient and inexpensive means to identifyand characterize amines as well as to protect an amino functionality ina multistep synthetic process.[1] In addition, benzoylation is used for theresolution of amino acids.[2] A number of reagents can be used for carry-ing out this reaction, such as benzoyl chloride,[3] benzoic anhydride,[4]

N-benzoyltetrazole,[5,6] 2-benzoylthio-1-methylpyridinium chloride,[7]

and benzoyl cyanide.[8] Though benzoyl chloride may be a health hazardbecause of toxicity, it is widely used because of its ready availabilityand low cost. In the well-known Schotten–Baumann method,[9] for thebenzoylation of amines, excess of benzoyl chloride is used in alkali, andthe benzoyl derivative frequently occludes unchanged benzoyl chloride,which escapes hydrolysis and poses difficulty in isolating the product.

Received April 8, 2008.Address correspondence to Gautam Chattopadhyay, Postgraduate Depart-

ment of Chemistry, Presidency College, Kolkatta 700073, India. E-mail: g_chattopadhyay2002@yahoo.co.in

Synthetic Communications1, 38: 4068–4075, 2008

Copyright # Taylor & Francis Group, LLC

ISSN: 0039-7911 print=1532-2432 online

DOI: 10.1080/00397910802250929

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Thus, development of an efficient and convenient methodology is animportant area of research. Considering the importance of benzoylationand environmental factors, as well as our interest in green chemicalprocesses, we report here a brine-mediated efficient and convenient ben-zoylation of primary amines and amino acids using a stoichiometricamount of benzoyl chloride.

The primary amine or amino acid is dissolved (or suspended) in brine(scale: 1 g of sodium chloride in 3 ml of water) and then an equivalentamount of benzoyl chloride in acetone (1:1) is added dropwise withstirring. The desired product is finally obtained by treating the reactionmixture with saturated bicarbonate solution.

To gain insight into the role of the brine, it is assumed that the highconcentration of Cl� ion in the reaction mixture resists the hydrolysis ofbenzoyl chloride and is also responsible for the slow decomposition of thetetrahedral intermediate formed by the nucleophilic attack of the aminogroup toward the benzoyl chloride. The rationale is supported by the factthat when the reaction is carried out only in water (instead of brine), theyield is drastically reduced. In the case of o- and p- aminobenzoic acids,the sodium salt of the benzoyl derivatives are separated because of thecommon ion (Naþ) effect. From the sodium salt, the required derivativesare obtained by usual acid workup followed by washing with hot water toremove traces of benzoic acid. It is worth mentioning that the usualSchotten–Baumann method to obtain the benzoyl derivative of alaninerequires longer reaction time coupled with tedious workup.[2] In all thecases examined, the derivatives are crystallized from methanol=methanol–water=water and identified by comparing them with authenticsamples. The results are summarized in Table 1.

In conclusion, we have developed a very simple, inexpensive, non-toxic, and environmentally friendly method for the benzoylation of aminesand amino acids.

EXPERIMENTAL

Melting points were determined in open capillaries and are uncorrected.Reagent-grade chemicals were purchased from a commercial source and usedwithout further purification. IR spectra were recorded in KBr discs onSchimadzu FTIR-8300, and NMR spectra were recorded on Bruker AV 500.

General Procedure

To a mixture of 25 mmol of primary amine or amino acid (water-insoluble compounds are taken in 20–30 ml of acetone) and 50 ml of

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Table 1. Brine-mediated benzoylation of amines and amino acids

Entry Substrate (R–NH2)

Substrate to sodiumbicarbonate(eqv. Amt.)

Yield(%)

Mp=lit. mp ofbenzoate (�C)

1 1:2 56 57=57a

2 1:2 60 148=149

3 1:2 72 106=105

4 1:2 80 163=163

5 1:2 62 145=144

6 1:2 80 157=158

7 1:2 82 156=154a

(Continued )

4070 G. Chattopadhyay, S. Chakraborty, and C. Saha

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Table 1. Continued

Entry Substrate (R–NH2)

Substrate to sodiumbicarbonate(eqv. Amt.)

Yield(%)

Mp=lit. mp ofbenzoate (�C)

8 1:2 76 99=99

9 1:2 82 194=193

10 1:2 76 98=98

11 1:2 78 157=157

12 1:2 84 199=199

13 1:2 45 160=161

(Continued )

Benzoylation of Amines and Amino Acids 4071

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Table 1. Continued

Entry Substrate (R–NH2)

Substrate to sodiumbicarbonate(eqv. Amt.)

Yield(%)

Mp=lit. mp ofbenzoate (�C)

14 1:2 60 152=—a

15 1:3 51 166=166a

16 1:4 49 178=176a (anhyd.)

17 1:3 80 183=182

18 1:3 70 252=248

19 1:3 80 284=278

20 1:3 60 248=— (dec.)

aProducts were characterized by their spectral data.

4072 G. Chattopadhyay, S. Chakraborty, and C. Saha

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brine (10 ml for water-soluble compounds), 25 mmol of benzoyl chloridein 3 ml of acetone are added in portions with continuous stirring during15 min. The requisite amount (Table 1) of the saturated solution ofsodium bicarbonate is added, and the reaction mixture is stirred for afurther period of 15 min. The sparingly soluble benzoyl derivative ofprimary amine is separated as solid. In the case of amino acids suchas m-aminobenzoic acid, DL-alanine, DL-aspartic acid, and sulfanilicacid, the sodium salt remains in solution, whereas for the amino acidssuch as o-and p-aminobenzoic acids, the sodium salt separates as solid.From the sodium salt, the corresponding benzoyl derivative is obtainedby usual acid workup (for sulphanilic acid, acidification is accomplishedby conc. H2SO4) followed by washing with hot water to removetraces of benzoic acid. The benzoyl derivatives are crystallized frommethanol=methanol–water=water. In the cases of DL-alanine andDL-aspartic acid, the benzoyl derivatives after crystallization werepurified by vacuum sublimation.

Representative Spectral Data of Benzoyl Derivatives

Entry 1

1H NMR (500 MHz, DMSO-d6) d, ppm, 7.85 (d, J¼ 7.7 Hz, 2H), 7.53–7.44 (m, 3H), 3.09 (t, 2H), 1.85 (m, 1H), 0.90 (d, J¼ 7 Hz, 6H);13C NMR (125 MHz, DMSO-d6) d, ppm, 166.23, 134.76, 130.77,128.03 (�2), 127.07 (�2), 46.64, 28.02, 20.07 (�2); IR (KBr) n, cm�1,3296, 2958, 2916, 2873, 1633.

Entry 7

1H NMR (500 MHz, DMSO-d6) d, ppm, 7.95 (d, J¼ 7.6 Hz, 2H), 7.68 (d,J¼ 8.2 Hz, 2H), 7.58–7.51 (m, 3H), 6.94 (d, J¼ 8.2 Hz, 2H), 3.75 (s, 3H);13C NMR (125 MHz, DMSO-d6) d, ppm, 164.90, 155.54, 134.96, 132.13,131.22, 128.20 (�2), 127.42 (�2), 121.88 (�2), 113.62 (�2), 55.06; IR(KBr) n, cm�1, 3330, 2900, 2805, 1647.

Entry 14

1H NMR (500 MHz, DMSO-d6) d, ppm, 8.11 (s, 1H), 8.09 (s, 1H), 7.66–7.29(m, 5H); 13C NMR (125 MHz, DMSO-d6) d, ppm, 164.97, 158.63, 137.44,132.38, 132.07, 128.43 (�2), 128.01 (�2), 113.71; IR (KBr) n, cm�1, 3109,2935, 1676.

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Entry 15

1H NMR (500 MHz, DMSO-d6) d, ppm, 7.89 (d, J¼ 7.7 Hz, 2H), 7.56–7.46 (m, 3H), 4.42 (quintet, 1H), 1.41 (d, 3H); 13C NMR (125 MHz,DMSO-d6) d, ppm, 174.13, 166.09, 133.89, 131.24, 128.14 (�2),127.34 (�2), 48.08, 16.83; IR (KBr) n, cm�1, 3369, 2981, 2933, 1724,1705, 1627.

Entry 16

1H NMR (500 MHz, DMSO-d6) d, ppm, 7.85 (d, J¼ 7.3 Hz, 2H), 7.57–7.47 (m, 3H), 4.76 (q, 1H), 2.78 (overlapping dd, 2H); 13C NMR(125 MHz, DMSO-d6) d, ppm, 172.55, 171.82, 166.13, 133.83, 131.45,128.89 (�2), 127.80 (�2), 49.40, 35.85; IR (KBr) n, cm�1, 3319, 3037,2937, 1706, 1649.

ACKNOWLEDGMENT

We are thankful to D. K. Neogi, director, School of Tropical Medicine,for his interest in the work. We are also thankful to the Council of Scien-tific and Industrial Research (CSIR), New Delhi, India, for providing ajunior research fellowship to one of the authors (S. C.).

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