Note Protection of Amino Group As N-Phthaly\ De
Indianlourn al of Chemistry VoI.4 IB , May2002,pp. 1083-1085
Note
Protection of amino group as N-phthaly\ de an alkyl halide with potassium phthalimide alone or in 8 rivative using microwave irradiation a non-polar solvent , or by heating ami ne with phthalic anhydride in presence of triethyl amine9 or Shushan M Kh adilkar* & Virendra R Madyar with carbethoxythiobenzoic acid 10. After synthetic Applied Organic Chemistry Laboratory, University Department of transformation's phthalyl group can be easily Chemical Technology, University of Mumbai, Matunga, removed by hydrazonolysis using hydrazine hydrate Mumbai 400019, India. Fax 91-022-4145619, to yield amine and phthalyl hydrazide. From the Received 23 November 2000; accepted (revised) 9 October 2001 literature it was seen that the methods available for the preparation of N-(2-hydroxyethyl)phthalimide The amino groups for various substrates are protected as N were those described by Giles Ralph et al. II in which phthalyl derivatives usi ng solvent free neat condition under large excess of anhydride to ethanol amine is used, microwave exposure. and this mixture is then heated to high temperature at about ISO°C for 1 hr and vacuum distilled so as to get The selection of an appropriate protective group is an moderate yields of the desired products. In yet another important step in the development of a synthetic l2 method described by Yataro Obata a mixture of K methodology. The reports of new protective groupsl pthalimide and l-chloroethanol were heated in a and methods for its protection and cleavage appear sealed tube at 132°C for 6 hr to give the expected regularly in the literature. It is necessary that the product in low yields. chosen protective group must be selectively removed There is a growing popularity of using microwave in good yields by readily available, preferably irradiation to carry out solventless reactions and hence nontoxic reagents that do not attack the regenerated has become an attractive method for chemical functional group. I3 16 synthesis . . It involves neat reactants to be exposed The amino group is vulnerable to alkylation, to microwave irradiation so as to get greater selectivity acylation, oxidation and a variety of other reactions, and achieve high yields within a short reaction time so it is necessary to protect it while other parts of the and with ease in experimentation. Furthermore, the molecule are undergoing chemical changes. This is solid state reaction (or solvent-free reactions) has many especially true in peptide synthesis. This can be done advantages: reduced pollution, low cost, simplicity in by converting the amino group to a derivative that is process and handling. These factors are especially very l7 stable under the reaction conditions to be employed important in industry. Recently an informative review and from which the amino group can be regenerated by Toda et at. clearly points out the superiority of thi s without affecting the rest of the molecule. The amino solvent-free or the use of "dry" reaction conditions in group can be protected 2-4 by acyl type, urethane type chemical synthesis. and arylidene type protecting groups using Schiff From our knowledge and interest in thi s upcoming bases of aromatic aldehydes or ketones, allyl and aryl field of solventless microwave synthesis it was inter type protecting groups such as benzyl or dibenzyl esting and convenient for us, to apply microwave derivatives or trialkylsilyl derivatives. heating in carrying out the synthesis of N- (2- hydroxy During our studies aimed at the synthesis of ethyl)phthalimide under microwave irradiation. An 5 6 Arnlodipine . , a calcium channel blocker, we required equimolar amount of phthalic anhydride and etha an amjne function in ethanolamine to be protected as nolamine were mixed in a conical flask, covered with an N-pthalyl derivative. Acyclic N,N-diacyl derivatives are hydrolysed easily that they are generally of no practical use, although they have been used very occasionall/. In contrast, the cyclic imides such as N-substituted phthalimides, are very stable and have been wictely . used. The phthalyl group can be introduced by heating Scheme I 1084 INDIAN J. CHEM., SEC B, MA Y 2002
Table 1-N-Phthalyl derivative preparation by MW irradiation Entry Subst rate MW (sec.) Yie ld (%) m.p.oC (Lit.)19. 20
I P - Chloroaniline 240 98 194-96 (197)
2 III - Chloroaniline 180 82 16 1-62 (163)
3 0 - Chloroaniline 180 58 142-43 (143)
4 0 - Nitroaniline 240 84 198-99 ( 199)
5 III - Nitroani line 120 94 240-4 1 (240)
6 0- Toulidine 180 80 176-77 (178) 7 m-Tou lidine 180 74 175-76 (176) 8 p - Aminobcnzoic acid 300 91 280-82 9 p - Aminophenol 120 88 286-88 (29 I) 10 p-Ani sidine 180 96 161-62 (162) I I Aniline 180 6 1 2 I 0- I I (2 I 0) 12 Butylamine 120 100 33-34 (34) 13 Hexylamine 45 65 130-32 14 2 - Phenylcthylamine 120 70 13 I -32 (130) 15 2- Chloroethylamine 45 77 58-60 16 Ethanolamine 30 90 127 -28( I 26-28) 17 Glycine 60 96 19 I -92 ( 192) 18 (±)Tyrosin e 30 74 266-68 (268) 19 L (-) Phenylalanine 45 82 172-74 20 L (-) Leucin e 30 12 116 ( 116) All products show sa ti sfactory phys ica l and spectral data.
a funnel and this neat mixture was irradiated under ethanolamine (3.054g). The conical flask was covered microwave (MW). Within 30 sec. the mixture fused with a glass funnel , which worked as a condenser. and this liquid on cooling gave N-(2-hydroxyethyl) This system was then irradiated in a domesti c phthalimide. microwave oven (IFB, 750W output) for 30 sec. The As gi ven in the Table I N-phthalyl derivative of reaction mi xture got fused and liquefied. After th e various aromatic amines, aliphatic amines and amino microwave irradiation the liquid was gradually cooled acids were also synthesized. We observed that the to room temperature (25°C) to give crystals. The neat mixtures of phthalic anhydride and solid amines crystals were washed with 10 mL of ethanol and dried di d not react on microwave irradiation, but the to give crystals of N- (2-hydroxyethyl)phthalimide in reaction completed within seconds on addition of few 90% yield, having a sharp mp of 127-28 dc. drops of high dielectric solvent such as DMF. It will be important to note that many (entries 1 toW) of the References I Greene T W & Wuts P G M, Protective groups in organic N-phthalyl derivatives prepared in this reaction are synthesis (John Wiley & Sons Inc. New York), 1991, 309. used as plant growth regulants and as phytocides 2 Wolman y, Protection of the amino group in the chemistry of l 8 hence the process has a commercial importance . the amino group, Vol. 4, chapter I I, edited by S Patai, Inter In conclusion, we have developed an easy, fast and science publishers a division of John Wiley & Sons, Grea t a simple method for protection of the amino group in Britain), 1968669. 3 Corey E 1, Bock M G, Kozikowski A P, Ramarao A V, Floyd solvent-free condition using microwave irradiation. D & Lipsh utz B, Tetrahedron Lett, 1978, 1051. At present we are pursuing the work of hydrazonoly 4 Barton J W, Protection of N-H bonds and NR3 in protective sis under microwave irradiation to deprotect N groups in organic chemistry, edited by J F W McOmie, (Ple phthalyl derivatives and to get the free amine. num Press, New York & London), 1973,46. 5 Merck Index, 12th Edition 1986, 86. 6 Lednicer D, Mitscher L A & Georg G I, The organic chemis· Experimental Section try of drug synthesis, Vol. 4 (Wiley Intcrscicnce Publication, In a 100 mL conical flask 0.05 mole of phthalic New York), 1990, 106. anhydride (7.74g) was mixed with 0.05 mole of 7 Sheehan J C & Corey E J, JAm Chem Suc, 74, 1952,4555. NOTES 1085
8 Gabriel S, Chem Ber, 20, 1887,2224. 15 Varma R S, Green Chem, I, 1999,43. 9 Bose A K, Greer F & Price C C, J Org Chem, 23,1958, 1335. 16 Cresswell S L & Haswell S J, Chem Ind (London), 16, 1999, 10 Balenovic K & Gaspert B, Chel1l Ind (Londoll), 1960, 624. 62l. 11 Giles R R & Weaver M A, US Patent, 3394 144, Chem Abstr 17 Tanaka K & Toda F, Chem Rev, 100,2000, 1025. 69:7844l. 18 Chem Abstr35 : P 8194 d, 50 : P 7384 h, 51 : PI523 i. 12 Yataro Obata, J Agr Chel1l Soc Japan, 17, 1941,823, Chem Abstr_41 :4474. 19 Textbook of practical organic chemistry illcluding qualitative 13 Adamo F & Alberto B, Pure Appl Chem, 71 , 1999, 573. organic analysis, by Vogel, Fourth Edition (Longman Scien 14 Bose A K, Banik B K, Lavlinskakia N, Jayaraman M & Man- tific & Technical, New York), 1987, 1229, 1242. 3 3 has M S, Chel1ltech, 1997, 18. 20 Gem Abstr_37: 102 ,3 1:5787 ,41 :4474a.