Note. Zinc chloride promoted efficient and facile BOC protection of amines

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1 Indian Journal of Chemistry Vol. 51B, August 2012, pp ote Zinc chloride promoted efficient and facile BC protection of amines M Arifuddin* a, Lakshmikant b, Rajasekar b & D B Shinde c a ational Institute of Pharmaceutical Education and Research (IPER yderabad), Balanagar, yderabad , India b AVRA Laboratories Pvt. Ltd., Plot o. 9/15(2&3), Road o. 6, IDA acharam, yderabad , India c Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada Univeristy, Aurangabad , India arifabib@yahoo.com Received 13 September 2010; accepted (revised) 28 May 2012 Amines are efficiently protected as their BC derivatives under mild reaction conditions when reacted with BC anhydride in presence of ZnCl 2. The present method is applicable to a variety of amines including aliphatic, aromatic as well as heteroaromatic amines. This protocol appears to be competitive and in some cases superior to previously reported procedures that work under basic conditions. Keywords: Amine protection, -BC protected amine, ZnCl 2, Lewis acid The development of mild and selective methods for the protection / deprotection of functional groups continue to be an important tool in synthetic organic chemistry 1. The BC group has been used extensively for the protection of amines due to its ease of formation, stability under basic conditions and ease of removal 2. BC protected aryl amines are important intermediates in organic synthesis and have been used for the directed lithiation of aromatic rings 3 and preparation of unsymmetrical ureas 4, etc. Aryl amines are particularly difficult to protect with the BC group because of the reduced nucleophilicity of the nitrogen atom when compared to primary or secondary aliphatic amines. Thus, their synthesis often requires the Curtius rearrangement of aryl azides followed by trapping with tertbutylalcohol 5. owever, recent reports have demonstrated that the reaction of aryl amines with one equivalent of di-tertiary butyldicarbonate (BC 2 ) requires extended reaction times 6, elevated temperature 7, or the addition of a base i.e., DMAP 8, aq. a (Ref 9), pyridine 10 and amds 11. n the other hand, methods using a Lewis acid catalyst to perform BC protection are rare. Till date, only few reports on such reactions are found i.e., Yttriumzirconium based strong Lewis acid is used for BC protection. owever, the preparation of this catalyst is quite elaborate 12. Recently, LiCl 4 (Ref 13), Zn(Cl 4 ) 2 (Ref 14) and ZrCl 4 (Ref 15) have also been reported for BC protection of amines. In the past few years zinc chloride has emerges as a mild Lewis acid for various organic transformations 16 such as Beckmaan rearrangement 17, thiophenols 18, cycloaddition reaction 19, substitution 20, addition reactions 21 and selective reduction 22. Furthermore, ZnCl 2 is also used in the synthesis of 1,2-diarylacetylenes 23, fluoroalkylated quinolines 24, 4-aryl-1,2-3,4-tetrahydroisoquinolines 25, -arylation of pyridine- 3(2)one 26, Ferrier reaction 27, alkylation of imines with terminal alkynes 28 and nitration of aromatic compounds 29. Although ZnCl 2 has been extensively used as Lewis acid in various organic transformations, it has not been used for the protection of amines as their BC derivatives. This prompted the use of ZnCl 2 for the BC protection of amines. erein is reported the ZnCl 2 promoted selective BC protection of amines under mild condition with high yield (Scheme I). A variety of amines were treated with BC 2 in the presence of ZnCl 2, the corresponding -BCprotected amines were obtained in excellent yields. The substrates examined in the present studies and the results obtained are summarized in Table I. Thus the present procedure for introducing the BC protecting group is quite general as a wide range of amines underwent reaction smoothly with BC 2. In the case of 2-chloroaniline (entry 1i) and 3-nitro aniline (entry 1j) the yields are low (20%). It contributes to the low reactivity of these deactivated anilines. It is noteworthy that the reaction is chemoselective i.e., 2- amino phenol (entry 1h) as the amine being more nucleophilic than alcohol underwent reaction faster giving corresponding -BC protected product in high yield (94%). Moreover, it is important to highlight that any side reaction, such as biscarbonylation or the formation of isocyanate or R (BC) 2, ZnCl 2 C 2 Cl 2, RT Scheme I R

2 TES 1169 Table I ZnCl 2 promoted BC protection of the amines Entry Substrate Product Time (Min) Yield (%) Reaction condition C 2 Cl 2, RT C 2 Cl 2, RT 3 BC C 2 Cl 2, RT C 2 Cl 2, RT C 2 Cl 2, RT C 2 Cl 2, RT C 2 Cl 2, RT F F C: 2 (1:1) Cl 9 Cl C 2 Cl 2, RT Contd

3 1170 IDIA J. CEM., SEC B, AUGUST 2012 Table I ZnCl 2 promoted BC protection of the amines Contd Entry Substrate Product Time (Min) Yield (%) Reaction condition C: 2 (1:1) C 2 Cl 2, RT C 2 Cl 2, RT 14 S C 2 Cl 2, RT S C: 2 (1:1) C 2 Cl 2, RT (a) Products were charecterized by comparison with spectroscopic data. (b) Isolated Yields. urea was not observed. Surprisingly, when these reaction conditions was applied to protect 6-amino quinoline, 8-aminoquinoline, 2-ethyl aniline and 4- isopropyl aniline, the desired product does not form but only a white complex is obtained which may be due to complexation with ZnCl 2. Whereas, 3- aminoquinoline (entry 1p) gives only 10% of BC protected product after 24 hr of the reaction. The BC protection of tryptamine (entry 1k), 2- aminophenol (entry 1h) and β-alanine (entry 1o) is carried out in acetonitrile / water (1:1) as they are not soluble in C 2 Cl 2. The reaction with 0.25 equiv or 0.5 equiv of ZnCl 2 is very slow. Therefore, the reaction is carried out using 1:1:1 molar ratio of substrate, reactant and Lewis acid. To check the effect of other Lewis acids under the present reaction conditions, the BC protection of aniline, 4-aminopyridine and 3-nitroaniline was carried out using InCl 3 (20% mol) as Lewis acid. Although, the InCl 3 also promots the BC protection of amines, it took a relatively longer time to complete the reaction, i.e., aniline took 3 hr to afford the corresponding BC protected aniline, 4- aminopyridine gives the required product in 5 hr whereas, 3-nitroaniline gave only traces of BC protected compound even after 24 hr. The plausible mechanism can be visualized as the activation of carbonyl group of BC anhydride by the attack of ZnCl 2 followed by nucleophillic attack of amine on the BC anhydride. This facilitates the extrusion of tert-butanol and carbon dioxide as leaving entities eventually leading to the formation of -BC protected amines (Scheme II). Experimental Section Melting points were determined in open capillaries and are uncorrected. Reagents grade chemicals were purchased from commercial sources and used as

4 TES 1171 Scheme II received. IR spectra were recorded in KBr discs on a Perkin-Elmer analyzer. 1 MR spectra were recorded on a Bruker 300 (300 Mz) spectrometer using TMS as internal standard. The progress of the reaction was monitored by TLC run on silica gel G (Merck) General procedure for the BC protection of amines To a solution of amine (1 mmol) in dichloromethane (10 ml), BC 2 (1 mmol) and ZnCl 2 (1 mmol) were added and the reaction mixture was stirred for the specified time given in Table I. After completion of the reaction as indicated by the TLC, the solvent was removed under reduced pressure and the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer separated and dried over anhydrous a 2 S 4 and concentrated under reduced pressure. The residue obtained was purified by column chromatography over silica gel by using 10% EtAc:exane as eluent to give the pure product. In conclusion, ZnCl 2 promotes the protection of amines as BC derivatives. The present method works with various aromatic, aliphatic and hetero aromatic amines under mild conditions. Moreover, this protocol appears to be competitive and in some cases superior to previously reported procedures that require basic conditions. Although Zn(Cl 4 ) has been reported for the BC protection of amines, the present procedure is superior as compared to the method reported with Zn(Cl 4 ) In particular, with aniline (entry 1d) the present results are superior as the reaction is complete in 20 min whereas Zn(Cl 4 ) required 12 hr to complete the

5 1172 IDIA J. CEM., SEC B, AUGUST 2012 reaction. In the case of heterocyclic amines, excellent yields were obtained in short reaction time as compared to literature methods. Acknowledgements The Authors AM, L and R thank Dr. A. V. Rama Rao, Managing Director and Dr. Chandra Rama Rao, Director, AVRA Laboratories Pvt. Ltd for their constant encouragement and support. Rerences 1 (a) Greene T W & Wutts P G M, in Protective Group in rganic Synthesis, 3 rd edn (John Wiley and Sons, ew York), 1999; (b) Kocienski P J, in Protecting Group (George Thieme Verlag, Stuttgart, ew York), Stahl G L, Walter R & Smith C W, J rg Chem, 43, 1978, Snieckns V, Chem Rev, 1990, Lamothe M, Perez M, Colovray-Gotteland V & alazy S, Synlett, 6, 1996, Thorton T J & Jarman M, Synthesis, 1990, Boger D L & Mckie J A, J rg Chem, 60, 1995, Muchowski J M & Venuti M C, J rg Chem, 45, 1980, (a) Barlin G B & Pfleideror W, J Chem Soc, B, 1971, 1425; (b) Darubrough S, Mervic M, Condon S M & Burns C J, Synth Commun, 31, 2001, Maeda, Suzuki M, Sugano, Yamamura M & Ishida R, Chem Pharm Bull, 36, 1988, Arya D P, Warner P M & Jebaratnam D J, Tetrahedron Lett, 34, 1993, Kelly T A & Mceil D W, Tetrahedron Lett, 35, 1994, Pandey R K, Ragade S P, Upadayay R K, Dongare M K & Kumar P, Arkivoc, 2002, eydari A & osseini S E, Adv Synth Catal, 347, 2005, Bartoli G, Bosco M, Locatelli M, Marcantoni E, Massacceri M, Melchiorre P & Sambri L, Synlett, 10, 2004, Sharma G V M, Reddy J J, Lakshmi P S & Krishna P R, Tetrahedron Lett, 45, 2004, icotra F, Panza L & Russo G, Tetrahedron Lett, 32, 1991, Lay L, icotra F, Panza L & Russo G, Synlett, 1995, Pachon L D, Games P, Brussel J J M & Reedijk J, Tetrahedron Lett, 44, 2003, (a) Chou P S-S & Sun D-J, Chem Commun, 1988, 1176; (b) Liu -J, Ulibarri G & Brown E C, Can J Chem, 70, 1992, (a) Williams R M, Sinclair P J, Zhai D & Chen D, J Am Chem Soc, 110, 1988, 1547; (b) Carlock J T, Bradshaw J S & Zmolek W, Tetrahedron Lett, 16, 1975, Chiba T & akai T, Chem Lett, 1987, 2187; (b) Taguch T, Kitagawa, hkawa S, Suda Y, ashimoto Y & Litaka Y, Tetrahedron Lett, 29, 1988, 5291; (c) Fort F Y, Feghouli A, Vaderse R & Canbore P, J rg Chem, 54, 1989, Pfrengli W & Kunz, J rg Chem, 55, 1990, Chen X B, An Z-W, Jin L & Gao A-A, Chin J Chem, 23, 2005, Kao F Z, Yang X & Liu J, Tetrahedron, 60, 2004, Raju B C, eelakantan P & Bhalerao U T, Tetrahedron Lett, 45, 2004, Kim J-J, Park Y D, Cho S D, Kim K, Chung A, Lee S G, Falck J R & Yoon Y J, Tetrahedron Lett, 45, 2004, Bettadaiah B K & Srinivas P, Tetrahedron Lett, 44, 2003, Jiang B & Si Y-G, Tetrahedron Lett, 44, 2003, Kamal A, Arifuddin M & Adil S F, Ultrasonic Sonochemistry, 12, 2005, 429.