View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by IR@NEIST - North East Institute of Science and Technology (CSIR) Current Organic Chemistry, 2011, 15, 1593-1624 1593 Recent Developments on the Carbamation of Amines Devdutt Chaturvedi* Natural Products Chemistry Division, North-East Institute of Science and Technology (CSIR), Jorhat-785006, Assam, India. Abstract: Organic carbamates represent an important class of compounds showing various interesting properties. They find wide utility in various areas as pharmaceuticals, agrochemicals (pesticides, herbicides, insecticides, fungicides etc.), intermediates in organic synthe- sis, protection of amino group in peptide chemistry, and as linker in combinatorial chemistry etc. Classical synthesis of carbamates in- volves use of harmful reagents such as phosgene, its derivatives and carbon monoxide. Recently, various kinds of synthetic methods have been developed for the synthesis of organic carbamates. In the present review, I would like to highlight the recent developments on the synthesis of organic carbamates using variety of reagents. Keywords: Carbamation, amines, carbamates. 1. INTRODUCTION in organic synthesis [7], for the protection of amino groups in pep- tide chemistry [8], as linkers in combinatorial chemistry [9] etc. Organic carbamates are the stable class of compounds derived Functionalization of amines as carbamates offers an attractive from the unstable carbamic acid (H N-COOH) by the substitution 2 method for the generation of derivatives, which may have interest- of amino and acid ends through the various kinds of structurally ing medicinal and biological properties [10]. Organic carbamates diverse alkyl/aryl, aryl-alkyl or substituted alkyl/aryl and aryl-alkyl have been extensively used as useful synthons for the synthesis of groups, and are identified by the presence of the linkage O-CO-NH- structurally diverse synthetic intermediates/molecules of biological [1, 2]. When the carbamate linkage is present in a cyclic system, significance [11]. Therefore, considerable interest has been gener- this class of compounds is referred to as cyclic carbamates [3]. ated in the recent past for the development of efficient and safe When the carbamate group is attached with any inorganic atom methodologies for carbamate esters synthesis. either metal or non metal, such compounds are referred to as inor- ganic carbamates [4]. Organic carbamates have frequently been employed as de- mandable pharmaceuticals in the forms of drugs and prodrugs [12]. The reaction of carbamation of amines has frequently been util- In recent years, several reports have indicated that carbamate link- ized in the synthesis of organic carbamates which holds unique age present in between the active pharmacophores of various struc- applications in the field of pharmaceuticals [5], agrochemicals (pes- turally diverse molecules increases manifold biological activities of ticides, herbicides, insecticides, fungicides etc.) [6], intermediates semisynthetic/synthetic natural/synthetic molecules [13]. Further- O R1 OH O OH H3CHN O R2 O N NH O R3 O N O O Physostigmine: Anti-alzheimer drug OH AcO OH O O O O N N O O Taxol analogues: anticancer drugs F NH Linezolid: Antibacterial drug N O Cl S N O NHCH3 O N O NH2 Cl Carbaryl: Insecticide Capravirine: anti-HIV Fig. (1). Biologically active drug molecules bearing carbamate linkage. *Address correspondence to this author at the Natural Products Chemistry Division, North-East Institute of Science and Technology (CSIR), Jorhat-785006, Assam, India; Tel: ------- ----------; Fax: 91-376-2370011; E-mail: [email protected] 1385-2728/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd. 1594 Current Organic Chemistry, 2011, Vol. 15, No. 10 Devdutt Chaturvedi Carbamates Inorganic Organic Metal Non metal Saturated Unsaturated Symmetrical Unsymmetrical Aliphatic Aliphatic-aromatic Aromatic Others Simple Substituted Simple Activated Cyclic Simple Functional Thio Imido Ortho Pyro Linear Branched Alicyclic Linear-alicyclic Symmetrical Unsymmetrical Symmetrical Unsymmetrical Simple Substituted Fig. (2). Classification of carbamates. more, the role of carbamate linkage have been extensively studied toxic which limits its use. Safer substitutes have been proposed in structurally diverse natural/semisynthetic molecules against vari- such as 1,1,1-Trichloromethylformate (Diphosgene, 2) [17], and ous disease such as anti-cancer, anti-bacterial, anti-fungal, anti- bis-(1,1,1-trichloromethyl) carbonate (Triphosgene 3) [18], which malarial, anti-viral, anti-HIV, anti-estrogenic, anti-progestational, are frequently used in recent years. Depolymerization of 3 into 1 anti-osteoporosis, anti-inflammatory, anti-filarial, anti-tubercular, has widely replaced phosgene by triphosgene, which is relatively anti-diabetic, anti-obesity, anti-convulsant, anti-helminthes, Alz- safer to use [19]. Thus, carbamates 6 synthesis has been achieved heimer disease, CNS and CVS active etc [14, 15, 13, 5]. Some of through the reaction of an amine 4 with an alcohol 5 using either 1, the important biologically active drug molecules bearing carba- or 2 or 3 as source of carbonyl equivalent (Scheme 1). mates have shown in Fig. (1). O O Cl Cl O Cl Cl Cl Cl 2. CLASSIFICATION OF CARBAMATES C C Cl Cl Cl O O O Carbamates can be mainly classified into two groups, namely 1 23Cl Cl Cl inorganic and organic. Depending upon the structural variations on the attached moieties they are further classified as shown in Fig. O O (2). R NH + + R OH 1 2 X X 2 4 NHR1 OR2 3. METHODS OF PREPARATION (either 1 or 2 or 3) 5 6 3.1. Phosgenation Technique Scheme 1. Phosgene (1) is a potentially useful, versatile building block in organic synthesis [16]. It offers the possibility of binding two nu- Chloroformates and isocyanates are intermediates produced cleophilic units to the same carbon atom and such two-component from phosgene, have frequently been employed in the synthesis of system is particularly well suited for the combinatorial synthesis of organic carbamates. Chloroformates [20] 7, can be obtained through carbonate, ureas and carbamate (Scheme 1). Phosgene is extremely the reaction of alcohol/phenol 5 with phosgene 1, reacts with Recent Developments on the Carbamation of Amines Current Organic Chemistry, 2011, Vol. 15, No. 10 1595 amines/substituted amines 4 (i.e. aminolysis) afforded carbamates ketone 11 in the presence of Sn4+ modified Zeolite H (H-SnA) at [21] 6 (Scheme 2). Carbamates synthesis through the chlorofor- room temperature (Scheme 5). mates route has been achieved using different reaction conditions O O such as use of strong bases [22] (NaOH, NaHCO3, Et3N, pyridine 11 and triphenylphosphene), metals [23], ultrasound [24], RNH2 + ClCOOR1 bis(trimethylsilyl)acetamide [21] in combination with azides [23]. 24h, 68-75% 4 7 RNCOOR1 4 12 O O O R1NH2 R2OH + Scheme 5. 5 Cl Cl R O Cl 1 2 7 R2O 6 NHR1 More recently, Kim and Jung have reported [28] a simple and efficient synthesis of carbamates 6, through reacting equimolar Scheme 2. amounts of amines 4, chloroformates 7, and Indium metal (Scheme In recent years, there has been much attention on the synthesis 6). Thus, carbamates of structurally diverse substituted aliphatic, of carbamates using chloroformates as key intermediate. Thus, aromatic, heterocyclic amines were prepared using various kinds of Pandey et al have reported [25] an efficient synthesis of carbamates chloroformates. 6 through the reaction of variety of amines 4 with chloroformates 7 O using catalytic amount of Yttria-Zirconium based Lewis acid cata- O lyst (Scheme 3). In, OR RNH2 + Cl OR RHN 1 Yttria-zirconia based 1 rt, 7-12h, 4 7 6 Lewis acid catalyst 73-91% RNH + ClCOOR1 RNHCOOR 2 1 R = - CH ,-CH=CH , Bn r.t., 5 min-6h, 88-96% 1 3 2 4 7 6 Scheme 6. Scheme 3. Isocyanates [29] 13, obtained through the reaction of phosgene Later on, Mormeneo et al have reported [26] a versatile method 1 and amines 4, react with hydroxy compounds 5 (i.e. alco- for the synthesis of carbamates 6 through an in-situ generated hols/phenols) afforded the corresponding carbamates (Scheme 7) polymer supported chloroformate resin 9. Bis-trichloromethyl car- [30]. Polyurethanes [31], the building blocks of isocyanates have bonate (BTC) has been used as a phosgene equivalent to afford a been used in industry. Synthesis of carbamates starting from isocy- supported chloroformate 9, which on sequential one-pot reaction of anates could be achieved through the use of strong bases [32], and variety of alcohols 5 with amines 4 afforded the corresponding metal halides [33] etc. Carbamates could be converted into isocy- carbamates 6 in high yields (Scheme 4). O O 5 BTC RCH OH OH 2 O Cl O OCH R Pyr 2 Pyr 10 8 9 R1 75-99% NH R2 4 O R1 N OCH2R 6 R2 Scheme 4. O O + R2OH + RNH2 R1-N=C=O 4 - R2OH R O NHR Cl Cl 13 2 1 1 6 Scheme 7. Raje et al have reported [27] an efficient, one-pot synthesis of anates by thermal decomposition at higher temperatures using dif- N-substituted (3-oxobutyl) carbamates 12, via tandem condensation ferent reaction conditions such as use of metal catalysts [34], of primary amines 4, with methyl chloroformate 7 followed by the chlorocatecholborane/boron halides with triethylamine [35], silanes conjugate addition of the resulting carbamates with methyl vinyl [36], chlorosilanes [37], dichlorosilanes [38], Mitsunobu’s reaction 1596 Current Organic Chemistry, 2011, Vol. 15, No. 10 Devdutt Chaturvedi conditions [39], montmorillonite K-10 [40], Bi2O3 [41], and re- NEt4Cl as a cocatalyst that the alcohol participates in the catalytic cently used basic metal oxide nanoparticles [42] etc. cycle, since when it was absent, practically no isocyanate was ob- tained (Scheme 9). 3.2. Reductive Carbonylation of Nitro-aromatics Several reports have been published by Gladfelter and Cenini The reductive carbonylation of aromatic nitro-compounds 14 to giving more insight into the mechanism of the catalytic cycle of the the corresponding carbamates is an interesting approach towards rhodium and ruthenium catalysts.