2402 Send Orders for Reprints to [email protected] Current Organic Chemistry, 2019, 23, 2402-2435 REVIEW ARTICLE (cid:25)(cid:2)(cid:2)(cid:16)(cid:16)(cid:16)(cid:16)(cid:17)(cid:17)(cid:11)(cid:11)(cid:18)(cid:18)(cid:19)(cid:19)(cid:21)(cid:20)(cid:21)(cid:24)(cid:22)(cid:22)(cid:23)(cid:23)(cid:12)(cid:22)(cid:20)(cid:24)(cid:12)(cid:26)(cid:21)(cid:21) Recent Advances in the Hofmann Rearrangement and Its Application to Natural Product Synthesis (cid:2)(cid:8)(cid:12)(cid:3)(cid:5)(cid:13)(cid:6)(cid:14)(cid:4)(cid:7)(cid:12)(cid:5)(cid:9)(cid:15)(cid:6)(cid:10)(cid:7)(cid:11) (cid:9)(cid:2)(cid:3)(cid:10)(cid:4)(cid:11)(cid:3)(cid:5)(cid:4)(cid:6)(cid:7)(cid:10)(cid:8)(cid:3) Pradip Debnath1,* 1Department of Chemistry, Maharaja Bir Bikram College, Agartala, Tripura-799004, India Abstract: C-N bond formation reactions are the most important transformations in (bio)organic chemistry because of the widespread occurrence of amines in pharmaceuti- cals, natural products, and biologically active compounds. The Hofmann rearrangement is A R T I C L E H I S T O R Y a well-known method used for the preparation of primary amines from amides. But, the Received: August 03, 2019 traditional version of the Hofmann rearrangement often gave relatively poor yields due to Revised: October 07, 2019 Accepted: October 09, 2019 over-oxidation or due to the poor solubility of some amides in aqueous base, and created an enormous amount of waste products. Developments over the last two decades, in par- DOI: 10.2174/1385272823666191021115508 ticular, have focused on refining both of these factors affecting the reaction. This review covers both the description of recent advances (2000-2019) in the Hofmann rearrangements and its applications in the synthesis of heterocycles, natural products and complex molecules of biological interest. It is revealed that organo-catalytic systems especially hypervalent y iodine-based catalysts have been developed for the green and environmentally friendly conversion of carboxamides to primary amines and carbamates. r t Keywords: Amides, Hofmann rearrangement, hypervalent iodine, primary amines, carbamates, heterocycles, natural products. s i m 1. INTRODUCTION mary amines or their derivatives with one fewer carbon atom. The In the late 19th century, three closely related reactions involving reaction is named after its discoverer-August Wilhelm von Hofmann [2]. Generally, alkaline hypohalites or a combination of e a stereospecific rearrangement of an alkyl group from an acyl car- halogens and alkaline hydroxides are used in aqueous solutions. bon to an electron-deficient nitrogen were reported by Wilhelm h Primary amines are generally obtained from the initial isocyanate Clemens Lossen [1], August Wilhelm von Hofmann [2], and Julius products when DBU or aqueous NaOH is used as a base, whereas C Wilhelm Theodor Curtius [3]. Among them, J.W.T. Curtius re- carbamates [7] are obtained in the presence of alcohols or alkoxides ported [3] the thermal rearrangement of acyl azides, and W.C. [8]. The usual Hofmann reaction proceeds under alkaline condi- Lossen [1] and A.W. von Hofmann [2] reported a base-promoted tions; hence, it cannot be applied to compounds containing alkali c rearrangement of hydroxamic acids and N-haloamides, respectively. labile functional groups. For these compounds, the alternative The Schmidt reaction (1923) [4] is the name given to a group of i reactions that involve the addition of hydrazoic acid to carboxylic Hofmann reaction can be used under mildly acidic conditions. n Many oxidizing agents such as lead tetraacetate, N-bromosucci- acids, ketones, aldehydes, alcohols, and alkenes under strongly nimide, or hypervalent iodine reagents have been developed to acidic conditions. In chronological order of their publication, the a affect the Hofmann reaction under mild acidic reaction conditions reactions are Lossen rearrangement (1872), the Hofmann rear- (Scheme 2). This classical reaction has found countless applications g rangement (1881), the Curtius rearrangement (1890), and the in synthetic organic chemistry and it has been industrially valor- Schmidt rearrangement (1923). Since these reactions provide a r ized. In this review, the last twenty years of developments (2000- practical procedure for replacing a carboxy group by an amino 2019) of the Hofmann rearrangement in terms of catalyst, solvent, O group, they have been extensively used since discoveries [5, 6]. The yields and environmental concern have been discussed. Application choice of a particular nitrogen insertion reaction depends largely on of the rearrangements in the synthesis of heterocycles and natural the availability of the corresponding starting material and the de- products are also considered. t sired synthetic outcome (Scheme 1). The order of popularity among n the reactions beginning with carboxylic acid derivatives is Cur- 2. GENERAL MECHANISTIC ASPECTS AND STEREO- tius>Hofmann>Lossen> Schmidt which reflects the ease of obtain- e CHEMISTRY ing the respective intermediates for each process. The Hofmann r rearrangement involves the conversion of primary amides to pri- Mechanistically, the Hofmann, Curtius, and Lossen rearrange- ments are related as shown in Scheme 3 [9]. Mechanistic studies on r these four rearrangements have revealed that: (i) these are concerted u * Address correspondence to this author at the Department of Chemistry, Maharaja intramolecular rearrangements; (ii) stereochemical configuration of Bir Bikram College, Agartala, Tripura-799004, India; Tel: 03812526607; the stereogenic migrating groups are completely retained. The ki- C Fax: 03812516728; E-mail: [email protected] netic studies of these reactions revealed that all these reactions are 1875-5348/19 $58.00+.00 © 2019 Bentham Science Publishers Recent Advances in the Hofmann Rearrangement and Its Application Current Organic Chemistry, 2019, Vol. 23, No. 22 2403 HO, H+ or OH- O Lossen 2 R-NH2 R NHX O R1NH2 RNH NHHR1 O O Hofmann O N C O R OH R NH2 R R1OH O RNH OR1 Curtius O R N3 R1SH RNH SR1 Schmidt O R1COOH RNH R1 Scheme 1. Hofmann, Curtius, Schmidt and Lossen rearrangement. MOX or X, MOH 2 M = Na, K O X = Cl, Br N C O R-NH2 R NH2 Basic conditions R 2 1 Pb(OAc) or PhI(OAc) 4 2 Acidic conditions Scheme 2. Hofmann rearrangement under basic and acidic conditions. HO, H+ or OH- 2 R NH 2 O Halogen species O base O -CO2 2 X N C O R NH2 R NHX R N R O 1 4 5 6 Nu R Hofmann: X = Cl, Br, I etc N Nu H Curtius: X = N2 3 (Nu = OR, NHR, SR etc) Lossen: X = OCOR N 2 O HN HO NH N N2 O and/or O 3 Schmidt: R R1 H+ R R1 and/or R R1 R NHR1 HNR R1 intermediates Scheme 3. General mechanistic aspects of Hofmann, Curtius, Lossen and Schmidt rearrangement. first-order, and neither carbocations nor free radical intermediates bamates 3 (Nu = OR), ureas (Nu = NHR), or related compounds are formed during rearrangements. In the 1970s, the kinetic isotope (Scheme 3). Isolation of isocyanates may also be possible under effects (KIEs) of the Hofmann reaction were measured and deter- some reaction conditions, especially when the rearrangement is mined to strongly support a concerted mechanism [10]. Linear free conducted in aprotic solvents. These reactions are very popular energy relationships observed in the Lossen and Hofmann reactions because isocyanates are versatile synthetic intermediates. Cycload- were comparable, suggesting related mechanisms for the two trans- dition reactions of isocyanates are also well known [12]. Many of formations [11]. Each of these reactions begins with the generation the recent developments in this field involve the simultaneous use of a reactive N–X amidate or its formal equivalent. The Hofmann of the Hofmann or Curtius reactions with other transformations and Lossen reactions each go through literal amide anions 5 gener- [13]. ated in situ by basic treatment of species 4, where X is a halogen or An important pragmatic consideration is that rearrangement an acyloxy group, respectively. Once formed, these intermediates step essentially takes place with retention of configuration of a undergo rearrangement coupled with the loss of the X− group (hal- stereogenic migrating group R. For example, (S)-2-phenylpropanic ide in case of Hofmann reaction) to afford an isocyanate 6 as the acid and its derivatives undergo the Hofmann, Curtius, Schmidt, primary product which on solvolysis in protic solvent (under acidic and Lossen rearrangements to give (S)-1-phenylethylamine (8) with or basic conditions) gives primary amine 2 with the release of car- more than 99% retention of configuration (Scheme 4) [14, 15]. bon dioxide or is attacked by with other nucleophiles to afford car- Conversion of (S)-2-cyano-2-methyl-3-phenylpropionic acid (9) to 2404 Current Organic Chemistry, 2019, Vol. 23, No. 22 Pradip Debnath COOH NH2 Hofmann, Curtius, Me H Me H Ph Schmidt, or Lossen Ph (S)-(+)-2-Phenylpropanic acid (7) (S)-(-)-1-Phenylethylamine (8) NH COOH Hofmann, Curtius, 2 Me H Me CN CH Ph Schmidt, or Lossen CH2Ph 2 (S)-2-Cyano-2-methyl-3-phenylpropionic acid (9) (S)-α-Methylphenylalanine (10) Scheme 4. Retention of configurartion in Hofmann rearrangement. O O O Cl Cl Br Br Me O O O N N N N Me S Br N Br O N O O N O N N Br NBr Ph N Br3 O Cl Br Br Me O NBS TCCA TBCA DBDMH TsNBr2 Cl , Br, MeOBr, NaOCl, NaBrO 2 2 2 Fig. (1). Common halogen reagents used in the Hofmann rearrangement. O H N OMe NBS, NaOMe NH 2 MeOH, reflux, 10 min O R R 85-100% 11 12 R = H (95%), Me (85%), OMe (85%), Cl (98%), CF (100%) 3 Scheme 5. Hofmann rearrangement of aromatic amides with NBS. (S)-α-methylphenylalanine (10) through the Hofmann rearrange- deficient nitrogen atom, which is deprotonated by a base. Then, the ments followed by hydrolysis also proceeds with nearly complete rearrangement occurs by heating to generate intermediate isocy- retention of configuration [16]. anate, which on treatment with acid or base to yields a carbamic acid that itself undergoes loss of carbon dioxide to afford a primary 3. HOFMANN REARRANGEMENT WITH HALOGEN amine or is attacked by nucleophile to afford a diverse range of REAGENTS products. In traditional Hofmann rearrangement, the halogen reagents Halogen reagents mediated Hofmann rearrangement of aro- such as sodium or potassium hypobromite (or bromine with sodium matic amides having oxidation sensitive group is not always possi- or potassium hydroxide), sodium hypochlorite, calcium hypochlo- ble because halogen reagents can cause further oxidation of the rite or barium hypobromite, etc are used as an oxidant and the pro- Hofmann rearranged products. Huang and Keillor reported [17] a cedure requires harsh conditions to convert primary amides to re- modified Hofmann rearrangement for the substrates having oxida- spective isocyanates. In order to improve the reaction conditions tion sensitive groups using NBS and NaOMe in methanol solvent and yield, many novel oxidative reagents have been developed to (Scheme 5). A variety of p-substituted aromatic carboxamides were affect the Hofmann rearrangement. The reagents can be classified converted into methyl carbamates using NBS as an oxidant and into two groups: halogen reagents and hypervalent iodine species. NaOMe as a base in methanol under refluxing conditions. Although The common oxidizing reagents employed in the halogen- this protocol is useful for the preparation of various p-substituted promoted Hofmann reaction include N-bromosuccinimide (NBS) anilines, the method is not suitable for the preparation of aromatic [17-19], trichloroisocyanuric acid (TCCA) [20-22], 1,3-dibromo- carbamates having p-NMe2 or p-NO2 group. 5,5-dimethylhydantoin (DBDMH) [23-25], 1,3-dichloro-5,5-dimet- The Hofmann rearrangement through the use of NBS and a hylhydantoin (DCDMH) [26], N-bromoacetamide (NBA) [27], mild base, DBU in methanol has also been reported by Keillor and bis(1,3-dimethyl-2-imidazolidinone) hydrotribromide [28], N,N- co-workers [18]. This DBU based modified protocol is widely use- dibromo-p-toluenesulfonamide (TsNBr ) [29], tribromoisocyanuric ful for the conversion of alkyl and aryl carboxamides to the corre- 2 acid (TBCA) [30], bromine, tetraalkylammonium tribromide, and sponding methyl carbamates in excellent yields (Scheme 6). Due to similar reagents (Fig. 1). the mild nature of DBU, this protocol is suitable for the preparation Halogen reagents were the first activating species to be em- of aromatic carbamates having p-NO2, p-NMe2 groups. The authors observed that electron-rich amides generally provide a higher yield ployed in the Hofmann rearrangement. Halogen reagent first reacts with amide to afford N-halogenated amide, containing an electron- of carbamate products than their electron-deficient counterparts. Recent Advances in the Hofmann Rearrangement and Its Application Current Organic Chemistry, 2019, Vol. 23, No. 22 2405 O NBS, DBU H N OMe R NH2 MeOH, reflux, 25 min R O 1 43-95% 3 NHCOOMe H N OMe H H N OMe N OMe O Me(CH2)8 Me(CH2)14 O O 95% 90% 73% R R = H (95%), OMe (95%), NO (70%), Me (84%), Cl (94%), NMe (43%) 2 2 Scheme 6. Hofmann rearrangement with NBS and DBU base. Me O NH 2 Me O Me KOH, HO O K 2 Me N NH2 Br N O N O -5 oC, 16 h KO N Br 14 NH C O Br O -20 oC, 16 h Me N NH2 Me N NH2 13 NBS 16 15 81 % Me H N O Me N N H 17 Scheme 7. Mode of reactivity of NBS in the Hofmann rearrangement. O TCCA O MeONa H N OMe Cl R R NH2 Acetone/CHCl3 R N MeOH H O 1 r.t., 4 h 4 0°C, 20 h 3 46-98 % ( 2 steps) Scheme 8. Hofmann rearrangement of carboxamides with trichloroisocyanuric acid. In an attempt to understand the mode of reactivity of NBS, the [20]. The first step is the preparation of N-haloamide using a halo- Hofmann rearrangement using NBS was closely studied by genated reagent such as tert-butyl hypochlorite, calcium hypochlo- Senanayake and co-workers [19]. The authors observed that NBS rite, or TCCA [20]. The rearrangement is then initiated by treating has two modes of reactivity: in the absence of a base, it acts as a the N-chloroamide with sodium methoxide in methanol to afford free radical-brominating agent, whereas in the presence of a base, methyl carbamates in high yields [21]. Hiegel and Hogenauer syn- an electropositive N-halogenating species is generated. Using low- thesized a variety of N-substituted carbamates by the Hofmann temperature NMR, it was found that the actual oxidizing reagent in rearrangement of N-chlorocarboxamides 15 using trichloroiso- this reaction was not NBS but N-bromosuccinic acid dipotassium cyanuric acid (TCCA) as the halogen source (Scheme 8) [21]. salt 13 (Scheme 7). At low temperatures, its formation could be The one-pot Hofmann reaction with halogen reagents is most clearly achieved, affording consistent yields of the desired frequently employed using aliphatic amides. The amide must be Hofmann product. However, when the temperature was allowed to primary, whereas the α-carbon centre can be variously substituted. rise more than 20°C, incomplete reaction resulted from the decom- In this context, Crane and co-workers observed that TCCA is a very position of 13. effective reagent to affect the Hofmann rearrangement of chiral In Hofmann rearrangement, N-halogenation and rearrangement carboxamides [22]. Thus, the treatment of a variety of carbox- are usually carried out in a single vessel with halogen-containing amides with TCCA in the presence of DBU base in methanol af- reagent and base. However, a two-step procedure is also available forded the corresponding carbamates in good to excellent yields. 2406 Current Organic Chemistry, 2019, Vol. 23, No. 22 Pradip Debnath O O O TCCA MeO O O Boc2O/THF/DMPA H2N OMe HN OMe HN OMe then NaOMe/MeOH 2 DBU, MeOH r.t. to reflux, 18 h 20 18 19 77 % Hofmann Rearrangement H O HN OMe H H N OMe N OMe N OMe N OMe O H N O O O R 84% 85% 80% 65% R = H (92%), Me (96%), Cl (75%) Scheme 9. One-pot Hofmann rearrangement of carboxamides with TCCA. O O O P(OEt)2 NaOBr P(OEt)2 P(OEt)2 R R R Br CONH2 NaOH NH2 COOH 21 22 23 R = Et, Ph 70-80% R = Me (70 %), PhCH2 (80%) Scheme 10. Hofmann rearrangement of phosphonoacetamides. O BocHN Bn N 24 N 1. DBDMH, NaOH/H2O, HO TESO MeCN, r.t. 30 min BocHN BocHN NH2 2. HCl, r.t., 4 h NH2 Bn Bn O 91 % 25 (96:4 dr) 26 (94:6 dr) Scheme 11. Hofmann rearrangement using N,N-dibromo-5,5-dimethylhydantoin (DBDMH). The authors investigated the scope of the protocol to a number of Very recently, Katuri and Nagarajan utilized 1,3-dichloro-5,5- functional groups including olefin, ester, halogens, nitro, ether, etc, dimethylhydantoin (DCDMH) as a reagent to affect the Hofmann and observed that the rearrangement of optically active amide oc- rearrangement of various carboxamides and cyclic imides to car- curs with complete retention of configuration (Scheme 9). bamates and amino acid derivatives, respectively (Scheme 13) [26]. An attempted Hofmann reaction of phosphonoacetamides with All the reactions proceed smoothly with DCDMH (1.1 eq.) in the alkaline sodium hypobromite shows a dramatic substituent effect presence of either DBU or MeO- base at 60˚C to give a high yield [23]. The rearrangement occurs when the alkyl residue (R) is either of carbamate products. The protocol is applicable for the gram- an ethyl or phenyl group, while only bromination occurs when R is scale synthesis of gabapentin and (S)-pregabalin. a hydrogen or benzyl (Scheme 10). In a one-pot process, Jevtic and co-workers utilized N- A novel procedure employing N,N-dibromo-5,5-dimethyl- boromoacetamide (NBA) to affect the Hofmann rearrangement of hydantoin (DBDMH) in Hofmann rearrangement is reported by Engstrom and co-workers [24]. This route was used to prepare an aromatic and aliphatic amides [27]. A variety of methyl and benzyl amino alcohol 26, the core portion of HIV protease inhibitor A- carbamates were obtained in high yields with NBA in the presence 79611 from phenylalanine-derived epoxide 24 (Scheme 11). of lithium hydroxide or lithium methoxide (Scheme 14). Amides McDermott and co-workers [25] also applied 1,3-dibromo-5,5- possessing a β-phenylamino groups gave the corresponding cyclic dimethylhydantoin promoted Hofmann rearrangement for the syn- ureas in good yields. Under the optimal reaction conditions, cis- thesis of amine coupling partner 28 in the total synthesis of dipepti- and trans-2-(phenylamino)cyclohexanecarboxamides gave five- dyl peptidase-4 inhibitor, ABT-297 (Scheme 12). membered cyclic ureas stereospecifically. Recent Advances in the Hofmann Rearrangement and Its Application Current Organic Chemistry, 2019, Vol. 23, No. 22 2407 O NH CN 2 NH2 DBDMH O N TBAB, NaOH N N N N N Na2SO3, THF H HO, 0 °C, 1.5 h CN COOH 2 N N ABT-279 87 % COOBut COOBut 29 27 Hofmann Rearrangement 28 Scheme 12. 1,3-Dibromo-5,5-dimethylhydantoin promoted Hofmann rearrangement. DCDMH (1.1 eq.) H O DBU or NaOMe (1.5 eq.) N OR1 R C R NH2 R1OH, 60 oC, 20 min O 3 1 DBU: 55-97%; MeONa:90-98% H H H N OMe N OMe N OMe O O O N ON 2 MeONa: 96% MeONa: 98% MeONa: 92% DBU: 92% DBU: 97% DBU: 90% F H F H N O N O CO2Me F Cl O O NHCOMe 2 Gabapentin DBU: 84% DBU: 55% MeONa: 77%; DBU: 79% Scheme 13. Hofmann rearrangement using 1,3-dichloro-5,5-dimethylhydantoin. Ph H O N NBA, LiOH HN OMe N Ph or R O or R NH2 MeOH O N CONH 2 1 30 0 oC to r.t, 24h 3 31 H Ph Ph O O NHCO2Me N N NHCOMe Bn N 2 O O Ph N N H H 8 N N NHCOMe H H 2 94% 77% 80% 85% 82% Scheme 14. N-Bromoacetamide mediated Hofmann rearrangement. In 2019, Matsubara prepared an air-stable bromine complex, (DMI) HBr and NaOMe in MeOH under refluxing conditions for 2 3 bis(1,3-dimethyl-2-imidazolidinone) hydrotribromide (DITB) 4h (Scheme 15). [(DMI)2HBr3] to carry out the Hofmann rearrangement of carbox- In 2012, Phukan and co-workers [29] employed N,N-dibromo- amides [28]. A variety of carbamates were obtained by the p-toluenesulphonamide (TsNBr ) to affect the Hofmann rearrange- 2 Hofmann rearrangement carboxamides with 1.2 equiv. of ment of a wide range of carboxamide substrates. The reaction of 2408 Current Organic Chemistry, 2019, Vol. 23, No. 22 Pradip Debnath O DITB (1.2 equiv) O NaOMe (4.5 equiv) H HBr N OMe 3 N N R R NH2 MeOH, reflux, 4h O 2 1 57-98% 3 DITB H H N OMe H N OMe CH N OMe 5 11 C H 10 21 O O O R 91% 95% R = H (92%), OMe (98%), Br (82%), CF (71%), NO (57%) 3 2 Scheme 15. Hofmann rearrangement with bis (1,3-dimethyl-2-imidazolidinone) hydrotribromide. O TsNBr, DBU H 2 N OR R R NH 2 ROH, reflux, 10-20 min O 1 3 78-97 % H R N OR H H N OMe N OEt O O O N R = Me (95%), Et (85%), nPr (86%), nBu (82%) R = Cl (90%), Br (97%) 78% H H N OMe N OMe O O R R R = OMe (94%), Me (97%), Cl (97%) R = H (92%), Me (93%), OMe (92%) Scheme 16. Hofmann rearrangement with TsNBr. 2 O H N OMe MeOH, TBCA, KOH NH 2 O MW, 5 min, 60 oC R R 11 75-95 % 12 R = H, NO, OMe, Cl 2 Scheme 17. Tribromoisocyanuric acid mediated Hofmann rearrangement. carboxamides with TsNBr in the presence of DBU at 65˚C in alco- under microwave irradiation afforded the methyl carbamates in 2 hol afforded methyl carbamates in high yields within 10-20 min of high isolated yields for cases including 4-nitrobenzamides (Scheme reaction time (Scheme 16). A variety of aromatic, heteroaromatic, 17). Under the microwave irradiation conditions, the reagent shows and aliphatic amides bearing various functional groups are well- the highest chemo-selectivity as no brominated products were ob- tolerated under the optimal reaction conditions. served under the reaction conditions. Miranda et al. reported that tribromoisocyanuric acid (TBCA) The use of solid-supported reagents has become ubiquitous due is an effective reagent to affect the Hofmann rearrangement of ben- to enhanced reactivity and selectivity, milder reaction conditions, zamides under microwave irradiation conditions [30]. The authors convenient work-ups, and decreased solvent waste. Gogoi and observed that a reaction system comprised of TBCA/KOH/MeOH Konwar reported a modification in the Hofmann rearrangement Recent Advances in the Hofmann Rearrangement and Its Application Current Organic Chemistry, 2019, Vol. 23, No. 22 2409 O H NaOCl, KF/AlO N OMe 2 3 R R NH2 MeOH, reflux, 30 min O 1 3 O O HN OMe HN OMe H N OMe MeO O O N N S H R 84% 90% 91% R = H (95%), Me (87%), OMe (94%), Cl (90%), NMe (73%) 2 Scheme 18. Hofmann rearrangement using KF/AlO as solid support. 2 3 COOH -OBr COOH But But CONH2 NH2 32 33 Scheme 19. Hofmann rearrangement of malonic acid derivatives. O KBr ( 20 mol%), t-BuOCl (3.0 equiv) COR 2 R1 NH R1 t-BuOK ( 4.0 equiv) NHCO2R 34 O MeOH, 60 oC, 7-24h 35 anthranilic acid or amino acid aromatic or aliphatic imide NHCOMe COMe 2 Me CO2Me CO2Me 2 N NHCOMe Me NHCO2Me NHCO2Me 2 87% 93% 86% CO2Me 84% CO2Me H COOH H MeOC N N 2 COMe N MeO2C CO2Me 2 NH2.HCl NHCO2Me 81 % 95 % 90% Gabapentin.HCl (90%) Scheme 20. Hofmann rearrangement of cyclic imides with KBr oxidant. using NaOCl as an oxidant in the presence of KF/Al O (40% KF in and co-workers [32] utilized the half-amide of malonic acids as 2 3 Al O ) as solid support (Scheme 18) [31]. A variety of aliphatic and Hofmann rearrangement substrates for the preparation of α-amino 2 3 aromatic amides were converted into the respective methyl carba- acids. For example, neopentylglycine is conveniently prepared from mates in high yields under solid-supported Hofmann reaction con- neopentylmalonamic acid by the action of hypobromite (Scheme ditions. KF/Al O basicity stems from the formation of KOH in the 19). 2 3 initial preparation of the solid-supported material by the reaction of Recently, Togo and co-workers developed a new protocol for KF with alumina supports. Under these highly basic reaction the preparation of amino acids via a Hofmann type rearrangement conditions, hypochlorite ion is the predominant form of chlorine, of cyclic imides through the oxidation of an alkali metal bromide reacting with the amide to form an N-chloroamide, which later [33]. The authors observed that KBr is a very effective catalyst for undergoes rearrangement to the isocyanate. In the presence of the Hofmann rearrangement of various aliphatic and aromatic methanol, the isocyanate is rapidly converted into the corres- imides. The reaction of a variety of commercially available imides ponding methyl carbamate. with 20 mol% of KBr, t-BuOCl, and t-BuOK in MeOH at 60˚C On several occasions, the Hofmann rearrangement is applied afforded the aromatic and aliphatic amino acids in excellent yields for the synthesis of a variety of amino acid derivatives. Pospisek (Scheme 20). This is an environmentally sustainable protocol as the 2410 Current Organic Chemistry, 2019, Vol. 23, No. 22 Pradip Debnath KBr + t-BuOCl O NH + DBU Cl Br 34 O Cl O N C O Br N Br CO2R 38 36 O MeOH O NHCO2Me Br N CO2R CO2R 35 37 Scheme 21. Mechanism of the Hofmann rearrangement of cyclic imides. O NHTs NaOH, Br O NHTs 25-30 oC NHTs 2 N H2N COOH 5-10 oC BrHN CO2Na 30 min O C CO2Na 15 min 41 40 Na -Tosylasparagine (39) rearrangement O NHTs HN NTs HN 2 COH 2 CONa 2-(S)-(Tosylamino)-β-alanine (43) 42 2 Scheme 22. Hofmann rearrangement of N-tosylasparagine amide. desired products are obtained without the release of organic waste Recently, Peng and co-workers [35] conducted a theoretical in the form of halogen reagents. They applied this protocol for the study using the density functional theory (DFT) and Coupled- synthesis of gabapentin, which is widely used as an add-on therapy Cluster Singles and Doubles (CCSD) method, to compute the ener- for the treatment of epilepsy. getics evaluations of several possible courses for the formation of The authors suggested a catalytic cycle in which KBr is oxi- 3-amino-4-nitro-furoxan by the Hofmann rearrangement of 3- dized by tBuOCl to generate bromine-chloride in situ. This fol- amino-4-nitro-furoxan with sodium hypochlorite in water and ben- zene solvents. They observed that the mechanism of the Hofmann lowed by the formation of N-bromo phthalimide and then alcoholy- rearrangement is dependent on the polarity of the solvent. In polar sis to give isocyanate (38) via the elimination of bromide ion. In the solvent (water), hydroxyl ion (OH-) is shown more to be likely first presence of methanol, the isocyanate is rapidly converted into the attacker than the hypochlorite ion (OCl-) which dominates in ben- corresponding methyl carbamate (Scheme 21). zene solvent. The benzene solvent is more suitable than the water A similar study of the Hofmann rearrangement of protected as- solvent for the formation of reaction products due to a lower active paragines was carried out by Amato and co-workers [34]. They barrier of 46.4 kcal/mol. synthesized 2-(S)-(tosylamino)-β-alanine (43) in kilogram quanti- The electroorganic method also induces the Hofmann reaction, ties by the Hofmann rearrangement of Nα-tosylasparagine (39). by use of potassium bromide as a catalytic mediator, giving methy- The authors found that each step of the reaction is highly tempera- lurethanes [36]. Since the reaction proceeds without heating under ture dependent and studied the calorimetric of the reaction to find neutral conditions, this method can be applied to a base labile ep- out the sequence of intermediates involved in the reaction of so- oxyamide 44, which undergoes decomposition under usual alkaline dium hypobromite with Nα-tosylasparagine. The treatment of N- conditions of the Hofmann reaction (Scheme 23). tosylasparagine amide (39) with bromine and sodium hydroxide Another electrochemical induced (EI) Hofmann rearrangement generated N-brominated amide 40. Subsequent Hofmann rear- of carboxamides have been reported by Matsumura and co-workers rangement, imidazolidine hydrolysis, and decarboxylation afforded [37]. This EI induced protocol is mild, operationally simple, and amine 43 (Scheme 22). The key step to obtaining a consistently applicable to a variety of aliphatic and aromatic amides for the high yield in this reaction was to maintain tight control of reaction synthesis of methyl carbamates (Scheme 24). An epoxy functional temperature and to ensure that all amide 39 was consumed before group in the amide and alcohol is well tolerated during the elec- initiating the rearrangement step. trolysis process. Recent Advances in the Hofmann Rearrangement and Its Application Current Organic Chemistry, 2019, Vol. 23, No. 22 2411 -2e- O O CONH 2 NHCOMe MeOH-KBr 2 44 18.4 F mol-1 45 Scheme 23. Hofmann rearrangement of epoxyamide. H O EI-Hofmann rearrangement N OR1 + R1OH R R NHR MeCN O 1 40-98% 3 Scheme 24. Electrochemical induced Hofmann rearrangement of carboxamides. O O Pt(+)Pt(-) Me R O R NH MeCN/MeOH 2 1 undivided cell, 50 oC 3 58-93% O O 2MeO- + H2 Br2 R NH2 Me 1 R O MeO- 3 O Br- Br MeO- 2MeOH R N H R-N=C=O anode cathode 4 6 O C2H4NHCO2Me NHCOMe 2 H H H N OMe N OMe H O O O O PrNOS 2 2 H 88% 68% 85% 63% Scheme 25. Electrochemical Hofmann rearrangement using NaBr as mediator. Zhang and co-workers reported another electrochemical 120˚C (Scheme 26). Similarly, Xu and co-workers designed another Hofmann rearrangement of carboxamides using Pt-plate as elec- microreactor system, constructed with two micromixers and a delay trode and NaBr as mediator [38]. The authors observed that an elec- loop, to intensify the synthesis of Gabapentin [40]. trochemical reaction of amides using 50 mol% of NaBr in an undi- Graphene quantum dots (GQDs) are regarded as promising ma- vided cell containing platinum plate electrodes gave carbamate in terials in the building of biocompatible nanodevices. Recently, Liao high yield. They proposed a catalytic cycle in which the cathodic and co-workers [41] reported an interesting protocol to construct reaction of MeOH produces H2 and base MeO-. With the assistance the amine-functionalized graphene quantum dots 51 (afGQDs) via of the in situ base MeO-, the anode generated bromine is intercepted the Hofmann rearrangement of ammonia reduced graphene oxide by the amide, thereby forming the active N-Br species 4. This in- using sodium hypobromite as reagent (Scheme 27). The authors termediate proceeds through the classical Hofmann rearrangement observed that the size of the afGQDs can be controlled by the ad- and a sequential nucleophilic reaction with MeO- to afford carba- justment of sodium hypobromite dosage during the reaction. mates 3 (Scheme 25). Morimoto and co-workers reported the synthesis of a new axi- Ley and co-workers designed a microreactor technique to affect ally chiral phosphine-sulfonamide ligand from a chiral component the Hofmann rearrangement of carboxamides [39]. The protocol is (R)-2-amino-2/-diphenylphosphinyl-1,1/-binaphthyl [42]. This chi- applied for the preparation of a series of methyl carbamates from ral component was synthesized involving hydrolysis of cyano group carboxamides using NBS as reaction initiator and DBU as a base at of (R)-2-cyano-2/-diphenylphosphinyl-1,1/-binaphthyl followed by