210 PREVIOUS REACTION TABLE OF CONTENTS NEXT REACTION SEARCH TEXT HOFMANN REARRANGEMENT (References are on page 602) Importance: [Seminal Publications1-5; Reviews6-15; Modifications & Improvements16-30] In 1881, A.W Hofmann found that by treating acetamide with one equivalent of bromine (Br2) and sodium or potassium hydroxide it afforded N-bromoacetamide Upon further deprotonation and heating, N-bromoacetamide gave an unstable salt that in the absence of water readily rearranged to methyl isocyanate.1 However, in the presence of water and excess base the product was methylamine The conversion of primary carboxamides to the corresponding one-carbon shorter amines is known as the Hofmann rearrangement (also known as the Hofmann reaction) According to the standard procedure, the amide is dissolved in a cold solution of an alkali hypobromite or hypochlorite and the resulting solution is heated to ~70-80 °C to bring about the rearrangement The general features of this transformation are: 1) the hypohalite reagents are freshly prepared by the addition of chlorine gas or bromine to an aqueous solution of KOH or NaOH; 2) the amides cannot contain base-sensitive functional groups under the traditional basic reaction conditions, but acid-sensitive groups (e.g., acetals) remain unchanged; 3) the isocyanate intermediate is not isolated, since under the reaction conditions it is readily hydrolyzed (or solvolyzed) to the corresponding one-carbon shorter amine via the unstable carbamic acid; 4) when the reaction is conducted under phase-transfer catalysis conditions, the isocyanates may be isolated;31,25 5) if the starting amide is enantiopure (the carbonyl group is directly attached to the stereocenter), there is a complete retention of configuration in the product amine; 6) the Hofmann rearrangement gives high yields for a wide variety of aliphatic and aromatic amides but the best yields for aliphatic amides are obtained if the substrate has no more than carbons (hydrophilic amides); and 7) α,β-unsaturated amides and amides of α-hydroxyacids rearrange to give aldehydes or ketones.32,33 Since the discovery of the Hofmann rearrangement, several modifications were introduced: 1) for hydrophobic amides, the use of methanolic sodium hypobromite (bromine added to sodium methoxide in methanol) results in high yields of the corresponding methylurethanes;6 2) for acid- and base-sensitive substrates the use of neutral electrochemically 18,26,28 3) in order to extend the scope of the reaction for baseinduced Hofmann rearrangement was developed; sensitive substrates, the oxidative Hofmann rearrangement may be carried out with LTA or hypervalent iodine 16,23,14,29 reagents (PIDA, PIFA, PhI(OH)OTs, etc.) under mildly acidic conditions; and 4) when hypervalent iodine reagents or LTA are used in the presence of an amine or an alcohol, the generated isocyanate is in situ converted to the corresponding carbamate or urea derivative.17 MOR or M(OR)2 MOX or NaBrO2 H2O / °C O R1 ∗ NH2 R1 heat R R1, R2 = alkyl, aryl, H N C O R1 H R1 ∗ N H2O R M = Na, K, Ba, Ca X = Cl, Br 1° carboxamide ∗ OH NH2 R 1° Amine - O=C=O R2 O carbamic acid (unstable) isocyanate (not isolated) ∗ H2O LTA or PhI(OCOR)2 or PhI(OH)OTs or PhIO pH = 1-3 / solvent / H2O R1 or solvent / R OH or R3NH2 R3 = alkyl, aryl H R1 ∗ N H R1 ∗ N OR3 NHR3 or N C O R2 R2 Mechanism: ∗ isocyanate (not isolated) R2 O O Urea derivative Carbamate 34-40,19,41 The mechanism of the Hofmann rearrangement is closely related to the Curtius, Lossen and Schmidt rearrangements The first step is the formation of an N-halogen substituted amide Next, the N-haloamide is deprotonated by the base to the corresponding alkali salt that is quite unstable and quickly undergoes a concerted rearrangement to the isocyanate via a bridged anion This mechanistic picture is strongly supported by kinetic 36-39 As a result, the Hofmann rearrangement proceeds with complete retention of configuration evidence O R1 ∗ R2 X O N H H 1° carboxamide MOH R1 ∗ - HOH R2 O O M R ∗ N H R2 N X H N-haloamide MOH - HOH R1 ∗ O O O N R2 N-haloamide salt C -X X N R ∗ N X R2 bridged anion ∗ R R2 Isocyanate TABLE OF CONTENTS PREVIOUS REACTION NEXT REACTION 211 SEARCH TEXT HOFMANN REARRANGEMENT Synthetic Applications: 42 The enantioselective total synthesis of (–)-epibatidine was accomplished in the laboratory of D.A Evans The key steps in the synthetic sequence included a hetero Diels-Alder reaction and a modified Hofmann rearrangement The primary carboxamide was subjected to lead tetraacetate in tert-butyl alcohol that brought about the rearrangement and gave the corresponding N-Boc protected primary amine in good yield A few more steps from this intermediate led to the completion of the total synthesis O O Cl NH2 Cl Pb(OAc)4, t-BuOH N O t-BuO NH NH Cl steps N N 50 °C; 70% O H H (−)-Epibatidine H The first asymmetric total synthesis of the hasubanan alkaloid (+)-cepharamine was completed by A.G Schultz et al.43 In order to construct the cis-fused N-methylpyrrolidine ring, the advanced tetracyclic lactone was first converted to the primary carboxamide by treatment with sodium amide in liquid ammonia Next the Hofmann rearrangement was induced with sodium hypobromite in methanol initially affording the isocyanate, which upon reacting with the free secondary alcohol intramolecularly gave the corresponding cyclic carbamate in excellent yield PMPO OMe RO PMPO NaNH2 (xs) liq NH3 quant O O RO OMe Br2 NaOMe MeOH O NH2 O O RO OMe OMe O -78 °C, 1h then reflux, 1h 93% O HO O PMPO HO O steps O MeO O R = MOM N Me (+)-Cepharamine NH O R Verma and co-workers developed a silicon-controlled total synthesis of the antifungal agent (+)-preussin using a modified Hofmann rearrangement as one of the key steps in the final stages of the synthetic sequence.44 The primary carboxamide was exposed to LTA in DMF in the presence of benzyl alcohol, which resulted in an efficient Hofmann rearrangement to afford the Cbz-protected primary amine As expected, there was no loss of optical activity in the product The silicon group was finally converted to the corresponding secondary alcohol by the Fleming-Tamao oxidation R O LTA, BnOH DMF 100 °C, 15h O O C9H19 NH2 TsOH, acetone H2O, reflux, 2.5h 75% for steps Bn R = PhMe2Si O OH R H N C9H19 Bn steps OBn C9H19 N O Bn Me (+)-Preussin Cbz-protected primary amine During the late stages of the asymmetric total synthesis of capreomycidine IB it was necessary to transform an 45 asparagine residue into a diaminopropanoic acid residue R.M Williams et al employed a chemoselective Hofmann rearrangement, thereby avoiding protection and deprotection steps that would have been necessary had the diaminopropanoic acid been introduced directly The complex pentapeptide was treated with PIFA and pyridine in the presence of water to afford the primary amine in high yield O H2 N H N H H BocNH O NHBoc Me N N H H BocNH N H BocHN H O HN PhI(O2CCF3)2 pyridine O O DMF, H2O; 87% HN CO2Et EtO OEt N H BocHN O NHBoc O HN Me O O HN CO2Et EtO OEt ... Diels-Alder reaction and a modified Hofmann rearrangement The primary carboxamide was subjected to lead tetraacetate in tert-butyl alcohol that brought about the rearrangement and gave the corresponding...TABLE OF CONTENTS PREVIOUS REACTION NEXT REACTION 211 SEARCH TEXT HOFMANN REARRANGEMENT Synthetic Applications: 42 The enantioselective total synthesis of (–)-epibatidine... converted to the primary carboxamide by treatment with sodium amide in liquid ammonia Next the Hofmann rearrangement was induced with sodium hypobromite in methanol initially affording the isocyanate,