Primary carboxamides

Chlorosulfonyl isocyanate has been used to introduce 3-carboxamide groups. The initial product, an A -chlorosulfonylcarboxamide, is treated with tri-n-butylstannanc to form the primary carboxamide[15], 3-Cyano groups can also be introduced using chlorosulfonyl isocyanate. The intermediate N-chlorosulfonylindole-3-carboxamide is converted to 3-cyanoindole on reaction with triethylamine[16] or DMF[17],... 

The positive electrostatic charge of Ru(II) polypyridyl complexes has been combined with hydrogen-bond donating primary carboxamide groups in Beer s 68 to yield anion-sensitive luminescent systems. Structural variations have allowed strong biasing of Cr/HjPO selectivity in either direction. Macrocyclic 69 also raises interesting questions about PET/EET processes (Section 13) across... 

With some exceptions, BTI is considered to be the best choice for the Hofmann type degradation of carboxamides to primary amines. Generally, treatment of an aliphatic primary carboxamide with BTI in aqueous acetonitrile (at an acidic pH 1-3), followed by addition of hydrochloric acid delivers the corresponding amine hydrochloride in excellent yield. 

A reaction of considerable interest is the Hofmann type degradation of primary carboxamides to amines. Several examples have been reported of such efficient conversions, notably with the system IOB in formic acid (in water of acetonitrile), which forms in situ PhI(OOCH)2 [44], Other hypervalent iodine reagents have also been used extensively for these transformations (Sections 4.4.1 and 7.4.1). Yields may vary widely as illustrated for three similar amines obtained from the corresponding carboxamides with IOB-formic acid and with [hydroxy-(tosyloxy)iodo]benzene [45] ... 

Although BTI (Section 4.4.1) is the reagent of choice for the conversion of primary carboxamides into amines, other hypervalent iodine reagents are also of importance... 

It should be noted that Jochims and coworkers first carried out the reaction starting from carboxamides139,140. Until recently almost no acylated persubstituted amidinium salts 306 were obtained by reaction of nitrilium salts with tertiary carboxamides 305 (equation 84). Starting from secondary carboxamides 307, mixtures of A1-acylated A A -disubstituted amidinium salts 308 and 309 are isolated (equation 85). Primary carboxamides 310 undergo dehydration by the nitrilium hexachloroantimonates 290 to... 

The oxidative Hofmann rearrangement of primary carboxamides occurs by use of lead tetraacetate (LTA) and several hypervalent organoiodine compounds IF5 (28), PhI(OCOCP3)2 (29), PhI(OH)OTs (30) and PhIO (31) under mildly acidic conditions. 

Iodine pentafluoride (28) in hot pyridine works like LTA as a Hofmarm reagent for aliphatic primary carboxamides (equation 21). lodination occurs together with rearrangement when benzamide is treated under similar reaction conditions. 

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 fert-butyl alcohol that brought about the rearrangement and gave the corresponding A/-Boc protected primary amine in good yield. A few more steps from this intermediate led to the completion of the total synthesis. 

The first asymmetric total synthesis of the hasubanan alkaloid (+)-cepharamine was completed by A.G. Schultz et al. In order to construct the c/s-fused A/-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. 

Hofmann rearrangement Conversion of primary carboxamides to one-carbon shorter primary amines. 210... 

The Hofmann amide rearrangement is a conversion of a primary carboxamides 230 into amines using aqueous NaOH and bromine (see review in Reference 330). This reaction is, in effect, an elimination of the carbonyl group from the amide and is therefore usually... 

With dimethylacetylene dicarboxylate (DMAD) 1-acylimidazoles form novel functionalized derivatives as a consequence of electrophilic attack on the pyridine nitrogen followed by intramolecular transacylation (Scheme 112) <88CC1151,90JCS(P1)1821,92CB1939>. Ketoximes undergo Beckmann rearrangement and primary carboxamides are dehydrated to nitriles on treatment with (170)... 

Known examples are the partial Hofmann degradation of pyridine-2,3-dicarbox-amides,134 the Lossen degradation of pyridine-2,3-bis(hydroxamic) acid,135 this giving both possible products, i.e. 3-hydroxypyrido[2,3-(/]pyrimidine-2,4(l//,3//)-dione and 3-hydroxy-pyrido[3,2-d]pyrimidine-2,4(l//,3//)-dione as a 5 1 mixture, and the conversion of a primary carboxamide function into an intermediate isocyanate in the 2-position by oxidation with lead(IV) acetate.136... 

The reactions of nitriles to give amidines, amides and ketone derivatives were only briefly mentioned in CHEC-I <84CHEC-I(3B)1>. The nitriles are reactive and, for example, 3-amino-4-pyridazinecarbonitriles are readily hydrolyzed in good yields to primary carboxamides with aqueous ammonia <88JHCl 19>. The enzymatic hydrolysis of pyridazine nitriles using Rhodococcus species has been investigated <92JHC93>. 

RCONH2 — RCHO.1 Reduction of carboxamides to aldehydes with LiAlH4 is useful only with N,N-disubstitutcd carboxamides. This new hydride (1) can reduce primary carboxamides to aldehydes al 25° in 12 hours in yields of 50-90%. 

Prepared by reaction of LiAlHa with HN( RCONH2 — RCHO. Reduction of ca useful only with N,N-disubstituted cartwxai primary carboxamides to aldehydes at 25 in... 

Preparation of Acyl Isocyanates and Aryl Isocyanates. Certain primary carboxamides can be converted to acyl isocyanates in yields from 36-97% with the reagent (eq 22) Phosgene gives nitriles under similar conditions. Oxalyl chloride has found limited application for the preparation of triazine and quinone isocyanates. ... 

The Hofmann rearrangement, commonly referred to as the Hofmann degradation, converts a primary carboxamide to a primary amine fScheme 4.25T After formation of an N-bromoamide 66 under base-mediated bromination conditions, a nitrene 67 is generated via a-elimination of HBr. Subsequent rearrangement of the nitrene results in the formation of an isocyanate 68 which is hydrolyzed to a primary amine 69 after CO2 extrusion. 

Analogously, reaction of a P,y-unsaturated primary carboxamide with a nickel(O) complex affords nickelacycle 36 (Eq. As before,... 

The Hofmann Rearrangement (HR), which is often called the Hofmann Reaction or Hofmaim Degradation but should not be confused with the Hofmann Elimination, describes the multistep transformation of a primary carboxamide 1 to a primary amine 3 via an intermediate isocyanate 2 under the action of bromine and sodium hydroxide. " As will be shown, many variations of this rearrangement are known and widely used today. 

A frequently applied method for converting primary carboxamides into cyanides is dehydration with phosphorus pentoxide. It can be performed in two ways, the first in solution, and the second without any solvent in a two-phase solid/liquid or even a solid/solid phase reaction. Often, the nitrile can be easily distilled off. An Organic... 

The well-known and less-toxic peptide coupling reagent PyBOP (benzotriazol-1-yloxy-tris(pyrrolidino)phosphoirium hexafluorophosphate) has been employed in the selective dehydration of aromatic and aliphatic primary carboxamides to the corresponding nitriles. The reaction conditions are mild, the dehydration being performed at 40 °C reaction times are 5-8 h, and yields are 80-95% [1138]. 

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