Amides heterocyclic

Bernstein etal, US Patent 5,521,179 (May 28, 1996) Assignee Zeneca Limited 

Utility Human Neutrophil Elastase Inhibitor in the Treatment of 

Acetophenone (30.6 g) and N,N-dimethylformamide dimethylacetal (100 g, 94% by weight) in acetonitrile were refluxed overnight, cooled, and concentrated. The solid was dissolved in 400 ml DMF, cyanoacetamide (19.4g) and sodium methoxide added, and the mixture heated 5 hours at 100 °C. It was cooled, diluted with water, acidified with HCl to a pH = 5, and the product isolated. H-NHR data supplied. 

The product from Step 1 (8.54 g) was suspended in 100 ml HOAc and 50 ml HBr, refluxed overnight, cooled, diluted with 50 ml water, brought to pH 5 using 10% NaOH, and the product isolated. MS and H-NMR supplied. 

The product from Step 2 (lOg) was suspended in 260 ml dioxane containing 7.8 ml triethylamine, 11.1 ml diphenylphosphoryl azide added, and the mixture heated 4 hours at 120 °C. Benzyl alcohol (9.58 g) was added, the mixture refluxed overnight, cooled, diluted with 600 ml water, and a solid isolated. The solid was purified by chromatography using chloroform/methanol, 20 1, recrystallized using chloroform, and the product isolated. H-NMR data supplied. 

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The N-bromination of amides with bromine and alkali has been extensively researched as the first step of the Hofmann degradation. However, it is difficult to isolate the N-bromoamides because of their subsequent reaction to produce amines, which proceeds very readily under excessive alkaline conditions. Now, the reaction of amides with a stoichiometric amount of BTMA Br3 and sodium hydroxide in ice-water gave N-bromoamides in fairly good yields. Our method can be applied to various types of aliphatic, aromatic, and heterocyclic amides (Fig. 31) (ref. 39). 

A first review of our work in this field was published under the title Syntheses Using Heterocyclic Amides (Azolides) in Angewandte Chemie in 1962 an updated version co-authored by W. Rohr was included in Vol. V of the series Newer Methods of Preparative Organic Chemistry (Verlag Chemie, Weinheim 1967). Since then, however, azolide reactions, due to their versatility, ease of handling, and mild reaction conditions, have become widely used in very diverse fields of chemistry and biochemistry, as will be shown in this book. 

The compounds referred to as azolides are heterocyclic amides in which the amide nitrogen is part of an azole ring, such as imidazole, pyrazole, triazole, tetrazole, benzimidazole, benzotriazole, and their substituted derivatives. In contrast to normal amides, most of which show particularly low reactivities in such nucleophilic reactions as hydrolysis, alcoholysis, aminolysis, etc., the azolides are characterized by high reactivities in reactions with nucleophiles within the carbonyl group placing these compounds at about the same reactivity level as the corresponding acid chlorides or anhydrides. 11... 

Some heterocyclic amides, in principle similar to those described above, were shown to cyclize in a Michael type reaction to give anellated pyridones in excellent yield 1-1393... 

A reagent composed of tetra-n-butylammonium nitrate and TFAA in methylene chloride has been used to nitrate a series of A-alkyl and A-aryl amides (40-90 %). The formation of significant amounts of A-nitrosamides was noted. Tetra-n-butylammonium nitrate and triflic anhydride in methylene chloride has been used to successfully nitrate a variety of heterocyclic amides, imides and ureas (66). ... 

Kraton Trade name for an ABA block copol5mer of st5rene-butadiene-styrene. lactam Heterocyclic amide with one nitrogen atom in the ring. 

Attempts to extend this process to the related 2-pyridone system have been less successful, with only a small proportion of C-6 lithiation being observed with l-methyl-2-pyridone [85CC1021 88JCS(P1)1]. In fact, the major mode of reaction involves lithiation of the exocyclic methyl group, to give a carbanionic species that is dipole-stabilized by the heterocyclic amide group (Scheme 120) (83MI1). 

We also note a comparison of acyclic and heterocyclic amides with the corresponding imines in which it was asserted that 3-indazolinone has considerably less... 

H. A. Staab, Syntheses Using Heterocyclic Amides (Azolides), Angew. Chem. Int. Ed. EnGl. 1962, 1, 351-367. 

Typical examples are barriers to rotation in dimethylamino heterocycles and barriers to rotation in heterocyclic amides and thioamides. 

PFP 29 esters have been recommended for the synthesis of heterocyclic amides, when DCC 17 or DIC 25 alone had failed (58). HOSu 30 is coupled to acids easily using A,A -disuccinimidyl carbonate (see chapter on DIC) and, being water soluble, it can be removed readily at the purification stage (59). 

Alkylmercaptomethyleneiminium salts as well as alkoxymethyleneiminium salts are transformed to amide thioacetals (443 equation 206) by alkali metal thiolates and thiols. - The action of alcoholic alkoxides on 2-alkoxy-2-dialkylaminocarbonitriles (444 equation 207) produces amide acetalsJ Spi-locyclic amide acetals (446 Scheme 82) were prepared from oxazolium salts (445) and substituted sal-icyl aldehydes. The addition of alcohols to the l,3-oxazolium-4-olate (447) affords heterocyclic amide acetals (448). ... 

The electrolysis of DMF in alcohols affords a product mixture in which amide acetals, e.g. (475) and (476) (equation 219), are present. The heterocyclic amide acetal (479 equation 220) was obtained by reaction of the ynamine (478) with the o-quinonimine derivative (477). ° An azomethine ylide, generated in situ from the iminium salts (480 equation 221), transforms m-nitrobenzaldehyde to the oxazolidine derivative (481). ... 

Functionalized oxadiazoles have received considerable attention in the pharmaceutical industry as heterocyclic amide and ester isosteres [95]. Oxadiazoles have been employed in the design of biologically active templates, e. g. core structures for muscarinic agonists, kinase inhibitors, anti-inflammatory agents, histamine H3 antagonists, monoaminic oxidase inhibitors, etc. 

Another useful synthetic route to amides 25 utilized the methyl ester (12 R = Me) prepared by ring expansion of the corresponding benziso-thiazoline ester 8 (R = OMe).9 Methylation of 12 produced ester 28. Combination of various amines with ester 28, or the corresponding ethyl ester, gives analogs of compound 25.7,817,18 The use of heterocyclic amines in this reaction has produced the N-heterocyclic amides sudoxicam (20)19 and piroxicam (29),2 0 21 potent anti-inflammatory agents that are discussed more fully in Section II,D. 

Syntheses using heterocyclic amides (azolides) , Newer Methods of Prep. Org. Chem., 1968, 5, 61. 

Arylation. Traditionally, arylation of nucleophiles is carried out in the presence of copper catalysts, the use of FeCls as an alternative, with its scope has now been delineated. In the synthesis of diaryl ethers, l,3-di-t-butyl-l,3-propanedione serves an additive (ligand for the Fe ion) and CS2CO3 as base. A,A -Dimethylethylenediamine appears to be an excellent ligand in the reaction with A-nucleophiles (A-heterocycles, amides" ) in a nonpolar solvent (toluene) where a milder base (K3PO4) suffices, arylation of alkanethiols calls for t-BuONa. ... 

R = H, alkyl, aryl amide, heterocyclic amide R = nitrile, aryl ketone R = nitrile, ester, aryl ketone... 

These same authors observed a similar reactivity pattern with 5-fluoro-2-heteroaryl-4-(trifluoromethyl)oxazoles 650. The starting materials were readily prepared from a heterocyclic amide according to their earlier protocol. Here again, displacement of fluoride in 650 was readily accomplished to afford 651, 652 and 653 (Scheme 1.179). 

A microwave-promoted domino Knoevenagel-hetero Diels-Alder reaction of aldehydes, amides, and dienophiles has been used for the synthesis of a large variety of carbo- and heterocyclic amides (Scheme 4.11). This mechanism involves the initial formation of a l-(Af-acylamino)-l,3-butadiene by reaction... 

N-Heterocyclic amides have been efficiently prepared by homo-lytic carbamylation with formamide. Under mild conditions amides can be converted into nitriles with pyrophosphoryl chloride Another mild, efficient, and novel method is the oxidation of lactams to imides with peroxy acids or hydroperoxides in the presence of transition metal ions... 

Brown, M.F. and Poss, C.S. (2001) Heterocyclic amide derivatives useful as inhibitors of MlP-lalpha binding to CCRl receptors, W0200157023. 

Steiab H.A., Syntheses with heterocyclic amides (azolides), Angew. Chem., 74, 1962,407-423. 

Benzamide and 1 eq. PhCH2Me3N Bfj" added to 4 eqs. aq. NaOH, and the mixture stirred at room temp, for 2 h - aniline. Y 72%. The method is applicable to a variety of aromatic and heterocyclic amides, but acylureas were obtained predominantly from aliphatic amides beyond Cg (cf. Synth. Meth. 43, 277). The reagent can be handled safely and easily. F.e.s. S. Kajigaeshi et al., Chem. Letters 1989, 463-4. 

Similarly, heterocyclic amides can be bis-metallated the dianion (437) can be coupled with different electrophiles, the first attacking the more reactive 3-position, although perhaps predictably yields of 2,3,5-unsymmetrically substituted thiophenes are only moderate. The ability of amide groups in general to direct metallation to the usually less reactive 3-position in these types of heterocycles has been summarized. 

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