Acylamino cyclization

Acylamino cyclization.l0 The indolizidine alkaloid (- )-swainsonine (3) has been synthesized by radical cyclization of the acylamine 1, derived from D-tartaric acid, to provide the indolizidinones 2 in 71% yield. Conversion to the alkaloid (3) included removal of the keto group by conversion to the thiolactam by Lawesson s reagent (97%) followed by desulfurization with Raney nickel (96% yield). 

Af-Oxides, e.g. (125), were similarly prepared using hydroxylamine to give intermediates such as (124) (79JOC1695, 78H(9)1327), and an alternative synthesis of Af-oxides involves cyclization of 3-acylamino-2-aroylpyridine oximes (126) —> (127) (69MIP21500). 

Pulici and coworkers have reported a solid-phase variation of the Robinson-Gabriel for the production of parallel libraries of ox azole-containing molecules." The preparation is based on a solid supported 2-acylamino ketone 16 that can be cleaved by means of a volatile anhydride and cyclized in solution to obtain a substituted oxazole ring (17) that does not contain traces of the linker moiety. 

Shaw and McDowellhave prepared imidazolone derivatives by cyclization of a-acylamino amides. In a variation of this reaction the azlactone (30) was gradually converted to the hydroxamic acid (31) by methanolic hydroxylamine. Sodium methoxide and hydroxylamine readily gave the acyclic hydroxamic acid (32) which could be cyclized to 31 by dilute acid. Benzyloxyurea has been used in the sjrnthesis of pyrimidine hydroxamic acids (33) by reaction with /S-diketones followed by catalytic hydrogenation of the benzyl group. Protection... 

Related are the Bischler Napieralski-type cyclizations of 2-(acylamino)diphenylmethancs 24 which provide useful access to a range of ll/7-dibenz[7>,e]azcpines 25.2S-76-104... 

The 3-[2-(acylamino)phenyl]-2-azidoprop-2-enoates 1 undergo a Staudinger reaction on treatment with triphenylphosphane at 20 C to give the stable imino-/.5-phosphanes 2 in nearly quantitative yields. The latter cyclize to 3/7-1,3-benzodiazepines 3 (40-50%) when heated in refluxing xylene for 15 hours. No further details were reported.19... 

V-[2-(Acylamino)phenyl]-A-alkylarylamincs 1 cyclize in phosphoryl chloride or in polyphos-phoric acid to the dibenzodiazepines 2. Selected example are given, exact yields were not reported.44 309... 

Acylamino)benzaldehyde oximes 2 cyclize under the influence of sulfuric acid to afford high yields of benzoxadiazepines 3. Selected examples arc given yields were generally not reported.314... 

The addition of a-(acylamino) esters to 3-aryl-2-propenoates, with sodium ethoxide in ethanol or sodium hydride in benzene as base, is a frequently ultilized procedure9-" A The initial Michael adducts cyclize to 3-aryl-5-oxo-2-pyrrolidinecarboxylic acids with modest to high trans diastereoselectivities 10°. 

The reaction of triphenylphosphine with 2-acylamino-2-(chloro)acetophenones gives the salts (113), which may be cyclized to the oxazolylphosphonium salts (114).113 Similarly, the halogenocarboxamides (115) react readily with triphenylphosphine to give the enamide phosphonium salts (116), which on treatment with primary or secondary amines give the salts (117).114... 

C-Acyclic nucleoside analogs of inosine and guanosine 8-[(/ 5)-2,3-dihydroxypropyl]imidazo[l,5-fl]-l,3,5-triazin-4(3//)-ones were synthesized. The route involved the cyclization and rearrangement of 5-acylamino-5-allyl-6-amino-4,5-dihydropyrimidin-4-ones (1122) to 8-allylimidazo[l,5-a]-l,3,5-triazin-4(3//)-ones (1123). Osmium tetroxide hydroxylation gave 1124. None of these analogs showed appreciable antiviral or antitumor cell activity (84NAR263 87MI6). 

FVP of Tacylnaphtho[l,8- ( ][l,2,3]triazines 575 gave exclusively the corresponding 2-substituted-naphth[l,8- ][l,3]oxazines 576 (Equation 69). The reaction was presumed to start with the elimination of N2 to give l-(acylamino)naphthalene diradicals, which then underwent intramolecular cyclization to give the oxazines 576 <2005T10507>. 

Saturated 5(4//)-oxazolones are easily obtained from //-acylamino acids in the presence of a cyclization agent and have been used extensively in coupling reactions as synthetic equivalents of a-amino acids in the synthesis of peptides. In this context, tautomeric equilibrium can be a significant problem due to the racemization associated with the isomerization. For example, trifluoroacetylation of tryptophan in ether affords the 5(4//)-oxazolone 5 without racemization. However, upon dissolution in acetonitrile, 5 completely racemizes. Further, upon heating, an aqueous dioxane solution of 5 cleanly isomerizes to the isomeric 5(2//)-oxazolone 6 (Scheme 7.2). 

Other amino acid precursors have been used as starting materials in the Erlenmeyer reaction. A classical reaction of oxazolones is ring opening to give dehydroamino acid derivatives but there are a number of examples when the reverse reaction has been exploited including cyclizations of A-benzoyl-a,p-dehydrophen-ylalanine," a-(acetylamino)cinnamic esters," and 2-(acylamino)-2-alkenamides (Scheme 7.118)." ... 

In general, the reaction of unsaturated 5(4//)-oxazolones 497 with nitrogen nucleophiles effects ring opening to give the corresponding unsaturated acylamino amides 498 (Scheme 7.158). Depending on the nucleophile, for example, amines, hydrazines, oximes, and so on, the products obtained can be cyclized and this process allows the synthesis of a wide variety of new heterocyclic compounds. 

Heterocyclic amines have also been used for aminolysis. Subsequent cyclization of the acylamino amides leads to imidazolones that show a diverse range of biological activities as antibacterial, antifungal, antiviral, antihelmintic, and anti-Parkinsonian agents, as well as central nervous systems (CNS) stimulants. 

Amino acids " " and aminobenzoic acids " " react as nitrogen nucleophiles to effect ring opening of unsaturated 5(4//)-oxazolones. Cyclization of the intermediate acylamino amide has opened the way for the synthesis of new series of imidazolones that now incorporate a carboxylic acid moiety into the N-1 substituent. These compounds are readily further elaborated into derivatives with diverse biological activity. 

A number of recent papers have appeared in the literature related to the synthesis of saturated 5(477)-oxazolones that were not yet covered in our contribution. 4-Acyl-2,4-dialkyl-5(477)-oxazolones 776 have been obtained from A-acylglycines. Thus, cyclization of an A-acylglycine in the presence of thionyl chloride affords a monosubstituted 5(477)-oxazolone 775. Acylation of 775 with an aroyl chloride in the presence of magnesium chloride occurred at C-4 to produce 776. Hydrolysis and decarboxylation of 776 gave the A-acylamino ketones 777 that are valuable intermediates to prepare oxazoles 778 (Scheme 7.236). 

A -Acylamino aromatic ketones 790 can be prepared by arylation of saturated oxazolones in the presence of Lewis acids. Cyclodehydration of 790 leads to 2,5-diaryloxazoles 791. For example, saturated 5(4//)-oxazolones 789 from 7/-benzoyl-alanine or A-benzoylvaline undergo Friedel-Crafts arylation to afford substituted A-benzoylphenacylamines 790. In the presence of POCI3, 790 cyclizes to produce 5-aryl-2-phenyloxazoles 791 (Scheme 7.241). ... 

Hu et al. (91MI1) report the Dimroth rearrangement of 2-hydrazino- to 2,3-diamino quinazolin-4-ones under catalysis of carboxylic acid derivatives this reaction is followed by an in situ cyclization in which the same carboxylic acid derivatives serve as C,-synthons. l-Acylamino-2-alkylthiopyrimidines are hydrazinolyzed and cyclized to 3-amino-1,2,4-triazolofl, 5-a]pyrimidinium salts (89EGP270711). 

Acylation of 95 with acid anhydrides or acid chlorides gives the acylamino-pyrazoles 97, which cyclize into pyrazolo[3,4-t/]pyrimidines upon treatment with alkaline or acidic media. Intermediates 98 or 99 have been proposed (56JA784 59JA2452). The acetylpyrazole 97 (R = R = H, R = CH3) is... 

Indolo[ 1,2-a]quinazoline s (67) were prepared through the formation of their diazine rings, by cyclizing 2-acylamino-l-phenyl-indoles (66) with phosphoryl chloride (81KGS844). 

Catalytic reduction of iminoethers derived from 4-aminoisoxazoles (85TL3423, 87JOC2714) or 4-amino-5(477)-isoxazolones (91S127) leads to a-(acylamino)enaminones (231) which cyclize in the presence of bases to form 4-acylimidazoles (Scheme 34). Treatment of the enaminone with a primary amine incorporates a substituted amino function in the (3-position with concomitant expulsion of ammonia and allows access to 1-substituted and 1,2-disubstituted 4-acylimidazoles in 75-92% yields (87JOC2714). 

Cyclization of l-(acylamino)pyrimidine hydroiodides (1) with alkyl ammonium acetates gave 3//J5//-l,2,4-triazolo[l,5-a]pyrimidines (2) (87 EGP246999 89ZC378). Condensation of the l-(acylamino)pyrimidinium salt 3 with hydrazine hydrate gave 4, which upon cyclization with acetic acid in the presence of perchloric acid afforded the 3-amino-l,2,4-triazolo [l,5-a]pyrimidinium salt 5 (89EGP270711) (Scheme 2). 

Cyclization of a-(acylamino)acrylohydrazides (684) with sodium hydroxide or acetic acid/acetic anhydride is the most commonly used method for preparing l,2,4-triazin-6-ones (685) <78HC(33)189, p.258). But since the acrylohydrazides (684) are usually made by hydrazinolysis of azlactones (c/. also 586 -> 588, Section 2.19.4.1.4), this method can also be treated as a [4+2] atom fragment method. 

The bromocyclization of A/,jV-dialkylaminomethyl ethers of allyl and propargyl alcohols to form oxa-zolidinium salts has been reported, but not used in synthesis.255 The heterocyclization of /V-acylamino-methyl ethers with mercury salts has been used for stereoselective synthesis of a variety of 1,2-amino alcohol systems. These cyclizations form rans-4,5-dialkyl oxazolidine products with good to excellent stereoselectivities (equation 120 and Table 33). As shown by entry 5, 6-endo cyclization predominates (6 3) with an internal double bond of ( )-configuration, but this mode of cyclization is reduced with substrates containing a (Z) double bond and/or allylic oxygen substitution (Table 33, entries 6-9). 

The placement of heteroatoms adjacent to the radical center often slows the rate of cyclization and, although low concentration techniques are required, good yields of cyclic products can still be obtained. Hart s systematic studies on the cyclizations of acylamino radicals were among the first to demonstrate the preparative utility of radical cyclizations.78 Scheme 19 provides some recent examples. In general,... 

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