Benzamides cyclization

A -Acylguanidines and iV-(alkylaminomethyl)benzamides cyclize on treatment with phosgene to give l,3,4-oxadiazin-2-ones (199) <76S38> and 3,4-dihydro-2//-l,3,5-oxadiazin-2-ones (200) <82SZP630245>, respectively. 

When the benzamide derivative of 3-picoline 17 was subjected to the cyclization conditions with -BuLi, the reaction failed to yield the desired indole 18. However, when -BuLi was replaced by LDA, the desired azaindole 18 was isolated in 22% yield." ... 

Treatment of 2-phenyl-l,3-benzoxazepines with hydrochloric acid in acetic acid gives benzo-furans by hydrolytic opening of the oxazepine ring, followed by loss of benzamide and re-cyclization.23... 

Cyclization of co-amidophenyl sulfoxides 1244 for n=l, 2, 3 with O-silylketene acetal 1214 affords 5-, 6-, and 7-membered lactams 1245 in 100, 54, and 57% yields, respectively, and [Me3CSi(Me)]20 94 a [47, 48], whereas cyclization of N-mefhyl-2-methylsulfenyl benzamide 1246 with silylketene acetal 1214 and Znl2 gives 85% 3-mefhyl-2,3-dihydro-l,3-benzofhiazine-4-one 1247 and [Me3CSi(Me)2]20 94a [48] (Scheme 8.18). 

Tandem mass spectrometry has been used to demonstrate that M+ as well as MH+ of substituted A-(ort/zo-cyclopropylphenyl)benzamides isomerizes before the fragmentation, with formation of 3-aryl-1-ethyl-lH-benzoxazines and 5-ethyl-2-oxodi-benzoazepines (Scheme 5.14). The methyl group in /V-[ortho-( 1 -methylcvclopropyl )-phenyl]benzamides quenches the latter process, leaving the formation of benzoxazines as the only cyclization reaction. A subsequent chemical experiment in solution confirmed the mass spectral predictions [24]. A similar study confirmed the analogy of cyclization of substituted A-(ort/zo-cyclopropylphenyl)-A -aryl ureas and N- ortho-cyclopropylphenyl)-A -aiyl thioureas in the ion source of mass a spectrometer and in solution [25]. 

The first case presented is that of 2-[(acyloxy)methyl]benzamides of the general structure 8.187 (Fig. 8.22) [239]. Two model compounds were examined (NRR = MeNH or morpholino, R" = Me) they reacted, as expected, to give the secondary amine and phthalide in quantitative yields. At pH 9.3 and 60°, chemical hydrolysis was 2-10 times faster than the subsequent cyclization-elimination. At pH 7.4 and 37°, the chemical hydrolysis was slow (f1/2 ca. 400 h), while hydrolysis in human plasma was fast (tm 3.2 and 1.4 h, respectively). 

Fig. 8.22. 2-[(Acyloxy)methyl]benzamides (8.187) as double prodrugs of active amines. Activation is by cyclization-elimination in a two-step sequence, namely hydrolase-catalyzed hydrolysis of the carboxylate moiety followed by an intramolecular nucleophilic substitution with...

The classical Harley-Mason cyclization was utilized en route to (—)-aspidospermidine 84. 9 The synthesis of 84 required 12 steps from the chiral benzamide 12 (X = SiMcs) and was carried out with an overall yield of 19%. 

It has been shown that, in the presence of lithium diethylamide at —70 °C, bromoben-zoic acids form arynes which may react with arylacetonitriles to yield, predominantly, 2-cyanobenzoic acids. The reaction of alkyl and aryl isocyanides with benzyne may yield benzamide derivatives, showing their ability to act as charge-reversed equivalents to isocyanates. The generation and cyclization of a benzyne-tethered alkyllithium have been reported, and lead to a convenient synthetic route for 4-substituted indans. ... 

Cyclization of o-acylaminobenzamides 759 leads to 2-substituted 4(3//)-quinazolinones 760. The benzamide may be generated in situ from an ester and an amine, and the ring closure can be performed under either acidic or basic conditions <1996HC(55)1, 1997IJH101, 2002JHC351, 2004808(16)573, 2006JOC382, 2007TL3243>. 

In a base-catalyzed substitution reaction with benzamide, ethyl 2-cyano-3,3-bis(methylsulfanyl)acrylate 280 gave the 3-aminoacrylate derivative 281, which on thermal cyclization yielded the functionalized 6-imino-l,3-oxazine 282 (Scheme 52) <1995BML695>. 

Mathias and Moore (30-33) described a new synthesis of isomiinchnones 55 via the thermal cyclization of A-(chloroacetyl)lactams (54) (Scheme 10.7). These isomiinchnones can be captured by NPM to give fused 2-pyridones in moderate yields. Cycloadducts from the reaction with DMAD are produced in much lower yields (<17%), and other olefinic dipolarophiles (fumarate, maleate, acrylate, and dicyanocyclobutene) are unreactive. Reaction of 7/-(chloroacetyl)benzamide (57) in the presence of NPM gave 58 in low yield. 

Base-catalyzed cyclization of A -benzoyl-a-chloroacetamide is a classical method used to prepare 2-phenyl-4(5//)-oxazolone. Extension of this methodology to the A -aroylcinnamides 35 afforded a series of 5-arylidene analogues 37 albeit in unstated yield (Scheme 6.12). " Thus, acylation of the sodium salt of a benzamide with a cinnamoyl chloride gave the imides 35 that were converted to 36 via a bromination-dehydrobromination sequence. Cyclization to 37 was affected with sodium hydride in 1,2-dimethoxyethane (DME). The authors noted that catalytic reduction of 37 afforded the 5-(arylidene)oxazolidine from which 37 could be regenerated in the presence of air. 

A very popular route to piperid-4-ones is by a Dieckmann or Thorpe cyclization of appropriate diesters or dinitriles. In most cases the nitrogen atom is tertiary, to avoid the formation of amides as by-products. A simple example is provided by the synthesis of the piperidone ester (129) which, after hydrolysis and decarboxylation, gives the piperid-4-one (130) (45JOC277). The diesters are available by addition of amines to acrylates and so the two ester fragments can be different. For the production of AT-benzoylpiperid-4-one (132) the whole operation from benzamide and ethyl acrylate to the ester (131) can be achieved... 

Benzothiazepines of type (401) can be prepared by the Bischler-Napieralsky cycliz-ation of N- (arylthioethyl)benzamides and reactions of the same type have been used in the synthesis of dibenzo[6,/][ 1,4]thiazepines (70JHC409). 

A one-step construction of both of heterocyclic rings of the title compounds (415 and 416) was accomplished when anthranilamides reacted with 5-oxoalkanoic acids (68JOC2402 69USP3441566 75USP3883524) or when anthranilic acids reacted with l-cyano-4-haloalkanes (79KGS1427), respectively. Cyclization of 2-(2-carboxyethylamino)benzamide (417) with ethyl chloroformylacetate gave 4-ethoxycarbonyl-I,2-dihydropyrido[I,2-a]quinazoline-3,6-dione (419) (83CPB2234). 

Ammonia and amines open pyran-2-one rings and the acyclic products may cyclize again on acidification to pyridones or a benzene ring, a reaction reminiscent of those of pyrylium salts (Section 2.23.2.3). Under mild conditions, unsaturated amino acids such as (275) are formed but at higher temperatures and longer reaction times, a pyridone (276) or benzamide (277) is formed. The probable course of benzamide formation is as shown in Scheme 14 (74JOU852). 

A more conventional route is the acid-catalyzed cyclodehydration of amides already containing the appropriate numbers of atoms. For example, carbamates (213) may be cyclized to oxazinediones (214) with concentrated sulfuric acid (76JCS(Pl)1969) and the dihydrobenzoxazin-4-ones and -thiazin-4-ones (216) can be prepared from the appropriate benzamides (215), again by treatment with acidic reagents (53AP437). 

Benzazepinones can be prepared on cross-linked polystyrene by intramolecular Heck reaction (Entry 6, Table 15.35). In the presence of sodium formate, the intramolecular Heck reaction of iodoarenes with alkynes yields methylene benzazepinones (Entry 7, Table 15.35). Surprisingly, when this reaction was performed in solution, the main product (65% yield) was a dehalogenated, non-cyclized benzamide. In the synthesis on cross-linked polystyrene, however, this product was not observed [419]. 

Another preparative route for synthesis of benzisoselenazol-3(27/)-ones is based on the lithiation of the benzamides, followed by the conversion of dilithium derivatives by direct treatment with selenium, or via 2-[(carbamoyl)phenyl]methyl selenides or 2,2 -bis[(carbamoyl)phenyl] diselenides [167-172], These diselenides are oxidatively cyclized and, depending on the oxidant used, benzisoselenazol-3 (2H)-ones or their 1-oxides are produced in high yields [92, 173],... 

Dimethylcherylline, dimethylether of alkaloid cherylline, has been prepared (15% total yield) from the appropriately substituted /V-methyI benzamide, via condensation with the corresponding benzaldehyde and subsequent cyclization.137,152... 

Radical cyclization of suitably substituted benzamides yields the reduced 1-isoquinolinone (Equation 124) <1999TL2125>. In the illustrated example, the reactive intermediate was formed on the nitrogen as an amidyl radical, and this was followed by tandem cyclization. 

The electrophilic cyclization of the benzamide 527 to 3,6-bis(dimethylamino)thioxanthone is accomplished in high yield using POCI3 (Equation 187) <20050M3807>. 

A related reaction accompanied by cyclization occurred with ortho-substituted benzamides (and also non-cyclic amides such as RCH(CONH2)2 [60]. Several compounds with a primary amino group, such as t-butylamine, p-tol uenesulphona-mide, ethyl carbamate, etc. were oxidized by DIB in presence of alkenes or nitroso compounds to give, respectively, aziridines or azoxy compounds. 

Oxazoles are the products of the rearrangement of isoxazoles and of C-acylazirines, these processes being intimately related (81MI41800, 76ACR37I, 77H(6)143). Photolysis of 3-acylazirines gives nitrile ylides which cyclize thermally to oxazoles (equation 131). Flash vacuum pyrolysis of 3,5-diphenylisoxazole yields as major products 2,5-diphenyloxazole, 1,2-diphenylazirine, 2-phenylindole and benzamide. 13C labelling experiments indicate that the first two compounds are formed as shown in Scheme 31. 

The anti-tumour properties of cryptopleurine (33) continue to stimulate synthetic work in this area, and two new syntheses have been reported this year. Snieckus and co-workers25 have described a short, efficient synthesis of the alkaloid, utilizing a benzamide-directed metallation reaction (Scheme 6). In the other synthesis,26 the piperidine derivative (35), prepared by a nitrone cycloaddition reaction, is cyclized... 

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