7- -butyric acid cyclization

Tctrahydro-l 1 //-pyrido[2,l - quina/olin-l 1 -one was prepared by cyclization of 2-(4-hydroxybutyl)quinazo-linH(3//)-onc upon treatment with NaH, and TsOH in THF at room temperature <2004T3417>. Cyclization of 4-(4-oxo-3,4-dihydroquinazolin-2-yl)butyric acid and its 2-acetylamino derivative in refluxing AC2O gave 6-acetyl-... 

The 3,4-dihydrodiol of BcP was synthesized from 4-oxo-l,2,3,4-tetrahydro-BcP (15) by Method I (66). The ketone L was itself prepared from 4-oxo-l,2,3,4-tetrahydrophenanthrene via a multistep sequence entailing Reformatsky reaction with methyl bromocrotonate, dehydration of the resulting alcohol, isomerization to the aryl-butyric acid, and cyclization of its acid chloride with SnCl - Full... 

The first member of the 1-benzazepine series to be described was 2,3,4,5-tetrahydro-l//-l-benzazepin-2-one (I, R1 = R2 = H), which was synthesized by von Braun in 1907 by cyclization of 4-(2-aminophenyl)butyric acid [1]. 

Cagniant and Cagniant have reported that succinoylation of benzo[6]thiophene under Friedel-Crafts conditions yields a separable mixture of the y-ketobutyric acids 42a and 43a in a ratio of 9 1 (combined yield 85%). Huang-Minlon reduction of 42a to the butyric acid (90%) followed by cyclization of the derived acid chloride (90%) was reported to yield 4-keto-l,2,3,4-tetrahydrodibenzothiophene (44a) (69% overall). Likewise, acylation of benzo[6]thiophene with the ester chloride of succinic acid in carbon disulfide-aluminum chloride gave a separable mixture (80%) of the 2- and 3-y-ketobutyric esters. Two alternative... 

As noted earlier, most classical antidepressant agents consist of propylamine derivatives of tricyclic aromatic compounds. The antidepressant molecule tametraline is thus notable in that it is built on a bicyclic nucleus that directly carries the amine substituent. Reaction of 4-phenyl-l-tetralone (18) (obtainable by Friedel-Crafts cyclization of 4,4-diphenyl butyric acid) with methyl amine in the presence of titanium chloride gives the corresponding Schiff base. Reduction by means of sodium borohydride affords the secondary amine as a mixture of cis (21) and trans (20) isomers. The latter is separated to afford the more active antidepressant of the pair, tametraline (20). 

Phenprocoumon Phenprocoumon, 3-(a-ethylbenzyl)-4-hydroxycoumarin (24.1.14), is synthesized by acylating sodium salts of diethyl ester (l-phenylpropyl)butyric acid with acetylsalicylic acid chloride, which forms the compound 24.1.12, which upon reaction with sodium ethoxide cyclizes to 3-(a-ethylbenzyl)-2-carboethoxy-4-hydroxycoumarin (24.1.13). Alkaline hydrolysis of this product and further decarboxylation gives phenprocoumon (24.1.14) [21-28]. 

Challenger and Harrison found both thienothiophene 1 and its isomer 2 in the products of the reaction between acetylene and sulfur. To identify these compounds, Challenger et developed syntheses of unsubstituted and 2-alkyl-substituted thieno[3,2-f>]thiophene (2) from thiophene derivatives. Cyclization of (3-thienylthio)acetic acid in the presence of sulfuric acid gave 2,3-dihydrothieno[3,2-6]thiophen-3-one (22) (R = H) in 14% yield reducing the latter with lithium aluminum hydride resulted in thienothiophene (2) formation in 80% yield [Eq. (9)]. Similarly 2-methyl- and 2-ethyl-2,3-dihydrothieno[3,2-/>]thiophen-3-one were obtained from a-(3-thienylthio)propionic and a-(3-tWenylthio)-butyric acids in 30% and 27% yields, respectively their reduction yielded 2-methyl (32%) and 2-ethylthieno[3,2-6]thiophenes (52%). The parent acids were prepared from 3-mercaptothiophene. ... 

Cyclization of 2-bromo-4-(2-pyridylthio)butyric acid hydrobromide... 

Tetrahydrobenzo[6]thiophen-4-one (103) may be prepared from y-(2-thienyl)butyric acid by cyclization with phosphoric acid854 or by Friedel-Crafts cyclization of the corresponding acid chloride.194, 355.358 j s 5-methyl,357 2-ethyl,194 2-isopropyl,358 2- and 3-tert-butyl,359 2,3-dimethyl,360 2-ethyl-3-methyl,360 and 2-bromo 354 derivatives and diethyl 4,5,6,7-tetrahydrobenzo[6]thiophene-4,5-di-carboxylate861 may be prepared similarly. 4,5,6,7-Tetrahydrobenzo-[6]thiophen-7-one (104)357 362,863 and its 5- and 6-methyl 357 and 2-chloro 362 derivatives are obtained from the appropriately substituted y-(3-thienyl)butyric acid, A recent patent 364 describes the vapor phase cyclization of y-(2-thienyl)butyric acid to 103. Ketones (103 and 104) are useful intermediates for the synthesis of 4- and 7-substituted benzo[6]thiophenes, respectively their reactions are discussed in Section VI, B, 4. 

Friedel-Crafts acylation of benzo[6]thiophene and its derivatives with succinic anhydride132,439,662,663 or the ester chloride of succinic acid614, 618, 650,662 gives a y-keto acid (or ester), which is reduced to the corresponding y-(benzo[6]thienyl)butyric acid by the Huang Minion or Clemmensen method. y-(Benzo[6]thienyl)butyric acids may alternatively be prepared by the diethyl malonate synthesis on the appropriate halide,439,499 by the Arndt-Eistert reaction on the corresponding propionyl chloride,409,618 or by cyclization.347,618 The ketones (317 R = Hor OMe)347 have been prepared by cyclization... 

Intramolecular acylations of pyrrole and indolecarboxylic acids have also been effected. Compound 6b was obtained from a reaction of /3-(l-pyrrolyl)butyric acid (13a) using polyphosphoric acid (PPA) as a catalyst. No yield was given but the analogous cyclization of /3-(l-pyrrolyl)glutaric acid (13b) gave 75% of the pyrrolizinone (6c).12... 

Pummerer cyclization. Pummerer rearrangement of 4-(phenylsulfinyl)butyric acids (1) catalyzed by TsOH results in 4-phenylthio-4-butanolides (2). Oxidation followed by thermolysis results in either 3 or 4, depending on the substitution pattern. 

The fact that sixrmemhered rings are formed in preference to five-mem-bered ones was demonstrated by the cyclization of a-benzyl-y-phenyl-butyric acid (V) to 2-benzyltetralone-l (VI).6-6... 

The examples of intramolecular acylation by the use of aluminum chloride in the Friedel-Crafts reaction occur in the literature so frequently that no attempt has been made here to enumerate all of them. Table VII includes several different types of arylpropionic and aryl-butyric acids which have been cyclized by this method. 

Tt is interesting to note that in the reverse reaction, that of lactone formation from the free [Eq. (XVI.5.11)] 7-OH-butyric acid, the slow step (reaction 6) is now the cyclization of the conjugate acid of the starting reactant. This rate law for this step should follow ho and not (H+), and this is indeed what is observed (Long et al., loc. dt),... 

CycHzation of y-arylbutyric acids. Eisenbraun et al.1 greatly prefer use of PPA to the acid chloride-AlCl3 procedure for cyclization of 4-(2,5-dimethylphenyl)-2-methyl-butyric acid (1) to 2,5,8-trimethyI-l-tetralone (2). 

Reissert compounds of the type 33 (n = 330,49 and 430) undergo an intramolecular alkylation on treatment with sodium hydride in dimethyl-formamide to give the tricyclic compounds (34). A similar reaction also takes place in the quinoline series.30 When 33 (n = 3) and isopropyl bromide are treated with sodium hydride, cyclization to 34 (n = 3) takes place rather than alkylation with the isopropyl bromide however, treatment of 33(n = 3) and carbon disulfide-methyl iodide with sodium hydride gives 35 rather than cyclization.30 Alkaline peroxide converts the nitrile 34 (n = 3) into an amide, and acid or base hydrolysis gives 4-(l-isoquinolyl)butyric acid.30... 

Ketone 67a is formed directly by cyclization of y-(2-thienyl)butyric acid with PPA-Ac20290,291 under these conditions, the 2-acetyl derivative 67 (R1 = Ac, R2 = R3 = H) is formed as a by-product.148,291 Similar attempts to prepare the 3-methyl analog 67 (R1 = R3 = H, R2 = Me) gave the 2-acetyl derivative 67 (R1 = Ac, R2 = Me, R3 = H) in high yield, even under mild conditions.291 Ketone 67a is probably best prepared by dehydrogenation of... 

This ketone may be obtained (80%) by direct oxidation of 4,5,6,7-tetra-hydrobenzo[i>]thiophene with a Ce(IV) salt294 or by cyclization of the rather inaccessible y-(3-thienyI)butyric acid.300 y-(2,5-Di-t-butyl-3-thienyl)-butyric acid is cyclized by PPA with the expulsion of the 2-r-Bu group, to give 72 (R = r-Bu).3012-Acetylthiophene reacts with but-2-ene in the presence of a Mn(III) salt, to give the 4,5-dimethyl derivative of 72 (R = H).302... 

The first compound in the 1-benzazepine series was prepared by von Braun,4 who observed that 4-(2-aminophenyl)butyric acid (4, R1 = R2 = H), when freed from its salts, spontaneously cyclized to give 5 (R -R8 = H) almost quantitatively. The spontaneity of this ring closure was later... 

Condensation of the allylic alcohol 646 with methyl orthopropionate in butyric acid gave ester 647 which, after hydrolysis, was treated with methyllithium to give ketone 648. Fischer indole cyclization with poly-phosphoric acid of the phenylhydrazone of 648 gave the indole 649. The iV-oxide of 649 in trifluoroacetic anhydride at 0° gave in 92% yield the hexahydroellipticine 650, convertible with palladium-charcoal to 267 in 35% yield. The overall yield from 646 is on the order of 19% (Scheme 43). 

Direct introduction of a C4-bridge is unsuccessful, because upon acylation of y-butyric acid homoannularly cyclization selectively occurs [68], This is why C4- and C 5-bridges have to be constructed by stepwise ring extension reactions... 

Cyclization of benzo[Z ]thieno[3,2-Z ]thiophene-2-butyric acid in the presence of P2O5 gives benzo[Z ]thieno[3,2-Z ]benzo[Z ]thiophene (121) in 80% yield (92BCJ1855). 

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