Friedel-Crafts reactions cyclization

An anionic equivalent of the Friedel-Crafts cyclization reaction has been developed for the formation of the C /C-5 bond of the 1,2-benzothiazine structure (Equation 35 Table 5) <1997SL1079>. In this reaction, directed metalation of sulfonamide-substituted aromatic systems 233 with an excess of LDA affords aryl lithium species 234 in a regiocontrolled fashion. This intermediate then reacts in situ with a proximal amide to form l,2-benzothiazine-4-one 1,1-dioxides 235. The yields of this transformation appear to be highly dependent upon the substitution pattern in 233. The authors attribute the low yield when = methyl and = H to a-deprotonation of the amide moiety. 

The Fries rearrangement can be viewed as a type of Friedel-Crafts acylation reaction. Two examples of this reaction are given in Scheme 5.1-61. The first is the rearrangement of 4,4 -diacetoxybiphenyl to 4,4 -dihydroxy-3,3 -diacetoxybiphenyl in a NaCl/AlCl3 (X(A1C13) = 0.69) molten salt [93]. The second example is the rearrangement of phenyl 3-chloropropionate to 2 -hydroxy-3-chloropropiophenone, followed by cyclization to an indanone [94]. 

Dibenzo[/>,/]thiepin derivative (39) has been obtained by cyclization of 2-arylthio-5-nitrophenylpyruvic acid (38) in the presence of polyphosphoric acid 33>. The use of this Friedel-Crafts type reaction is restricted to the synthesis of the stable di- and tri-annelated thiepins such as 40 33), 41 7), and 42 34). 

The quinolizine derivative 276 was obtained through a Friedel-Crafts acylation reaction onto the C-3 indole position of 275. This precursor was obtained by a sequence comprising a Fischer cyclization leading to 5-methyl-2-(2-pyridyl)indole 274, catalytic hydrogenation, N-alkylation with ethyl bromoacetate, and hydrolysis of the ester group (Scheme 59) <1999FA479>. 

Finally, the reactions were examined in order to determine their compatibility with the initiation of Friedel-Crafts cyclizations (Scheme 19, Eq. 2). Both the use of an a-stannyl ether and an a-stannyl amide substrates led to cyclized product. 

The Friedel-Crafts cyclization of biphenyl-2-sulfonyl chloride to give dibenzothiophene sulfone has been described (55%) ° however, thermal cyclization in octachloronaphthalene at 250°, under nitrogen, is reported to yield dibenzothiophene itself rather than the sulfone (47%). Reaction of biphenyl compounds with oleum (H2SO4 + SO3) to yield derivatives of dibenzothiophene 5,5-dioxide is widely used for the preparation of dyestuff intermediates (Section VI, E, 2). A typical example is shown in Eq. (3), starting from o-tolidine. ... 

An alternative route to dibenzothiophenebut3o ic acids has been developed involving reaction of 4-lithiodibenzothiophene with menthyl levulate, yielding, after ester hydrolysis, y-hydroxy-y-methyl-4-dibenzothiophenebutyric acid (139). The bulky menthyl group was employed to direct reaction to the ketone moiety of the levulate. Dehydration followed by catalytic hydrogenation yields y-methyl-4-dibenzothiophenebutyric acid, Friedel-Crafts cyclization of which yielded the ketone (140). ... 

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). 

As mentioned in the introduction, recent synthetic developments now allow access to the 1,2-thiazine structure via disconnection type C (Figure 23). This process can be accomplished by a Friedel-Crafts-type cyclization of sulfamoyl chlorides. The initial report of this reaction utilized a stoichometric amount of aluminium chloride promoter <19920PP463>. Recently, however, A -ethyl phenethylsulfamoyl chloride 214 was shown to undergo Friedel-Crafts cyclization to form sultam 215 with just a catalytic amount of In(OTf)3 (Equation 33) <2002SL1928>. 

The ketone (48) can be obtained by Dieckmann cyclization, but this reaction failed for other isomers of (48) (72JCS(Pl)885). Friedel-Crafts cyclization has been used to obtain the N-tosyl ketone (49) (72JCS(Pl)2l3). Ring expansion reactions based on dibromocarbene additions have also been used to prepare benzo derivatives (72JCS(Pl)889). 

An alternative focus based on known antitumor activity of adriamycin-type systems stimulated the synthesis of the aza-anthraquinones 599 and 600 (Scheme 177) (84CC897). Thus, synergistic chloro-oxazoline directed metalation of 597 with methyllithium followed by treatment with 2,5-dimethoxybenzaldehyde and acid-promoted cyclization provided the lactone 598. Radical bromination and base-induced hydrolysis gave an intermediate keto acid which, upon Friedel-Crafts cyclization with methanesulfonic acid, led to the aza-anthraquinone 599 in modest yield. The azanaphthacene dione 600 was prepared by an analogous series of reactions starting with 597. 

Reaction between benzylmercaptans and haloacetic acids yield benzylmercaptoacetic acids (57) which, via their acid chlorides, undergo an intramolecular Friedel-Crafts cyclization to produce isothiochromanones as in Eq. (24).233-235 Attempts to cyclize 57 with sulfuric acid,... 

The reaction of 2-phenylethyl trimethylsilyl ether (298) with 1-iodoethyl trimethylsilyl ether yields 1-methylisochroman (78JOC3698). Displacement of iodide affords the oxonium iodide (299), which through loss of trimethylsilyl iodide gives the ether (300). Friedel-Crafts cyclization of the iodoether is considered to complete the synthesis (Scheme 83). 

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 cyclization products have been observed for the reaction of 277 with SO3 in the presence of dioxane as a mediator. The reaction has been shown to occur via /i-sultone 278, initially formed at —60 °C, which undergoes a spontaneous conversion to the final product 279 at > — 20 °C401. 

Carbon-carbon bond formation by Friedel-Crafts reactions was a versatile procedure for benzo- and dibenzothie-pines. Some new methods to synthesize thiepine rings by Friedel-Crafts-type reactions have been reported. Carbon-sulfur bond formation has been used for dihydro-, tetrahydrothiepines, and thiepanes. New cyclization methods involving carbon-sulfur and carbon-carbon bond formation have been added. 

The cyclization phase of the process is an intramolecular Friedel-Crafts acylation reaction. It requires conversion of the carboxylic acid to the acyl chloride (thionyl chloride is a suitable reagent) followed by treatment with aluminum chloride. 

Intramolecular Friedel-Crafts acylation reactions that produce five-membered or six-membered rings occur readily. Cyclization must take place at the position ortho to the reacting side chain. 

From a general survey of the literature it appears that the most common causes of poor yields in the Friedel-Crafts cyclization of acid chlorides are (a) reaction conditions which are too drastic, and (b) reagents of inadequate purity. The optimum conditions are those which are mild but still sufficient to complete cyclization. An apparent necessity for heating the reaction mixture in order to induce cyclization may be due, in part, to insufficient purity of reagents. The vital effect of the presence of impurities on the Friedel-Crafts reaction is fairly well known,62 63 but the advantage of mild conditions has not been generally appreciated. 

The Friedel-Crafts cyclization of the acid chloride (19a) occurs normally at — 70°, with the formation of the azacycloheptenone (20), but the sole product at 5° is 5,6-dihydro-5-tolylsulfonylphenanthridine (21). Similarly, the related acid (19b) gives phenanthridine when heated with polyphosphoric acid at 60°.53 Presumably a 5,6-dihydro-phenanthridine is formed which undergoes dehydrogenation in the reaction medium (cf. Das Gupta et aZ.48). 

When ( )-[(/i-arylethyl)vinyl]phenyliodonium tetrafluoroborates are heated in various solvents (at 40 °C or 60 °C), Friedel-Crafts cyclizations occur and dihydronaphthalenes are obtained (equation 26l)127. 6-Bromo-2i7-chromene can be prepared in the same way (equation 262). The alkenylation of benzene with 4-rm-butyl-1 -cyclohexenyl-(phenyl)iodonium tetrafiuoroborate, an intermolecular version of these reactions, has also been demonstrated (equation 263)127. From a stereochemical standpoint, the cyclization reactions are constrained to occur with inversion of configuration at vinyl carbon, while the cyclohexenylation of benzene must proceed with retention. 

A practical ligand-free palladium-catalyzed intramolecular reductive Heck cyclization was developed by Liu et al. <07TL2307>. The authors found that water was an essential component of the reaction mixture. Using a series of aryl halide intermediates this cyclization resulted in the desired 1,2,3,4-tetrahydroisoquinolines in high yields. Cook and co-workers found that InCU was an efficient catalyst for an intramolecular Friedel-Crafts cyclization of Ar-(4-bromobut-2-enyl)-A-(bcnzyl)-4-methylbcnzcncsulfonamidc to form the desired 3-substituted tetrahydroisoquinolines <07OL1311>. 

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