Friedel intramolecular cyclizations

The synthesis of thieno[3,2-c]benzazepine derivative 106b has been reported by Friedel-Crafts intramolecular cyclization of isocyanates 105 (Equation (15) (2002S355)). Noteworthy, lactam 106b is formed in 51% yield, while dione 106a can not be obtained due to the electron-withdrawing effect of the carbonyl group. 

Benzopyrrolo[l,2]oxazepines 68 (X = O) can be obtained from the corresponding acids 67 by an intramolecular Friedel-Crafts acylation (Scheme 14, Section 2.1.1.5 (1996JMC3435, 2002JMC4276)). Similarly, pyrrolo-benzoxazepines 261 are accessible by intramolecular Friedel-Crafts cyclization of acids 260... 

Related to these intramolecular Friedel-Crafts cyclizations are the aluminum chloride and PPA catalyzed ring closures of 3-phenylpropyl iso- and thioiso-cyanates to 2H-2-benzazepin-l-ones and their -1-thiones respectively (79H(12)131i, 77JCS(Pl)2357). The method has also been applied to the cyclization of o-isocyanatodiphenylmethanes to 5,6-dihydro[6,e]azepin-6-ones (65HCA336). 

Quallich and Woodall described the first asymmetric synthesis utilizing a catalytic enantioselective reduction of the ketoester 35 with (S)-terahydro-l-methyl-3,3-diphenyl-lH,3W-pyrrolo[l,2-c][l,3.2]oxazaborole (CBS) to give the desired hydroxyester 36 (90% ee). After mesylation, Sn2 displacement with a higher-order cuprate derived from copper cyanide gave the diaryl r-butyl ester 37 with good chirality transfer. Intramolecular Friedel-Crafts cyclization gave the tetralone 31 in 90% ee (Scheme 7). ... 

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 intramolecular cyclization of 2-(3,4-dimethoxybenzyl)-3-(N-ben-zyl-4-piperidinyl)propionic acid 1 followed by treatment with HC1 [18] as shown in Scheme 3.6. Cyclization of compound 1 was carried out under Friedel-Crafts reaction conditions, optionally with previous derivatization of the carboxylic group to a halocarbonyl group. Preferably, the cyclization process was carried out in the presence of protic acids or Lewis acids or a mixture of protic and Lewis acids gives donepezil 2 which is converted to the hydrochloride salt 3. 

A Lewis-acid-promoted Friedel-Crafts intramolecular cyclization of 2-O-benzyl ethers 583 provides fused isochro-mans 584. The reaction unexpectedly fails in the absence of a TMS substituent on the aromatic ring, but this can be easily removed upon treatment of the cyclized product with TFA. The silyl group is proposed to promote the cyclization by stabilization of a carbocationic intermediate (Equation 241) <2002OL3797>. 

The major route to isothiochromans involves intramolecular cyclization under Friedel-Crafts conditions during which either the C(4)-ring or C(l)-ring bond is formed as illustrated in Equations (162)—(168). Of special note is the synthesis of both (R)- and (.y)-4-ethylisothiochroman using this methodology (Equations 162 and 163). 

The intramolecular Friedel-Crafts cyclization of 3-(4-chlorophenylthio)butanoic acid to 6-chloro-2-methylthio-chroman-4-one is efficiently catalyzed by Bi and rare-earth triflates (Equation 195) <2003TL4007>. The cyclization of (3-arylthiopropanoic acids to thiochroman-4-ones by PPA is facilitated by microwave irradiation. Formation of these acids from the sodium salts of thiophenols and 3-chloropropanoic acid is similarly accelerated <2004JCM394>. 

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>. 

Cyclization of allylic sulfones In the presence of aluminum chloride, allylic sul-fones can undergo intramolecular cyclization of the Friedel-Crafts type with displacement of the sulfone group. Examples are the cyclization of 1 and 4 to 2 and 5. respectively. 

Based on the benzyl derivative (26), the first stable carborane-containing simple enol (27) was synthesized2 (Scheme 8). The acid chloride (28) readily enters into a Friedel-Crafts reaction with mesitylene to give ketone (29). Under the action of BuLi on a benzene-ether solution of ketone (29) enolate (30) is formed. Treatment of the latter with diluted HC1 solution results in enol (27). Starting from the benzyl derivative (31), carboranyl-substituted indene (32) was synthesized by intramolecular cyclization with a formation of ketone (33), whose reduction (34) followed by dehydration results in (32) (Scheme 9). 

Table 18. Intramolecular cyclization via Friedel-Crafts alkylation. Ar-H Titanium salt Product...

An intramolecular cychzation of an aryl ether to the carbonyl of a pendant aryl ketone, on clay with microwave irradiation, led to a benzofuran via Friedel-Crafts cyclization and ehmination of water. 

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