Friedel tandem

Fluoroalkjiations are frequentiy performed indirectly using tandem reactions. Arenes react with sodium borohydride in trifluoroacetic acid to afford otherwise difficult to obtain l,l,l-trifluoro-2,2-diarylethanes. Presumably sodium borohydride reacts initially with the trifluoroacetic acid to produce the trifluoroacetaldehyde or its equivalent, which rapidly undergoes Friedel-Crafts-type condensation to give an intermediate carbinol. The carbinol further alkylates ben2ene under the reaction conditions giving the observed product. The reaction with stericaHy crowded arenes such as mesitylene and durene... 

A similar synthetic strategy was applied in the synthesis of menogaril 83, another important anthracycline antitumour antibiotic, and to the synthesis of the tricyclic core of olivin 87, the aglycon of the antitumour antibiotic olivomycin [61,62]. In both cases a tandem benzannulation/Friedel-Crafts cyclisation sequence yielded the tetracyclic and tricyclic carbon core, respectively (Scheme 42). 

During the same year, both an acid-catalyzed [60] and a TiCl4-catalyzed [61] ortho-alkylation of anilines with styrene were published, but offering only a very low selectivity. The reaction of anisole and styrene catalyzed by Mo(CO)6 [62] afforded the corresponding branched diaryl product with a comparable yield and selectivity as shown by our protocol. Furthermore, Michelet and coworkers successfully employed substituted styrenes in a gold-catalyzed tandem Friedel-Crafts-type addition-carbocyclization reaction [63]. 

A synthesis of this compound was devised by Ohmizu, Iwasaki and co-workers and featured a three-component tandem conjugate addition/enolate trapping as key step (Scheme 12.24) [82]. In this synthesis, the acyl anion equivalent cyanohydrin 165 was first treated with LDA and allowed to react with methyl crotonate 166. The resulting enolate was trapped with 2,3,5-trimethoxy benzylbromide 168 to afford crude intermediate 169, which was immediately deprotected in situ to afford ketone product 170. Both the ester and the ketone functionalities were then reduced at low temperature to afford the corresponding diol 171. Upon treatment with trifluoroacetic acid, the desired Friedel-Craft cyclization adduct 172 was obtained. The latter tricyclic compound was then further elaborated to the final target 164 through a short sequence of standard transformations. 

The synthesis of the optically active chroman 489 can be achieved by use of a catalytic asymmetric tandem oxa-Michael addition Friedel-Crafts alkylation sequence between 3-methoxyphenol and (/. (-methyl 2-oxo-4-phenylbut-3-enoate. The chiral C2-symmetric box managanese(n)- complex 490 exerts excellent stereocontrol upon the reaction (Equation 200) <20030BC1953>, whereas only moderate enantioselectivity is observed in the presence of a chiral C2-symmetric 2,2 -bipyridyl copper(n)- complex (42% = ee) <20050L901>. 

The synthesis of 11-deoxydaunomycinone by Wulff and Xu is presented in Scheme 39 and involves the benzannulation of the non-chelated o-methoxyphenyl complex (280) with the alkyne (281). ° The utilization of a t-butyl ester in the alkyne (281) makes possible a one-pot construction of the tetracyclic dione (282) via a tandem benzannulation-Friedel-Cr ts cyclization. After the reaction between the... 

Nazarov-Friedel-Crafts reaction tandem. l-Alkenyl-2,2-dichlorocyclopropyl... 

In a series of papers, Wong and co-workers detailed the preparation and use of 3,4-bis(trimethylsilyl)furans. Thus, after heating an equimolar mixture of 4-phenyloxazole and bis(trimethylsilyl)acetylene with 5 mol % of triethylamine in a sealed tube at 250°C for 2 days, an 80% yield of the desired furan 130 was obtained (Fig. 3.38). If the same reaction is performed in the presence of a catalytic amount of formic or trifluoroacetic acid instead of triethylamine, the analogous 2,4-bis-trimethylsilylfuran is obtained in good yield. Furan 130 itself reacts with alkynes in a tandem Diels-Alder retro-Diels-Alder sequence to provide other fiirans, e.g., 3,4-furandicarboxylic acid dimethyl ester 131. Friedel-Crafts acylations can also be performed using 130. In addition, 130 reacted with boron... 

A tandem, double Friedel-Crafts reaction of 2-formylbiphenyl (182) with 2-substituted indoles leading to 9-(3-indolyl)fluorene derivatives (183) with up to 96% ee which was catalyzed by chiral phosphoric acid ( S)-(184), have been reported by You and co-workers (Scheme 50). ... 

A tandem phospha Friedel—Crafts reaction has been used to transform dichloro(m-teraryl)phosphine into triarylphosphine derivatives, such as (1), where the curved n-conjugated framework allows extended conjugation over the whole molecule. The reaction of the metallabenzyne (2) with electrophiles shows that it exhibits aromatic... 

Reactions of phenols and acyl chlorides in the presence of TfOH occur with 0-acylation (Friedel-Crafts acylation), while with concentrated TfOH, C-acylation (Fries rearrangement) is observed. A tandem Prins/Friedel-Crafts reaction has been reported for the construction of the indeno-tetrahydropyridine core of the haouamine alkaloids (Scheme 92). ... 

Alkynylaziridines carrying an aryl group have been reported to give spiro [isochroman-4,2 -pyrrolines] with gold salts as catalysts and involve a Friedel-Crafts-type intramolecular reaction followed by cyclization of the aminoaUene intermediate, both initiated by the dual a and n Lewis acidities of gold. Tandem Au(in)-catalysed heterocyclization/Nazarov cyclizations leading to substituted carbocycle fused fiirans have been reported and computational studies support the function of solvent (Scheme 114). ° ... 

It was also possible to perform the pyrrole 5 Michael addition with a variety of a,p-unsaturated ketones 2 catalyzed by MSSA in the same fashion, affording 2-substituted pyrroles 6 in good yields (Scheme 1.3b). Furthermore, MSSA was used as a solid acid heterogeneous catalyst to synthesize 1,1,3-triindolyl compounds through the tandem Michael addition and Friedel-Craft reaction of a, P-unsaturated aldehydes or ketones and indole (3) (Scheme 1.4). The authors found two protocols of general applicability employing 1 mmol of a,P-unsaturated compound and 4 mmol... 

An interesting one-pot tandem Lewis Acid Friedel-Crafts intermolecular acylation method with concomittant in situ reduction of the aryl ketone product has been reported by Jaxa-Chamiec. Treatment of toluene (13) with 4-chlorobutanoyl chloride and AICI3 gave an intermediate ketone 15 which was reduced in situ by use of either of EtsSiH of PMSH (polymethylhydroxysilane) to afford 16 in an impressive 85% yield from 13. 

Lewis acid conditions gave an intermediate F-C acylation adduct regioselectively which underwent decarboxylation at 100 °C to afford 1-indanone 24 in 85-90% yield. " An impressive example of reaction regioselectivity involving a tandem Friedel-Crafts acylation-alkylation sequence is the elegant synthesis of benzopyrrole calcium channel blocker 25... 

Polysubstituted 3,4-dihydro-3-nitro-2ff-chromans are obtained from the enantioselective Michael—Michael cascade reaction of chalcone enolates and nitromethane catalyzed by bifunctional thiourea 19 (Scheme 31) (13JOC6488) and tandem Friedel—Crafts alkylation—Michael addition reaction of nitroolefin enoates and 1-methylindole promoted by Zn(OTf)2 (13S601).A squaramide-tertiary amine catalyst promotes the asymmetric sulfa-Michael—Michael cascade reaction of thiosalicylates with nitroalkene enoates which leads to polysubstituted chromans in high yields with excellent stereoselectivities (13OL1190). 

T. Arai, N. Yokoyama, Angew. Chem. Int. Ed. 2008, 47,4989-4992. Tandem catalytic asymmetric Friedel-Crafts/Henry reaction control of three contiguous acyclic stereocenters. 

Scheme 13.18 Tandem carboalkoxylation-Friedel-Crafts alkylation catalyzed by Yb(OTf)3.

In 2002, Wang and Yu reported that tris(2-pyridyl)-phosphine complex [P(2-py)3 W(C0)(N0)2] (Bp4)2 was found to be an efficient Lewis acid catalyst for the tandem reactions of Friedel-Crafts/aldehyde cyclotrimerization of (151) and (26a) that lead to the formation of a series of hyperbranched star polymers (153) (Scheme 16.40) [47]. These tandem reactions are carried out in neat substrates at ambient temperature with a low catalyst loading (0.05-1 mol%) to afford quantitative insoluble polymers almost instantaneously. The hyperbranched star structure and high contents of heterocycles are difficult to generate through conventional synthetic methods, and they are believed to be important elements for high-temperature polymers. 

Scheme 2.36 Three-component tandem ot-alkylation-double Friedel-Crafts reaction catalysed by a chiral thiourea, an iV-Boc-protected amino acid, and a chiral phosphoric acid.

Scheme 7.66 Tandem double Friedel Crafts reaction catalysed by chiral thiourea catalysis and gold catalysis followed by a rearrangement.

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