Friedel-Crafts adducts

Answer Disconnection of the ether reveals a 1,2-diX compound (24) and an alcohol (25) easily made by reduction from a Friedel-Crafts adduct (26). 

Akiyama and coworkers extended the scope of electrophiles applicable to asymmetric Brpnsted acid catalysis with chiral phosphoric acids to nitroalkenes (Scheme 57). The Friedel-Crafts alkylation of indoles 29 with aromatic and aliphatic nitroalkenes 142 in the presence of BINOL phosphate (7 )-3r (10 mol%, R = SiPhj) and 3-A molecular sieves provided Friedel-Crafts adducts 143 in high yields and enantioselectivities (57 to >99%, 88-94% ee) [81]. The use of molecular sieves turned out to be critical and significantly improved both the yields and enantioselectivities. 

Scheme 6.5 Nitroalkene activation via double hydrogenbonding enhances electrophilicity at (J-position and facilitated Michael-type attack of the (hetero)aromatic nucleophile resulting in Friedel-Crafts adducts.

To demonstrate the catalytic efficiency of thiourea 9 and urea 16 (each 10mol% loading), Friedel-Crafts alkylation of various aromatic and heteroaromatic substrates was performed at room temperature in toluene as well as under solvent-free conditions. The results for the products 1-7 shown in Scheme 6.6 revealed that in all cases the 9-catalyzed reactions gave higher yields. In toluene N-methylpyrroIe reacted smoothly to give the 2-substituted Friedel-Crafts adduct 1, while the adducts 3-5 and 7 formed slowly and required longer reaction times (72 h). The... 

Black, K.D., andF.D. Gunstone, The Friedel-Crafts Adducts of Methyl Oleate with Benzene and Toluene, Chem. Phys. Lipids 79 87—94 (1996). 

It is significant that when the reaction was carried out by first pre-treating the mixture of KCN, benzene and alumina with ultrasound for 3 h followed by conventional mechanical agitation for 24 h only 14% of the Friedel-Crafts adducts were formed and there was no substitution. Clearly simultaneous sonication is essential for the nucleophilic substitution reaction to take place. In the absence of KCN the mixture of toluene and benzyl bromide gave the Friedel-Crafts adducts smoothly in high yield (80%) in 3 h either with conventional agitation or under sonication. These results indicate that ultrasound assists the contact of KCN with alumina to decrease the catalytic ability of alumina for a Friedel-Crafts reaction and to enhance nucleophilic attack by CN ion at the alumina surface. 

First of all, two examples of the change in selectivity of catalytic reactions performed in "silent" or ultrasound conditions should be recalled (for a discussion, see Ch. 4, p. 145). The classical paper by Ando 2 refers to the reaction between benzyl bromide and potassium cyanide on alumina in toluene. In the sonochemical reaction, the main product is benzyl cyanide, while in a silent condition it is the Friedel-Craft adduct. When the Strecker synthesis of a-amino nitriles from an aldehyde, potassium cyanide, and an amine in acetonitrile is performed with alumina and ultrasound, the main product (selectivity = 90%) is the a-amino nitrile. In the same conditions, except for the absence of ultrasoimd, the selectivity for the same product is only 64%. If ultrasound is used without alumina, the selectivity is 23%, and 6% if only stirring is used. 

This phosphoric acid derived from (i )-BINOL was also applied by Akiyama et al. as an organocatalyst to promote the highly enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes, generating the corresponding Friedel-Crafts adducts with high yields and excellent enantioselectivities of up to 94% ee for a broad range of substrates in the presence of 3-A molecular sieves (Scheme 10.2). ... 

The annelation of the tricarbonyldiene-iron complex (200) of myrcene, to (201), has been described via the Friedel-Crafts adduct derived from oxalyl chloride (Scheme 36), and in an approach to the simultaneous construction of a seven-ring carbocycle fused to an a-methylene-y-butyrolactone unit, Semmelhack and Wu ... 

The first report of the enantioselective Friedel-Crafts reaction catalyzed by phosphoric acid 1 was presented by Terada and coworkers (Scheme 11.19) [34]. They reported the 1,2-aza-Friedel-Crafts reaction of 2-methoxyfuran (72) with N-Boc aldimines 5 by means of a catalytic amount of chiral phosphoric acid. In this reaction, stericaUy hindered 3,5-dimesitylphenyl-substituted catalyst Ij was the most effective and the corresponding Friedel-Crafts adducts 73 were obtained with excellent enantioselectivities (86-97% ee). Notably, the reaction could be performed in the presence of as low as 0.5 mol% of Ij without any loss of selectivity (Ar = Ph, 95% yield, 97% ee). 

You and coworkers employed 4,7-dihydroindoles 79 instead of indoles 75 in the Friedel-Crafts reaction with nitroalkenes 77 (Scheme 11.22) [41]. Catalyst Ig with a 9-anthryl group displayed excellent performance. The notable point in this reaction is the use of the syringe pump technique to achieve high enantioselectivities and suppress the background reaction. Subsequent oxidation of Friedel-Crafts adducts 80 by p-benzoquinone afforded 2-substituted indole derivatives 81 in excellent yields without racemization. This approach and the simple asymmetric Friedel-Crafts reaction of indoles are complementary methods for obtaining the different substitution patterns of chiral indole derivatives. 

Figure 11.5 Absolute stereochemistry of Friedel-Crafts adducts 83 and 84.

The key step of this synthetic route is an iminium organocatalyzed Friedel-Crafts reaction of an in situ generated activated boronate 20 intermediate and crotonaldehyde (21), forming a non-traditional Friedel-Crafts adduct 22, as the result of an unexplored regjoselectivity (C2 versus C3). Additionally, the feasible structural variations on the starting heteroaryl trifluoroborate salt could allow straightforward access to various natural product analogues. 

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