Retro-Friedel-Crafts reaction

The only way to functionalize the upper rim of 4-f-butylcalix[4]arene is to remove the f-butyl group and replace it with something more useful. Two methods have been reported by which this de-ferf-butylation, sometimes referred to by the more evocative term of neutering , may be achieved. The first method is probably the more conventional of the two and involves the use of aluminium trichloride and phenol. It is in essence a Friedel-Crafts reaction where a f-butyl group is attached to either benzene or phenol the innovation is that the source of the f-butyl substituent comes from the calixarene [1]. This retro-Friedel-Crafts reaction is thus an effective method for transalkylation that removes an unwanted alkyl group from calix[4]arenes as shown in Figures 3.10 and 3.11. Moreover, it is possible to subtly alter the reaction conditions and partially de-ferf-butylate... 

The retro-synthetic analysis ouflined in Scheme 6.1 shows that in addition to the Pictet-Spengler route previously used by discovery, several others are also possible. The Bischler-Napieralski condensation of 5-methyltryptamine and 2-cyclohexylacetic acid chloride as well as the Friedel-Crafts reaction of the N-protected 5-methyltryptamine allows preparation of the prochiral imine derivative 7. The 2-cyclohexylmethyl side chain may also be introduced via alkylating an unsubstituted THpC by 2-cyclohexylmethyl chloride. As shown in Scheme 6.1, all of these routes involve 5-methyltryptamine as a common building block. 

Fischer and Hafner have developed the first general synthetic method from metal halides, AICI3 and Al. This method is not applicable to functional arenes, mostly because of the exothermic complexation of the heteroatom by AICI3. This method also leads to the isomerization of the methyl- and alkylaromatics by retro-Friedel-Crafts reaction, especially for the 2 - and 3 -row transition metals. It has been applied with success for V, Cr, Fe, Co and Ni with benzene and its polymethyl derivatives, in particular QMeg with Co and Ni. The monocations [Cr(r -arene)2] are produced after hydrolysis, and the dications are obtained with the P -row transition metals ... 

Mohanty et al. were the first to introduce pendent r-butyl groups in die polymer backbones. The resulting material was quite soluble in aprotic dipolar solvents.83 The PEEK precursors were prepared under a mild reaction condition at 170°C. The polymer precursor can be converted to PEEK in die presence of Lewis acid catalyst A1C13 via a retro Friedel-Crafts alkylation. Approximately 50% of die rerr-butyl substitutes were removed due to die insolubility of the product in die solvent used. Later, Risse et al. showed diat complete cleavage of f< rf-butyl substitutes could be achieved using a strong Lewis acid CF3SO3H as both die catalyst and the reaction medium (Scheme 6.15).84... 

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... 

Disconnection of acetophenone TM 2.1a is denoted as re/ro-Friedel-Crafts (retro-F.-C.) since its synthesis is completed by the Friedel-Cralits reaction. It is important to note that there is no need to generate the phenyl anion in the synthetic direction since benzene is an acceptable reagent for highly reactive acetyl chloride activated by Lewis acid. 

In the refro-Mannich step, disconnection of two bonds affords three reagents, ketone TM 4.16b, formaldehyde and morpholine derivative TM 4.16c. Two consecutive retro-Friedel-Crafts disconnections of TM 4.16b result in the available commodities as starting materials. The disconnection of TM 4.16c in Scheme 4.48 is one among more possible ones and corresponds to industrial synthesis. Scheme 4.49 outlines the s3mthesis of fenpropimorph and indicates some reaction conditions on the industrial scale. 

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