Benzene by acylation-reduction

Besides avoiding carbocation rearrangements, another advantage of preparing alkyl-substituted benzenes by acylation-reduction rather than by direct alkylahon is that a large excess of benzene does not have to be used (Sechon 15.14). Unlike alkyl-substituted benzenes, which are morereachve than benzene (Section 16.3), acyl-substituted benzenes are less reactive than benzene, so they will not undergo addihonal Friedel-Crafts reactions. 

Because acylation of an aromatic ring can be accomplished without reanangement, it is frequently used as the first step in a procedure for the alkylation of aromatic compounds by acylation-reduction. As we saw in Section 12.6, Friedel-Crafts alkylation of benzene with primary alkyl halides nonrrally yields products having rearranged alkyl groups as substituents. When a compound of the type ArCFl2R is desued, a two-step sequence is used in which the first step is a Friedel-Crafts acylation. 

Because polyacylation does not occur (cf. p.145), it is often preferable to prepare alkyl-benzenes by acylation, followed by Clemmensen or other reduction, rather than by direct alkylation ... 

Representative Electrophilic Aromatic Substitution Reactions of Benzene 457 Mechanistic Principles of Electrophilic Aromatic Substitution 458 Nitration of Benzene 459 Sulfonation of Benzene 461 Halogenation of Benzene 462 Biosynthetic Halogenation 464 Friedel-Crafts Alkylation of Benzene Friedel-Crafts Acylation of Benzene Synthesis of Alkylbenzenes by Acylation-Reduction 469 Rate and Regioselectivity in Electrophilic Aromatic Substitution 470 Rate and Regioselectivity in the Nitration ofToluene 472... 

Compounds 15 can be prepared either by acylation of bis(o-aminophenyl) ditelluride (88KGS276 89KGS120) or by reduction of A -acyl-2-trichlorotelluro-benzenes with sodium sulfide (88MI1). 

V-Acylsaccharins prepared by treatment of the sodium salt of saccharin with acyl chlorides were reduced by 0.5 molar amounts of sodium bis(2-methoxyethoxy)aluminum hydride in benzene at 0-5° to give 63-80% yields of aliphatic, aromatic and unsaturated aldehydes [1108 Fair yields (45-58%) of some aliphatic aldehydes were obtained by electrolytic reduction of tertiary and even secondary amides in undivided cells fitted with platinum electrodes and filled with solutions of lithium chloride in methylamine. However, many secondary and especially primary amides gave 51-97% yields of alcohols under the same conditions [130]. 

In order to prepare the cyclohexenaldehyde 8, 3-hydroxy-2-pyrone 14 and ethyl 4-hydroxy-2-methyl-2-butenoate 15 are subjected to a Diels-Alder reaction in the presence of phenylboronic acid which arranges both reactants to the mixed boro-nate ester 19 as a template to enable a more efficient intramolecular Diels-Alder reaction with optimal control of the regiochemical course of the reaction. Refluxing in benzene affords the tricyclic boronate 20 as primary product. This liberates the intermediate cycloadduct 21 upon transesterification with 2,2-dimethylpropane-l,3-diol which, on its part, relaxes to the lactone 22. Excessive i-butyldimethyl-silyltriflate (TBSTf) in dichloromethane with 2,6-lutidine and 4-7V,A-dimethyl-aminopyridine (DMAP) as acylation catalysts protects both OH goups so that the primary alcohol 23 is obtained by subsequent reduction with lithiumaluminum-hydride in ether. 

Labeling of phenobarbital, a barbiturate used in the treatment of convulsions, was carried out by acylation of p-aminophenobarbital 15 by the acid chloride of cymantrene 11 (Scheme 8.8). Synthesis of 15 was performed by nitration of the benzene ring of phenobarbital [35] to give a mixture of m- andp-nitrophenobarbital 13 and 14 followed by reduction of p-nitrophenobarbital by hydrogenation in the presence of palladium on charcoal [36]. 

In this case each of the products 52 and 53 may be considered to result from Cy 6, from Cy 5, or from both. On the basis of simpler examples it appears that a high selectivity toward the (Cy 6) radical in the Cy6/Cy5 case is the rule. For instance, 5-hexenal with BP in cyclohexane at 80°C gives cyclohexanone (41% yield) resulting from the (Cy 6) radical, with no trace of 2-methylcyclopentanone which would arise from the (Cy 5) radical.A similar result has been observed by Cekovic, who generated the unsaturated acyl radical by tributylstannyl reduction of the corresponding acyl chloride in boiling benzene. In this way 5-hexenoyl chloride afforded cyclohexanone in 36% yield with no trace of Cy5 products. 

The selectivity of the Friedel-Crafts acylation for single substitution allows for the selective introduction of carbon chains into the benzene nucleus, a task that proved difficult to accomplish by Friedel-Crafts alkylation (Section 15-12). Since we know how to convert the carbonyl function into an alcohol by hydride reduction (Section 8-6) and the hydroxy substituent into a leaving group that can be further reduced by hydride (Section 8-7), we can synthesize the corresponding hydrocarbon. This sequence of acylation-reduction... 

The ready reduction of acyl- to alkylarenes also provides a way to synthesize alkyl-benzenes without the complication of alkyl group rearrangement and overalkylation. For example, butylbenzene is best synthesized by the sequence of Friedel-Crafts acylation with butanoyl chloride, followed by Clemmensen reduction. 

We have already seen that the products of Friedel-Crafts acylations may be converted into alkyl benzenes by using Cletnmensen reduction. Wolff-Kishner deoxygenation also is frequently employed for this purpose and is particularly useful for add-sensitive, base-stable substrates. 

Outline a synthesis of 2-methyl-l-phenylpropane (iso-butylbenzene) starting from benzene using a Friedel-Crafts reaction. Answer Friedel—Crafts acylation followed by Clemmensen reduction. 

At first sight, this looks demanding both of the substituents are ortho,para-diiecting—but they are meta to each other. But both of the substituents are usually prepared by reductions—the amino group is usually prepared by the reduction of a nitro group, and the ethyl substituent could be prepared by the reduction of an acyl benzene. So in a new form, our problem would be to make 13.8 ... 

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