Acylation-reduction, alkylation benzene

Isoquinoline can be reduced quantitatively over platinum in acidic media to a mixture of i j -decahydroisoquinoline [2744-08-3] and /n j -decahydroisoquinoline [2744-09-4] (32). Hydrogenation with platinum oxide in strong acid, but under mild conditions, selectively reduces the benzene ring and leads to a 90% yield of 5,6,7,8-tetrahydroisoquinoline [36556-06-6] (32,33). Sodium hydride, in dipolar aprotic solvents like hexamethylphosphoric triamide, reduces isoquinoline in quantitative yield to the sodium adduct [81045-34-3] (25) (152). The adduct reacts with acid chlorides or anhydrides to give N-acyl derivatives which are converted to 4-substituted 1,2-dihydroisoquinolines. Sodium borohydride and carboxylic acids combine to provide a one-step reduction—alkylation (35). Sodium cyanoborohydride reduces isoquinoline under similar conditions without N-alkylation to give... 

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. 

Methods of synthesis for carboxylic acids include (1) oxidation of alkyl-benzenes, (2) oxidative cleavage of alkenes, (3) oxidation of primary alcohols or aldehydes, (4) hydrolysis of nitriles, and (5) reaction of Grignard reagents with CO2 (carboxylation). General reactions of carboxylic acids include (1) loss of the acidic proton, (2) nucleophilic acyl substitution at the carbonyl group, (3) substitution on the a carbon, and (4) reduction. 

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 ... 

This method is used for the reduction of acyl benzenes to alkyl benzenes, but it also reduces aldehydes and ketones to alkanes. 

Aryl amine intermediates for azo and triphenylmethane dyes, as well as a number of vat dye (anthraquinone) intermediates, are made from compounds such as benzene, alkyl benzenes (toluene and higher homologues), phenol and naphthalene. A limited number of reactions are used to produce the most important dye intermediates, including nitration, reduction, halogenation, sulfonation, /V-alkylation, /V-acylation and alkali fusion33,34. 

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. 

Another category of reductions involves aryl ketones. The Friedel-Crafts acylation reaction reacts benzene with an acid chloride such as butanoyl chloride (49) to give an aryl ketone, 50. Complete removal of the oxygen from this ketone constitutes a method to make straight-chain arenes, which cannot be prepared via Friedel-Crafts alkylation (see Section 21.3.2). At least two classical methods are used to accomplish this reaction, which is formally a reduction. If 50 is treated with zinc metal in HCl, the product is 1-phenylbutane, 105. This acidic reduction involves a mineral acid such as HCl and an active metal, and it is called the Clemmensen reduction. 

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... 

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. 

Tetralone 31 could also be synthesized much more efficiently by employing a chemoselective ketone reduction of 32 to give the lactone 33. A double Friedel-Crafts alkylation/acylation sequence employing a variety of Lewis or protic acids and benzene gave the tetralone 31 directly. Triflic acid and HF produced the highest yields of tetralone, presumably through the intermediacy of the diaryl acid 34 (Scheme 6)... 

Unlike alkylation, acylation is controlled easily to give monosubstitution, because once an acyl group is attached to a benzene ring, it is not possible to introduce a second acyl group into the same ring. Because of this, a convenient synthesis of alkylbenzenes starts with acylation, followed by reduction of the carbonyl group with zinc and hydrochloric acid (Section 16-6). For example, propylbenzene is prepared best by this two-step route because, as we have noted, the direct alkylation of benzene with propyl chloride produces considerable amounts of isopropylbenzene and polysubstitution products ... 

Finally, as examples of similar types of reactions, photolytic treatment of O-acyl ester (D) of benzophenone oxime, A-acyloxy-phthalimide (E), and O-acyl ester (F) of A-hydroxy-2-pyridone with a mercury lamp generates the corresponding alkyl radicals via decarboxylation. However, these reactions can be used only for the alkylation of aromatics (solvents such as benzene) and reduction [86-89], so their synthetic utility is extremely limited. 

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