Two-step Friedel-Crafts alkylation

The CH3 group in o-nitrotoluene is an ortho, para director and the NO2 group is a meta director. Because the two substituents are ortho to each other, the ortho, para director must be introduced first. The synthesis thus involves two steps Friedel-Crafts alkylation followed by nitration. 

Toluene is an obvious starting material for the preparation of 4-fert-butyl-2-nitrotoluene. Two possibilities, both involving nitration and alkylation of toluene, present themselves the problem to be addressed is in what order to carry out the two steps. Friedel-Crafts alkylation must precede nitration. 

Figure 6.18 Schematical Synthesis of (AII-rac)-a-Tocopherol (Vitamin E) via Two-Step Friedel-Crafts Alkylation-Cyclization of 2,3,6-Trimethylhydroquinone (TMHQ) with Isophytol (IP).

Although the two-step method seems more roundabout, it must be used to synthesize certain alkyl benzenes that cannot be prepared by the one-step Friedel-Crafts alkylation because of rearrangements. 

Add the alkyl group by the two-step process—Friedel-Crafts acylation followed by reduction. It is not possible to prepare butylbenzene by a one-step Friedel-Crafts alkylation because of a rearrangement reaction (Problem 18.10). 

Draw the mechanism of the following reaction, which involves two consecutive Friedel-Crafts alkylations. When drawing the mechanism, do not try to draw the two alkylations as occurring simultaneously (such a mechanism would have too many curved arrows and too many simultaneous charges). First draw the steps that install one alkyl group, and then draw the steps that install the second alkyl group. 

Because acylation of an aromatic ring can be accomplished without rearrangement it is frequently used as the first step m a procedure for the alkylation of aromatic compounds by acylation-reduction As we saw m Section 12 6 Friedel-Crafts alkylation of ben zene with primary alkyl halides normally yields products having rearranged alkyl groups as substituents When a compound of the type ArCH2R is desired a two step sequence IS used m which the first step is a Friedel-Crafts acylation... 

Dichloroalkyl)chlorosilanes undergo the Friedel-Crafts alkylation type reaction with biphenyl in the presence of aluniinurn chloride catalyst to afford 9-((chlorosilyl)alkyl)fluorenes through two step reactions (Eq. (16)). The results obtained from the alkylation of biphenyl and the cyclization reaction to 5-membered-ring product are summarized in Table XIIE... 

This reaction takes place in two stages, the rate-determining step (rate constant kr) being the alkylation of the aromatic compound this is followed by a fast proton transfer to monomer [100]. The reaction is in fact a Friedel-Crafts alkylation of all the transfer... 

Regardless of whether the Pd-catalyzed coupling or alkyne metathesis is utilized to make PAEs, the critical step is the synthesis of the diiodoarene monomers. In this section some of the more interesting syntheses are showcased. The synthesis of dipropynyldi-tert-butylnaphthalene is shown in Scheme 5. Starting from naphthalene, Friedel-Crafts alkylation with 2-chloro-2-methylbutane gives a mixture of two di-tert-butylnaphthalenes that are separated by crystallization. Iodination of the correct isomer is followed by a Pd-catalyzed coupling of propyne to the diiodide to give the desired l,5-dipropynyl-3,8-di-tert-butyl-naphthalene [56] ready for ADIMET. 

It has been demonstrated9 that photo-protonation of 2-diphenylmethyl-l,3-dimethoxy-benzene (4) to the cyclohexadienyl cation (5) not only results in dissociative cleavage of the diphenylmethyl cation (the reverse of the step in a Friedel-Crafts alkylation that produces the cyclohexadienyl cation), but is accompanied by a surprising rearrangement to the isomeric 2,4-dimethoxybenzenium ion (6). This (see Scheme 3) represents the first example of a system where rearrangement involving two isomeric... 

HF calculations with the 6-31G(d) basis set were used to study the mechanism of the Michael addition (or Friedel-Crafts alkylation) reaction of indole with dimethyl alkylidenemalonate. This reaction proceeds through two transition states, TSi and TS2 in the first step, assumed to be rate determining, the new C-C bond is formed, whereas in the second step, proton transfer from indole to malonate occurs with the formation of the new C-H bond. The calculations show that the transfer and interaction of the 7r-electrons in the reactant molecules may play an important role in the cleavage of the original C=C bond and the formation of the new bonds (C-C and C-H) the electron transfer is believed to be the driving force for the reaction to occur. 

Aromatic compounds react mainly by electrophilic aromatic substitution, in which one or more ring hydrogens are replaced by various electrophiles. Typical reactions are chlorination, bromination, nitration, sulfonation, alkylation, and acylation (the last two are Friedel-Crafts reactions). The mechanism involves two steps addition of the electrophile to a ring carbon, to produce an intermediate benzenonium ion, followed by proton loss to again achieve the (now substituted) aromatic system. 

This two-step sequence can synthesize many alkylbenzenes that are impossible to make by direct alkylation. For example, we saw earlier that n-propylbenzene cannot be made by Friedel-Crafts alkylation. Benzene reacts with n-propyl chloride and AICI3 to give isopropylbenzene, together with some diisopropylbenzene. In the acylation, however, benzene reacts with propanoyl chloride and A1C13 to give ethyl phenyl ketone (propiophenone), which is easily reduced to n-propylbenzene. 

Ferrocene reacts with acetyl chloride and aluminum chloride to afford the acylated product (287) (Scheme 84). The Friedel-Crafts acylation of (284) is about 3.3 x 10 times faster than that of benzene. Use of these conditions it is difficult to avoid the formation of a disubstituted product unless only a stoichiometric amount of AlCft is used. Thus, while the acyl substituent present in (287) is somewhat deactivating, the relative rate of acylation of (287) is still rapid (1.9 x 10 faster than benzene). Formation of the diacylated product may be avoided by use of acetic anhydride and BF3-Et20. Electrophilic substitution of (284) under Vilsmeyer formylation, Maimich aminomethylation, or acetoxymercuration conditions gives (288), (289), and (290/291), respectively, in good yields. Racemic amine (289) (also available in two steps from (287)) is readily resolved, providing the classic entry to enantiomerically pure ferrocene derivatives that possess central chirality and/or planar chirality. Friedel Crafts alkylation of (284) proceeds with the formation of a mixture of mono- and polyalkyl-substituted ferrocenes. The reaction of (284) with other... 

Friedel-Crafts alkylation occurs by the usual two-step process addition of the carbocation followed by loss of a proton to form the alkylated product. 

Recall from Section 18.5C that propylbenzene cannot be prepared by a Friedel-Crafts alkylation. Instead, when benzene is treated with 1-chloropropane and AICI3, isopropylbenzene is formed by a rearrangement reaction. Propylbenzene can be made, however, by a two-step procedure using Friedel-Crafts acylation followed by reduction. 

S. L. Schreiber et al. carried out the total synthesis of the potent cytotoxin (+)-tri-0-methyl dynemicin A methyl ester. The key step was a regioselective Friedel-Crafts alkylation of an extremely sensitive aromatic enediyne with 3-bromo-4,7-dimethoxyphthalide. The coupling of these two fragments took place in the presence of silver triflate at 0 °C in 1 minute, and after methylation, gave a 1 1 mixture of diastereomers in 57% yield. 

In the laboratory of G.A. Posner, semisynthetic antimalarial trioxanes in the artemisinin family were prepared via an efficient Friedel-Crafts alkylation using a pyranosyi fluoride derived from the natural trioxane lactone artemisinin. The alkylating agent, pyranosyi fluoride, was prepared from the lactone in two steps reduction to the lactol followed by treatment with diethylaminosulfur trifluoride. The highly chemoselective alkylation was promoted by BF3-OEt2 and several electron-rich aromatic and heteroaromatic compounds were alkylated in moderate to high yield using this method. 

To produce the monoalkylated product in an acceptable yield, we can use a two step method. First we can acylate the benzene ring by using a Friedel-Crafts acylation (differs from Friedel-Crafts alkylation in that an acyl halide is... 

A new technique was developed recently, by introducing cationic to anionic transformation. A living carbocationic polymerization of isobutylene is carried out first. After it is complete, the ends of the chains are transformed quantitatively to polymerization-active anions. The additional blocks are then built by an anionic polymerization. A triblock polymer of poly(methyl methacrylate)-polyisobutylene-poly(methyl methacrylate) can thus be formed. The transformation involves several steps. In the first, a compound like toluene is Friedel-Craft alkylated by a,6t>"di-rerr-chloro-polyisobutylene. The ditolylpolyisobutylene which forms is lithiated in step two to form a,cu-dibenzyllithium polyisobutylene. It is then reacted with 1,1-diphenylethylene to give the corresponding dianion. After cooling to -78 °C and dilution, methyl methacrylate monomer is introduced for the second polymerization in step three. 

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