Friedel-Crafts disconnection

Direct Friedel-Crafts disconnection is no good (p T 39 ) as it led to the other isomer. Preliminary C-Cl disconnection is the answer, with anhydride (2) providing the chemoselectivity. 

Answer Friedel-Crafts disconnection requires the half ester, half acid-chloride (16) which we could make from Daleic anhydride (17) as on p T 39. An easier solution is to use the anhydride in the Friedel-Crafts reaction. The two methyl groups cooperate to activate the right position and the yield is excellent,... 

Answer Friedel-Crafts disconnection reveals 1,2-diX compound (21) easily made from thiol (22) and chloro-acetic acid. Thiol (22) can be made by the thiourea route (p T 37 ). 

Either Friedel-Crafts disconnection will do, but o-toluic acid (27) is available from the oxidation of o-xylene so that route is preferred as no separation of o, p-isomers is involved. 

Friedel-Crafts disconnection (38a) Is unambiguous because of the synunetry of (39). Further disconnection requires FGA. A carbonyl group next to the aromatic ring gives a 1,4-dicarbonyl compound (40) and allows disconnection of an acyl anion equivalent to give an enone (41). This can be made by Mannich reaction from (42). 

In Corey s synthesis16 of a marine allomone, he wanted the cyclic ketone 68. The Friedel-Crafts disconnection gives some derivative of the carboxylic acid 69 and disconnection between the branchpoints gives the unsaturated acid 70 (it doesn t matter whether this is the E- or Z- isomer as the alkene disappears). 

The alternative Friedel-Crafts disconnection requires (18)—a rather unstable compound. This is hardly a problem as (18) is unstable because it cyclises readily to (17). The reaction occurs at 35 C and (18) need not be... 

FGA has an important part to play in the synthesis of functionalised compounds too. In the synthesis of tetralone (47) it solves a problem of regio-selectivity. Friedel-Crafts disconnection of both Ar-C bonds is unacceptable as acylation will occur para to the MeO group and the wrong isomer (48) will be formed. 

The alternative strategy is to leave the three-membered ring alone and to use a Friedel-Crafts disconnection. Intermediate (37) would be easy to make if the 1X-CH2 group were not there (38) as it would then be a diazoester addition to styrene, a route we discussed in Chapter 30. We can use our chain lengthening procedure (Chapter 31) to go from (38) to (37). 

The coronary vasodilator Benziodarone (27) is an iodination product of phenol (28). Friedel-Crafts disconnection is sensible as the a-position on the benzofuran (29) is blocked. The synthesis of (29) is discussed in the next section. 

Disconnection of the benzofuran (29) by the usual methods gives a phenolic ketone (33). Further Friedel-Crafts disconnection, e.g. to (34), is unpromising as the carbonyl group in (33) is in a most unhelpful position. If it were one nearer the ring, (33) could be made by a Friedel-Crafts reaction one atom further away and we could use FGA (Chapter 24). 

Typical Friedel-Crafts disconnections involving alcohol and alkene precursors are... 

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. 

The classic approach to A -acetylated para-aminophenols comprises the nitration of phenol, reduction of the nitro to amino group and A -acetylation. The acetylation step proceeds with limited chemoselectivity, however, accompanied by the formation of A, A -diacetylated and 0-acetylated products. The proposed retrosynthesis represents an elegant solution retra-Beckmann to oxime as the key step, followed by FGI to ketone and retro-Friedel-Crafts disconnection to phenol (Scheme 8.2). 

The most promising route arose from a retrosynihetic analysis which incorporated two Friedel-Crafts reactions (Scheme 12). The first disconnection involves formation of a 7-membered ring, which has recent precedent in Friedel-Crafts chemistry of furans.(27) Addition of a ketone (in a retrosynihetic sense) then generates a second Friedel-Crafts disconnection, and a well-precedented starting material derived fi om 3-carboxyfuran.(2[Pg.52]

TM (14) This time the usual disconnection corresponds to a Friedel-Crafts acylation Cp T 7 ),... 

Answer The nitro groups must be put in by nitration but the orientation is wrong. The methyl group cannot be disconnected as a Friedel-Crafts alkylation would never work on the available but extremely unreactive m-dinitro benzene. The solution (guideline 5) is to introduce a dummy amino group in such a position that it can activali... 

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). 

Optically active ketone (6) was needed for a study of asymmetric induction It could be made from acid (7) by a Friedel Crafts route or from nitrile (8) by Grignard addition, but neither of these compounds could be made by alkylation as the branchpoint is on the 3 carbon ( in each). The 1,3 C-C disconnection, e.g. (6b) is not good as it destroys the chiral centre. 

Answer Ester disconnection gives a tertiary alcohol (4S), Of the three possible Grignard disconnections, (a) is most helpful as it requires the Mannich product (49) of an aryl ketone (50) available by the Friedel-Crafts reaction. 

A solution to all these problems can be found by an alternative disconnection. Enone (1) could be made by an aliphatic Friedel-Crafts reaction from acid (7). Disconnection of the allyl group now gives synthon (8) and the regioselectivity problem disappears. 

Two main limitations of CHAOS are i) it does not recognise stereochemical features and ii) it does not deal with typical aromatic electrophilic substitution (only Friedel-Craft-type disconnections are performed). 

As mentioned in the introduction, recent synthetic developments now allow access to the 1,2-thiazine structure via disconnection type C (Figure 23). This process can be accomplished by a Friedel-Crafts-type cyclization of sulfamoyl chlorides. The initial report of this reaction utilized a stoichometric amount of aluminium chloride promoter <19920PP463>. Recently, however, A -ethyl phenethylsulfamoyl chloride 214 was shown to undergo Friedel-Crafts cyclization to form sultam 215 with just a catalytic amount of In(OTf)3 (Equation 33) <2002SL1928>. 

The useful disconnection 6a corresponds to Friedel-Crafts acylation of aromatic rings and is the obvious one on the ketone 6 having the perfume of hawthorn blossom. Reaction2 of ether 7 with MeCOCl and AICI3 gives 6 in 94-96% yield—a good reaction indeed. 

In both this reaction and the nitration of toluene we used to make benzocaine, the reagent is a cation MeCO+ for the Friedel-Crafts and NC>2+ for the nitration. Our first choice on disconnecting a bond to a benzene ring is to look for a cationic reagent so that we can use electrophilic aromatic substitution. We know not only which bond to break but also in which sense electronically to break it. In principle we could have chosen either polarity from the same disconnection a (we actually chose) or b (we did not). 

Enantiomerically pure chloro-ester 26 was needed for an investigation into the stereochemistry of the Friedel-Crafts reaction. Disconnecting the ester we reach the one piece of carbon skeleton and see that it has a 1,3-diX relationship 27. However we need a carbonyl group and an ester 28 should ensure conjugate addition of chloride to 29. 

The ketone 64 still has a 1,2-diX relationship but at the carbonyl oxidation level, so we disconnect to another molecule of triazole 62 and the a-halo ketone 66 is easily made by a Friedel-Crafts reaction using available chloroacetyl chloride. This time we buy the 1,2-diX relationship in the form of chloroacetyl chloride. 

The halogenation of ketones must be carried out in acid solution to avoid polyhalogenation.1 So the synthesis of reagent 22, used to make derivatives of carboxylic acids in chapter 6, is simple providing that we notice the directing effects of the two groups on the benzene ring in 23 and disconnect with Friedel-Crafts in mind. 

The tertiary alcohol is an obvious place to disconnect. Rejecting the poor disconnection of one carbon atom 20a, we have a choice between 20b and 20c giving one of two ketones 23 or 24 and Grignard reagents made from one of two halides 22 or 25. We can easily make 22 and 24 by halogenation or Friedel-Crafts acylation of toluene. But what about 23 and 25 ... 

We used this strategy in chapter 6 under two-group C-X disconnections where bromination of ketones was the usual functionalisation. More relevant here are conversions of carbonyl compounds into 1,2-dicarbonyl compounds by reaction with selenium dioxide SeC>2 or by nitrosation. So acetophenone 57 gives the ketoaldehyde10 58 with SeC>2. These 1,2-dicarbonyl compounds are unstable but the crystalline hydrate 59 is stable and 58 can be reformed on heating. Since aromatic ketones such as 57 would certainly be made by a Friedel-Crafts reaction the disconnection 58a is not between the two carbonyl groups and offers an alternative strategy. 

The double bond in the ring can be part of a benzene ring so that Nazarov disconnection of 13 reveals an aromatic ketone that can surely be made by a Friedel-Crafts reaction on some derivative of the acid 16. 

The Robinson annelation is by no means the only ionic reaction that makes six-membered rings. Six-membered rings form easily so trapping a Nazarov intermediate (chapter 35) makes good sense. The Friedel-Crafts-like disconnection 18 suggests a most unlikely cation 19 until we realise that it would be formed in the Nazarov cyclisation of the dienone 20 whose synthesis is discussed in the workbook. 

Corey1 wanted to make the ketone 2 as an intermediate in the synthesis of the marine allomone 1 (a substance exuded by an organism and used by a predator). Disconnection 2a (Friedel-Crafts alkylation) would be easy to realise as it occurs para to the powerful o,p-directing OMe group. But disconnection 2b is more difficult as it must occur meta to OMe. So we should make the formation of bond b a cyclisation and disconnect it first. 

A simple example is the anti-inflammatory fentiazac7 36. Doing both disconnections at once we get available thiobenzamide 37 and the a-halo-ketone 38. This can be made from the parent ketone 39, available by a Friedel-Crafts reaction using a cyclic anhydride (chapter 25). 

These five-membered rings have lone pair(s) delocalised from the heteroatom round the ring and are electron-rich . They react all too easily with electrophiles and are unstable in acid whether protic or Lewis. We have to find reactions that can be used in neutral or only weakly acidic solution. The synthesis of tolmetin 99 illustrates the two most important reactions.14 The disconnection of the ketone would lead naturally to an AICI3-catalysed Friedel-Crafts reaction between the acid chloride 100 and the pyrrole 101. 

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