Intramolecular aromatic alkylations

The Delft synthesis makes use of an acid-catalyzed ring closure - in fact an intramolecular aromatic alkylation - of a l-(3,5-dihydroxy-4-methoxybenzyl) isoquinoline derivative that is prepared starting from (natural) gallic acid. One of the hydroxyl groups is removed via a Pd/ C hydrogenation of the benzyl ether. Other catalytic steps play an important role some steps were improved recently [27]. The crucial step in the Rice synthesis makes use of a l-(2-bromo-5-hydroxy-4-methoxybenzyl)isoquinoline derivative that is also cyclized in an acid-catalyzed ring closure to the morphinan skeleton, followed by catalytic removal of the bromo substituent (Scheme 5.8). 

Other nucleophiles such as trimethylsilyl azide or trimethylsilyl acetate reacted in the same way and the azido or acetoxy group was similarly introduced to the aromatic substrate. Phenol ethers incorporating a /i-diketonic moiety at the metaposition underwent an analogous intramolecular aromatic alkylation [24] ... 

Participation by aromatic rings is also possible and there are now several examples of electro M]ic aromatic substitution involving Pummerer intermediates. Equation (20), the alkylation of benzene with dimethyl sulfoxide in trifluoroacetic anhydride, illustrates the process in its inq>lest foim. As widi al-kenes, reaction with aromatics has been more widely exploit in intramolecular versions for the construction of carbocycles and heterocycles. In many cases the sulfoxide precursor is of the keto variety, thus ensuring regiospecificity in the point of cyclization. Equation (21) (formation of a six-monber carbocycle), equation (22) (formation of a six-membered sulfur heterocycle), equation (23) (formation of a six-membered nitrogen heterocycle) and equation (24) (formation of a seven-membered nitrogen, sulfur heterocycle) provide illustrations of the versatility of diis form of intramolecular aromatic alkylation. 

The intramolecular aromatic alkylation of the tetrahydropyridine derivative (95) in hydrobromic acid is stereoselective and leads to cts-3,lob-dimethyl-1, 2,3,4, 4a,5,6,lOb-octahydrobenzo[f]isoquinoline (E. Reimann, Ann., 1978, 1963). 

Compared to the intramolecular aromatic alkylation with nucleophilic radicals, the analogous process with electrophilic radicals is far less common. Citterio carefully studied the Mn(OAc)3-mediated intramolecular homolytic aromatic substitution of various dialkyl malonates [71, 73]. He showed that the reaction is well suited for the formation of 5- (see 45), 6- (see 46) and 7-membered benzanellated rings (see 47). For cyclizations forming a 6-membered ring, high yields were obtained in the alkylation of electron-rich as well as electron-poor arenes. However, the formation of the 7-membered ring occurred only with electron-rich arenes. Cerium(IV) ammo-... 

Scheme 10. Intramolecular aromatic alkylation with electrophilic C-radicals...

Dai and co-workers [183] have reported a one-pot U-4CR followed by an intramolecular O-alkylation sequence starting from a 2-aminophenol in combination with an a-bromoalkanoic acid, an aromatic aldehyde and an isocyanide under controlled microwave irradiation. The U-4CR was carried out in MeOH and the resulting acyclic intermediate 131 was turned into the 3,4-dihydro-3-oxo-2/f-1,4-benzoxazines 132, without isolation, upon treatment with an aqueous solution of K2CO3 to promote the intramolecular 0-aUcylation in high yields (Scheme 102). 

Synthesis of polycyclic hydrocarbons by intramolecular C-alkylation of phosphine-alkylenes, An aromatic compound oftype (I) can be converted by reaction with I mole of triphenylphosphine into a monophosphonium salt (2) which with base gives the corresponding phosphinealkene (5). 

Biphenylcarboxylic acids 3.43.6.7 Intramolecular reductive alkylation 3.43.7 Aromatic Carboxylic Esters 3.4.3.8 Aromatic Amides 3.43.9 Aromatic Ketones... 

An extension of the palladium(0) catalyzed direct arylation reactions was reported by Lautens et al. in 2005. Based on the Catellani reaction [32], a direct intramolecular arylation of indole (C2) followed ort/m-alkylation, via a norbor-nene-mediated tandem aromatic alkylation/Heck reaction (Scheme 17) [33]. An analogous process was later developed for thiophenes and furans, allowing formation of a range of interesting hetero-aryl polycyclic products (Scheme 17) [34]. 

Furthermore, iminyl radicals, which are supposed to be intermediates in the annulations discussed above (see 32), have been directly generated from the corresponding oximes [56] or hydrazones [57] and applied in the intramolecular homolytic aromatic substitution. The intramolecular radical alkylation of arenes [58] and heteroarenes [59-62] was investigated by various research groups. As for the aryl radicals, the alkyl radicals used in these reactions are generally generated from the... 

Grewe (1946) introduced a vital alkylation reaction via a very specific stereo-selective (trans) synthesis followed by acid-catalyzed intramolecular, aromatic substitution, which caused the B/C-c/s CfD-trans ring fusions found to be common in either morphine or its natural congeners. This study has paved the way for an altogether new morphinan analogues known as benzomorphans . A few classical examples of this group of compoimds are listed below, viz., levorphanol tartrate dextromethorphan hydrobromide butorphanol tartrate ... 

Recently, the group of Hanessian reported an extension of MacMillan s organocatalytic aromatic alkylation to 3-aminocrotonaldehyde in the concise synthesis of an advanced precursor of a drug prototype for the treatment of migraine headaches [83]. An example that does not involve indoles as aromatic nucleophiles but pyrroles in the synthesis of natural products was reported in 2006 by Banwell and coworkers [84]. They accompHshed, via the common intermediate 94 obtained by means of an intramolecular F-C type alkylation, the syntheses of the alkaloids (—)-rhazinal, (—[-rhazinilam, (—[-leuconolam, and (-l-)-ept-leuconolam via the highly enantioselective creation of a quaternary stereocenter (Scheme 35.25). 

Lithiated indoles can be alkylated with primary or allylic halides and they react with aldehydes and ketones by addition to give hydroxyalkyl derivatives. Table 10.1 gives some examples of such reactions. Entry 13 is an example of a reaction with ethylene oxide which introduces a 2-(2-hydroxyethyl) substituent. Entries 14 and 15 illustrate cases of addition to aromatic ketones in which dehydration occurs during the course of the reaction. It is likely that this process occurs through intramolecular transfer of the phenylsulfonyl group. 

Preformed Carbocationic Intermediates. Propargyl cations stabilized by hexacarbonyl dicobalt have been used to effect Friedel-Crafts alkylation of electron-rich aromatics, such as anisole, /V, /V- dim ethyl a n il in e and 1,2,4,-trimethoxybenzene (24). Intramolecular reactions have been found to be regio and stereo-selective, and have been used ia the preparatioa of derivatives of 9JT- uoreaes and dibenzofurans (25). 

Many Jluonnaled aromatic compounds are alkylated with alkyl halides under Fnedel-Crafis conditions For example, the intramolecular alkylation of 3-fluoro-At-(chloroaee-tyl)amhne with alununum chlonde gives 6-fluorooxmdole [5] (equation 5) Similarly, 3 -chloro-4-fluoropropiophenone affords 5-fluoromdanone [6] (equation 6)... 

Antidepressant activity is retained when the two carbon bridge in imipramine is replaced by a larger, more complex, function. Nucleophilic aromatic substitution on chloropyridine 31 by means of p-aminobenzophenone (32) gives the bicyclic intermediate 33. Reduction of the nitro group (34), followed by intramolecular Schiff base formation gives the required heterocyclic ring system 35. Alkylation of the anion from 35 with l-dimethylamino-3-chloropropane leads to tampramine 36 [8]. 

Treatment of 6-arylidenehydrazino-3-alkyl-5-nitrouracils 510 with etha-nolic KOH caused a benzylic acid type of rearrangement to give 511, which were alkylated to give 512, whose cyclization with diethyl azodicar-boxylate gave (80H1295) 513 by intramolecular cycloaddition through valence isomerization and then aromatization with diethyl azodicarboxylate (Scheme 107). 

---