Ortho directors

Huorine is an especially powerful ortho director in lithiation of aromatic systems Gilday, J.P. Negri, J.T. Widdowson, D.A. Tetrahedron, 1989, 45, 4605. 

The sydnone ring has also been used as an ortho-director of lithiation. Thus, on reaction with Bu Li-TMEDA, 3-phenylsydnone has been found to form a dilithio species which can be regiospecifically acylated at the ort/io-position by a weak electrophile. 

Dihydrooxazoles are also effective ortho directors for nucleophilic addition to naphthalene and some heteroaromatic derivatives. Tandem additions result if the reaction mixtures are quenched with electrophiles (Scheme 72). 

Sulfones and sulfonamides - the S+O class are similarly powerful directors,141 and do not suffer electrophilic attack at sulfur (though occasionally suffer nucleophilic attack on the aromatic ring)134143 but are less useful because of their more limited synthetic applications.144 143 Aryl J-butylsulfoxides are also powerful ortho-directors,145 but less hindered diaryl sulfoxides are susceptible to attack by organolithiums at sulfur146 (see section 3.3.3 for discussion of this sulfur-lithium exchange ). 

BuLi, clean ortho+a double lithiation occurs, giving 229 the SCH2Li group is itself an ortho-director,207 though a weaker one than OMe, since doubly lithiated 230 has the regiochemistry 231.208 A methylthio substituent in conjunction with a methoxy substituent directs to their mutual ortho position (232 - 233). 

Groups bearing amino substituents even further from the aromatic ring are very weak ortho-directors.102... 

Interestingly, indoles are lithiated at either the 2- or the 3-position, depending on protectoin at N.342 For 2-lithiation, probably the best technique is in situ protection of nitrogen by C02. The lithiocarbamate group of 388 acts as a good ortho-director.343... 

Nitration puts in a substituent para to the alkyl group, which, after reduction, becomes a powerful ortho director so that the bromine is directed meta to the original alkyl group (Chapter 22). Removal of the amino group by reduction allows the preparation of meta bromo alkyl benzenes that cannot be made directly. 

Secondary amides may direct ortho lithiation, but they must first be deprotonated. This makes them somewhat weaker ortho directors than tertiary amides, but they may still serve the purpose quite well. For example, the lithiation and addition of benzamide (12) to aldehyde (13) was us in a synthesis of 11-deoxycaiminomycinone (Scheme 8). More recently, it has been shown that the amide monoanion may be obtained by addition of a phenylsodium to an isocyanate. ... 

Oxazolines may be used as ortho directors in phthalide syntheses analogous to those shown in Schemes 11-14. The phthalides derived from oxazolines have been further transformed to polycyclic aromatics by a route that is analogous to, and perhaps more general dian, those shown in Scheme 12. An efficient synthesis of the lignin lactones chinensin and justicidin along such lines was reported by Meyers (Scheme 15). ... 

The ortho lithiation of phenolic urethanes was reported by Snieckus in 1983. In addition to being an efficient ortho director (as expected considering the pllTt data in Table 1), the O-phenylurethane also is capable of an anionic Fries rearrangement. This rearrangement allows substitution ortho to the urethrae, then lithiation rad rearrangement at the ortho position, resulting in introduction of a tertiary... 

Substituted pyiToles and indoles nonnally undergo lithiadon at the 2-position (a-metaladon), so when there is an ortho director on the nitrogen, metalation is facilitated. For example, the lithiation of -t-BOC pyrrole and its addition to benzaldehyde occurs in 75% yield. Similar litl tions of -t-BOC indole and -benzenesulfonylindole have also been reported. Examples of these reacticxis are illustrated in Scheme 25. 

The regioselective functionalization of A -pyirolines at the 2-position by metalatitm of the derived r-butylfomuunidine (21) is shown in Scheme 27." Metalation at the 2-position of a pyirole having an ortho director at the 3-position is readily achieved. Functionalization of a pyrrole at the 3-position by ortho metalation of a 2-substituted derivative is more problematic, with a mixture of 3- and 5-substituted... 

The pATa data listed in Table 1 note that tertiary amides are mote acidic than several other functional groups, suggesting thermodynamic acidity as an important component of the mechanistic rationale for their lithiation. Indeed tertiary amides are the strongest ortho directing group, taking preference over all other functional groups tested in both intra- and inter-molecular competition experiments. - N.. A -Tetramethylphosphonic diamides also promote efficient ortho metalation. The use of tertiary amides as ortho directors was reviewed in 1982, so this discussion will focus only on developments since then. 

Dihydrooxazoles are also effective ortho directors for nucleophilic addition to naphthalene and some heteroaromatic derivatives. Tandem additions result if the reaction mixtures are quenched with electrophiles (Scheme 54). When chiral oxazoles are used, asymmetric syntheses, such as that of scopadulcic acid, are achieved. Although most of the oxazoles employed have chelating groups to enhance stereoselectivity, the steric bias provided by valinol or t-leucinol derived oxazoles is often equivalent or superior. 

One ortho-director rearranges into another - the anionic Fries reaction Halogens... 

There are plenty of other groups which are known to be ortho-directors. The halogens can behave as ort/w-dircctors and fluorine is perhaps the best (which is why it is in a box in the figure). However, if you were attempting to use either bromine or iodine as an ortho-director then you d better watch out. It would be essential not to use butyl lithium as the lithiating reagent—they... 

Oxazolines are versatile functional groups. It is entirely possible for one ortho-director to direct the introduction of a new group that is then an ortho-director in its own right. This leads to all sorts of interesting possibilities and is discussed in Several Lithiations. 

There are two ortho positions in the first case, three in the second, and four in the third. We notice, of course, that although all four sites in the para case can react, there are only two different sorts of proton due to the plane of symmetry. The para substitution pattern is the example we look at first. Oxazoline 75 has two para related ortho-directors and two possible sites for lithiation on the ring. We can clearly see from the result that the oxazoline ring was the more potent director because the product 76 has the new methyl group ortho to it rather than ortho to the methoxy group. 

Further, a carbamate - the most potent ortho-director of the three - sits in between the other two. This can be used. We will come back and look at this compound again in the next section and disconnect it further but apply another concept to its analysis - that of multiple orffto-lithiation. For now we restrict ourselves to the one disconnection. 

The amide is a good ort/zo-director but so is the acetal function. The regioselectivity (actually there is the issue of chemoselectivity here too) of the lithiation reaction will depend upon which of the two is the more potent. Amides were one of our three kings of the ortho-directors and are more powerful than acetals. Now it is time for an anionic Fries rearrangement (in the retrosynthetic direction) to give the starting material 127. 

Fluorine is a good ortho-director.24 It directs the lithiation of fluorobiphenyl without the assistance of another directing group and does so very efficiently. 

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