LiTMP lithiation

Pyridines bearing secondary amides may be lithiated with n-BuLi at —78°C with tertiary amides the optimum conditions are LiTMP, DME, 5-15 min (Scheme 23) . Lithiated tertiary amidopyridines react well with carbonyl electrophiles but poorly with alkylating agents. Lithiation of the bromopyridine 49 with LDA is a key step in the synthesis of eupoluramine . ... 

Nitriles will direct lithiation with non-nucleophilic bases such as LiTMP, particularly in conjuction with another nitrile group . The nitriles presumably act by an acidifying effect alone—no intramolecular N-Li coordination is possible in the intermediate (Scheme 60). 

In the pyridine- and quinolinecarboxyhc acid series, the greater acidity of the ring protons means that LDA or LiTMP can be used for metallation all three pyridinecarboxylic acids 156-158 are lithiated in good yield (Scheme 77). ... 

Successful lithiation of aryl halides—carbocyclic or heterocyclic—with alkyUithiums is, however, the exception rather than the rule. The instability of ortholithiated carbocyclic aryl halides towards benzyne formation is always a limiting feature of their use, and aryl bromides and iodides undergo halogen-metal exchange in preference to deprotonation. Lithium amide bases avoid the second of these problems, but work well only with aryl halides benefitting from some additional acidifying feature. Chlorobenzene and bromobenzene can be lithiated with moderate yield and selectivity by LDA or LiTMP at -75 or -100 °C . 

Bipyridines can be lithiated with LiTMP (if only in moderate yield), with one nitrogen atom directing the lithiation of the other ring (Scheme 89) . Both 2,2 - and 2,4-bipyridines 177 and 178 can be lithiated in this way. 

More powerful directing groups such as those based on amides and sulphonamides are successful with pyridines as with carboxylic rings, and will not be discussed separately. The enhanced acidity of pyridine ring protons makes the simple carboxylate substituent an ideal director of lithiation in pyridine systems . The pyridinecarboxylic acids 232-234 are deprotonated with BuLi and then lithiated with an excess of LiTMP all the substitution patterns are lithiated nicotinic acid 233 is lithiated in the 4-position (Scheme 113). The method provides a valuable way of introducing substituents into the picolinic, nicotinic and isonicotinic acid series. 

Halogenated quinolines very often nndergo nncleophilic addition with BuLi, so must be lithiated with LDA or LiTMP " The regioselectivity of their reactions parallels that of the pyridines, and similar halogen migrations are observed (Scheme 116) . ... 

The protons of pyrimidines, pyrazines and pyridazines are relatively acidic even without halogen activation, and the three simple heterocycles 240-242 have been lithiated (with varying success) with LiTMP (Scheme 120). ... 

This acidity means that even iodopyrimidines and iodopyrazines may be lithiated because hindered, non-nucleophilic lithium amide bases will deprotonate them. For example, the base 244, which is easily made by BuLi attack on the imine, deprotonates 243 a to N rather than ortho to and the lithiation of 245 with LiTMP is also successful (Scheme 121). ... 

Methoxypyrazines 249 and 250 are lithiated with LiTMP as shown in the two syntheses in Scheme 123 , the first being part of a route to kelfizine and sulphalene . 

Lateral lithiation of nitriles can be achieved—and self-condensation avoided—if LiTMP is used in THF at —78°C (Scheme 199/ . 

The least acidic of the three available position on oxazole is the 4-position, but even this can be lithiated under the appropriate conditions (86CRV845). Thus, while 2,5-diphenyloxazole gives a mixture of products on treatment with n-BuLi, clean metalation at C-4 can be achieved using LDA or KDA (86CRV845), or with 5-BuLi and a catalytic amount of LiTMP (Scheme 86)(91JOC3058). 

Examples of the 3-lithiation of both 2- and 2,6-disubstituted chloro- and methoxypyrazines, as well as 2-thiomethylpyrazine are known (88S881 90JOC3410 91JHC765, 91JOM(412)301] (Scheme 117). As with pyridazine, LiTMP has so far been the only base employed, and this same base system has also recently been used for the directed metalation of pyrazine... 

Lithiation of 2-bromo-4-trifluoromethylpyrimidine 298 with LiTMP also occurred predominantly at the 6-position, but in this case only the dimeric product 299 was obtained, even when the reaction was performed in the presence of trimethylsilyl chloride <2006EJ01593>. 

The synthesis of substituted quinazolin-4(. 7/)-ones and quinazolines via directed lithiation has been reviewed <2000H(53)1839>, and the topic has also been briefly discussed in a more general review on the synthesis of quinazolinones and quinazolines <2005T10153>. For example, the lithiation of 4-methoxyquinazoline 312 with LiTMP followed by reaction with acetaldehyde gave only a minor amount of the 2-substituted product 313, with the major product 314 being the result of lithiation at the 8-position in the benzene ring <1997T2871>. 

Related metalations (n-BuLi) of 6-chloro-2,4-dimethoxypyrimidine (C-5 TMS and C-5 SnMe3 products) [88JOM(342)l] has also been done. 5-Methoxy, as well as 2,4,4,6-dimethoxy, and 2,4,6-trimethoxy pyrimides were lithiated under similar conditions (LiTMP/THF/-78°C), leading respectively to the 4- and 5-substituted derivatives in medium to high yields (90JOC3410). 

Chiral a-methylene-y-lactones.1 (R)-( + )-Alkyl p-tolyl sulfoxides (2), readily obtainable in almost quantitative yield from (l),2 on lithiation (LiTMP) and reaction with lithium a-bromomethylacrylate (3) are converted into a-methylene-y-sulfinyl carboxylic acids (4), which can be separated by chromatography or crystallization. Reduction of optically pure 4 provides y-tolylthio acids [(S)-5], which on methylation and treatment with potassium f-butoxide are converted into (4R)-a-methylene-y-lactones (6), with inversion of chirality. 

The cyano group has been used as an ortho -directing group for lithiation in the pyridine series.79 Lithiation of 4-cyanopyridine using LiTMP and trapping the lithio intermediate with electrophiles have provided an efficient and straightforward access to ortho -substituted-4-cyanopyridines. 

Trifluoromethyl benzocyclobutenol derivatives 595 undergo ring opening upon treatment with LiTMP followed by reaction with aromatic aldehydes to furnish highly substituted isochroman-l-ols 596 via a laterally-lithiated trifluoromethylketone intermediate (Equation 246, Table 27) <1996SL57>. 

These amides are a-lithiated because no other deprotonation can compete. With less hindered aromatic N,A-dimethylamides, a-lithiation still takes precedence over ortholithiation but the organolithium is immediately acylated by another molecule of amide. For example, LiTMP a-lithiates 46 even though ortholithiation could compete, but the product rapidly forms 47.7 With less readily lithiated groups on nitrogen (such as ethyl or isopropyl) ortholithiation (see section 2.3) takes over as the main reaction pathway. 

Lithium amides (LiTMP) can give good yields of products resulting from ortholithiation of both ketones and lithium carboxylates. Benzophenone 288, for example, with LiTMP gives a good yield of the ortholithiation-dimerisation product 289.103 In general, however, ketones and aldehydes are best lithiated by the method developed by Comins described in section 2.3.2.1.2. 

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