Lithium in Barbier-Type Reactions

Lithiation of I with n-butyllithium followed by reaction with an electrophile such as dimethylformamide yielded ortto-substituted tert-butylbenzamides in fair yields  

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At the end of the 1960s interest grew in the use of lithium in Barbier-type reactions. 

Lithium in Barbier-Type Reactions 87 Table 3.5. Yields of ketones from reaction of various nitriles with organobromides and lithium [23]... 

Lithium in Barbier-Type Reactions 91 Table 3. Yields of Li-Barbier reactions under ultrasonic irradiation [29]... 

Conclusion Regarding Lithium-Activation. The great advantages of the use of lithium in Barbier-type reactions, as demonstrated in Sect. 3.3, have grown even more in importance by the use of ultrasound and the addition of an electron-transfer agent. 

The same polymeric arenes that served as metallation catalysts in equation 119 can also be used for silylation in Barbier-type reactions (equation 131). The polymer is presumably converted to a lithium arene adduct that activates metallic lithium for metallation of the halogenated substrates, before addition of an electrophile to achieve the synthetic goal. Equations 132-135 illustrate some of the cases investigated. The products can be characterized by the usual spectroscopic methods . 

After having started this monograph with one-step carbon-carbon bond formation reactions in which magnesium was the metallic reagent (chap. 2) and then having progressed on to the use of lithium and zinc, some attention will now be focussed on the application of numerous other metals in Barbier-type reactions. 

Reaction of the ultrasonically generated alkyllithiums with carbonyl compounds provides an extremely facile route to secondary and tertiary alcohols in a lithium-mediated Barbier-type reaction. 

Benzamides 565 without any substituent at the para position reacted with lithium and a catalytic amount of naphthalene under Barbier-type reaction conditions (in the presence of a carbonyl compound) in THF at —78 °C to give, after hydrolysis, the corresponding dearomatized products 566 (Scheme 151). When 567 was used as starting material with a 4-ferf-butyl group in p-position, and using 3-pentanone as electrophile and under the same reaction conditions, the fraw -product 568 was the only one isolated . 

E = H) resulting from a lithium—hydrogen exchange in intermediate 198. This hydrogen abstraction from the reaction medium, probably from THF at the a-position, has already been observed in other cases for very reactive organolithium intermediates. The use of Barbier-type reaction conditions did not improve the obtained results124. 

In addition to serving as a useful replacement for lithium or magnesium in Barbier-type coupling reactions, SmI also provides advantages over zinc as a reductant in Reformatsky-type coupling reactions (equation 54).The latter only performs well when an activated form of zinc is utilized, and thus the homogeneous conditions afforded by SmI provide the advantage of enhanced reactivity under milder conditions. 

Lithium 4,4 -di-t-butylbiphenylide (LDTBB). 13, 162-163 16, 195-196 17, 164 Lithium-halogen exchange. The reagent has been proven particularly effective for chloro compounds, as shown in the Barbier-type reactions involving chloromethyl ethyl ether, l,4-dichloro-2-butyne and -2-butenes. Vinylic chlorides also readily undergo exchange, and actually 2,3-dichloropropene is converted to the dilithio reagent. ... 

Lithium-halogen exchange. The reagent is useful for preparation of organo-lithiums from acetal-containing substrates, dihaloarenes (monofunctionalization), and halopyridines. Dechlorination of /V-(/3-chloroalkyl)amides apparently cannot be achieved with BuLi alone (stops at (V-deprotonation ), and the use of LN is required." Of course the N,C-dithio derivatives may be employed in C-C bond formation (remarkably the coupling with aryl and vinyl halides). Barbier-type reactions have been achieved."... 

Table 3.1. Yields of alcohols from Barbier-type reactions of organic halides with lithium and a substrate in THF as the solvent [14]...

Table 3.7. Results of Barbier-type reactions of cage-structure bromides with adamantone and lithium in diethyl ether at — 20 °C [25]...

The inclusion in this group of 1-bromoadamantane (p. 117, ref. [100b]), with which successful Barbier-type reactions have been reported mainly with lithium in Sect. 3.3.6, indicates that other less reactive halides will soon follow. 

In a recent study [51] on some fundamental aspects of the sonochemical Barbier-type reaction of benzaldehyde, 1-bromoheptane and lithium it was... 

Lithium bromide and lithium chloride can also enhance the reactivity of Sml2 in THF (Fuchs et ah, 1997 Miller et ah, 2000). Addition of anhydrous LiCl and LiBr to Sml2 resulted in rate enhancement and better yields in pinacol coupling of cyclohexanone. In the Barbier type reaction of 1-iodobutane with 2-octanone, the presence of LiBr and LiCl resulted in the formation of pinacol coupling product (diol from 2 moles of 2-octanone) as the major product rather than the nucleophilic addition of halide to ketone (eq. (52), table 8). 

When (Z)-6-chloro-l-phenylhex-l-ene 200 was lithiated under DTBB catalysis, the cyclized product 202 was always obtained either at —78 or at —30 °C. After the first chlorine-lithium exchange a carbolithiation took place to yield the intermediate 201, which by reaction with electrophiles, E, and final hydrolysis gave products 202 (Scheme 60). At —78 °C the reaction under Barbier-type conditions did not work. Also in this case, the corresponding reduced product (202 with E = H) was the main by-product detected. 

A series of aryltriethoxysilanes 14 were synthesized from the reaction of aryl bromides 13 with magnesium powder, 1,2-dibromoethane and tetraethylorthosilicate in tetrahydrofuran via sonochemical Barbier-type conditions. DeShong previously reported the preparation of aryltrialkoxysilanes via treatment of aryl Grignard or lithium reagents with... 

Masked lithium homoenolates of type XII are of interest in synthetic organic chemistry and can be considered as three-carbon homologating reagents with umpolung reactivity [122]. The lithiation of the jS-chloro orthoester 147 with lithium in the presence of a catalytic amount of DTBB, under Barbier-reaction conditions, and using carbonyl compounds as electrophiles, followed by acidic hydrolysis, led to lactones 149 as reaction products, the masked lithium homoenolate 148 bang proposed as a reaction intermediate (Scheme 2.20) [123]. 

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