Butyllithium reaction with heterocycles

Modification of functional groups incorporated in a heterocycle is possible via ylide reactions. The 5-methylisoxazole (578) on reaction with n-butyllithium and methanesulfenyl... 

The heterocycles react directly with alkali metals or undergo exchange reactions with, for example, sodium amide and hydride, n-butyllithium and thallium ethoxide, to form the TV-heteroaryl salts. The salts of the alkali metals exist as solvent separated ion-pairs or as contact ion-pairs (71JOC3091), as do the quaternary ammonium salts, whereas the salts of the heavier metals are generally considered to have a high N—metal covalent character. These characteristics, which can be modified by a change in the polarity of the solvent, control the reactions of the heteroaryl anions. 

So far the reactivity of epoxides has involved their use as an electrophile. However, oxtranyl anions can serve as functionalized nucleophiles in their own right. Thus, the sulfonyl substituted epoxide 107 can be deprotonated with -butyllithium to provide a stabilized anion which engages in facile Sn2 reaction with triflate 108 <03JOC9050>. Other examples of such stabilized epoxide anions include those derived from oxazolinyloxiranes (e.g., 110), which react with nitrones to provide the spirotricyclic heterocycles of type 112, Hydrolysis provides the epoxy amino acids 113, in which the carboxylic acid moiety was provided by the oxazoline nucleus and the amine functionality was derived from the nitrone <03OL2723>. A recent report has demonstrated that oxiranyl anions can also be stabilized by the amide functionality <03H(59)137>. 

Carbanions 128, generated from the corresponding Fischer carbene complexes with -butyllithium, reacted with 2-methylthio-l,3-dithiolium salts 123 to give heterocyclic organometallic carbenes 129. Reactions of allylic carbanions 130 afforded a mixture of mono- and diheterocyclic condensation products 131 and 132, respectively (Scheme 11) <2004TL7843>. 

Stille reactions of FcSn0i and FcSnn with heterocyclic halides RX give the substituted ferrocenes (RCsH Fe sHs) and (RCsH Fe.129-131 Butyllithium reacts with FcSnn by mono- and di-transmetallation, but BC13 surprisingly gives a rearranged product.132... 

Unlike lithiated tetrahydroisoquinolines, a-lithio derivatives of saturated heterocycles are configurationally stable [202-204] (review [163]), and they have a considerably higher kinetic barrier to deprotonation. Nevertheless, there have been a number of activating groups developed for the alkylation of a-lithio amines. In 1991, Beak showed that the complex of sparteine and sec-butyllithium enantioselectively deprotonates BOC-pyrrolidine, and that the derived organolithium is a good nucleophile for the reaction with several electrophiles, as shown in... 

Phospholes and other related heterocycles are an important class of main group compounds. The chemistry of phospholes and their preparation has been reviewed extensively by Mathey.3 We provide details here for a simple, one-pot procedure for the preparation of 1-phenyl-2,3,4,5-tetramethylphosphole applying zirconocene chemistry.4 The procedure involves reduction of (n-CsHsteZrCIa with butyllithium in the presence of 2-butyne which (as reported initially by Negishi, et al.s) forms a zirconium metallacycle. Addition of dichlorophenylphosphine to this reaction mixture produces the phosphole. One other procedure for the preparation of 1-phenyl-2,3,4,5-tetramethylphosphole has been reported by Nief, et al.2 That procedure involved aluminum chloride - coupling of 2-butyne, followed by reaction with dichlorophenylphosphine to form a chlorophospholium tetrachloroaluminate which was then reduced with tributylphosphine to produce the phosphole in 68% yield. 

Reaction of the anion (243) with trimethylsilyl chloride, D2O and benzophenone, respectively, gave compounds (245), (246), and (247). Acid-treatment of (247) afforded ring-enlarged heterocycle (249) rather than the ketene dithioacetal (248), but (248) could he obtained by deprotonation of the trimethylsilyl derivative (245) with butyllithium and reaction with benzophenone <76TL1251>. 

In 2006, Matsumoto and Tomioka developed a chiral symmetric N-heterocyclic earbene generated from a dihydroimidazolium salt and strong base (potassium hydride or /r-butyllithium) and applied these catalysts to asymmetric intramolecular Stetter reactions with up 80% ee. It is remarkable to note that high temperature (reflux in toluene) is crucial for the formation of cyclic products with relatively high enantioseleetivity. Racemization of the product was almost sufficiently suppressed by adjusting the ratio of base to dihydroimidazolium salt to 1 2. 

In 1993, Corriu et al. studied the synthesis of nitrogen-containing heterocycles from (Z)-3-(tribulylstannyl)allylamine, which was prepared by the reaction of Af-(trimethylsilyl)allylamine with 2 mol of ra-butyllithium followed by treatment with chlorotributyltin and subsequent hydrolysis. The unprotected (Z)-3-(tributylstannyl)allylamine underwent a palladium-catalyzed cross-coupling reaction with aromatic bromides affording a stereospecific preparation of substituted allylic amines with Z configuration of the carbon-carbon double bond. The reactions of o/t/zo-functionalized aryl bromides offer a one-step preparation of 7-membered nitrogen heterocycles in high yields (Scheme 4.18). 

When compound 14 was deprotonated using -butyllithium instead of KN(SiMe3)2, the product was a neutral imidazolyl complex which turned out to be too unstable for isolation. Its reaction with triflic acid afforded a stable, cationic complex featuring an heterocyclic carbene (NH)—NHC Hgand (Scheme 25), which could be crystallized as its triflate salt and characterized in the soHd state by single-crystal X-ray diffraction, and in solution by IR and NMR. This difference in reaction outcome as a function of the base employed su ests a relative stabilization of the deprotonated N-methylimidazole as a result of the interaction of its C2 carbon atom with lithium, a smaller, more polarizing cation than potassium. 

The Kyoto group has developed some interesting chemistry based upon this readily available alcohol. / -Fluoro vinamidinium salts with potential for the synthesis of fluorinated heterocycles were prepared according to Eq. (89) [265]. Treatment of the tosylate of tetrafluoropropanol with n-butyllithium achieves regioselective dehydrofluorination a short reaction time appears to be critical [266]. 

Complexation of indoles with chromium hexacarbonyl, which reduces the electron density of the heterocyclic system, promotes nucleophilic attack at the 7-position and, to a lesser extent, also at the 4-position of the indole ring and provides a viable synthetic route to 7-formyl-l-methylindole (78CC1076). Curiously, although the benzenoid ring is rendered susceptible to nucleophilic attack, the reaction of the chromium complex with butyllithium results in abstraction of the proton from the 2-position. However, if this position is... 

Finally, a synthesis of 2-arylselenazopyridines has been reported to occur by reaction between aromatic selenoesters and pyridines with adjacent amino and chloro substituents, in the presence of butyllithium (equation 179)958. These previously unattainable heterocycles have potential use as pharmaceuticals. 

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