Butyllithium, reaction with amines

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

Johnson, Elliot and Penning introduced this reagent, easily made from /-ephedrine, for 31P-NMR analysis of alcohols and amines40. The method for amines is simpler as the reaction with alcohols requires butyllithium. 

Some further examples of stereoselective deprotonation/alkylation reactions of tricarbonyl-chromium complexed (V-methyl tetrahydroisoquinolines have been reported27. Starting with the enantiomerically pure (35)-methyl tetrahydroisoquinoline reaction with hexacarbonyl-chromium led to a mixture of endo- (40%) and exo- (60%) complexes, which were deprotonated with butyllithium and subsequently methylated with iodomethane. In this way methylation occurred firstly at the 4- and secondly at the 1-position. In all cases, the methyl group entered anti to the chromium complexed face. After separation of the alkylated complexes by chromatography and oxidative decomplexation, the enantiomerically pure diastereomers (—)-(l 5,35,47 )-and ( + )-(17 ,35,45)-1,2,3,4-tetrahydro-l,2,3,4-tetramethylisoquinolme were obtained, benzylic amines such as tetrahydroisoquinoline to 2-amino-4,5-dihydrooxazoles. Deprotona... 

An additional modification in the above synthetic scheme is possible by introducing the aromatic diamine in the form of its trimethylsilyl derivative [72]. Monotrimethylsilyl-substituted amines are readily prepared from the free amine with hexamethyldisilazane or trimethylsilyl chloride in the presence of a tertiary amine [73, 74] whereas bis(trimethylsilyl)-substituted amines require more aggressive reagents, such as butyllithium in conjunction with trimethylsilyl chloride [75]. As illustrated in Scheme 19, monotrimethylsilyl-substituted amines react with acyl chlorides to form the corresponding amides and liberate trimethylsilyl chloride. Monotrimethylsilyl-substituted amines are reported to display increased reactivity with acyl chlorides [76], This is of great synthetic importance since the increased reactivity allows for reaction with low basicity amines. Bis(trimethylsilyl)-substituted amines, on the other hand, react with acyl chlorides to form the corresponding JV-trimethylsilyl amides, see Scheme 20. The JV-trimethylsilyl amides are much more soluble in common organic solvents. However, they are hydrolytically unstable and readily convert back to the free amides. 

Bromo-l-(triisopropylsilyl)pyrrole undergoes initial reaction with butyllithium followed by reaction with A -fluorobis(phenylsulfonyl)amine (la) to give 3-fluoro-l-(triisopropylsilyl)pyr-role (8).144... 

Protection of primary amines. Primary amines form the cyclic adducts 2 ("Stabasc adducts ) on reaction with I and a base (triethylamine for amines with pK 10 II, -butyllithium for less basic amines). The adducts are stable to n- and. KT-BuLi (-25°), LDA, H 0, CH3OH, KF, and NaHCOj but unstable to HOAc, HC1, KOH, and NaBH. ... 

Lithiation of dibenzofuran with butyllithium and mercuration both occur at the 4-position. Thallation occurs at the 2-position, however (57IZV1391). The mercury and thallium derivatives serve as a source of the iodo compounds by reaction with iodine. Bromodibenzofurans undergo bromine/lithium exchange with butyllithium and the derived lithio compounds may be converted into phenols by reaction with molecular oxygen in the presence of a Grignard reagent, into amines by reaction with O-methylhydroxylamine, into sulfinic acids by reaction with sulfur dioxide, into carboxylic acids by reaction with carbon dioxide and into methyl derivatives by reaction with methyl sulfate (Scheme 100). This last reaction... 

Interestingly, the alkene to allene conversion can be carried out directly without isolation of the intermediate dihalocyclopropane. This process involves the treatment of the alkene with 1 equiv. of carbon tetrabromide and 2 equiv. of methyllithium in ether at -65 °C.163 Ultrasonic irradiation facilitates the formation of cyclopropylidenes, and therefore the allenes, from dihalocyclopropanes under the influence of Li, Na or Mg.1 The reactions are usually complete in 5-15 min. A report165 on the use of n-butyllithium complexed with the chiral tertiary amine (-)-sparteine, leading to optically active allenes, seems to be of questionable value. 

The synthesis of FQ (Fig. 20) is simple and quite economical, which renders FQ attractive for the development of an antimalarial drug intended for use in areas, concerned by malaria, that are mostly overlaying with low-income countries. FQ was obtained starting from the commercially available AQV-dimethyl-1-ferrocenylmethanamine. The ferrocenic aldehyde results from a C-C bond formation, a two-step sequence involving metallation with tert/o-butyllithium and a reaction with DMF. This step has been previously studied and the 1,2 orientation of the two substituents of the cyclopentadienyl has been unambiguously established [125], The aldehyde is converted to the corresponding oxime, which is then reduced to the primary amine. The SNat reaction between the amine and 4,7-dichloroquinoline leads to the desired FQ [121]. 

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>. 

Monohalogenothiazoles, 567 nucleophilic substitution reactions, 322 with amines. 567 with ArSH, 567 with benzamide, 567 with OH", 567 with OR", 567 relative reactivities, 568 with SR", 567 with sulfinic acid salts, 567 with sulfonamide, 567 reactions, with alkyl halides, 574 with n-butyllithium, 573 with Gtignard reagents, 573 reeduction of, with nickel, 573 with zinc, 573... 

Allyl silanes react with epoxides, in the presence of Bp3 OEt2 to give 2-allyl alcohols.The reaction of a-bromo lactones and CH2=CHCH2Si(SiMe3)3 and AIBN leads to the a-allyl lactone.On the other hand, silyl epoxides have been prepared from epoxides via reaction with iec-butyllithium and chlorotri-methylsilane. ° a-Silyl-A-Boc-amines were prepared in a similar manner from the A-Boc-amine. " Arylsilanes were prepared by reaction of an aryl-lithium intermediate with TfOSi(OEt)3. In the presence of BEs etherate, allyl silane and a-methoxy A-Cbz amines were coupled. Benzyl silanes coupled with allyl silanes to give ArCHa—R derivatives in the presence of VO(OEt)Cl2 " and allyltin compounds couple with allyl silanes in the presence of SnCl4. Allyl silanes couple to the a-carbon of amines under photolysis conditions. 

Lithium diisopropylamide (LDA) is a strong, non-nucleophilic base that is widely used. Because of its reactivity with many solvents, it has historically been generated in the laboratory by reaction of w-butyllithium and diisopropyl amine. Recently, LDA has become commercially available as a solution in THF/heptane/ethyl benzene. The commercially available material is frequently colored, making titration difficult. 

The use of sodium amide or potassium amide in liquid ammonia with bromo- or chlorobenzene leads inevitably to the capture of benzyne by its reaction with ammonia. However, the utility of bromo- or chlorobenzene as a benzyne precursor is extended to ethereal solvent systems by employing the conjugate base of a hindered secondary amine (diisopropylamine, 2,2,6,6-tetramethylpiperidine) which can be formed in situ from the amine and alkyllithium. Alternatively, butyllithium itself is used with the halogeno-benzene, and pentafluorobenzene and butyllithium are the usual source of tetrafluorobenzyne. In all of these reactions the aryne is generated by decomposition of an o-halogenoaryl anion at temperatures below 0°C. 

The transformation of 3-phenylindazol-l-amine (3a) into 4-phenyl-l,2,3-benzotriazine (7a) by reaction with butyllithium and tosyl azide has been reported.115... 

Since then, further work by Langer and his co-workers has shown that this is a general reaction with the higher homologs of TMEDA (5, 8). Preparation of these lithiated tertiary diamines and a number of synthetic reactions are given in those references. As further background to the possible reactions that may occur with other tertiary amines and diamines, the work of Lepley and co-workers with n-butyllithium and aromatic tertiary amines should also be examined (29-33). 

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... 

Nucleophilic reactions take place on the hetero ring of isoquinoline, preferably in the 1-position. For instance, the Chichibabin amination with NaNH2 in liquid ammonia yields 1-aminoisoquinoline 5. The Ziegler reaction with w-butyllithium furnishes the 1-substituted product 7 as with quinoline, benzene ring annulation stabilizes the primary addition product 6 (1,2-dihydroisoquinoline), which can be isolated and dehydrogenated to 7 by nitro compoxmds ... 

As imido esters, dihydro-1,3-oxazines of type 14 display reactivity similar to 2-oxazolines (see p 135). The a-C-H bonds of the 2-alkyl group are CH-acidic. They are metalated by reaction with butyllithium and then undergo C-C forming reactions with electrophiles such as haloalkanes, oxiranes or carbonyl compounds. The dihydro-1,3-oxazines 16, which are obtained from 15 by a-metalation and alkylation, undergo reduction with NaBH4 forming 17. Acid hydrolysis cleaves the cyclic aminal function of 17 yielding aldehydes 18 ... 

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