Butyllithium, reaction with amides

There is a rather useful reaction with amides. Organolithium reagents react with DMF to give aldehydes.. An example is the reaction of 231 with s c-butyllithium to give the aryl-lithium reagent (see sec. 8.5.F for directed ortho metalation reactions). Subsequent reaction with DMF and hydrolysis gave a 91% yield of aldehyde 232 in Yamaguchi s synthesis of the radulanins. ... 

Alteration of the relative reactivity of the ring-positions of quinoline is expected and observed when cyclic transition states can intervene. Quinoline plus phenylmagnesium bromide (Et20,150°, 3 hr) produces the 2-phenyl derivative (66% yield) phenyllithium gives predominantly the same product along with a little of the 4-phenylation product. Reaction of butyllithium (Et 0, —35°, 15 min) forms 2-butylquinoline directly in 94% yield. 2-Aryl- or 6-methoxy-quinolines give addition at the 2-position with aryllithium re-agents, and reaction there is so favored that appreciable substitution (35%) takes place at the 2-position even in the 4-chloroquinoline 414. Hydride reduction at the 2-position of quinoline predominates. Reaction of amide ion at the 2-position via a cyclic... 

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. 

Two years later, the same group reported a formal synthesis of ellipticine (228) using 6-benzyl-6H-pyrido[4,3-f>]carbazole-5,ll-quinone (6-benzylellipticine quinone) (1241) as intermediate (716). The optimized conditions, reaction of 1.2 equivalents of 3-bromo-4-lithiopyridine (1238) with M-benzylindole-2,3-dicarboxylic anhydride (852) at —96°C, led regioselectively to the 2-acylindole-3-carboxylic acid 1233 in 42% yield. Compound 1233 was converted to the corresponding amide 1239 by treatment with oxalyl chloride, followed by diethylamine. The ketone 1239 was reduced to the corresponding alcohol 1240 by reaction with sodium borohydride. Reaction of the alcohol 1240 with f-butyllithium led to the desired 6-benzylellipticine quinone (1241), along with a debrominated alcohol 1242, in 40% and 19% yield, respectively. 6-Benzylellipticine quinone (1241) was transformed to 6-benzylellipticine (1243) in 38% yield by treatment with methyllithium, then hydroiodic acid, followed... 

Unlike analogous reactions with a carbon nucleophile, the initial attack of the lithium amide was reversible. A strong piece of supporting evidence was the exclusive formation of the butyl addition product 504 when w-butyllithium was added after initial formation of the aza enolate 505 (Scheme 8.164). The reaction outcome is therefore heavily dependent on the secondary reaction with the... 

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. 

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. 

Dioxepins derived from 1,4-diols and a-phenylsulfonylacetaldehyde diethyl acetal have proved to be robust protection groups for 1,4-diols under a variety of reaction conditions. They are stable to 60% AcOH, 6M HC1, and 0.1 M H2SC>4, and they resist /3-elimination by reaction with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Cleavage was achieved with either lithium amide in liquid ammonia at —33 °C or -butyllithium at 35 °C (Scheme 24) <2003SC895>. 

Efficient methods for the preparation of pentadienyl compounds of the alkali metals have now been developed. Treatment of 1,4-dienes with butyllithium in the presence of tetrahydrofuran (thf) at —78° yields deep orange solutions which contain pentadienyllithiums (36,37). Any excess butyllithium may be destroyed by its reaction with thf by allowing the mixture to warm up briefly to room temperature (38). Similar results are obtained using potassium amide in liquid ammonia (39). 1,3-Dienes, however, do not yield pentadienyl anions under these conditions, unless the diene is conjugated with a phenyl (40), vinyl (41), trimethylsilyl (48), or similar stabilizing group. Unfortunately, 1,4-dienes are not very readily accessible. However, 1,3- as well as 1,4-dienes can be metallated using a 1 1 mixture of butyllithium and potassium tm-butoxide (49). Trimethylsilylmethylpotassium is also effective (44). 

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>. 

Ketones can also be obtained by treatment of the lithium salt of a carboxylic acid with an alkyllithium reagent (16-28). For an indirect way to convert carboxylic esters to ketones, see 16-82. A similar reaction with hindered aryl carboxylic acids has been reported. " Treatment of a p-amido acid with two equivalents of M-butyllithium, followed by reaction with an acid chloride leads to a p-keto amide.Carboxylic acids can be treated with 2-chloro-4,6-dimethoxy[l,3,5]-triazine and the RMgX/Cul to give ketones. " ... 

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. 

Reaction with active-hydrogen compounds [1, 96, before references]. Hauser11 reports that n-butyllithium can afford dilithio salts from active-hydrogen compounds when use of potassium amide in liquid ammonia is ineffective. Thus acetanilide (1) reacts with n-butyllithium in THF or ether to form a dilithio derivative formulated as (2). This disalt on alkylation with benzyl chloride gives (3). 

An extensive study of the decomposition of the N,N-dimethylbenzyl-anilinium ion 22 was recently carried out by Lepley and coworkers 93.99) As expected, displacement reactions occur exclusively with hydroxide and alkoxide, an orf/io-rearrangement occurs with amide, and a variety of products are formed with various organolithium reagents. The products found when butyllithium was employed are listed below. 

As the hydrogen atoms in (Ph2Si0)8[Al(0)0H]4 are quite acidic, an obvious step was to replace them by electropositive elements such as lithium, potassium or divalent tin and thus to create molecular alumosilicates. The reactions can easily be performed with reactants like butyllithium, phenyllithium, lithium amide, potassium tert-butoxide, tin di(fert-butoxide), bis(hexamethyldisilazyl)-... 

The (S)-lactone acid 1, obtained from L-glutamic acid by nitrous acid deamination, was converted to the acid chloride, then treated with excess diazomethane followed by hydrogen iodide to yield the keto-lactone 2. Amidation occurred quantitatively to give the partially racemized amide 3, which was purified by repeated recrystallizations. The vicinal diol resulting from reaction with excess methylmagnesium iodide was protected as the acetonide 4. An isomeric mixture of olefins (Z , 26 74) was obtained from the subsequent Wittig reaction. Reduction followed by separation on silver nitrate coated silica gel gave the (Z)-and ( )-alcohols in 20% (6) and 61% (5) yield, respectively. Conversion of the (S)-( )-alcohol (5) to the chloride then afforded the thioether (7) on reaction with sodium phenylsulfide. The thio ether anion was formed by treatment with n-butyllithium. Alkylation with the allylic chloride" (8), followed by removal of sulfur, then yielded the diene 9, which was converted in several steps to (/ ) (-t-)-10,11 -epoxy famesol. 

Several improvements in acylation techniques were announced. Butyllithium wwas determined to be superior to sodium amide in preparation of amide ions for ammonolysis reactions with esters. Phosgene is more reactive than ethyl chloroformate toward eneamines. The intermediate acyl chlorides may then be converted to a variety of products. a-Acetylenic aldehydes are easily prepared by the action of acetylenic Grignard reagents upon ethyl formate. ... 

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