Butyllithium reaction with aldehydes

The ylide obtained from (methyl)triphenylphosphonium bromide reacts with morpholine derivatives 597 to give phosphonium salts 598 which upon treatment with -butyllithium are converted to new ylides 599. In a reaction with aldehydes, ylides 599 form iV-(l,3-disubstituted allyl)-morpholines 602 (Scheme 94) <1996AQ138>. Another less common nucleophile that can be used for substitution of the benzotriazolyl moiety in Af-(a-aminoalkyl)benzotriazoles is an adduct of iV-benzylthiazolium salt to an aldehyde which reacts with compounds 597 to produce adducts 600. Under the reaction conditions, refluxing in acetonitrile, salts 600 decompose to liberate aminoketones 601 <1996H(42)273>. 

Trifluoromethyl)furan 147 was prepared in 67% yield by heating 4-methyl-oxazole 5 and 3,3,3-trifluoropropyne in toluene at 180°C for 13 h (Fig. 3.44). Metalation of 147 at the 2 position with n-butyllithium and subsequent reaction with aldehydes gave 3-(trifluoromethyl)-2-furyl carbinols 148. ... 

Reactions with Aldehydes and Ketones. The carbanion derived from the treatment of (Me0)2P(0)CH(SMe)2 with a base reacts with cyclic and acyclic, aliphatic and aromatic aldehydes and ketones in a Horner—Wadsworth—Emmons reaction to give ketene 5,5-thioacetals in high yields " (eq 2 ). The carbanion is generated using either butyllithium in THE at —78 °C > or, less commonly, sodium hydride in DME. Alternatively, with aromatic aldehydes the reaction may be performed under two-phase conditions using benzyltriethylammonium chloride (TEBA) as a phase-transfer catalyst. ... 

Phosphoniosilylation. Cyclic enones treated with TBDMS triflate and triphenylphosphine in THF at it provide the corresponding l-(3-f-butyldimethylsilyloxy-2-cycloalkenyl)triphenyl-phosphonium triflates (eq 8) which, upon lithiation with n-butyllithium followed by Wittig reaction with aldehydes, afford various conjuated dienes. ... 

Epoxysilanes may be prepared by a variant of this approach. Lithiation of chloromethyItrimethyIsilane with 5ec-butyllithium gives an a-chloro carbanion which affords epoxysilanes on reaction with aldehydes and ketones. 

Another approach to a-silyl carbanions involves Sn-Li exchange reaction of a-stannylsilanes using BuLi [257, 258]. Transmetallation of a-stannylalkylsilanes 140 with butyllithium affords the corresponding lithium reagents, which are then suitably predisposed for the Peterson reaction with aldehydes to give the corresponding alkenes (Scheme 2.90) [259]. 

The titanium species derived from sequential treatment of a-alkoxy-substituted allylsilanes with s-Butyllithium then Ti(0-i-Pr)4 engages in a Peterson alkenation reaction with aldehydes to give, via electrophilic attack at the a-terminus of the allyl anion, 2-oxygenated 1,3-butadienes which can be hydrolyzed to the corresponding vinyl ketone (eq 19). ... 

In ( )-[2-(l-propenyl)-l, 3-dithian-2-yl]lithium, no problem of EjZ selectivity arises. It is easily prepared by deprotonation of the allylic dithiane87,88 with butyllithium in THF, whereas deprotonation of the 2-propylidene-l, 3-dithiane requires the assistance of HMPA. The addition to saturated aldehydes proceeds with excellent y-regioseleetivity and anti selectivity88,89. As often observed in similar cases, aldehydes which bear an, p2-carbon atom adjacent to the carbonyl group give lower selectivities. The stereoselectivity decreases with ketones (2-bu-tanone y/a 84 16, antiisyn 77 23)88. The reaction with ethyl 2-oxopropanoate is merely nonstereoselective90, but addition of zinc chloride improved the syn/anti ratio to 96 4, leading to an efficient synthesis of ( )-crobarbatic acid. 

Metalation ofa-sulfinyl dimethylhydrazones with terf-butylmagnesium bromide, butyllithium or lithium diisopropylamide, and reaction of the generated azaenolates with aldehydes, provides aldol adducts (e.g., 6) as mixtures of diastereomers. Reductive desulfurization leads to fi-hydroxy dimethylhydrazones (e.g., 7) which are cleaved to the desired /(-hydroxy ketones in 25% overall yield10 u. The enantiomeric excesses are about 50%, except for (- )-3-hydroxy-4-methyl-1-phenyl-1-pentanone (8) which was obtained in 88% ee. 

Metalation of 4,5-dihydro-2-[(7 )-sulfinylmethyl]oxazoles (e.g., 2) with butyllithium at -90 C and reaction of the chiral azaenolates with aldehydes furnishes the hydroxyalkylated sulfinylox-azole derivatives 3 which are desulfurized to give the 4,5-dihydro-2-(2-hydroxyalkyl)oxazoles 4. The corresponding 3-hydroxy acids 5 are obtained by acidic hydrolysis in 60-85% overall yield and 26-53% ee31. 

Trimethylsilylepoxides can be prepared by an addition-cyclization process. Reaction of chloromethyltrimethylsilane with sec-butyllithium at very low temperature gives an a-chloro lithium reagent that leads to an epoxide on reaction with an aldehyde or ketone.291... 

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. 

The C-H bond in CBnHi2 and related anions can be metallated by butyllithium and then converted into C-substituted anions with aldehydes, alkyl halides, Ph3SiCl, and Ph2PCl.322-329 C-halogenated (F,Cl,Br, or I) derivatives are made from the C-copper derivative with (PhS02)2NF or the corresponding N-halosuccinimide.330 The l-Me-2,3>4,5,6,7,8,9,10,ll>12-Fu-CBii- anion is made from the reaction of the corresponding Fn anion with... 

The metalation of vinyl ethers, the reaction of a-lithiated vinyl ethers obtained thereby with electrophiles and the subsequent hydrolysis represent a simple and efficient method for carbonyl umpolung. Thus, lithiated methyl vinyl ether 56 and ethyl vinyl ether 54, available by deprotonation with t- or n-butyllithium, readily react with aldehydes, ketones and alkyl halides. When the enol ether moiety of the adducts formed in this way is submitted to an acid hydrolysis, methyl ketones are obtained as shown in equations 72 and 73 . Thus, the lithiated ethers 56 and 54 function as an acetaldehyde d synthon 177. The reactivity of a-metalated vinyl ethers has been reviewed recently . 

An important complement to the Wittig reaction is the reaction of phosphonate carbanions with carbonyl compounds.151 The alkylphosphonate esters are made by the reaction of an alkyl halide, preferably primary, with a phosphite ester. Phosphonate carbanions are more nucleophilic than an analogous ylide, and even when R is a carbanion-stabilizing substituent, they react readily with aldehydes and ketones to give alkenes. Phosphonate carbanions are generated by treating alkylphosphonate esters with bases such as sodium hydride, w-butyllithium, or sodium ethoxide. Alumina coated with KF or KOH has also found use as the base.152... 

Few reports describe reactions of substituents at the benzene ring of benzotriazoles. The facile deprotonation of the methyl group in N-Boc-7-methyl-1-aminobenzotriazole (403) with butyllithium followed by reactions with electrophiles gives substituted products (404) (Scheme 78). The electrophile can be an alkyl halide, an aldehyde or a ketone, and the Boc group is removed by brief exposure to CF3CO2H in CH2CI2 <93TL6935>. 1-Acetylbenzotriazole (405) is hydrolyzed to form 3-(177-5-hydroxybenzotriazol-6-yl)propionic acid (406), which is then converted (Scheme 79) to... 

The protocol is used for the preparation of 25 kg of the aldehyde in Banyu, and applied to the synthesis of a muscarinic receptor agonist. It is noteworthy that halogen-metal exchange reactions with other metal reagents such as butyllithium or isopropylmagnesium bromide led to more complex mixtures. The Banyu protocol was applicable to similar monoformylation reactions of dibromoheteroarenes (Table 12). 

The use of 4-bromo-3-formylthiophene (175) led to the third classical thieno[3,4-6]thiophene (8) via analogous reactions. The aldehyde (175) was protected by ketalization, and then subjected to bromine-metal exchange with n-butyllithium to give a lithio derivative which was reacted with sulfur, followed by methyl chloroacetate. The resulting ester-aldehyde derivative (176a) was condensed under the influence of base to give, after decarboxylation, thieno[3,4-6]thiophene (8 Scheme 61) <76AHC(19)123). 

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