Ketones reactions with lithiated

Among the carbon electrophiles, carbonyl compounds [113,114] were first applied in the reaction with lithiated ferrocenylalkyl amines (Sect. 4.S.3.3 and Fig. 4-18). Analogously, carboxylic acids are obtained from CO2 [153]. The reactivity pattern of palladated ferrocenylalkyl amines with carbon electrophiles is somewhat different. Carbon monoxide in alcohols leads to the formation of esters of substituted ferrocenecarboxylic acids [124]. With prochiral alcohols, a moderate asymmetric induction is observed [154]. a, -Unsaturated ketones react with palladated ferrocenylalkyl amines not with addition to the carbonyl group, but with substitution of a hydrogen at the carbon—carbon double bond, allowing the introduction of longer side chains at the ferrocene ring (Fig. 4-27c) [124, 152]. 

Lithiated indoles can be alkylated with primary or allylic halides and they react with aldehydes and ketones by addition to give hydroxyalkyl derivatives. Table 10.1 gives some examples of such reactions. Entry 13 is an example of a reaction with ethylene oxide which introduces a 2-(2-hydroxyethyl) substituent. Entries 14 and 15 illustrate cases of addition to aromatic ketones in which dehydration occurs during the course of the reaction. It is likely that this process occurs through intramolecular transfer of the phenylsulfonyl group. 

Isoxazolyl Grignard reagents react normally in that a 4-carboxylic acid or 4-methanol can be obtained by reaction with CO2 or ketones (63AHC(2)365). Lithiation of 3,5-disub-... 

Mixtures of anhydrous hydrogen fluoride and tetrahydrofuran are successfully used as fluorinating agents to convert 1,1,2-trifluoro-l-allcen-3-ols, easily prepared from bromotrifluoroethene via lithiation followed by the reaction with aldehydes or ketones, to 1,1,1,2-tetrafluoro-2-alkenes The yields are optimal with a 5 1 ratio of hydrogen fluoride to tetrahydrofuran The fluorination reaction involves a fluonde lon-induced rearrangement (Sf,j2 mechanism) of allylic alcohols [65] (equation 40)... 

The effect of substrate structure on product profile is further illustrated by the reactions of cis- and trons-stilbene oxides 79 and 83 with lithium diethylamide (Scheme 5.17) [32]. Lithiated cis-stilbene oxide 80 rearranges to enolate 81, which gives ketone 82 after protic workup, whereas with lithiated trans-stilbene oxide 84, phenyl group migration results in enolate 85 and hence aldehyde 86 on workup. Triphenylethylene oxide 87 underwent efficient isomerization to ketone 90 [32]. 

The titaniated (25)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazines derived from cyclo(L-Val, Gly) or cyclo(L-Val, Ala) (1, R1 = H, CH3) react with a,/I-unsaturatcd aldehydes exclusively by 1.2-addition (cf. nearly exclusive 1,4-addition of ,//-unsaturated ketones with cuprate complexes of 2,5-dialkoxy-3,6-dihydropyrazines, see Section D. 1.5.2.3.1.4.) in a highly diastereoselective mode to give virtually only the (l S,2R)-diastereoniers 2 ". In reactions with the corresponding lithiated pyrazines both regioselectivity and diastereofacial differentiation at C-2 are also remarkably high (dc 95 %), but the diastereomeric excess at C-l is substantially smaller (30 50%) ... 

This is known as the directed aldol reaction. Similar reactions have been performed with oc-lithiated dimethylhydrazones of aldehydes or ketones and with a-lithiated... 

In THF at -20°C the N-trimethylsilylated 2-pyrrolidinone 388 is converted by LDA into the a-anion which, on reaction with 1949 and subsequent acidification with AcOH, gives 43% 3-hydroxy-2-pyrrolidinone 1962 [150]. Lithium enolates of ketones such as camphor react with BTSP 1949 to give >95% of a mixture of exo-and mdo-2-hydroxycamphor [151]. Lithiated methyl heterocycles such as lithiated 2-methylpyridine 1963 are converted into mixtures of the 0-SiMe3 1964 and C-SiMe3 1965 compounds and C-methylated compounds such 1966 [152]. 2-Lithioto-luene 1967 is oxidized by 1949 into 1968 [140, 145] (Scheme 12.42). 

A phenyl substituent at the y-carbon atom is a much weaker electron donor in comparison with the discussed above ethoxy and morpholin-4-yl groups. Nevertheless, l-(y-phenylallyl)benzotriazole 484 is still lithiated exclusively at the carbon a as it is evident from its reaction with aldehydes and ketones leading to dienes 486, resulting from... 

Similarly, polysulfone has been sulfophenylated by lithiation and anionic reaction with 2-sulfobenzoic acid cyclic anhydride (Figure 12). This provides another method to modify polysulfones by attaching pendant sulfonated phenyl groups via ketone links. It would be interesting to see if the phase separation in these materials was affected by the additional functionality of the ketone or the pendant attachment of the sulfonic acid, as opposed to direct attachment of ionic groups to the aromatic polymer backbone. 

High levels of iyn-diastereoselectivity have been achieved on reaction of lithiated chiral phosphine oxides [apparently existing as rapidly equilibrating diastereomeric lithiated species such as RCH(Me)CHLiP=0(Ph)2] with electrophilic ketones, esters or MesSiCl. ... 

O-Protection of this 2-pyridone was followed by lithiation to give 271 with BuLi and i-PriNH followed by reaction with a diastereoisomeric mixture of the aldehyde 272. Oxidation gave a diastereoisomeric mixture of the ketones 273 whose deprotection yields a stereoisomeric mixture of 255. 

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

The benzenesulfonyl substituent has also been used in conjunction with the lithiation of an azaindole derivative (86FRP2574406 89FRP26274931), and thus 1-benzenesulfonyl-1//-pyrrolo[3,2-c ]pyridine was able to be successfully lithiated and alkylated with p-methoxybenzaldehyde, although reaction with more hindered ketones could not be achieved (Scheme 19)[91JCS(P1)3I73]. 

Very little attention has been given to the metalation of the quinoxaline system, although lithiation of the 2-methoxy and 2-methylthio derivatives has recently been achieved (Scheme 118) (91JHC765). Reaction with N-methoxy-/V-methylbenzamide occurred at -78°C to give the analogous phenyl ketones in moderate yield. Highly colored insoluble solids were also produced, and these were the sole products when metalation of 2-chloroquinoxaline was attempted. 

The metalation chemistry of the imidazoline system has received attention only recently, with the lithiation of l-benzyl-2-imidazoline being found to occur at the 2-position (90TL1767). Although the reactivity of the lithi-ated species with alkyl halides was poor, better results were achieved with disulfide and carbonyl electrophiles (90TL1767,90TL1771). The products formed by reaction with ketones were found to be unstable with respect to fragmentation, and this result was utilized to provide a new route for the synthesis of unsymmetric ketones (Scheme 138). 

In contrasi to many acetylenes RCsCH, chloroacetylene can be successfully coupled with ketones in liquid ammonia via the lithium compound [80,85], The excellent yield in the reaction with acetone indicates that practically no formation of enolate occurs. Similar good results have been obtained with lithiated ethynyl thioethers, (LiCsCSR), lithiated enyne thioethers, (LiCsCCH=CHSR), lithiated 1,3-diynes (RC=CC=CLi), and lithiated aiylacetylenes (LiCsCAryl)[2], A possible explanation for the small extent of enolization of the ketone is that all these acetylides are less basic due to some stabilization of the anion. 

In contrast to the chemical properties of enolates, azaenolates of imines exhibit a marked thermodynamic preference for the syn configuration at the C-N partial double bond (syn effect)2 due to the repulsion between the lone pair density at nitrogen and the 7t-electron density at the carbon. Thus, lithiation of imines derived from ketones occurs with strong regioselectiv-ity at the least substituted carbon, followed by a regioselective reaction with electrophiles exclusively at the carbon of the ambident azaalkyl moiety. 

Chiral 2,2-disubstituted cyclobutanones have been obtained by asymmetric rearrangement of chiral sulfinyl- 177,178 and sulfanylcyclopropanes.179 Using readily available cyclopropyl 4-tolyl (/ )-sulfoxide (l),180 the requisite sulfinylcyclopropanes 3 and 3 were obtained by a sequence of lithiation, reaction with carboxylic acid esters and stereoselective addition of Grignard reagents to the ketones 2 thus formed.178 The corresponding sulfanylcyclopropanes 4 and 4 resulted from a sequence of protection, reduction and deprotection.179... 

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