Carbonylation alkyl halides

At-Phenyltriflamide is a useful reagent for the mdd oxidation of alkyl halides to carbonyl compounds through a multistep one-pot procedure [II2] (equation 56)... 

Iron-acyl enolates such as 1, 2, and 3 react readily with electrophiles such as alkyl halides and carbonyl compounds (see Houben-Weyl, Vol. 13/9a p418). The reactions of these enolatc species with alkyl halides and similar electrophiles are discussed in Section D.1.1.1.3.4.1.3. To date, only the simple enolates prepared by a-deprotonation of acetyl and propanoyl complexes have been reacted with ketones or aldehydes. 

The procedure involves C-alkylation of an a-sulfonyl carbanion derived from 245 with alkyl halides or carbonyl compounds, followed by cleavage of the cyclopropanols 247 produced by deprotection of the hydroxy group of 246 to give (E)-substituted aldehydes141. 

Rhodium catalyzed carbonylations of olefins and methanol can be operated in the absence of an alkyl iodide or hydrogen iodide if the carbonylation is operated in the presence of iodide-based ionic liquids. In this chapter, we will describe the historical development of these non-alkyl halide containing processes beginning with the carbonylation of ethylene to propionic acid in which the omission of alkyl hahde led to an improvement in the selectivity. We will further describe extension of the nonalkyl halide based carbonylation to the carbonylation of MeOH (producing acetic acid) in both a batch and continuous mode of operation. In the continuous mode, the best ionic liquids for carbonylation of MeOH were based on pyridinium and polyalkylated pyridinium iodide derivatives. Removing the highly toxic alkyl halide represents safer, potentially lower cost, process with less complex product purification. 

Sulfur compounds are useful as nucleophilic acyl equivalents. The most common reagents of this type are 1,3-dithianes, which on lithiation provide a nucleophilic acyl equivalent. In dithianes an umpolung is achieved on the basis of the carbanion-stabilizing ability of the sulfur substituents. The lithio derivative is a reactive nucleophile toward alkyl halides and carbonyl compounds. 11... 

Vinyl halides (example 17, Table VII) were first observed by Kroper to form acrylic esters by reaction with carbon monoxide under pressure and tetracarbonylnickel in methanol at 100°C. These reactions were later shown to occur under much milder conditions. Highly stereospecific reactions were observed c/s-vinyl halides gave cis-carbonylation products and trans-vinyl halides trans-carbonylation products (example 18, Table VII). Retention of configuration of alkyl substrates in carbonylation seems to be a general feature in carbon monoxide chemistry (193a). 

Addition of Bu3SnLi or McsSnI.i to 4-t-butylcyclohexanone affords mixtures of trans and cis adducts in ratios that depend on reaction conditions (Table ll)68. In THF, a 93 7 mixture is obtained with both reagents. This ratio is thought to represent the thermodynamic distribution—the axial stannane being favored. In ether, the cis isomer predominates, suggesting a kinetic preference for equatorial addition. Each of the two isomers can be lithiated with BuLi. Subsequent treatment with alkyl halides or carbonyl compounds affords the substituted alkoxy cyclohexanes with retention of stereochemistry. 

Acceptor-substituted allenes can be prepared from the corresponding propargyl precursors by prototropic isomerization (see Section 7.2.2). Conversely, such allenes can also be used to synthesize propargyl compounds. For example, treatment of the sulfoxides 417 with 1 equivalent of a lithiation reagent leads to the intermediates 418, which furnish propargyl sulfoxides 419 by hydrolysis (Scheme 7.55) [101]. If the electrophiles used are not protons but primary alkyl halides or carbonyl compounds, the products 420 or 421, respectively, are formed by C,C linkage. 

Alkylation at the 2-position can be achieved by formation of the anion with sodium hydride in 1,2-dimethoxyethane (DME) at 0°C followed by reaction with an alkyl halide at room temperature. Alternatively, selective alkylation at C-4 Involves sequential treatment with sodium hydride (at 10°C) and butyllithlum in DME (at -40°C) to form the dianion, followed by kinetic alkylation with an alkyl halide (or carbonyl compound). ... 

The metalated hydrazones are alkylated by alkyl halides, dialkyl sulfates or alkyl sulfonates at low temperatures in tetrahydrofuran (—95°C) or diethyl ether (— 110°C) to form the a-sub-stituted hydrazones in nearly quantitative yields. The ambident azaenolates react exclusively at the C-terminus side products resulting from N-, di-, or polyalkylation are not observed. The crude alkylated hydrazones can be purified by distillation or silica gel chromatography (diethyl ether/pentane) without epimerization. However, in most cases, they are pure enough to be directly cleaved to the desired alkylated carbonyl compound. 

E+ = alkyl halides, epoxides, carbonyl compounds, 2,/1-unsaturated carbonyl compounds... 

Other additions, such as addition of alkyl halides and carbonyl compounds, are discussed in Chapter 5, whereas Chapter 7 covers addition reactions involving carbon monoxide (hydroformylation, carboxylations). Hydrogen addition is discussed in Chapter 11. The nucleophilic addition of organometallics to multiple bonds is of great significance in the anionic polymerization of alkenes and dienes and is treated in Chapter 13. 

Reissert compounds (cf Section 3.2.1.6.8.iv) can be deprotonated (NaH/HCONMe2) to give anions (e.g. 507) which react with electrophiles to give intermediates (508) which can be hydrolyzed to substituted heterocycles (509). Electrophiles utilized include alkyl and reactive aryl halides and carbonyl compounds. 

Oxathiolane 3,3-dioxide (332) metallates in its 2-position to yield an anion which reacts with various electrophiles (alkyl halides and carbonyl compounds) to give substituted oxathiolanes (333) in good to excellent yield (79TL3375). Pyrolysis of these alkylated products affords the corresponding aldehydes or 2-hydroxyaldehydes in addition to sulfur dioxide and isobutylene (Scheme 71). The oxathiolane (332) thus becomes another member of the already burgeoning class of carbonyl anion equivalents. 

Trialkylaluminums, 21 By geminal alkylation of carbonyl groups Dichlorodimethyltitanium, 216 From reduction of alkyl halides, alkyl sulfonates and similar compounds From acetates or other esters Triphenylsilane, 334 From alcohols... 

The ring opening of tetrahydro-l,3-oxazines to aldehydes has recently found wide application through the work of Meyers.2-3 2-Alkylidene-tetrahydro-l,3-oxazines, prepared from the readily available 5,6-dihydro-4//-1,3-oxazines, possess strong nucleophilic properties and can react with alkyl halides and carbonyl compounds. The derivatives so obtained can be reduced to tetrahydro-l,3-oxazines, and through ring opening the latter can furnish acyclic, alicyclic, and a,jS-unsaturated aldehydes and their C-l deuterated derivatives.221-223 228... 

Enals vinyl silyl ketones.1 The anion of I reacts smoothly with va rious electrophiles (alkyl halides, epoxides, carbonyl compounds). The products are converted to (E)-enals by oxidation with 30% H202. 

Dinuclear carbonyl complexes, with copper, 2, 187-188 Dinuclear chromium(III) complexes, with halides, alkyls, aryls, 5, 317... 

An alkyl halide can undergo an elimination reaction if it has a susceptible proton situated on a (1-carbon, i.e. the carbon next to the C-X group. This proton is lost during the elimination reaction along with the halide ion. In some respects, there is similarity here between alkyl halides and carbonyl compounds (Following fig.). Alkyl halides can have susceptible protons at the (1-position whilst carbonyl compounds can have acidic protons at their a-position. By comparing both structures, it can be seen that the acidic/ susceptible proton is attached to a carbon neighbouring an electrophilic carbon. 

Also ketones and aldehydes react with the lithiated bis-lactim ether 7 with rather high asymmetric induction to give the aldol-type adduct 13 (Table 2). Like alkyl halides, the carbonyl compounds enter trans to the methyl group at C-6 i.e. (R)-configuration is induced at C-3 13). 

Oxathiolane 2,2-dioxide undergoes metallation with n-butyllithium as expected at the 3-position (81JOC101). The anion may be alkylated with alkyl halides or carbonyl compounds. The isomeric 1,3-oxathiolane 3,3-dioxides also undergo metallation ortho to the sulfone and, when the 4-position is blocked, metallation at the 2-position may be used as an efficient conversion of alkyl halides into aldehydes as shown in Scheme 22 (79TL3375). 

We have already encountered one type of organometallic compound with a negative charge on carbon sodium acetylides, covered in Section 9-7. Terminal alkynes are weakly acidic, and they are converted to sodium acetylides by treatment with an unusually strong base, sodium amide. These sodium acetylides are useful nucleophiles, reacting with alkyl halides and carbonyl compounds to form new carbon-carbon bonds. 

You have now seen how enols and enolates react with electrophiles based on hydrogen (deuterium), carbon, halogens, silicon, sulfur, and nitrogen. What remains to be seen is how new carbon-carbon bonds can be formed with alkyl halides and carbonyl compounds in their normal electrophilic mode. These reactions are the subject of Chapters 26-29. We must first look at the ways aromatic compounds react with electrophiles. You will see similarities with the behaviour of enols. 

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