Formylation reactions alkyl halides

The formylation reaction is a mixed success. While the coupling of aryl, vinyl, or allyl halides (triflates) is effective, quite often the conditions are harsh. The formylation of alkyl halides or hydroformylation olefins and acetylenes with palladium is not the method of choice for preparing the corresponding aldehydes. 

The triazole 76, which is more accurately portrayed as the nucleophilic carbene structure 76a, acts as a formyl anion equivalent by reaction with alkyl halides and subsequent reductive cleavage to give aldehydes as shown (75TL1889). The benzoin reaction may be considered as resulting in the net addition of a benzoyl anion to a benzaldehyde, and the chiral triazolium salt 77 has been reported to be an efficient asymmetric catalyst for this, giving the products (/ )-ArCH(OH)COAr, in up to 86% e.e. (96HCA1217). In the closely related intramolecular Stetter reaction e.e.s of up to 74% were obtained (96HCA1899). 

The (V-methyldihydrodithiazine 125 has also been used as an effective formyl anion equivalent for reaction with alkyl halides, aldehydes, and ketones (77JOC393). In this case there is exclusive alkylation between the two sulfur atoms, and hydrolysis to give the aldehyde products is considerably easier than for dithianes. However, attempts to achieve a second alkylation at C2 were unsuccessful, thus ruling out the use of this system as an acyl anion equivalent for synthesis of ketones. Despite this limitation, the compound has found some use in synthesis (82TL4995). 

Lithioisothiazoles (72AHC(l4)l) and 2-lithiothiazoles undergo many of the expected reactions, including carbonization (with C02), formylation (with DMF), alkylation (with alkyl halides), acylation (with acid anhydrides), halogenation (with Br2 or I2), etc. 

The classical procedure for the reaction involves heating the alkyl halide (usually the chloride or bromide) with sodium or potassium cyanide in metha-nolic or ethanolic solution. The method is clearly of value for the extension of the carbon chain by one carbon atom, since the cyano group may be converted into a carboxyl group by hydrolysis (Section 5.11.2, p. 671) or into an amino-methyl group (—CH2-NH2) by reduction (Section 5.16.1, p. 771), or into a formyl group by controlled reduction to the imine followed by hydrolysis (Section 5.7.4, p. 594). ... 

This mechanism is quite general for this substitution reaction in transition metal hydride-carbonyl complexes [52]. It is also known for intramolecular oxidative addition of a C-H bond [53], heterobimetallic elimination of methane [54], insertion of olefins [55], silylenes [56], and CO [57] into M-H bonds, extmsion of CO from metal-formyl complexes [11] and coenzyme B12- dependent rearrangements [58]. Likewise, the reduction of alkyl halides by metal hydrides often proceeds according to the ATC mechanism with both H-atom and halogen-atom transfer in the propagation steps [4, 53]. 

While porphyrins are famed for their substitutional flexibility [39], available corroles were initially restricted to a few compounds with small alkyl substituents at the (3-pyrrole positions. However, the library of free-base corrole complexes has expanded greatly since the advent of new syntheses, [4CM-2] especially those which allowed for the synthesis of corroles with aryl or alkyl substituents at the meso positions [29, 43] with no (3-substituents. These can be derivatized by a variety of electrophilic substitution reactions [44-47] to place nitro, formyl, sulfonate, and halide groups on the ring. 

Hydride Transfer Reactions of Metal Formyl Complexes. We have found that metal formyl complexes can act as hydride donors to electrophiles such as ketones, alkyl halides, and metal carbonyls. EUNHrans-[ (CeHsO) 3P] (CO) 3FeCHO" reacts with 2-butanone overnight at ambient temperature to give a 95% yield of 2-butanol. The possibility that 2-butanone is reduced by (CO)4FeH formed in situ from decomposition of the metal formyl complex is excluded since the metal formyl complex reacts with 2-butanone much faster than it decomposes to (CO)4FeH and since no reaction between (CO)4FeH and 2-butanone was observed by IR spectroscopy. 

Alkylations. Treatment of 1 with various primary alkyl halides provides the corresponding substituted dithianes (eqs 3-5 ). Removal of the dithiane under the Lewis acid conditions, illustrated in eqs 3-5, unmasks the acyl silane for subsequent transformations such as photolysis, radical reactions, and heterocyclic synthesis. Other conditions for removing the dithiane moiety of 2-substituted-2-f-butyldimethylsilyl-l,3-dithianes include anodic oxidation, ceric ammonium nitrate (CAN)/NaHC03 in CH3CN/H2O, iodomethane/CaC03 in THF/H20, 8 and l2/CaC03 in THF/H2O. The formyl sUane of 2-t-butyl-dimethylsilyl-l,3-dithiane has also been reported." ... 

C-Alkylations of or-formyl esters are usually impractical, but if the thallium(l) salts of these compounds are used then reasonable yields can be realized given that the extent of enolization is small and that the electrophile is not bulky. Acetoacetic esters can undergo mono-C-alkylation with both alkyl halides and alkyl sulphates by absorbing the ester onto basic alumina and then treating this with neat alkylating reagent. Yields are 50—76% but long reaction times are... 

Reaction of /3-ketoaldehydes with potassamide in liquid ammonia and addition of alkyl halide leads to alkylation at the methylene site remote from the aldehydo group e.g. Fig. 1.46. The formyl group can then be removed by treatment with alkali. This comparatively recent method of protection has been... 

Formylation of an alkyllithium (1, 280).1 Formylation of an alkyllithium or a Grignard reagent with DMF (Bouveault reaction) is generally unsatisfactory because of side reactions. However, sonication of the mixture of an alkyl or aryl halide, lithium, and DMF substantially improves the rate and the yield. The method is applicable to primary, secondary, and tertiary bromides or chlorides. Typical yields are in the range 65-85%. 

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