Alkyl halides with 3-diketones

In practice this reaction is difficult to carry out with simple aldehydes and ketones because aldol condensation competes with alkylation Furthermore it is not always possi ble to limit the reaction to the introduction of a single alkyl group The most successful alkylation procedures use p diketones as starting materials Because they are relatively acidic p diketones can be converted quantitatively to their enolate ions by weak bases and do not self condense Ideally the alkyl halide should be a methyl or primary alkyl halide... 

OL Alkylation of aldehydes and ketones (Section 18.15) Alkylation of simple aldehydes and ketones via their enolates is difficult. p-Diketones can be converted quantitatively to their enolate anions, which react efficiently with primary alkyl halides. 

Hydroxymethy lene compounds are O-alkylated by potassium carbonate and an alkyl halide in acetone, but these conditions produce only the usual C-alkylation with /J-diketones or keto esters.423 Nitro-compounds have also been reported to give either O- or C-alkylation.424 While acylation of the sodium derivative of acetoacetic ester normally takes place on carbon, O-acylation is the result in pyridine. 

Little is known so far about a-ketoenamines, probably because they are sometimes not directly accessible from the corresponding diketones. Nevertheless, they are useful synthones, especially for heterocyclic synthesis. Compared with / -ketoenamines, the chemical behaviour of the a-keto-derivatives is somewhat different. They react as enamines, as well as a,/ -unsaturated ketones, which means that they act either as an electrophile or as a nucleophile in the -position. For example, protonation usually occurs at the fi-C atom with subsequent enolization308. Aminomethylation according to Mannich takes place in the -position as well309. The alkylation with alkyl halide, however, is reported to occur at nitrogen310,311. In addition to electrophilic and nucleophilic chemistry, a-ketoenamines are useful synthons in photochemistry and electrocyclic reactions. 

When ethoxide is used as a base to abstract a-proton, it could react with the alkyl halide (Sn2) to form ether. However, the acid-base equilibrium with the diketone prefers the more stable, less basic enolate over the ethoxide, essentially consuming the ethoxide. Thus, the very stable enolates from 1,3-dicarbonyl compounds are able to undergo Sn2 reactions with alkyl halides without competition from the alkoxide catalyst. 

Reaction of 1-benzyl-2,5-dicyanopyrrolidine with an alkyl halide gives unsymmetiical 2,5-dialkylated products (47) in high yield. Hy -olysis of (47) provides a y-diketone, which serves as a precursor for jas-mone analogs (Scheme 22). ... 

Direct alkylation of P-diketones may be accomplished with reactive alkylating reagents such as primary alkyl iodides and allylic and benzylic halides. 

Allylic 3-(benzotriazoM-yl)-3-ethoxyalkenes are conjugated acyl anion equivalents. Thus, deprotonation with BuLi and reaction with alkyl halides or esters furnish enones and unsaturated a-diketones," respectively. l-(Benzotriazol-l-yl)-3-(diphenylphosphoryl)-l-ethoxy-l-propene is a propanoic ester P, 3-dianion equivalent. 

The titanium(IV) chloride-promoted reactions of enol silyl ethers with aldehydes, ketones, and acetals, known as Mukaiyama reaction, are useful as aldol type reactions which proceed under acidic conditions (eq (23)) [20], Enol silyl ethers also undergo the Michael type reactions with enones or p.y-unsaturated acetals (eq (24)) [21]. Under similar reaction conditions, enol silyl ethers are alkylated with reactive alkyl halides such as tertiary halides or chloromethyl sulfides (eq (25)) [22], and acylated with acid halides to give 1,3-diketones (eq (26)) [23]. 

For d1 reagents which will add Michael fashion to any unsaturated carbonyl compound, amino-nitriles are best. They were invented by Stork13 for this very purpose and used in his cis jasmone 65 synthesis. This TM has perhaps been more synthesised than any other, though its simple structure and obvious enone disconnection to 66 make it a rather uninspiring choice these days. The 1,4-diketone 66 does indeed cyclise to 65 presumably under thermodynamic control, and the double disconnection 66 [cf. the disconnection of pyrenophorin 23] requires a d1 reagent that will react with enones 67 in the Michael sense and with alkyl halides 69. 

The amino nitrile 70 is simply and cheaply made (90% yield) and does react with alkyl halides.14 Aldehydes are easily released from 71 with aqueous oxalic acid. After a second alkylation or Michael addition an even milder method of hydrolysis, aqueous Cu(II) salts at near neutrality, releases diketones such as 57. Cyclisation in base gives m-jasmonc13 65. 

A one-step synthesis of this alkaloid is consequent upon the reaction of thallous salts of nonchelated j8-diketones with alkyl halides. In the present instance the thallous salt of 4-hydroxyquinolone (93) reacted with 3-chloro-3-methyl-l-butyne to generate flindersine (94) in 28% yield 111). 

The a-diketones, e.g. (37), made by oxidation of benzoin or acyloin products, can be converted into acetylenes either by removing both oxygens with P(OR)j or via the 6is-hydrazone (38) and oxidation with Hg(ll). This method is useful for acetylenes such as (39) which cannot be made by displacement on alkyl halides by acetylide ion (Chapter 16). In this case, the starting material (37) is made from benzoin (Chapter 23) by nitric add oxidation. 

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