Aldehydes by ozonolysis

The double bond in 7 is cleaved to an aldehyde by ozonolysis (see Chapter 5) and subsequent reductive workup with tnbutylphos-phine Crotylation with reagent 25.15 developed by Brown, produces only a single diastereomer, which is then transformed into benzoate 8 with benzoyl chloride in pyridine. 

A different oxidative approach toward die preparation of aldehydes uses tire ozonolysis of vinyl groups. If a vinyl group is present in a molecule, it can be oxidatively cleaved to an aldehyde by ozonolysis. This process cleaves tire carbon-carbon double bond, but it is mild and very successful in many cases. 

Resolution of a-substituled aldehydes. The SASP hydrazones of a-substituted aldehydes can be resolved by high-performance liquid chromatography. The separahility factors are sufficient for analytical and preparative purposes. The (S,S)-isomer elutes consistently before the (S,R)-isomer. Both isomers can be cleaved to the enantiomerically pure aldehydes by ozonolysis or acid hydrolysis, with resolution yields of 35-70%. 

In the preparation of aldehydes by ozonolysis of alkenes, it is important to add the correct amount of ozone to the solution because an excess of O3 can lead to side reactions. Ozonolysis in alcoholic solvents traps the carbonyl oxide as a hydroperoxide. Dimethyl sulfide reduces hydroperoxides under very mild conditions and generates the corresponding aldehydes in excellent yields. This workup procedure is recommended when the aldehyde is the desired reaction product. 

Hydroformylation and hydrocyanation The reagent adds to nitroalkenes, giving adducts that are transformed into nitro aldehydes by ozonolysis and into nitro nitriles by treatment with a peracid. 

Nucleophiles other than hydrides can be used, such as aUylsilanes, siloxy-dienes, or silyl enol ethers, to access substituted THPs from cyclic ketals. Rych-novsky et al. and Wipf et al. synthesized one THP of leucascandrolide A from ketal 76 by using a nucleophilic addition of aUylsilane in the presence of BF3 Et20. The diastereoselectivity of the reaction was explained by an axial attack on the half-chair oxocarbenium intermediate. The double bond was then transformed into the corresponding aldehyde by ozonolysis to afibrd further functionalizations (Scheme 38) (2001JA8420 2002CC2066). 

In Chapter 8 we also saw how this procedure has utility in structure determination. The following examples illustrate the synthesis of aldehydes by ozonolysis of alkenes. 

We have seen three laboratory methods for the preparation of ketones in earlier chapters 1. Ketones (and aldehydes) by ozonolysis of alkenes (discussed in Section 8.17B). 

Merrifleid resin, MBHA, or (Met)Expansion, X = Fmoc, Boc Figure 12. Synthesis of peptide aldehydes by ozonolysis of the linker. 

The final step can involve introduction of the amino group or of the carbonyl group. o-Nitrobenzyl aldehydes and ketones are useful intermediates which undergo cyclization and aromatization upon reduction. The carbonyl group can also be introduced by oxidation of alcohols or alkenes or by ozonolysis. There are also examples of preparing indoles from o-aminophcnyl-acetonitriles by partial reduction of the cyano group. 

As mentioned previously, aldehydes can be prepared by Stephen s method of reduction of nitriles by stannous chloride (37, 91). Polaro-graphic reduction of thiazolecarboxylic acids and their derivatives gives lower yields of aldehydes (58). Ozonolysis of styrylthiazoles, for example, 2-styryl-4-methylthiazole, followed by catalytic reduction gives aldehyde with 47% yield of crude product (30). 

Alkenes are cleaved to carbonyl compounds by ozonolysis This reaction IS useful both for synthesis (preparation of aldehydes ketones or car boxyhc acids) and analysis When applied to analysis the carbonyl com pounds are isolated and identified allowing the substituents attached to the double bond to be deduced... 

Aldehyde (139a) was synthesized independently from (141) by ozonolysis followed by ring closure of the seco-keto-aldehyde (140). 

In general however, ozonolysis is of limited synthetic importance. For quite some time ozonolysis has been an important tool for structure elucidation in organic chemistry, but has lost its importance when spectroscopic methods were fully developed for that purpose. The identification of the aldehydes and/or ketones obtained by ozonolysis of unsaturated compounds allowed for conclusions about the structure of the starting material, but has practically lost its importance since then. 

The aldehyde or ketone functionalities in the Michael adducts are restored by ozonolysis of the hydrazone moiety resulting in am/-3,4-disubstituted-5-oxoalkanoates 1. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Bieber reported that the reaction of bromoacetates is greatly enhanced by catalytic amounts of benzoyl peroxide or peracids and gives satisfactory yields with aromatic aldehydes. A radical chain mechanism, initiated by electron abstraction from the organometallic Reformatsky reagent, is proposed (Scheme 8.27).233 However, an alternative process of reacting aldehydes with 2,3-dichloro-l-propene and indium in water followed by ozonolysis provided the Reformatsky product in practical yields.234 An electrochemical Reformatsky reaction in an aqueous medium and in the absence of metal mediator has also been reported.235... 

When a sufficient amount of sample is available (ca. 1 pg), monoenyl compounds can be analyzed by micro-ozonolysis with and without a solvent [146, 165]. Ozonides, directly injected into GC-MS, are reductively decomposed into two aldehydes by heat. Besides this chemical reaction, the double-bond position is easily and high-sensitively confirmed by making an adduct with DMDS, which... 

Iridium-catalyzed transfer hydrogenation of aldehyde 73 in the presence of 1,1-dimethylallene promotes tert-prenylation [64] to form the secondary neopentyl alcohol 74. In this process, isopropanol serves as the hydrogen donor, and the isolated iridium complex prepared from [Ir(cod)Cl]2, allyl acetate, m-nitrobenzoic acid, and (S)-SEGPHOS is used as catalyst. Complete levels of catalyst-directed diastereoselectivity are observed. Exposure of neopentyl alcohol 74 to acetic anhydride followed by ozonolysis provides p-acetoxy aldehyde 75. Reductive coupling of aldehyde 75 with allyl acetate under transfer hydrogenation conditions results in the formation of homoallylic alcohol 76. As the stereochemistry of this addition is irrelevant, an achiral iridium complex derived from [Ir(cod)Cl]2, allyl acetate, m-nitrobenzoic acid, and BIPHEP was employed as catalyst (Scheme 5.9). 

Treatment of 122 with (R,R)-tartrate crotyl-boronate (E.R.R)-W 1 provides the alcohol corresponding to 123 with 96% stereoselectivity. Benzylation of this alcohol yields 123 with 64% overall yield. The crude aldehyde intermediate obtained by ozonolysis of 123 is again treated with (Z,R,R)-111 (the second Roush reaction), and a 94 5 1 mixture of three diastereoisomers is produced, from which 124 can be isolated with 73% yield. A routine procedure completes the synthesis of compound 120, as shown in Scheme 3-44. Heating a toluene solution of 120 in a sealed tube at 145°C under argon for 7 hours provides the cyclization product 127. Subsequent debromination, deacylation, and Barton deoxygenation accomplishes the stereoselective synthesis of 121 (Scheme 3-44). 

This aldol reaction was employed for an asymmetric synthesis of the azetidinone 9 from the adduct (5) of acetaldehyde and l.5 Azetidinone 9 is a versatile precursor to the antibiotic thienamycin 10. The configurationally stable aldehyde 6, obtained by ozonolysis of the silyl ether of 5, undergoes addition with allylzinc chloride to afford 7, which on transamination is converted to the N-methoxy amide 8. This product is converted in several steps to the desired 9 in 34% overall yield. An interesting feature of this synthesis is the early incorporation of the hydroxyethyl side chain at C6, a step that is difficult to effect after formation of the (3-lactam ring. 

Oxidative cleavage of the terminal double bond of 49 by ozonolysis to the aldehyde followed by permanganate oxidation to the acid and esterification with diazomethane produced the methyl ester 50. Dieckmann cyclisation of 50, following the procedure developed in Holton s laboratory (LDA, THF, -78 °C, 0.5 h, then HOAc, THF), gave the enol ester 5J in 93% yield (90% conversion). Decarbomethoxylation of 5J. was carried out by temporarily protection of the secondary alcohol (p-TsOH, 2-methoxypropene, 100%), and heating the resulting compound 52 with PhSK in DMF, at 86 °C (3 h) to provide 53a or, after an acidic workup, the hydroxy ketone 53b. 92% yield. 

The synthesis of the non-racemic cyclopentanone (+)-93 is outlined in Scheme 15. Starting with 2-methyl-cyclopent-2-enone (90), sequential cuprate addition and enolate alkylation afforded the racemic cyclopentanone rac-92 as a single diastereomer. The double bond was cleaved by ozonolysis, the resulting aldehyde chemoselectively reduced in the presence of the keto function and the primary hydroxyl function was subsequently protected as a silyl ether to provide racemic rac-93. This sequence has been applied fre-... 

Lactol 128 has been converted into a variety of racemic C-nucleosides. The unstable aldehyde 130 was prepared from 128 by way of oxazolidine 129. Lactone 131 was also derived from 128 and used as starting material in the synthesis of racemic C-nucleosides. Adducts 77 + 77 were transformed into epoxide 132. Opening of the epoxide, followed by ozonolysis and reduction allowed one to... 

The alkenes 149 and 150 are easily cleaved by ozonolysis either directly or after protection of the hydroxy gronp. Depending on the workup conditions of the ozonolysis, either diols 151 or 0-protected aldehydes 152 can be obtained. The C2 symmetric ketone 153 dr 75 25) is available from another addition of the dilithium reagent 148 (R = Ph)... 

---