Ene aldehydes

C1 4H1 9M0NO3, Carbonyl- (7 -cyclopentadienyl) - (2,2-dimethyl-hex-4-ene-aldehyde)nitrosylmolybdenum, 45B, 916 Cl4H1gNb, Bis(eyelopentadienyl)ethyl(ethylene)niobium, 40B, 750 Cl4H2iCl2NPt, cis-Dichloro(1,5-hexadiene)platinum(II) - (S)-a-meth-ylbenzylamine complexes, 37B, 476... 

Thus, carbonyl ene reactions can be used to prepare cyclic alcohols with an exo-cyclic double bond in 3-position (Scheme 3.78). To gain stereocontrol with respect to an on-ring methyl group, the Lewis acid catalyst is of predominant importance [127]. Therefore, the action of relatively small aluminum species such as dimethylaluminum chloride on ene-aldehyde 403 leads to cis-cyclohexanol 406 with dr 9 1. If, however, the bulky MABR is used, the trans-isomer 407 is formed with dr 32 1. This reversal of stereoselection may be attributed to an equilibrium of adducts 408 and 409. For small Lewis acids, the tendency of the methyl substituent to adopt an equatorial position prevails and 406 is generated. For an increasing bulk of the Lewis acid, the repulsion between the methyl group and the Lewis acid enforces conformer 409 and hence formation of the trans-cyclohexanol 407. 

Ene reaction with aldehydes is catalyzed by Lewis Acids (Et2AlCl)... 

The PdCli-catalyzed instantaneous rearrangement of A -carbethoxy-S-azabi-cyclo[5.1.0]oct-3-ene (60) takes place at room temperature to give A -car-bethoxy-8-azabicyclo[3.2.1]oct-2-ene (61)[50], The azepine 62 undergoes a smooth skeletal rearrangement to give 63, and the diazepine 64 is converted into the open-chain product[51]. Beckmann fission of the oxime 65 of ketones and aldehydes to give the nitrile 66 is induced by a Pd(0) complex and oxygen [52,53]. 

By analogy to the hydration of alkenes hydration of an alkyne is expected to yield an alcohol The kind of alcohol however would be of a special kind one m which the hydroxyl group is a substituent on a carbon-carbon double bond This type of alcohol IS called an enol (the double bond suffix ene plus the alcohol suffix ol) An important property of enols is their rapid isomerization to aldehydes or ketones under the condi tions of their formation... 

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone appHes a tandem Claisen rearrangement and intramolecular ene-reaction (Eig. 23). StereochemicaHy pure (185) is synthesized from (2R)-l,2-0-isopropyhdene-3-butanone in an overall yield of 86% in four chemical steps. Heating a toluene solution of (185), enol ether (187), and 2,6-dimethylphenol to 180°C in a sealed tube for 60 h produces (190) in 76% yield after purification. Ozonolysis of (190) followed by base-catalyzed epimerization of the C8a-hydrogen to a C8P-hydrogen (again similar to conversion of (175) to (176)) produces (184) in 46% yield from (190). Aldehyde (184) was converted to 9,11-dehydroestrone methyl ether (177) as discussed above. The overall yield of 9,11-dehydroestrone methyl ether (177) was 17% in five steps from 6-methoxy-l-tetralone (186) and (185) (201). 

Selective fluonnation in polar solvents has proved commercially successful in the synthesis of 5 fluorouracil and its pyrimidine relatives, an extensive subject that will be discussed in another section Selective fluonnation of enolates [47], enols [48], and silyl enol ethers [49] resulted in preparation of a/phn-fluoro ketones, fieto-diketones, heta-ketoesters, and aldehydes The reactions of fluorine with these functionalities is most probably an addition to the ene followed by elimination of fluonde ion or hydrogen fluoride rather than a simple substitution In a similar vein, selective fluonnation of pyridmes to give 2-fluoropyridines was shown to proceed through pyridine difluondes [50]... 

The reaction of methoxybutenone with salicylic aldehyde (20°C, MeOK, toluene, MeOH, 15 h) affords 3-acetyl-2-methoxy-chromo-3-ene (291) in 14% yield (80MI1). 

Primary amines, RNH2, add to aldehydes and ketones to yield imines, R2C=NR. Secondary amines, R2NH, add similarly to yield enamines, R2N—CR=CR2 (ene + amine = unsaturated amine). 

The strategy for the construction of 13 from aldehyde 16 with two units of phosphonate 15 is summarized in Scheme 12. As expected, aldehyde 16 condenses smoothly with the anion derived from 15 to give, as the major product, the corresponding E,E,E-tri-ene ester. Reduction of the latter substance to the corresponding primary alcohol with Dibal-H, followed by oxidation with MnC>2, then furnishes aldehyde 60 in 86 % overall yield. Reiteration of this tactic and a simple deprotection step completes the synthesis of the desired intermediate 13 in good overall yield and with excellent stereoselectivity. 

A simple and practical synthesis of (+)-2- bromobicycio [2.2.1 ]hept-5-ene-2-carbox-aldehyde via chiral Lewis-acid catalyzed [4 + 2] cycloaddition [100]... 

The Lewis acid-catalyzed ene reaction of 3-methylene-2,3-dihydrofuran (available by Wolflf-Kishner reduction of 3-furaldehyde <93TL5221>) with aldehydes gives the corre onding alcohols in good to excellent yields <96TL7893>. 5- >ttto-dig iodocyclizations of alk-3-yn-l,2-diols. 

Another successful reaction of aldehyde 56 is the diastereoselective carbonyl-ene reaction, pictured in Scheme 44, leading to products 60 [63]. 

An unusual reaction was been observed in the reaction of old yellow enzyme with a,(3-unsat-urated ketones. A dismutation took place under aerobic or anaerobic conditions, with the formation from cyclohex-l-keto-2-ene of the corresponding phenol and cyclohexanone, and an analogous reaction from representative cyclodec-3-keto-4-enes—putatively by hydride-ion transfer (Vaz et al. 1995). Reduction of the double bond in a,p-unsaturated ketones has been observed, and the enone reductases from Saccharomyces cerevisiae have been purified and characterized. They are able to carry out reduction of the C=C bonds in aliphatic aldehydes and ketones, and ring double bonds in cyclohexenones (Wanner and Tressel 1998). Reductions of steroid l,4-diene-3-ones can be mediated by the related old yellow enzyme and pentaerythritol tetranitrate reductase, for example, androsta-A -3,17-dione to androsta-A -3,17-dione (Vaz etal. 1995) and prednisone to pregna-A -17a, 20-diol-3,ll,20-trione (Barna et al. 2001) respectively. 

A variety of double bonds give reactions corresponding to the pattern of the ene reaction. Those that have been studied from a mechanistic and synthetic perspective include alkenes, aldehydes and ketones, imines and iminium ions, triazoline-2,5-diones, nitroso compounds, and singlet oxygen, 10=0. After a mechanistic overview of the reaction, we concentrate on the carbon-carbon bond-forming reactions. The important and well-studied reaction with 10=0 is discussed in Section 12.3.2. 

The best carbonyl components for these reactions are highly electrophilic compounds such as glyocylate, pyruvate, and oxomalonate esters, as well as chlorinated and fluorinated aldehydes. Most synthetic applications of the carbonyl-ene reaction utilize Lewis acids. Although such reactions may be stepwise in character, the stereochemical outcome is often consistent with a cyclic TS. It was found, for example, that steric effects of trimethylsilyl groups provide a strong stereochemical influence.28... 

Examples of catalyst control of stereoselectivity have been encountered in the course of the use of the ene reaction to elaborate a side chain on the steroid nucleus. The steroid 4 gave stereoisomeric products, depending on the catalysts and specific aldehyde that were used.33 This is attributed to the presence of a chelated structure in the case of the SnCl4 catalyst. 

The use of Lewis acid catalysts greatly expands the synthetic utility of the carbonyl-ene reaction. Aromatic aldehydes and acrolein undergo the ene reaction with activated alkenes such as enol ethers in the presence of Yb(fod)3.35 Sc(03SCF3)3 has also been used to catalyze carbonyl-ene reactions.36... 

Most carbonyl-ene reactions used in synthesis are intramolecular and can be carried out under either thermal or catalyzed conditions,43 but generally Lewis acids are used. Stannic chloride catalyzes cyclization of the unsaturated aldehyde 5. 

Fig. 10.2. Structures of complexed aldehyde reagent (a) and transition structure (b) for enantios-elective catalysis of the carbonyl-ene reaction by BINOL-Ti(IV). Reproduced from Tetrahedron Lett., 38, 6513 (1997), by permission of Elsevier.

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