P-Substituted carbonyl compound

Oxoalkyltriphenylbisniuthonium salts (83) reacted with some of the same nucleophiles as the 2-oxoalkyl derivatives, to afford the corresponding p-substituted carbonyl compounds. Moreover they also react with protic and aprotic solvents to yield mixtures of P-substituted carbonyl compounds and a,p-unsaturated carbonyl compounds, together with stoichiometric recovery of triphenylbismuthane. (Scheme 6.5)... 

Keywords Ligand, Ether, Amine, Nucleophilic addition, Organolithium, Grignard reagent, Organozinc, Copper, Phosphorus, Conjugate addition. Alkylation, Phosphine, Activated olefin, P-Substituted carbonyl compound... 

Catalytic asymmetric hydrogenation is a well-established method for the conversion of the stereo chemically defined a,P-unsaturated carbonyl compounds to the chiral P-substituted carbonyl compounds in high enantioselectivity [87,88]. 

A significant advance in the synthesis of monoorganotin trihaHdes was the preparation of P-substituted ethyl tin trihaHdes in good yield from the reaction of stannous chloride, hydrogen haHdes, and a,P-unsaturated carbonyl compounds, eg, acryHc esters, in common solvents at room temperature and atmospheric pressure (153,154). The reaction is beHeved to proceed through a solvated trichlorostannane intermediate (155) ... 

If, on the other hand, unsymmetrically substituted carbonyl compounds such as monosubstituted benzophenones (X = OCH3, CH3, Cl), tert-butyl methyl ketone, acetophenone, acetaldehyde, or benzaldehyde are used for trapping 39a, diastere-omeric mixtures are formed in each case they could all be resolved except for the products obtained with p-methoxybenzophenone and acetophenone 33>. An X-ray structure analysis has been performed for the E-isomer 57g 36) which, in conjunction with H-NMR studies, permitted structural assignment in cases 56 and 57e, g and h35>. Additional chemical evidence for the structure of the six-membered heterocycles is provided by the thermolysis of 56 a considered in another context (see Sect. 3.1). In general the reaction 39a- 56 or 57 is accompanied by formation of phosphene dimers, presumably via [4 + 4]- and via [4 + 2]-cycloaddition 35). 

Of course, the use of tris(trimethylsilyl) phosphite213 214 provides facile access to the free a-hydroxyphosphonic acids. These silyl reagents have been used for the preparation of a wide range of a-substituted phosphonates and -phosphonic acids, starting with ketene,215 a-ketophosphonates,216 ketoesters,217 218 and a,P-unsaturated carbonyl compounds,207/219-221 as well as simple aldehydes and ketones.205 210/219 224 Their use for the preparation of compounds of significant biological interest has been reviewed.125... 

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

The general usefulness of the developed methodology can be verified also in different areas. Thus chemoselec-tive reactions could be also carried out with p-unsubsti-tuted a-phenylthio substituted a, p-unsaturated carbonyl compounds and enol ethers as outlined in Scheme 6 (21). Naturally occuring 2,3,6-trideoxy and 4-amino-2,3,4,6-tetradeoxy sugars are obtained quite readily from this methodology. 

The inverse type hetero-Diels-Alder reaction of functionally substituted a, p-unsaturated carbonyl compounds was also possible with -alkyl substituted enol ethers (Scheme 9) (25). This was demonstrated in the synthesis... 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

The behavior of 2-substituted- or 2-unsubstituted-5(4//)-oxazolones is completely different. Reaction of electrophiles with 2-substimted-5(47/)-oxazolones usually occurs at C-4, whereas reaction of electrophiles with 2-unsubstituted-5(47/)-oxazolones affords the corresponding 5(2//)-oxazolones. The best example of the behavior of 2-unsubstituted-5(47/)-oxazolones involves 4-isopropyl-5(47/)-oxazolone 143, the anion of which can be considered as a formyl anion equiva-lent. ° ° Thus, reaction of 143 with a catalytic amount of triethylamine gives 144 that reacts with a,p-unsaturated carbonyl compounds to afford Michael adducts or with aldehydes to produce the corresponding aldol adducts. Mild acid hydrolysis of 145 yields the corresponding aldehydes (Scheme 7.42). 

In terms of Michael additions at the indole C-3-position, montmorillonite KIO has been shown to be effective in promoting the conjugate addition of indoles to a,p-unsaturated carbonyl compounds <99MC929>. In what is also a Michael process, microwave irradiation has been shown to be effective in promoting the trimolecular condensation of substituted indoles 111 with... 

In general, LiBr and NEt3 are employed in 1.5 and 1.2 equiv, respectively. Although the reaction becomes rather slower, catalytic amounts of LiBr/NEt3 (0.1 equiv each) are also sufficient. In reactions with the highly reactive dipolarophile N-methylmaleimide, the catalytic reaction results in a better yield. A similar lithiation is possible with a-substituted (alkylideneamino)acetates and (alkylideneamino)-acetamides to generate lithium enolates (86). Cycloadditions with a variety of cc,p-unsaturated carbonyl compounds leads to endo cycloadducts. However, the reaction with acrylonitrile is again nonstereoselective. 

Substituting vinylic hydrogen in a,P-unsaturated carbonyl compounds with vinylic fluorine does not affect their dienophilic character negatively Indeed, 3,3-difluoroacrylic acid is more reactive toward furan than its nonfluonnated counterpart [95] (equation 81) Consistent with this observation is the fact that tetrafluorobenzoquinone forms only a bis-Diels-Alder adduct in 68% yield in its reaction with cyclopentadiene at room temperature [96, 97 ... 

Phosphomolybdic acid-Potassium di-chromate-Copper(II) sulfate, 248 Tin(II) trifluoromethanesulfonate, 301 Other unsaturated carbonyl compounds Lead tetraacetate, 155 Pyrylium perchlorate, 263 Zinc-copper couple, 348 a-Substituted-a, p-unsaturated carbonyl compounds... 

Other a-substituted-a, P-unsaturated carbonyl compounds Benzeneselenenyl halides, 26 P-Substituted-a, p-unsaturated carbonyl compounds... 

Vinyl substitutions with N,N-dialkylbenzylamine-cyclopalladated complexes have been studied most thoroughly. In the presence of triethylamine the substitution occurs quite selectively with styrene derivatives19 and a,p-unsaturated carbonyl compounds.20 For example, chloride-bridged cyclopalladated NJ4-dimethylbenzylamine dimer and methyl vinyl ketone give 92% of o-dimethylaminomethylbenzalacetone in 1 h at 110 C (equation 6). 

In the past, Darzens methodology was primarily used for the synthesis of aldehydes and ketones, as a homologation reaction without any consideration of stereocontrol in the epoxide formation. For this sequence, saponification of the a,P-epoxy ester followed by decarboxylation gives the substituted carbonyl compound ... 

Even in the presence of nucleophiles like methanol, these sterically hindered enols only afforded benzofurans under oxidative conditions. Importantly, when stable enols of the Fuson type, which are less sterically hindered in the P-position, were oxidized with one-electron oxidants a-substituted carbonyl compounds 31 and 34 were obtained with water and various alcohols [64]. With acetonitrile, formation of the oxazole 32 was observed. A related example of this chemistry can be found in the context of Fuson s oxidation studies using Pb(OAc)4 [123] that provided the a-acetoxy aldehyde 31c from 30. To explain the products 31 and 34, three different mechanistic hypotheses were advanced (Scheme 3) [64] similar to the ones rationalizing the benzofuran formation. 

Asymmetric Coiyugate Addition of Allyl- and Crotylphosphonamides/ The asymmetric C-allylation of a, 3-unsaturated carbonyl compounds is a powerful tool for the functionalization of a carbonyl compound in the P-position. Since such a process normally leads to the corresponding enolate derivative when anionic reagents are used, there exists the possibility of trapping with an electrophile. Thus sequential addition and trapping can lead to vicinally substituted carbonyl compounds. Asymmetric allylation has been achieved previously with simple cycloalkenones using phosphorus and sulfur based reagents that must be prepared in diastereomerically pure form. 

Rather less common are condensations between a-hydroxyketones, ammonia and an imidate. Equivalent amounts of the hydrochloride salt of the imidate and the or-substituted carbonyl compound (cr-halogeno-and a-acetoxyketones also take part) are heated (40-70°C) in liquid ammonia (3-48 h) at elevated pressures. Yields of imidazoles vary between 10 and 90%, but the requirements of working with liquid anomonia in an autoclave may make this approach unappealing if alternatives are available [42,43]. Examples include 4-hydroxymethyl- (35%), 4-hydroxymethyl-2-phenyl- (73%), 4-hydroxymethyl-2-(p-tolyl)- (68%) and 2-benzyl-4-hydroxymethylimidazoles (85%) [44]. 

The reaction of allenylsilanes with electron deficient ir-systems constitutes a powerful and general method for the tegio- and stereo-selective preparation of substituted cyclopentenes. As first reported, (trimethylsilyl)allenes function as three-carbon nucleophiles in TiCU-promoted (trimethylsilyl)cyclopen-tene annelations (Scheme 31). The annelation process involves the polarization of an a,p-unsaturated carbonyl compound by TUTU to generate an alkoxyallylic cation. Regiospecific electnqrhilic substitution of this cation at C-3 of the allenylsilane produces a silicon-stablizied vinyl cation. A 1,2-shift of the tri-... 

The mechanistic picture for addition of organocuprates to a,P-unsaturated carbonyl compounds is no less complex than that for substitution reactions. On the basis of current information, conjugate addition of lithiocuprates to a, P-unsaturated ketones and esters may proceed via a initial reversible copper(I)-olefin-lithium association, which then undergoes oxidative addition followed by reductive elimination. ... 

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