Ketones intermolecular additions

The selective intermolecular addition of two different ketones or aldehydes can sometimes be achieved without protection of the enol, because different carbonyl compounds behave differently. For example, attempts to condense acetaldehyde with benzophenone fail. Only self-condensation of acetaldehyde is observed, because the carbonyl group of benzophenone is not sufficiently electrophilic. With acetone instead of benzophenone only fi-hydroxyketones are formed in good yield, if the aldehyde is slowly added to the basic ketone solution. Aldols are not produced. This result can be generalized in the following way aldehydes have more reactive carbonyl groups than ketones, but enolates from ketones have a more nucleophilic carbon atom than enolates from aldehydes (G. Wittig, 1968). 

A polyfluorinated P,y-unsaturated ketone is formed m situ from tributylamine and 3,4-bis(tnfluoromethyl)-3-(pentafluoroethyl)-5,5,6,6,6-pentafluoro-2-hex-anone. The enol form of the unsaturated ketone cyclizes via an intermolecular addition-elimination reaction that involves exclusive attack by oxygen rather than by carbon. This reaction demonstrates the hardness of a F-C= site toward... 

Almost 15 years ago Sakurai and Hosomi, in pioneering work, showed that intermolecular addition of an allylsilane to a,j6-unsaturated ketones in the presence of titanium(IV) chloride as the Lewis acid gave the desired 1,4-addition products1 4. In the case of 4,4a,5,6,7,8-hexahy-dro-2(3//)-naphthalenone, reaction was shown to proceed by 1,4-addition with exclusive production of the ris-fused product in high chemical yield. 

Intermolecular Addition with Rearrangement Formation of Unsaturated Ketones... 

The proposed mechanism of the isomerization of polyfluorooxiranes to ketones does not involve a 1,2-fluorine shift, but rather coordination of the Lewis acid with the epoxide oxygen, ring opening to the carbocation, and intermolecular addition and elimination of fluoride.29 45... 

Analogous results obtain in intermolecular addition of alkyl radicals to unsaturated amides. Thus addition of n-hexyl radical to the unsaturated amide 4 derived from (S,S)-1 results in four products, two by addition a to the ketone and two by addition a to the amide enol. The former products are formed with slight selectivity, (60 40), but the latter products (5) are formed in ratio of 93 7.3... 

Recently Betrand et al. have reported the sensitized intermolecular addition of tertiary amines derived from pyrrolidines to (5R)-5-menthyloxy-2[5//]-furanone (328) using ketonic sensitizers (Scheme 73, Table 13) [329]. 

The most feasible pathway to coupled products is intramolecular ketyl addition to the Sm -coordi-nated ketone (see Scheme 6). Several examples of ketyl addition to Lewis acid activated carbonyls have been reported in the literature. Clerici and Porta have demonstrated in detailed experiments that intermolecular addition of ketyls to carbonyls can be a rapid process. Generally, ketyl addition to carbonyls is a reversible reaction. However, reversibility can be greatly affected by Lewis acid chelation of the complex, and further reduction of the radical intermediate (8) by the second equivalent of Smh would serve to make the process irreversible. ... 

Stereochemistry of addition reactions involving allylsilanes 23.4.12 Intermolecular additions to aldehydes, ketones and acetals... 

Intramolecular transition metal-catalyzed hydro acylation reactions have opened up a new area of synthesizing cyclic ketones. This reaction can also be extended to intermolecular addition reactions. Miller et al. found the first example of an intermolecular hydroacylation of an aldehyde with an olefin giving ketones, when they were studying the mechanism of the rhodium-catalyzed intramolecular cyclization of 4-pentenal using ethylene-saturated chloroform as the solvent (Eqs.46,50) [112]. 

Intermolecular additions of silyl enolates to alkynes were introduced by Yamaguchi et al. (Scheme 10.102) [271]. In the presence of SnCl4 and I ujN reaction of SEE with terminal alkynes gives a,/ -unsaturated ketones wifh high E selectivity. 

The chiral molecular receptor (35) has been used to effect enantioselective cyclization of the enone (36). The complex of (36) and (35) undergoes energy transfer from the ketonic acceptor to (36) and results in its conversion into the cyclobutanes (37) and (38) in a total yield of 21%. Bach et aV have continued their investigations of enantioselective additions mediated by the chiral lactam hosts (39). The present reactions involve intra and intermolecular additions of quinolone systems (40) at -60°C in toluene as solvent. The irradiation affords the cycloadducts (41) and (42). As can be seen, the ee of the products is high and the chemical yields are also good. An extension of the work to intermolecular reactions of the quinolone (43) was also reported. The additions of the alkenes... 

The most important synthetic asset of the xanthate transfer methodology lies in its ability to induce carbon-carbon bond formation by intermolecular addition to unactivated olefins. Again, this is possible because the initial radical has a comparatively long lifetime in the medium. Unhindered, terminal olefins are the best substrates, but other types of olefins (especially strained or lacking allylic hydrogens) may be made to react in some cases. Three examples of additions are collected in Scheme 18. The first involves formation and capture of a trifluoroacetonyl radical, a species hitherto only studied by mass spectrometry but never employed in synthesis [34a]. This reaction represents a convenient route to various, otherwise inaccessible, trifluoromethyl ketones. In the second example a tetrazolylmethyl radical, also a previously unused intermediate, is intercepted by a latent allyl glycine [34b]. The amino acid moiety may be part of the xanthate partner as highlighted by the last example [34c]. 

Few examples of what might be described as an intermolecular coupling reaction on inactivated alkenes has appeared [62], Thus ketyl radicals generated from aromatic aldehydes and ketones underwent intermolecular addition to the para position of another aldehyde. Cross-coupling reactions are not feasible in these systems and typically yields are quite low. 

In a series of interesting investigations, Suggs and Jun [152] have shown ready C-C cleavage by directed attack in quinoline-derived ketones where the metal binds in such a way as to bring it into close proximity with the bond to be cleaved (Eq. 2.60 R = CH2Ph, Et py = pyridine). Addition of PPha causes reductive elimination back to the starting ketone. Intermolecular versions of this reaction were also observed [153]. 

A variety of catalysts have been used for these hydroary lation reactions of the C-H bonds in aromatic ketones, imines, and 2-arylpyridines. The intermolecular additions of aromatic C-H bonds of aryl ketones to olefins reported by Murai were conducted with RuH fCO) (PPh3)3 as catalyst. [RuH2(H2)(PCy3)2] was shown subsequently to catalyze this process at room temperature and even the much different Rh(I) complex [Cp Rh(C,H3SiMe,),] catalyzes this reaction. Additions of the C-H bonds to N-Bu and N-Bn benzaldimines... 

Lewis acid complexes of p-substituted a,p-unsaturated ketones and aldehydes are unreactive toward alkenes. Crotonaldehyde and 3-penten-2-one can not be induced to undergo ene reactions as acrolein and MVK do. 34 The presence of a substituent on the p-carbon stabilizes the enal- or enone-Lewis acid complex and sterically retards the approach of an alkene to the p-carbon. However, we have found that a complex of these ketones and aldehydes with 2 equivalents of EtAlQ2 reacts reversibly with alkenes to give a zwitterion. 34 This zwitterion, which is formed in the absence of a nucleophile, reacts reversibly to give a cyclobutane or undergoes two 1,2-hydride or alkyl shifts to irreversibly generate a p,p-disubstituted-o,p-unsaturated carbonyl compound (see Figure 19). The intermolecular addition of an enone, as an electrophile, to an alkene has been observed only rarely. The specific termination of the reaction by a series of alkyl and hydride shifts is also very unusual. 35 The absence of polymer is remarkable. 

Intermolecular addition of aldehydes and ketones to 1,6-enynes is also feasible. 1,6-Enynes with a tenninaUy monosubstituted alkene 1-9 react with carbonyl compounds to give tricychc derivatives of type I-IO with a highly diastereose-lective control (Scheme 2.3) [Ref. 229 in Chap. 1]. The reaction proceeds with complete diastereoselectivity with respect to the stereogenic centers Cla, C3, C3a, and C6a. 

Fig. 2.2 Products of the intermolecular addition of different aldehydes and ketones to 1,6-enynes 1-9...

Intermolecular addition of alcohols to catalytic ruthenium vinylidenes is far more difficult than the addition of water except when allylic alcohols are employed (Scheme 9) [92-96]. In this case, the reaction of an allylic alcohol with a terminal alkyne catalyzed by CpRuCl(PPh3)2 afforded a p,Y-unsaturated ketone. The initial ruthenium oxacarbene obtained by addition of the alcohol to the ruthenium vinylidene evolves through a Claisen rearrangement to a Jt-allyl ruthenium species. Reductive elimination then gives rise to the final unsaturated ketone. 

Scheme 9 p.y-Unsaturated ketones from intermolecular addition of allylic alcohols to terminal alkynes... 

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