Hydroacylation intermolecular

Because the rates of hydroacylation are often slow, and decarbonylation can compete with hydroacylation, strategies to overcome these limitations have been devised. One strategy is to conduct reactions with substrates that will form stable metallacycles after cleavage of the aldehyde C-H bond. A second strategy is to conduct the hydroacylation with imine derivatives of the aldehyde because de-insertion of an isocyanide is less favorable than de-insertion of CO. 

Chapter 18 closes with a brief description of perhaps the most common type of C-H activation process H/D exchange. Shilov reported H/D exchange almost 40 years ago. Far too many examples of this reaction are now known to summarize in this forum. However, this reaction has been a test-bed for the capability of transition metal complexes to cleave aliphatic and aromatic C-H bonds. H/D exchange reactions have been conducted with homogeneous catalysts and either deuterium gas or a relatively inexpensive source of deuterium, such as benzene-d or Seminal papers on the use of Crabtree s cata- 

Selective Hydrocarbon Adivation Davies, ]. A., Watson, P. L., liebman, ]. F, Greenberg, A., Eds. VCH Publishers New York, 1990. 

Hartung, C. G. Snieckus, V. The Directed Ortho Metabtion Reaction. A Point of Departure for New Synthetic Aromatic Chemistry Wiley-VCH New York, 2002. 

Siegmeier, R. Mayr, W. In Ullmanns Encyclopedia oflndustrml Chemistry Wiley New York, 2002 http / /www.mrw.intersdence.wiley.com/ueic/artides/al9 199/sect2. 

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Although intermolecular hydroacylations have been known for over 30 years, attempts to carry out intermolecular versions have traditionally been hampered due to competitive decarbonylation processes (Scheme 25). 

Based on Watanabe s intermolecular hydroacylation of olefins with aldehydes,348 Kondo and Misudo developed the first ruthenium-catalyzed hydroacylation of 1,3-dienes with aldehydes (Scheme 71). Usually, palladium-mediated hydroacylations of 1,3-dienes with aldehydes give tetrahydropyran and/or open-chain homoallylic alcohol derivatives.350 However, in the present ruthenium-catalyzed transformations, the corresponding /3,7-unsaturated... 

An intermolecular hydroacylation of alkynes or electron-poor alkenes (e.g. CH2= CHCChMe) with /3-thioacetal-substituted aldehydes, catalysed by [(dppe)Rh]C104, has been reported to occur in acetone at 50 °C. The reaction is believed to proceed via a chelated rhodium acyl intermediate.111... 

Research on intermolecular hydroacylation has also attracted considerable attention. The transition-metal-catalyzed addition of a formyl C-H bond to C-C multiple bonds gives the corresponding unsymmetrically substituted ketones. For the intermolecular hydroacylation of C-C multiple bonds, ruthenium complexes, as well as rhodium complexes, are effective [76-84]. In this section, intermolecular hydroacylation reactions of alkenes and alkynes using ruthenium catalysts are described. 

In 1980, Miller et al. [76] reported the first example of an intermolecular hydroacylation of an aldehyde with an olefin to give a ketone, during their studies of the mechanism of the rhodium-catalyzed intramolecular cyclization of 4-pentenal using ethylene-saturated chloroform as the solvent. Later James and Young [77] reported that the reaction of propionaldehyde with ethylene can be conducted in the presence of RuCl2(PPh3)3 as the catalyst without any solvent at 210 °C, resulting in the formation of 3-pentanone in 2-4% yield (turnover number of 230) (Eq. 49). 

Later, they also reported an intermolecular hydroacylations of 1,3-dienes with aromatic aldehydes yielding the corresponding j8,y-unsaturated ketones (Eq. 51) [79]. This reaction does not require a CO atmosphere. The addition of formyl C-H bond in formic acid esters and amides to olefins and conjugate... 

The first ruthenium-catalyzed intermolecular hydroacylation of 1,3-dienes with aldehydes via a jt-allylmthenium intermediate has been reported (Eq. 5.36) [60],... 

Aldehydes also react with alkenes to give hydroacylated products, unsymmetric ketones. Isnard and coworkers reported the first intermolecular hydroacylation, though the yields of the products were low (Eq. 11.20) [61]. 

Intermolecular hydroacylation is difficult because decarbonylation of aldehyde is predominant, and ketone is not formed. However, this problem can be overcome by charging the pressure of CO [62]. 

T.B. Marder, D.C Roe, and D. Milstein pointed out that these results with respect to the RuCl2(PPh3)3-catalyzed intermolecular hydroacylation have not yet been duplicated. See footnote 4 of reference 117. 

The stereochemistry of the intermolecular hydroacylation of alkenes with aldehydes has not been studied in detail and no applications have been reported in stereoselective organic synthesis up to now. 

A rapid and eflEcient molybdenum-catalyzed, MW-accelerated asymmetric allylic alkylation under noninert conditions has been reported [226]. Intermolecular hydroacylation of 1-alkenes with aldehydes has been presented as a greener alternative to the classical approach using a homogeneous catalyst in toluene. 

Lactols can be cyclized under the typical hydroacylation conditions (eq 28), presumably via equilibrium amounts of the corresponding aldehyde. Finally, intermolecular hydroacylation has been formally achieved in the reaction of a pyridyl aldimine with ethylene under pressure at 160 °C here the pyridine functionality anchors the aldimine to the rhodium, and decarbonylation is impossible (eq 29). 

Hydroacylations. Wilkinson s catalyst is an extremely powerful catalyst for intermolecular hydroacylation when combined with several organococatalysts such as 2-amino-3-picoline, aniline, and benzoic acid (for details, see 2-amino-3-picoline) Equation 63 illustrates how benzaldehyde undergoes intermolecular hydroacylation very efficiently with terminal olefins by the chelation-assistance of 2-amino-3-picoline by a process involving C-H bond activation. 

Asymmetric Intermolecular Hydroacylation Reactions of Alkenes and Allenes... 

Compared with asymmetric intramolecular hydroacylation reactions of alkenes, the corresponding intermolecular versions have been relatively less developed. In 2007, Stemmier and Bolm reported the first example of enanti-oselective intermolecular hydroacylation reactions between salicylaldehydes 40 and norbornadiene-type alkenes 41 (Scheme 8.20). It was found that the diastereoselectivity of the reaction could be modulated through changing the chiral ligands. With ferrocene-based bisphosphine ligand L5, the exo-product 42a was obtained exclusively with up to 82% ee. When monodentate phos-phoramidite ligand L6 was employed, the e do-isomer 42b was obtained as major product with moderate enantioselectivity (54% ee). 

Guided by the double-chelation assisted hydroacylation between salicylaldehydes and dienes developed by the group of Tanaka and Suemune, Dong and co-workers presented the asymmetric intermolecular hydroacylation reactions between salicylaldehydes and sulfide-functionalized terminal alkenes. High levels of enantio- and regio-selectivity control was obtained when biindane-derived phosphoramidite ligand L7 was used (Scheme 8.22). 

Scheme 8.21 Asymmetric intermolecular hydroacylation reaction reported by Tanaka and Suemune.

In 2009, Tanaka and co-workers achieved Rh-catalyzed highly enantioselective intermolecular hydroacylation reactions of aliphatic aldehydes 48 with 1,1-substituted acrylamides 49 by using a cationic Rh/QuinoxP complex as the catalyst (Scheme 8.24a). Unfortunately, the reaction of simple benzaldehyde with acrylamide 49a was sluggish and the enantioselectivity was moderate, but utilizing (i ,R)-Me-DuPhos as the ligand could improve both yield and enantioselectivity (Scheme 8.24b). When cyclopentene-substituted amide 49b was subjected to the standard reaction conditions, a thermodynamically stable hydroacylation product 50b was generated with excellent diastereoselectivity (>99 1 dr) and enantioselectivity (97% ee), although dramatically reduced reactivity was observed (5% yield) (Scheme 8.24c). This report represents the first example of an asymmetric hydroacylation reaction of a trisubstituted alkene. 

Scheme 8.24 Asymmetric intermolecular hydroacylation reactions of acrylamides reported by Tanaka.

Scheme 8.25 Asymmetric intermolecular hydroacylation reactions of allenes reported by Willis.

The trans-effect was also invoked to explain enantioselectivity in the Rh-catalyzed intermolecular hydroacylation (Figure 11.15). The preferred S-enantiomer formation is consistent with the productdetermining ketone insertion step where the ligand cooperatively renders the hydride more nucleophilic and the ketone more electrophilic. This synergy facilitates formation of the S-stereoisomer of the product in Figure 11.15. Conversely, the alternative complex is stabilized by the trans-effect, and the barrier to migratory insertion is increased as a consequence of this ground sate stabilization. 

A series of l-benzazepin-5-ones were furnished via a rhodium-catalyzed intermolecular hydroacylation of an allyl amine onto an aryl aldehyde (14AGE3688) while a one-step synthesis of a number of tetrahydro-3-benzazepines was achieved through the palladium-mediated reaction of phenylethylamines with allenes (14JOC9578). 

Double-Chelation-Assisted Rh-Catalyzed Intermolecular Hydroacylation Between Salicylaldehydes and 1,4-Peneta- or 1,5-Hexadienes... 

Jim et al. [24] reported the above reaction in an article entitled Chelation-Assisted Intermolecular Hydroacylation Direct Synthesis of Ketone from Aldehyde and 1-Alkene in 1997 [24]. They also reported on the reaction mechanism, as shown in Scheme 7.1 [24]. 

In the reactions of sulfanyl aldehydes with aUcenes in the presence of a rhodium catalyst, hydroacylation proceeds via an intramolecular five-membered ring intermediate with the insertion of an alkenyl moiety between the rhodium and carbonyl carbon at the y-position to the coordinating atom [112-114], For example, p-methylsulfanyl aldehyde reacts with an amide alkene to give an intermolecular hydroacylation product with the insertion of an amide alkenyl moiety at a high yield, as shown in Eq. (7.56) [112]. 

The catalytic addition of a formyl C-H bond across an olefin to generate a ketone (Equation 18.83) is called "hydroacylahon." Intramolecular hydroacylations were reported before intermolecular hydroacylations. The intramolecular reaction can be a valuable route to carbocycles, and it has been conducted enantioselectively. The intermolecular reaction could be a valuable route to acyclic ketones. However, both reactions are under... 

The intramolecular hydroacylation of olefins typically occurs in higher yields than the intermolecular hydroacylation of olefins. In its simplest form, the reaction of 4-pentenone in the presence of stoichiometric amoimts of V 5Udnson s catalyst at room temperature in ethylene-saturated solvent formed the isomeric cyclopentanone in good yield after long reaction times (Equation 18.86). Many different cyclopentanones were prepared by related methods. " ... 

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