Heteroatom Functionalization

In this chapter, we will outline the application of organocatalysis for the enantio-selective a-heteroatom functionalization of mainly aldehydes and ketones. Attention will be focused on enantioselective animation-, oxygenation-, fluorination-, chlorination-, bromination-, and sulfenylation reactions catalyzed by chiral amines. The scope, potential and application of these organocatalytic asymmetric reactions will be presented as the optically active products obtained are of significant importance, for example in the life-science industries. 

Optically active molecules having a chiral carbon atom attached to a heteroatom adjacent to a carbonyl functionality (Fig. 2.4) are of fundamental use in a large number of fields in chemistry. 

A variety of methods are available for the stereochemical construction of these optically active a-heteroatom-substituted carbonyl compounds, and in recent years a large number of new procedures have been developed applying asymmetric catalysis to carbonyl compounds, or their equivalents, as substrates [1]. The trick to these reactions is the direct C-H to C-Het transformation, as outlined in 

Several catalytic asymmetric approaches can be considered for the C-H to C-Het transformation demonstrated in Eq. (1), and the use of chiral Lewis acid-and chiral organic molecules has attracted considerable attention during recent years. 

The configuration of the chiral carbon atom formed in the a-position of the carbonyl functionality is thus dependent on the type of interaction between the 

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Heteroatom functionalized terpene resins are also utilized in hot melt adhesive and ink appHcations. Diels-Alder reaction of terpenic dienes or trienes with acrylates, methacrylates, or other a, P-unsaturated esters of polyhydric alcohols has been shown to yield resins with superior pressure sensitive adhesive properties relative to petroleum and unmodified polyterpene resins (107). Limonene—phenol resins, produced by the BF etherate-catalyzed condensation of 1.4—2.0 moles of limonene with 1.0 mole of phenol have been shown to impart improved tack, elongation, and tensile strength to ethylene—vinyl acetate and ethylene—methyl acrylate-based hot melt adhesive systems (108). Terpene polyol ethers have been shown to be particularly effective tackifiers in pressure sensitive adhesive appHcations (109). 

Ring syntheses in which a bond is formed between the heteroatom and a carbon atom are conveniently considered according to whether the heteroatom functions as a nucleophile, an electrophile, a radical or other electron deficient species. 

Displacement reactions involving a heteroatom and a carbon atom are very common in the synthesis of heterocyclics of many sizes. Most often, the heteroatom functions as a... 

Reactions in chloroaluminate(III) salts and other related binary salts often proceed smoothly to give products. However, it should be noted that these salts are water-sensitive and must be handled under dry conditions. They react with water to give hydrated aluminium(III) ionic species and HCl. When a reactant or product contains a heteroatomic functional group, such as a ketone, a strong ketone/alumini-um(III) chloride adduct is formed. In these cases, this adduct can be difficult to separate from the ionic liquid at the end of a reaction. The isolation of the product often... 

Y = RS", RCOO, or RO" (where R is a hydrocarbon residue or an organic moiety containing one or more heteroatom functionalities). 

X = heteroatom function L = large substituent S = small substituent... 

The 1,3-dipolar eyeloaddition, also known as the Huisgen cycloaddition, is a elassie reaetion in organic chemistry consisting in the reaetion of a dipolar-ophile with a 1,3-dipolar compound that allows the produetion of various five-membered heteroeyeles. This reaction represents one of the most productive fields of modern synthetic organic chemistry. Most dipolarophiles are alkenes, alkynes, and molecules possessing related heteroatom functional... 

Many chiral diphosphine ligands have been evaluated with regard to inducing enantioselectivity in the course of the hydroformylation reaction [25,26]. However, a real breakthrough occurred in 1993 with the discovery of the BI-NAPHOS ligand by Takaya and Nozaki [65]. This was the first efficient and rather general catalyst for the enantioselective hydroformylation of several classes of alkenes, such as aryl alkenes, 1-heteroatom-functionalized alkenes, and substituted 1,3-dienes, and is still a benchmark in this area [66,67]. But still a major problem in this field is the simultaneous control of enantio-... 

Improvement of selectivity by using heteroatom functionalities for the control of the electrochemistry and reactivity during electrochemical transformations ... 

This chapter focuses on heteroatomcuprates and a-heteroatomalkylcuprates and the potential they offer in the development of synthetic strategies. Alkylcuprate chemistry involving heteroatom functionality at a location other than the a-position is the topic of Chapt. 2. 

Since dioxiranes are electrophilic oxidants, heteroatom functionalities with lone pair electrons are among the most reactive substrates towards oxidation. Among such nucleophilic heteroatom-type substrates, those that contain a nitrogen, sulfur or phosphorus atom, or a C=X functionality (where X is N or S), have been most extensively employed, mainly in view of the usefulness of the resulting oxidation products. Some less studied heteroatoms include oxygen, selenium, halogen and the metal centers in organometallic compounds. These transformations are summarized in Scheme 10. We shall present the substrate classes separately, since the heteroatom oxidation is quite substrate-dependent. 

In the case of substrates containing OR or related heteroatom functionality, additional coordination complexes and transition states are involved. If a hydroxy group is present, hydride transfer preferably occurs from the corresponding alkoxyaluminate species (i.e., 113) (Scheme 6.68). Substituents of this kind tend to be syn-directing (20-23,140,141,297). 

There are a number of important reactions in this category and all of them involve at least one heteroatom functioning as a nucleophile and another as an electrophile. Diazo-tization of a variety of ortho-substituted anilines for instance, followed by intramolecular nucleophilic trapping of the corresponding diazonium salts by either nitrogen or carbon nucleophiles, is the basis of a series of very important syntheses of 1,2,3-benzotriazine and cinnoline derivatives, and this general approach has been widely exploited for the preparation of polycyclic systems. Representative examples are given in equations (51)—(54). 

In the 1,4-dinucleophile - 1,2-dielectrophile approach the most common situation is where heteroatoms function as nucleophiles and 1,2-dicarbonyl compounds, 1,2-dihalides or sulfonate esters, a-halocarbonyl compounds, etc., as the dielectrophile component. Representative examples are given in equations (76)-(79). Condensation of hydrazine and its derivatives with 1,4-dicarbonyl compounds is the common situation in the 1,2-dinucleophile- 1,4-dielectrophile approach, and the vast majority of pyridazine derivatives are prepared in this way (e.g equations 80 and 81). Sulfur 1,4-dielectrophiles have been used in related processes, but the method is not readily adaptable to the synthesis of oxygen heterocycles. 

It is important to note that SNAr displacement reactions of heteroatom functional groups other than halides have been demonstrated on purine substrates, including mesitylenesulfonates <20000L927>, sulfones (see Section 10.11.7.5), nitro substituents <2006S2993>, and T-azoles (see Section 10.11.7.3.2). Halopurines have been reduced using sodium naphthalenide <1997T6295>. 

A cyclopentadienylmagnesium bromide containing a heteroatom-functionalized substituent at the cyclopentadienyl group has also been structurally characterized. When l-[2-(dimethylamino)ethyl]-2,3,4,5-tetramethylcyclopentadienylmagnesium bromide is recrystallized from dichloromethane, dimeric [(Mc2N(CH2)2)Me4C5MgBr]2 (206) (Figure 88) is obtained. Its X-ray crystal-structure determination reveals a structure in the solid state... 

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