Hetero-substituents

Benzyl-type carbanions and their metallo compounds, derived from aromatic or hetero-aromatic precursors, bearing carbon- or hetero-substituents, are readily available with variable substitution patterns due to their mesomeric stabilization (see Section 1.3.2.2)2. Even dicarbanions are accessible without difficulty3,4. The equilibrium acidities of many aromatic hydrocarbons have been determined5-7. The acidities of a-hetero-substituted toluenes8 are similar to those of the corresponding allylic compounds and can usually be generated by the same methods. 

Allyl anion synthons A and C, bearing one or two electronegative hetero-substituents in the y-position are widely used for the combination of the homoenolate (or / -enolate) moiety B or D with carbonyl compounds by means of allylmetal reagents 1 or 4, since hydrolysis of the addition products 2 or 5 leads to 4-hydroxy-substituted aldehydes or ketones 3, or carboxylic acids, respectively. At present, 1-hetero-substituted allylmetal reagents of type 1, rather than 4, offer the widest opportunity for the variation of the substitution pattern and for the control of the different levels of stereoselectivity. The resulting aldehydes of type 3 (R1 = H) are easily oxidized to form carboxylic acids 6 (or their derivatives). 

Hydroxy-l-alkenyl diisopropylcarbamates 2 (X = OCb), in this respect, occupy a medium position since they are stable in strongly acidic and basic protic solvents. For deblocking vinyl carbamates, the presence of catalytic amounts of mercuric or palladium(II) salts is required. Due to this stability, several reactions of homoallylic alcohols, proceeding with high diastereo-selectivity, e g., epoxidation, are applicable in order to introduce further hetero-substituents. 

Disubstituted allyl derivatives, bearing hetero substituents have also been investigated86. As observed for the titanium(IV) counterparts, the regio- and stereochemical features depend largely on the type of substituents. 

Heterolysis of Amides Bearing an a-Hetero Substituent (with Respect to Nitrogen)... 

The resulting carbene complex 41b bears a hetero substituent and shows activity in the ring-opening/cross metathesis of strained bicyclic alkenes and... 

Several benzothiazinone analogs have been synthesized in an attempt to introduce hetero substituents at the a-carbon center in these heterocyclic compounds. The required a-halo-benzothiazinone intermediate 148 was prepared by chlorination with sulfiiryl chloride. This material was used successfully in an Arbuzov reaction to prepare the phosphonate diester 149,... 

Aldehydes bearing a-hetero substituents also typically afford anti products, and the general solution to syn selective a-heteroatom substituted aldehyde-aldehyde aldol processes via enamine catalysis also still remains to be discovered. Nevertheless, the anti process is remarkably useful because a variety of highly substituted aldehydes can be accessed in a single operation using only very inexpensive catalysts, such as proline 6 or the phenylalanine-derived imidazohdinone 46 (Scheme 21) [114, 116, 117, 119-121, 188]. 

TABLE 5. Aryllithiums Li—R lacking hetero-substituents by metal insertion into haloarenes, the reactions being generally conducted in diethyl ether and in the temperature range of 0°C to +40°C (refluxing ether)... 

Being less basic than the saturated analogs, vinyllithium as all other acyclic or cyclic 1-alkenyllithiums can be prepared from iodo or bromo and sometimes even chloro precursors using butyllithium or fert-butyUithium (Tables 12 and 13). Hetero-substituents such as dialkylamino, alkoxy and silyloxy groups or halogen atoms again accelerate the exchange process considerably (Table 14). This holds for 0-lithiated hydroxy or carboxy functions as well (Table 15). 

Bromo- and iodoarenes are the oldest and most typical substrates for permutational halogen/metal interconversions. Butyllithium is routinely used for this purpose (Table 16). Hetero-substituents such as dialkylamino or bis(trialkylsilyl)amino, cyano or nitro (Table 17), alkoxy and 2-tetrahydropyranyloxy (Table 18), lithiooxy or lithiooxycarbonyl (Table 19) and fluoro or trifluoromethyl (Table 20) and chloro, bromo or iodo (Table 21) are well tolerated. 

As pointed out above, neither methane nor its higher homologs (ethane, propane, hexane) can be effectively metalated. The introduction of a hetero-substituent changes this outset profoundly. Second-row and third-row elements (such as silicon, phosphorus and sulfur) will not be considered in this context as they are known to acidify hydrocarbons strongly due to d-orbital resonance (or polarization) effects. But also the first-row elements nitrogen, oxygen and fluorine can distinctly facilitate the deprotonation of paraffinic hydrocarbons. 

Substituted malondialdehydes form pyrimidines substituted in the 5-position with an alkyl, aryl, halo, or hetero substituent. The pyrimidine is unsubstituted in the 4- and 6-positions. /3-Dialdehyde equivalents are frequently used in these reactions, for example, 3-alkoxy- or 3-aminoacroleins. With aldehydo ketones, the pyrimidine carries a substituent in the 4- or 6-position. The formyl group in the ketone is normally masked as an alkoxymethylene ketone or as an aminomethylene ketone. A commonly used procedure involves the preparation of a dimethylaminomethyl-ene ketone 645 by reaction of a methyl ketone 644 with DMF dimethylacetal and subsequent reaction with an amidine or guanidine to form the target pyrimidine 646 <2003MI237, 2004JHC461>. 

Since the activity seemed highly dependent on the positions of hetero-atom substituents, the compounds were stereochemically classified into two groups, meso- and (//-analogs, according to their hetero-substituent positions as shown in Fig. 12. QSAR analyses for insecticidal activity of these groups were performed separately to give Eq. 52 and 53 74). 

The transformation of one hetero substituent into another is a reaction frequently observed in the 1,2,4-triazine series. Oxo group transformations are indicated in Scheme 8. They can be transformed into thioxo groups by phosphorus pentasulfide or Lawesson s reagent. Pyridine seems to be the best solvent for the phosphorus pentasulfide reaction and a small amount of water (0.1% or less) seems to improve results. An oxygen in the 5-position is more easily replaced than one in the 3- or 6-position. Transformation of the oxo (hydroxy) group into a chloro substituent is achieved by phosphorus oxychloride, phosphorus penta-chloride, or thionyl chloride and DMF. In this reaction also the oxygen is most reactive in the 5-position. 

The synthetic utility of a-phosphorus- and a-thio-stabilized carbanions is the subject of numerous reviews.21 Notable are additions of phosphonium ylides (237),183 sulfonium ylides (238),l84 ° oxosulfo-nium ylides (239)184 " and sulfoximine ylides (240)184,1 to electron-deficient alkenes which afford nucleophilic cyclopropanation products. In contrast, with a-(phenylthio)-stabilized carbanions, which are not acyl anion equivalents, either nucleophilic cyclopropanation or retention of the hetero substituent occurs, depending on the acceptor and reaction conditions used. For example, carbanion (241) adds to 1,1-... 

The chemical shifts for hydrogens and methyl groups at C-4 of 5-hydroxy-and 5-amino-A2-1,2,3-triazolines depend on the orientation relative to the hetero substituent at C-5. This has been extensively used for assignment of relative configurations at C-4 and C-5 of variously substituted A2-tria-zolines.216,259 lH-NMR spectra show that 5-alkoxy- and 5-hydroxy-A2-1,2,3-triazolines prefer an envelope conformation218 (63) with the hetero substituent at C-5 pseudoaxial at the flap and the N-l substituent pseudoequatorial, probably because of the anomeric effect. The cis and trans coupling constants in the 5-amino-, 5-hydroxy-, and 5-aIkoxy-A2-l,2,3-triazolines are very constant, being 7.0-9.8 and 2.0-3.4 Hz, respectively.218... 

A few examples of a vinylic fluorine with geminal hetero-substituents are given in Scheme 3.61. 

Amines, amides, carbamates, and imides bearing one or two hetero substituents on nitrogen, i.e., R R2NX or RNX2, can be induced to react with alkenes by heterolytic or homolytic cleavage of the N —X bond1-7. 

Extensive work by Smiles and his collaborators and by other groups clarified the main features of the rearrangement involving nitro-, sulfonyl- and halo-substituted aromatic rings. Rearrangement of 2-amino-pyridine derivatives has also been extensively studied. Reactions involved the replacement of hetero-substituents, a C - O bond by a C - N bond (N - 0), C - S by C - N (N - S) and C - S by C - O (O - S), etc. Early work has been reviewed by Bun-nett [3] (1951) and Truce [4] (1970). 

Although Smh is more chemoselective than traditional dissolving metal reagents, it does react with sulfoxides, epoxides, the conjugated double bonds of unsaturated ketones, aldehydes and esters, alkyl bromides, iodides and p-toluenesulfonates. It does not, however, reduce carboxylic acids, esters, phosphine oxides or alkyl chlorides. In common with most dissolving metal systems, ketones with an a-hetero substituent suffer loss of the substituent rather than reduction of the carbonyl group. ... 

Generation of azomethine ylides with a hetero substituent on the nitrogen has been demonstrated by the thermolysis of 1-phthalimidoaziridines, leading to the corresponding N-aminoazomethine ylides 15 (83JOC481). This reaction occurs even at the boiling temperature of dichloromethane. 

Not all x-hetero substituents enhance acidity e.g., the pK s of PhS02Me and PhS02CH20Me are 29 and 30.7, respectively (see Table 2). This is also indicated by base-catalyzed hydrogen exchanges being retarded when x-RO groups are present. 

This general type of metal carbenes is termed Schrock carbenes . These carbenes differ from Fischer carbene complexes (those with o-hetero-substituents) in a number of ways. Schrock carbenes are viewed as X2 ligands with -i-2 charge, whereas Fischer carbenes are considered neutral L ligands. Fischer carbenes are electrophilic at the a-carbon and Schrock carbenes are nucleophilic. Thus complexes 1 and 2 are formally W(VI) and Mo(VI) complexes [66]. 

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