Reactions at the 3-carbon

Due to the electron-withdrawing nature of the pyrimidine ring, alkenylpyrimidines can undergo addition reactions at the /3-carbon, and while this is a well-established route to substituted pyrimidine derivatives <1994HC(52)1, 1996CHEC-II(6)93>, it has also been used to prepare quinazolinone derivatives 578 from 2-alkenyM(3//)-quinazo-linones 577 <2000T7245>. 

Thus, Sn2 reactions at the 1° carbon atom in CH3Br are much faster than the analogous reaction at the 3° carbon atom in (CH3)3CBr. 

As pointed out by Stork and coworkers in their definitive 1963 paper , the reaction with electrophilic alkenes is especially successful since reaction at nitrogen is reversible. Reaction at the )3-carbon is (usually) rendered irreversible by, in the case of cyclohexanone enamines, internal proton transfer of the axial C-)S proton to the anionic centre of the initially formed zwitterionic intermediate (34), under conditions of stereoelectronic control (Scheme 22). When this intramolecular proton transfer cannot occur in aprotic solvents, or when the product produced in protic solvents is a stronger carbon acid than adduct 35 (i.e. when Z = COR, NO2), then carbon alkylation is also reversible and surprising changes in the regioselectivity of reaction may be observed vide infra see also Section VI.D and Chapter 26). Cyclobutanes (36) and, in the case of a,jS-unsaturated... 

Lactones are known to polymerize by both anionic and cat yonic mechanisms depending upon the substituents on the lactone ring. In general, however, 3-substituted-6-lactones are polymerized only with cationic initiators, presumably because an anionic polymerization occurs by an 3 2 reaction at the 3-carbon atom and steric hindrance from the substituents at the 3-position would interfere with the propagation step. 

The use of dichloromethyllithium for the synthesis of functionalized branched-chain sugars has been reported (Scheme S). For example, ketone (13) reacts with the reagent to give the 0-lithiated derivative (14) which on hydrolysis and reduction, affords compounds (15) and (16). Alternatively, heating (14) gives the spiro-chloroepoxide (17). Compound (17) reacts with nucleophiles such as azide or hydride with complete regiospecificity and S, 2 reaction at the 3-carbon with respect to chlorine as shown in the Scheme. Reaction with methoxide anion occurs at the a-carbon. 

Vinyl acetate reacts with the alkenyl triflate 65 at the /3-carbon to give the 1-acetoxy-1,3-diene 66[68]. However, the reaction of vinyl acetate with 5-iodo-pyrimidine affords 5-vinylpyrimidine with elimination of the acetoxy group[69]. Also stilbene (67) was obtained by the reaction of an excess of vinyl acetate with iodobenzene when interlamellar montmorillonite ethylsilyl-diphenylphosphine (L) palladium chloride was used as an active catalyst[70]. Commonly used PdCl2(Ph3P)2 does not give stilbene. 

The LUMO, which is the frontier orbital in reactions with nucleophiles, has a larger coefficient on the /3-carbon atom, whereas the two occupied orbitals are distorted in such a way as to have larger coefficients on oxygen. The overall effect is that the LUMO is relatively low-lying and has a high coefficient on the /3-carbon atom. The frontier orbital theory therefore predicts that nucleophiles will react preferentially at the /3-carbon atom. 

It is becoming increasingly apparent that a very extensive chemistry is associated with the dimetal species (1), and (3) - (13). Three types of reaction may be identified (i) aSTdition of other metal ligand fragments, discussed in the next Section, (ii) replacement of peripheral ligands on the metal centres, and (iii) reactions at the bridging carbon atom. One example of (ii) and (iii) will suffice to illustrate the scope and potential for new chemistry. 

We referred earlier to the significance of reactions at the alkylidyne carbon atoms of the dimetal species. Our studies in this area are in a preliminary stage, but Schemes 1 and 2 summarise some chemistry at the bridged carbon centres for the compounds (1 ) and (3,)(12). It will be noted that protonation of the neutral bridged al ylidyne compounds yields cationic alkylidene species in which one C—C bond of the tolyl group is n2 co-ordinated to tungsten, a feature revealed by both n.m.r. and X-ray diffraction studies. 

The addition reactions of nucleophilic and electrophilic reagents to optically active a, /3-unsaturated sulfoxides have also been found to proceed in an asymmetric way. Addition of piperidine to chiral (i )-cis-propenyl p-tolyl sulfoxide 309 affords a 87 13 mixture of diastereomeric sulfoxides 310 (318). The configuration at the 3-carbon atom of the predominant diastereomer (i yS )-310 was determined by means of chemical correlation starting from optically... 

A functional group may act either as a reactive group (reactions at the ipso-carbon atom) or as an activating group (reactions at the a- and/or 3-carbon atoms and only very seldom at the y-carbon atom) ... 

Nucleophilic substitution at the 3-carbon of 2/7-1,4-thiazines 192 <1969JHC247> and 193 <1992CPB1025> and nucleophilic addition to the 3-carbon of 2/7-1,4-benzothiazine 194 <1999TL2565> have been reported (Scheme 15). The catalyst used in the reaction of 194 is prepared from praseodymium(lll) isopropoxide and (R)-binaphthol. 

If a carboxylic acid ester side chain is introduced at the 3-position of a thiazine with a free NH group, lactam formation may occur <1987J(P1)1027>. Compound 78 is a result of lactam formation, and the synthesis of similar compounds is shown in Scheme 44 (Section 8.09.7). Reactions where the nitrogen reacts with a side chain introduced by a nucleophilic attack at the 3-carbon of 277-dihydrothiazines are shown in Schemes 6 and 27. 

As indicated in Scheme 3.7, the first step of an ElcB mechanism can be reversible and therefore deprotonation at the 3-carbon does not always lead to product formation. By applying a steady-state approximation to the carbanion concentration, the following rate law is obtained for an ElcB reaction ... 

The nucleophilic capture of tricyclane radical cations 115 " and 117 " supports the role of conventional steric hindrance 115 reacts at the 3° carbon ( 116 ), whereas the chiral isomer 117 + is captured by backside attack at the less hindered 3° carbon ( 118 ). " Both reactions are regio- and stereospecific and avoid attack at the neopentyl-type carbon (denoted by an asterisk). 

Reactions at the a-Carbon Atom of Carbonyl Groups Alkylation of Imino- and Enamino Compounds ... 

Methacrylonitrile (1) differs from 2 only in that it has a methyl (CH3) group on the a-carbon atom. It too is widely used in the preparation of homopolymers and copolymers, elastomers, and plastics and as a chemical intermediate in the preparation of acids, amides, amines, esters, and other nitriles. In a study conducted by the NTP in which 1 was administered orally to mice for 2 years, there was no evidence that it caused cancer, although other less serious toxic effects were noted [27]. Because 1 does not cause cancer, but undergoes many of the same nucleophilic addition reactions as 2 at the (3-carbon, it is sometimes used as a safer commercial replacement for 2, such as in the manufacture of an acrylonitrile-butadiene-styrene-like polymer that provides improved barrier properties to gases such as carbon dioxide in carbonated beverage containers. 

MECHANISM FIGURE 22-18 Tryptophan synthase reaction. This enzyme catalyzes a multistep reaction with several types of chemical rearrangements. An aldol cleavage produces indole and glyceraldehyde 3-phosphate this reaction does not require PLP. Dehydration of serine forms a PLP-aminoacrylate intermediate. In steps and this condenses with indole, and the product is hydrolyzed to release tryptophan. These PLP-facilitated transformations occur at the /3 carbon (C-3) of the amino acid, as opposed to the a-carbon reactions described in Figure 18-6. The /3 carbon of serine is attached to the indole ring system. Tryptophan Synthase Mechanism... 

Many common reactions of aliphatic amines, ethers and sulfides (1) involve initial attack by an electrophilic reagent at a lone pair of electrons on the heteroatom salts, quaternary salts, coordination compounds, amine oxides, sulfoxides and sulfones are formed in this way. Corresponding reactions are very rare (c/. Section 3.3.1.3) with pyrroles, furans and thiophenes. These heterocycles react with electrophilic reagents at the carbon atoms (2-3) rather than at the heteroatom. Vinyl ethers and amines (4) show intermediate behavior reacting frequently at the (3-carbon but sometimes at the heteroatom. 

Similar procedures can be used to prepare AAbu (both E- and Z-isomers) from Thr derivatives. Srinivasan et al/891 found that (3-elimination of the Thr derivative, Ac-(2R,35)-Thr-OMe 37 (threo type), gave only the stable Z-isomer 38 upon O-tosylation and subsequent elimination by DABCO as a base (Scheme 14). The underlying mechanism for this reaction may be a traits E2-elimination. (25,3R)-2-Acetamido-3-chlorobutanoic add methyl ester (erythro) 39, derived from the Thr threo form by chlorination with inversion of configuration at the (3-carbon, yields predominantly the E-isomer 38 by brief treatment with DBU as a base. However, a prolonged reaction time and use of DABCO as a base causes a significant amount of isomerization to the Z-isomer. 

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