Addition to carbon-nitrogen double bonds

In addition to the acid-catalysed hydrolysis of oximes, a kinetic study has also been made of the addition of bromine to a number of substituted benzal-dehyde phenylhydrazones . The measurements were made in 70% acetic acid v/v, in the presence of 0.1 M potassium bromide. The attacking species was shown to be predominantly molecular halogen, and not the tribromide ion, since a graph of 2(1 -t- X[Br ]) against [Br ] was linear, and of zero intercept, k-2 being defined by the equation 

The observed values of also did not change with changing initial concen- 

The reaction rate was increased when electron-donating groups were present in the benzylidene system (p = —0.62) and decreased when electron-attracting species were present. Introducing similar substituents to the phenylhydrazine system had a much more apparent effect (p = —2.17) similar to that found in the styrene system . The reaction evidently involves electrophilic attack it would be interesting to know the mechanism of the process in more detail since it apparently involves substitution at unsaturated carbon, which may proceed through an addition-elimination sequence (assumed here) or a one-step substitution process. 

Some preliminary kinetic work has been reported on the ozonolysis of nitrones. Ozone has been established as an electrophile towards carbon-carbon unsaturated systems in its reaction with some p-substituted-N-phenylbenzaldoximes in chloroform at —60°C the order of reactivity p-OMe H p-Cl has been established . Such a sequence could be accommodated by a process such as 

However, the similar reaction between aldehydes and ozone has been described as complex , and probably does not involve direct addition to the carbonyl group. A sequence such as (7.6) may be a gross simplification. 

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Ester enolates which contain the chiral information in the acid moiety have been widely used in alkylations (see Section D.1.1.1,3.) as well as in additions to carbon-nitrogen double bonds (sec Section D.1.4.2.). Below are examples of the reaction of this type of enolate with aldehydes720. The (Z)-enolate generated from benzyl cinnamate (benzyl 3-phenylpropcnoate) and lithium (dimethylphenylsilyl)cuprate affords the /h/-carboxylic acid on addition to acetaldehyde and subsequent hydrogenolysis, The diastereoselectivity is 90 10. 

Lewis acid-mediated nucleophilic additions to carbon-nitrogen double bond have been applied to the synthesis of homoallylic amines.1 3 Three-component syntheses of homoallylic amines starting from aldehydes, amines, and allyltributyltin are realized in the presence of Lewis acids such as La(OTf)3, Bi(OTf)3, LiClOa (Equation (47)).154-156... 

Nitrilimine Addition to Carbon-Nitrogen Double Bonds.198... 

Without additional reagents Preferential nucleophilic addition to carbon-nitrogen double bonds 1,1-Diamines from cyclic azomethines... 

There are many reports on the asymmetric addition of nucleophiles to carbon-nitrogen double bonds [6]. However, the majority of these reports are based on substrate control and rely on chiral auxiliaries in imines. Moreover, almost all of these reports are just for aldo-imine cases [7]. 

Without additional reagents Addition of carboxylic acid chlorides to carbon-nitrogen double bonds N-Acyl-2-chloraziridines from J -azirines... 

Addition of the cyanide ion to carbon-nitrogen double bonds was exploited for the preparation of Reissert compounds (p. 122). Isoquinoline and dihydro-isoquinoline compounds add cyanide ca. 6 times faster under sonication (Eq. 22), but the yields are not substantially changed and are even lower for the addition to 3,4-dihydroisoquinoline.54... 

Synthesis of hydrazines from hydrazones Addition of organometallic compounds to carbon-nitrogen double bonds... 

Gycloaddition Reactions. Isocyanates undergo cyclo additions across the carbon—nitrogen double bond with a variety of unsaturated substrates. Addition across the C=0 bond is less common. The propensity of isocyanates to undergo cycli2ation reactions has been widely explored for the synthesis of heterocycHc systems. Substrates with C=0, C=N, C=S, and C=C bonds have been found to yield either 2 + 2, 2 + 2 + 2, or 2 + 4 cycloadducts or a variety of secondary reaction products (2). 

Polyurethane Formation. The key to the manufacture of polyurethanes is the unique reactivity of the heterocumulene groups in diisocyanates toward nucleophilic additions. The polarization of the isocyanate group enhances the addition across the carbon—nitrogen double bond, which allows rapid formation of addition polymers from diisocyanates and macroglycols. 

Related to this process is the hydrolysis of isocyanates or isothiocyanates" where addition of water to the carbon-nitrogen double bond would give an N-substituted carbamic acid (3). Such compounds are unstable and break down to carbon dioxide (or COS in the case of isothiocyanates) and the amine ... 

These enzymes catalyze the addition of the elements of water to carbon-carbon double bonds (C=C), carbon-carbon triple bonds (C C), carbon-nitrogen double bonds (C=N), or carbon-nitrogen triple bonds (C N). These reactions are completely different from oxidoreductases since no redox reactions are involved. Illustrative examples include the following ... 

Efavirenz (1) is the second NNRTI development candidate at Merck. Prior to the development of 1, we worked on the preparation of the first NNRTI development candidate 2 [2]. During synthetic studies on 2, we discovered and optimized an unprecedented asymmetric addition of an acetylide to a carbon-nitrogen double bond. The novel asymmetric addition method for the preparation of 2 also provided the foundation for the process development of Efavirenz . Therefore, in this chapter we will first discuss chemistries for the preparation of 2 in two parts process development of large scale synthesis of 2 and new chemistries. Then, we will move into process development and its chemistries on Efavirenz . 

Acetylide addition in the racemic version Originally, 4equiv of lithium 2-pyridylacetylide (6) in THF/hexane was added to a mixture of 5 and 4equiv of Mg(OTf)2 in Et20 at room temperature. Precoordination with Mg(OTf)2 and 5 was reported to be essential to prevent reduction of the carbon-nitrogen double bond in 5 [2]. However, it turned out that precoordination was unnecessary for this reaction, as shown in Scheme 1.4, and racemic adduct 7 was obtained in 86% yield by treatment with 1.3 equiv of 6 at -15 °C in THF without Mg(OTf)2. 

N-AryInitrones (XIII) formed by oxidation of N-hydroxy-N-methyl arylamines, show high reactivity toward carbon-carbon and carbon-nitrogen double bonds in non-aqueous media (21,203) (Figure 10). Under physiological conditions, however, it appears that N-arylnitrones exist as protonated salts that readily hydrolyze to formaldehyde and a primary N-hydroxy arylamine and efforts to detect N-arylnitrone addition products in cellular lipid, protein or nucleic acids have not been successful (204). Nitroxide radicals derived from N-hydroxy-MAB have also been suggested as reactive intermediates (150), but their direct covalent reaction with nucleic acids has been excluded (21). 

A less common reactive species is the Fe peroxo anion expected from two-electron reduction of O2 at a hemoprotein iron atom (Fig. 14, structure A). Protonation of this intermediate would yield the Fe —OOH precursor (Fig. 14, structure B) of the ferryl species. However, it is now clear that the Fe peroxo anion can directly react as a nucleophile with highly electrophilic substrates such as aldehydes. Addition of the peroxo anion to the aldehyde, followed by homolytic scission of the dioxygen bond, is now accepted as the mechanism for the carbon-carbon bond cleavage reactions catalyzed by several cytochrome P450 enzymes, including aromatase, lanosterol 14-demethylase, and sterol 17-lyase (133). A similar nucleophilic addition of the Fe peroxo anion to a carbon-nitrogen double bond has been invoked in the mechanism of the nitric oxide synthases (133). 

The 2,3-, 2,5- and 3,4-dihydropyridines all contain a highly polarized carbon-nitrogen double bond and should be reactive toward nucleophilic reagents. From the limited information in the literature, this appears to be the situation. The 2,3-dihydropyridine is readily reduced by sodium borohydride (equation 58) (64JHC13). Hydride addition occurs in a 1,2 rather than 1,4 sense. 

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