Nitrogen substituents

Category Ic cyclizations involve formation of the C3-C3a bond and require aniline derivatives with a nitrogen substituent appropriate for such reaction. Some, but not all, such cyclizations also require an o-substituent, frequently halogen. The rctrosynthetic transformations corresponding to the most important of this group of syntheses are shown in Scheme 4.1... 

While both 2- and 3-vinylindole have been synthesized and characterized[l,2], they arc quite reactive and susceptible to polymerization. This is also true for simple l-alkyl derivatives which readily undergo acid-catalysed dimerization and polymerization[3]. For this reason, except for certain cases where in situ generation of the vinylindoles is practical, most synthetic applications of vinylindoles involve derivatives stabilized by EW-nitrogen substituents[4]. 

The most widely used method for the laboratory synthesis of a ammo acids is a modification of the malonic ester synthesis (Section 21 7) The key reagent is diethyl acetamidomalonate a derivative of malonic ester that already has the critical nitrogen substituent m place at the a carbon atom The side chain is introduced by alkylating diethyl acetamidomalonate m the same way as diethyl malonate itself is alkylated... 

A number of isoquinoline derivatives have fungicidal properties, eg, 1,2,3,4-tetrahydroisoquinoiines bearing acyl nitrogen substituents like (36) [41910-26-3] (189). Substituted isoquinolines (37) have proved to be effective in controlling undesired vegetation, insects, acarina, and fungi (190). 

Several types of nitrogen substituents occur in known dye stmetures. The most useful are the acid-substituted alkyl N-substituents such as sulfopropyl, which provide desirable solubiUty and adsorption characteristics for practical cyanine and merocyanine sensitizers. Patents in this area are numerous. Other types of substituents include N-aryl groups, heterocycHc substituents, and complexes of dye bases with metal ions (iridium, platinum, zinc, copper, nickel). Heteroatom substituents directly bonded to nitrogen (N—O, N—NR2, N—OR) provide photochemically reactive dyes. 

Thermal Cope-type rearrangements between C-vinyl and nitrogen substituents bearing appropriately labeled unsaturation are also known, e.g. (147) -> (148) (67JA60S, 71JOC3076). 

The interaction of acid chlorides (167 X = Cl) with imines in the presence of bases such as triethylamine may involve prior formation of a ketene followed by cycloaddition to the imine, but in many cases it is considered to involve interaction of the imine with the acid chloride to give an immonium ion (168). This is then cyclized by deprotonation under the influence of the base. Clearly, the distinction between these routes is a rather fine one and the mechanism involved in a particular case may well depend on the reactants and the timing of mixing. Particularly important acid chlorides are azidoacetyl chloride and phthalimidoacetyl chloride, which provide access to /3-lactams with a nitrogen substituent in the 3-position as found in the penicillins and cephalosporins. 

An interesting and useful property of enamines of 2-alkylcyclohexanones is the fact that there is a substantial preference for the less substituted isomer to be formed. This tendency is especially pronounced for enamines derived from cyclic secondaiy amines such as pyrrolidine. This preference can be traced to a strain effect called A or allylic strain (see Section 3.3). In order to accommodate conjugation between the nitrogen lone pair and the carbon-carbon double bond, the nitrogen substituent must be coplanar with the double bond. This creates a steric repulsion when the enamine bears a p substituent and leads to a... 

The pH of the solution is of overwhelming importance in determining the course of these hydrolyses. In basic solution, oxygen elimination is dominant. This is because the unprotonated nitrogen substituent is a very poor leaving group and is also more effective at facilitating the alkoxide elimination by electron donation ... 

In more recent work, Lockhart and Thompson have formed derivatives of 3 by substituting the secondary nitrogen. Substituents include CO—CH2—CH2—CH2—COOH and CH2CH2CH2 0Et. The latter compound should exhibit quite interesting binding properties for alkali metals, but binding constants for these compounds do not appear to have been determined. 

Most N-phenyl quaternary salts are not prepared by direct quater-nization but rather by introducing the nitrogen substituent before ring closure. It has recently been found that diphenyl iodonium boro-fluoride reacts smoothly with pyridine the phenyl carbonium ions formed give the 1-phenylpyridinium ion good yield. ... 

Just as with cefpimazole, cefepime (54) has a quaternary nitrogen substituent at C-3 whose electron withdrawing character and excellent nucleofugic properties increases the reactivity of the... 

Resonance effect (Section 16.4) The donation or withdrawal of electrons through orbital overlap with neighboring 7r bonds. For example, an oxygen or nitrogen substituent donates electrons to an aromatic ring by overlap of the O or N orbital with the aromatic ringp orbitals. 

More recently, Davis and co-workers developed a new method for the asymmetric syntheses of aziridine-2-carboxylates through the use of an aza-Darzens-type reaction between sulfinimines (N-sulfinyl imines) and a-haloenolates [62-66]. The reaction is highly efficient, affording cis- N-sulfmylaziridine-2-carboxylic esters in high yield and diastereoselectivity. This method has been used to prepare a variety of aziridines with diverse ring and nitrogen substituents. As an example, treatment of sulfinimine (Ss)-55 (Scheme 3.18) with the lithium enolate of tert-butyl bromoacetate gave aziridine 56 in 82% isolated yield [66],... 

Despite the effectiveness of chloramine-T in this new method, removal of the toluenesulfonyl group from the newly introduced nitrogen substituent requires harsh conditions. The finding that the N-chloramine salt of tert-butylsulfonamide is also an efficient nitrogen source and the terminal oxidant for aziridination of... 

Scheme 12.20 Influence of the nitrogen substituent (sulfonyl, acyl) on the regioselectivity of aziridine opening.

As the results show, the chirality of the a-alkoxy center, as well as the type of allyl metal employed, are the two most important determinants for the stereochemical outcome of the reaction. In other words, the 1,2-asymmetric induction combined with the right choice of the allyl organometallic overrides the influence of the chiral nitrogen substituent. 

This chapter embraces quinoxalines bearing nitrogenous substituents that are joined to the quinoxaline nucleus through their nitrogen atom. However, isocyano-, isocyanato-, and isothiocyanatoquinoxalines will be found in Chapter 7 to ensure that they are adjacent to quinoxalinecarbonitriles. 

---