Amino acids with electron-withdrawing groups

All three mononuclear amines and 3-amino-2,l-benzisothiazole can be diazotized and coupled to form azo dyes (see Section 4.02.3.5), but 3-amino-1,2-benzisothiazole reacts with nitrous acid to give 3,3 -bis(l,2-benzisothiazoline) (72AHC(14)43), and 5-aminoisothiazoles bearing an electron-withdrawing group at the 4-position form iV-nitrosoamines (72AHC(14)1). 

The substrate scope is limited, as electron-withdrawing groups (X = p-N02 or p-CF3) on the aromatic substituent are not tolerated. However, this route does provide valuable intermediates to unnatural a-amino phosphonic acid analogues and the sulfimine can readily be oxidized to the corresponding sulfonamide, thereby providing an activated aziridine for further manipulation, or it can easily be removed by treatment with a Grignard reagent. 

If an aliphatic amino group is next to an electron-withdrawing group such as CO2R, CN, CHO, COR and has a hydrogen, reaction with aqueous nitrous acid gives a diazo compound (Eq. 11.4). Such compounds are used widely in 1,3-dipolar cycloaddition reactions, which will be covered in Chapter 12. 

The Alper group [163] reported on a highly efficient double carbohydroamination for the preparation of a-amino carboxylic acid amides 6/1-345, starting from aryl iodides and a primary amine 6/1-344, in usually high yield (Scheme 6/1.88) both, aryl iodides with electron-donating and electron-withdrawing groups can be used. 

The degree of instability of the (3-lactam ring depends on the availability of the electrons for attack, so modification of penicillins with the addition of electron withdrawing groups near the amide carbonyl decreases the availability of these electrons and significantly improves acid stability. For example, the amino group of amoxicillin and ampicillin makes these molecules acid stable. 

A-(Monosubstituted amino)pyridiniums (972) are in prototropic equilibrium with A-imides (973) and dications (971). For R = H or allyl, the A-imides (973) are very strong bases and cannot usually be isolated if R is an electron-withdrawing group (e.g. acyl, sulfonyl, nitro), then the imide (973) is less basic and more stable. The cations (971) are only obtained in very strongly acid media. 

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