Intermediate amino

Ethoxymethylene- and aminomethylene-amino intermediates are also of use for preparation of 4-ones and 4-imines, e.g. (121) — (122) — (123) from o-aminopyridine esters (78KGS1671) and nitriles (e.g. 75JCS(P1)2182>. 

Hydrogenation of unsaturated nitro compound 37 (10% Pd/C, toluene) gives a saturated amino intermediate that can be treated with PTSA under Dean-Stark conditions to give the target keto isomer of cryptoheptine 38 in a 44% two-step yield (Scheme 7 (2000JNP643)). 

V-Alkoxy-V-chloroureas (77) have also been reacted with nitrogen nucleophiles resulting in Sat2 displacement of chloride. The products suggest that the reaction proceeds via an unstable V-alkoxy-V-amino intermediate (78), which under the influence of hydrochloric acid formed in the reaction, decomposed as illustrated to diaminomethane (79) and urea (80) (Scheme 15), although the exact mechanism is unclear . 

Chlorouracil, in its protected form, can be formally viewed as a precursor in pyrrolo[2,3-rf pyrimidine preparations. Thus 135 is treated with 136, which presumably gives a 6-amino intermediate by displacing the chloro group, and subsequently cyclizes to 137 (Scheme 13) <1995JOC5069>. 

Sodium a-butoxycarbonyl-a-nitromethanesulfonate (257) gave 3,6-dihydro-2,5(1//, 4//)-pyrazinedione (260) [Pd/C, EtOH—H20, H2, 20°C, 24 h 60% the mechanism involved disproportionation of the initial amino intermediate (258) into disodium a-amino-a-butoxycarbonylmethanedisulfonate (259) (isolated in 72% yield) and butyl glycinate, which self-condensed spontaneously to give the product (260)].1111... 

The pathways outlined in Scheme 3.3 overcome low yields encountered when 4-methoxybenzylmagnesium halides react with 5,6,7,8-tetrahy-droisoquinolinium salts (e.g., 2). Other routes were devised to achieve the same objective. Grewe et a/.(21) exploited the 1-lithium derivative of the tetrahy-droisoquinoline derived via the 1-amino intermediate, Scheme 3.4. 

One of the essential questions relating to the mechanism is whether the catalytic process involves any covalent intermediates between the substrate moieties and the enzyme. In the case of pepsin two possible intermediates could be formed the amino intermediate which involves the transfer of the amino moiety of the substrate to one of the carboxyl groups on the enzyme and the acyl intermediate which involves the transfer of the acyl moiety as shown on page 165. The examples used are substrates involved in transpeptidation reactions in which the respective intermediate has been demonstrated see below). 

Evidence for the formation of an amino intermediate comes from the work of Neumann et al (121) and Fruton et al. (122). Neumann et al 121) showed that when substrates such as Z-Glu-Tyr or Z-Phe-Tyr are incubated with pepsin, detectable amounts of Tyr-Tyr are formed. Fur-... 

The evidence for involvement of an acyl intermediate comes from the fact that pepsin catalyzes the exchange of between free carboxyl groups of acyl amino acids (products) and water 126, 127). This is fully discussed by Knowles 108) and Fruton 46). Attempts to trap putative acyl enzymes have failed so far. Furthermore, Shkarenkova et al. 128) showed that is rapidly incorporated from H2 into an active site carboxyl group of pepsin in the absence of an acyl amino acid, and that the rate of loss from labelled pepsin is similar to the pepsin-catalyzed rate of exchange with acetylphenylalanine. The 0-exchange experiments, therefore, do not require the formation of an acyl intermediate. With this in mind Knowles proposed a mechanism for pepsin-catalyzed reactions 108) which involves a covalent amino intermediate but not an acyl intermediate. 

Only the amino intermediate exists as proposed by Fruton (73), Knowles (108), and others while acyl intermediates are involved only in transpeptidation reactions of the type observed in our laboratory. 

Only the acyl intermediate exists in hydrolytic reactions while amino intermediates are involved only in transpeptidation reactions. 

The evidence for the amino intermediate comes from the transpeptidation reaction and from the kinetic studies of Greenwell et al. 123). In both types of studies poor substrates (N-substituted dipeptides) were used. No evidence for an amino intermediate has been obtained as yet from good substrates (substrates with high kcat). Similarly, the evidence for the acyl intermediate comes from transpeptidation studies as discussed. So far these reactions too have been observed using poor substrates. Thus, there is no a priori reason for preferring one of the intermediates over the other for the hydrolytic reaction. 

The possibility that hydrolysis proceeds without the formation of covalent intermediates has been mentioned by Fruton (73) and must be given serious attention in future studies. Because of the very large eflFects of the secondary binding sites on the catalytic efficiency, it is essential that these studies be carried out with good substrates. Silver and Stoddard (120) suggest that hydrolysis of small substrates proceeds without an amino intermediate. However, they did not consider an acyl intermediate. 

There is also the possibility that both acyl and amino intermediates are required for all the pepsin-catalyzed reactions. Bender and Kezdy (131) suggested that two carboxylic acid groups on the enzyme could reversibly form an anhydride. It could then undergo an exchange reaction with the peptide substrate to form an amino intermediate from... 

We therefore propose that not all pepsin-catalyzed reactions proceed via the same mechanism. We suggest that the nature of the substrate will determine the type of covalent intermediate formed on the pathway of the reaction. The proposed pathways are summarized in Figure 3. The first step would, of course, be the formation of an enzyme substrate complex (Reaction I). Reaction II presents the alternative formation of an acyl intermediate or an amino intermediate, depending on the substrate. 

Manufacture of many important amino intermediates used for dyes and other purposes is usually by conversion or replacement of a substituent. For example, as already mentioned, in substituted nitro compounds, the nitro groups may be reduced with iron/hydrochloric acid, hydrogen and catalyst, or zinc in aqueous alkali. Partial reductions can be brought about with sodium sulfide. Amino groups may be introduced by replacing halogens in the aromatic ring. Another approach to amination is by attack on a substituted aromatic compound with ammonia or amines. Thus, for example, direct amination of p-chloronitrobenzene (15a) in the presence of a copper catalyst affords p-nitroaniline (15b) in almost quantitative yield l,4-dichloro-2-nitrobenzene (16) is converted in a similar way to 4-chloro-2-nitroaniline (17). Reactions of ammonia with carboxylic acids or anhydrides are carried out on an industrial scale. 

In many cases a l-chloro-2-amino derivative is used as a starting material. The 2-aryl-selenazolopyridine (51) can be prepared directly from the l-chloro-2-amino intermediate without prior selenation by reaction of the lithium amide with the arylselenoester (Equation (8)) <87S363, 94H(37)323>. 

Vninonaphthalene-1,7-disulphonic acid EINECS 201-629-5 1-Naphthylamine-4,6-disulfonic acid 1,7-Naphthalenedisulfonlc acid, 4-amino-. Intermediate in synthesis of dyestuffs. Readily soluble in H2O, Eton... 

Similarly, the formylpyrrolidine compound (108) was reduced with an excess of Raney nickel to afford the amino intermediate, which was then treated with trifluoroacetic acid in dichloromethane-methanol to result in cyclization, thus giving rise to the pyrrolidinobenzothiadiazepine (109) (75% yield) <89H(29)1529>. The ethoxycarbonyl derivative (110) was also reduced with iron powder in glacial acetic acid to form the corresponding amino derivative, which was then cyclized to the 1,2,5-benzothiadiazepin-4-one (111) (60% yield) by heating at 170°C in the presence of 2-hydroxypyridine as a bifunctional catalyst <92SC1433>. 

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