3-Alkyl-2-amino- -bromid

Scheme 10.91 Grignard crosscoupling of 1-phenylethylmagnesium chloride and vinyl bromide with S-alkylated amino phosphine ligands.

Polystyrene-bound secondary aliphatic amines and /V-alkyl amino acids can be ally-lated by treatment with a diene and an aryl iodide or bromide in the presence of palla-dium(II) acetate (Entry 14, Table 10.3). As the diene, 1,3-, 1,4-, and 1,5-dienes can be used, and, besides aryl halides, heteroaryl bromides have also been successfully used [63], This remarkable reaction is likely to proceed via the formation of an aryl palladium complex, with subsequent insertion of an alkene into the C-Pd bond. The resulting organopalladium compound does not undergo ( -elimination (as in the Heck reaction), but isomerizes to an allyl palladium complex, which reacts with the amine to give the observed allyl amines. 

In a separate study, N -protected histidine and lysine were reacted with allyl bromide, 1-bromobutyne and 2-bromoacetophenone to prepare the corresponding N-alkylated amino acids (141). Miscellaneous Conjugations... 

While the majority of studies of j8-amino group participation have centered on alkyl amino groups in the types of systems mentioned above, some other system types have received attention. Mihalic et have reported on the regio- and stereoselectivity of bromide displacement in derivatives of the aryl amine (39). Some examples of amino group participa-... 

First, the 2-azanorbomene precursor, 108, is obtained by the aqueous imino Diels-Alder reaction between cyclopentadiene and the iminium ion derived from formaldehyde and 2-bromoethylamine hydrobromide. Exposure of a solution of amino bromide 108 to silver triflate provides the spiroaziridinium salt, 109, in good overall yield. The ability of 109 to function as an alkylating agent has been demonstrated with a variety of enolates [37]. 

Zinc enolates like 41 served as nucleophiles in a study aimed at a rhodium-catalyzed reaction with enantiomerically enriched allylic phosphates. Nonracemic products were obtained under efficient chirality transfer from the substrate and with remarkable diastereoselectivity [23]. Kazmaier enolates were used to manipulate the backbone of small peptides [27] by palladium-catalyzed allylations of a terminal glycine ester [28]. In the course of these studies, central glycine was also allylated in a diastereoselective manner through assumed chelated zinc enolates of glycine in a peptidic bond to proline or JV-alkyl amino acids [29]. Although this is, of course, not an asymmetric synthesis, the protocol is remarkable inasmuch as, in contrast to the palladium-mediated conversion, the noncatalyzed reaction of the enolate with the corresponding allylic bromide occurs in a more or less stereorandom manner. 

Benzyl bromide will readily alkylate amino groups. Reactions are normally carried out in the presence of additional base and dibenzylation of primary amines is usually predominant. Selective quatemization of a less hindered tertiary amine in the presence of a more hindered tertiary amine has been described." Amide and lactam nitrogens can be benzylated under basic conditions, as can those of sulfonamides" and nitrogen heterocycles. ... 

Alkylation of 3-methyl-4-phenylisoxazolin-5-one with allyl bromide gave a mixture of N- and C(4)- alkylation in a 2 1 ratio. Heating the mixture changed the ratio to 1 99 and this conversion is believed to take place by an amino-Claisen rearrangement (Scheme 91) (69TL543). 

Independent synthesis of IQ, eliminating the alkylating reaction step, involved the cyclizations of 7-R-5-amino-6-methylaminoquinolines with cyanogen bromide. When " C-labeled BrCN was used, the corresponding 2- " C-labeled analogues of IQ and MelQ were synthesized (83ACSI57). The diamines are available from 5-nitroderivatives, which in turn have been prepared by nitration of methylami-noderivatives (82CPB1857). 

The 6-methylacetylamino-l,2,3,4-tetrahydroquinoline, after nitration and separation of isomers, following reduction and deprotection, gave the 7-amino-6-methylamino derivative, which cyclized with cyanogen bromide. Alkylation of the cyclization products afforded inhibitors of thymidylate synthase, 5-substituted 2-amino-l//-l-methyl-5,6,7,8-tetrahydroimidazo[4,5-g]quinolines 136, designed for use in iterative protein crystal analysis (Scheme 42) (92JMC847). 

In a similar vein, the amino group in sulfide 14 (obtained presumably by an aromatic displacement reaction) is first converted to the bromide by Sandmeyer reaction to give 25. Reduction of the nitro group (16) followed by cyclization gives the substituted phenothiazine. Alkylation with the familiar halide (3) affords dimethothiazine (18). ... 

As described in Section 2.3.2, vinylaziridines are versatile intermediates for the stereoselective synthesis of (E)-alkene dipeptide isosteres. One of the simplest methods for the synthesis of alkene isosteres such as 242 and 243 via aziridine derivatives of type 240 and 241 (Scheme 2.59) involves the use of chiral anti- and syn-amino alcohols 238 and 239, synthesizable in turn from various chiral amino aldehydes 237. However, when a chiral N-protected amino aldehyde derived from a natural ot-amino acid is treated with an organometallic reagent such as vinylmag-nesium bromide, a mixture of anti- and syn-amino alcohols 238 and 239 is always obtained. Highly stereoselective syntheses of either anti- or syn-amino alcohols 238 or 239, and hence 2,3-trans- or 2,3-as-3-alkyl-2-vinylaziridines 240 or 241, from readily available amino aldehydes 237 had thus hitherto been difficult. Ibuka and coworkers overcame this difficulty by developing an extremely useful epimerization of vinylaziridines. Palladium(0)-catalyzed reactions of 2,3-trons-2-vinylaziri-dines 240 afforded the thermodynamically more stable 2,3-cis isomers 241 predominantly over 240 (241 240 >94 6) through 7i-allylpalladium intermediates, in accordance with ab initio calculations [29]. This epimerization allowed a highly stereoselective synthesis of (E) -alkene dipeptide isosteres 243 with the desired L,L-... 

Certain alkylated ammonium, phosphonium, or sulfonium compounds are effective, in relatively low concentrations, in interfering with the growth of gas hydrate crystals [972] and therefore are useful in inhibiting plugging by gas hydrates in conduits containing low-boiling hydrocarbons and water. For example, tetrabutylammonium bromide will be active. Gas hydrate or ice formation is further inhibited in lines by adding amino acids or amino alcohols [523]. 

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