Aziridinium intermediates

The reaction of iminium salts such as 66 with salts of trichloroacetic acid has been shown to yield amides such as 84 on hydrolysis 126). It was suggested that the reaction proceeds by addition of dichlorocarbene to give an aziridinium intermediate (85), which was opened by trichloroacetate followed by hydrolysis to give the observed products 126). The observed products from the reaction can be accounted for by formation of CCI3,... 

Coughing is a useful physiologic device utilized to clear the respiratory tract of foreign substances and excessive secretions. Coughing, however, does not always serve a useful purpose but can rob the patient of sleep. A number of agents are available to suppress this. Many of these are narcotic and have an undesirable abuse potential. One of the agents available which is claimed to be nonnarcotic is amicibone (45). The synthesis involves base-catalyzed alkylation of benzyl cyclohexan-ecarboxylate (44) with p-hexamethyleneiminoethyl chloride a reaction which may go through an aziridinium intermediate. 

That the metabolism of melphalan occurs by the same reaction mechanism as that of mechlorethamine has been demonstrated in in vitro studies [65]. Under physiological conditions of temperature and pH, formation of the first and second aziridinium intermediates en route to the bis(hydroxyethyl) metabolite occurred with rate constants of ca. 0.017 and 0.041 min-1, respectively. After 60 min, ca. 2/3 of the drug had been converted to the monohydroxy and dihydroxy products in comparable amounts. In the presence of a phosphate buffer, competition between hydrolysis and phosphatolysis was seen, such that at completion of the reaction (4 h) the two major products were the dihydroxy and the hydroxy/phosphate metabolites, with the dihydroxy derivative produced in small amounts. Similar hydrolytic dehalogena-tion has also been observed for ifosfamide in acidic aqueous solution [69]. 

A very powerful inhibitor, which is a bicyclic analogue of (33), is 6-acetamido-6-deoxycastanospermine (49), a compound synthesized from castanospermine and tested by Liu and co-workers [99]. This compound, amongst many other 6-modified castanospermine derivatives, was also prepared by the Furneaux team [100]. Furthermore, by controlled ring-contraction of suitably substituted castanospermine derivatives, these workers gained access to 8-acetamido-8-deoxyaustraline (50), a byciclic analogue of l-acetamido-l,2,5-trideoxy-2,5-imino-D-mannitol (44). This ring contraction reaction, which proceeds via a tricyclic aziridinium intermediate, is based on the same principle as the approach by Peter et al. to compound (45) [95]. 

In a similar way, 6-evo-iodo or bromo-2-azabicyclo [2.2.0]hexanes rearranged into 5,6-difunctionalized 2-azabicyclo[2.1.1]hexanes on treatment with silver or mercury salts. An aziridinium intermediate was probably formed in the presence of silver ions. Opening of this aziridinium then occurred in a stereocontrolled manner by addition of the silver counterion (Scheme 3.10).21... 

In the first reaction, the amine migrates from the primary to the secondary position in the other from secondary to primary. Both go through very similar aziridinium intermediates, so the difference must be due to the regioselectivity with which this aziridinium opens in each case. 

Several thiazolidines were synthesized via titanium tetrachloride catalytic cyclization <2005JOC227>. The reaction proceeds via an intramolecular attack on the nitrile by the aziridine nitrogen to provide bicyclic aziridinium intermediate 91. Subsequent ring opening by chloride yields thiazolidine 92 (Scheme 25). 

N-Allylation of aziridines is often complicated by side reactions. The classical solution to this problem, reductive amination, can also be problematic due to the increased strain energy of the aziridinium intermediate. A way to avoid this difficulty was developed by Yudin and co-workers <2005JA17516, 2004JA5086>. The results obtained showed that NH-aziridines such as 197 or 198 underwent a palladium-catalyzed allylic amination with various allyl acetates affording the desired allylated product 199 and 200 with high levels of regioselectivity and in high isolated yields (Scheme 54). 

Pyrrolizidine alkaloids ( )-trachelanthamidine (240) and ( )-supinidine (244) were synthesized, based on the Michael addition of an aziridine to an a,/J-unsaturated ester and subsequent ring opening of an aziridinium intermediate. Interest in these alkaloids stems from their biological activities. Treatment of ethyl 6-chloro-2-hexenoate (236) with excess aziridine at 0°C gave the pyrrolidine derivative 238 in one step, probably via the aziridinium salt 237 in 73% yield. The intramolecular cyclization of 238 with lithium diisopropylamide in tetrahydrofuran provided the thermodynamically more stable ester 239 as the sole product, (86%), which was then converted to ( )-trachelanthamidine (240) by reduction with lithium aluminum hydride. Since necine bases must contain a 1,2-didehydro system in their molecule to exhibit physiological activity, the following reactions were carried out to introduce a 1,2-didehydro system. Treatment of 238 with 2.4 equiv of lith-... 

The reaction of sodium azide with chloromethyl heterocycles (8) derived from morpholine, thiazine, piperazine and piperidine gave the corresponding ring-expanded compounds (11) along with the normally substituted compounds (10) via the postulated aziridinium intermediate (9) (Scheme 2) (94JCS(P1)2565). 

Enamines may serve as precursors as well (Eqs. 85195 and 8674). The latter reaction is of interest for the formation of rearrangement product 48, which apparently has not been followed up as a means of preparing a-amino aldehydes. A mechanism involving an aziridinium intermediate has been proposed.74... 

A review of the synthesis of morphinans includes discussion of the possible mechanism of formation of isomorphinans/ The amine (91 R = H) has been used as the key intermediate in the total synthesis not only of 3,14-dihydroxymorphinans and 9a-hydroxy-3-methoxyhasubanans but also of the first 3,14-dihydroxyisomorphinans, e.g. (94), (Scheme 7). Treatment of the morphinan thiocarboxamide (90 R = CSNHPh) with acid, instead of giving a 14-mercaptomorphinan derivative, caused isomerization first to the hasubanan (95) (presumably via an aziridinium intermediate) and then to the thiazinohasubanan (96) (cf. Scheme 8). Mechanisms for these transformations have been discussed in the light of deuterium incorporations observed when H2S04 or HCl was used. The last compound was converted, via an 8-mercapto-compound, into the hasubanan (97 R = H). The structure of this was confirmed by synthesis from (91 R = H) of the product obtained from its Hofmann degradation. 

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