Aziridines, deprotonation

The Hoch-Campbell reaction of a-hydroxy ketoximes do not alter the course of the reaction although deprotonation probably took place concurrently for both the alcohol and the oxime. Treatment of oxime 40 afforded aziridine 42 in 30%, presumably via the intermediacy of azirine 41. a-Keto ketoximes would behave similarly to the a-hydroxy ketoximes in the Hoch-Campbell reaction after addition of the first equivalent of the Grignard reagent to the ketone. Therefore, the reaction between a-keto ketoxime 43 and phenylmagnesium bromide gave aziridine 45 in 41% yield, presumably via the intermediacy of azirine 44. 

Attempts to induce valence isomerization of 5W-dibcnz[c,e,]azepine (3) to dihydrophenanthro-[9,10-6]azirine under thermal conditions have failed.85 However, the aziridine 5 is formed, albeit in low yield (3 %), by irradiating the dibenzazepinc 3 in dichloromethane solution. Isomerization can also be achieved by deprotonation of SH-dibenzIr.eJazepine with lithium diiso-propylamide at — 78 "C, and then allowing the resulting anion 4 to reprotonate by heating the reaction mixture at 50°C.85... 

Seebach and coworkers examined the deprotonation/electrophile trapping of phe-nylthioaziridine carboxylates 236 (Scheme 5.58). These thioesters were found to be more stable than their oxy-ester congeners when lithiated treatment of 236 with LDA at -78 °C, followed by trapping with Mel at -100 °C, stereoselectively afforded aziridine 237 [83]. 

A tert-butyl ester serves as an efficient organyl-stabilizing group for a lithiated aziridine when the N-protecting group is a chelating moiety. Deprotonation/elec-... 

Florio et al. have employed heteroaromatic rings as organyl-stabilizing groups for metalated aziridines as well as for metalated epoxides. Regioselective deprotonation of aziridine 246 with n-BuLi, followed by addition of Mel, gave aziridine 247 (Scheme 5.62) [88]. 

Direct deprotonation/electrophile trapping of simple aziridines is also possible. Treatment of a range of N-Bus-protected terminal aziridines 265 with LTMP in the presence ofMe3SiCl in THF at-78 °C stereospecifically gave trans-a, 3-aziridinylsi-lanes 266 (Scheme 5.67) [96]. By increasing the reaction temperature (to 0 °C) it was also possible to a-silylate a (3-disubstituted aziridine one should note that attempted silylation of the analogous epoxide did not provide any of the desired product [81],... 

A novel C-3 functionalization of methylene aziridines has also been reported <06T8447>. Selective deprotonation of 98 to form 99 and the reaction 99 with an electrophile yielded 100 in good yields. In this way, a variety of alkyl groups could be selectively placed on the aziridine. These researchers also found that (S)-a-methylbenzyl substituted methylene aziridines, 101, when deprotonated and reacted with a variety of electrophiles gave 102 in moderate yields and with good diastereoselectivity. 

As shown for the aziridines, BETMIP (68) has proved to be useful in the synthesis of azepines (Scheme 118). Treatment with methylenephosphorane leads to a phosphonium salt which in turn is deprotonated with BuLi and cyclized with benzene-l,2-dialdehyde in a Wittig and aza-Wittig step to form benzazepine 326 (93JOC1987). 

Attempts at deprotonation of epoxyketone 190 with EDA or n-BuLi at —95°C result only in reduction or addition to the carbonyl moiety. By contrast, deprotonation of the epoxy imine 191 leads to the aziridine 192 through a stereoselective dimerization/aza-Darzens//3-deprotonation process (Scheme 84). No example of reaction of this lithiooxirane with other electrophiles is reported. 

There are a few reports on the use of oximes as electrophilic amination reagents. Since 1984, ketone O-sulfonyloxknes have found applicability as amino transfer reagents to car-banions. In the reaction of organometaUic compounds with oximes, carbanions attack the carbonyl carbon of the oxime, giving Af-substituted hydroxylamines as addition products (Scheme 53, path a). However, a number of scattered reports have been also published on the formation of aziridines by a-deprotonation, followed by addition (path b) or formation of azirines by a-deprotonation before addition (path c). Addition of carbanions to azirines also yields aziridines, which are hydrolyzed to a-aminoalcohols. 

The following equations show the difference a strategically located ester group can make in the direction of aziridine opening [76]. The ester favors deprotonation at the conjoint benzylic position, leading to the benzazepine as the major product. 

Carbanions at C(2) of the aziridine ring may be generated by deprotonation or by exchange, e.g. tin-lithium. A major problem with the deprotonation approach is the necessity of a strong base which may also react by a nucleophilic ring-opening process. /V-(f-Butoxycarbonyl)aziridines may be deproto-nated with BusLi/TMEDA, as shown in Scheme 20 (94JOC276). 

Aziridination of ( )-chalcones can be carried out with other aminoimines which are formed by deprotonation of A-amino-A-methyhnorpholinium salts [58]. 

When A-tosylaziridines were reacted with amines or thiols in acetonitrile in the presence of 5 mol% DABCO,50 the nucleophile attacked regiospecifically at the least substituted carbon of the aziridine ring. When a benzyl carbon was present in the aziridine ring, both possible products were obtained although the major product was from attack at the benzyl carbon. The catalytic role of DABCO (which may form an ammonium zwitterion which can deprotonate the nucleophile) is under investigation. 

The nature of the /V-subsiiiuen1 of the aziridine moiety has been found to play an important role in the deprotonation reaction of oxazolinylaziridines.16 An electron-donating group appeared to be the /V-subsiilucnt of choice when the oxazoline moiety has a cis relationship with respect to the proton to be removed. The high stability of the resulting aziridinyllithium may be due to the coordinative effect of the oxazoline ring. 

Regio- and stereo-selective deprotonation of (V-t-butylsulfonyl-protected terminal aziridines with LiTMP has generated a non-stabilized aziridinyl anion that undergoes in situ or external electrophile trapping under experimentally straightforward conditions to give tran.v-disuhstituted aziridines in good to excellent yields.92... 

Diazoacetates are commonly used for the formation of aziridines from imines under Lewis or Bronsted acidic conditions - a process known as the aza-Darzens reaction. A useful twist on the reaction is achieved if the 1,2-addition intermediate undergoes deprotonation of the a proton prior to intramolecular aziridine formation with N2 extrusion. Such an interrupted aza-Darzens reaction accomplishes a... 

As in catalytic ylide epoxidation (see Section 10.2.1.1), an alternative catalytic cycle can be based on generation of the ylide in situ by reaction of a sulfide with an alkyl halide to form a salt, which can then be deprotonated [76]. In 2001, Saito et al. reported the asymmetric version of this cycle using a 3 1 ratio of alkyl halide to sulfonyl imine (see Scheme 10.18) [81]. Good yields and ee-values were reported for aryl- and styryl-substituted aziridines using stoichiometric amounts of sulfide 24, and the diastereoselectivities ranged from 1 1 to 4 1. Unfortunately, when loadings were reduced the reaction times became longer and lower yields were reported (see Table 10.2). 

Scheme 10.18 Catalytic asymmetric aziridination via alkylation of sulfide 24 and deprotonation.

Similar examples of de-aromatizing anionic cyclization reactions have also been described by other authors. Aggarwal and Ferrara have reported that cis-aziridine 254, on treatment with BuLi followed by quenching with iodomethane, gives the tricyclic aziridine 255 as a single diastereoisomer. This product probably arises from deprotonation of the benzylic carbon followed by intramolecular nucleophilic addition of the anion on the tosyl ring and subsequent methylation (Scheme 67)117. 

Aziridines can also be employed as nucleophiles. When one of the carbon atoms in the aziridine ring is equipped with an electron-withdrawing substituent, these substrates can often be cleanly deprotonated and used for subsequent carbanion chemistry. For example, the anion derived from the trifluoromethyl aziridine 162 engages in nucleophilic addition onto benzaldehyde to give the aziridinyl alcohol 163 in 83% yield <03TL6319>. Similarly, deprotonation of the oxazolinylaziridine 164 followed by treatment with methyl iodide gave mainly the methylated product 165 <03TL2677>. 

Hydroxymethylaziridine 67 undergoes ring opening in the presence of either carbon- or heteroatom-based nucleophiles upon treatment with 2 equiv of potassium hydride to provide the t)7aminoalcohol derivative 69. The key step of the reaction is considered to be an aza-Payne rearrangement of the deprotonated aziridine methanol to the... 

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