A mild and convenient synthesis of N-carbobenzyloxy ketimines

Abstract

N-Carbobenzyloxy (Cbz) ketimines were prepared conveniently from N-Cbz amines by oxidation with N-tert-butylbenzenesulfinimidoyl chloride.N-Carboalkoxy aldimines are often used as nitrogen-containing electrophiles for carbon-carbon bond forming reactions, especially for highly enantioselective reactions such as the Mannich type reaction 1 and the aza-Henry reaction. 2,3 N-Carboalkoxy amines having a chiral tertiary carbon center are stereoselectively constructed by these reactions. Given this, N-carboalkoxy ketimines should be attractive electrophilic targets for creating chiral quaternary carbon centers; however, only a few N-carboalkoxy ketimines have been prepared 4-11 and most did not have acidic a-protons. Preparation of N-carboalkoxy ketimines is more difficult than preparation of N-carboalkoxy aldimines 4 because of the lower reactivity of ketones and the tendency of N-carboalkoxy ketimines to tautomerize into the corresponding ene carbamates. Hoch reported that N-carboethoxy ketimines were prepared from diethyl ketals and NH 2 CO 2 Et in the presence of a trace amount of PhNH 3 Cl at 90-100 uC, 5 but it was later found that N-carboethoxy ketimines obtained by Hoch's method included ene carbamate. 6,7 N-Carboalkoxy ketimines are also prepared from NH ketimines 8,9 or N-silyl ketimines, 10 though available NH ketimines and N-silyl ketimines have been limited to non-enolizable ones; i.e., diaryl and aryl tert-butyl ketimines. 11 We have found that N-tert-butylbenzenesulfinimidoyl chloride (1){ oxidized various organic compounds under very mild reaction conditions. 12 We expected that the above-mentioned labile Ncarboalkoxy ketimines would be synthesized under mild conditions by 1-mediated oxidation of the corresponding N-carboalkoxy amines. We describe here the oxidation of a variety of N-carbobenzyloxy (Cbz) amines to N-Cbz ketimines using 1.First, oxidation of N-Cbz-1-phenylethylamine (2a) to the corresponding N-Cbz ketimine 3a was tried using the following procedure: 2a was treated with n-BuLi in THF at 278 uC and then 1 was added at the same temperature. As expected, the 1-mediated oxidation of 2a proceeded rapidly at 278 uC and the desired product 3a was obtained in 97% yield after chromatography on silica gel. It was noted that ene carbamate 3a9 13 was not obtained by this procedure. The crystalline product 3a was stable in a refrigerator for several months, while a part of 3a tautomerized to 3a9 after keeping the solution of 3a in chloroform at room temperature for 10 days. The scope and limitations of the present 1-mediated oxidation were investigated for the reaction of various N-Cbz protected amines 2 giving N-Cbz aryl alkyl ketimines 3 (Table 1). N-Cbz phenyl ethyl ketimine 3b, N-Cbz phenyl propyl ketimine 3c, and N-Cbz phenyl isopropyl ketimine 3d were isolated in high yields regardless of the steric hindrance. It was found that yields of N-Cbz aryl ketimines 3 depended strongly on the substituents on the phenyl ring. In the presence of an electronattracting group, such as chloride, ketimine 3g ...

Recent Developments in the Stereoselective Synthesis of Nitrogen‐Containing Heterocycles using N‐Acylimines as Reactive Substrates

“…Condensation of amides or carbamates with carbonyl derivatives does not represent a viable procedure for the preparation of N ‐acylimines because of the unfavorable equilibrium for the imine formation. Thus, apart from some particular procedures involving acylation of N ‐trimethylsilylimines, condensation with iminophosphoranes, or oxidation of N ‐carbamoylamines, the general method for the preparation of compounds 1 involves a three component coupling of the amido derivative with an aldehyde and an heteronucleophile capable of generating stable compounds of type 3 – 5 (Scheme ). The obtained compounds are usually stable derivatives, easy to purify and store, which upon treatment with a suitable base suffer elimination of the heteronucleophilic moiety R 3 XH generating the N ‐acylimine 6 .…”

Synthesis of N-Boc-Propargylic and Allylic Amines by Reaction of Organomagnesium Reagents with N-Boc-Aminals and Their Oxidation to N-Boc-Ketimines

“…We found that the oxidation of α-alkynyl and alkenyl-substituted N -Boc-propargylic amines 4 with manganese dioxide afforded unprecedented N -Boc-protected dialkynyl ketimines and alkenyl alkynyl ketimines 6 in good yields (Table ). , While N -Boc-dialkynyl ketimines were obtained as a 1:1 mixture of E - and Z -isomers (entries 1–3 and 5), Z -ketimine 6d was formed exclusively in the case of an N -Boc-alkenyl alkynyl ketimine (entry 4), and a cis / trans isomerization of the styryl group was not observed (entry 4)…”

Recent Advances in Stereoselective Syntheses Using N-Acylimines

“…18,19 N-Benzyloxycarbonyl ketimines 11 are also prepared by oxidation of lithiated N-Cbz amines 9 using sulfinylimidoyl chloride 10 at low temperature (Scheme 2). 20 This procedure works on a range of a-substituted amines, but in some of the reported examples, when R 1 = Me or with N-Cbz cycloalkylamines, a consistent amount of the parent enecarbamate 12 is observed as co-product. In order to avoid this tautomerization, the reaction mixture is treated at -78°C with methanol that traps the ketimine as the corresponding N,O-ketal, as demonstrated here for the reaction of cyclohexanamine derivative 13 converted into ketal 15 via imine 14.…”