Efficient Aldol‐Type Reaction of O‐Protected α‐Hydroxy Aldehydes and N‐Trimethylsilyl Ketene Imines: Synthesis of β,γ‐Dihydroxy‐Nitriles

Abstract

An uncatalyzed aldol‐type reaction of aromatic N‐trimethylsilyl ketene imines with O‐protected α‐trialkylsilyloxy or α‐benzyloxy aldehydes is reported. It is shown that N‐trimethylsilyl ketene imines (SKIs) are essential for the success of this aldol‐type reaction, and that almost complete control of stereochemistry in the formation of the stereocentre vicinal to the stereogenic centre present in the starting aldehyde is seen when these compounds are used. A very high syn stereoselectivity was observed at room temperature, and a reversal of stereoselectivity to favour the formation of the anti product may be achieved at low temperature. Preliminary theoretical calculations support the hypothesis that the aldol‐type reaction is facilitated by the formation of a cyclic transition state, with concomitant silatropic migration from the ketene imine‐nitrogen to the aldehyde oxygen. The catalyst‐free aldol reaction has been applied to aromatic N‐trimethylsilyl ketene imines bearing two different aromatic groups. In these reactions, the diastereoselectivity for the stereocentre arising from aldehyde sp2 carbon remained extremely high, but the stereoselectivity for the formation of the new quaternary stereocentre was unsatisfactory.

Molecular titanium nitrides: nucleophiles unleashed

“…Given the insoluble nature of this yellow solid (presumably KNCCPh), we proceeded to treat it with Me 3 SiCl, immediately forming a salt (KCl) and a neutral species which was unequivocally identified to be the azaallene Me 3 SiNCCPh 2 based on 1 H NMR spectroscopic comparison to a literature report. 89 …”

α‐Alkyl‐α‐aryl (Trimethyltin) Nitriles: Versatile Nucleophilic Intermediates in Aldol‐Like Reactions

“…The calculations show that both the ketene imine and the nitrile forms can react with formaldehyde to give rise to the same oxy‐nitrile via the two different cyclic transition states TS‐ 6m and TS‐ 4m (Figure 2 and Scheme ). The ketene imine route (Path A, Scheme ) is characterized by six‐membered transition state TS‐ 6m , analogous to that found for trimethylsilyl ketene imines but with a significantly lower activation energy (6.2 against 27.4 kcal mol –1 ) 12. On the contrary, the [2+2] course (Path B, Scheme ) is characterized by a four‐membered transition state TS‐ 4m with a very high activation energy (46.9 kcal mol –1 ).…”

“…SKIs have found applications as highly versatile nucleophiles in catalytic asymmetric synthesis,4d,4f aldol‐type uncatalyzed reactions,12 catalytic asymmetric protonation,13 and acylation reactions 10a,14. In the context of a general study focusing on N ‐metalated imines15 and N ‐metalated ketene imines,12,14 we recently described a catalyst‐free class of aldol‐type reactions between diaryl‐trimethylsilyl‐substituted ketene imines and α‐hydroxy aldehydes to furnish β,γ‐dihydroxy nitriles with good yields and diastereoselectivities 12. These catalyst‐free reactions failed, in our hands, if α‐aryl‐α‐alkyl nitriles [e.g., 2‐phenylpropanenitrile ( 1a )] are used as starting materials.…”

Arylcyanomethylenequinone Oximes: An Overview of Synthesis, Chemical Transformations, and Biological Activity

“…The opinions of various scientific researchers engaged in the study of the field turned out to be ambiguous. Thus, in works of different times, such as Davis et al in 1960 [ 45 ], Zsako et al in 1971 [ 93 ], Adam et al in 2000 [ 94 ], Suwiński et al in 2003 [ 81 ], Long et al in 2013 [ 95 ], Hong et al in 2015 [ 33 ], Kouakou et al in 2015 [ 59 ], and Eddahmi et al in 2019 [ 96 ], the authors exclude the possibility of existence of oxime-nitroso tautomerism in the arylcyanomethylenequinone oximes. On the other hand, some authors of recent decades allow the existence of oxime–nitroso tautomerism in these compounds.…”