Conversion of Imines into C,N-Dimagnesiated Compounds and Trapping with Electrophiles. One-Pot Access to 1-Azaspirocyclic Framework

Abstract

Under selected conditions, the Zr-catalyzed reaction of EtMgCl with imines produces C,N-dimagnesiated compounds, which can be further trapped with electrophiles. The overall transformation provides a new route to bifunctional or cyclic nitrogen-containing compounds. Particularly, 1-azaspirocyclic γ-lactams, pyrrolidines and azetidines can be obtained in this way.

Key Words

azetidines - Grignard reagents - imines - spiro compounds - zirconium

References

• 1 Gandon V. Bertus P. Szymoniak J. Eur. J. Org. Chem.  2001,  3677 
• 2 Takahashi T. Liu Y. Xi C. Huo S. Chem. Commun.  2001,  31 
• 3 For a recent review of Cp₂Zr(alkenes), see: Negishi EI. Takahashi T. Bull. Chem. Soc. Jpn.  1998,  71:  755 
• 4a Ethylmagnesiation of alkenes has been shown to afford variable amounts of the 1,4-carbodimagnesium products, which can be further transformed, see: Lewis DP. Muller PM. Whitby RJ. Jones RVH. Tetrahedron Lett.  1991,  32:  6797 
• 4b See also: Knight KS. Wang D. Waymouth RM. Ziller J. J. Am. Chem. Soc.  1994,  116:  1845 
• 4c See also: Lewis DP. Whitby RJ. Jones RVH. Tetrahedron  1995,  51:  4541 
• 7 The use of B(OMe)₃ proved to be unsuccessful. BF₃·OEt₂ was early employed for the synthesis of aryl- and alkylboranes from Grignard reagents, see: Gerrard W. The Organic Chemistry of Boron   Academic Press; London: 1961.  p.92 
• 1-Azaspirocyclic framework is encountered in a variety of biologically active molecules; for references and recent synthetic work, see:
• 8a Ito T. Yamazaki N. Kibayashi C. Synlett  2001,  1506 
• 8b Fenster MDB. Patrick BO. Dake GR. Org. Lett.  2001,  3:  2109 
• 8c Göbel A. Imhof W. Chem. Commun.  2001,  593 
• Although azetidines are an important class of heterocyclic compounds, only a few preparation methods are available, see:
• 9a Moore JA. Sellig Ayers R. In The Chemistry of Heterocyclic Compounds. Small Ring Heterocycles   Vol. 42, Part 2:  Hassner A. John Wiley and Sons; New York: 1982. 
• 9b Tilak BD. Gogte VN. Heterocycles  1977,  7:  1339 
• 9c Aben RWM. Scheeren JW. J. Org. Chem.  1987,  52:  365 
• 9d Barluenga J. Sanz R. Fañanás FJ. J. Org. Chem.  1997,  62:  5953 
• 10a 1a: Schnider P. Koch G. Pétrôt R. Wang G. Bohnen FM. Krüger C. Pfaltz A. Chem. Eur. J.  1997,  3:  887 
• 10b 1b: Knorr R. Schnegg A. Lattke E. Raepple E. Chem. Ber.  1979,  112:  3490 
• 10c 1c: Vejdelek ZJ. Protiva M. Collect. Czech. Chem. Commun.  1971,  36:  1611 
• 10d 1d: Cho BR. Namgoong SK. Bartsch RA. J. Org. Chem.  1986,  51:  1320 

5

We have previously demonstrated the feasibility of coupling F with benzaldehyde, see ref. [1]

6

The F:E ratio could easily be established by deuterolysis, see: ref. [1]