De la medición de resultados a la evaluación formativa

ESULTS AND ISCUSSION

1

N

P

TMPZnCl·LiCl BY Zn I

TMPCl.

A

F

D

1.1

INTRODUCTION

The preparation of functionalized aromatic molecules and heterocycles is of great importance due to their potential biological activity. These structures are present in many pharmaceuticals or agrochemicals.88 _{Direct metalation has proven to be an excellent tool for the regioselective}

functionalization of these compounds.89 _{Therefore, the availability of chemoselective as well as}

kinetically highly active bases is an important synthetic goal.90 Besides the already mentioned methods for the generation of organozincs, Kondo reported the use of LitBu2ZnTMP allowing an

efficient zincation due to the ate-character of this reagent (the structures of the metalated intermediates were extensively studied by Mulvey).91 _{The major drawbacks of this method are the}

low atom-economy, thus excess of base is necessary and consequently also a high excess of electrophile for achieving full conversion and the non-compatibility with sensitive functional groups like aldehydes or nitro groups.

Recently, Knochel and coworkers have shown that TMPZnCl·LiCl (5) is an exceptionally active and chemoselective base, allowing to perform highly selective zincations at a convenient temperature range (typically 0 °C to 80 °C).72 _{The preparation of}

5 has been done in two steps starting from 2,2,6,6-tetramethylpiperidine (2: TMPH) in >95% yield. Thus, the amine 2 is first deprotonated with nBuLi in hexanes (1 equiv, -10 °C, 1 h) leading to TMPLi (8) in quantitative yield. Transmetalation with ZnCl2 (1.05 equiv, -10 °C to 25 °C, 0.5 h) furnishes after evaporation of the hexanes:THF solvent

mixture and redissolving in dry THF 1.2-1.4 M solutions of TMPZnCl·LiCl (5). Although the overall yield of this synthesis is high (ca. 90%; Pathway A; Scheme 23), it has several drawbacks. The reaction conditions require the use of dry ZnCl2. Also nBuLi is only available in nonpolar solvents (alkanes or

toluene). Since this solvent mixture reduces significantly the solubility of TMPZnCl·LiCl (5) and therefore also its metalation power, a tedious solvent evaporation and redissolution is required. These impractical conditions as well as the relatively high price of nBuLi solution and safety considerations led to the design of a new synthesis of TMPZnCl·LiCl (5) which would be conducted in

88

a) T. Eicher, S. Hauptmann, The Chemistry of Heterocycles, Thieme, Stuttgart, 1995; b) A. R. Katritzky, C. W. Rees, E. F. V. Scriven, Comprehensive Heterocyclic Chemistry II; Pergamon: Oxford, 1996.

89

a) N. Chatani, Topics in Organometallic Chemistry: Directed Metallation, Springer, Berlin, 2007; b) G. Dyker, Handbook of C-H Transformations, Wiley-VCH, Weinheim, 2005; c) A. Turck, N. Plé, F. Mongin, G. Quéguiner, Tetrahedron 2001, 57, 4489; d) M. C. Whisler, S. MacNeil, P. Beak, V. Snieckus, Angew. Chem. 2004, 116, 2256; Angew. Chem. Int. Ed.2004, 43, 2206.

90

a) R. E. Mulvey, F. Mongin, M. Uchiyama, Y. Kondo, Angew. Chem.2007, 119, 3876; Angew. Chem. Int. Ed.2007, 46, 3802; b) B. Haag, M. Mosrin, H. Ila, V. Malakhov, P. Knochel, Angew. Chem.2011, 123, 9968; Angew. Chem. Int. Ed. 2011, 50, 9794.

91

a) Y. Kondo, H. Shilai, M. Uchiyama, T. Sakamoto, J. Am. Chem. Soc. 1999, 121, 3539; b) T. Imahori, M. Uchiyama, Y. Kondo, Chem. Comm.2001, 2450; c) P. F. H. Schwab, F. Fleischer, J. Michl, J. Org. Chem. 2002, 67, 443; d) M. Uchiyama, T. Miyoshi, Y. Kajihana, T. Sakamoto, Y. Otami, T. Ohwada, Y. Kondo, J. Am. Chem. Soc. 2002, 124, 8514; e) D. R. Armstrong, W. Clegg, S. H. Dale, E. Hevia, L. M. Hogg, G. W. Honeyman, R. E. Mulvey, Angew. Chem.2006, 118, 3859;

Angew. Chem. Int. Ed. 2006,45, 3775; f) M. Uchiyama, Y. Kobayashi, T. Furuyama, S. Nakamura, Z. Kajihara, T. Miyoshi, T. Sakamoto, Y. Kondo, K. Morokuma, J. Am. Chem. Soc. 2008, 130, 472; g) R. E. Mulvey, Acc. Chem. Res.2009, 42, 743; h) W. Clegg, S. H. Dale, E. Hevia, L. M. Hogg, G. W. Honeyman, R. E. Mulvey, C. T. O'Hara, L. Russo, Angew. Chem.2008, 120, 743; Angew. Chem. Int. Ed. 2008,47, 731; i) W. Clegg, B. Conway, E. Hevia, M. D. McCall, L. Russo, R. E. Mulvey, J. Am. Chem. Soc. 2009, 131, 2375.

a more favorable temperature range and involve cheap and safe reagents. TMPH (2) is readily converted either by chlorination with NCS or by treatment with an aq bleach solution (13% aq NaOCl) at 25 °C to the corresponding chloramine 1-chloro-2,2,6,6-tetramethylpiperidine (9: TMPCl) in 84% yield.92 A direct insertion of a metal (Met) into the nitrogen-chlorine bond of TMPCl (9) in the presence of LiCl, which would afford the metallic amides TMPMetCl·LiCl, has been envisioned.

1.2

NEW PREPARATION OF TMPZ

C

·L

C

Preliminary results showed that for Met = magnesium (turnings or powder), only reduction of the chloroamine (9) is observed. However, switching to zinc dust and performing a slow addition of the chloroamine via syringe pump at 0 °C allows the preparation of TMPZnCl·LiCl (5) in >90% yield as indicated by titration with benzoic acid93 _{(Pathway B; 50 mmol scale; Scheme 23).}

Scheme 23: Preparation of TMPZnCl·LiCl(5).

TMPZnCl·LiCl (5) was directly obtained in concentrations that made evaporation of solvents obsolete. The excess of zinc powder can simply be removed by filtration. Thus, a fast preparation of this organozinc base is possible starting from cheap commercial zinc and the N-chloroamine TMPCl (9). This method could also be applied to other N-chloroamines, like 1-chloro-diisopropylamine, 1-chloro- tert-butyl-isopropylamine or 1-chloro-piperidine.94 However, the yields of the corresponding zinc amides 10, 11 and 12 drop significantly compared to the yield of TMPZnCl·LiCl (5). A possible reason for this yield decrease could be imine formation in course of the insertion (Scheme 24).

92

a) N. Bodor, J. J. Kaminski, S. D. Worley, R. J. Colton, T. H. Lee, J. W. Rabalais, J. Pharm. Sci.1974, 63, 1387; b) N. C. Deno, R. Fishbein, J. C. Wyckoff, J. Am. Chem. Soc.1971, 93, 2065.

93

T. Huguchi, J. Concha, R. Kuramota, Anal. Chem.1952, 24, 685.

94

Note: N-chloroamines which can readily eliminate HCl are energy rich compounds that are inherently much less stable than TMPCl, as such considerable care must be taken during their preparation and use.

ESULTS AND ISCUSSION