The First Isolation of Crystalline Ethyl Bromozincacetate, Typical Reformatsky Reagent: Crystal Structure and Convenient Preparation

Abstract

The highly reproducible preparation of ethyl bromozinc­acetate was achieved by a convenient procedure in which an excess amount of zinc powder was subjected to activation by chlorotri­methylsilane, followed by dropwise addition of ethyl bromoacetate. From the resultant solution of this Reformatsky reagent, crystalline ethyl bromozincacetate was isolated and its crystal structure was elucidated as its tetrahydrofuran-coordinated dimer (BrZnCH₂CO₂Et·THF)₂ by X-ray crystal structure analysis. Although it had a dimeric structure similar to the tert-butyl bromo­zinc­acetate crystal, the two had different stereochemistry in the zinc-containing eight-membered ring (ZnCH₂CO)₂. The crystalline reagent obtained possessed satisfactory reactivity and stability for practical use. On the other hand, by preparing the tetrahydrofuran-free ethyl bromozincacetate in such solvents as 1,2-dimethoxyethane or cyclopentyl methyl ether, unintended crystallization could be successfully prevented.

Key words

Reformatsky reagent - ethyl bromozincacetate - isolation - tetrahydrofuran-coordinated dimer - convenient preparation

References

• 1a Furstner A. Encyclopedia of Reagents for Organic Synthesis   Vol. 4:  John Wiley & Sons; New York: 1995.  p.2402 
• 1b Lombardo M. Trombini C. The Chemistry of Organozinc Reagents   Marek I. Rappoport Z. John Wiley & Sons; Chichester: 2006.  p.797 
• 2a Dekker J. Boersma J. Gerrit JM. J. Chem. Soc., Chem. Commun.  1983,  553 
• 2b Dekker J. Budzelaar PHM. Boersma J. Gerrit JM. Organometallics  1984,  3:  1403 
• 5 Bachmann WE. Cole W. Wilds AL. J. Am. Chem. Soc.  1940,  62:  824 
• 6 Picotin G. Miginiac P. J. Org. Chem.  1987,  52:  4796 ; in this report, ethyl bromoacetate was reacted with zinc in the presence of a carbonyl substrate and Et₂O was used as solvent
• 7 Consulting the literature relating to Mg activation, I₂ and 1,2-dibromoethane were also examined, but TMSCl was most preferable. Indeed when I₂ was utilized for Zn activation in Et₂O, sometimes there was ‘an induction period’ and heating was needed for reaction to be initiated: Zitsman J. Johnson PY. Tetrahedron Lett.  1971,  12:  4201 
• 12 Orsini et al. reported that the ethyl bromozincacetate in THF that they prepared, was contaminated by ethyl acetoacetate; Orsini F. Pelizzoni F. Ricca G. Tetrahedron Lett.  1982,  23:  3945 
• 15 Kawakami J. Nakamoto K. Nuwa S. Handa S. Miki S. Tetrahedron Lett.  2006,  47:  1201 
• 17 Kawakami J, Nakamoto K, Nuwa S, Handa S, and Miki S. inventors; WO  2003059889. We have submitted an international patent application on the present work:
• 19 Altomare A. Burla MC. Camalli M. Cascarano M. Giacovazzo C. Guagliardi A. Polidori G. J. Appl. Crystogr.  1994,  27:  435 
• 20 Beurskens PT. Admiraal G. Beurskens G. Bosman WP. de Gelder R. Israel R. Smits JMM. The DIRDIF-94 program system, Technical Report of the Crystallography Laboratory   University of Nijmegen; The Netherlands: 1994. 

3

In the strongly coordinating solvent DMSO, the reagent was interpreted to be monomeric.

4

Both Orsini et al. (ref. 12) and Dekker et al. (ref. 2) clearly described that they failed to obtain the crystals of this reagent.

8

Metallic zinc ca. 96-97% (impurities: Pb, Cd, Fe), particle size 6 µm (average), Honjo Chemical Corporation.

9

Heat values calculated from the adiabatic reaction in a Dewar vessel were as follows: heat of reaction ΔH _m = 2.47 × 10⁵ J/mol, adiabatic temperature increase ΔT _ad = 81 °C.

10

Figure [4] shows the influence of the addition period of ethyl bromoacetate on the exothermic behavior of the reaction mixture. Fundamentally, the appropriate addition rate varies depending on the reaction scale, cooling capacity, stirring efficiency, etc., and, therefore, should be carefully determined on the basis of suitable safety evaluations.

Figure 4 Exothermic behavior in the preparation of ethyl bromozincacetate

11

Although we attempted to analyze impurities by an NMR study of the concentrated residue of the obtained ethyl bromozincacetate-THF solution, useful information could not be obtained due to residual THF and other complicated constituents; there was no trace of side products such as ethyl acetoacetate in the NMR spectrum of the isolated crystals. On the other hand, we observed molecular ion peaks of ethyl acetoacetate, diethyl succinate, and other unknown compounds in the GC-MS of the hydrolytically quenched THF soln; adequate GC methods for quantitative analysis of the reagent solution could not be set up.

13

The ethyl derivative was rotationally symmetric, while the tert-butyl derivative was point symmetric.

14

We have been concerned that the reactivity of the reagent itself, not its reactivity in slurry state, was inhibited by irreversible changes during crystallization. However, there were no problems with this crystalline reagent.

16

Even when these solutions were concentrated, crystallization did not occur. On the other hand, the crystallization could not be prevented when DME or another solvent was added after preparing the reagent as the THF solution.

18

The crystallographic data have been deposited at the Cambridge Crystallographic Data Center; deposition number CCDC 656586.

21

Sheldrick, G. M. SHELXL-97, University of Göttingen: Germany, 1997.