INTRAMOLECULAR CARBOLITHIATION-LITHIUM/ZINC TRANSMETALLATION: A VERSATILE SYNTHETIC COMBINATION FOR S_N2’ REACTIONS

 Miguel Yus^* and Rosa Ortiz

 Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain. 

Abstract: The reaction of 6-chlorohex-1-ene (1) with lithium powder and a catalytic amount of 4,4’-di-terc-butylbiphenyl (DTBB, 2.5 mol %) in THF at –30ºC affords the corresponding organolithium intermediate 3 via an intramolecular carbolithiation reaction. Treatment of organolithium compound 3 with zinc bromide and copper cyanide (2 equivalents of each salt) at room temperature, followed by addition of different allylic and propargylic halides at the same temperature, provides exclusively the corresponding products 4-8 resulting from an S_N2’ reaction.

 Keywords: catalysed lithiation, intramolecular carbolithiation, lithium/zinc exchange, S_N2’ reactions.

INTRODUCTION

 Carbolithiation¹ is an interesting synthetic methodology because starting from an organolithium compound,² by reaction with a carbon-carbon double (or triple) bond, together with the formation of a new carbon-carbon bond, an organolithium compound is formed, which can be used for the reaction with electrophiles. The intramolecular version of the process is particularly interesting because in the mentioned carbon-carbon bond formation a cyclic structure is generated.³ Concerning the formation of unsaturated organolithium intermediates,² that are necessary for the intramolecular carbolithiation, the most commonly methodology used involves a halogen-lithium exchange starting from brominated or iodinated materials and using an alkyllithium reagent.⁴ Very recently,⁵ we have performed an intramolecular carbolithiation by generating the corresponding unsaturated  organolithium intermediate by a chloro-lithium exchange. For the lithiation step, which has to be carried out at low temperature, a methodology consisting in the use of an excess of lithium powder and a catalytic amount of 4,4’-di-terc-butylbiphenyl (as electron carrier) was employed.^6-8 In the communication we report our preliminary results on the transformation of the cyclised  organolithium intermediate into the corresponding organozinc compound,⁹ exploring then their reactivity towards different electrophiles in reactions which are not possible with organolithium reagents.

RESULTS AND DISCUSSION

 The reaction of commercially available 6-chlorohex-1-ene (1) with lithium (ca. 1:6 molar ratio) and a catalytic amount of 4,4’-di-terc-butylbiphenyl (DTBB; 1:0.05 molar ratio; theoretical 1:2 molar ratio, 2.5 mol %) in THF at –30ºC led to the formation of the organolithium compound 3, resulting from an intramolecular carbocyclisation of the unsaturated organolithium 2 initially formed.⁵ After filtration of the excess of lithium, the resulting solution containing intermediate 3 was successively treated with a solution of zinc bromide (1:2 molar ratio) in THF and the complex CuCN·2LiCl (1:2 molar ratio) also in THF, both at 0ºC. Then, the resulting mixture was treated with cinnamyl chloride at the same temperature giving, after hydrolysis with hydrochloric acid, the corresponding compound 4, resulting from an S_N2’ reaction (Scheme 1).¹⁰

Scheme 1. Reagents and conditions: (i) Li, DTBB (2.5 mol %), THF, -30ºC; (ii) ZnBr₂, THF, 0ºC; (iii) CuCN·2LiCl, THF, 0ºC; (iv) (E)-PhCH=CHCH₂Cl, 0ºC; (v) H₂O, 3M HCl and a saturated solution of NH₄Cl, 0ºC to rt.

When the same process shown in Scheme 1 was applied to (E)- 1,4-dibromobut-2-ene or geranyl chloride, the expected products 5 and 6 were, respectively, obtained also resulting for S_N2’ reaction.

The S_N2’ reaction observed for allylic chlorides or bromides can also be applied to propargylic derivatives in order to prepare diene systems. Thus, using 1‑chlorohept‑2‑yne as electrophile the expected allene 7 was isolated.

Finally, the reaction with 1,4-dichlorobut-2-yne under the same conditions indicated in Scheme 1, but with half equivalent of the electrophile, afforded the diene 8.¹¹ In this case, after the first addition, the allene 9 initially formed (which is still an “allylic” chloride) suffered a second attack of the organolithium intermediate to yield the final product 8.

CONCLUSIONS

In conclusion, in this short communication, we report our preliminary results obtained combining an intramolecular carbolithiation and a lithium-zinc transmetallation. After activation with copper (I), a highly regioselective S_N2’ reaction with allylic and propargylic halogenides represents an adequate methodology to prepare unsaturated cyclic compounds.¹² It is worthy to note that the reaction shown in Scheme 1 did not work in the absence of the copper salt (only a metal-hydrogen exchange was observed giving the “reduced” compound) or both the zinc and copper reagents (an intractable mixture of products resulting from deprotonation and cross-coupling reactions from the electrophile, as well as a lithium-hydrogen exchange, was obtained). In addition, no S_N2 reaction products were observed in any case. Work is in progress to establish the scope of this process.

ACKNOWLEDGEMENTS

This work was generously supported by the Dirección General de Enseñanza Superior (DGES) of the current Spanish Ministerio de Ciencia y Tecnología (McyT; grant no. BQU2001-0538). Rosa Ortiz thanks the MECD (Ministerio de Educación, Cultura y Deportes) for a scholarship.

REFERENCES AND NOTES

1.   For a review, see: Clayden, J. Organolithiums: Selectivity for Synthesis; Pergamon: Amsterdam, 2002; Chapter 7.

2.   For a monograph on organolithium compounds, see: Wakefield, B. J. Organolithium Methods; Academic: London, 1988.

3.   For recent accounts see, for instance: (a) Norsikian, S.; Baudry, M.; Normant, J. F. Tetrahedron Lett. 2000, 41, 6575-6578. (b) Wei, X.; Taylor, R. J. K. Angew. Chem. Int. Ed. 2000, 39, 409-412. (c) Bailey, W. F.; Mealy, M. J. J. Am. Chem. Soc 2000, 122, 6787-6788. (d) Gil, G. S.; Groth, U. M. J. Am. Chem. Soc 2000, 122, 6789-6790. (e) Krief, A.; Remecle, B.; Mercier, J. Synlett 2000, 1443-1446. (f) Deiters, A.; Fröhlich, R.; Hoppe, D. Angew. Chem. Int. Ed. 2000, 39, 2105-2107. (g) Myers, A. G.; Goldberg, S. D. Angew. Chem.. Int. Ed. 2000, 39, 2732-2735. (h) Brémand, N.; Mangeney, P.; Normant, J. F. Tetrahedron Lett. 2001, 42, 1883-1885. (i) Bailey, W. F.; Luderer, M. R.; Mealy, M. J. Tetrahedron Lett. 2003, 44, 5303-5305.

4.   See, for instance: (a) Bailey, W. F.; Carson, M. W. J. Org. Chem. 1998, 63, 9960-9967. (b) Bailey, W. F.; Carson, M. W. Tetrahedron Lett. 1999, 40, 5433-5437.

5.   (a) Yus, M.; Ortiz, R.; Huerta, F. F. Tetrahedron Lett. 2002, 43, 2957-2960. (b) Yus, M.; Ortiz, R.; Huerta, F. F. Tetrahedron 2003, 59, 8525-8542.

6.   For reviews, see: (a) Yus, M. Chem. Soc. Rev. 1996, 25, 155-161. (b) Ramón, D. J.; Yus, M. Eur, J. Org. Chem. 2000, 225-237. (c) Yus, M. Synlett 2001, 1197-1205. (d) Yus, M.; Ramón, D. J. Lat. J. Chem. 2002, 79-92. (e) Ramón, D. J.; Yus, M. Rev. Cubana Quim. 2002, 14, 75-115. (f) Yus, M. In The Chemistry of Organolithium Compounds; Rapopport, Z., Marek, I., Eds.; Wiley: Chichester, 2003; in press.

7.      For mechanistic studies, see: (a) Yus, M.; Herrera, R. P.; Guijarro, A. Tetrahedron Lett. 2001, 42, 3455-3458. (b) Yus, M.; Herrera, R. P.; Gujarro, A. Chem. Eur. J. 2002, 8, 2574-2584. (c) Herrera, R. P.; Guijarro, A.; Yus, M. Tetrahedron Lett. 2003, 44, 1309-1312. (d) Herrera, R. P.; Guijarro, A.; Yus, M. Tetrahedron Lett. 2003, 44, 1313-1316. (e) Yus, M.; Herrera, R. P.; Guijarro, A. Tetrahedron Lett. 2003, 44, 5025-5027.

8.      For a polymer supported arene-catalysed version of this reaction, see: (a) Gómez, C.; Ruiz, S.; Yus, M. Tetrahedron Lett. 1998, 39, 1397-1400. (b) Gómez, C.; Ruiz, S.; Yus, M. Tetrahedron 1999, 55, 7017-7026. (c) Yus, M.; Gómez, C.; Candela, P. Tetrahedron 2002, 58, 6207-6210. (d) Arnauld, T.; Barret, A. G. M.; Hopkins, B. T. Tetrahedron Lett. 2002, 43, 1081-1083. For a polymer supported arene-catalysed lithiation used in the activation of nickel, see: (e) Alonso, F.; Candela, P.; Gómez, C.; Yus, M. Adv. Synth. Catal. 2003, 345, 275-279. (f) Candela, P.; Gómez, C.; Yus, M. Russ. J. Org. Chem. 2003, in press.

9.      Reviews on organozinc compounds: (a) Knochel, P. Synlett 1995, 393-403. (b) Knochel, P.; Almena, J.; Jones, P. Tetrahedron 1998, 54, 8275-8319. (c) Erdik, E. Orgnozinc Reagents in Organic Synthesis, CRC Press, Boca Raton, 1996. (d) Knochel, P. in Metal-Catalysed Cross-Coupling Reactions (Eds: F. Diederich, P. J. Stang), Wiley-VCH, Weinheim, 1998. (e) Organozinc Reagents, A Practical Approach (Eds: P. Knochel, P. Jones), Oxford University Press, Oxford, 1999.

10.    For the application of this process to form functionalized organolithium reagents, see: Yus, M.; Gomis, J. Eur. J. Org. Chem. 2003, 2043-2048.

11.    For a similar reaction, see: Zhu, L.; Rieke, R. D. Tetrahedron Lett. 1991, 32, 2865-2866.

12.    Yields have not been optimised.