1. 1 CATALYTIC ASYMMETRIC NOZAKI- HIYAMA-KISHI REACTION: ROLE OF ORGANOCHROMIUM COMPOUNDS AND NOVEL SALEN LIGANDS A RKAJYOTI C HAKRABARTY Prof. Uday Maitra’s Group Department of Organic Chemistry Indian Institute of Science GRADUATE COLLOQUIUM 3.12.08

2. 2 CONTENTS OF THE TALK  INTRODUCTION TO ORGANOCHROMIUM COMPOUNDS  ‘NOZAKI-HIYAMA-KISHI’ REACTION  CATALYTIC AND ENANTIOSELECTIVE VERSION OF ‘NHK’ REACTION  NOVEL SALEN LIGANDS ( I & II ) IN ENANTIOSELECTIVE CATALYSIS  CONCLUSION AND REFERENCES

3. 3 ORGANOCHROMIUM COMPOUNDS  Chromium(II) reagents are powerful one electron reducing agents  Cr(II) readily inserts into allyl-, alkenyl-, alkynyl-, propargyl- and aryl halides and sulfonates under aprotic conditions, giving rise to the corresponding organochromium(III) reagents  Traces of nickel salts exert a catalytic effect on the formation of the C-Cr(III) bond

4. 4 ORGANOCHROMIUM COMPOUNDS AS NUCLEOPHILES A. Furstner, Chem. Rev. 1999, 99, 991-1045

5. 5 ‘NOZAKI-HIYAMA-KISHI’ REACTION  In Nozaki-Hiyama-Kishi reaction, CrCl 2 adds to unsaturated halide to form organochromium(III) compounds, which are used as nucleophiles for coupling with aldehyde  For less reactive substrates such as alkenyl and aryl halides or triflates, doping CrCl 2 with catalytic amount of Ni(II) or Mn(0) is a standard trick  The driving force of these reactions is the formation of highly stable O-Cr(III) bond

6. 6 TYPICAL EXAMPLES OF NHK REACTIONS A. S. K. Hashmi, J. Prakt. Chem. 1996, 338, 491-495

7. 7 NHK REACTIONS CATALYTIC IN CHROMIUM A. Furstner et al., J. Am. Chem. Soc. 1996, 118, 12349-12357

8. 8 ENANTIOSELECTIVE VERSION OF NOZAKI-HIYAMA-KISHI REACTION  First report of enantioselective NHK reaction involves salen as chiral ligand derived from trans-1,2-diaminocyclohexane (R,R)-N,N’-bis(3,5-di-tert-butyl-salicylidene)-1,2-cyclohexanediamine ( I ) A. Umani-Ronchi et al., Angew. Chem. Int. Ed. 1999, 38, 3357-3359

9. 9 HOW DOES SALEN ( I ) WORK AS THE CHIRAL LIGAND? Cr(Salen)

10. 10 ENANTIOSELECTIVE NHK REACTIONS CATALYZED BY [Cr (salen)] COMPLEX EntryR-XYield [ % ]ee [ %] 1. 2. 3. 67 65 70 84 ( R) 65 ( R) 0 Table-1: Enantioselective addition of various allyl halides to PhCHO catalyzed by [Cr(salen)] complex

11. 11 ENANTIOSELECTIVE NHK REACTIONS CATALYZED BY [Cr (salen)] COMPLEX EntryR’CHOYield of 2 [ % ] Yield of 3 [ % ] ee of 2 [%] 1. 2. 3. 67 41 42 16 40 0 78 ( R ) 77 ( R ) 89 ( R ) Table-2: Enantioselective addition of allyl chloride to aldehyde catalyzed by Cr (salen) complex

12. 12 SYN DIASTEREOSELECTIVE ADDITION PROMOTED BY CHIRAL Cr(salen) COMPLEX Hypothetical open transition state for the addition of crotyl bromide to ArCHO

13. 13 A BRIEF EXPLANATION  This syn diasteroselective addition is unique as normally aldehydes react with stereogenic allylchromium reagents to afford homoallylic alcohols with excellent degree of anti selectivity  A cyclic Zimmerman-Traxler transition state is thought to be involved in this reaction  Two molecules of Cr-salen complexes are involved in the transition state A. Umani Ronchi et al., Polyhedron 2000, 19, 537-539

14. 14 LIMITATIONS OF SALEN LIGAND ( I ) IN ENANTIOSELECTIVE NHK REACTION  The substrate spectrum is fairly narrow  Ally bromide and iodide were found to add with only moderate ( 52 % ee ) or no selectivity to benzaldehyde  Using this asymmetric NHK process, enantiomerically enriched allylic alcohols can not be generated starting from vinylic halides

15. 15 HOW TO SURPASS THE CURRENT LIMITATIONS?  Modification of the chiral diamine backbone of the salen ligand can lead to better catalytic properties in NHK reactions  A chiral diamine having a larger nitrogen-atom separation may prove to be useful building block for a highly enantioselective catalyst in the asymmetric NHK reaction Salen ( I ) A Highly Enatioselective Catalyst

16. 16 A NOVEL SALEN LIGAND ( II ) BASED ON DIANANE  This chiral salen ligand has the advantages of possessing C 2 symmetry and having a rigid hydrocarbon backbone and the separation between nitrogen atom is larger which plays an important role in improving the catalytic properties Ian Paterson et al., Angew. Chem Int. Ed. 2003, 42, 1032-1035

17. 17 ENANTIODIVERGENT SYNTHESIS OF (S,S)-2 AND (R,R)-2

18. 18 ENANTIODIVERGENT SYNTHESIS OF (S,S)-2 AND (R,R)-2 ( CONTD...)

19. 19 CATALYTIC PERFOMANCE OF (S,S)-2 Entry Aldehyde Halide Product ee ( % ) Yield ( % ) 1 90 72 2 31 Not Determined 3 79 76 4 54 78 5 64 Not Determined

20. 20 CATALYTIC PERFOMANCE OF (S,S)-2 ( CONTD…..) Entry Aldehyde Halide Product ee ( % ) Yield ( % ) 6. 92 69 7. 75 59 8. 61 54

21. 21 SALIENT FEATURES OF THE CATALYTIC PERFOMANCE OF (S,S)-2  The addition of allyl bromide to benzaldehyde proceeded with high enantioselectivity ( 90 %) and good yield ( 72 % )  THF proved to be the best solvent for these catalytic asymmetric reactions and catalyst concentration of 0.025 M gave the best results  In contrast to salen ligand 1, ligand 2 was able to effect an enantioselective addition of allyl iodide

22. 22 SALIENT FEATURES OF THE CATALYTIC PERFOMANCE OF (S,S)-2 ( CONTD…)  Using this ligand, it was possible to synthesise alylic alcohols in enantioselective fashion from vinyl iodides and triflates  Presence of 2 mol % of Ni II was required for these coupling reactions to occur efficiently  Vinyl halide gave 59 % yield with 75 % ee  Vinyl triflate gave 61 % ee

23. 23 CONCLUSION  Organochromium reagents take part as nucleophiles in versatile C-C bond forming reaction involving wide range of functionality  The novel salen ligands ( I & II ) play important role in catalytic and enantioselective Nozaki-Hiyama-Kishi reactions  The DIANANE-based salen ligands, (S,S)-II and (R,R)-II promote the asymmetric additions of allyl iodide and vinyl halides and triflates with useful levels of enatioselectivity

24. 24 REFERENCES 1. A. Frustner, Chem. Eur. J. 1998, 4, 567-570 2. C. Chen, K. Tagami, Y. Kishi, J. Org. Chem. 1995, 60, 5386-5387 3. M. Bandini, P.G. Cozzi, A. Umani-Ronchi, Chem. Commun. 2002, 919-927 4. R. T. Hawkins, R. S. Hsu, S. G. Wood, J. Org. Chem. 1978, 43, 4648-4650

25. 25 THANK YOU