Organocopper Chemistry

Transcription

1 rganocopper Chemistry ave a great historical importance, but still remain highly useful reactions. If not the first organometallic reactions developed they are among the first. Most often used in conjugate addition reactions and couplings with sp 2 carbons, but are also quite useful in epoxide openings, S N 2 and S N 2' reactions, and alkyne addtions. While there are a few generaliteis that can be made, this area is still quite empirical and experimentation is critical. Finding a close example in the literature is recommended. We will discuss mechanism a bit, but the details are still debated and are not well understood. Most reactions are still run with stoichiometric amounts of Cu, but catalytic methods are becoming more important. Lipshutz, B.. rganocopper Chemistry, in rganometallics in Synthesis: A Manual, 2nd Ed; Schlosser, M., Ed.; Wiley: New York, 2002, pp

2 rganocopper Chemistry Initial bservations Gilman,.; Straley, J. M. ecl. Trav. Chim. Pays-Bas Belg. 1936, 55, Gilman,.; Jones,. G.; Woods, L. A. J. rg. Chem. 1952, 17, MgX + CuI 1 Cu Et 2 1 equiv 1 equiv insoluble 1 2 CCl 2 1 low to moderate yields Li + CuI 2 equiv 1 equiv Et 2 2 CuLi soluble as since become known as the Gilman reagent Kharasch, M. S.; Tawney, P.. J. Am. Chem. Soc. 1941, 63, MgBr 1 mol% CuCl MgBr 91% 1,2-addition no 1,4-addition Et ºC Et ºC 83% 1,4-addition 7% 1,2-addition CuCl was unique, no other metal halide additive gave higher than ~5% 1,4-addition.

3 rganocopper Chemistry Key ectivity Papers ouse,..; espess, W. L.; Whitesides, G. M. J. rg. Chem. 1966, 31, CuLi M M = Li, MgBr, or Cu high yields, with >99% 1,4-addition quick reaction times (<1 hr) Ac 2 Ac Corey, E. J.; Posner, G.. J. Am. Chem. Soc. 1967, 89, I 2 CuLi Et 2 I 75% Br 89% Br Br 75% 81%

4 Lower rder Gilman Cuprates 2 CuLi Soluble, thermally unstable; typically generate in situ; often the "recipe" used to make the regent and/or react with substrate is critical to success; often discovered emperically Can utilize and transfer virtually any sp 2 or sp 3 hybridized carbon Because of low basicity, diorganocuprates undergo alkylation reactions with a variety of organic electrophiles; generally with high levels of inversion and little elimination; typically reacts in S N 2' manner if available order of reactivity primary > secondary > > tertirary iodide > bromide > chloride alkenyl halides and triflates work as well, with retention of configuration (cis, trans) CCl > aldehydes > tosylates ~ epoxides > iodides > ketones > esters > nitriles Some examples: Tr 2 CuLi Cl Cl 2 CuLi Ac Et Et J. Am. Chem. Soc. 1976, 98, 7854 J. Am. Chem. Soc. 1970, 92, 737 Tr

5 Lower rder Gilman Cuprates 2 CuLi Undergoes conjugate addition reactions with α,β-unsaturated electrophiles; the intermediate enolate can be trapped with a variety of electrophiles Ketones most reactive, only slightly diminished rates with substitution at α or β position Esters less reactive than ketones, dramtically lower rates with substitution at α or β position Esters less reactive than ketones, dramtically lower rates with substitution at α or β position Sulfones are competent substrates; carboxylic acids do not react; amides and anhydrides have seen limited work; aldehydes see competing 1,2-addition Addition of phosphine lignads can often speed up troublesome reactions Some examples: Bu 3 PCu (C 2 ) 4 C 3 (C 2 ) 3 C 2 TBS I (C 2 ) 3 C 2 J. Am. Chem. Soc. 1988, 110, 4726 TBS (C 2 ) 4 C 3 Ac 2 CuLi Ac J. rg. Chem. 1971, 36, 877

6 Lower rder Mixed Cuprates t r CuLi A major problem associated with Gilman-type organocuprate reagents is that they require two alkyl groups, but only transfer one. This is particularly problematic when wanting to transfer "precious" alkyl groups. Also can be quite unstable, so excess reagent often needed. To address this problem modified reagents have been developed with one "transferable" group and one "residual" group. These are often stable at higher temps ( 20 ºC and 0 ºC). ften the reactivity is altered (for better or worse) relative to Gilman-type reagents. Best to compare with known systems. CuSPh Li Cu(SPh)Li Cut-Bu Li Cu(t-Bu)Li lithium phenylthio(alkyl)cuprate lithium t-butoxy(alkyl)cuprate Can also have mixed "alkyl"cuprates with spectator ligands (these are most popular): C CLi CuI C C Cu Li C C Cu()Li lithium acetylide(alkyl)cuprate S Li CuI S Cu Li S Cu()Li 2-thienyl lithium lithium 2-thienyl(alkyl)cuprate

7 Lower rder Mixed Cuprates t r CuLi Can also use P- and N-based ligands; these are especially stable (still reactive after 24 rt) Cy 2 NLi Cy 2 PLi CuI CuI Cy 2 NCu Cy 2 PCu Li Li Cu(NCy 2 )Li Cu(PCy 2 )Li J. Am. Chem. Soc. 1982, 104, 5824 J. rg. Chem. 1984, 49, 1119 lower oder cyanocuprates, ease of preparation (start from CuCN), but less reactive than other mixed cuprates, but are quite useful in epoxide openings CuCN Li Cu(CN)Li TMS Cu(CN)Li J. rg. Chem. 1979, 44, 4467 TMS "igher order cyanocuprates" can be made by addition of two equivalents of Li to CuCN; Brings reactivity mor ein line with Gilman reagents, but are still more stable Li (2 equiv) CuCN 2 Cu(CN)Li 2

8 Additives BF 3 Et 2 If the cuprate of choice is unreactive at low temperature and especially unstable at higher temperatures, the use of BF 3 Et 2 or 3 SiCl may improve reactivity. [ 2 CuLi] BF 3 3 Cu 2 Li + Li BF 3 + BF 3 J. Am. Chem. Soc. 1989, 111, 1351 Li 2 Cu BF 3 Et 2 Et 2, 78 ºC 71% yield, 2x J. rg. Chem. 1982, 47, 1845 (ex) 2 CuLi BF 3 Et 2 Et 2, 78 to 55 ºC 89% yield, 1 diastereomer ex Tetrahedron Lett. 1984, 25, 3083

9 Additives BF 3 Et 2 with cyanocuprates the effect is more complex and likely involves coordination of the BF 3 to the nitrile at some point. 2 Cu(CN)Li 2 + BF 3 2 Cu(CN BF 3 )Li 2 Cu(CN)Li + Li BF 3 J. Am. Chem. Soc. 1988, 110, 4834 Ph 2 Cu(CN)Li 2 BF 3 Et 2 TF, 78 to 50 ºC >95% yield Ph Tetrahedron Lett. 1984, 25, 5959 TBS C 2 2 Cu(CN)Li 2 BF 3 Et 2 TBS C 2 Ts J. Am. Chem. Soc. 1986, 108, 7420

10 Additives 3 SiCl Exactly how 3 SiCl modifies the Gilman reagents is debated; 3 SiBr can also be used and may give improved benefit C Bu 2 CuLi 3 SiCl, MPA TF, 70 ºC 80% yield, 98:2 E:Z Bu TMS Tetrahedron 1989, 45, Ge Cu(CN)Li 3 Ge 3 SiBr, TF, 78 to 48 ºC 83% yield (34% yield with TMSCl)

11 chanistic Studies The question of how cuprates undergo 1,4-addition has been greatly depated over the years. chanism A Cu (I).A. Cu + (I) Li.E. chanism B Cu (III) + Cu (I) 2 CuLi + electron transfer 2 Cu + Li + π-complexes and Cu(III) intermediates have been observed by NM, see: J. Am. Chem. Soc. 2002, 124, J. Am. Chem. Soc. 2007, 129, 7208 J. Am. Chem. Soc. 2007, 129, 11362

12 chanistic Studies Evidence for adical Pathway Isomerization without conjugate addition t-bu C 2 t-bu <1 equiv 2 CuLi t-bu C 2 t-bu via t-bu Li t-bu adical clocks 2 CuLi + 55% Et 39% 2 CuLi Tetrahedron Lett. 1971, % + 49% 1.3 x 10 8 s -1

13 adical clocks, cont'd chanistic Studies Evidence for adical Pathway Ct-Bu 2 CuLi Ct-Bu radical anion intermediate is very rapidly trapped by cuprate reagent, or mechanism change is occuring Trapping of radical anion Ts 2 CuLi no conjugate addition observed Tetrahedron Lett. 1975, 187

14 chanistic Studies Evidence for adical Pathway eduction potentials J. Am. Chem. Soc. 1972, 94, CuLi 2 CuLi + e E ox = 2.35 V Substrates that react (78 98% yield) and their E red Ph 1.63 V t-bu 2.12 V 2.33 V 2.20 V Substrates that don't react (>90% recovery) and their E red Bu Et C 2 t-bu t-bu 2.43 V 2.45 V 2.50 V

15 rbital Picture Both conjugate additions and S N 2' reactions can be explained by d π* interactions electron repulsion in highly occupied d orbitals of Cu make them quite diffuse and sterically accessible some S N 2 character anti-s N 2' in allylic systems addition to alkynes conjugate additions cross-coupling reactions Tetrahedron Lett. 1984, 25, 3063

16 Transmetallation nto Copper "Functionalized" cuprates can be prepared through transmetallation routes FG X Zn CuX FG ZnX FG Cu()ZnI organozinc halide compatible with many different functional groups reactions copper sources: CuCN 2LiCl, Cu(Tf) 2, CuBr S 2 compatibility of zinc species allows catalytic copper to be used in many cases Transmetallation from other organometals (M=Sn, Zr, Al, Te) possible as well, many times 2 CuLi is used and serves as a spectator ligand Bu 3 Sn 2 CuLi Li()Cu

17 Stereoselection Diastereoselectivity can generally be predicted with existing models and chair-like transition states 3,4-selectivity ' 2 CuLi ' + ' axial addition Major major minor Minor 3,5-selectivity ' 2 CuLi + ' major minor ' both conformations approximately equal, but only one is reactive axial addition blocked

18 Stereoselection Fused rings 2 CuLi N N TP 2 CuLi TP consider the radical anion intermediate "Equitorial" approach favored by large nucleophiles (cuprates), but slowed by 1,2-torsional interactions Li "Axial" approach disfavored by large nucleophiles due to 1,3-diaxial interactions

19 Stereoselection exocyclic olefins 2 CuLi t-bu t-bu EWG t-bu preferred by large nucleophiles (cuprates) acyclic electrophiles NBn 2 C 2 Et 2 CuLi TMSCl NBn 2 C 2 Et >95:5 Angew. Chem. Int. Ed. Engl. 1989, 28, 1706 A 1,2 Bn NBn 2 C 2 Et Bn C 2 Et NBn 2 Favored