Organocopper Chemistry

Have 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 sp2 carbons, but are also quite useful in epoxide openings, SN2 and SN2' 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. H. Organocopper Chemistry, in Organometallics in Synthesis: A Manual, 2nd Ed; Schlosser, M., Ed.; Wiley: New York, 2002, pp 665–815. Organocopper Chemistry – Initial Observations

Gilman, H.; Straley, J. M. Recl. Trav. Chim. Pays-Bas Belg. 1936, 55, 821–834. Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem. 1952, 17, 1630–1634.

R2COCl O R1 MgX + CuI R1 Cu low to moderate Et2O 2 1 yields 1 equiv 1 equiv insoluble R R

Me Li + CuI Me CuLi Has since become known as 2 the Gilman reagent Et2O 2 equiv 1 equiv soluble

Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308–2316.

HO Me O O 1 mol% CuCl MeMgBr MeMgBr

Et2O Et2O Me Me 5–12 ºC Me Me 5–12 ºC Me Me Me Me Me Me 91% 1,2-addition 83% 1,4-addition no 1,4-addition 7% 1,2-addition CuCl was unique, no other metal halide additive gave higher than ~5% 1,4-addition. Organocopper Chemistry – Key Rectivity Papers

House, H. O.; Respess, W. L.; Whitesides, G. M. J. Org. Chem. 1966, 31, 3128–3141.

R O Me2CuLi R O R O M Me Me R R R R R R M = Li, MgBr, or Cu high yields, with >99% 1,4-addition Ac O quick reaction times (<1 hr) 2 R OAc Me R R

Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1967, 89, 3911–3912.

Me2CuLi R I R Me Et2O I Me Br Me 75% 89%

Br Me Br Me

75% 81% Lower Order Gilman Cuprates – R2CuLi 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 sp2 or sp3 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 SN2' 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) RCOCl > aldehydes > tosylates ~ epoxides > iodides > ketones > esters > nitriles

Some examples: Me

Me Me Me OTr Cl Cl Me2CuLi Me2CuLi

OAc Me Et Et Me

J. Am. Chem. Soc. 1976, 98, 7854 Me OTr

J. Am. Chem. Soc. 1970, 92, 737 Lower Order Gilman Cuprates – R2CuLi 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: (CH ) CO Me O 2 3 2 O Bu3PCu (CH2)4CH3

OTBS O O

I (CH2)3CO2Me (CH2)4CH3 O O TBSO J. Am. Chem. Soc. 1988, 110, 4726

Me Me Me OAc OAc Me2CuLi

O O H H J. Org. Chem. 1971, 36, 877 Lower Order Mixed Cuprates – RtRrCuLi 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). Often the reactivity is altered (for better or worse) relative to Gilman-type reagents. Best to compare with known systems.

RLi RLi CuSPh RCu(SPh)Li CuOt-Bu RCu(Ot-Bu)Li lithium phenylthio(alkyl)cuprate lithium t-butoxy(alkyl)cuprate

Can also have mixed "alkyl"cuprates with spectator ligands (these are most popular):

CuI RLi R C CLi R C C Cu R C C Cu(R)Li lithium acetylide(alkyl)cuprate S S S Li CuI Cu RLi Cu(R)Li

2-thienyl lithium lithium 2-thienyl(alkyl)cuprate Lower Order Mixed Cuprates – RtRrCuLi

Can also use P- and N-based ligands; these are especially stable (still reactive after 24 hrs @ rt)

CuI RLi Cy NLi Cy NCu RCu(NCy )Li 2 2 2 J. Am. Chem. Soc. 1982, 104, 5824 J. Org. Chem. 1984, 49, 1119 CuI RLi Cy2PLi Cy2PCu RCu(PCy2)Li lower oder cyanocuprates, ease of preparation (start from CuCN), but less reactive than other mixed cuprates, but are quite useful in epoxide openings RLi CuCN RCu(CN)Li OTMS OTMS Me MeCu(CN)Li O OH R R J. Org. Chem. 1979, 44, 4467

"Higher order cyanocuprates" can be made by addition of two equivalents of RLi to CuCN; Brings reactivity mor ein line with Gilman reagents, but are still more stable RLi (2 equiv) CuCN R2Cu(CN)Li2 Additives – BF3•Et2O If the cuprate of choice is unreactive at low temperature and especially unstable at higher temperatures, the use of BF3•Et2O or Me3SiCl may improve reactivity.

[R2CuLi]2 + 2 BF3 R3Cu2Li + RLi•BF3 + BF3

J. Am. Chem. Soc. 1989, 111, 1351

Me Me Me LiMe2Cu BF3•Et2O

Et2O, –78 ºC 71% yield, 2x O Me O Me J. Org. Chem. 1982, 47, 1845

Me (Hex)2CuLi Me O BF3•Et2O HO Me O Me O Me Me Et2O, –78 to –55 ºC Hex H 89% yield, 1 diastereomer H

Tetrahedron Lett. 1984, 25, 3083 Additives – BF3•Et2O with cyanocuprates the effect is more complex and likely involves coordination of the BF3 to the nitrile at some point.

R2Cu(CN)Li2 + BF3 R2Cu(CN–BF3)Li2 RCu(CN)Li + RLi•BF3

J. Am. Chem. Soc. 1988, 110, 4834

O O

Ph2Cu(CN)Li2 BF3•Et2O

THF, –78 to –50 ºC >95% yield Ph

Tetrahedron Lett. 1984, 25, 5959

OTBS Me2Cu(CN)Li2 OTBS BF3•Et2O CO2Me CO2Me

OTs Me J. Am. Chem. Soc. 1986, 108, 7420 Additives – Me3SiCl

Exactly how Me3SiCl modifies the Gilman reagents is debated; Me3SiBr can also be used and may give improved benefit

Bu2CuLi Me3SiCl, HMPA CHO Bu OTMS THF, –70 ºC 80% yield, 98:2 E:Z

Tetrahedron 1989, 45, 349

Me3Ge Me3Ge Cu(CN)Li

Me3SiBr, THF, –78 to –48 ºC 83% yield O (34% yield with TMSCl) O Mechanistic Studies

The question of how cuprates undergo 1,4-addition has been greatly depated over the years.

Mechanism A O.A. Me Cu Me O (I)

Me Cu Me+ (I) R.E. OLi O

O + Me Cu Me ( ) Me Cu III Me Mechanism B (I)

Me2CuLi + electron transfer O π-complexes and Cu(III) intermediates have been observed by NMR, see: O J. Am. Chem. Soc. 2002, 124, 13650 Me Cu + Li+ J. Am. Chem. Soc. 2007, 129, 7208 2 J. Am. Chem. Soc. 2007, 129, 11362 Mechanistic Studies – Evidence for Radical Pathway

Isomerization without conjugate addition

<1 equiv t-Bu OLi Me CuLi CO2t-Bu 2 t-Bu via CO t-Bu t-Bu 2 Ot-Bu

Radical clocks Me

Me2CuLi + O O O Et 55% 39%

Me2CuLi + 1.3 x 108 s-1 O O O Me 43% 49% Tetrahedron Lett. 1971, 2875. Mechanistic Studies – Evidence for Radical Pathway

Radical clocks, cont'd

Me Me Me2CuLi radical anion intermediate is very rapidly trapped by cuprate reagent, or COt-Bu COt-Bu mechanism change is occuring Me

Trapping of radical anion

OTs

Me2CuLi no conjugate addition observed

O O Tetrahedron Lett. 1975, 187 Mechanistic Studies – Evidence for Radical Pathway

Reduction potentials J. Am. Chem. Soc. 1972, 94, 5495

– Me2CuLi Me2CuLi + e Eox = –2.35 V

Substrates that react (78–98% yield) and their Ered

O Me O

Ph Me O Me OMe t-Bu OMe –1.63 V –2.12 V O –2.33 V –2.20 V

Substrates that don't react (>90% recovery) and their Ered

OBu OEt CO2Me

O t-Bu t-Bu O –2.45 V –2.50 V –2.43 V Orbital Picture

Both conjugate additions and SN2' 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 SN2 character anti-SN2' in allylic systems

addition to alkynes conjugate additions

Tetrahedron Lett. 1984, 25, 3063 cross-coupling reactions Transmetallation Onto Copper

"Functionalized" cuprates can be prepared through transmetallation routes

Zn CuX FG R X FG R ZnX FG R Cu(R)ZnI organozinc halide • compatible with many different functional groups reactions

copper sources: CuCN•2LiCl, Cu(OTf)2, CuBr•SMe2 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 Me2CuLi is used and Me serves as a spectator ligand O

O

Me2CuLi Bu3Sn Li(Me)Cu Stereoselection Diastereoselectivity can generally be predicted with existing models and chair-like transition states

3,4-selectivity R O O O O Major H R'2CuLi + axial addition R' R' H

R R R R O Minor major minor H 3,5-selectivity O O O

R'2CuLi + R R R' R R' major minor

R axial addition blocked both conformations O approximately equal, R H O but only one is reactive H Stereoselection Fused rings Me O O Me2CuLi N N H H

OTHP OTHP Me Me Me2CuLi

O O Me consider the radical anion intermediate

"Equitorial" approach favored by large nucleophiles (cuprates), but slowed by 1,2-torsional interactions Me H

H H LiO

"Axial" approach disfavored by large nucleophiles due to 1,3-diaxial interactions Stereoselection exocyclic olefins Me Me2CuLi

O O t-Bu t-Bu

H H EWG t-Bu H H H preferred by large nucleophiles (cuprates) acyclic electrophiles R Me CO Et R CuLi Me CO Et 2 2 2 Angew. Chem. Int. Ed. Engl. 1989, 28, 1706 NBn TMSCl NBn 2 2 >95:5

NBn2 H Bn CO2Et CO2Et H H Bn H H H A1,2 NBn2 Favored