Reactions of organocopper reagents

Last updated

Reactions of organocopper reagents involve species containing copper-carbon bonds acting as nucleophiles in the presence of organic electrophiles. Organocopper reagents are now commonly used in organic synthesis as mild, selective nucleophiles for substitution and conjugate addition reactions. [1]

Contents

Since the discovery that copper(I) halides catalyze the conjugate addition of Grignard reagents in 1941, [2] organocopper reagents have emerged as weakly basic, nucleophilic reagents for substitution and addition reactions. The constitution of organocopper compounds depends on their method of preparation and the various kinds of organocopper reagents exhibit different reactivity profiles. As a result, the scope of reactions involving organocopper reagents is extremely broad.

Mechanism and Stereochemistry

Substitution Reactions

The mechanism of nucleophilic substitution by lower-order organocuprates depends in a profound way on the structure of the substrate, organocuprate, and reaction conditions. Early evidence suggested that a direct SN2 displacement was occurring; [6] however more recent results suggest that invertive oxidative addition of copper(I) into the carbon-leaving group bond takes place, generating a copper(III) intermediate which then undergoes reductive elimination to generate the coupled product. [7] Both of these mechanisms predict inversion at the electrophilic carbon, which is observed in a number of cases. [8] On the other hand, experiments with radical traps and the observation of racemization during substitution suggest a radical mechanism. [9]

(1)

CopperMech1.png

Conjugate Addition Reactions

In 1941, Kharash discovered that Grignard reagents add to cyclohexenone in presence of Cu(I) resulting in 1,4-addition instead of 1,2-addition. [10] This work foreshadowed extensive studies on the conjugate additions to enones with organocuprates. Note that if a Grignard reagent (such as RMgBr) is used, the reaction with an enone would instead proceed through a 1,2-addition. The 1,4-addition mechanism of cuprates to enones goes through the nucleophilic addition of the Cu(I) species at the beta-carbon of the alkene to form a Cu(III) intermediate, followed by reductive elimination of Cu(I). [11] In the original paper describing this reaction, methylmagnesium bromide is reacted with isophorone with and without 1 mole percent of added copper(I) chloride (see figure). [10]

Coppercatalyzedenonegrignardaddition.png

Without added salt the main products are alcohol B (42%) from nucleophilic addition to the carbonyl group and diene C (48%) as its dehydration reaction product. With added salt the main product is 1,4-adduct A (82%) with some C (7%).

A 1,6-addition is also possible, for example in one step of the commercial-scale production of fulvestrant: [12]

Fulvestrant organic synthesis brazier 2010.svg

Enantioselective Variants

Diastereoselective conjugate addition reactions of chiral organocuprates provide β-functionalized ketones in high yield and diastereoselectivity. A disadvantage of these reactions is the requirement of a full equivalent of enantiopure starting material. [13]

(3)

CopperStereo1.png

More recently, catalytic enantioselective methods have been developed based on the copper(I)-catalyzed conjugate addition of Grignard reactions to enones. The proposed mechanism involves transmetalation from the Grignard reagent to copper, conjugate addition, and rate-determining reductive elimination (see the analogous upper pathway in equation (2)). [14]

(4)

CopperStereo2.png

Catalytic reactions

Vinyl and aryl Grignard reagents couple with primary alkyl halides in the presence of a catalytic amount of a copper(I) halide salt. The use of Li2CuCl4 rather than simple copper(I) halide salts (CuX) improves yields of these coupling reactions. [15]

(5)

CopperScope1.png

The addition of Grignard reagents to alkynes is facilitated by a catalytic amount of copper halide. Transmetalation to copper and carbocupration are followed by transmetalation of the product alkene back to magnesium. The addition is syn unless a coordinating group is nearby in the substrate, in which case the addition becomes anti and yields improve. [16]

(6)

CopperScope2.png

Stoichiometric reactions

Propargyl methanesulfinates are useful substrates for the synthesis of allenes from stoichiometric organocopper complexes. In this case, the complexes were generated in situ through the combination of a Grignard reagent, copper(I) bromide, and lithium bromide. Organocopper complexes very often need Lewis acid activation in order to react efficiently; magnesium bromide generated in situ serves as an activating Lewis acid in this case. [17]

(7)

CopperScope3.png

Alkenylcopper complexes, easily generated through carbocupration, are useful for the introduction of a vinyl group in the β position of a carbonyl compound. In this case, as above, magnesium bromide is serving as an activating Lewis acid. [18]

(8)

CopperScope4.png

Epoxide opening with organocuprates is highly selective for the less hindered position. Substitution takes place with complete inversion of configuration at the electrophilic carbon. [19]

(9)

CopperScope5.png

Generally, organocuprates react with allylic electrophiles in an anti SN2 fashion. In the reaction below, nearly complete inversion of configuration was observed despite the presence of a second stereocenter in the ring. [20]

(10)

CopperScope6.png

Conjugate addition of organocuprates is widely used in organic synthesis. Vinyl ether cuprates serve as convenient acyl anion equivalents in conjugate addition reactions to enones. The resulting enol ethers can be hydrolyzed to 1,4-diketones, which are difficult to access using conventional carbonyl chemistry. [21]

(11)

CopperScope7.png

The use of additives in conjunction with a stoichiometric amount of organocopper complexes enhances the rate and yield of many reactions. Organocopper complexes in particular react sluggishly in the absence of a Lewis acid. Although magnesium bromide generated in situ from the reaction of Grignard reagents and copper(I) halides can serve this role (see above), external Lewis acids are also useful. In the presence of boron trifluoride etherate, organocopper complexes are able to add to sterically congested enones in moderate yield (effecting the same transformation with an organocuprate would be difficult). [22]

(12)

CopperScope8.png

Boron trifluoride etherate is also useful as an additive in reactions of higher-order cyanocuprates. The use of the 2-thienyl group as a "dummy" substituent in the cyanocuprate conserves the potentially valuable organolithium reagent used to generate the cyanocuprate (as only the dummy group is present in copper-containing byproducts). In the absence of boron trifluoride etherate, no reaction was observed in this case. [23]

(13)

CopperScope9.png

Conjugate addition reactions of higher-order cyanocuprates represent another useful application for boron trifluoride etherate. The vinyl group is transferred selectively in this reaction (there is a mistake in a scheme); this is in contrast to substitution reactions employing the same reagent, which result in selective transfer of the methyl group. [24]

(14)

CopperScope10.png

Alkylation of amines

Secondary amines can be alkylated with cuprates. The reaction is based on the oxidative coupling of lithium alkyl copper amide which is reported to form in situ during the reaction between lithium dialkylcuprates and primary or secondary amides. [25]

Cooper based Amine alkylation.jpg

Synthetic Applications

Because the stereoselectivity of carbocupration is extremely high, the reaction has been applied to the synthesis of pheromones in which the geometric purity of double bonds is critical. One example is the insect pheromone of Cossus cossus, which is synthesized by syn-selective carbocupration of acetylene and alkylation of the resulting organocuprate in the presence of added phosphite. [26]

(15)

CopperSynth.png

Related Research Articles

Gilman reagent

A Gilman reagent is a lithium and copper (diorganocopper) reagent compound, R2CuLi, where R is an alkyl or aryl. These reagents are useful because, unlike related Grignard reagents and organolithium reagents, they react with organic halides to replace the halide group with an R group (the Corey–House reaction). Such displacement reactions allow for the synthesis of complex products from simple building blocks.

In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons.

Organolithium reagent

Organolithium reagents are organometallic compounds that contain carbon–lithium bonds. These reagents are important in organic synthesis, and are frequently used to transfer the organic group or the lithium atom to the substrates in synthetic steps, through nucleophilic addition or simple deprotonation. Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers. They have also been applied in asymmetric synthesis in the pharmaceutical industry. Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C−Li bond is highly ionic. Owing to the polar nature of the C−Li bond, organolithium reagents are good nucleophiles and strong bases. For laboratory organic synthesis, many organolithium reagents are commercially available in solution form. These reagents are highly reactive, and are sometimes pyrophoric.

Copper(I) chloride Chemical compound

Copper(I) chloride, commonly called cuprous chloride, is the lower chloride of copper, with the formula CuCl. The substance is a white solid sparingly soluble in water, but very soluble in concentrated hydrochloric acid. Impure samples appear green due to the presence of copper(II) chloride (CuCl2).

Metalation is a chemical reaction that forms a bond to a metal. This reaction usually refers to the replacement of a halogen atom in an organic molecule with a metal atom, resulting in an organometallic compound. In the laboratory, metalation is commonly used to activate organic molecules during the formation of C—X bonds, which are necessary for the synthesis of many organic molecules.

The Corey–House synthesis (also called the Corey–Posner–Whitesides–House reaction and other permutations) is an organic reaction that involves the reaction of a lithium diorganylcuprate (R2CuLi) with an organic pseudohalide (R'X) to form a new alkane, as well as an ill-defined organocopper species and lithium halide as byproducts.

Copper(I) cyanide Chemical compound

Copper(I) cyanide is an inorganic compound with the formula CuCN. This off-white solid occurs in two polymorphs; impure samples can be green due to the presence of Cu(II) impurities. The compound is useful as a catalyst, in electroplating copper, and as a reagent in the preparation of nitriles.

Grignard reagent Organometallic compounds used in organic synthesis

A Grignard reagent or Grignard compound is a chemical compound with the generic formula R−Mg−X, where X is a halogen and R is an organic group, normally an alkyl or aryl. Two typical examples are methylmagnesium chloride Cl−Mg−CH3 and phenylmagnesium bromide (C6H5)−Mg−Br. They are a subclass of the organomagnesium compounds.

Methyllithium Chemical compound

Methyllithium is the simplest organolithium reagent with the empirical formula CH3Li. This s-block organometallic compound adopts an oligomeric structure both in solution and in the solid state. This highly reactive compound, invariably used in solution with an ether as the solvent, is a reagent in organic synthesis as well as organometallic chemistry. Operations involving methyllithium require anhydrous conditions, because the compound is highly reactive toward water. Oxygen and carbon dioxide are also incompatible with MeLi. Methyllithium is usually not prepared, but purchased as a solution in various ethers.

Organozinc compound

Organozinc compounds in organic chemistry contain carbon to zinc chemical bonds. Organozinc chemistry is the science of organozinc compounds describing their physical properties, synthesis and reactions.

Organocopper compound Compound with carbon to copper bonds

Organocopper compounds in organometallic chemistry contain carbon to copper chemical bonds. Organocopper chemistry is the science of organocopper compounds describing their physical properties, synthesis and reactions. They are reagents in organic chemistry.

Boronic acid

A boronic acid is a compound related to boric acid in which one of the three hydroxyl groups is replaced by an alkyl or aryl group. As a compound containing a carbon–boron bond, members of this class thus belong to the larger class of organoboranes. Boronic acids act as Lewis acids. Their unique feature is that they are capable of forming reversible covalent complexes with sugars, amino acids, hydroxamic acids, etc.. The pKa of a boronic acid is ~9, but they can form tetrahedral boronate complexes with pKa ~7. They are occasionally used in the area of molecular recognition to bind to saccharides for fluorescent detection or selective transport of saccharides across membranes.

A carbometalation is any reaction where a carbon-metal bond reacts with a carbon-carbon π-bond to produce a new carbon-carbon σ-bond and a carbon-metal σ-bond. The resulting carbon-metal bond can undergo further carbometallation reactions or it can be reacted with a variety of electrophiles including halogenating reagents, carbonyls, oxygen, and inorganic salts to produce different organometallic reagents. Carbometalations can be performed on alkynes and alkenes to form products with high geometric purity or enantioselectivity, respectively. Some metals prefer to give the anti-addition product with high selectivity and some yield the syn-addition product. The outcome of syn and anti- addition products is determined by the mechanism of the carbometalation.

Vicinal difunctionalization refers to a chemical reaction involving transformations at two adjacent centers. This transformation can be accomplished in α,β-unsaturated carbonyl compounds via the conjugate addition of a nucleophile to the β-position followed by trapping of the resulting enolate with an electrophile at the α-position. When the nucleophile is an enolate and the electrophile a proton, the reaction is called Michael addition.

Electrophilic amination is a chemical process involving the formation of a carbon–nitrogen bond through the reaction of a nucleophilic carbanion with an electrophilic source of nitrogen.

The Payne rearrangement is the isomerization, under basic conditions, of 2,3-epoxy alcohols to isomeric 1,2-epoxy alcohols with inversion of configuration. Aza- and thia-Payne rearrangements of aziridines and thiiraniums, respectively, are also known.

Reactions of alkenyl- and alkynylaluminium compounds involve the transfer of a nucleophilic alkenyl or alkynyl group attached to aluminium to an electrophilic atom. Stereospecific hydroalumination, carboalumination, and terminal alkyne metalation are useful methods for generation of the necessary alkenyl- and alkynylalanes.

Heteroatom-promoted lateral lithiation is the site-selective replacement of a benzylic hydrogen atom for lithium for the purpose of further functionalization. Heteroatom-containing substituents may direct metalation to the benzylic site closest to the heteroatom or increase the acidity of the ring carbons via an inductive effect.

Vinyl iodide functional group

In organic chemistry, a vinyl iodide functional group is an alkene with one or more iodide substituents. Vinyl iodides are versatile molecules that serve as important building blocks and precursors in organic synthesis. They are commonly used in carbon-carbon forming reactions in transition-metal catalyzed cross-coupling reactions, such as Stille reaction, Heck reaction, Sonogashira coupling, and Suzuki coupling. Synthesis of well-defined geometry or complexity vinyl iodide is important in stereoselective synthesis of natural products and drugs.

In organometallic chemistry, metal–halogen exchange is a fundamental reaction that converts a organic halide into an organometallic product. The reaction commonly involves the use of electropositive metals and organochlorides, bromides, and iodides. Particularly well-developed is the use of metal–halogen exchange for the preparation of organolithium compounds.

References

  1. 1 2 Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135. doi : 10.1002/0471264180.or041.02
  2. ↑ Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc.1941, 63, 2308.
  3. ↑ Kansal, V. K.; Taylor, R. J. K. J. Chem. Soc. Perkin Trans. 11984, 703.
  4. ↑ Posner, G. H. Org. React.1975, 22, 253.
  5. ↑ Lipshutz, B. H.; Wilhelm, R. S.; Floyd, D. M. J. Am. Chem. Soc.1981, 103, 7672.
  6. ↑ Tamura, M.; Kochi, J. K. J. Organomet. Chem.1972, 42, 205.
  7. ↑ Corey, E. J.; Boaz, N. W. Tetrahedron Lett.1984, 25, 3059.
  8. ↑ Johnson, C. R.; Dutra, G. A. J. Am. Chem. Soc.1973, 95, 7777.
  9. ↑ Ashby, E. C.; Coleman, D. J. Org. Chem.1987, 52, 4554.
  10. 1 2 Kharasch, M. S.; Tawney, P. O. (1941). "Factors Determining the Course and Mechanisms of Grignard Reactions. II. The Effect of Metallic Compounds on the Reaction between Isophorone and Methylmagnesium Bromide". Journal of the American Chemical Society. 63 (9): 2308–2316. doi:10.1021/ja01854a005. ISSN   0002-7863.
  11. ↑ Nakamura, Eiichi; Mori, Seiji (2000). "Wherefore Art Thou Copper? Structures and Reaction Mechanisms of Organocuprate Clusters in Organic Chemistry". Angewandte Chemie. 39 (21): 3750–3771. doi:10.1002/1521-3773(20001103)39:21<3750::AID-ANIE3750>3.0.CO;2-L. PMID   11091452.
  12. ↑ Fulvestrant: From the Laboratory to Commercial-Scale Manufacture Eve J. Brazier, Philip J. Hogan, Chiu W. Leung, Anne O’Kearney-McMullan, Alison K. Norton, Lyn Powell, Graham E. Robinson, and Emyr G. Williams Organic Process Research & Development 2010, 14, 544–552 doi : 10.1021/op900315j
  13. ↑ Malmberg, H.; Nilsson, M.; Ullenius, C. Tetrahedron Lett.1982, 23, 3823.
  14. ↑ Harutyunyan, S.; López, F.; Browne, W.; Correa, A.; Peña, D.; Badorrey, R.; Meetsma, A.; Minnaard, A.; Feringa, B. L. J. Am. Chem. Soc.2006, 128, 9103.
  15. ↑ Nunomoto, S.; Kawakami, Y.; Yamashita, Y. J. Org. Chem.1983, 48, 1912.
  16. ↑ Jousseaume, B. Ph.D. Thesis, University of Bordeaux, France, 1977.
  17. ↑ Kleijn, H.; Elsevier, C. J.; Westmijze, H.; Meijer, J.; Vermeer, P. Tetrahedron Lett.1979, 3101.
  18. ↑ Marfat, A.; McGuirk, P. R.; Helquist, P. J. Org. Chem.1979, 44, 3888.
  19. ↑ Johnson, M. R.; Nakata, T.; Kishi, Y. Tetrahedron Lett.1979, 4343.
  20. ↑ Goering, H. L.; Kantner, S. S. J. Org. Chem.1981, 46, 2144.
  21. ↑ Boeckman, R. K.; Ramaiah, M. J. Org. Chem.1977, 42, 1581.
  22. ↑ Yamamoto, Y.; Yamamoto, S.; Yatagai, S.; Ishihara, Y.; Maruyama, K. J. Org. Chem.1982, 47, 119.
  23. ↑ Lipshutz, B. H.; Parker, D. A.; Kozlowski, J. A.; Nguyen, S. L. Tetrahedron Lett.1984, 25, 5959.
  24. ↑ Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A. J. Org. Chem.1984, 49, 3938.
  25. ↑ Yamamoto, H.; Marouka, K. (1980). "Novel N-alkylation of amines with organocopper reagents". J. Org. Chem. 45 (13): 2739–2740. doi:10.1021/jo01301a048.
  26. ↑ Cahiez, G.; Alexakis, A.; Normant, J. F. Tetrahedron Lett.1978, 2027.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.