Carbozincation reactions involve the addition of an organozinc reagent to a carbon-carbon π bond. The reaction has been applied to alkenes, alkynes, allenes, and metalated unsaturated systems. The resulting organozinc products react further with electrophiles, ultimately resulting in vicinal difunctionalization of the π bond.
Carbometalations in general represent a highly useful class of reactions for vicinal difunctionalization of carbon-carbon π bonds. Carbozincation reactions in particular involve the addition of the carbon-zinc bond of an organozinc reagent across a carbon–carbon multiple bond (Eq. 1). Beyond establishing a carbon-carbon bond, these reactions establish a new carbon-zinc bond in the product that can react further with electrophiles. In contrast to organolithiums, Grignard reagents, and many other classes of organometallic compounds, organozincs exhibit remarkable functional group tolerance, making them attractive late-stage intermediates in synthesis.(1)
Organozincs also react cleanly with other unsaturated organometallic reagents. Carbozincation reactions of alkenyl- and alkynylmetal reagents (in particular, organolithiums and Grignard reagents) ultimately afford bismetalated products in which transmetalation to zinc has occurred. In some cases when the two carbon-zinc bonds in the product are heterotopic, sequential functionalization at the metalated carbon can be used to install two different groups.
Issues of site selectivity and stereoselectivity can arise in reactions of differentially substituted alkenes and alkynes. Intramolecular cyclizations avoid site selectivity issues and can be applied to establish complex carbocyclic frameworks; in other cases, nitrogen or oxygen is used as a directing group to encourage addition of zinc proximal to the heteroatom. Stereoselectivity becomes a concern when the addition reaction establishes one or more new stereocenters. Intramolecular cyclizations often exhibit high diastereoselectivity owing to a chair-like transition state (see Mechanism and Stereochemistry). Chiral ligands attached to the organozinc reactant, chiral catalysts, and chiral auxiliaries have been employed in enantioselective variants of the reaction.
Mechanism and Stereochemistry
Organozincs typically add to alkynes in a syn manner, but isomeric alkenylzincs 1 and 2 may form in reactions of unsymmetrical alkynes (Eq. 2).(2)
Use of a directing group (often in the homoallylic position) or a tether between the organozinc and the alkyne often leads to high site selectivity in these reactions. Reactions of 1,2-disubstituted alkenes may afford diastereoisomers in addition to constitutional isomers (Eq. 3). Unlike reactions of alkynes, additions to alkenes may proceed in a syn or anti manner. The configurational stability of the product alkylzinc species also plays a role in the stereoselectivity of the reaction, particularly when the organozinc is treated with an electrophile.(3)
Allylzinc bromide adds to a variety of alkenylmetal species to give bismetalated products. Two limiting alternatives are useful in understanding the mechanisms of these reactions. The γ-carbon and zinc may add in a single step via a zinc-ene process; alternatively, transmetalation to zinc may occur in a first step followed by a metallo-Claisen process and re-association of the metal. Calculations involving vinyl lithium and vinyl magnesium bromide support initial formation of a complex between allylzinc bromide and the vinylmetal (Eq. 4). After carbozincation (a zinc-ene process), the bismetalated product oligomerizes.(4)
In figures that follow, bismetalated products are drawn as monomers for clarity.
Chiral auxiliaries have been employed with success in enantioselective intramolecular additions of zinc enolates to alkenes (Eq. 5). In these and other intramolecular carbozincation reactions, a chair-like transition state has been proposed to rationalize the high diastereoselectivity observed. As in related carbozincations of homoallylic amines, coordination of the nitrogen atom to zinc plays an important role in the stereoselectivity; an interaction between zinc and the benzene ring in the auxiliary has also been proposed in the stereodetermining transition state.(5)
Scope and Limitations
Organozinc precursors are most commonly prepared via the insertion of zinc metal into organic halides. Although the insertion reaction is best performed in THF, carbozincations are more rapid in less polar solvents such as diethyl ether. A highly reactive form of zinc powder can be prepared using the reduction of zinc bromide with lithium naphthalenide in THF followed by washing with and suspending in ether. Iodine-zinc exchange between an alkyl iodide and a simple dialkylzinc is broadly effective for the preparation of diorganozincs, which are also used in carbozincation reactions.
Despite its low bond dissociation energy, the carbon-zinc bond is characterized by a large degree of covalent character due to the similar electronegativities of carbon and zinc. Thus, organozincs typically react more rapidly with carbon-carbon π bonds than polar functional groups such as carbonyls, imines, and nitriles. Low-energy empty orbitals on the zinc atom facilitate transmetalation from other metals such as lithium and magnesium.
Among uncatalyzed additions of organozincs to alkynes, reactions of pre-formed zinc enolates display broad substrate scope and moderate yields (Eq. 6). Additions of zinc methylmalonate to terminal alkynes favor the branched isomer except in cases where bulky groups are present at the propargylic position in the alkyne, which encourages formation of the linear isomer.(6)
With the exception of di(tert-butyl)zinc, dialkylzincs generally do not react with alkynes in the absence of a catalyst. Zirconocene diiodide catalyzes the addition of diethylzinc to 1-octyne in good yield with a branched-to-linear ratio of 75:25 (Eq. 7). The same catalyst is effective in the addition of diallylzinc to internal alkynes.(7)
Allylic organozinc reagents are much more reactive than dialkylzincs in additions to alkenes. Even so, a heteroatom in the homoallylic position is often required in intermolecular reactions (Eq. 8). Coordination of the heteroatom to zinc brings the alkene and organozinc into close proximity and is proposed to account for exclusive formation of the linear product in this reaction.(8)
Intramolecular additions of allylzincs to alkenes afford five- or six-membered products and proceed more easily than intermolecular reactions in general. Two types of intramolecular zinc-ene reactions are distinguished by the position of the tether within the allylic system (Eq. 9). Type I cyclizations establish five-membered rings while type II cyclizations establish six-membered rings.(9)
Transmetalation of propargylic lithium and Grignard reagents to zinc affords allenylzinc species, which undergo intramolecular additions to tethered double bonds in a zinc-ene-allene process (Eq. 10). The reaction is highly diastereoselective owing to a chair-like transition state in which the alkene and allene groups are roughly parallel to one another. The resulting alkylzinc products react with a variety of electrophiles in nucleophilic addition and cross-coupling reactions.(10)
Zinc enolates add readily to alkenes in intramolecular reactions as well, in some cases displaying significantly greater reactivity than the corresponding lithium and magnesium enolates. A few different methods exist for the synthesis of zinc enolates in this context. In one elegant application, conjugate addition of a mixed cyanocuprate affords a zinc enolate, which cyclizes spontaneously to afford a substituted pyrrolidine after quenching with acid (Eq. 11). A chair-like transition state structure in which the benzyl group is pseudoequatorial accounts for the observed diastereoselectivity.(11)
Metalated alkenes, particularly alkenyllithiums and Grignard reagents, undergo addition reactions with allylzincs to afford gem-bismetalated products (Eq. 12), which themselves undergo a variety of reactions. For example, treatment with aldehydes affords 1,5-dienes with excellent selectivity for the (E)-diastereomer. Although monoalkylation is generally not possible, selective reaction of one of the carbon-zinc bonds occurs in the presence of benzenesulfonylchloride. The resulting α-chlorozinc carbenoid participates in a few different types of geminal difunctionalization reactions.(12)
Additions of allylzinc reagents to metalated allenes afford allylic 1,1-dimetallic reagents analogous to the alkyl-substituted products described above. Coordination of a heteroatom or carbon-carbon π bond to one of the zinc atoms can serve as the basis for stereoselective reactions of the gem-dizincated species. For example, addition of allylzinc bromide to a lithiated allene derived from a propargyl ether gives exclusively the (E)-diastereomer after deuterolysis (Eq. 13).(13)
Intramolecular carbozincation with a nickel catalyst is effective for the preparation of five-membered oxygen or nitrogen heterocycles (Eq. 14). This method has been applied in syntheses of (+)-methyl epi-jasmonate, (–)-methylenolactocin, and other natural products.(14)
The intramolecular zinc-ene reaction has been applied in the synthesis of natural products for the formation of carbocylic frameworks. Precursors to allylic zinc reagents such as allylic halides and sulfones are easily prepared and the resulting organometallics display good functional-group tolerance. Furthermore, the carbon-zinc bond established during carbozincation provides a handle for further reactions. For example, a palladium-catalyzed zinc-ene reaction established the spiro ring system of (–)-erythrodiene (Eq. 15). Subsequent iodination and elimination afforded the natural product in 60% overall yield from (–)-perillyl alcohol.(15)
Comparison to Other Methods
Like analogous compounds of other metals, alkyl- and arylzinc derivatives are relatively unreactive in addition reactions. Nonetheless, the propensity of organozinc species to undergo transmetalation reactions with transition metal complexes has led to the development of catalytic additions of organozincs to carbon-carbon π bonds. The configurational stability of the carbon-zinc bond is a significant advantage in stereoselective reactions, as single isomers can often be isolated in high yield after treatment with an electrophile.
Allylzinc reagents are unique in their reactivity towards carbon-carbon π bonds–no other allylmetal species is as reactive. Allylzincs add to carbon-carbon double bonds via a metallo-ene process, and current evidence indicates that the zinc-ene reaction displays broader scope than the analogous magnesium-ene reaction of allyl Grignard reagents. Other delocalized organozinc species participate in addition reactions that are particular to zinc, such as the zinc-ene-allene and -yne-allene reactions of propargylic zinc halides and additions of zinc enolates across carbon-carbon double and triple bonds.
The functional-group compatibility of organozincs is an important advantage of these compounds over other organometallics. Although intramolecular carbolithiation and -magnesiation reactions are known, neither of these methods can tolerate moderately electrophilic functional groups in the substrate. Both zinc insertion into carbon-halogen bonds and intramolecular carbozincation proceed smoothly in the presence of functional groups such as esters and ketones.
Experimental Conditions and Procedure
Neat dialkylzincs, alkyllithiums, and trialkylaluminums are often pyrophoric and should be handled with extreme care in dry, inert environments. Gas-tight syringes or cannulas are recommended for transfer of these reagents and the use of argon as the inert gas is recommended. Care should be taken in the removal and quenching of organozincs at the end of reactions such as zinc-iodine exchange, which involve the use of excess organozinc reagent. Dilute solutions of diethylzinc with acetone, toluene, or tetrahydrofuran are not pyrophoric and can be safely handled in air.
The form of zinc plays an important role in the efficiency of oxidative addition into carbon-halogen bonds. Fine zinc dust is typically the most effective form for this purpose; when an especially reactive form of zinc is required, Riecke zinc can be prepared via the treatment of zinc bromide in diethyl ether with lithium naphthalenide.
To a cooled (0 °C) solution of 3-(tert-butoxy)hex-1-yne (309 mg, 2 mmol) in anhydrous Et2O (10 mL) was added dropwise 1.6 M n-BuLi (hexane, 1.6 mL, 2.6 mmol, 1.3 equiv). The mixture was allowed to warm to rt and was stirred for an additional 1 h after which a pale yellow suspension was obtained. The suspension was cooled to –30 °C, then 1.38 M allylmagnesium bromide (Et2O, 1.9 mL, 2.6 mmol, 1.3 equiv) was added dropwise. The solution was warmed to –10 °C, 1 M ZnBr2 (2.6 mL, 2.6 mmol, 1.3 equiv) was added, and the mixture stirred at for 0.5 h. The resulting yellow solution was then hydrolyzed with 1 M aq HCl at 0 °C, allowed to warm to rt, and the aqueous layer was extracted twice with Et2O. The combined extracts were stirred for 4 h with aq Na2S. The new aqueous layer was extracted twice with Et2O. After usual work-up, flash chromatography on silica gel (cyclohexane/EtOAc, 98:2) of the crude product yielded the title product (353 mg, 90%) as a clear liquid: 1H NMR (CDCl3, 200 MHz) δ 5.95–5.75 (m, 1H), 5.15–4.85 (m, 3H), 4.75 (m, J = 1.6 Hz, 1H), 3.87 (t, J = 7.1 Hz, 1H), 2.83 (dd, J = 15.0 Hz, 6.7 Hz, 1H), 2.70 (dd, J = 15.0 Hz, 7.4 Hz, 1H), 1.55–1.15 (m, 4H), 1.14 (s, 9H), 0.87 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 50 MHz) δ 152.0, 136.9, 116.1, 110.4, 75.6, 74.1, 38.7, 35.7, 28.8, 19.5, 14.2. Anal. Calcd for C13H24O: C, 79.54; H, 12.32. Found: C, 79.40; H, 12.29.
- ↑ Sklute, G.; Cavendar, H.; Marek, I. Org. React. 2015, 87, 507. (link)
- ↑ Marek, I. J. Chem. Soc., Perkin Trans. 1 1999, 535.
- ↑ Marek, I.; Schreiner, P. R.; Normant, J. F. Org. Lett. 1999, 1, 929.
- ↑ a b Lorthiois, E.; Marek, I.; Normant, J. F. Tetrahedron Lett. 1997, 38, 89.
- ↑ Zhu, L. S.; Rieke, R. D. Tetrahedron Lett. 1991, 32, 2865.
- ↑ Bertrand, M. T.; Courtois, G.; Miginiac, L. Tetrahedron Lett. 1975, 3147.
- ↑ Negishi, E.; Vanhorn, D. E.; Yoshida, T.; Rand, C. L. Organometallics 1983, 2, 563.
- ↑ Courtois, G.; Miginiac, L. Bull. Soc. Chim. Fr. 1969, 3330.
- ↑ Mauze, B.; Courtois, G.; Miginiac, L. C. R. Acad. Sci. Hebd. Seances. Acad. Sci. C 1969, 269, 1225.
- ↑ Oppolzer, W. Angew. Chem., Int. Ed. 1989, 28, 38.
- ↑ Meyer, C.; Marek, I.; Courtemanche, G.; Normant, J. F. J. Org. Chem. 1995, 60, 863.
- ↑ Denes, F.; Chemla, F.; Normant, J. F. Eur. J. Org. Chem. 2002, 3536.
- ↑ Knochel, P.; Normant, J. F. Tetrahedron Lett. 1986, 27, 1039.
- ↑ Chemla, F.; Normant, J. Tetrahedron Lett. 1995, 36, 3157.
- ↑ Normant, J. F.; Quirion, J. C.; Alexakis, A.; Masuda, Y. Tetrahedron Lett. 1989, 30, 3955.
- ↑ Vaupel, A.; Knochel, P. Tetrahedron Lett. 1994, 35, 8349.
- ↑ Stadtmuller, H.; Knochel, P. Synlett 1995, 463.
- ↑ Vaupel, A.; Knochel, P. Tetrahedron Lett. 1995, 36, 231.
- ↑ Deng, K.; Chalker, J.; Yang, A.; Cohen, T. Org. Lett. 2005, 7, 3637.
- ↑ Knochel, P.; Jones, P. Organozinc Reagents: A Practical Approach; Oxford University Press: Oxford, 1999.
- ↑ Jones, P.; Knochel, P. J. Org. Chem. 1999, 64, 186.
- ↑ Chemla, F.; Marek, I.; Normant, J. F. Synlett 1993, 665.