6-Lithio-2,3-dihydro-4H-pyran1

[72081-15-3]  · C5H7LiO  · 6-Lithio-2,3-dihydro-4H-pyran  · (MW 90.05)

(acyl anion equivalent which reacts with a variety of carbon and other electrophiles via substitution and 1,2-addition;2-6 after conversion to other organometallics via conjugate addition7 and Pd0-catalyzed coupling,5 the resulting adducts are utilized for the preparation of substituted cyclopentenones and cyclohexenones and polycyclic spiro acetals2,8,9)

Alternate Name: 6-lithio-3,4-dihydro-2H-pyran.

Physical Data: white to off-white, highly moisture and air sensitive solid which may be pyrophoric.10 13C NMR (22.625 MHz in d8 THF): d 201.2, 111.1 (1J13C-1H = 154.8 Hz), 62.8, 24.71, 20.99.10

Solubility: sol anhydrous THF, anhydrous ether, and mixtures of saturated hydrocarbons and THF; insol pure hydrocarbons. At high concentrations (> ca. 1M), the reagent will sometimes precipitate from THF-pentanes at -78 °C.

Form Supplied in: not commercially available.

Analysis of Reagent Purity: the extent of metalation can be assessed by deuteration of an aliquot and 1H NMR analysis of the recovered 2,3-dihydropyran,10 or by direct observation using 1H NMR.2,11 The concentration of solutions of the reagent can be determined by titration.12

Preparative Methods: three basic preparative methods have been described: metalation with the t-BuLi-2THF complex (lemon yellow) in pentane at about -10 °C;2 metalation with n-BuLi or t-BuLi in hexane or pentane containing a catalytic amount of TMEDA at 0 °C to room temperature or slightly above (the reagent precipitates from solution);10,13 or metalation with n-BuLi in hexanes at 50-60 °C for several hours (also results in a precipate of the lithium reagent).14 For difficult cases, the Schlosser base (n-BuLi/KO-t-Bu) has been used, usually followed by trapping with chlorotrialkylstannanes and transmetalation of 6-trialkylstannyl-2,3-dihydro-4H-pyran and substituted derivatives thereof with n-BuLi in THF at -78 °C,8,15-21 or by palladium-catalyzed coupling of chlorotrialkylstannanes with enol triflates derived from d-lactones.22

Purification: none is normally required; the reagent is used as prepared.

Handling, Storage, and Precautions: the reagent is customarily utilized shortly after preparation. Solvents and reagents should be anhydrous and free of oxygen. Commercial 2,3-dihydropyran is distilled before use. Solutions of the reagent must be protected from air and moisture utilizing standard inert atmosphere/syringe techniques.

Metalation of 2,3-Dihydro-4H-pyran (2) and Related Substituted 2,3-dihydro-4H-pyrans.

Recommended Procedure for (1).

Metalation of the parent 2,3-dihydro-4H-pyran (3,4-Dihydro-2H-pyran) (2) proceeds smoothly under a variety of reaction conditions to afford exclusively the 6-lithio derivative (1) (eq 1).2 The preferred procedure employs the yellow 2t-BuLi-THF complex prepared by treatment of t-Butyllithium in pentane with a minimum amount (~2 equiv) of THF.2,11 On a substantial scale, care must be taken to avoid localized heating owing to the heat of solvation which can cause loss of t-BuLi.23 Thus it is advisable to provide efficient stirring and cooling, and to precool the THF to be added. Addition of dihydropyran at -78 °C and slow warming to ca. -10 to 0 °C results in decolorization of the yellow color and the formation of a colorless homogeneous solution of the metalated pyran (1). Since metalation is significantly exothermic and does not proceed rapidly at temperatures below -10 °C, when working at concentrations above ~0.25 M it is advisable to add a precooled solution of the dihydropyran to the solution of 2t-BuLi-THF complex dropwise at about -10 to 0 °C with efficient stirring.2,11 Solutions of (1) are typically diluted with additional anhydrous THF and recooled to -78 °C prior to use (at higher concentrations, the reagent will sometimes precipitate from solution).

This procedure is suitable for use with many substituted dihydropyrans, and dihydrofurans, provided there are not additional remote coordinating heteroatoms present. In the absence of remote heteroatom substituents, the rates of metalation are related to the type of substitution at the b-position of the vinyl ether double bond.2,11 Electron-deficient substituents and substituents containing heteroatoms suitably positioned to assist metalation by coordination of the metalating agent, and/or stabilize the metalated species by chelation, accelerate metalation (e.g. Cl, (CH2)nOR (n = 1,2)) and alkyl substituents retard it, although examples of successful metalation of a b-methyl substituted system have been reported.2,3,24

Other Procedures.

Less reactive metalating agents such as n-Butyllithium can only be employed in saturated hydrocarbon solvents since complete metalation requires 1-2 h at 50-60 °C (incompatible with ethereal solvents), affording (1) as a precipitate.14 Either n-BuLi at rt to ~30-40 °C or t-BuLi at 0 °C to rt can also be employed in the presence of a catalytic amount of N,N,N,N-Tetramethylethylenediamine to assist deaggregation of the alkyllithium metalation reagent, also affording (1) as a precipitate.10,13

In the cases where metalation fails with the usual procedures, successful metalation can often be achieved by use of the Schlosser base n-Butyllithium-Potassium t-Butoxide.25,26 Although the species formed can, in principle, be reacted directly with electrophiles, often the basicity of the species is such that clean reactions do not result. In these instances, trapping with chlorotrialkylstannanes cleanly affords the trialkylstannane from which the required lithiopyran can be regenerated by transmetalation with n-BuLi (eq 2).8,15-21 In the presence of heteroatom substituents, use of excess t-BuLi with or without subsequent stannylation (eq 3)2,20,27 or the Schlosser base/stannylation procedure is generally required.2,8,15-21 The choice of protecting groups for oxygen and nitrogen is crucial to the success of the metalation. Generally, simple alkyl ether, MOM,19 and TIPS21 protecting groups are suitable, but benzyl ethers are not owing to competing metalation of the aromatic ring.16 Oxygenated dihydropyrans bearing TBDMS protecting groups have been metalated,27,28 but sometimes competing metalation of the methyl groups on the silicon occurs.29-31 If the system undergoing metalation is exceedingly sterically congested, loss of regiospecificity during metalation has been observed.32

Addition of (1) and Related Systems to Carbonyl Derivatives and Activated Alkenes.

Addition of lithiopyran (1) to all manner of carbonyl electrophiles generally occurs cleanly and in excellent yield (eqs 4-9),2,6,36,37 although extensive purification of the resulting adducts is not advisable owing to their acid sensitivity.2,3,13,33 Lithiopyran (1) behaves in all respects like a typical strongly nucleophilic and basic organolithium reagent in that multiple addition occurs to acid halides, esters, and related acylating agents, and 1,2-addition occurs exclusively in conjugated carbonyl compounds, including (E)-b-trimethylsilylacrolein which affords the corresponding ketone upon oxidation.2,34 Successful addition of lithiopyran (1) exclusively 1,2 to a quinone monoacetal has also been reported.35 Even complex aldehydes prone to epimerization and b-elimination undergo smooth addition.36 Addition of lithiopyran (1) to acylsilanes followed by Brook rearrangement, ring opening, and silylation affords allenolsilanes very efficiently.15 Amides, oxalic ester amides, nitriles, and g-lactones can be employed to afford aldehydes, imines, ketones, and a-ketoamides.2,3,37-39 Carboxylation affords the corresponding acid and the derived esters.3,18 1,4-Addition of (1) has been observed to an unsaturated sulfone.6 Addition of (1) to fluoroacetylene (prepared in situ by metalation/elimination of 1,1-difluoroethylene at -110 °C) followed by elimination of fluoride also occurs.6 These carbanions function as masked acyl anion equivalents and have been employed to prepare a variety of cyclopentenones, cyclohexenones, and 4- and 5-oxo esters.2

Alkylation and Related Substitution Reactions of (1) and Related Systems.

Lithiopyran (1) undergoes smooth alkylation by Iodomethane as well as a variety of primary saturated and homoallylic alkyl bromides and iodides, including examples containing protected oxygen functions and remote unsaturation (eqs 10-13).2-4,8,14,19,40-48 Alkylation of (1) by primary and secondary allylic and benzylic bromides, as well as occasionally chlorides, has been reported to occur in good yield in many cases,2,13,20 but sometimes a-metalation of the allylic halide competes.2 To overcome this limitation, (1) has been converted to its less basic organocopper derivative for reaction with allyl iodide.27 As is usual for hard organolithium reagents, (1) and its derivatives react poorly with epoxides,2 and other organometallic derivatives are used (see below). Of course, (1) and related systems react readily with trialkylsilyl and trialkylstannyl halides, disulfides, and even sources of positive halogen such as NBS to afford the expected substitution products.2,5,8,19-22,29,49-51 A conceptually related process involving alkylation-elimination of 2-phenylsulfonylpyrans has also been described.52

Conversion of (1) and Related Systems to Other Organometallic Derivatives and Subsequent Reactions.

In order to effect opening of epoxides in high yield, conversion of (1) and related systems to mixed diorganocuprate reagents is generally required (eq 14).53-55 In highly functionalized systems, Boron Trifluoride Etherate has been employed as an additional Lewis acid to assist the opening.56

Lithiopyran (1) and related systems upon reaction with mixed cyanocuprate reagents at 0 °C and above afford stereoselectively (E) disubstituted and trisubstituted alkenic alcohols arising from ring cleavage by apparent substitution at the a-alkenic center by the alkyllithium reagent in an overall inversion at the a-alkenic carbon (eq 15).53 This process may proceed by way of one of several mechanisms.55 A conceptually similar reaction is observed between vinyl ethers and Grignard reagents catalyzed by nickel(II) complexes.24 Lithiopyran (1) and related systems have also been found to react directly with simple alkyllithium derivatives to give the same spectrum of products with the same stereoselectivity upon quenching with protons, CO2, and alkyl halides as occurs with the cyanocuprate derivatives of (1) and related systems.57 The latter reaction does not occur with acyclic analogs of (1).

A derivative of (1) has been converted to a C-glycoside derivative by Pd0-catalyzed coupling of the zinc derivative with an aryl iodide (eq 16).28 Furthermore, aluminates formed from (1) undergo a novel 1,2-migration reaction upon treatment with benzaldehyde in the presence of BF3.Et2O, affording trans-2-methyl-3-(1-hydroxy-1-phenylmethyl)tetrahydropyrans and -furans (eq 17).57

Finally, in reaction with sterically hindered ketones, conversion to the dichlorocerium reagent by transmetalation of (1) and related derivatives with anhydrous Cerium(III) Chloride minimizes enolization of the substrate (eq 18).58

Conversion of (1) and Related Systems to Trialkylstananes and Regeneration of the Lithium Derivative or Direct Palladium-Catalyzed Crossed Coupling.

In addition to the aforementioned methods involving stannylation of lithiopyran (1) and related systems by reaction with chlorotrialkylstannanes (eqs 2 and 3),5,8,16,18,20,21,51 a route from six- or seven-membered ring lactones is available (eq 19).22 The method fails for five- and eight-membered rings owing to the inability to form the required enol triflates under the usual conditions.22 These stannane derivatives are precursors for the lithium species by transmetalation (eq 2),8,16,18,37,51 as well as undergoing direct Pd0-catalyzed coupling with aryl, allyl, benzyl, and acyl halides (eqs 20 and 21).5,20,21,50 The oxidative dimerization of the parent alkylstannane, derived from (1), catalyzed by Cu(NO3)2 has also been reported.59

Metalation and Reactions of Other Cyclic and Acyclic Vinyl Ethers.

Dihydrofurans2,19,60,61 and the parent dihydrooxepin10 afford the analogous a-lithio derivatives. Metalation of 1,4-dioxene derivatives has also been reported, although loss of metalation regiospecificity has been noted in hindered systems.32,50 Metalation of acyclic vinyl and dienyl ethers has also been reported where metalation regiospecificity can be controlled by use of MOM ethers.62-66 Selectivity for metalation of the a-vinyl H vs. allylic metalation is also observed and a theoretical model has been proposed.67,68 Reactions of these lithiated ethers parallel those of lithiodihydropyran (1).2,4,5,10,19,21,24,38,44,48,49,57,58,62,64,69-71

Related Reagents.

(Z)-2-Ethoxyvinyllithium; 1-Ethoxyvinyllithium; 5-Lithio-2,3-dihydrofuran; 1-Methoxyvinyllithium.


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Robert K. Boeckman, Jr.

University of Rochester, NY, USA



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