5-Lithio-2,3-dihydrofuran1

[75213-94-4]  · C4H5LiO  · 5-Lithio-2,3-dihydrofuran  · (MW 76.02)

(nucleophilic nonbasic carbanion,1 formally equivalent to a cyclic acyl anion,2 which may be interacted readily with many electrophiles3)

Physical Data: 13C NMR chemical shifts4 (22.6 MHz, 308 K, THF/hexane, TMS): d (ppm) = 30.7 (C-3), 66.0 (C-2), 109.6 (C-4), 202.3 (C-5).

Solubility: sol ether, THF.

Form Supplied in: prepared in situ and used directly.

Preparative Methods: the easy deprotonation of 2,3-dihydrofuran (commercially available) at position 5 by strong bases has been known for some time5 and extensively studied by several groups. While the original procedures described for the title reagent (1) employed a stoichiometric amount of t-Butyllithium in a minimum quantity of THF at low temperature,1,2 it since has been reported that the deprotonation reaction takes place with mixtures of n-Butyllithium and N,N,N,N-Tetramethylethylenediamine in hexane at 0 °C3 or n-BuLi in ether at 0 °C.6,7 A representative procedure consists of the addition of 0.8 equivalent of t-BuLi (1.8 M in pentane) to a THF solution of freshly distilled 2,3-dihydrofuran at -40 °C for 0.5 to 1 h.3 An alternative deprotonation method uses a 1:1:1 mixture of n-BuLi, Potassium t-Butoxide, and TMEDA in hexane for 15 min at -30 °C.8 (1) can be used in THF solution or in ether after evaporation of the original solvents.3,9 The THF solution is stable for at least a few hours at room temperature.1 However, lithiodihydrofuran in THF partly decomposes after 24 h at 25 °C into lithium alkynolate and ethylene.10 This reaction in the presence of excess base and silylating reagent leads to bis(silyl)ketenes (eq 1).10

The deprotonation is regioselective, no allylic metalation having been observed to date, a result explained on the ground of orbital calculations as well as steric and electronic considerations.11 The carbon-13 NMR spectrum of the lithiated compound exhibits a large downfield shift for the two carbon atoms of the double bond.4

Handling, Storage, and Precautions: must be prepared and transferred under inert gas (Ar or N2) to exclude oxygen and moisture.

Reactivity.

(1) reacts readily with a variety of electrophiles, providing the expected substitution product in good to excellent yields. Some examples of its addition to ketones have been reported.1,12 Acetone gives the expected carbinol in 78% yield.1 Cyclobutanone yields a cyclobutanol derivative which rearranges quantitatively with ring expansion in the presence of Dowex-50X at room temperature (eq 2).12b Reiteration of this addition-ring expansion process gives access to belted spirocyclic tetrahydrofurans, which behave as potent ionophoric polyethers with extraction equilibrium constants close to those of 12-Crown-4.

Similarly, 1,2-addition of an unsaturated nitrile has been shown to yield an imine13 and interaction with silyl (as well as germanyl and stannyl) chlorides afforded the expected 5-silylated3,4,14 (germanylated14b,c and stannylated3,15) 2,3-dihydrofuryl derivatives. A related reaction with disulfides leads to cyclic ketene thioacetals.8

Alkylation Reactions: Stereoselective Synthesis of Homoallylic Alcohols.

Alkylations represent a major application of reagent (1). The early demonstration of the reactivity of (1) toward primary alkyl bromides or iodides2 followed by the mild hydrolysis of the product illustrates the utility of 5-lithio-2,3-dihydrofuran as a protected substituted acyl anion (eq 3). While the first alkylation reactions have been conducted at moderate temperatures (-78 to 20 °C) in a THF/HMPA mixture,1,2 later experiments have used THF only, sometimes at temperatures up to 50 °C (eq 3).3,16

The alkylation products easily rearrange, placing the double bond into the exocyclic position, as noticed at room temperature in deuteriochloroform (eq 4).3,17

This reaction has since been applied extensively to the preparation of 5-alkyldihydrofurans whose Ni0-catalyzed coupling with Grignard reagents leads with high stereocontrol to homoallylic alcohols.18a Among the numerous examples and applications to the stereoselective synthesis of trisubstituted alkenes,3,9,16,19 an especially attractive example is the coupling with MeMgBr. This yields a useful isoprenoid structure well suited for the iterative approach to the terpene series adopted by Kocienski and colleagues.19c In this work, (1) is alkylated by 1-iodo-4-methylpent-3-ene in THF at -30 °C to provide the 5-substituted 2,3-dihydrofuran. The latter compound then is coupled with Methylmagnesium Bromide in benzene in the presence of a catalytic amount of a Ni0 complex, providing efficient (89%) access to homogeraniol with almost total control (&egt;97%) of the stereochemistry of the double bond. Conversion of this alcohol into the iodo compound provides the substrate for the next iteration, viz alkylation of (1), Ni0-catalyzed coupling with MeMgBr, and iodination (see Iodine). A third iteration is then applied, leading in excellent overall 46% yield (9 steps) to homogeranylgeraniol (eq 5).

The reaction, however, is restricted to Grignard reagents. On coupling of 5-(trimethylsilyl)- or 5-(trimethylstannyl)dihydrofuran with methylmagnesium bromide a versatile vinyl silane is obtained,3 which, for instance, could be brominated with complete stereochemical inversion (eq 6).

The stereoselective access to (E)-disubstituted alkenes is within this methodology's reach.3,18,20 The use of a Grignard reagent bearing b-hydrogen(s) involves a reduction reaction competing with the coupling reaction,18a supposedly through a b-hydride elimination process and formation of nickel hydride complexes. The observed stereoselectivity depends strongly on the nature of the Ni ligands.3,20 A recent application of this reduction process is the stereoselective synthesis of the macrolactonic fungal metabolite (±)-recifeiolide.20

The title compound can undergo double C-5 substitution. This reaction has been reported to proceed with copper catalysis,15,19a,21 but has been observed also in the absence of any transition metal.7 The dihydrofuran moiety is exposed to two successive reactions, first with a nucleophilic (Grignard or organolithium) reagent and then with an electrophilic partner, in a one-pot procedure.7,15 The copper-catalyzed coupling reaction has been proposed to involve higher or lower order cuprate intermediates, followed by a 1,2-alkyl migration or a dyotropic rearrangement (eq 7).15,19d

Depending on the alkyllithium partner, this reaction may become catalytic in copper, a feature explained through a catalytic cycle involving ligand exchange at the metal.19d

Unlike the reaction of Grignard reagents with 2,3-dihydrofuran under Ni0 catalysis18,22 (coupling with retention of configuration), the corresponding CuI-catalyzed reaction appears to proceed with inversion of configuration, leading to di- or trisubstituted homoallylic alcohols (E &egt; 97% stereoselectivity). In the absence of any alkyl ligand on copper, this reaction leads to the self coupling of the enol ether, providing spiroacetals.19d The first application to natural product chemistry derived from this methodology is the synthesis of the antihypotensive agent lacrimin A.23 In the case of the uncatalyzed reaction, an addition-elimination mechanism with a dilithiated intermediate has been proposed (eq 8).7

Other Transmetalation Reactions.

Only a few examples have been described. It has been shown that the low temperature addition of the THF solution of (1) to trialkylaluminum in hexane leads to the corresponding dihydrofuranyl triorganoaluminates.24 These add to electrophiles such as cyclohexene oxide in the presence of a stoichiometric amount of Boron Trifluoride Etherate to yield the substituted cyclohexanols with a good diastereoselectivity. A 1,2-alkyl migration is proposed to explain this unexpected reactivity. On the other hand, the ring-opened product is obtained by treatment with the same Lewis acid in the absence of any electrophile,24 a reaction resembling the copper-catalyzed coupling described above (eq 9).19d

Dihydrofuranyl nickel(II) complexes have been prepared6 starting from (1) and have been shown to yield Ni carbene complexes. Some of them could be crystallized.6,25

Related Reagents.

1-Ethoxyvinyllithium; 6-Lithio-2,3-dihydro-4H-pyran.


1. Boeckman, Jr, R. K.; Bruza, K. J. T 1981, 37, 3997.
2. Boeckman, Jr, R. K.; Bruza, K. J. TL 1977, 4187.
3. Kocienski, P. J.; Pritchard, M.; Wadman, S. N.; Whitby, R. J.; Yeates, C. L. JCS(P1) 1992, 3419.
4. Oakes, F. T.; Sebastian, J. F. JOC 1980, 45, 4959.
5. Paul, R.; Tchelitcheff, S. CR(C) 1952, 235, 1226.
6. Wada, M.; Sameshima, K.; Nishiwaki, K.; Kawasaki, Y. JCS(D) 1982, 793.
7. Nguyen, T.; Negishi, E. TL 1991, 32, 5903.
8. Verkruijsse, H. D.; Brandsma, L.; Schleyer, P. von R. JOM 1987, 332, 99.
9. Barber, C; Bury, P.; Kocienski, P.; O'Shea, M. CC 1991, 1595.
10. Groh, B. L.; Magrum, G. R.; Barton, T. J. JACS 1987, 109, 7568. See in relation the decomposition reaction of 5-lithio-3,4-dihydrofuran in Ref 11.
11. Oakes, F. T.; Yang, F.-A.; Sebastian, J. F. JOC 1982, 47, 3094.
12. (a) Paquette, L. A.; Maleczka, Jr., R. E. JOC 1991, 56, 912. (b) Negri, J. T.; Rogers, R. D.; Paquette, L. A. JACS 1991, 113, 5073.
13. Blechert, S.; Wirth, T. TL 1991, 32, 7237.
14. (a) Lukevics, E.; Gevorgyan, V.; Goldberg, Y.; Popelis, J.; Gavars, M.; Gaukhman, A.; Shimanska, M. H 1984, 22, 987. (b) Lukevics, E.; Gevorgyan, V. N.; Goldberg, Y. S.; Shymanska, M. V. JOM 1985, 294, 163. (c) Gevorgyan, V.; Borisova, L.; Lukevics, E. JOM 1990, 393, 57.
15. Kocienski, P.; Wadman, S.; Cooper, K. JACS 1989, 111, 2363.
16. Whitby, R.; Yeates, C.; Kociénski, P.; Costello, G. CC 1987, 429.
17. Kocienski, P.; Dixon, N. J.; Wadman, S. TL 1988, 29, 2353.
18. (a) Wenkert, E.; Michelotti, E. L.; Swindell, C. S.; Tingoli, M. JOC 1984, 49, 4894. (b) Ducoux, J. P.; Le Ménez, P.; Kunesch, N.; Kunesch, G.; Wenkert, E. T 1992, 48, 6403.
19. (a) Kociénski, P.; Wadman, S.; Cooper, K. TL 1988, 29, 2357. (b) Kocienski, P.; Love, C.; Whitby, R.; Roberts, D. A. TL 1988, 29, 2867. (c) Kocienski, P.; Wadman, S.; Cooper, K. JOC 1989, 54, 1215. (d) Kocienski, P.; Barber, C. PAC 1990, 62, 1933.
20. Ducoux, J. P.; Le Ménez, P.; Kunesch, N.; Wenkert, E. JOC 1993, 58, 1290.
21. Fujisawa, T; Kurita, Y.; Kawashima, M.; Sato, T. CL 1982, 1641.
22. Wadman, S.; Whitby, R.; Yeates, C.; Kocienski, P.; Cooper, K. CC 1987, 241.
23. Takle, A.; Kocienski, P. T 1990, 46, 4503.
24. Alexakis, A.; Hanaïzi, J.; Jachiet, D.; Normant, J.-F. TL 1990, 31, 1271.
25. Miki, K; Taniguchi, H.; Kai, Y.; Kasai, N.; Nishiwaki, K.; Wada, M. CC 1982, 1178.

Jacques F. Maddaluno & Nicole Kunesch

Université Paris V, France

Ernest Wenkert

University of California, San Diego, CA, USA



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