The synthesis and reaction of zinc reagents in ionic liquids

Abstract

The syntheses and reactions of alkynyl zinc reagents and Reformatsky-type reactions in ionic liquids as a safe recyclable reaction medium are described.

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Green Context

The utility of ionic liquids in a range of reaction types continues to expand. This contribution describes the ability of ionic liquids as an environment for organozinc reagents, and describes their preparation and use in the Reformatsky reaction. Yields are at least as good as with conventional solvents, product extraction is straightforward, and no VOC problem is encountered.

DJM

The challenge in chemistry to develop practical processes, reaction media, conditions and/or utility of materials based on the idea of green chemistry is one of the most important issues in the scientific society.¹ Recently, in synthetic chemistry, studies of reusable media such as fluorous fluids² and molten salts (ionic liquids)³ have been having an important impact on organic reactions. Especially, studies of ionic liquids are having an important impact on organic reactions such as Friedel–Crafts reactions,⁴ alkylation reactions,⁵ Diels–Alder reactions,⁶ palladium catalyzed allylation,⁷ asymmetric hydrogenation,⁸ and the Horner–Wadsworth–Emmons reaction.⁹ While organometallic reagents have been recognized to be useful for organic synthesis,¹⁰ and usually, their reactions are carried out in polar organic solvents (such as THF, Et₂O etc), their synthetic value in ionic liquids still appears to be grossly underestimated. Obviously, practical generation and synthetic applications for organometallic reagents in ionic liquids remains an important synthetic challenge.

Here, we describe the utility of reusable molten salts for Reformatsky reactions and the synthesis and reaction of alkynyl zinc reagents.

Reformatsky reaction

The first synthetic application to generate organometallic reagents are Reformatsky-type reagents¹¹ based on the addition of α-halo esters and carbonyl substrates to a suspension of zinc powder in an ionic liquid. It is known that the preparation of Reformatsky reagents derived from ethyl bromodifluoroacetate in tetrahydrofuran proceeds at 50–55 °C in 70–85% yield.^12–14

In the present reaction, when the reaction was attempted in tetrahydrofuran and in an ionic liquid ([EtDBu][OTf]) at room temperature, the yields of the Reformatsky reaction were 65 and 52% (entry 1), respectively. However, under heating at 50–60 °C the reaction (entry 2) smoothly proceeded to give the target material in 76% yield. Table 1 summarises the results from the reactions of various types of Reformatsky-type reagents with carbonyl materials. The reaction of ethyl bromodifluoroacetate with benzaldehyde proceeded under the applied conditions {bromodifluoroacetate (2 equiv.), benzaldehyde (1 equiv.) and zinc powder (2 equiv.) in an ionic liquid ([EtDBU][OTf], 1 g) at 50–60 °C} to give the corresponding carbinol. Furthermore, in this system, since the reaction intermediates (zinc reaction intermediates) were converted to the carbinols (along with a small amount of water containing diethyl ether), ionic liquids were recovered smoothly after extracting the target material with commercially available diethyl ether. Moreover, in this reaction system, the yield was increased to 93% when increasing the molar ration of PhCHO∶BrCF₂CO₂Et (1∶3; entry 3).

Table 1 Reformatsky reaction

Reuse of the recovered ionic liquid in the same reaction yielded amounts of product almost as high as in the first cycle as shown in Fig. 1.

Fig. 1 Recycling ionic liquids

Alkynyl zinc reagent

Recently, the preparation of propargylic alcohols by direct addition of teminal alkynes to aldehydes in the system Et₃N–toluene at 23 °C, has been reported with yields of these reactions being 50–99%.¹⁵ To clarify the generation and/or synthetic scope of alkynyl zinc reagents in ionic liquids, we examined the direct addition of terminal alkynes to aldehydes in the presence of zinc trifluoromethanesulfonate and base. The reactions proceeded smoothly under the applied conditions {terminal alkyne (3 equiv.), aldehyde (1.5 equiv.), zinc trifluoromethanesulfonate (2 equiv.), and 1,8-diazabicyclo[5,4,0]-7-undecene (DBU, 3 equiv.) in an ionic liquid ([EtDBU][OTf], 1 g) at room temperature}, giving the corresponding propargylic alcohols. The present reaction (summarized in Table 2) proceeded smoothly at room temperature in molten salt.

Table 2 Preparation of propargylic alcohols

In this reaction system, no reaction occurred in the absence of base and/or Zn(OTf)₂. The alkynylzinc reagents were prepared in situ from the reaction of terminal alkynes and Zn(OTf)₂ in the presence of base in an ionic liquid for the reaction of the zinc reagents with the aldehydes proceeding slowly. After 24–48 h of stirring at room temperature, the cerresponding propargyl alcohol was obtained upon extraction with diethyl ether, and the ionic liquid was recovered. Before the use and reuse of ionic liquids, ionic liquids were purified under dynamic vacuum at 70–80 °C for 1 h, and their purity checked by ¹H and ¹⁹F NMR spectroscopy (no other peaks except those of the ionic liquid).

In conclusion, we have shown that ionic liquids are a good alternative reaction media for the generation and synthesis of zinc reagents.

Experimental

General

All commercially available reagents were used without further purification. ¹H (300 MHz) and ¹³C NMR (75 MHz) spectra were recorded in ppm (δ) downfield from the internal standard (Me₄Si, δ 0.00) in CDCl₃. The ¹⁹F (282 MHz) NMR spectra were recorded in ppm downfield from the intenral standard C₆F₆ in CDCl₃ using a VXR 300 instrument.

Ethyl 2,2-difluoro-3-hydroxy-3-phenylpropionate^13,14

A mixed solution of benzaldehyde (321 mg, 3.02 mmol), ethyl bromodifluoroacetate (1.29 g, 6 mmol) and zinc powder (392 mg) in 8-ethyl-1,8-diazabicyclo[5,4,0]-7-undecenium trifluoromethanesulfonate (1 g) was stirred for 3 h in oil bath (50–60 °C). The product was extracted with crude diethyl ether (10 × 20 ml), and the ionic liquid recovered. The organic layer was dried over anhydrous MgSO₄ and on removal of the solvent, the yield (76%) was determined by the ¹⁹F NMR integral intensities using trifluoroacetic acid as an internal standard. Ethyl 3-hydroxy-3-phenyl-2,2-difluoropropionate 1a was purified by column chromatography on silica gel using hexane–ethyl acetate (10∶1) as eluent.

¹H NMR (CDCl₃): δ 1.29 ( 3H, t, J = 7.15 Hz), 2.84 (1 H, s), 4.30 (2 H, q, J = 7.14 Hz), 5.17 (1 H, dd, J = 15.4, 7.97 Hz), 7.37–7.50 (Ar-H). ¹³C NMR (CDCl₃): δ 13.76, 63.10, 73.54 (dd, J = 24.33, 27.48 Hz), 113.72 (dd, J = 250.8, 254.64 Hz), 127.54, 128.16, 128.95, 134.42 (d, J = 1.72 Hz), 163.46 (t, J = 32.4 Hz).¹⁹F NMR (CDCl₃): δ 41.3 (dd, J = 261.9, 14.65 Hz), 47.9 (dd, J = 261.9, 7.75 Hz). IR: 3480 (OH), 1770 (C[double bond, length half m-dash]O) cm⁻¹.

Ethyl 2,2-difluoro-3-hydroxy-5-phenylbutyrate¹⁵

In the above reaction 3-phenylpropanal (402 mg, 3 mmol), ethyl bromodifluoroacetate (1.29 g, 6 mmol) and zinc powder (392 mg) in 8-ethyl-1,8-diazabicyclo[5,4,0]-7-undecenium trifluoromethanesulfonate (1 g) were used, and then worked-up similarly.

¹H NMR (CDCl₃): δ 1.34 (3H, t, J = 7.14 Hz), 2.52 (OH), 4.36 (2 H, q, J = 7.14 Hz), 4.75 (1 H, m), 6.24 (1 H, dd, J = 15.9, 6.59 Hz), 6.81 (1 H, d, J = 15.9 Hz), 7.26–7.43 (Ar-H). ¹⁹F NMR (CDCl₃): δ 40.5 (d, J = 13.8 Hz), 41.7 (dd, J = 13.8 Hz).

1,3-Diphenylhydroxyprop-2-yne¹²

(a) To a mixed solution of benzaldehyde (318 mg, 3 mmol), phenylacetylene (612 mg, 6 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (912 mg, 6 mmol) in 8-ethyl-1,8-diazabicyclo[5,4,0]-7-undecenium trifluoromethanesulfonate 1 (1 g), zinc trifluoromethanesulfonate (1.45 g, 4 mmol) was added at room temperature. After 48 h of stirring at room temperature, the product was extracted with diethyl ether (10 × 20 ml) and the ionic liquid was recoved. The organic layer was dried over anhydrous MgSO₄, and then the solvent was removed. The yield (47%) was determiend by the ¹H NMR integral intensities using nitromethane as an internal standard. 1,3-Diphenyl-1-hydroxypropyne was purified by column chromatography on silica agel using a mixture of hexane–ethyl acetate (10∶1) as an elutent.

¹H NMR (CDCl₃): δ 2.34 (OH, d), 5.69 (1 H, d, J = 6.05 Hz), 7.31–7.61 (Ar-H). ¹³C NMR (CDCl₃): δ 64.868, 86.427, 88.704, 122.213, 126.565, 128.090, 128.166, 128.363, 128.424, 131.531, 140.396. IR: 3350 (OH), 2229 (C[triple bond, length half m-dash]C) cm⁻¹.

(b) In the above reaction, 1-butyl-3-methyl-1H-imidozolium tetrafluoroborate (1 g) was used and worked up similarly, giving 1,3-diphenyl-1-hydroxypropyne in 59% yield. (c) In the above reaction, 1-butyl-3-methyl-1H-imidozolium hexafluorophosphate (1 g) was used and worked up similarly, giving 1,3-diphenyl-1-hydroxypropyne in 35% yield.

1-Phenyl-1-hydroxyhept-2-yne

¹H NMR (CDCl₃): δ 0.92 (3 H, t, J = 7.32 Hz), 1.39–1.46 (2 H, m), 1.48–1.53 (2 H, m), 2.17 (1 H, s), 2.28 (2 H, td, J = 7.08, 1.95 Hz), 7.2–7.64 (Ar-H). ¹³C NMR (CDCl₃): δ 13.672, 18.554, 22.056, 30.664, 64.132, 79.701, 87.884, 115.074, 115.358, 128.272, 128.382. IR: 3349 (OH), 2229 (C[triple bond, length half m-dash]C) cm⁻¹.

1-Phenyl-1-hydroxynon-2-yne

¹H NMR (CDCl₃): δ 0.89 (3 H, t, J = 6.87 Hz), 1.23–1.60 (8 H, m), 2.27 (2 H, td J = 7.15, 1.92 Hz), 5.45, 7.35–7.53 (Ar-H). ¹³C NMR (CDCl₃): δ 14.108. 18.865, 22.587, 28.570, 28.600, 31.335, 64.746, 79.872, 87.626, 126.485, 128.006, 128.340, 141.091. IR: 3386 (OH), 2226 cm⁻¹.

1-(4-Fluorophenyl)-3-phenyl-1-hydroxyprop-2-yne

¹H NMR (CDCl₃): δ 2.99 (OH, s), 5.63 (1 H, s), 7.00–7.57 (Ar-H). ¹⁹F NMR (CDCl₃): δ 48.02 (1 F, m) from internal C₆F₆. ¹³C NMR (CDCl₃): δ 64.215, 86.674, 88.411, 115.288 (J_C–F = 21.47 Hz), 122.016, 128.169, 128.412 (J_C–F = 8.59 Hz), 128.541, 131.534, 136.23 (J_C–F = 3.44 Hz), 162.385 (J_C–F = 246.2 Hz). IR: 3350 (OH), 2199 (C[triple bond, length half m-dash]C) cm⁻¹.

1-(4-Fluorophenyl)-1-hydroxyhept-2-yne

¹H NMR (CDCl₃): δ 0.92 (3 H, t J = 7.14 Hz), 1.43–1.53 (4 H, m), 2.77 (2 H, td, J = 7.14, 2.20 Hz), 5.44 (OH), 7.02–7.54 (Ar-H). ¹⁹F NMR (CDCl₃): δ 47.51 (1 F, m) from internal C₆F₆. ¹³C NMR (CDCl₃): δ 13.613, 18.476, 21.993, 30.593, 63.947, 79.665, 87.730, 115.108 (d, J_C–F = 21.47 Hz), 128.268 (d, J_C–F = 8.25 Hz), 136.883 (d, J_C–F = 3.15 Hz), 162.267 (d, J_C–F = 245.92 Hz). IR: 3375 (OH), 2226 (C[triple bond, length half m-dash]C) cm⁻¹.

1-(4-Fluorophenyl)-1-hydroxynon-2-yne

¹H NMR (CDCl₃): δ 0.90 (3 H, m), 1.25–1.60 (6 H, m), 2.20–2.30 (2 H, m), 5.42 (1 H, d, J = Hz), 7.08, 7.58 (Ar-H). ¹⁹F NMR (CDCl₃): δ 47.51 (1 F, m) from internal C₆F₆. ¹³C NMR (CDCl₃): δ 14.135, 18.854, 22.606, 28.551, 28.623, 31.343, 64.101, 79.686, 87.949, 115.201 (d, J_C–F = 21.47 Hz), 128.329 (d, J_C–F = 8.59 Hz), 136.937, 162.358 (d, J_C–F = 245.92 Hz). IR: 3361 (OH), 2225 (C[triple bond, length half m-dash]C) cm⁻¹.

1-(4-Nitrophenyl)-3-phenyl-1-hydroxyprop-2-yne

¹H NMR (CDCl₃): δ 2.47 (OH, d, J = 5.77 Hz), 5.80 (1 H, d, J = 5.76 Hz), 7.36–8.39 (Ar-H). ¹³C NMR (CDCl₃): δ 63.991, 87.361, 86.558, 121.599, 123.708, 127.304, 128.298, 128.472, 128.924, 130.313, 131.622, 133.154, 147.271.

(E)-1,5-Diphenyl-3-hydroxypent-4-enyl-1-yne

¹H NMR (CDCl₃): δ 5.29 (CHOH, dd, J = 5.77 Hz), 6.39 (1 H, dd, J = 15.65, 6.05 Hz), 6.85 (1 H, dd, J = 17.66, 1.10 Hz), 7.27–7.50 (Ar-H). ¹³C NMR (CDCl₃): δ 63.400, 74.432, 87.861, 110.096, 122.213, 126.310, 126.682, 127.881, 127.968, 128.177, 128.461, 131.348, 131.599, 131.849, 135.901, 141.607, 144.148. IR: 3385 (OH), 2203 cm⁻¹.

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