An Investigation of the Reactions of Substituted Homoallylic Alcohols with Various Oxidation Reagents

Abstract

Substituted homoallylic alcohols have been synthesised both by [2,3]-Wittig rearrangement of unsymmetrical bis-allylic ethers and reaction of alkenyl chloromethyl oxiranes with Mg/THF. These substrates were then oxidized using four different oxidants. When the substituted homoallylic alcohols were oxidized with pyridinium chlorochromate or zinc chlorochromate nonahydrate the corresponding carbonyl compounds were produced. The same substrates formed the corresponding allylic oxidation products together with epoxidation products when oxidized with t-BuOOH. When and t-BuOOH and catalytic amounts of OsO₄ were used the allylic oxidation reaction was prevented and the only products formed were those in which the substituted double bond was epoxidized.

Introductıon

Oxidation reactions are very important processes for biological systems and in organic chemistry. There are numerous oxidation reagents for organic compounds and new ones are added to this list almost every day. It is well known that different organic substrates can be converted into varied oxidation products depending on the type of oxidant used. For example, Zn(ClCrO₃)₂·9H₂O (ZCC) is an oxidant which can be used under very mild conditions [1]. Pyridinium chlorochromate (PCC) will oxidize a primary alcohol to an aldehyde and stop at that stage. PCC also does not attack double bonds [2,3].

t-Butyl hydroperoxide (t-BuOOH) oxidizes olefins to epoxides and allylic oxidation products in the presence of a Cr(VI) catalyst. The allylic oxidation and the t-BuOOH decomposition are free-radical reactions, but the epoxidation is evidently not [4]. Under microwave irradiation 3Å molecular sieves promote the oxidation of secondary (linear and cyclic) and benzylic alcohols to the corresponding carbonyl compounds by t-BuOOH. Under the same conditions α,β-unsaturated alcohols are converted into α,β–epoxy alcohols in a regio-and diasteroselective manner [5]. OsO₄ can be used to oxidize alkenes to 1,2-diols (syn hydroxylation). If t-BuOOH is used with OsO₄ allylic alcohols have been converted into α,β-epoxy alcohols. Beck and Seifert have investigated the oxidation of steroidal allylic alcohols with t-BuOOH and catalytic amounts of OsO₄ [6].

Substituted homoallylic alcohols have been used in the synthesis of pheromones and antibiotics [7,8] and these compounds show very strong antimicrobial activities [9]. Various methods have been reported in the literature for the synthesis of substituted homoallylic alcohols [10,11,12,13,14,15]. The oxidation reactions of substituted homoallylic alcohols have not been investigated in detail. Therefore we have now studied the oxidation of these compounds with four different oxidation reagent systems.

Results and Discussion

When compounds 4a-d were oxidized with PCC (Method A) or ZCC (Method B) the corresponding carbonyl compounds 5a-d were formed (Scheme 1).

Scheme 1. The oxidation of substituted homoallylic alcohols by Methods A and B.

Scheme 1. The oxidation of substituted homoallylic alcohols by Methods A and B.

a: R₁=R₂=H, R₃ = CH₃; b: R₂ = H, R₁ = R₃ = CH₃; c: R₁ = CH₃, R₂ = R₃ = H; d: R₁= phenyl, R₂ = R₃=H

On the other hand, 2-methyl-1,5-hexadiene-3,4-dione (6a) together with 5a was formed when 4a was oxidized with ZCC. This could be expected since ZCC in CH₂Cl₂ is reported to be a strong oxidizing agent that oxidizes benzylic and allylic C-H bonds to give carbonyl groups [1]. Compound 6a was thus formed from oxidation of both the allylic hydrogen and hydroxyl groups of 4a.

Oxidation of 4d with PCC and ZCC produced benzaldehyde (6d), 3-Phenylpropenal (7d) and 1-phenyl 1,5-hexadiene-3-one (5d). The yield of benzaldehyde formed is higher when Method A is used compared to Method B. Thus the oxidation products of 4d included small molecules (such as 6d and 7d), formed by the breakage of the bonds close to the phenyl group

The oxidation of olefinic molecules containing allylic hydrogen atoms is thought to follow two possible pathways: allylic oxidation and direct attack on the double bond. When using oxygen-transfer reagent, such as t-BuOOH or H₂O₂ and a metal catalyst, the metal can serve as a relay for the transfer of the oxygen atom from the hydroperoxide to the olefin via an oxometal intermediate. The dismutation of t-BuOOH in the presence of transition–metal catalysts to produce t-BuOH and O₂ has been documented [4]. t-BuOOH oxidizes olefins to epoxides and allylic oxidation products in the presence of a transition-metal catalyst. Catalytic epoxidation and allylic oxidation reactions follow different paths. The epoxidation is an oxygen transfer reaction (Scheme 2) while the allylic oxidation follows a free radical reaction. The epoxidation could occur via the activation of the peroxidic oxygens.

Scheme 2. The oxidation of substituted homoallylic alcohols by Methods C-D.

Scheme 2. The oxidation of substituted homoallylic alcohols by Methods C-D.

c: R₁=CH₃; d: R₁= phenyl

When the substituted homoallylic alcohols 4c,d are oxidized with t-BuOOH under OsO₄ catalysis (Method C), the substituted double bonds of 4c,d were epoxidized and no allylic oxidation products are formed. Thus, when compound 4d was oxidized by this method only the α,β−epoxyalcohol and benzaldehyde were formed.

Compounds 4c,d when oxidized with only t-BuOOH (Method D) gave allylic oxidation products and epoxidation products. The oxidation reaction of 4c,d with t-BuOOH shows completely radical character. While all the substituted-1,5-hexadien-3-ols 4a-d have allylic hydrogen and hydroxyl groups, compound 4d compound has benzylic hydrogens in addition to allylic hydrogen and hydroxyl groups. t-BuOOH thus oxidized the hydroxyl group to a carbonyl group and simultaneously one or both of double bonds were converted to an epoxide.

Experimental

General

CrO₃, ZnCl₂, n-Bu₄NHSO₄, n-BuLi (1.6 M hexane solution), t-BuOOH (as 3M isooctane solution), pyridine, trans-2-butene-1-ol, trans-3-phenyl-2-propene-1-ol, t-BuOH were obtained from commercial sources and all the solvents were used without further purification. PCC and ZCC have been prepared according to the literature [1,2]. Oxidation reaction times were determined with thin layer chromatography (aluminium sheets silica gel 60 F₂₅₄) and the products were purified by column chromatography using one of the following eluent systems: (A) 5:1 hexane-ethyl acetate; (B) 4:1 hexane-ethyl acetate; (C): 4:1:1 hexane-ethyl acetate-acetone: (D) 4:1:1:0.5 hexane-ethyl acetate-acetone-dimethyl ether. IR spectra (NaCl, thin film) were measured on a Mattson series FT-IR 1000 model spectrometer and ¹H- and ¹³C-NMR spectra were measured on a JEOL FX-90 Q instrument at 90 and 22.5 MHz, respectively, using CDCl₃ as solvent. Shift values are reported in ppm relative to TMS. GC/MS (eV, EI) and elemental analysis measurement were determined in The Scientific and Technical Research Council of Turkey (TUBITAK). Substituted homoallyllic alcohol starting materials were prepared as outlined in Scheme 3.

Scheme 3. Synthetic routes for the synthesis of substituted homoallylic alcohols

Scheme 3. Synthetic routes for the synthesis of substituted homoallylic alcohols

a: R₁ =R₂ = H, R₃ = CH₃; b: R₁ = R₃ = CH₃, R₂ = H; c: R₁ = CH₃; d: R₁ = C₆H₅

Compounds 3a,b and 4a,b were prepared as described in the literature [9,11,12]. Unsymmetrical bis-allylic ethers 2c-d were synthesised from trans-2-butene-1-ol (1c) or trans-3-phenyl-2-propene-1-ol (1d) with allyl bromide, KOH and n-Bu₄NHSO₄ as phase transfer catalyst. Substituted homoallylic alcohols 4c,d have then been synthesised via a [2,3]-Wittig rearrangement reaction of the unsymmetrical bis allyl ethers under an argon atmosphere and at –75 ^oC in high yields according to literature methods [13,14,15].

Unsymmetric bis allyl ethers:

(2E)-1-(Allyloxy)-2-butene (2c): Yield: 69%; Rf: 0.713 (eluent system A); b.p: 48-49^oC (50 mmHg); IR: 3080, 1650, 1130, 960, 936; ¹H-NMR: 1.57-1.71 (d, J=7 Hz, 3H), 3.88 (m, 4H), 5.02-5.22 (m, 2H), 5.22-6.15 (m, 3H); ¹³C-NMR: 17.6, 71, 116.3, 128.4, 128.7, 135.5; Anal.Calcd.for C₇H₁₂O: C, 75.0; H, 10.7; Found: C, 74.6; H, 10.4.

[3-(Allyloxy) prop-1-enyl]benzene (2d): Yield: 71%; Rf: 0.658 (eluent system A); b.p: 118-120^oC (10 mmHg); IR: 3080, 3040, 1657, 1140, 965, 750-700; ¹H-NMR: 3.95 (m, 4H), 4.84 -5.35 (m, 2H), 5.54-6.66 (m, 3H), 6.94-7.53 (m, 5H); ¹³C-NMR: 70.6, 116.2, 124.9, 127, 128.5, 130.9, 131.5, 134.3; Anal. Calcd. for C₁₂H₁₄O: C, 82.8; H, 8.0; Found: C, 83.1; H, 8.3.

(5E)-1,5-Heptadiene-4-ol (4c): Yield: 62%; Rf: 0.586 (eluent system A); b.p: 72-74^oC (35 mmHg); IR: 3600-3200, 3040, 1651, 1260, 1065, 935; ¹H-NMR: 0.94-1.02 (d, J = 4 Hz, 3H), 2.23 (m, 2H), 3.94 (q, J = 6 Hz, 1H ), 5.14 (m, 2H), 5.82 (m, 3H); ¹³C-NMR: 16.0, 38.6, 76.7, 116.2, 139.3, 140.8; Anal. Calcd. for C₇H₁₂O: C, 75.0; H, 10.7; Found: C, 75.4; H, 10.9.

1(E)-Phenyl-1,5-hexadiene-3-ol (4d): Yield: 72%; Rf: 0.504 (eluent system B); b.p: 130-132^oC (2 mmHg); IR: 3600-3200, 3040, 1651, 1260,740; ¹H-NMR: 3.78-4.25 (m, 3H), 4.95-5.46 (m, 2H ), 5.6-6.72 (m, 3H) 7.1-7.8 (m, 5H); ¹³C-NMR: 71.8, 117, 127.3, 128.5, 129.4, 133, 135.8, 137.7; Anal. Calcd. for C₁₂H₁₄O: C , 82.8; H, 8.1; Found: C, 82.1; H, 7.9.

Oxidation Reactions of Substituted Homoallylic Alcohols: Method A: Oxidation of 4a-d with PCC (General Method)

PCC (1.5 mmol) is dissolved in CH₂Cl₂ (2 mL) and then NaOAc (0.03 mmol) is added to this solution. The substituted homoallylic alcohol (1 mmol) dissolved in CH₂Cl₂ (15 mL) and then added dropwise to the PCC solution. After 1-2 hours, the reaction is checked by TLC to determine completion. The reaction mixture is filtered, the residues are washed with twice with ether, dried with MgSO₄, and concentrated in vacuo give the crude product that was purified by column chromatography over silica gel.

Method B: Oxidation of 4a-d with ZCC (General Method).

A solution of substituted homoallylic alcohol (8 mmol) in CH₂Cl₂ (70 mL) was prepared in a 200 mL round-bottomed flask equipped with a magnetic stirrer. The ZCC (16 mmol) was added in four separate portions within 15 min. with vigorous stirring. Stirring was continued for 2 hours. The mixture was diluted with CH₂Cl₂ (120 mL) and filtered. The filtrate was evaporated on a rotatory evaporator under reduced pressure.

Method C: OsO₄-catalyzed oxidation of 4c,d with t-BuOOH

Compound 4c or 4d (50 mmol) was dissolved in t-BuOH (125 mL) and 20 % aqueous NEt₄OH (6.5 mL), t-BuOOH (3 M isooctane, 34 mL, 103 mmol) and OsO₄ solution (2.5 % in t-BuOH, 2.6 mL 0,2 mmol) were added. After standing for 12 hour in room temperature, 5% Na₂SO₃ solution (65 mL) was added, then the reaction mixture was extracted with diethyl ether, the ether phase was washed with saturated NaCl solution, dried over MgSO₄ and the solvent was distilled in vacuo.

Method D: Oxidation of 4c,d with t-BuOOH

Oxidation of compounds 4c and 4d with t-BuOOH is described in Method C. In this method the OsO₄ was omitted.

Oxidation Products

5-Methyl-1,5-hexadiene-3-one (5a): Yields: 67.5% (Method A), 62.4% (Method B); Rf: 0.737 (eluent system C); IR: 3080, 1680, 1625, 935; ¹H-NMR: 2.2 (s, CH₃, 3H), 4.47 (s, CH₂, 2H), 4.75 (s, =CH₂, 2H), 6.27-6.31 (m, CH₂=CH, 3H); Anal. Calcd. for C₇H₁₀O: C, 76.4; H, 9.1; Found: C 75.0; H, 8.8; GC/MS: M^+.110, base peak: 55.

(5E)-2-Methyl-1,5-heptadiene-4-one (5b): Yields: 58.3% (Method A), 46.7% (Method B); Rf: 0.713 (eluent system C); IR: 3040, 1680, 1625, 990, 935; ¹H-NMR: 2.10 (d, CH₃, 3H, J=7 Hz ), 2.24 ( s, CH₃, 3H), 4.43 (s, CH₂, 2H), 4.72 (s, =CH₂, 2H), 6.02-6.76 (m, CH=CH, 2H); Anal. Calcd. for C₈H₁₂O: C, 77.4; H, 9.7 Found: C, 77.1; H, 9.5; GC/MS: M⁺ 124, base peak: 109.

(5E)-1,5-Heptadien-4-one (5c): Yields: 50.3% (Method A), 42.2% (Method B); Rf: 0.702 (eluent system C); IR: 3040, 1680, 1625, 990; ¹H-NMR: 1.97 (d, J=7 Hz, CH₃, 3H), 4.37 (m, CH₂, 2H), 5.05-5.63 (m, CH₂=CH, 3H), 6.02-6.76 (m, CH=CH, 2H); ¹³C-NMR: 17, 37, 124, 128, 130, 137, 197; Anal. Calcd. for C₇H₁₀O: C, 76.4; H, 9.1; Found: C, 76.8; H, 8.9.

(1E)-1-Phenyl-1,5-hexadiene-3-one (5d): Yields: 48.2% (Method A), 36.1% (Method B); Rf: 0.512 (eluent system C); IR: 3040, 1680, 1625, 1080, 990, 760; ¹H-NMR: 4.34 (m, CH₂, 2H), 5.0-5.71 (m, CH₂=CH, 3H), 6.25-6.91 (m, CH=CH, 2H), 7.17-7.33 (m, aromatic protons, 5H); ¹³C-NMR: 37, 123, 127, 128, 129, 131, 137, 197; Anal. Calcd. for C₁₂H₁₂O: C, 83.7; H, 7.0; Found: C, 83.2; H,7.3; GC/MS: M^+. 172, base peak: 171.

2-Methyl-1,5-hexadiene-3,4-dione (6a): Yield: 3.0%; Rf: 0.711 (eluent system C); IR: 1625, 1680; ¹H-NMR: 2.57 (s, CH₃, 3H), 4.84 (s, CH₂=, 2H), 6.21-6.35 (m, CH₂=CH, 3H); Anal. Calcd. for C₇H₈O₂: C, 67.7; H, 6.5; Found: C, 67.3; H, 6.8; GC/MS: M^+. 124, base peak: 109.

1-[3-Methyloxiranyl]-but-3-en-1-ol (8c): Yield: 48.8%; Rf: 0.644 (eluent system D); IR: 3450-3340, 3060, 1642, 1250, 965; ¹H-NMR: 1.32 (d, CH₃, 3H, J=7 Hz), 2.98 (s, OH, 1H), 3.41(m, CH₂, 2H), 3.94-4.40 (m, CH-, 1H), 4.26-4.98 (m, CH-CH, 2H), 5.11-5.73 (m, CH₂=CH, 3H); Anal. Calcd. for C₇H₁₂O₂: C, 65.6; H,9.4; Found: C , 65.7; H, 9.6; GC/MS: M^+.128, base peak: 55.

1-[3-Phenyloxiranyl]-but-3-en-1-ol (8d): Yield: 32.2%; Rf: 0.486 (eluent system D); IR: 3480-3550, 1641, 1245, 970, 740; ¹H-NMR: 3.38 (m, CH₂, 2H), 3.76 (s, OH, 1H), 4.23-4.35 (m, CH-,1H), 4.42-4.83 (m, CH-CH, 2H), 5.05-5.67 (m ,CH₂=CH, 3H) , 7.2-7.3 (m, aromatic protons, 5H); Anal. Calcd. for C₁₂H₁₄O₂: C, 75.8; H, 6.3; Found: C, 75.1; H,6.7; GC/MS: M^+. 190, base peak: 91.

1-[3-Methyloxirane-2-yl]-3-butene-1-one (9c): Yield: 10.8%; Rf: 0.630 (eluent system D); IR: 3040, 1715, 1640, 1080, 1245, 970, 760; ¹H-NMR: (1.41, CH₃, J=7 Hz), 3.95 (m, CH₂, 2H), 4.29-5.25 (m, CH-CH, 2H), 5.1-5.67 (m, CH₂=CH, 3H), 7.2-7.3 (m, aromatic protons, 5H); Anal. Calcd. for C₇H₁₀O₂: C, 66.7; H, 7.4; Found: C, 66.9; H, 7.9; GC/MS: M^+. 126, base peak: 59.

1-[3-Phenyloxiranyl]-but-3-en-1-one (9d): Yield: 16.4%; Rf: 0.442 (eluent system D); IR: 3040, 1715, 1640, 1245, 1080, 970, 765; ¹H-NMR: 3.95 (m, CH₂, 2H), 4.66-5.49 (m, CH-CH, 2H), 5.10-5.71 (m, CH₂-CH, 3H), 7.2-7.3 (m, aromatic protons, 5H); Anal. Calcd. for C₁₂ H₁₂ O₂: C, 76.6; H, 6.4; Found: C, 76.2; H, 6.9; GC/MS: M^+. 188, base peak: 118.

1-[3-Methyloxiranyl]-2-oxiranyletanone (10c): Yield: 33.2%; Rf: 0.656 (eluent system D); IR: 1720, 1250, 1100; ¹H-NMR: 1,34 (d, CH₃, 3H, J=7 Hz), 3.42 (m, CH₂, 2H), 3.81-4.69 (m, CH₂-CH, 3H), 4.78-5.41 (m, CH-CH, 2H); Anal. Calcd. for C₇H₁₀O₃ C, 59,2; H, 7,0.Found: C, 59.9 ;H,7.4; GC/MS: M^+.142, base peak: 71.

2-Oxiranyl-1-[3-phenyloxiranyl]ethanone (10d): Yield: 13.4%; Rf: 0.357 (eluent system D); IR: 3040, 1715, 1250, 1100; ¹H-NMR: 3.40 (m,CH₂, 2H), 3.77-4.66 (m, CH₂-CH, 3H), 6.34-6.93 (m, CH-CH, 2H), 7.2-7.3 (m, aromatic protons, 5H); Anal. Calcd. for C₁₂H₁₂O₃: C, 70.6; H, 5.9; Found: C,70.2; H,5.6; GC/MS: M^+. 204, base peak: 130.