PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Tetrahedron. Author manuscript; available in PMC 2010 July 6.
Published in final edited form as:
Tetrahedron. 2009 June 27; 65(26): 5024–5029.
doi:  10.1016/j.tet.2009.03.068
PMCID: PMC2897757
NIHMSID: NIHMS123356

Hydroacylation of 2-Butyne from the Alcohol or Aldehyde Oxidation Level via Ruthenium Catalyzed C-C Bond Forming Transfer Hydrogenation

Abstract

Under the conditions of ruthenium catalyzed transfer hydrogenation, 2-butyne couples to alcohols 1a–1j to deliver α,β-unsaturated ketones 3a–3j in good to excellent isolated yields with complete E-stereoselectivity. Under identical conditions, aldehydes 2a–2j couple to 2-butyne to provide an identical set of α,β-unsaturated ketones 3a–3j in good to excellent isolated yields with complete E-stereoselectivity. Nonsymmetric alkyne 4a couples to alcohol 1d or aldehyde 2d in good yield to deliver enone 3k as a 5:1 mixture of regioisomers. Thus, intermolecular alkyne hydroacylation is achieved from the alcohol or aldehyde oxidation level. In earlier studies employing the same ruthenium catalyst under slightly different conditions, alkynes were coupled to carbonyl partners from the alcohol or aldehyde oxidation level to furnish allylic alcohols. Therefore, under the conditions of C-C bond forming transfer hydrogenation, all oxidation levels of substrate (alcohol or aldehyde) and product (allylic alcohol or α,β-unsaturated ketone) are accessible.

1. Introduction

Whereas rhodium catalyzed intramolecular alkene hydroacylation using aldehydes as acyl donors is well developed,1 intermolecular variants typically suffer from competitive aldehyde decarbonylation.2,37 While exceptions exist for certain substrate combinations,3,4 efficient intermolecular alkene hydroacylation generally requires acyl donors that exploit β-chelation to suppress decarbonylation, such as γ,δ-unsaturated aldehydes,5a salicylaldehydes,5b–eβ-sulfido-aldehydes5f,9c–e,g and (N-2-pyridyl)aldimines.5g While cobalt6 and ruthenium7 catalysts have been explored, rhodium appears unique in its ability to promote intermolecular alkene hydroacylation under mild conditions in a selective fashion, notwithstanding the aforementioned limitations. Alkyne hydroacylation is far less developed. To our knowledge, efficient and stereoselective intermolecular alkyne hydroacylation is restricted to systems that exploit β-chelation to suppress decarbonylation,9,10 and the first efficient intramolecular alkyne hydroacylations only recently were disclosed by Fu and Tanaka (2001).8

In prior work from our laboratory, ruthenium catalyzed diene-alcohol and diene-aldehyde transfer hydrogenative C-C couplings were developed.11a,b,12 The former process belongs to a broad new subset of alcohol-unsaturate C-C couplings that are related conceptually to hydrogen auto-transfer processes.12,13 Whereas conventional hydrogen auto-transfer reactions provide products of alcohol substitution by way of oxidation-condensation-reduction mechanisms, alcohol-unsaturate couplings provide products of carbonyl addition by way of hydrogen shuffling to generate nucleophile-electrophile pairs. A unique feature of alcohol-unsaturate C-C coupling resides in the ability to achieve formal C-H functionalization at the carbinol carbon through introduction of a non-stabilized carbanion equivalent (Scheme 1).

Scheme 1
Simplified schematic depictions of the catalytic mechanism of an alcohol-unsaturate C-C coupling reaction and a related hydrogen auto-transfer process.

Remarkably, for the ruthenium catalyzed diene-alcohol and diene-aldehyde transfer hydrogenative C-C couplings, conditions were identified such that formation of either the homoallylic alcohol or β,γ-unsaturated ketone is achieved from the alcohol or aldehyde oxidation level, the latter process representing a formal diene hydroacylation from the alcohol or aldehyde oxidation level.11b The step-economy associated with the ability to access alternate oxidation levels of starting material or product compelled us to explore the generality of this concept in the context of alkyne-carbonyl coupling.11e,14 Here, we report that under the conditions of ruthenium catalyzed C-C bond forming transfer hydrogenation,11,12 efficient intermolecular alkyne hydroacylation is achieved from either the alcohol or aldehyde oxidation level with complete levels of E/Z-stereoselectivity, and in the absence of β-chelation assistance. As in earlier studies conditions for ruthenium catalyzed alkyne-carbonyl coupling en route to products of carbonyl vinylation were established,11e all oxidation levels of substrate (alcohol or aldehyde) and product (allyl alcohol or α,β-unsaturated ketone) are accessible (Scheme 2).

Scheme 2
Transcending the boundaries of oxidation level through C-C bond forming transfer hydrogenation.

2. Results and Discussion

In previously disclosed alkyne-carbonyl couplings employing Ru(O2CCF3)2(CO)(PPh3)2 as precatalyst,11e small quantities of α,β-unsaturated ketone accompanied formation of the desired allylic alcohols. Hence, it was postulated that efficient formation of conjugated enones could be achieved simply by conducting the reaction at higher temperature and longer reaction times. Higher reaction concentration also should promote oxidation of the initially formed allylic alcohol by facilitating formation of the allylic ruthenium alkoxide, which upon β-hydride elimination generates the enone. This hypothesis was borne out experimentally in the coupling of 2-butyne to p-nitrobenzyl alcohol 1a. By extending reaction time from 13 hours to 30 hours, modestly raising the temperature from 95 °C to 110 °C and increasing concentration from 0.2 M to 2.0 M, the α,β-unsaturated ketone 3a was formed in 88% isolated yield to the exclusion of the allylic alcohol (Table 1, Entry 1).

Table 1
(Left) Hydroacylation of 2-butyne from the alcohol oxidation level.a

To explore the scope of this process, 2-butyne was coupled to benzylic alcohols 1a–1g. In each case, good to excellent isolated yields of enones 3a–3g were obtained. As demonstrated by the formation of 3h–3j, aliphatic alcohols also participate in the coupling. For all coupling products 3a–3j, the enone moiety appears as a single geometrical isomer (>95:5, E:Z selectivity). For the corresponding aldehyde couplings, isopropanol, a hydride donor, is required to initiate the purported hydrometallative mechanism. Although, in principle, only substoichiometric quantities of isopropanol are required to initiate the catalytic cycle, slightly better isolated yields were obtained using one equivalent of isopropanol. Notably, an identical set of enone products 3a–3j were formed as single geometrical isomers (>95:5, E:Z selectivity) from the aldehydes 2a–2j (Table 2). Thus, ruthenium catalyzed hydroacylation of 2-butyne is achieved with equal facility from the alcohol or aldehyde oxidation level.

Table 2
(Right) Hydroacylation of 2-butyne from the aldehyde oxidation level.a

Preliminary studies on the hydroacylation of nonsymmetric alkynes reveal promising levels of regioselectivity in certain cases. For example, the coupling of nonsymmetric alkyne 4a to alcohol 1d occurs in good isolated yield to deliver enone 3k as a 5:1 mixture of regioisomers and as a single geometrical isomer (>95:5, E:Z selectivity). Similarly, the coupling of nonsymmetric alkyne 4a to aldehyde 2d provides enone 3k in comparable isolated yield and as a single geometrical isomer (>95:5, E:Z selectivity) (Scheme 3).

Scheme 3
Regioselective hydroacylation of nonsymmetric alkyne 4a from the alcohol or aldehyde oxidation level.

3. Conclusion

In summary, we report a protocol for alkyne hydroacylation under the conditions of ruthenium catalyzed transfer hydrogenation.11,12 Unlike the prototypical rhodium catalyzed alkyne hydroacylations,9 efficient intermolecular coupling is observed in the absence chelation assistance. Furthermore, through C-C bond forming transfer hydrogenation, enone formation is achieved from the alcohol or aldehyde oxidation level. In earlier studies employing the same ruthenium catalyst under less forcing conditions, alkynes were coupled to carbonyl partners from the alcohol or aldehyde oxidation level to furnish allylic alcohols. Thus, all oxidation levels of substrate (alcohol or aldehyde) and product (allylic alcohol or α,β-unsaturated ketone) are accessible.

The alcohol-unsaturate C-C couplings developed in our laboratory, as well as related amine-unsaturate C-C couplings (termed hydroaminoalkylation),15 may be viewed as carbonyl or imine additions from the alcohol or amine oxidation levels, respectively. These transformations, in which a redistribution of hydrogen accompanies covalent bond formation, may be viewed as hydrogen-autotransfer processes.13 The ability to circumvent reductive preactivation of nucleophiles (discrete carbanion generation) and oxidative preactivation of electrophiles (discrete alcohol oxidation) is inherently step-economic and redox-economic and defines a departure from the use of preformed organometallic reagents in carbonyl and imine addition chemistry.

4. Experimental Section

4.1. General

All reactions were run under an atmosphere of argon, unless otherwise indicated. Anhydrous solvents were transferred via oven-dried syringe. Reaction tubes were oven-dried and cooled under a stream of argon. Reaction tubes were purchased from Fisher Scientific (catalog number 14-959-35C). Tetrahydrofuran was purified using the Pure-Solv MD-5 Solvent Purification System (Innovative Technology, inc).

Ru(O2CCF3)2(CO)(PPh3)2 was prepared in accordance with literature procedure.16 Anhydrous isopropanol (99.5% over molecular sieves) was purchased from Acros and used as received. Commercially available alcohols and alkynes were used as received. Alkyne 4a was prepared according to literature procedure.17 Commercially available aldehydes were purified via distillation or recrystallization prior to use.

Analytical thin-layer chromatography (TLC) was carried out using 0.2-mm commercial silica gel plates (DC-Fertigplatten Kieselgel 60 F254) and products were visualized by UV, KMnO4, vanillin and/or anisaldehyde stain. Preparative column chromatography employing silica gel was performed according to the method of Still.18 Solvents for chromatographic separation are listed as volume:volume ratios. Infrared spectra were recorded on a Perkin-Elmer 1600 spectrometer. High-resolution mass spectra (HRMS) were obtained on a Karatos MS9 and are reported as m/z (relative intensity). Accurate masses are reported for the molecular ion [M+H]+ or a suitable fragment ion. Proton nuclear magnetic resonance (1H NMR) spectra were recorded with a Varian Gemini (400 MHz or 300MHz) spectrometer. Chemical shifts are reported in delta (δ) units, parts per million (ppm) downfield from trimethylsilane. Coupling constants are reported in Hertz (Hz). Carbon-13 nuclear magnetic resonance (13C NMR) spectra were recorded with a Varian Gemini 300 (75 MHz) or 400 (100 MHz) spectrometer. Chemical shifts are reported in delta (δ) units, ppm relative to the center of the triplet at 77.0 ppm for deuteriochloroform. 13C NMR spectra were routinely run with broadband decoupling.

4.2.1. General Procedure A for the coupling of 2-butyne to alcohols

To a pressure tube equipped with magnetic stir bar was added Ru(O2CCF3)2(CO)(PPh3)2 (13.2 mg, 0.015 mmol, 5 mol%). At this stage, solid alcohol substrates (0.300 mmol, 100 mol%) were added. The tube was then sealed with a rubber septum, purged with argon and THF (1.5 mL, 0.2 M concentration with respect to the alcohol) was added. At this stage, liquid alcohol coupling partners (0.300 mmol, 100 mol%) were added. The reaction vessel was cooled to −78 °C. 2-Butyne (35 μL, 0.450 mmol, 150 mol%) was added and the rubber septum was quickly replaced with a screw cap. The reaction vessel was allowed to reach room temperature and the reaction mixture was heated to the specified temperature and for the indicated time. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (SiO2) under the conditions noted to furnish the α,β-unsaturated ketone.

4.2.2. General Procedure B for the coupling of 2-butyne to aldehydes

To a pressure tube equipped with magnetic stir bar was added Ru(O2CCF3)2(CO)(PPh3)2 (13.2 mg, 0.015 mmol, 5 mol%). At this stage, solid aldehyde substrates (0.300 mmol, 100 mol%) were added. The tube was then sealed with a rubber septum, purged with argon and THF (1.5 mL, 0.2 M concentration with respect to the aldehyde) and 2-propanol (36 μL, 0.300, 100 mol%) were added. At this stage, liquid aldehyde coupling partners (0.300 mmol, 100 mol%) were added. The reaction vessel was cooled to −78 °C. 2-Butyne (35 μL, 0.450 mmol, 150 mol%) was added and the rubber septum was quickly replaced with a screw cap. The reaction vessel was allowed to reach room temperature and the reaction mixture was heated to the specified temperature and for the indicated time. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (SiO2) under the conditions noted to furnish the α,β-unsaturated ketone.

4.2.3. Synthesis of (E)-2-Methyl-1-(4-nitrophenyl)but-2-en-1-one (3a)

Procedure A was employed using alcohol 1a. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 1:9 ethyl acetate:hexanes) to furnish the title compound (54 mg) as a light brown oil in 88% yield. Procedure B was employed using aldehyde 2a. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 1:9 ethyl acetate:hexanes) to furnish the title compound (52.5 mg) as a light brown oil in 85% yield. 1H NMR (400 MHz, CDCl3): δ8.27 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 6.41 (q, J = 6.8 Hz, 1H), 1.99 (s, 3H), 1.93 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 196.7, 149.0, 144.6, 144.2, 137.7, 129.7, 123.2, 15.0, 11.7. FTIR (neat): 3022, 1709, 1650, 1524, 1347, 1278, 1104, 748, 715, 667 cm−1. HRMS (CI): Calcd. for C11H12NO3[M+H]+: 208.0809, Found: 208.0811.

4.2.4. Synthesis of (E)-2-Methyl-1-phenylbut-2-en-1-one (3b)

Procedure A was employed using alcohol 1b. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 5:95 ether:pentane) to furnish the title compound (39 mg) as a clear oil in 79% yield. Procedure B was employed using aldehyde 2b. In a modification to Procedure B, 2-methyltetrahydrofuran was used as solvent. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 5:95 ether:pentane) to furnish the title compound (41 mg) as a clear oil in 85% yield. 1H NMR (400 MHz, CDCl3): δ 7.60(d, J = 8.3 Hz, 2H), 7.49 (dt, J = 8.3, 1.2 Hz, 1H), 7.40 (dt, J = 8.3, 1.2 Hz, 2H), 6.40 (q, J = 6.8 Hz, 1H), 1.97 (s, 3H), 1.88 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 198.9, 141.5, 138.8, 137.6, 131.2, 129.1, 127.9, 14.7, 12.1. FTIR (neat): 3057, 2919, 2847, 1628, 1268, 1023, 970, 698 cm−1. HRMS (CI): Calcd. for C11H13O [M+H]+: 161.0965, Found: 161.0966.

4.2.5. Synthesis of (E)-2-Methyl-1-(3-methoxyphenyl)but-2-en-1-one (3c)

Procedure A was employed using alcohol 1c. After heating the reaction at 130 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 5:95 ethyl acetate:hexanes) to furnish the title compound (55 mg) as a clear oil in 71% yield. Procedure B was employed using aldehyde 2c. In a modification to Procedure B, 2-methyltetrahydrofuran was used as solvent. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 5:95 ethyl acetate:hexanes) to furnish the title compound (55 mg) as a clear oil in 74% yield. 1H NMR (400 MHz, CDCl3): δ 7.33 – 7.27 (m, 1H), 7.18 – 7.14 (m, 2H), 7.03 (ddd, J = 8.4, 2.6, 0.8 Hz, 1H), 6.43 (q, J = 6.8 Hz, 1H), 3.83 (s, 3H), 1.96 (s, 3H), 1.87 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 198.6, 159.2, 141.5, 140.1, 137.5, 128.9, 121.7, 117.3, 113.9, 55.3, 14.7, 12.1. FTIR (neat): 3003, 2941, 2839, 1642, 1584, 1272, 1241, 1027, 724 cm−1. HRMS (CI): Calcd. for C12H15O2 [M+H]+: 191.1072, Found: 191.1074.

4.2.6. Synthesis of (E)-2-Methyl-1-(4-bromophenyl)but-2-en-1-one (3d)

Procedure A was employed using alcohol 1d. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 5:95 ethyl acetate:hexanes) to furnish the title compound (64 mg) as a pale yellow oil in 90% yield. Procedure B was employed using aldehyde 2d. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 5:95 ethyl acetate:hexanes) to furnish the title compound (60 mg) as a pale yellow oil in 84% yield. 1H NMR (400 MHz, CDCl3): δ 7.55 (dd, J = 8.5, 2.1 Hz, 2H), 7.49 (dd, J = 8.5, 2.1 Hz, 2H), 6.38 (q, J = 6.8 Hz, 1H), 1.96 (s, 3H), 1.88 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 197.5, 141.6, 137.4 (2 carbons), 131.2, 130.7, 125.9, 14.7, 12.0. FTIR (neat): 3057, 2919, 2847, 1628, 1575, 1392, 1067, 1005, 1277, 832, 738 cm−1. HRMS (CI): Calcd. for C11H12BrO [M+H]+: 239.0066, Found: 239.0066.

4.2.7. Synthesis of (E)-Methyl 4-(2-methylbut-2-enoyl)benzoate (3e)

Procedure A was employed using alcohol 1e. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 0:100 – 5:95 ethyl acetate:hexanes) to furnish the title compound (59.4 mg) as a colorless crystalline solid in 91% yield. Procedure B was employed using aldehyde 2e. After heating the reaction at 110 °C for 40 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 0:100 – 5:95 ethyl acetate:hexanes) to furnish the title compound (49.5 mg) as a colorless crystalline solid in 76% yield. 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 6.41 (q, J = 7.3 Hz, 1H), 3.95 (s, 3H), 1.97 (s, 3H), 1.90 (d, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 198.0, 166.3, 143.0, 142.8, 137.6, 132.0, 129.2, 128.8, 52.3, 14.9, 11.8. FTIR (neat): 2952, 1722, 1647, 1435, 1404, 1271, 1178, 1106, 720 cm−1. HRMS (CI): Calcd. for C13H15O3 [M+H]+: 219.1021, Found: 219.1024.

4.2.8. Synthesis of (E)-2-Methyl-1-(3,5-dimethylphenyl)but-2-en-1-one (3f)

Procedure A was employed using alcohol 1f. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 5:95 ether:pentane) to furnish the title compound (57 mg) as a pale yellow oil in 80% yield. Procedure B was employed using aldehyde 2f. In a modification to Procedure B, 2-methyltetrahydrofuran was used as solvent. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 5:95 ether:pentane) to furnish the title compound (57 mg) as a pale yellow oil in 80% yield. 1H NMR (400 MHz, CDCl3): δ 7.20 (s, 2H), 7.12 (s, 1H), 6.39 (q, J = 6.8 Hz, 1H), 3.41 (s, 6H), 1.95 (s, 3H), 1.87 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 199.2, 141.1, 138.9, 137.7, 137.5, 132.7, 126.9, 21.2, 14.7, 12.1. FTIR (neat): 3043, 2914, 2856, 1646, 1596, 1303, 1232, 1152, 738 cm−1. HRMS (CI): Calcd. For C13H17O [M+H]+: 188.1279, Found: 188.1281.

4.2.9. Synthesis of (E)-2-Methyl-1-(4-trifluoromethyl)phenyl)but-2-en-1-one (3g)

Procedure A was employed using alcohol 1g. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 5:95 ethyl acetate:hexanes) to furnish the title compound (69 mg) as a colorless oil in 82% yield. Procedure B was employed using aldehyde 2g. After heating the reaction at 130 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 5:95 ethyl acetate:hexanes) to furnish the title compound (55 mg) as a colorless oil in 80% yield. 1H NMR (400 MHz, CDCl3): δ 7.68 (s, 4H), 6.40 (q, J = 7.2 Hz, 1H), 1.98 (s, 3H), 1.91 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 197.5, 143.2, 142.2, 137.7, 132.5, 129.2, 125.0, 122.3, 14.9, 11.8. FTIR (neat): 3057, 2932, 2852, 1646, 1321, 1277, 1140, 1125, 1063, 845, 694 cm−1. HRMS (CI): Calcd. for C12H11F3O [M+H]+: 229.0840, Found: 229.0838.

4.2.10. Synthesis of (E)-3-Methyl-1-phenylpent-3-en-2-one (3h)

Procedure A was employed using alcohol 1h. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 5:95 ether:pentane) to furnish the title compound (39 mg) as a pale yellow oil in 81% yield. Procedure B was employed using aldehyde 2h. In a modification to Procedure B, the reaction was conducted in 2-methyltetrahydrofuran, with 10 mol% catalyst loading. After heating the reaction at 110 °C for 24 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 5:95 ether:pentane) to furnish the title compound (39 mg) as a pale yellow oil in 81% yield. 1H NMR (400 MHz, CDCl3): δ 7.36 – 7.18 (m, 5H), 6.87 (q, J = 6.8 Hz, 1H), 3.97 (s, 2H), 1.86 (d, J = 6.8 Hz, 3H), 1.78 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 199.1, 138.7, 137.9, 135.5, 129.2, 128.5, 126.5, 44.1, 14.9, 11.1. FTIR (neat): 3030, 2919, 2852, 1655, 1490, 1277, 1023, 1063, 720, 694 cm−1. HRMS (CI): Calcd. For C12H15O [M+H]+: 175.1123, Found: 175.1124.

4.2.11. Synthesis of (E)-3-Methyldodec-2-en-4-one (3i)

Procedure A was employed using alcohol 1i. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 5:95 ether:pentane) to furnish the title compound (44 mg) as a clear oil in 70% yield. Procedure B was employed using aldehyde 2i. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 5:95 ether:pentane) to furnish the title compound (43 mg) as a clear oil in 69% yield. 1H NMR (400 MHz, CDCl3): δ 6.73 (q, J = 6.8 Hz, 1H), 2.63 (t, J = 7.3 Hz, 2H), 1.85 (d, J = 6.8 Hz, 3H), 1.77 (s, 3H), 1.62 – 1.55 (m, 2H), 1.27 (s, 10H), 0.88 (t, J = 7.3, 3H). 13C NMR (100 MHz, CDCl3): δ 202.1, 138.3, 136.8, 37.2, 31.8, 29.4 (2 carbons), 29.2, 25.0, 22.6, 14.7, 14.1, 11.0. FTIR (neat): 2924, 2854, 1667, 1644, 1460, 1415, 1075, 983 cm−1. HRMS (CI): Calcd. For C13H25O [M+H]+: 197.1905, Found: 197.1904.

4.2.12. Synthesis of (E)-2-(4-Methyl-3-oxohex-4-enyl)-isoindole-1,3-dione (3j)

Procedure A was employed using alcohol 1j. After heating the reaction at 110 °C for 40 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 1:9 ethyl acetate:hexanes) to furnish the title compound (76.8 mg) as a colorless crystalline solid in 99% yield. Procedure B was employed using aldehyde 2j. After heating the reaction at 130 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 1:9 ethyl acetate:hexanes) to furnish the title compound (51.2 mg) as a colorless crystalline solid in 66% yield. 1H NMR (400 MHz, CDCl3): 7.84 (dd, J = 5.5, 3.1 Hz, 2H), 7.72 (dd, J = 5.5, 3.1 Hz, 2H), 6.74 (q, J = 6.8 Hz, 1H), 4.00 (t, J = 7.5 Hz, 2H), 3.10 (t, J = 7.5 Hz, 2H), 1.84 (d, J = 6.8 Hz, 3H), 1.77 (s, 3H). 13C NMR (100 MHz, CDCl3): 198.6, 168.1, 138.1, 133.9, 132.0, 123.2, 35.4, 34.0, 14.8, 10.8 (only 10 signals were observed). FTIR (neat): 2927, 1772, 1709, 1663, 1439, 1392, 1365, 998, 910, 717 cm−1. HRMS (CI): Calcd. for C15H16NO3[M+H]+: 258.1130, Found: 258.1130.

4.2.13. Synthesis of (E)-2-(2-benzyloxy)ethyl-1-(4-bromophenyl)but-2-en-1-one (3k)

In a modification to procedures A and B, alkyne 4a was used in place of 2-butyne. Procedure A was employed using alcohol 1d. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 1:9 ethyl acetate:hexanes) to furnish the title compound (76 mg) as a colorless oil in 70% yield as a 5:1 mixture of regioisomers. Procedure B was employed using aldehyde 2d. After heating the reaction at 110 °C for 30 hours the mixture was concentrated in vacuo and purified by flash column chromatography (SiO2, 1:9 ethyl acetate:hexanes) to furnish the title compound (70 mg) as a colorless oil in 65% yield as a 5:1 mixture of regioisomers. 1H NMR (400 MHz, CDCl3): δ 7.54 – 7.25 (m, 9H), 6.37 (q, J = 6.9 Hz, 1H), 6.48 (s, 2H), 3.60 (t, J = 6.5 Hz, 2H), 2.82 (t, J = 6.5, Hz, 1H), 1.91 (d, J = 6.9 Hz, 3H). Characteristic signals for regio-isomer: 7.81 – 7.60 (m, 2H), 5.9 (q, J = 6.5 Hz, 2H), 4.37 (s, 2H), 3.5 (t, J = 6.5 Hz, 2H), 2.93 (t, J = 6.5 Hz, 2H), 1.48 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 197.5, 138.9, 131.8, 131.2, 130.9, 129.5, 128.2, 127.5, 127.4, 72.8, 68.7, 38.4, 29.5, 27.0, 14.7. Characteristic signals for regio-isomer: 198.4, 138.3, 137.5, 131.9, 131.5, 130.7, 128.3, 127.6, 126.2, 72.9, 70.1, 36.0, 29.6, 25.7, 15.8. FTIR (neat): 3020, 2857, 1647, 1585, 1482, 1294, 1285, 1098, 1070, 729, 697 cm−1. HRMS (CI): Calcd. for C19H20OBr[M+H]+: 359.0645, Found: 359.0642.

Supplementary Material

01

Acknowledgments

Acknowledgment is made to the Robert A. Welch Foundation, the ACS-GCI Pharmaceutical Roundtable, the NIH-NIGMS (RO1-GM069445) for partial support of this research, and the C. M. Share graduate fellows program (R.L.P.).

Footnotes

Supporting Information

Supplementary information in association with this article can be found in the online version at doi:

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Bibliography

1. For selected reviews on metal catalyzed hydroacylation, see: (a) Bosnich B. Acc Chem Res. 1998;31:667. (b) Jun CH, Hong JB, Lee DY. Synlett. 1999:1. (c) Tanaka M, Sakai K, Suemune H. Curr Org Chem. 2003;7:353. (d) Fu GC. In: In Modern Rhodium-Catalyzed Organic Reactions. Evans PA, editor. Chapter 7. 2005. pp. 79–91. (e) Jun CH, Jo EA, Park JW. Eur J Org Chem. 2007:1869.
2. For rhodium-catalyzed aldehyde decarbonylation, see: (a) Doughty DH, Pignolet LH. J Am Chem Soc. 1978;100:7083. (b) O’Conner JM, Ma J. J Org Chem. 1992;57:5075. (c) Beck CM, Rathmill SE, Park YJ, Chen J, Crabtree RH. Organometallics. 1999;18:5311.
3. For certain substrate combinations, efficient intermolecular rhodium catalyzed alkene hydroacylation is observed in the absence of β-chelation: (a) Marder TB, Roe DC, Milstein D. Organometallics. 1988;7:1451. (b) Tanaka K, Shibata Y, Suda T, Hagiwara Y, Hirano M. Org Lett. 2007;9:1215. [PubMed] (c) Roy AH, Lenges CP, Brookhart M. J Am Chem Soc. 2007;129:2082. [PubMed]
4. Efficient intermolecular Rh-catalyzed alkene hydroacylation employing anhydrides as acyl donors and hydrogen as terminal reductant is observed in the absence of β-chelation: Hong YT, Barchuk A, Krische MJ. Angew Chem Int Ed. 2006;128:6885. [PubMed]
5. For chelation-assisted intermolecular Rh-catalyzed alkene hydroacylation, see: (a) γ,δ–unsaturated aldehydes: Vora KP, Lochow CF, Miller RG. J Organomet Chem. 1980;192:257.(b) salicylaldehydes: Tanaka M, Imai M, Yamamoto Y, Tanaka K, Shimowatari M, Nagumo S, Kawahara N, Suemune H. Org Lett. 2003;5:1365. [PubMed] (c) Imai M, Tanaka M, Tanaka K, Yamamoto Y, Imai-Ogata N, Shimowatari M, Nagumo S, Kawahara N, Suemune H. J Org Chem. 2004;69:1144. [PubMed] (d) Tanaka K, Tanaka M, Suemune H. Tetrahedron Lett. 2005;46:6053. (e) Imai M, Tanaka M, Nagumo S, Kawahara N, Suemune H. J Org Chem. 2007;72:2543. [PubMed](f) β-sulfido-aldehyde: Willis MC, McNally SJ, Beswick PJ. Angew Chem Int Ed. 2004;43:340. [PubMed]Also see references 9c–e,g. (g) (N-2-pyridyl)aldimines: Suggs JW. J Am Chem Soc. 1979;101:489. (h) Jun CH, Lee H, Hong JB. J Org Chem. 1997;62:1200. (i) Jun CH, Lee DY, Lee H, Hong JB. Angew Chem Int Ed. 2000;39:3070. [PubMed] (j) Jun CH, Chung JW, Lee DY, Loupy A, Chatti S. Tetrahedron Lett. 2001;42:4803. (k) Willis MC, Sapmaz S. Chem Commun. 2001:2558. (l) Ya ez X, Claver C, Castillon S, Fernandez E. Tetrahedron Lett. 2003;44:1631.
6. Efficient intermolecular cobalt catalyzed hydroacylation is restricted to the use of vinyl silanes as coupling partners: (a) Lenges CP, Brookhart M. J Am Chem Soc. 1997;119:3165. (b) Lenges CP, White PS, Brookhart M. J Am Chem Soc. 1998;120:6965.
7. Intermolecular Ru-catalyzed hydroacylation generally requires exceptionally high reaction temperatures and provides mixtures of linear and branched coupling products: (a) Isnard P, Denise B, Sneeden RPA, Cognion JM, Durual P. J Organomet Chem. 1982;240:285. (b) Isnard P, Denise B, Sneeden RPA, Cognion JM, Durual P. J Organomet Chem. 1983;256:135. (c) Kondo T, Tsuji Y, Watanabe Y. Tetrahedron Lett. 1987;28:6229. (d) Kondo T, Akazome M, Tsuji Y, Watanabe Y. J Org Chem. 1990;55:1286. (e) Kondo T, Hiraishi N, Morisaki Y, Wada K, Watanabe Y, Mitsudo TA. Organometallics. 1998;17:2131.
8. For intramolecular rhodium catalyzed alkyne hydroacylation, see: (a) Fu GC, Tanaka K. J Am Chem Soc. 2001;123:11492. [PubMed] (b) Fu GC, Tanaka K. Angew Chem Int Ed. 2002;41:1607. [PubMed] (c) Fu GC, Tanaka K. J Am Chem Soc. 2002;124:10296. [PubMed] (d) Bendorf HD, Colella CM, Dixon EC, Marchetti M, Matukonis AN, Musselman JD, Tiley TA. Tetrahedron Lett. 2002;43:7031. (e) Fu GC, Tanaka K. J Am Chem Soc. 2003;125:8078. [PubMed] (f) Takeishi K, Sugishima K, Sasaki K, Tanaka K. Chem Eur J. 2004;10:5681. [PubMed] (g) Tanaka K, Sasaki K, Takeishi K, Hirano M. Eur J Org Chem. 2007:5675.
9. For chelation-assisted intermolecular alkyne hydroacylation, see: (a) Kokubo K, Matsumasa K, Miura M, Nomura M. J Org Chem. 1997;62:4564. (b) Jun CH, Lee H, Hong JB, Kwon BI. Angew Chem Int Ed. 2002;41:2146. [PubMed] (c) Willis MC, Randell-Sly HE, Woodward RL, Currie GS. Org Lett. 2005;7:2249. [PubMed] (d) Moxham GL, Randell-Sly HE, Brayshaw SK, Woodward RL, Weller AS, Willis MC. Angew Chem Int Ed. 2006;45:7618. [PubMed] (e) Willis MC, Randell-Sly HE, Woodward RL, McNally S, Currie GS. J Org Chem. 2006;71:5291. [PubMed] (f) Rueda XY, Castillon S. J Organomet Chem. 2007;692:1628. (g) Moxham GL, Randell-Sly HE, Brayshaw SK, Weller AS, Willis MC. Chem Eur J. 2008;14:8383. [PubMed]
10. There exists an example of Ni-catalyzed intermolecular alkyne hydroacylation that does not require chelation-assistance, however, incomplete regio- and E/Z-stereoselectivity is observed: Tsuda T, Kiyoi T, Saegusa T. J Org Chem. 1990;55:2554.
11. For Ru-catalyzed C-C bond forming transfer hydrogenation, see: (a) Shibahara F, Bower JF, Krische MJ. J Am Chem Soc. 2008;130:6338. [PubMed] (b) Shibahara F, Bower JF, Krische MJ. J Am Chem Soc. 2008;130:14120. [PubMed] (c) Ngai MY, Skucas E, Krische MJ. Org Lett. 2008;10:2705. [PubMed] (d) Patman RL, Williams VM, Bower JF, Krische MJ. Angew Chem Int Ed. 2008;47:5220. [PMC free article] [PubMed] (e) Patman RL, Chaulagain MR, Williams VM, Krische MJ. J Am Chem Soc. 2009;131:2066. [PubMed]
12. For reviews encompassing Ru-catalyzed C-C bond forming transfer hydrogenation, see: (a) Shibahara F, Krische MJ. Chem Lett. 2008;37:1102. [PMC free article] [PubMed] (b) Bower JF, Kim IS, Patman RL, Krische MJ. Angew Chem Int Ed. 2009;48:34. [PMC free article] [PubMed]
13. For recent reviews of conventional hydrogen auto-transfer processes, see: (a) Guillena G, Ramòn DJ, Yus M. Angew Chem, Int Ed. 2007;46:2358. [PubMed] (b) Hamid MHSA, Slatford PA, Williams JMJ. Adv Synth Catal. 2007;349:1555.
14. For selected examples of nickel catalyzed alkyne-carbonyl reductive coupling, see: (a) Oblinger E, Montgomery J. J Am Chem Soc. 1997;119:9065. (b) Tang XQ, Montgomery J. J Am Chem Soc. 1999;121:6098. (c) Tang XQ, Montgomery J. J Am Chem Soc. 2000;122:6950. (d) Huang WS, Chan J, Jamison TF. Org Lett. 2000;2:4221. [PubMed] (e) Miller KM, Huang WS, Jamison TF. J Am Chem Soc. 2003;125:3442. [PubMed] (f) Takai K, Sakamoto S, Isshiki T. Org Lett. 2003;5:653. [PubMed] (g) Mahandru GM, Liu G, Montgomery J. J Am Chem Soc. 2004;126:3698. [PubMed] (h) Knapp-Reed B, Mahandru GM, Montgomery J. J Am Chem Soc. 2005;127:13156. [PubMed]
15. For amine-unsaturate C-C coupling (hydroaminoalkylation), see: (a) Maspero F, Clerici MG. Synthesis. 1980:305. (b) Nugent WA, Ovenall DW, Homes SJ. Organometallics. 1983;2:161. (c) Herzon SB, Hartwig JF. J Am Chem Soc. 2007;129:6690. [PubMed] (d) Herzon SB, Hartwig JF. J Am Chem Soc. 2008;130:14940. [PubMed] (e) Kubiak R, Prochnow I, Doye S. Angew Chem Int Ed. 2009;48:1153. [PubMed] (f) Bexrud JA, Eisenberger P, Leitch DC, Payne PR, Schafer LL. J Am Chem Soc. 2009;131:2116. [PubMed]
16. Dobson A, Robinson SD, Uttley MF. J Chem Soc, Dalton Trans. 1975:370.
17. Alonso F, Osanto I, Yus M. Tetrahedron. 2006;63:93.
18. Still WC, Kahn M, Mitra A. J Org Chem. 1978;43:2923.