electrophilic alkynylation: synthesis of α

Oct 4, 2018 - Sequential Michael addition/electrophilic alkynylation: synthesis of α-alkynyl-β-substituted ketones and chromanones. Bruno V. M. Teod...
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Sequential Michael Addition/Electrophilic Alkynylation: Synthesis of α‑Alkynyl-β-Substituted Ketones and Chromanones Bruno V. M. Teodoro* and Luiz F. Silva, Jr.† Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil

J. Org. Chem. 2018.83:13604-13611. Downloaded from pubs.acs.org by UNIV OF LOUISIANA AT LAFAYETTE on 11/02/18. For personal use only.

S Supporting Information *

ABSTRACT: We describe the synthesis of α-alkynyl-β-substituted cyclic ketones and analogue chromanones via one-pot Michael addition/hypervalent iodine-based α-alkynylation. Cu(I)-catalyzed Michael addition using either alkyl-aluminum or Grignard reagents, followed by diastereoselective electrophilic alkynylation of the resulting enolate by 1-ethynyl-1λ3,2benziodoxol-3(1H)-one (EBX) resulted in the α-alkynyl-β-substituted cyclic ketones or chromanones within 34−89% yield (16 examples). The reaction was successfully upscaled to the 5 mmol scale, and further functionalization of a model alkynylated ketone was demonstrated. Scheme 1. Methods for the Preparation α-Alkynyl-βSubstituted Cyclic Ketones Bearing a Quaternary Center

T

he insertion of alkynyl groups into organic molecules produces versatile building blocks for chemical synthesis.1 The unique electronic character of alkynes results in excellent chemoselectivity and effective coordination to transition metals, which has been exploited in cyclization, disproportionation, homologation, and isomerization reactions.2,3 The stoichiometric activation of terminal alkynes with metal bases generates nucleophilic metal acetylides that can react with carbon-based electrophiles. However, the alkynylation of enolates depends on electrophilic acetylene synthons.4−7 Hypervalent iodine(III) reagents containing alkynyl ligands, such as ethynyl benziodoxolones (EBXs),8−10 were successfully used for the enantioselective alkynylation of β-keto esters, nucleophilic fluorocarbons,11 heterocycles,12−14 and other transformations that involve transition-metal catalysis.15−22 Using EBX reagents, our group developed methods for the electrophilic alkynylation of ketones23 and aldehydes,24 which led to α-alkynyl ketones and propargylic alcohols. The α-alkynyl-β-substituted cyclic ketone framework has been used for the total synthesis of four new sesquiterpenes of the drimane class25 and the left fragment of azadirachtin and meliacarpin-type limonoids.26,27 However, the direct synthesis of alkynylated cyclic ketones is scarcely described. Liu and coworkers reported the diastereoselective synthesis of such compounds from substituted pentadienones and potassium alkynyltrifluorborate using the interrupted Nazarov strategy (Scheme 1). Although this approach is convenient, it is limited to cyclopentanones and substituted alkynes.28 © 2018 American Chemical Society

In this work, we describe a one-pot method for the diastereoselective preparation of α-alkynyl-β-substituted cyclic ketones and analogue chromanones directly from α,βunsaturated carbonyl compounds. Michael 1,4-addition of alkylaluminum or Grignard reagents into cyclic enones results in β-substituted activated enolates that are trapped by TMSEBX, resulting in α-alkynyl-β-substituted cyclopentanones, cyclohexanones, and chromanones bearing quaternary centers. The potential of this methodology to prepare alkynylated building blocks is demonstrated by the chemical modification Received: August 31, 2018 Published: October 4, 2018 13604

DOI: 10.1021/acs.joc.8b02251 J. Org. Chem. 2018, 83, 13604−13611

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The Journal of Organic Chemistry Table 2. Substrates Scopea

of 2-ethynyl-3-methyl-2-phenylcyclohexan-1-one via triazole functionalization, Sonogashira coupling, and chemoselective carbonyl reduction. Michael addition using copper complexes as catalysts is efficient and broad in scope.29−33 The reaction of 2phenylcyclohex-2-one (1a) and trimethylaluminum in the presence of catalytic CuBr·SMe2 and at 0 °C produced a βmethyl enolate intermediate, which was successfully trapped by the addition of TMS-EBX (2a)/TBAF at −72 °C. The product 3aa was obtained in 74% yield, in high diastereoisomeric ratio (entry 1, Table 1). The conjugate addition does not occur at −72 °C (entry 2), and reducing the excess of AlMe3 from 2.0 to 1.5 equiv dramatically lowers the reaction yield (entry 3). Table 1. Optimization of Reaction Conditionsa

entry 1 2 3 4 5 6 7 8 9 10

copper source CuBr.SMe2 CuBr.SMe2 CuBr.SMe2 (Me)2CuLi· LiCNd,e (n-Bu)2CuLi· LiCNd,e CuI CuCl Cu(OTf)2 CuCN CuCNf

AlMe3 (equiv)

temp (°C)

yield (%)b

2.0 2.0 1.5 −

0 −72 0 −72

74 0 22 0

−

−72

0

0 0 0 0 0

10 31 64 84 2

2.0 2.0 2.0 2.0 2.0

drc 99.7:0.3 − 99.5:0.5 − − 100:0 98.2:1.8 99.6:0.4 99.6:0.4 100:0

a

Reaction conditions: 1 (0.3 mmol, 1.0 equiv), Al(R2)3 (0.6 mmol, 2.0 equiv), and CuCN (0.03 mmol, 10 mol %) in THF (3.0 mL) at 0 °C until consumption of all starting material, then 2a (0.39 mmol, 1.3 equiv) and TBAF (0.039 mmol, 1.3 equiv) at −72 °C.

a

Reaction conditions: 2a (0.1 mmol, 1.0 equiv), AlMe3 (X equiv), and copper (10 mol %) in THF (1.0 mL) for 1 h, then 2a (0.13 mmol, 1.3 equiv) and TBAF (0.13 mmol, 1.3 equiv) for 2h. bGC yield using a dodecane which internal standard. cDetermined by GC d1.0 equiv. eMichael addition step was carried out in 5 h. f10 mol % of PPh3.

converted into the alkynylated ketones 3ca−3ka in 34−80% yield and in high diastereoselectivity. Product 3da (p-OMe) was obtained in lower yield compared to the p-Me analogue, probably due to the decomposition of the enolate intermediate, as evidenced by the darkening of the reaction after addition of TMS-EBX. This protocol allows the conversion of 2-methylcyclohexen1-one (1l) into product 3la in 36% yield, which is the first example of alkynylation of an α-alkyl enolate. Our previous attempts to alkynylate 4-phenylcyclohexanone using TMS-EBX and LDA failed.23 The attempt to carry out the alkynylation of 2-methylcyclohexanone using the protocol developed by our group23 did not yield the desired alkynylated product, and only starting material was recovered. Therefore, one can infer that the presence of Al(III) and Cu(I) in the reaction media promotes the alkynylation of enolate. Ethyl 2-coumarincarboxylate (1m) was converted into the 2-chromanone 3ma in 88% yield, proving that the transformation can be performed using either AlEt3 or AlMe3. Thus, products 3ab and 3mb were obtained in 89% and 80% yield, respectively. Attempts to alkynylate [(phenyl)ethynyl]-1,2-benziodoxol-3(1H)-one (2b,

Although Michael reactions using methyl and n-butyl Gilman cuprates have been used for the preparation of αaryl-β-substituted cyclic ketones,34 attempts to replace CuBr· SMe2 by (alkyl)2CuLi·LiCN were unsuccessful (entries 4 and 5, Table 1). In fact, the choice of copper salt has a major effect on reaction yields (entries 6−9). Optimized conditions (84% yield, dr >99:1) were obtained using copper(I) cyanide (entry 9). The use of CuCN/PPh3 led to traces of 3a (entry 10). Although we did not attempt to perform an asymmetric 1,4addition step, the procedure can be modified by replacing CuCN by chiral copper complexes based on phosphoramidite35−38 and SimplePhos39,40 ligands. The scope of this reaction was investigated using 13 αsubstituted enones and one coumarin (Table 2). The transformation is suitable for both 2-phenyl-2-cyclohexen-1one (1a) and 2-phenyl-2-cyclopenten-1-one (1b), although the functionalization of the former is more efficient. 2-Phenylcyclohexen-2-ones bearing p-Me, p-OMe, o-Me, p-Ac, m-Ac, pF, p-Cl, p,o-Cl2, and o-NO2 substituents were successfully 13605

DOI: 10.1021/acs.joc.8b02251 J. Org. Chem. 2018, 83, 13604−13611

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The Journal of Organic Chemistry

the alkynylation of an enolate bearing an alkyl group in the αposition was reported. The scalability of the method was illustrated by the 5 mmol scale of synthesis of compound 3aa. We could demonstrate that these kinds of structures can be useful precursors to obtain more complex frameworks through synthetic modifications such as 1,3-dipolar cycloaddition, borohydride reduction, and Pd-mediated cross coupling. The present method represents the first example in which an enolate was trapped with an alkynyl hypervalent iodine reagent to obtain α-alkynyl-β-substituted cyclic ketones or chromanone scaffolds.

Ph-EBX) were unsuccessful, and a complex mixture of products was obtained. The transformation was also carried out using vinyl magnesium bromide instead of aluminum complexes. Model substrate 1a was converted into the alkynylated product 3ac in 49% yield and dr >99:1. The alkynylation of 2-phenylcyclohex2-one (1a) was scaled up to the 5 mmol scale (roughly 1 g), without changing the reaction conditions; product 3aa was obtained in 83% yield (Scheme 2). Scheme 2. (a) Reaction with Substrate 1a and Vinylmagnesium Bromide and (b) Scale-up of Synthesis of 3aa

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EXPERIMENTAL SECTION

General Considerations. All solvents used for the reactions were dried and purified by standard methods. All commercially available reagents were used without further purification unless otherwise noted. TLC analyses were performed using silica gel 60-F254 plates, with detection by UV-absorption (254 nm) and by using panisaldehyde or sulfuric vaniline solutions. Flash column chromatography was performed using silica gel 200−400 mesh. The glassware which was used in all reactions was dried for several hours at 150 °C in an oven. Infrared spectra were registered on a PerkinElmer 1750FT spectrometer. High-resolution mass spectra (HRMS) (ESI-TOF) were obtained using a Bruker MicroTOF-QII mass spectrometer equipped with an electrospray ionization source operating in positive mode. All NMR analyses were recorded on a Varian (300 MHz for 1H and 75 MHz for 13C) or a Bruker (500 MHz for 1H and 125 MHz for 13 C) spectrometer using CDCl3. The chemical shifts are reported in ppm using TMS or residual solvent (δ 7.26 ppm for 1H and δ 77.0 ppm for 13C) as an internal standard. Coupling constants values J are given in Hz. Multiplicities are reported as follows: singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint) combinations or multiplet or unresolved signal (m). Enone 1l was commercially available and used without further purification. Enones 1a−b,41 1c,42 1d,41 1e,43 1f,41 and 1h−i444 are known compounds and were prepared by the procedure reported in the literature.41 Enone 1k45 is known compound and was prepared by the procedure reported in the literature.46 Coumarin 1m47 is a known compound and was prepared by the procedure reported in the literature.38 Enones 1g and 1j are new compounds and were prepared by the procedure reported in the literature.41 The hypervalent iodine reagents 2a−b48 are known compounds and were prepared by the procedure reported in the literature.48 Preparation of Substrates 1g and 1j. Following a reported procedure,41 to a solution of 2-iodocyclohex-2-en-1-one (0.333 g, 1.5 mmol, 1 equiv) and Na2CO3 (0.318 g, 3 mmol, 2 equiv) in DME:H2O (9 mL, 1:1) were added Pd/C (0.079 g, 5 mol %) and aryl

To exemplify the synthetic versatility of α-alkynyl-β-alkyl cyclic ketones, we submitted compound 3aa to transformations used to increase molecular complexity. First, we performed a Cu-catalyzed 1,3-dipolar cycloaddition using benzylazide to furnish the triazole 4a in 51% yield. The Sonogashira crosscoupling reaction was performed in the presence of iodobenzene, and the desired product 4b was obtained in 85% yield. Finally, a reduction of the carbonyl moiety using NaBH4 provided the product 4c in 95% yield (Scheme 3). In summary, we developed a method for the convenient conversion of cyclic enones or coumarin into α-alkynyl-βsubstituted cyclic ketones or chromanones using a one-pot method based on a sequential Cu(I)-catalyzed Michael addition/electrophilic alkynylation. Under the optimized reaction conditions, the desired compounds were isolated in up to 89% yield. Aluminum complexes and Grignard reagents were compatible with the present method. The first example of Scheme 3. Modification of Product 3aa

13606

DOI: 10.1021/acs.joc.8b02251 J. Org. Chem. 2018, 83, 13604−13611

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The Journal of Organic Chemistry boronic acid (3.0 mmol, 2 equiv). The suspension was kept vigorously stirring at rt for 12 h. After this time, the resulting solution was filtered in a Celite plug and washed with ethyl acetate (20 mL). The filtrate was washed with water (2 × 20 mL), dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by column chromatography (silica flash) to afford the 2aryl enone. 2-(3-Acetylphenyl)cyclohex-2-enone (1g). The title compound was prepared from (3-acetylphenyl)boronic acid (0.492 g, 3.0 mmol, 2.0 equiv). The crude material was purified by column chromatography (silica flash, 30% of ethyl acetate in hexanes), affording the title compound 1g. 0.214 g (1.00 mmol), 67% yield, colorless oil, Rf = 0.36 (30% of ethyl acetate in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.96−7.83 (m, 2H), 7.59−7.40 (m, 2H), 7.11 (t, J = 4.3 Hz, 1H), 2.67−2.51 (m, 7H), 2.14 (q, J = 6.0 Hz, 2H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 198.1, 197.7, 148.9, 139.6, 136.9, 136.9, 133.4, 128.5, 128.2, 127.5, 38.9, 26.7, 26.6, 22.8 ppm. IR (neat): 2925, 1680, 1427, 1358, 1289, 1249, 1202, 1154, 1124 cm−1. HRMS (ESI-TOF): m/z calcd for C14H15O2 (M + H)+ 215.1067, found 215.1061. 2-(3,4-Dichlorophenyl)cyclohex-2-enone (1j). The title compound was prepared from (3,4-dichlorophenyl)boronic acid (0.572 g, 3.0 mmol, 2.0 equiv). The crude material was purified by column chromatography (silica flash, 20% of ethyl acetate in hexanes), affording the title compound 1j. 0.203 g (0.84 mmol), 56% yield), yellow oil. Rf = 0.15 (20% of ethyl acetate in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.43−7.37 (m, 2H), 7.16 (dd, J = 8.3, 2.1 Hz, 1H), 7.06 (t, J = 4.3 Hz, 1H), 2.65−2.50 (m, 4H), 2.11 (q, J = 6.0 Hz, 2H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 197.3, 148.9, 138.4, 136.4, 132.0, 131.7, 130.5, 129.9, 128.0, 38.8, 26.6, 22.7 ppm. IR (neat): 2950, 2928, 2889, 2869, 1679, 1471, 1426, 1343, 1029, 1156, 1133, 1030 cm−1. HRMS (ESI-TOF): m/z calcd for C12H11Cl2O (M + H)+ 241.0182, found 241.0188. General Procedure from Alkynylation by Enolate Trapping. To a Schlenk flask equipped with a magnetic stir bar was added CuCN (3 mg, 0.03 mmol, 10 mol %). The flask was evacuated and filled with N2 for 3 times, and THF (0.5 mL) was added by syringe. The solution was then cooled to 0 °C, and AlR3 (0.60 mmol, 2.0 equiv) was added by syringe. The solution was stirred at 0 °C for 5 min, and the enone (0.30 mmol dissolved in 2.5 mL of THF, 1.0 equiv) was added by syringe. The reaction was stirred at 0 °C for the indicated time. After the conjugated addition was finished (monitored by TLC), 2a (0.134 g, 0.39 mmol, 1.3 equiv) was added, followed by addition of TBAF (1 M in THF, 0.39 mL, 0.39 mmol, 1.3 equiv). The reaction was stirred at −72 °C for the indicated time. After this time, the reaction was quenched with a saturated solution of NH4Cl (15 mL), and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (30 mL), dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by column chromatography (silica flash). (2S*,3S*)-2-Ethynyl-3-methyl-2-phenylcyclohexan-1-one (3aa). Following the general procedure, the title compound was prepared from 1a (0.052 g, 0.30 mmol, 1.0 equiv) and AlMe3 (2 M in toluene, 0.30 mL, 0.60 mmol, 2.0 equiv). The conjugated addition step was completed in 1 h, and the alkynylation step was completed in 2 h. 0.051 g (0.24 mmol), 80% yield, dr >99:1, colorless oil, purified by column chromatography (silica flash, 10% of ethyl acetate in hexanes), Rf = 0.33 (10% of ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3): δ 7.59−7.56 (m, 2H), 7.35−7.31 (m, 2H), 7.28−7.24 (m, 1H), 2.98 (ddd, J = 14.8, 9.6, 6.4 Hz, 1H), 2.61 (s, 1H), 2.57−2.43 (m, 2H), 2.37 (ddt, J = 13.8, 9.0, 4.4 Hz), 2.10−2.00 (m, 1H), 1.98−1.89 (m, 1H), 1.80 (dtd, J = 11.2, 6.7, 4.8 Hz, 1H), 0.97 (d, J = 7.1 Hz, 2H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 206.3, 137.2, 128.9, 127.8, 127.2, 85.8, 75.0, 59.0, 43.7, 38.4, 28.9, 22.6, 16.3 ppm. IR (neat): 3291, 2981, 2933, 1759, 1489, 1278, 1237, 1142 cm−1. HRMS (ESI-TOF): m/z calcd for C15H16O (M + H)+ 213.1274, found 213.1273. The relative stereochemistry of this compound was assigned by analogy with compound 3da. (2S*,3S*)-2-Ethynyl-3-methyl-2-phenylcyclopentan-1-one (3ba). Following the general procedure, the title compound was prepared

from 1b (0.060, 0.30 mmol, 1.0 equiv) and AlMe3 (2 M in toluene, 0.30 mL, 0.60 mmol, 2.0 equiv). The conjugated addition was completed in 1.5 h, and the alkynylation step was completed in 3 h. 0.031 g (0.15 mmol), 51% yield, dr >99:1, colorless oil, purified by column chromatography (silica flash, 20% of ethyl acetate in hexanes), Rf = 0.31 (20% of ethyl acetate in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.34−7.30 (m, 2H), 7.29−7.23 (m, 3H), 2.72−2.65 (m, 1H), 2.65−2.59 (m, 2H), 2.46 (s, 1H), 2.22 (dddd, J = 12.9, 7.8, 6.2, 4.9 Hz, 1H), 1.70−1.61 (m, 1H), 0.79 (d, J = 7.0 Hz, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 215.0, 136.2, 128.1, 128.0, 128.0, 127.4, 84.5, 72.6, 57.9, 45.5, 37.7, 26.9, 15.6 ppm. IR (neat): 3289, 2962, 2928, 2875, 1749, 1494, 1460, 1448, 1405, 1178, 1147, 1132, 1103 cm−1. HRMS (ESI-TOF): m/z calcd for C14H15O (M + H)+ 199.1117, found 199.1111. The relative stereochemistry of this compound was assigned by analogy with compound 3da. (2S*,3S*)-2-Ethynyl-3-methyl-2-(p-tolyl)cyclohexan-1-one (3ca). Following the general procedure, the title compound was prepared from 1c (0.056 g, 0.30 mmol, 1.0 equiv) and AlMe3 (2 M in toluene, 0.30 mL, 0.60 mmol, 2.0 equiv). The conjugated addition was completed in 1 h, and the alkynylation step was completed in 4 h. 0.053 g (0.23 mmol), 79% yield, dr >99:1, colorless oil, purified by column chromatography (silica flash, 10% of ethyl acetate in hexanes), Rf = 0.39 (10% of ethyl acetate in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.45 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 2.94 (ddd, J = 15.0, 9.1, 6.2 Hz, 1H), 2.60 (s, 1H), 2.56−2.36 (m, 3H), 2.33 (s, 3H), 2.13−1.74 (m, 4H), 0.99 (d, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 206.6, 136.9, 134.2, 128.8, 128.6, 86.0, 74.8, 58.7, 43.7, 38.3, 28.9, 22.8, 20.9, 16.3 ppm. IR (neat): 3291, 2928, 2873, 1719, 1607, 1511, 1458, 1413, 1379, 1281, 1242, 1193, 1165, 1119, 1090, 1040 cm−1. HRMS (ESI-TOF): m/z calcd for C16H18NaO (M + Na)+ 249.1250, found 249.1243. The relative stereochemistry of this compound was assigned by analogy with compound 3da. (2S*,3S*)-2-Ethynyl-2-(4-methoxyphenyl)-3-methylcyclohexan1-one (3da). Following the general procedure, the title compound was prepared from 1e (0.061, 0.30 mmol, 1.0 equiv) and AlMe3 (2 M in toluene, 0.30 mL, 0.60 mmol, 2.0 equiv). The conjugated addition was completed in 1 h, and the alkynylation step was completed in 4 h. 0.032 g (0.13 mmol), 44% yield, dr >99:1, colorless oil, purified by column chromatography (silica flash, 10% of ethyl acetate in hexanes), Rf = 0.22 (10% of ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3): 7.52−7.45 (m, 2H), 6.89−6.84 (m, 2H), 3.80 (s, 3H), 2.95 (ddd, J = 14.6, 9.5, 6.3 Hz, 1H), 2.60 (s, 1H), 2.54−2.41 (m, 2H), 2.36 (ddt, J = 13.7, 9.0, 4.4 Hz, 1H), 2.10−1.98 (m, 1H), 1.97−1.87 (m, 1H), 1.79 (dtd, J = 11.3, 6.8, 4.7 Hz, 1H), 0.97 (d, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ 206.6, 158.5, 130.0, 129.3, 113.2, 86.1, 74.8, 58.3, 55.2, 43.8, 38.3, 29.0, 22.8, 16.2 ppm. IR (neat): 3284, 2955, 2931, 2873, 1719, 1673, 1609, 1580, 1511, 1462, 1418, 1296, 1253, 1209, 1185, 1121, 1089, 1035 cm−1. HRMS (ESI-TOF): m/z calcd for C16H19O2 (M + H)+ 243.1380, found 243.1372. The relative stereochemistry was assigned based in NOESY 2D spectra. We observed a correlation between Ha of methyl group (0.97 ppm) and Hb of phenyl group (7.52−7.45 ppm).

(2S*,3S*)-2-Ethynyl-2-(2-methoxyphenyl)-3-methylcyclohexan1-one (3ea). Following the general procedure, the title compound was prepared from 1e (0.061 g, 0.30 mmol, 1.0 equiv) and AlMe3 (2 M in toluene, 0.30 mL, 0.60 mmol, 2.0 equiv). The conjugated addition was completed in 1 h, and the alkynylation step was completed in 5 h. 0.038 g (0.13 mmol), 53% yield, dr >99:1, colorless oil, purified by column chromatography (silica flash, 10% of ethyl acetate in hexanes), Rf = 0.41 (20% of ethyl acetate in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.58 (d, J = 7.6 Hz, 1H), 7.32−7.23 (m, 1H), 6.98 (td, J = 7.6, 1.2 Hz, 1H), 6.91 (dd, J = 8.2, 1.0 Hz, 1H), 3.73 (s, 3H), 2.99−2.79 (m, 1H), 2.72−2.62 (m, 1H), 2.52−2.40 (m, 13607

DOI: 10.1021/acs.joc.8b02251 J. Org. Chem. 2018, 83, 13604−13611

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The Journal of Organic Chemistry

column chromatography (silica flash, 10% of ethyl acetate in hexanes), Rf = 0.28 (10% of ethyl acetate in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.54−7.50 (m, 2H), 7.33−7.28 (m, 2H), 3.06 (ddd, J = 14.6, 10.5, 7.0 Hz, 1H), 2.64 (s, 1H), 2.54−2.39 (m, 3H), 2.10−1.91 (m, 2H), 1.79−1.69 (m, 1H), 0.90 (d, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 205.9, 135.9, 133.1, 130.4, 127.9, 75.6, 58.2, 43.8, 38.4, 28.9, 22.2, 16.0 ppm. IR (neat): 3297, 2948, 1723, 1492, 1459, 1141, 1120, 1096, 1015 cm−1. HRMS (ESITOF): m/z calcd for C15H16ClO (M + H)+ 247.0884, found 247.0876. The relative stereochemistry of this compound was assigned by analogy with compound 3da. (2S*,3S*)-2-(3,4-Dichlorophenyl)-2-ethynyl-3-methylcyclohexan-1-one (3ja). Following the general procedure, the title compound was prepared from 1j (0.084, 0.30 mmol, 1.0 equiv) and AlMe3 (2 M in toluene, 0.30 mL, 0.60 mmol, 2.0 equiv). The conjugated addition was completed in 1.5 h, and the alkynylation step was completed in 6 h. 0.058 g (0.23 mmol), 78% yield, dr >99:1, colorless oil, purified by column chromatography (silica flash, 20% of ethyl acetate in hexanes), Rf = 0.42 (20% of ethyl acetate in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.74−7.69 (m, 1H), 7.44−7.37 (m, 2H), 3.11 (ddd, J = 14.6, 11.0, 7.4 Hz, 1H), 2.69 (s, 1H), 2.63−2.38 (m, 3H), 2.13−1.91 (m, 2H), 1.82−1.66 (m, 1H), 0.88 (d, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 205.3, 137.8, 131.8, 131.4, 131.1, 129.4, 128.6, 84.9, 76.3, 57.9, 43.9, 38.5, 28.9, 22.0, 15.8 ppm. IR (neat): 3299, 2950, 2930, 2875, 1723, 1470, 1420, 1382, 1306, 1260, 1232, 1201, 1138, 1119, 1090, 1061, 1030 cm−1. HRMS (ESITOF): m/z calcd for C15H15Cl2O (M + H)+ 281.0494, found 281.0486. The relative stereochemistry of this compound was assigned by analogy with compound 3da. (2S*,3S*)-2-Ethynyl-3-methyl-2-(2-nitrophenyl)cyclohexan-1one (3ka). Following the general procedure, the title compound was prepared from 1k (0.065 g, 0.30 mmol, 1.0 equiv) and AlMe3 (2 M in toluene, 0.30 mL, 0.60 mmol, 2.0 equiv). The conjugated addition was completed in 6 h, and the alkynylation step was completed in 10 h. 0.026 g (0.10 mmol), 34% yield, dr >99:1, pale yellow solid (mp 116−118 °C), purified by column chromatography (silica flash, 20% of ethyl acetate in hexanes), Rf = 0.36 (20% of ethyl acetate in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.96 (dd, J = 8.1, 1.4 Hz, 1H), 7.67−7.58 (m, 1H), 7.54 (dd, J = 8.0, 1.5 Hz, 1H), 7.45 (ddd, J = 8.2, 7.2, 1.6 Hz, 1H), 3.38 (ddd, J = 12.6, 10.4, 8.2 Hz, 1H), 3.29− 3.16 (m, 1H), 2.91−2.74 (m, 1H), 2.65 (s, 1H), 2.39−2.29 (m, 1H), 2.13−1.99 (m, 2H), 1.84−1.56 (m, 2H), 0.84 (d, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 205.1, 149.8, 132.7, 129.3, 128.3, 125.6, 85.1, 74.9, 56.7, 42.9, 38.4, 28.4, 23.4, 14.0 ppm. IR (neat): 3287, 2949, 1721, 1529, 1456, 1441, 1356, 1300, 1122 cm−1. HRMS (ESI-TOF): m/z calcd for C15H16NO3 (M + H)+ 258.1125, found 258.1117. The relative stereochemistry of this compound was assigned by analogy with compound 3da. (2S*,3S*)-2-Ethynyl-2,3-dimethylcyclohexan-1-one (3la). Following the general procedure, the title compound was prepared from 1l (0,033 g, 0.30 mmol, 1.0 equiv) and AlMe3 (2 M in toluene, 0.30 mL, 0.60 mmol, 2.0 equiv). The conjugated addition was completed in 1 h, and the alkynylation step was completed in 20 h. 0.016 g (0.11 mmol), 36% yield, dr >99:1, colorless liquid, purified by column chromatography (silica flash, 10% of diethyl ether in pentane), Rf = 0.59 (10% of diethyl ether in pentane). 1H NMR (500 MHz, CDCl3): δ 2.81 (ddd, J = 13.7, 9.6, 6.2 Hz, 1H), 2.37 (s, 1H), 2.33 (dt, J = 13.7, 5.9 Hz, 1H), 2.29−2.20 (m, 2H), 1.96−1.79 (m, 2H), 1.58−1.50 (m, 1H), 1.30 (s, 3H), 0.95 (d, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ 209.1, 86.8, 72.3, 49.8, 42.6, 37.7, 28.9, 23.5, 19.7, 14.8 ppm. IR (neat): 2959, 2920, 2850, 1721, 1463, 1378, 1261, 1094, 1018, 801 cm−1. HRMS (ESI-TOF): m/z calcd for C10H15O (M + H)+ 151.1118, found 151.1116. The relative stereochemistry was assigned based in NOESY 2D spectra. We observed a correlation between Ha of methyl group in α position (1.30 ppm) and Hb of methyl group in β position (0.95 ppm).

2H), 2.15−1.89 (m, 3H), 1.74−1.55 (m, 2H), 1.00 (d, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 207.3, 156.7, 129.9, 128.8, 127.6, 120.8, 112.5, 86.1, 72.7, 56.3, 55.5, 42.4, 36.9, 27.38, 22.1, 16.7 ppm. IR (neat): 3281, 2938, 2874, 1722, 1599, 1584, 1491, 1461, 1436, 1377, 1287, 1249, 1131, 1111, 1076 cm−1. HRMS (ESITOF): m/z calcd for C16H19O2 (M + H)+ 243.1380, found 243.1389. The relative stereochemistry of this compound was assigned by analogy with compound 3da. (2S*,3S*)-2-(4-Acetylphenyl)-2-ethynyl-3-methylcyclohexan-1one (3fa). Following the general procedure, the title compound was prepared from 1f (0.064, 0.30 mmol, 1.0 equiv) and AlMe3 (2 M in toluene, 0.30 mL, 0.60 mmol, 2.0 equiv). The conjugated addition was completed in 3.5 h, and the alkynylation step was completed in 20 h. 0.037 g (0.15 mmol), 49% yield, dr >99:1, colorless oil, purified by column chromatography (silica flash, 20% of ethyl acetate in hexanes), Rf = 0.28 (20% of ethyl acetate in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.95−7.90 (m, 2H), 7.71−7.67 (m, 2H), 3.09 (ddd, J = 14.7, 10.6, 7.0 Hz, 1H), 2.67 (s, 1H), 2.60 (s, 3H), 2.56− 2.42 (m, 3H), 2.10−1.95 (m, 2H), 1.82−1.72 (m, 1H), 0.91 (d, J = 7.3 Hz, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 205.7, 197.8, 142.8, 135.8, 129.3, 127.7, 85.1, 75.9, 58.7, 43.7, 38.5, 28.8, 26.6, 22.1, 16.0 ppm. IR (neat): 3266, 2927, 2875, 2850, 1722, 1683, 1604, 1459, 1425, 1407, 1359, 1271 cm−1. HRMS (ESI-TOF): m/z calcd for C17H19O2 (M + H)+ 255.1380, found 255.1377. The relative stereochemistry of this compound was assigned by analogy with compound 3da. (2S*,3S*)-2-(3-Acetylphenyl)-2-ethynyl-3-methylcyclohexan-1one (3ga). Following the general procedure, the title compound was prepared from 1g (0.064, 0.30 mmol, 1.0 equiv) and AlMe3 (2 M in toluene, 0.30 mL, 0.60 mmol, 2.0 equiv). The conjugated addition was completed in 2 h, and the alkynylation step was completed in 6 h. 0.056 g (0.20 mmol), 67% yield, dr >99:1, colorless oil, purified by column chromatography (silica flash, 20% of ethyl acetate in hexanes), Rf = 0.27 (20% of ethyl acetate in hexanes). 1H NMR (300 MHz, CDCl3): δ 8.21 (t, J = 1.7 Hz, 1H), 7.91−7.84 (m, 1H), 7.78 (ddd, J = 7.9, 1.9, 1.1 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 3.11 (ddd, J = 14.6, 10.7, 7.0 Hz, 1H), 2.69 (s, 1H), 2.61−2.43 (m, 6H), 1.94−2.15 (m, 2H), 1.73−1.83 (m, 1H), 0.91 (d, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 205.9, 198.0, 138.0, 136.7, 133.9, 128.8, 127.9, 127.2, 85.3, 75.9, 58.5, 43.7, 38.5, 28.9, 26.6, 22.1, 15.9 ppm. IR (neat): 3264, 2952, 2929, 1721, 1684, 1598, 1581, 1458, 1428, 1358, 1272, 1228, 1188, 1121 cm−1. HRMS (ESI-TOF): m/z calcd for C17H18NaO2 (M + Na)+ 277.1199, found 277.1197. The relative stereochemistry of this compound was assigned by analogy with compound 3da. (2S*,3S*)-2-Ethynyl-2-(4-fluorophenyl)-3-methylcyclohexan-1one (3ha). Following the general procedure, the title compound was prepared from 1h (0.057, 0.30 mmol, 1.0 equiv) and AlMe3 (2 M in toluene, 0.30 mL, 0.60 mmol, 2.0 equiv). The conjugated addition was completed in 1 h, and the alkynylation step was completed in 6 h. 0.051 g (0.22 mmol), 74% yield, dr >99:1, colorless oil, purified by column chromatography (silica flash, 20% of ethyl acetate in hexanes), Rf = 0.31 (20% of ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3): δ 7.58−7.53 (m, 2H), 7.05−6.99 (m, 2H), 3.06 (ddd, J = 14.6, 10.7, 6.7 Hz, 1H), 2.64 (s, 1H), 2.53−2.41 (m, 3H), 2.09−1.91 (m, 2H), 1.79−1.71 (m, 1H), 0.91 (d, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ 206.2, 161.8 (d, 1JCF = 245 Hz), 133.1 (d, 4JCF = 2.5 Hz), 130.7 (d, 3JCF = 7.5 Hz), 114.6 (d, 2 JCF = 21.2 Hz), 85.7, 77.3, 75.5, 58.2, 43.9, 38.4, 28.9, 22.3, 16.0 ppm. IR (neat): 3302, 2955, 2929, 2874, 1723, 1606, 1509, 1459, 1259, 1231, 1182, 1164, 1141, 1120 cm−1. HRMS (ESI-TOF): m/z calcd for C15H16FO (M + H)+ 231.1180, found 231.1182. The relative stereochemistry of this compound was assigned by analogy with compound 3da. (2S*,3S*)-2-Ethynyl-2-(4-chlorophenyl)-3-methylcyclohexan-1one (3ia). Following the general procedure, the title compound was prepared from 1i (0.074, 0.30 mmol, 1.0 equiv) and AlMe3 (2 M in toluene, 0.30 mL, 0.60 mmol, 2.0 equiv). The conjugated addition was completed in 1.5 h, and the alkynylation step was completed in 5 h. 0.060 g (0.24 mmol), 81% yield, dr >99:1, colorless oil, purified by 13608

DOI: 10.1021/acs.joc.8b02251 J. Org. Chem. 2018, 83, 13604−13611

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The Journal of Organic Chemistry

C{1H} NMR (75 MHz, CDCl3): δ 205.9, 137.4, 137.2, 128.8, 128.1, 127.3, 116.8, 85.1, 75.3, 58.3, 51.9, 38.3, 27.1, 23.8 ppm. IR (neat): 2945, 1720, 1493, 1447, 1422, 1315, 1260, 1229, 1132, 1104 cm−1. HRMS (ESI-TOF): m/z calcd for C16H17O (M + H)+ 247.1093, found 247.1083. The relative stereochemistry of this compound was assigned by analogy with compound 3da. (2R*,3S*)-2-(1-Benzyl-1H-1,2,3-triazol-5-yl)-3-methyl-2-phenylcyclohexanone (4a). To a solution of 3aa (0.020 g, 0.094 mmol, 1.0 equiv) and N3Bn (0.133 g, 0.10 mmol, 1.1 equiv) in CH2Cl2:H2O (1 mL, 1:1) were added CuSO4 (0.001 g, 0.005 mmol, 5 mol %) and NaAsc (0.003 g, 0.014 mmol, 15 mol %). The resulting solution was stirred overnight at rt in a N2 atmosphere. The reaction mixture was diluted with CH2Cl2 (10 mL), washed with H2O (10 mL), dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by column chromatography (silica flash, 30% of ethyl acetate in hexanes) affording the title compound 4a. 0.016 g (0.048 mmol), 51% yield, yellow solid (mp 117−118 °C), Rf = 0.28 (30% of ethyl acetate in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.36−7.15 (m, 10H), 7.02 (s, 1H), 5.47 (d, J = 1.8 Hz, 2H), 3.36−3.22 (m, 1H), 2.60−2.37 (m, 2H), 2.09−1.74 (m, 4H), 0.96 (d, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 211.0, 150.7, 140.3, 134.7, 129.2, 129.0, 128.6, 127.9, 127.8, 126.8, 123.7, 62.3, 54.1, 39.4, 39.1, 28.2, 22.6, 18.0 ppm. IR (KBr): 2954, 2919, 2850, 1713, 1497, 1457, 1379, 1359, 1334, 1305, 1125, 1050 cm−1. HRMS (ESI-TOF): m/z calcd for C22H24N3O (M + H)+ 346.1914, found 346.1907. (2R*,3S*)-3-Methyl-2-phenyl-2-(phenylethynyl)cyclohexan-1one (4b). To a solution of 3aa (0.020 g, 0.094 mmol, 1.0 equiv), PhI (14 μL, 0.12 mmol, 1.3 equiv), and NEt4 (54 μL, 0.38 mmol, 4.0 equiv) in DMF (2 mL) were added Pd(PPh3)2Cl2 (0.002 g, 0.005 mmol, 5 mol %) and CuI (0.002 g, 0.01 mmol, 10 mol %). The resulting solution was stirred for 1 h at rt in a N2 atmosphere. The reaction mixture was diluted with diethyl ether (10 mL), washed with H2O (3 × 10 mL), dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by column chromatography (silica flash, 10% of ethyl acetate in hexanes) affording the title compound 4b. 0.023 g (0.080 mmol), 85% yield, colorless oil, Rf = 0.33 (10% of ethyl acetate in hexanes). 1 H NMR (300 MHz, CDCl3): δ 7.66−7.60 (m, 2H), 7.49−7.43 (m, 2H), 7.39−7.23 (m, 6H), 3.12 (ddd, J = 14.7, 10.8, 6.9 Hz, 1H), 2.67−2.42 (m, 3H), 2.18−1.89 (m, 2H), 1.87−1.72 (m, 1H), 0.95 (d, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 206.4, 138.0, 131.6, 129.1, 128.3, 128.2, 127.7, 127.1, 123.1, 91.5, 87.1, 59.4, 44.1, 38.8, 29.2, 22.2, 16.3 ppm. IR (KBr): 2927, 2873, 1721, 1598, 1491, 1445, 1419, 1305, 1229, 1201, 1177 cm−1. HRMS (ESI-TOF): m/z calcd for C21H21O (M + H)+ 289.1587, found 289.1576. (1R*,2S*,3S*)-2-Ethynyl-3-methyl-2-phenylcyclohexan-1-ol (4c). To a solution of 3a (0.020 g, 0.094 mmol, 1.0 equiv) in methanol (2 mL) was added NaBH4 (0.005 g, 0.14 mmol, 1.5 equiv) at 0 °C. The resulting solution was stirred for 2 h at 0 °C. After this time, the reaction was quenched with NH4Cl (10 mL) and washed with ethyl acetate (3 × 10 mL). The organic fractions were combined, washed with brine (30 mL), dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by column chromatography (silica flash, 30% of ethyl acetate in hexanes) affording the title compound 4c. 0.019 g (0.089 mmol), 95% yield, colorless oil, Rf = 0.44 (30% of ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3): δ 7.76−7.73 (m, 2H, major diast.), 7.55 (dd, J = 8.4, 1.1 Hz, 0.2H, minor diast.), 7.38−7.32 (m, 2.3H), 7.30− 7.25 (m, 1.2H), 4.35 (d, J = 10.0 Hz, 0.1H, minor diast.), 4.10 (dd, J = 10.9, 3.7 Hz, 1H, major diast.), 2.44 (s, 0.1H. minor diast.), 2.42 (s, 1H, major diast.), 2.28−2.18 (m, 1.2H), 1.98−1.87 (m, 2.2H), 1.77− 1.51 (m, 6.4H), 0.95 (d, J = 7.0 Hz, 3H, major diast.), 0.60 (d, J = 7.5 Hz, 0.3H, minor diast.) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ 141.8, 136.9, 130.3, 127.8, 127.0, 90.7, 87.1, 77.5, 74.00, 71.0, 66.9, 51.6, 41.7, 41.3, 32.3, 29.5, 29.4, 22.5, 19.3, 17.2, 14.3 ppm. IR (neat): 3545, 3436, 3304, 2931, 2871, 1495, 1457, 1446, 1377, 1086, 1058, 1036 cm−1. HRMS (ESI-TOF): m/z calcd for C15H18ONa (M + Na)+ 237.1250, found 237.1244. The relative stereochemistry was assigned based in NOESY 2D spectra. We observed a correlation between Ha 13

Ethyl (3S*,4S*)-3-Ethynyl-4-methyl-2-oxochromane-3-carboxylate (3ma). Following the general procedure, the title compound was prepared from 1m (0.065 g, 0.30 mmol, 1.0 equiv) and AlMe3 (2 M in toluene, 0.30 mL, 0.60 mmol, 2.0 equiv). The conjugated addition was completed in 1 h, and the alkynylation step was completed in 20 h. 0.072 g (0.26 mmol), 88% yield, dr >99:1, colorless oil, purified by column chromatography (silica flash, 20% ethyl acetate in hexanes), Rf = 0.34 (20% of ethyl acetate in hexanes). 1 H NMR (300 MHz, CDCl3): δ 7.37−7.15 (m, 3H), 7.09 (dd, J = 8.0, 1.1 Hz, 1H), 4.14−3.91 (m, 2H), 3.53 (q, J = 7.0 Hz, 1H), 2.67 (s, 1H), 1.71 (d, J = 7.0 Hz, 3H), 0.95 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 164.1, 163.5, 151.0, 129.0, 125.8, 125.1, 124.5, 116.3, 76.8, 76.2, 62.8, 54.5, 38.5, 13.5 ppm. IR (neat): 3282, 2983, 1776, 1744, 1489, 1455, 1230, 1198, 1182, 1169, 1130, 1109 cm−1. HRMS (ESI-TOF): m/z calcd for C15H15O4 (M + H)+ 259.0965, found 259.0951. The relative stereochemistry of this compound was assigned by analogy with compound 3da. (2S*,3S*)-3-Ethyl-2-ethynyl-2-phenylcyclohexan-1-one (3ab). Following the general procedure, the title compound was prepared from 1a (0.052 g, 0.30 mmol, 1.0 equiv) and AlEt3 (1 M in toluene, 0.60 mL, 0.60 mmol, 2.0 equiv). The conjugated addition step was completed in 3 h, and the alkynylation step was completed in 2 h. 0.060 g (0.27 mmol), 89% yield, dr >99:1, colorless oil, purified by column chromatography (silica flash, 10% of ethyl acetate in hexanes), Rf = 0.34 (10% of ethyl acetate in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.59−7.51 (m, 2H), 7.38−7.22 (m, 3H), 2.90 (ddd, J = 14.3, 8.2, 5.9 Hz, 1H), 2.59 (s, 1H), 2.53−2.40 (m, 1H), 2.40−2.27 (m, 1H), 2.26−2.14 (m, 1H), 2.10−1.79 (m, 3H), 1.65− 1.51 (m, 3H), 0.87 (t, J = 7.4 Hz, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 206.5, 137.5, 128.9, 128.0, 127.2, 86.0, 74.7, 59.4, 50.6, 38.4, 29.7, 24.3, 22.9, 22.5, 12.7 ppm. IR (neat): 3290, 2960, 2929, 2874, 1722, 1493, 1458, 1447, 1423, 1379, 1314 cm−1. HRMS (ESITOF): m/z calcd for C16H19O (M + H)+ 227.1430, found 227.1429. The relative stereochemistry of this compound was assigned by analogy with compound 3da. Ethyl (3S*,4S*)-4-Ethyl-3-ethynyl-2-oxochromane-3-carboxylate (3mb). Following the general procedure, the title compound was prepared from 1m (0.065 g, 0.30 mmol, 1.0 equiv) and AlEt3 (1 M in toluene, 0.60 mL, 0.60 mmol, 2.0 equiv). The conjugated addition step was completed in 2.5 h, and the alkynylation step was completed in 20 h. 0.065 g (0.24 mmol), 80% yield, dr >99:1, colorless oil, purified by column chromatography (silica flash, 10% of ethyl acetate in hexanes), Rf = 0.45 (20% of ethyl acetate in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.37−7.23 (m, 2H), 7.21−7.07 (m, 2H), 4.24−4.09 (m, 2H), 3.21 (dd, J = 10.1, 2.4 Hz, 1H), 2.46 (s, 1H), 2.26 (ddd, J = 14.1, 7.6, 2.6 Hz, 1H), 1.78 (ddd, J = 14.3, 10.2, 7.2 Hz, 1H), 1.15−1.04 (m, 6H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 164.8, 162.6, 150.9, 128.9, 127.4, 124.8, 124.2, 116.6, 76.6, 62.8, 53.5, 46.4, 22.5, 13.7, 12.8 ppm. IR (neat): 3283, 2974, 2937, 2879, 1780, 1745, 1613, 1588, 1488, 1456, 1368, 1334, 1298, 1253, 1231, 1194, 1158, 1109, 1078, 1054, 1035 cm−1. HRMS (ESI-TOF): m/z calcd for C16H16NaO4 (M + Na)+ 295.0941, found 295.0942. The relative stereochemistry of this compound was assigned by analogy with compound 3da. (2S*,3R*)-2-Ethynyl-2-phenyl-3-vinylcyclohexan-1-one (3ac). Following the general procedure, the title compound was prepared from 1a (0.052 g, 0.30 mmol, 1.0 equiv) and vinyl magnesium bromide (1 M in THF, 0.60 mL, 0.60 mmol, 2.0 equiv). The conjugated addition step was completed in 1.5 h, and the alkynylation step was completed in 3 h. 0.034 g (0.15 mmol), 49% yield, dr >99:1, colorless oil, purified by column chromatography (silica flash, 10% of ethyl acetate in hexanes), Rf = 0.33 (10% of ethyl acetate in hexanes). 1 H NMR (300 MHz, CDCl3): δ 7.53−7.47 (m, 2H), 7.35−7.21 (m, 3H), 6.05 (ddd, J = 17.3, 10.7, 6.8 Hz, 1H), 5.14 (dt, J = 4.2, 1.3 Hz, 1H), 5.10 (dt, J = 10.7, 1.4 Hz, 1H), 3.13−3.01 (m, 1H), 2.92−2.76 (m, 1H), 2.63 (s, 1H), 2.52−2.34 (m, 2H), 2.16−1.84 (m, 3H) ppm. 13609

DOI: 10.1021/acs.joc.8b02251 J. Org. Chem. 2018, 83, 13604−13611

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The Journal of Organic Chemistry of methyl group (0.95 ppm) and Hb of phenyl group (7.73−7.75 ppm). We observed also a correlation between Hd (4.10 ppm) and Hc (2.19−2.15 ppm).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02251. 1

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H and 13C NMR spectra of all new compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Bruno V. M. Teodoro: 0000-0002-9654-5608 Author Contributions

L.F.S., Jr. proposed the concept and directed the research. B.V.M.T. carried out the experiments, wrote the manuscript, and prepared the figures. Notes

The authors declare no competing financial interest. † Prof. Luiz Fernando da Silva Jr. passed away in June, 2017.

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ACKNOWLEDGMENTS The authors thank the São Paulo Research Foundation − FAPESP (grant 2015/00527-4), CAPES, and CNPq for financial support. B.V.M.T. thanks CNPq (grant 159176/ 2014-0) for a fellowship and Prof. Dr. Erick L. Bastos for his assistance finishing this manuscript.

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REFERENCES

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NOTE ADDED AFTER ASAP PUBLICATION This paper was published ASAP on October 12, 2018. Table 2 was updated. The revised paper was reposted on October 17, 2018.

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