Tandem Reaction of Enynyl Acetate: Precursor of Allenyl Ketones

Abstract

Deacetylation of enynyl acetates under basic conditions allows convenient access to reactive allenyl ketones, which can then undergo 1,4-addition of nucleophiles to furnish β,γ-unsaturated ketones. Benzofuran and indole derivatives have also been obtained from enynyl acetates with an o-hetero-atom-substituted aryl group via intramolecular 1,4-addition.

Reactions of functionalized allenes have been investigated in the past two decades.^1–8) Among them, α-allenyl carbonyl compounds are important building blocks for a variety of organic transformations. Cycloisomerization of allenyl ketones (Chart 1) in the presence of a transition metal catalyst is an efficient way to build substituted furans.^9–16) It was first reported by Marshall and Robinson⁹⁾ and later by Hashmi.¹¹⁾ In 2003, Gevorgyan and colleagues reported copper-catalyzed cycloisomerization of thioallenylketones via 1,2-migration of the thiogroup¹⁷⁾ and later developed a series of metal-catalyzed 1,2-migration/cycloisomerization methodology toward multisubstituted 3-seleno-,¹⁸⁾ acyloxy-,¹⁹⁾ halo-,²⁰⁾ aryl-, and alkyl-furans.²¹⁾ In some of those studies, alkynyl ketones or propargyl ketones were used as precursors of allenylketones, involving propargyl-allenyl isomerization prior to 1,2-migration/cycloisomerization.^13,15,16)

Chart 1. Allenyl Ketones in the Synthesis of Substituted Furans

During the course of our study on exploration of a new tandem reaction triggered by the reactivity of an alkyne triple-bond, we reported multisubstituted furan formation from (E)- or (Z)-enynyl acetates,²²⁾ which were prepared regio- and stereoselectively by Sonogashira coupling reaction of (E)- or (Z)-iodoenyl acetates, obtained from the reaction of alkyne with N-iodosuccinimide (NIS) and acetic acid²³⁾ (Chart 2). Treatment of (E)-enynyl acetates 2 and (Z)-enynyl acetates 3 with NIS afforded multisubstituted furans 5 via the common iodoallenyl ketones 4 regardless of the double-bond geometry of starting enynyl acetate.²⁴⁾ The proposed reaction pathway involves the formation of iodoallenyl ketone 4 by electrophilic addition of NIS to the triple-bond of enynyl acetate followed by 1,2-halogen migration²⁰⁾ of the resulting iodoallenyl ketone and cycloisomerization.

Chart 2. Multisubstituted Furan Formation from (Z)- or (E)-Enynyl Acetates

This result encouraged us to explore the possibility of enynyl acetates as precursors of allenyl ketones and application for a new tandem reaction. Hammond and colleagues reported regioselective reactions of alkynyl enolate^25,26) in which alkynyl enolates were generated by deprotonation of allenyl ketone or propargyl ketone. We hypothesized that deacetylation of enynyl acetate and subsequent trapping with an electrophile at γ-carbon would afford allenyl ketone via an alkynyl enolate intermediate (Chart 3). This resluting allenyl ketone is too electron-deficient, and succesive 1,4-addition of a nucleophile would give β,γ-unsaturated ketone. In the case with enynyl acetates possessing a nucleophilic moiety on the alkynyl substituent, cyclic compounds could be obtained via intramolecular 1,4-addition. Herein we report the reactions of enynyl acetate via an alkynyl enolate intermediate.

Chart 3. Reaction of Enynyl Acetates as Allenyl Ketone Precursors

First, deacetylation of enynyl acetate was carried out under basic conditions (Table 1). Treatment of enynyl acetate 6 with potassium carbonate (K₂CO₃) in a primary alcohol such as methanol, ethanol, or allyl alcohol afforded β,γ-unsaturated ketone 8 as a single diastereomer in good yields (entries 1–5). β,γ-Unsaturated ketones 8 were formed by the addition of alcohol to allenyl ketone intermediate 7 from the less hindered side, which is a γ-protonation product of alkynyl enolate. The E-configuration of product 8a was determined by a nuclear Overhauser effect spectroscopy (NOESY) NMR spectrum study (Fig. 1). Strong correlations were observed between the vinylic proton and the methoxy group and between the proton adjacent to the carbonyl group and the protons on the phenyl group. The reaction in 2-propanol did not lead to the desired product after 24 h at 60°C, but gave allenyl ketone 7 together with recovered 6a, probably due to the poor nucleophilicity of 2-propanol (entry 6). (Z)-Enynyl acetate 6d and e also afforded 8f and g in moderate yields accompanied by decomposed products (entries 7, 8). The NOESY experiments performed on 8b–g were also consistent with E-configuration, namely, correlation between the vinylic proton and the alkoxy group was observed.

Table 1. Deacetylation of Enynyl Acetates 6 in Alcohol

Entry	6	R	R′	R″OH	8	Yield (%)
1	6a (E)	Bu	Ph	MeOH	8a	98
2	6b (E)	Bu	p-MeC6H4	MeOH	8b	96
3	6c (E)	Bu	Bu	MeOH	8c	99
4	6a (E)	Bu	Ph	EtOH	8d	94
5	6a (E)	Bu	Ph	Allyl alcohol	8e	78
6a)	6a (E)	Bu	Ph	i-PrOH	—	—b)
7	6d (Z)	Ph	Bu	MeOH	8f	54
8	6e (Z)	Ph	Ph	MeOH	8g	66

a) 60°C, 24 h. b) Allenyl ketone 7 was obtained in 47% yield and 41% of 6a was recovered.

Fig. 1. NOESY Experiment of 8a and (Z)-12

Next, we tried the reaction of enynyl acetates 9 with a ω-hydroxyalkyl group as an alkynyl substituent that can undergo intramolecular Michael addition to allenyl ketone 10, affording oxacycles 11 (Table 2). When 9a was subjected to the same conditions as those shown in Table 1, five-membered product 12 was obtained as a mixture of E/Z isomers in good yield (E/Z=1 : 0.37, quant.) because double-bond isomerization of 11 to carbonyl-conjugated alkene 12 occurred under the basic reaction conditions (Table 2, entry 1). As shown in Fig. 1, the geometry of olefinic double bond of (Z)-12 was confirmed as cis by NOESY experiment between two methylene groups (vide supra). Mixed solvent systems (MeOH/tetrahydrofuran (THF)), MeOH/MeCN, and MeOH/1,2-dichloroethane (DCE)) resulted in poorer E/Z selectivity to give a 1 : 1 ratio of 12 (entries 2–4). Use of lithium hydroxide instead of K₂CO₃ slightly improved the E/Z selectivity (entry 5). When a 1 : 0.5 mixture of (E)- and (Z)-12 was subjected to LiOH/MeOH conditions, E/Z ratio of 12 was 1 : 0.15 after 24 h, suggesting that (E)- and (Z)-12 may be in equilibrium via enol intermediate. In contrast, isomerization of compound 8a was not observed after 24 h. The length of the tether of 9 affected the product distribution. The major products from 9b were methanol adducts 13a together with a small amount of 11 (entry 6). Enynyl acetate 9c exclusively gave 13b probably due to the difficulty of intramolecular cyclization (entry 7).

Table 2. Attempt for Intramolecular Reaction

Entry	9	n	Base	Solvent	Time (h)	11 (%)	12 (%, E/Z)a)	13 (%)
1	9a	2	K2CO3	MeOH	1	—	Quant. (1 : 0.37)	—
2	9a	2	K2CO3	MeOH/THF(1 : 4)	3 d	—	93 (1 : 0.84)	—
3	9a	2	K2CO3	MeOH/MeCN(1 : 1)	0.5	—	90 (1 : 0.96)	—
4	9a	2	K2CO3	MeOH/DCE(1 : 1)	1	—	Quant. (1 : 0.84)	—
5	9a	2	LiOH	MeOH	1	—	Quant. (1 : 0.15)	—
6	9b	3	LiOH	MeOH	1	Trace	—	78 (13a)
7	9c	1	LiOH	MeOH	1	—		71 (13b)

a) Ratio of isomers was determined by ¹H-NMR analysis of isolated product.

In order to facilitate intramolecular cyclization, enynyl acetates 14 with an o-heteroatom-substituted aryl group were prepared (Table 3). As expected, enynyl acetate with o-acetoxyphenyl group 14a underwent deacetylation at two acetyl groups followed by intramolecular cyclization to give the desired benzofuran 15a in 85% yield (entry 1). A carbamate nitrogen atom is also suitable for a nucleophile. Although ethoxy carbamate suffered from decomposition and afforded N–H indole 15b in modest yield, N-Boc indole 15c was obtained in good yield from 14c (entries 2, 3).

Table 3. Intramolecular Reaction

Entry	14	R	15 (%)
1	14a	OAc	15a (X=O, 85)
2	14b	NHCO2Et	15b (X=NH, 59)
3	14c	NHBoc	15b (X=NH, 10), 15c (X=N-Boc, 88)

In conclusion, we have demonstrated a new reaction to β,γ-unsaturated ketones from enynyl acetates as precursors of allenyl ketones, which involves deacetylation under basic conditions followed by nucleophilic addition of alcohol to the resulting allenyl ketones. Enynyl acetates with an o-hetero-atom-substituted aryl group were also suitable for this reaction, giving benzofuran and indole derivatives.

Experimental

General

The ¹H- and ¹³C-NMR spectroscopic data were recorded with a 600 MHz spectrometer. Chemical Shifts [δ (ppm)] are reported in ppm relative to an internal tetramethylsilane standard (δ 0.00 ppm) for ¹H-NMR spectra and to the solvent signals (δ 77.16 ppm for CDCl₃) for ¹³C-NMR spectra. The NMR data are described as follows: chemical shift, multiplicity [s (singlet), d (doublet), t (triplet), q (quartet), br (broad), and m (multiplet)], coupling constant [J (Hz)], relative integration value. Infrared spectra were obtained with an Fourier transform (FT) spectrometer. Mass spectroscopy experiments were performed on a double-focusing mass spectrometer by using electron ionization (EI) as the ionization mode. Analytical thin layer chromatography was performed on Merck silica gel 60 F254 TLC plates.

General Procedure for Deacetylation

To a solution of enynyl acetate 6 (0.15 mmol) in alcohol (1.5 mL) was added K₂CO₃ (0.45 mmol), and the mixture was stirred at room temperature until completion. Water was added to the reaction mixture and extracted with EtOAc (two times). The combined organic solution was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at reduced pressure. Column chromatography on silica gel using hexane/ethyl acetate as an eluent afforded β,γ-unsaturated ketones 8.

1-(4-Methoxyphenyl)-2-(2-phenyl-1λ⁵-vinylidene)hexan-1-one (7)

Colorless oil. ¹H-NMR (600 MHz, CDCl₃) δ: 7.82 (d, J=8.8 Hz, 2H), 7.35 (dd, J=7.7 Hz, 2H), 7.31–7.23 (m, 3H), 6.77 (d, J=8.8 Hz, 2H), 6.45 (t, J=2.7 Hz, 1H), 3.79 (s, 3H), 2.61–2.47 (m, 2H), 1.59–1.50 (m, 2H), 1.49–1.37 (m, 2H), 0.92 (t, J=7.3 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 213.4, 192.5, 163.0, 132.9, 131.2, 130.9, 128.9, 127.6, 127.1, 113.2, 110.6, 98.0, 55.4, 30.3, 28.8, 22.6, 14.0. IR (CHCl₃, cm⁻¹) 2960, 1931, 1643, 1601, 1509, 1459, 1313, 1256, 1172, 1031. MS (EI): m/z=306 (M⁺). High resolution (HR)-MS (EI): m/z Calcd for C₂₁H₂₂O₂: 306.1620. Found: 306.1620.

(E)-2-(1-Methoxy-2-phenylvinyl)-1-(4-methoxyphenyl)hexan-1-one (8a)

Pale yellow oil. ¹H-NMR (600 MHz, CDCl₃) δ: 7.59 (d, J=8.7 Hz, 2H), 7.38 (dd, J=7.6, 7.6 Hz, 2H), 7.27 (dd, J=7.6, 7.6 Hz, 1H), 7.23 (d, J=7.6 Hz, 2H), 6.74 (d, J=8.7 Hz, 2H), 5.68 (s, 1H), 4.44 (dd, J=8.4, 5.7 Hz, 1H), 3.82 (s, 3H), 3.57 (s, 3H), 2.28–2.18 (m, 1H), 1.84–1.75 (m, 1H), 1.39–1.28 (m, 4H), 0.91 (t, J=6.9 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 196.8, 163.3, 158.2, 137.2, 130.8, 129.6, 129.0, 128.7, 126.2, 113.4, 100.8, 55.5, 55.3, 48.4, 30.2, 29.6, 23.0, 14.2. IR (CHCl₃, cm⁻¹) 2960, 1676, 1641, 1601, 1511, 1465, 1309, 1252, 1240, 1116, 1032. MS (EI): m/z=338 (M⁺). HR-MS (EI): m/z Calcd for C₂₂H₂₆O₃: 338.1882. Found: 338.1879.

(E)-2-(1-Methoxy-2-(p-tolyl)vinyl)-1-(4-methoxyphenyl)-hexan-1-one (8b)

Pale yellow oil. ¹H-NMR (600 MHz, CDCl₃) δ: 7.62 (d, J=8.6 Hz, 2H), 7.19 (d, J=7.8 Hz, 2H), 7.12 (d, J=7.8 Hz, 2H), 6.74 (d, J=8.6 Hz, 2H), 5.64 (s, 1H), 4.42 (dd, J=8.6, 5.7 Hz, 1H), 3.82 (s, 3H), 3.55 (s, 3H), 2.39 (s, 3H), 2.29–2.19 (m, 1H), 1.83–1.73 (m, 1H), 1.39–1.26 (m, 4H), 0.91 (t, J=6.9 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 196.9, 163.3, 157.9, 135.7, 134.1, 130.8, 129.6, 129.4, 128.9, 113.4, 100.6, 55.5, 55.2, 48.5, 30.2, 29.6, 23.0, 21.3, 14.2. IR (CHCl₃, cm⁻¹) 2960, 1676, 1640, 1601, 1576, 1511, 1465, 1420, 1309, 1252, 1240, 1171, 1033. MS (EI): m/z=352 (M⁺). HR-MS (EI): m/z Calcd for C₂₃H₂₈O₃: 352.2038. Found: 352.2042.

(E)-2-Butyl-3-methoxy-1-(4-methoxyphenyl)oct-3-en-1-one (8c)

Pale yellow oil. ¹H-NMR (600 MHz, CDCl₃) δ: 7.94 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.41 (t, J=7.2 Hz, 1H), 4.13 (t, J=7.1 Hz, 1H), 3.85 (s, 3H), 3.37 (s, 3H), 2.21–2.09 (m, 2H), 2.06–1.96 (m, 1H), 1.76–1.67 (m, 1H), 1.40–1.24 (m, 8H), 0.93 (t, J=7.1 Hz, 3H), 0.90 (t, J=7.1 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 197.6, 163.2, 154.9, 130.5, 130.2, 113.5, 99.1, 55.5, 54.7, 49.5, 33.1, 29.9, 29.1, 26.6, 23.0, 22.6, 14.2, 14.2. IR (CHCl₃, cm⁻¹) 2958, 1675, 1659, 1601, 1576, 1511, 1466, 1308, 1256, 1171, 1115, 1033. MS (EI): m/z=318 (M⁺). HR-MS (EI): m/z Calcd for C₂₀H₃₀O₃: 318.2195. Found: 318.2197.

(E)-2-(1-Ethoxy-2-phenylvinyl)-1-(4-methoxyphenyl)hexan-1-one (8d)

Pale yellow oil. ¹H-NMR (600 MHz, CDCl₃) δ: 7.60 (d, J=8.8 Hz, 2H), 7.37 (dd, J=7.6, 7.6 Hz, 2H), 7.27–7.23 (m, 1H), 7.22 (d, J=7.6 Hz, 2H), 6.74 (d, J=8.8 Hz, 2H), 5.64 (s, 1H), 4.39 (dd, J=8.3, 5.7 Hz, 1H), 3.81 (s, 3H), 3.80–3.67 (m, 2H), 2.27–2.18 (m, 1H), 1.85–1.76 (m, 1H), 1.41–1.29 (m, 4H), 1.22 (t, J=6.9 Hz, 3H), 0.92 (t, J=7.0 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 196.8, 163.2, 157.5, 137.4, 130.7, 129.7, 129.0, 128.6, 126.1, 113.4, 101.2, 63.1, 55.5, 48.6, 30.2, 29.6, 23.0, 14.4, 14.2. IR (CHCl₃, cm⁻¹) 2960, 1680, 1636, 1601, 1576, 1510, 1258, 1238, 1175, 1171. MS (EI): m/z=352 (M⁺). HR-MS (EI): m/z Calcd for C₂₃H₂₈O₃: 352.2038. Found: 352.2039.

(E)-2-(1-(Allyloxy)-2-phenylvinyl)-1-(4-methoxyphenyl)hexan-1-one (8e)

Colorless oil. ¹H-NMR (600 MHz, CDCl₃) δ: 7.59 (d, J=8.9 Hz, 2H), 7.38 (dd, J=7.7, 7.7 Hz, 2H), 7.29–7.24 (m, 1H), 7.22 (d, J=7.7 Hz, 2H), 6.74 (d, J=8.9 Hz, 2H), 5.85 (ddt, J=17.2, 10.6, 4.9 Hz, 1H), 5.67 (s, 1H), 5.25 (dt, J=17.2, 1.5 Hz, 1H), 5.14 (dt, J=10.6, 1.5 Hz, 1H), 4.41 (dd, J=8.2, 5.6 Hz, 1H), 4.30 (dd, J=13.3, 4.9 Hz, 1H), 4.25 (dd, J=13.3, 4.9 Hz, 1H), 3.82 (s, 3H), 2.31–2.22 (m, 1H), 1.87–1.78 (m, 1H), 1.41–1.29 (m, 4H), 0.92 (t, J=7.0 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 196.7, 163.2, 157.0, 137.2, 133.0, 130.7, 129.7, 129.0, 128.7, 126.2, 116.8, 113.4, 102.0, 68.2, 55.5, 48.6, 30.2, 29.6, 23.0, 14.2. IR (CHCl₃, cm⁻¹) 2960, 1680, 1636, 1601, 1576, 1511, 1465, 1457, 1420, 1311, 1260, 1171, 1032. MS (EI): m/z=364 (M⁺). HR-MS (EI): m/z Calcd for C₂₄H₂₈O₃: 364.2038. Found: 364.2047.

(E)-3-Methoxy-1-(4-methoxyphenyl)-2-phenyloct-3-en-1-one (8f)

Colorless oil. ¹H-NMR (600 MHz, CDCl₃) δ: 8.00 (dd, J=8.9, 1.7 Hz, 2H), 7.36–7.23 (m, 5H), 6.91 (dd, J=8.9, 1.6 Hz, 2H), 5.52 (d, J=1.4 Hz, 1H), 4.56 (td, J=7.2, 1.4 Hz, 1H), 3.86 (s, 3H), 3.45 (s, 3H), 2.24–2.14 (m, 1H), 2.13–2.04 (m, 1H), 1.39–1.23 (m, 4H), 0.86 (td, J=7.1, 1.6 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 195.3, 163.3, 154.5, 137.7, 130.7, 130.1, 129.3, 128.3, 127.0, 113.7, 99.6, 55.7, 55.6, 54.9, 32.7, 26.5, 22.5, 14.1. IR (CHCl₃, cm⁻¹) 2960, 2933, 1684, 1659, 1601, 1511, 1465, 1454, 1313, 1262, 1169, 1118, 1032. MS (EI): m/z=338 (M⁺). HR-MS (EI): m/z Calcd for C₂₂H₂₆O₃: 338.1882. Found: 338.1880.

(E)-3-Methoxy-1-(4-methoxyphenyl)-2,4-diphenylbut-3-en-1-one (8g)

Pale yellow oil. ¹H-NMR (600 MHz, CDCl₃) δ: 7.75 (dd, J=8.9, 1.7 Hz, 2H), 7.40–7.28 (m, 7H), 7.27–7.21 (m, 1H), 7.17 (d, J=8.1 Hz, 2H), 6.80 (dd, J=8.9, 1.5 Hz, 2H), 5.85 (s, 1H), 5.65 (s, 1H), 3.83 (s, 3H), 3.65 (s, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 195.0, 163.4, 156.9, 137.9, 136.7, 130.9, 129.5, 129.3, 129.0, 128.6, 128.6, 127.2, 126.4, 113.6, 102.2, 55.6, 55.5, 55.4. IR (CHCl₃, cm⁻¹) 2938, 1679, 1643, 1601, 1576, 1511, 1496, 1465, 1314, 1260, 1169, 1032. MS (EI): m/z=358 (M⁺). HR-MS (EI): m/z Calcd for C₂₄H₂₂O₃: 358.1569. Found: 358.1576.

(E)-2-Butyl-6-hydroxy-1-(4-methoxyphenyl)hex-1-en-3-yn-1-yl Acetate (9a)

Orange oil. ¹H-NMR (600 MHz, CDCl₃) δ: 7.66 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.5 Hz, 2H), 3.80 (s, 3H), 3.69 (td, J=6.2, 0.8 Hz, 2H), 2.59 (td, J=6.2, 0.8 Hz, 2H), 2.21 (s, 3H), 2.20–2.16 (m, 2H), 1.74 (br, 1H), 1.57–1.50 (m, 2H), 1.41–1.33 (m, 2H), 0.93 (t, J=7.3 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 168.9, 159.8, 150.2, 129.0, 127.8, 113.4, 112.5, 91.1, 81.2, 61.2, 55.4, 31.2, 30.2, 24.3, 22.5, 20.9, 14.1. IR (CHCl₃, cm⁻¹) 3568, 2960, 1755, 1608, 1513, 1465, 1370, 1297, 1257, 1192, 1175, 1086, 1034. MS (EI): m/z=316 (M⁺). HR-MS (EI): m/z Calcd for C₁₉H₂₄O₄: 316.1675. Found: 316.1679.

(E)-2-Butyl-7-hydroxy-1-(4-methoxyphenyl)hept-1-en-3-yn-1-yl Acetate (9b)

Orange oil. ¹H-NMR (600 MHz, CDCl₃) δ: 7.67 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 3.81 (s, 3H), 3.70 (td, J=5.9, 5.9 Hz, 2H), 2.45 (t, J=6.9 Hz, 2H), 2.21 (s, 3H), 2.19–2.14 (m, 2H), 1.82–1.71 (m, 2H), 1.57–1.50 (m, 2H), 1.39–1.30 (m, 3H), 0.93 (t, J=7.3 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 168.9, 159.6, 149.5, 128.9, 127.7, 113.3, 112.6, 94.3, 79.5, 61.7, 55.3, 31.3, 31.3, 30.1, 22.4, 20.9, 16.3, 14.0. IR (CHCl₃, cm⁻¹) 3624, 2960, 1751, 1608, 1511, 1465, 1370, 1297, 1252, 1177, 1087, 1034. MS (EI): m/z=330 (M⁺). HR-MS (EI): m/z Calcd for C₂₀H₂₆O₄: 330.1831. Found: 330.1823.

(E)-2-(3-Hydroxyprop-1-yn-1-yl)-1-(4-methoxyphenyl)hex-1-en-1-yl Acetate (9c)

Orange oil. ¹H-NMR (600 MHz, CDCl₃) δ: 7.65 (d, J=8.9 Hz, 2H), 6.86 (d, J=8.9 Hz, 2H), 4.36 (s, 2H), 3.80 (s, 3H), 2.21 (s, 3H), 2.19 (t, J=7.6 Hz, 2H), 1.78 (br, 1H), 1.58–1.50 (m, 2H), 1.41–1.32 (m, 2H), 0.93 (t, J=7.4 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 168.8, 159.9, 151.0, 129.1, 127.4, 113.5, 111.7, 91.8, 84.4, 55.4, 51.9, 31.1, 30.1, 22.5, 20.9, 14.0. IR (CHCl₃, cm⁻¹) 3603, 2960, 2873, 1755, 1608, 1511, 1465, 1370, 1297, 1252, 1194, 1177, 1085, 1034, 1004. MS (EI): m/z=302 (M⁺). HR-MS (EI): m/z Calcd for C₁₈H₂₂O₄: 302.1518. Found: 302.1524.

2-(Dihydrofuran-2(3H)-ylidene)-1-(4-methoxyphenyl)hexan-1-one (12)

Compound 12 was isolated as a mixture of geometric isomers (73 : 27 E/Z). Colorless oil. ¹H-NMR (600 MHz, CDCl₃) δ: 7.77 (d, J=8.9 Hz, 0.54H, Z), 7.62 (d, J=8.8 Hz, 1.46H, E), 6.92–6.86 (m, 2H), 4.21 (t, J=6.8 Hz, 1.46H, -CH₂-, E), 4.01 (t, J=6.9 Hz, 0.54H, -CH₂-, Z), 3.85 (s, 3H), 2.75 (t, J=7.7 Hz, 0.54H, -CH₂-, Z), 2.48 (m, 2.92H, 2×-CH₂-, E), 2.33 (t, J=7.5 Hz, 0.54H, -CH₂-, Z), 2.05–1.99 (m, 0.54H, -CH₂-, Z), 1.96 (m, 1.46H, -CH₂-, E), 1.41–1.23 (m, 4H, 2×-CH₂-), 0.87 (t, J=7.2 Hz, 0.81H, CH₃-, Z), 0.84 (t, J=7.3 Hz, 2.19H, CH₃-, E). ¹³C-NMR (150 MHz, CDCl₃) δ: 198.0 (E), 196.6 (Z), 167.4, 162.6, 162.2, 161.1, 133.9, 132.9, 131.3 (Z), 130.6 (E), 113.5 (E), 113.2, 112.9, 109.1, 71.7 (Z), 71.1 (E), 55.4, 55.4, 31.8, 31.5, 31.1 (E), 30.3 (Z), 28.7 (Z), 27.9 (E), 25.2 (E), 23.8 (Z), 22.8, 22.7, 14.1. IR (CHCl₃, cm⁻¹) 2960, 1652, 1601, 1508, 1465, 1457, 1371, 1330, 1304, 1254, 1181, 1172, 1164, 1148, 1109, 1033. MS (EI): m/z=274 (M⁺). HR-MS (EI): m/z Calcd for C₁₇H₂₂O₃: 274.1569. Found: 274.1572.

(E)-2-Butyl-7-hydroxy-3-methoxy-1-(4-methoxyphenyl)hept-3-en-1-one (13a)

Colorless oil. ¹H-NMR (600 MHz, CDCl₃) δ: 7.95 (d, J=8.9 Hz, 2H), 6.90 (d, J=8.9 Hz, 2H), 4.41 (t, J=7.3 Hz, 1H), 4.14 (t, J=7.1 Hz, 1H), 3.85 (s, 3H), 3.68 (t, J=6.3 Hz, 2H), 3.40 (s, 3H), 2.32–2.19 (m, 2H), 2.05–1.96 (m, 1H), 1.77–1.60 (m, 3H), 1.46 (br, 1H), 1.42–1.24 (m, 4H), 0.90 (t, J=7.1 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 197.7, 163.3, 155.3, 130.6, 130.1, 113.6, 98.4, 62.5, 55.5, 54.8, 49.7, 33.7, 30.0, 29.2, 23.0, 23.0, 14.2. IR (CHCl₃, cm⁻¹) 2958, 1675, 1659, 1601, 1576, 1465, 1256, 1240, 1171, 1033. MS (EI): m/z=320 (M⁺). HR-MS (EI): m/z Calcd for C₁₉H₂₈O₄: 320.1988. Found: 320.1990.

(E)-2-(3-Hydroxy-1-methoxyprop-1-en-1-yl)-1-(4-methoxyphenyl)hexan-1-one (13b)

Yellow oil. ¹H-NMR (600 MHz, CDCl₃) δ: 7.98 (d, J=9.0 Hz, 2H), 6.91 (d, J=9.0 Hz, 2H), 4.79 (t, J=7.7 Hz, 1H), 4.37–4.24 (m, 3H), 3.86 (s, 3H), 3.46 (s, 3H), 2.08–1.98 (m, 1H), 1.80–1.70 (m, 1H), 1.40–1.32 (m, 2H), 1.32–1.25 (m, 3H), 0.90 (t, J=7.2 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 197.0, 163.4, 159.3, 130.7, 129.9, 113.8, 97.9, 58.7, 55.6, 55.1, 49.6, 30.0, 29.5, 22.9, 14.2. IR (CHCl₃, cm⁻¹) 3607, 2960, 2862, 1680, 1653, 1601, 1576, 1511, 1442, 1420, 1379, 1309, 1252, 1171, 1121, 1032. MS (EI): m/z=292 (M⁺). HR-MS (EI): m/z Calcd for C₁₇H₂₄O₄: 292.1675. Found: 292.1675.

(E)-2-(3-(Acetoxy(4-methoxyphenyl)methylene)hept-1-yn-1-yl)phenyl Acetate (14a)

Yellow oil. ¹H-NMR (600 MHz, CDCl₃) δ: 7.72 (dd, J=8.8, 1.6 Hz, 2H), 7.41 (d, J=7.6 Hz, 1H), 7.31 (dd, J=8.1, 7.5 Hz, 1H), 7.19 (dd, J=7.6, 7.5 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.88 (dd, J=8.8, 1.5 Hz, 2H), 3.82 (s, 3H), 2.28 (t, J=7.6 Hz, 2H), 2.24 (s, 3H), 2.09 (s, 3H), 1.67–1.60 (m, 2H), 1.44–1.37 (m, 2H), 0.95 (td, J=7.3, 1.4 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 169.1, 168.7, 160.0, 151.1, 151.0, 133.2, 129.3, 129.2, 127.6, 126.0, 122.5, 117.8, 113.6, 112.0, 93.2, 89.0, 55.4, 31.2, 30.2, 22.5, 21.0, 20.8, 14.1. IR (CHCl₃, cm⁻¹) 2962, 1757, 1608, 1511, 1487, 1443, 1370, 1300, 1252, 1192, 1177, 1099, 1057, 1034, 1011. MS (EI): m/z=406 (M⁺). HR-MS (EI): m/z Calcd for C₂₅H₂₆O₅: 406.1780. Found: 406.1783.

(E)-2-((2-((Ethoxycarbonyl)amino)phenyl)ethynyl)-1-(4-methoxyphenyl)hex-1-en-1-yl Acetate (14b)

Yellow solid; mp 42–44°C. ¹H-NMR (600 MHz, CDCl₃) δ: 8.12 (d, J=8.2 Hz, 1H), 7.71 (dd, J=8.9, 1.1 Hz, 2H), 7.33–7.28 (m, 2H), 7.20 (s, 1H), 6.97 (t, J=7.6 Hz, 1H), 6.90 (dd, J=8.9, 1.1 Hz, 2H), 4.19 (qd, J=7.1, 1.0 Hz, 2H), 3.81 (s, 3H), 2.36–2.30 (m, 2H), 2.26 (s, 3H), 1.69–1.62 (m, 2H), 1.49–1.39 (m, 2H), 1.29 (td, J=7.1, 1.0 Hz, 3H), 0.97 (td, J=7.3, 1.0 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 168.8, 160.1, 153.3, 151.2, 139.0, 131.8, 129.6, 129.1, 127.6, 122.5, 117.8, 113.7, 111.89, 111.86, 95.3, 88.8, 61.4, 55.4, 31.0, 30.4, 22.5, 21.0, 14.6, 14.1. IR (CHCl₃, cm⁻¹) 3400, 2962, 1748, 1732, 1608, 1580, 1521, 1512, 1452, 1370, 1305, 1250, 1240, 1194, 1176, 1098, 1063, 1034. MS (EI): m/z=435 (M⁺). HR-MS (EI): m/z Calcd for C₂₆H₂₉NO₅: 435.2046. Found: 435.2053.

(E)-2-((2-((tert-Butoxycarbonyl)amino)phenyl)ethynyl)-1-(4-methoxyphenyl)hex-1-en-1-yl Acetate (14c)

Yellow solid; mp 68–70°C. ¹H-NMR (600 MHz, CDCl₃) δ: 8.12 (d, J=8.2 Hz, 1H), 7.72 (d, J=8.9 Hz, 2H), 7.32–7.22 (m, 2H), 7.14 (s, 1H), 6.94 (dd, J=7.6, 7.6 Hz, 1H), 6.89 (d, J=8.9 Hz, 2H), 3.81 (s, 3H), 2.33 (t, J=7.6 Hz, 2H), 2.26 (s, 3H), 1.71–1.64 (m, 2H), 1.49 (s, 9H), 1.48–1.40 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 168.8, 160.1, 152.5, 151.1, 139.4, 131.7, 129.6, 129.1, 127.5, 122.2, 117.7, 113.7, 111.8, 111.7, 95.1, 89.1, 80.8, 55.4, 31.0, 30.3, 28.4, 22.5, 21.0, 14.1. IR (CHCl₃, cm⁻¹) 3403, 2962, 1750, 1726, 1608, 1580, 1513, 1449, 1370, 1305, 1240, 1176, 1157, 1098, 1051, 1033. MS (EI): m/z=463 (M⁺). HR-MS (EI): m/z Calcd for C₂₈H₃₃NO₅: 463.2359. Found: 463.2361.

2-(Benzofuran-2-yl)-1-(4-methoxyphenyl)hexan-1-one (15a)

Pale yellow oil. ¹H-NMR (600 MHz, CDCl₃) δ: 8.03 (d, J=8.9 Hz, 2H), 7.47 (d, J=7.6 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.21 (dd, J=8.1, 7.4 Hz, 1H), 7.17 (dd, J=7.6, 7.4 Hz, 1H), 6.92 (d, J=8.9 Hz, 2H), 6.54 (s, 1H), 4.76 (t, J=7.3 Hz, 1H), 3.85 (s, 3H), 2.24–2.16 (m, 1H), 2.10–2.01 (m, 1H), 1.39–1.30 (m, 4H), 0.88 (t, J=6.6 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 195.9, 163.7, 156.8, 154.8, 131.1, 129.6, 128.8, 123.8, 122.8, 120.8, 114.0, 111.2, 103.8, 55.6, 47.0, 31.3, 29.9, 22.8, 14.1. IR (CHCl₃, cm⁻¹) 2960, 1676, 1601, 1576, 1512, 1454, 1420, 1315, 1260, 1173, 1032. MS (EI): m/z=322 (M⁺). HR-MS (EI): m/z Calcd for C₂₁H₂₂O₃: 322.1569. Found: 322.1564.

2-(1H-Indol-2-yl)-1-(4-methoxyphenyl)hexan-1-one (15b)

Red oil. ¹H-NMR (600 MHz, CDCl₃) δ: 8.67 (s, 1H), 8.03 (d, J=8.6 Hz, 2H), 7.53 (d, J=7.8 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.12 (dd, J=8.1, 7.1 Hz, 1H), 7.05 (dd, J=7.8, 7.1 Hz, 1H), 6.92 (d, J=8.6 Hz, 2H), 6.40 (s, 1H), 4.83 (t, J=7.4 Hz, 1H), 3.85 (s, 3H), 2.15–2.06 (m, 1H), 1.98–1.89 (m, 1H), 1.39–1.25 (m, 4H), 0.84 (t, J=6.6 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 199.4, 164.0, 136.5, 136.5, 131.1, 129.5, 128.3, 121.7, 120.1, 119.8, 114.1, 111.0, 101.5, 55.7, 46.1, 33.9, 29.9, 22.7, 14.0. IR (CHCl₃, cm⁻¹) 3452, 2960, 1663, 1601, 1576, 1512, 1456, 1419, 1262, 1170, 1032. MS (EI): m/z=321 (M⁺). HR-MS (EI): m/z Calcd for C₂₁H₂₃NO₂: 321.1729. Found: 321.1735.

tert-Butyl 2-(1-(4-Methoxyphenyl)-1-oxohexan-2-yl)-1H-indole-1-carboxylate (15c)

Colorless oil. ¹H-NMR (600 MHz, CDCl₃) δ: 8.02 (dd, J=8.9, 1.2 Hz, 2H), 7.98 (d, J=8.4 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.22 (dd, J=8.4, 7.3 Hz, 1H), 7.16 (dd, J=7.6, 7.3 Hz, 1H), 6.89 (dd, J=8.9, 1.1 Hz, 2H), 6.43 (s, 1H), 5.64 (t, J=6.8 Hz, 1H), 3.83 (s, 3H), 2.17–2.08 (m, 1H), 1.95–1.85 (m, 1H), 1.70 (s, 9H), 1.47–1.29 (m, 4H), 0.88 (t, J=7.1 Hz, 3H). ¹³C-NMR (150 MHz, CDCl₃) δ: 197.6, 163.3, 150.9, 140.3, 136.4, 131.1, 130.0, 129.3, 123.8, 122.8, 120.5, 115.7, 113.8, 108.9, 84.4, 55.5, 46.1, 33.0, 30.3, 28.4, 23.0, 14.1. IR (CHCl₃, cm⁻¹) 2960, 1730, 1675, 1601, 1511, 1452, 1371, 1328, 1254, 1171, 1119, 1082, 1033. MS (EI): m/z=421 (M⁺). HR-MS (EI): m/z Calcd for C₂₆H₃₁NO₄: 421.2253. Found: 421.2255.

Acknowledgments

The authors gratefully acknowledge the Japanese Society for the Promotion of Science (JSPS), KAKENHI for a Grant-in-Aid for Scientific Research (C) (Grant 26460025 to R.Y. and Grant 15K07881 to T.S.). Dr. S. Yamaguchi (Setsunan University) is thanked for obtaining low-resolution mass spectrometry (LR-MS) and HR-MS data.

Conflict of Interest

The authors declare no conflict of interest.

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