HETEROCYCLES

Paper | Special issue | Vol. 84, No. 2, 2012, pp. 983-1012
Received, 1st July, 2011, Accepted, 26th September, 2011, Published online, 7th October, 2011.
DOI: 10.3987/COM-11-S(P)73

■ Synthesis of 8-Hydroxyisochromenes and 8-Hydroxyisocoumarins from 3-Ethoxycyclohex-2-en-1-one

George Majetich* and Jeremy L. Grove

Department of Chemsitry, The University of Georgia, Athens, Georgia 30602, U.S.A.

Abstract

Two strategies were developed to prepare 8-hydroxyisocoumarins from substituted 3-ethoxycyclohex-2-en-1-ones. The key reactions in the first strategy were the cyclization of a 2-hydroxymethyl-3-ethynyl-cyclohex-2-en-1-one, followed by the aromatization of the resulting cyclohexenone-pyran intermediate. The second approach featured the reaction of 2-hydroxymethyl-3-vinyl-cyclohex-2-en-1-ones with DDQ to directly produce isocoumarins. This new two-step sequence was used to prepare oospolactone in 57% overall yield.

INTRODUCTION
In the preceding manuscript we reported that enynone 2, prepared in straightforward manner from 3-ethoxy-cyclohex-2-en-1-one (1), cyclized to produce dihydropyran 3 in 82% yield. Subsequent aromatization of the cyclohexenone ring of 3, followed by the oxidation of the methylene group of 4, produced 6-hydroxyisocoumarin 5 in 71% overall yield (Scheme 1).1

We recognized that an enynone with a hydroxymethyl substituent at the C-2 position (i.e., 9) would produce pyran 8 (Scheme 2). Aromatization of the cyclohexenone ring of 8 would provide phenol 7 and oxidation of C-1 of 7 would furnish isocoumarin 6, (also known as a benzopyran-1-one). Enynone 9 would be produced by adding an acetylide anion in 1,2-fashion to known 1,3-dioxin 10.

The 8-hydroxyisochromene and 8-hydroxyisocoumarin scaffolds are present in a large number and wide variety of naturally-occuring compounds with antifungal, phytotoxic, and antimicrobial activity;2 ten representative examples are shown in Figure 1. Not surprisingly, general methods for the synthesis of these two classes have been widely studied and several excellent reviews focused on the isolation and synthetic approaches related to isocoumarins can be found in the literature.3 A comprehensive review on the isolation, activity, or synthesis of the isochromenes (also known as a 2-benzopyran) has not been published despite the extensive work from the laboratories of Larock,4 Yamamoto,5 and others.6 Our concise synthesis of multiply alkylated 8-hydroxyisochromenes and 8-hydroxyisocoumarins from 1,3-dioxin 10 is the focus of this article.

RESULTS AND DISCUSSION
In 1982 Crow and co-workers7 reported that dimedone (11) undergoes a Prins reaction with aliphatic aldehydes in the presence of BF3·Et2O to produce 1,3-dioxin 12 in 80-95% yield (Scheme 3). They proposed a mechanism wherein the Lewis acid-activation of an aldehyde equivalent catalyzes the initial Prins reaction with enol i, followed by dehydration to give intermediate enedione ii. 1,3-Dioxin 12 is formed when a second aldehyde molecule undergoes a [4+2]-cycloaddition with ii.

Smith et al. prepared 1,3-dioxin 10 from cyclohexane-1,3-dione (13) in 40% yield using 3 equivalents of BF3·Et2O with a slight excess of paraformaldehyde or in 84% yield when 1,3,5-trioxane was used.8 High dilution of the reagents and slow addition of diketone 13 minimized the formation of dimer 14. In our hands, using Smith’s conditions to prepare 10 from 13 instead favored the formation of 14. However, using 3-ethoxycyclohex-2-en-1-one (1) and Smith’s conditions produced dioxin 10 in 97% yield independent of the source of the formaldehyde. Furthermore, it did not require special methods of addition or high dilution; nor was dimer 14 detected. The mechanism for this modifcation to make 1,3-dioxin 10 was revealed due to a single alkylation (Scheme 4). When 3-ethoxy-6-methylcyclohex-2-en-1-one (15)9 was subjected to dioxin formation only dioxin 16 was produced (cf. isomeric dioxin 17). As independently proposed by Crow and Smith, the first step of this mechanism is an intermolecular Prins reaction between 15 and the Lewis-activated aldehyde (iii → iv). However, instead of eliminating to form enedione ii, the Lewis acid is transferred to a second molecule of aldehyde that reacts with alkoxide v to form acetal vi. The intramolecular transfer of the Lewis acid to the C-1 carbonyl group activates it for 1,2-addition by the resulting alkoxide vii. Although 1,2-addition to the alkylated, and thus activated, C-3 carbonyl is possible, steric effects between the C-3 alkylated carbonyl group and the C-2-sidechain preclude 1,2-addition at this site. The hydrolysis of acetal viii produces 1,3-dioxin 16 in 90% yield.

With an efficient route to 1,3-dioxin 10 in hand, we next sought to introduce the pyran motif (i.e., 9 → 8, Scheme 2). In their preparation of 10, Smith et al. also reported that 1,3-dioxin 10 underwent 1,2-addition with hydrides, Grignard reagents or organolithium reagents to give β-substituted α-hydroxymethylcyclohex-2-en-1-ones in high yield.8 1,2-Addition of lithium (trimethylsilyl)acetylide to 10, followed by acid hydrolysis and desilylation, produced enynone 9 in 73% yield (Scheme 5).

While enynone 9 underwent the expected 1,6-addition of EtSH in the presence of BF3·Et2O (cf. 18), longer reaction times, higher reaction temperatures, or larger amounts of BF3·Et2O, did not promote pyran formation and led to decomposition. Treatment of enynone 9 with H2SO4 also caused decomposition, whereas HCl added to the triple bond instead of promoting cyclization. Pryan formation was achieved by using organic BrÖnsted acids such as p-TsOH or triflic acid (TfOH). We observed, however, that TfOH is not very soluble in DCM and that the addition of co-solvents to increase its solubility decreased its reactivity. Optimal results for pyran formation were obtained using methanesulfonic acid (MsOH) (Scheme 6). While catalytic quantitities of MsOH produced pyran 8, the conversion was low. Treatment of enynone 9 with 1 equivalent of MsOH in dilute DCM gave pyran 8 in 61% yield via a 6-endo-dig cyclization (cf. ix).10 Enol ether 19, a 5-endo dig cyclization product produced by the addition of the alcohol to carbocation x, was not observed. When 2 equivalents of MsOH were used in refluxing DCM, pyran 8 was produced in 79% yield. Pyran 8 was unstable when isolated neat but could be stored for up to two weeks when left in solution and stored at -20 °C.

α-Selenylation of 8, followed by oxidative elimination,11 would produce dienone xi which would tautomerize (cf. xi) to produce 8-hydroxyisochromene 7 (Scheme 7). Simply stirring 8 in an appropriate

solvent in the presence of PhSeCl or PhSeBr did not generate the desired α-phenylselenide and instead caused decomposition.1 Fortunately, treatment of 8 with LDA at -78 °C, followed by the addition of freshly prepared PhSeCl, introduced a phenylselenyl group adjacent to the C-8 carbonyl. Oxidation of the selenylated material with H2O2 in EtOAc produced 8-hydroxyisochromene 7 in 93% yield. All attempts to oxidize isochromene 7 to isocoumarin 6 using selenium dioxide, Jones reagent, PCC, or manganese(II) oxide failed. Benzylic, allylic, and heteroatom-stabilized methylene and methine carbons can be oxidized using DDQ.12 To our satisfaction, treatment of isochromene 7 with 2.0 equivalents of DDQ in dioxane at room temperature and exposure to the air produced isocoumarin 6 in 92% yield. Isocoumarin 6 was also produced when 7 was oxidized with DDQ in degassed, or wet p-dioxane confirming that water is the oxygen source. Based on the work of Xu13 and others,14 the the DDQ first oxidizes 7 to isochromenylium intermediate xii. The trace water present in the p-dioxane adds to xii to generate hemiacetal xiii which is further oxidized to intermediate xiv by the excess DDQ. Intermediate xv forms isocoumarin 6 after tautomerization and deprotonation.

Subtle changes in our synthetic strategy would facilitate the preparation of more functionalized analogues of 6 and 7 (Scheme 8). For example, the reaction of 13 with acetaldehyde, propionaldehyde, isobutyraldehyde, or pentanal produced 1,3-dioxins 20A-D, respectively, as a mixture of diastereomers. All attempts to prepare aryl-substituted dioxins (R2 = C6H5) using either cyclohexane-1,3-dione (13) or 1 failed. Establishing the enynone motif was straightforward. Treating 1,3-dioxins 20A-D with 1.5 equivalents of lithium (trimethylsilyl)acetylide at 0 °C, followed by hydrolysis and TBAF deprotection, gave enynones 21A-D in excellent overall yield. When 1 equivalent of enynone 21A-D and an equal amount of MsOH were heated at reflux in DCM, pyran formation occurred albeit in only good yield. The

yield for these cyclizations improved when 2 equivalents of MsOH were added to the enynones dissolved in dichloroethane and stirred overnight at room temperature. The aromatization of the cyclohexenone-fused pyrans 22A-D gave C-1 substituted isochromenes 23A-D in very high yield.

The introduction of an alkyl substituent α to the C-8 carbonyl of 10 enables the formation of C-7 alkylated isochromenes and isocoumarins (Scheme 9). Thus, treatment of the kinetic enolate derived from 1,3-dioxin 10 at -78 °C with either methyl iodide, i-iodopropane, benzyl bromide, allyl chloride, or propargyl bromide produced alkylation products (24A-E) in excellent yield. In the case of preparation of 24B this alkylation failed -78 °C and generated propene at higher reaction temperatures; hence, the modest yield of 61%. Acetylide addition to 1,3-dioxins 24-E, followed by removal of the trimethylsilyl moiety, gave enynones 25A-E in excellent yield. The best conditions for pyran formation required that enynones 25A-E were dissolved in DCE, heated to reflux, followed by the addition of 2 equivalents of MsOH, for a total reaction time of only 15 minutes. Pyrans 26A-E were not stable on concentration; thus, they were purified and stored as a dilute solution at -20 °C. The aromatization of the cyclohexenone ring was achieved via a phenylselenylation/oxidation sequence to give C-5 substituted isochromenes 27A-E in good overall yield. In stark contrast to the oxidation of isochromene 7 to the oxidation of isochromene 7 to isocoumarin 6 (Scheme 7), the oxidation of the C-5 isocohromenes 27A-E

with excess DDQ failed to produce isocoumarins 28A-E mostly likely because of abstraction of a hydrogen atom by the DDQ from the C-5 benzylic position to generate a quinone-methide intermediate that decomposes despite the mild conditions used.

The preparation of C-3 substituted 8-hydroxyisochromenes required that different acetylide anions add to 1,3-dioxin 10 (Scheme 10). For example, 1-hexyne and phenylacetylene were each treated with n-BuLi at -78 °C, and then added to 10; acid hydrolysis of the 1,2-adduct afforded substituted enynones 29A and 29B in good yield. Butyl-substituted enynone 29A gave a 45% yield of pyran 30A whereas aryl-enynone 29B did not react with either TfOH or MsOH under a variety of reaction conditions. Pyran 30A was converted to C-3 alkylated isochromene 31A using the aforementioned aromatization conditions. Disappointingly, isochromene 31A could not be oxidized to its corresponding isocoumarin with DDQ, presumably because of the competing reactivity of the C-3 allylic position.

Concurrent with our study of alkylated enynones 25 and 29, dienone 33 was prepared from 1,3-dioxin 10 (Scheme 11). Many reagents are useful for the aromatization of cyclohexenones.15-17 DDQ has been used in the synthesis of chromenes from chromans, quinolines from saturated precursors, aromatic compounds from substituted cyclohexa-1,4-dienes, as well as in the oxidation of benzylic positions to carbonyl groups.18 We hoped that DDQ would first aromatize the cyclohexenone ring to form phenol 32, followed by the oxidation of the benzylic alcohol to a carboxylic acid, a known isocoumarin precursor.4 Our initial attempt to oxidize dienone 33 with excess DDQ in hot 1,4-dioxane directly gave isocoumarin 6 in good yield. Decreasing the quantity of oxidant used gave mostly recovered starting material, but the

formation of some 8-hydroxyisocoumarin 6 demonstrates that once formed the reaction intermediates are rapidly converted to 6. No reaction was observed when the reaction was carried out at room temperature. These results prompted us to extend its application to more substituted systems.

Scheme 12 shows the two steps needed to prepare three isocoumarins in good yield. For example, treatment of 10 with 2-propenyllithium gave dienone 34 which was cyclized with excess DDQ to isocoumarin 35 in 61% yield. Similarly, a C-3 methyl group was introduced by treating 10 with 1-propenyllithium and the resulting dienone product (36) was oxidized with DDQ to produce isocoumarin 37 in 55% yield. The hydrogenation of the C-3, C-4 double bond of 37 would produce mellein, a secondary fungal metabolite.2h,19 It is important to note that 1-propenyllithium was prepared from a 1:1 mixture of E:Z 1-bromopropene, giving 36 as a 1:1 mixture of E:Z dienones. Both geometric isomers cyclized to give 37. Oospolactone (40), a prominent toxin with antibiotic activity against plants and Gram-positive bacteria,2h was prepared when 10 was treated with 2-buten-2-yllithium, obtained from a 3:1 mixture of E:Z 2-bromo-2-butene, and the product (39) was oxidized with DDQ.19 Changing the vinyl equivalent and further functionalization of the products represents an attractive method for the preparation of C-3 substituted and C-4 substituted 8-hydroxyisocoumarins.

The preparation of 1,3-dioxins 24A-E that have an alkyl substituent at C-5 was discussed earlier (Scheme 9). 1,2-Addition of a vinylmagnesium bromide to enones 24A-E generated dienones 41A-E in high yield (Scheme 13). Treating these dienones with 4.0 equivalents of DDQ in 1,4-dioxane at 100 °C gave mixed results. For example, when an n-propyl, allyl, or propargyl group was present at the C-4 position, reaction with DDQ resulted in decomposition. Dienones 41A and 41C, on the other hand, yielded isocoumarins 28A and 28C in 43% and 33% yield, respectively. Clearly, additional studies are needed to fully understand the mechanism and the scope and limitations of this one-pot transformation.

Two new strategies were developed for the synthesis of 8-hydroxyisocoumarins. Both strategies form the pyran first, followed by the aromatization of the cyclohexenone ring. Presently, the preparation of multiply alkylated isocoumarins using this strategy is limited. A simple two-step synthesis of 8-hydroxyisocoumarins using DDQ was developed, albeit not fully investigated. This strategy introduced alkyl substituents at C-3 and C-4 and permitted a two-step synthesis of oopsolactone (40) from 1,3-dioxin 10 in good overall yield. Additional studies are planned to expand the generality of this isocoumarin synthesis and to understand the mechanism of the one-pot DDQ oxidation.

EXPERIMENTAL SECTION
General Procedures: All reactions were run under a nitrogen atmosphere and monitored by TLC analysis. Unless otherwise indicated, all extractive workups consisted of the following procedure: The reaction was slowly quenched by the addition of saturated aqueous NaHCO3. The aqueous layer was extracted with two portions of Et2O. The combined ether extracts were washed with water, brine, and dried over anhydrous sodium sulfate. Filtration, followed by concentration at reduced pressure on a rotary evaporator and at 100 torr to a constant weight, afforded a crude residue which was purified using silica gel 60 (230-400 mesh ASTM) and reagent grade petroleum ether (pet ether), Et2O, and EtOAc. 1H and 13C NMR spectra were recorded on Bruker AVB-400 and DRX-500 MHz spectrometers with 13C operating frequencies of 100 MHz and 125 MHz, respectively. 1H NMR spectra were obtained in CDCl3 and were calibrated using trace CHCl3 present (δ 7.27) as an internal reference. 13C NMR spectra were obtained in CDCl3 and were calibrated using trace CHCl3 present (δ 77.23) as an internal reference.

Preparation of 7,8-dihydro-4H-benzo[d][1,3]dioxin-5(6H)-one (10): To a solution of 1 (30.8 g, 0.22 mol) and 1,3,5-trioxane (42.0 g, 0.47 mol) in DCM (300 mL) at 0 °C was added dropwise BF3-Et2O (53 mL, 0.42 mmol) over 5-min. The resulting solution was stirred at rt for 16 h, at which time it was filtered through a short pad of Celite, which was rinsed with two 50 mL portions of DCM. The resulting solution was cooled to 0 °C and slowly quenched by the addition of saturated aqueous NaHCO3 (100 mL). Standard extractive workup, followed by silica gel chromatography (elution with pet ether/EtOAc = 2:1) gave 33.7 g (97%) of 10 as a yellow oil which was homogeneous by TLC analysis [Rf (10) = 0.37, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 5.10 (s, 2H), 4.39 (s, 2H), 2.33-2.40 (m, 2H), 2.27-2.35 (m, 2H), 1.90-1.99 (m, 2H); 13C NMR (100 MHz, CHCl3) δ 196.5, 170.5, 112.0, 91.6, 63.0, 36.7, 27.8, 20.8.

Preparation of 8-methyl-7,8-dihydro-4H-benzo[d][1,3]dioxin-5(6H)-one (16): To a solution of 159 (1.20 g, 8 mol) and 1,3,5-trioxane (1.35 g, 16 mmol) in DCM (15 mL) at 0 °C was added dropwise BF3-Et2O (2.1 mL, 16 mmol) over 5-min. The resulting solution was stirred at rt for 16 h, at which time it was filtered through a short pad of Celite, which was rinsed with two 10 mL portions of DCM. The resulting solution was cooled to 0 °C and slowly quenched by the addition of saturated aqueous NaHCO3 (5 mL). Standard extractive workup, followed by silica gel chromatography (elution with pet ether/EtOAc = 2:1) gave 1.15 g (88%) of 16 as a yellow oil which was homogeneous by TLC analysis [Rf (16) = 0.46, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 5.10-5.16 (m, 1H), 5.03-5.12 (m, 1H), 4.43 (s, 2H), 2.55-2.62 (m, 1H), 2.40-2.49 (m, 1H), 2.27-2.36 (m, 1H), 2.03-2.10 (m, 1H), 1.66-1.73 (m, 1H), 1.18-1.25 (m, 3H); 13C NMR (100 MHz, CHCl3) δ 196.4, 173.4, 111.0, 91.6, 63.0, 34.6, 32.4, 28.8, 16.5.

General Procedure A (1,2-Addition of an Acetylide Anion to a 1,3-Dioxin 10): To a solution of TMS-acetylene (1.4 equiv., ~21 mmol) in 50 mL of THF at -78 °C was added n-butyllithium (1.2 equiv., 2.5 M, ~18 mmol) over a 2-min period. The resulting mixture was stirred at -78 °C for 30-min, and then warmed to 0 °C over a 30-min period. A solution of 10 (1.0 equiv., ~15 mmol) dissolved in 15 mL of THF was then added via cannulation over a 5-min period. The resulting reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by the addition of water (10 mL), followed by the portion-wise addition of aqueous 6M HCl (40 mL). The resulting solution was subjected to standard extractive workup to yield the crude TMS-enynone, which was used in the next step without further purification or characterization. To a solution of crude TMS-enynone dissolved in 100 mL of THF at rt was added TBAF-trihydrate (1.5 equiv., ~23 mmol) in a single portion. The resulting solution was stirred at rt for a 5-min period. Standard extractive workup yielded the crude enynone.

Preparation of 3-ethynyl-2-(hydroxymethyl)cyclohex-2-en-1-one (9): 1,3-Dioxin 10 (4.20 g, 27 mmol) was reacted according to general procedure A. Purification using silica gel chromatography (elution with pet ether/EtOAc = 2.1) gave 2.92 g (73%) of 9 as a yellow oil which was homogeneous by TLC analysis [Rf (9) = 0.35, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 4.53 (d, J = 5.5 Hz, 2H), 3.81 (s, 1H), 2.87 (bt, J = 6.2 Hz, 1H), 2.54 (t, J = 5.8 Hz, 2H), 2.54 (t, J = 6.2 Hz, 2H), 2.49 (t, J = 5.8 Hz, 2H), 2.04 (pentet, J = 5.6 Hz, 2H); 13C NMR (100 MHz, CHCl3) δ 200.0, 142.1, 139.1, 92.3, 80.9, 59.9, 38.0, 31.2, 23.3.

General Procedure B (Acid-catalyzed Pyran Formation): To a solution of enynone (~7 mmol) in either DCM or DCE (40 mL) heated to a vigorous reflux was added MsOH (2 equiv., ~14 mmol) in one portion. The resulting solution was stirred at reflux for 15-min. The reaction mixture was cooled to rt and diluted with Et2O (60 mL) and filtered through a short pad of silica. The silica is flushed with three 15 mL portions of EtOAc. The organic portions were combined and concentration under reduced pressure gave pyran, which was immediately purified by silica gel chromatography, concentrated almost completely, and stored in the remaining column eluent for further use.

Preparation of 6,7-dihydro-1H-isochromen-8(5H)-one (8): Enynone 9 (1.00 g, 6.7 mmol) was reacted according to general procedure B using DCM. Silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 785 mg (79%) of 8 as a clear colorless oil which was homogeneous by TLC analysis [Rf (8) = 0.52, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.74 (d, J = 5.1 Hz, 1H), 5.29 (d, J = 5.1 Hz, 1H), 4.83 (s, 2H), 2.29-2.42 (m, 4H), 1.93-2.01 (m, 2H); 13C NMR (100 MHz, CHCl3) δ 196.0, 153.1, 150.5, 117.5, 105.3, 63.3, 37.5, 28.1, 22.4.

General Procedure C (Aromatization of the Cyclohexenone Ring): To a solution of pyran (~3 mmol) in THF (8 mL) at -78 °C was added dropwise a solution of LDA (1.8M, 3.6 mmol). The resulting solution was stirred at -78 °C for 1 h, at which time PhSeCl (4.2 mmol) in THF (1 mL) was added rapidly in one portion and the reaction mixture was stirred at -78 °C for a 30-min period. Standard ethereal workup gave the crude α-phenylselenide, which was used directly in the next step without purification or characterization. To a solution of phenylselenide in EtOAc (20 mL) at rt was added a solution of hydrogen peroxide (30% in water, 9 mmol). The resulting solution was stirred at rt for 30-min, at which time Et2O (20 mL) was added to the reaction mixture. The organic layer was washed with water (5 mL), 10% aqueous NaHCO3 (5 mL), four portions of water (5 mL), and brine (5 mL). The crude isochromene was obtained by drying over anhydrous sodium sulfate and concentration under reduced pressure.

Preparation of 1H-isochromen-8-ol (7): Pyran 8 (650 mg, 4 mmol) was reacted according to general procedure C. Purification using silica gel chromatography (elution with pet ether/EtOAc = 6:1) gave 595 mg (93%) of 7 as a red oil which was homogeneous by TLC analysis [Rf (7) = 0.37, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 7.03 (t, J = 7.8 Hz, 1H), 6.56 (m, 3H), 5.73 (d, J = 5.6 Hz, 1H), 5.17 (s, 2H), 4.80 (s, 1H); 13C NMR (100 MHz, acetone) δ 152.1, 146.2, 131.9, 128.6, 114.9, 114.3, 114.2, 105.1, 62.7.

Preparation of 8-hydroxy-1H-isochromen-1-one (6): To a solution of isochromene 7 (145 mg, 10 mmol) in 1,4-dioxane (~6-15 mL) at rt was added DDQ (2.0 equiv.) in one portion. The resulting suspension was stirred at rt until TLC analysis indicated the consumption of the starting isochromene. To the reaction mixture was added Et2O (20 mL). The reaction mixture was washed with H2O (4x4 mL) and brine (5 mL). The crude isocoumarin was obtained by drying over anhydrous sodium sulfate and concentration under reduced pressure. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 146 mg (92%) of isocoumarin 6 as a clear colorless oil which was homogeneous by TLC analysis [Rf (6) = 0.43, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, acetone) δ 11.0 (s, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 5.6 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 5.6 Hz, 1H); 13C NMR (100 MHz, acetone) δ 166.4, 161.9, 144.1, 137.6, 136.9, 110.1, 110.0, 108.6, 107.5.

General Procedure D (1,3-Dioxin Formation using Cyclohexane-1,3-dione): To a solution of cyclohexane-1,3-dione (13) (~45 mmol) and an aldehyde (3 equiv., ~135 mmol) in DCM (125 mL) at 0 oC was added dropwise BF3-Et2O (2 equiv., ~90 mmol) over a 5-min period. The resulting solution was stirred at rt for 5-7h, at which time it was cooled to 0 °C and quenched by the addition of saturated NaHCO3 (20 mL). Standard extractive workup gave the corresponding substituted 1,3-dioxin.

Preparation of 2,4-dimethyl-7,8-dihydro-4H-benzo[d][1,3]dioxin-5(6H)-one (20A): Diketone 13 (5.00 g, 45 mmol) was reacted with acetaldehyde according to general procedure D. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 6.5 g (81%) of 20A as a clear colorless oil which was homogeneous by TLC analysis but consisted of a mixture of two diastereomers by 1H and 13C NMR analysis [Rf (20A) = 0.36, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 5.26 (q, J = 5.1 Hz) and 5.03 (q, J = 5.1 Hz) (1H), 4.66-4.79 (m, 1H), 2.41 (t, J = 6.0 Hz, 2H), 2.36 (t, J = 6.7 Hz, 2H), 1.99 (pentet, J = 6.3 Hz, 2H), 1.38-1.53 (m, 6H); 13C NMR (100 MHz, CHCl3) δ 196.1, 170.9 + 169.9, 116.7 + 115.5, 97.1 + 91.9, 70.5 + 67.6, 37.2 + 37.1, 28.1 + 28.0, 20.8, 20.3 + 20.1, 19.9 + 19.8.

Preparation of 2,4-diethyl-7,8-dihydro-4H-benzo[d][1,3]dioxin-5(6H)-one (20B): Diketone 13 (5.00 g, 45 mmol) was reacted with propionaldehyde according to general procedure D and silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 8.7 g (93%) of 20B as a clear colorless oil which was homogeneous by TLC analysis analysis but consisted of a mixture of two diastereomers by 1H and 13C NMR analysis [Rf (20B) = 0.45, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 5.00 (t, J = 5.1 Hz) and 4.81 (t, J = 4.9 Hz) (1H), 4.60 (d, J = 6.2 Hz) and 4.45 (d, J = 10.7 Hz) (1H), 2.25-2.56 (m, 6H), 1.90-2.01 (m, 2H), 1.73-1.84 (m, 2H), 0.97-1.10 (m, 6H); 13C NMR (100 MHz, CHCl3) δ 196.6 + 196.5, 172.3 + 170.4, 117.6 + 115.1, 100.7, 95.6, 74.6, 73.0, 37.3 + 37.1, 28.4 + 28.1, 27.3 + 27.1, 26.0 + 25.8, 20.9, 20.2 + 20.1.

Preparation of 2,4-diisopropyl-7,8-dihydro-4H-benzo[d][1,3]dioxin-5(6H)-one (20C): Diketone 13 (5.00 g, 45 mmol) was reacted with isobutyraldehyde according to general procedure D. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 9.2 g (86%) of 20C as a clear colorless oil which was homogeneous by TLC analysis analysis but consisted of a mixture of two diastereomers by 1H and 13C NMR analysis [Rf (20C) = 0.55, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 4.92 (d, J = 5.0 Hz) and 4.59 (d, J = 4.2 Hz) (1H), 4.53 (s) and 4.36 (d, J = 7.0 Hz) (1H), 2.21-2.50 (m, 4H), 1.89-1.99 (m, 4H) 0.64-1.09 (m, 12H); 13C NMR (100 MHz, CHCl3) δ 196.2 + 196.0, 172.5 + 170.3, 114.9 + 113.7, 102.6 + 99.3, 77.3 + 74.9, 37.4 + 37.2, 32.2 + 32.1, 29.2, 28.5, 20.6 + 20.2, 19.5, 19.1 + 19.0, 16.9 + 16.5, 16.4 + 16.3, 14.6.

Preparation of 2,4-dibutyl-7,8-dihydro-4H-benzo[d][1,3]dioxin-5(6H)-one (20D): Diketone 13 (5.00 g, 45 mmol) was reacted with pentanal according to general procedure D. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 10.3 g (87%) of 20D as a clear colorless oil which was homogeneous by TLC analysis but consisted of a mixture of two diastereomers by 1H and 13C NMR analysis [Rf (20D) = 0.58, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 5.07 (t, J = 5.1 Hz) and 4.84 (t, J = 5.1 Hz)(1H), 4.61 (d, J = 7.2 Hz) and 4.54 (d, J = 10.2 Hz)(1H), 2.28-2.47 (m, 4H), 1.68-2.07 (m, 4H), 1.24-1.54 (m, 8H), 0.82-0.99 (m, 6H); 13C NMR (100 MHz, CHCl3) δ 196.4, 171.7 + 170.1, 115.7 + 115.2, 100.1 + 94.8, 74.1 + 71.7, 37.4 + 37.2, 33.8 + 33.6, 32.8 + 32.7, 28.4 + 28.2, 27.7 + 27.0, 25.8 + 25.7, 22.8 + 22.5, 22.6 + 22.5, 20.9 + 20.2, 14.2 +14.2, 14.0 + 14.0.

Preparation of 3-ethynyl-2-(1-hydroxyethyl)cyclohex-2-en-1-one (21A): 1,3-Dioxin 20A (4.40 g, 24 mmol) was reacted according to general procedure A. Purification using silica gel chromatography (elution with pet ether/EtOAc = 2:1) gave 3.49 (88%) of 21A as a clear colorless oil which was homogeneous by TLC analysis [Rf (21A) = 0.38, 2:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 4.87-4.99 (m, 1H), 3.94 (d, J = 11.4 Hz, 1H), 3.83 (s, 1H), 2.52 (t, J = 6.0 Hz, 2H), 2.47 (t, J = 6.2 Hz, 2H), 1.95-2.06 (m, 3H), 1.42 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 200.4, 144.7, 137.1, 93.2, 80.8, 68.8, 38.7, 31.1, 23.2, 22.2.

Preparation of 3-ethynyl-2-(1-hydroxypropyl)cyclohex-2-en-1-one (21B): 1,3-Dioxin 20B (4.90 g, 23 mmol) was reacted according to general procedure A. Purification using silica gel chromatography (elution with pet ether/EtOAc = 2:1) gave 3.69 g (86%) of 21B as a clear colorless oil which was homogeneous by TLC analysis [Rf (21B) = 0.47, 2:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 4.55-4.69 (m, 2H), 3.80 (s, 1H), 3.74 (d, J = 11.4 Hz, 1H), 2.54 (t, J = 6.0 Hz, 2H), 2.47 (t, J = 6.2 Hz, 2H), 1.93-2.04 (m, 2H), 1.73-1.85 (m, 1H), 1.63-1.72 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 200.7, 143.8, 138.0, 92.8, 81.1, 74.4, 38.8, 31.3, 30.3, 22.3, 10.8.

Preparation of 3-ethynyl-2-(1-hydroxy-2-methylpropyl)cyclohex-2-en-1-one (21C): 1,3-Dioxin 20C (4.10 g, 20 mmol) was reacted according to general procedure A. Purification using silica gel chromatography (elution with pet ether/EtOAc = 2:1) gave 3.57 g (96%) of 21C as a clear colorless oil which was homogeneous by TLC analysis [Rf (21C) = 0.50, 2:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 4.35 (t, J = 9.5 Hz, 1H), 3.79 (s, 1H), 3.64 (d, J = 11.4 Hz, 1H), 2.55 ( t, J = 5.8 Hz, 2H), 2.47 (t, J = 6.7 Hz, 2H), 1.85-2.07 (m, 3H), 1.07 (d, J = 6.5 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 200.9, 143.3, 138.9, 92.7, 81.5, 78.7, 38.9, 34.4, 31.5, 22.3, 16.6, 16.5.

Preparation of 3-ethynyl-2-(1-hydroxypentyl)cyclohex-2-en-1-one (21D): 1,3-Dioxin 20D (4.30 g, 16 mmol) was reacted according to general procedure F. Purification using silica gel chromatography (elution with pet ether/EtOAc = 2:1) gave 2.95 g (89%) of 21D as a clear colorless oil which was homogeneous by TLC analysis [Rf (21D) = 0.53, 2:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 4.65-4.76 (m, 1H), 3.81 (s, 1H), 3.73 (d, J = 11.4 Hz, 1H), 2.53 (t, J = 5.9 Hz, 2H), 2.46 (t, J = 6.2 Hz, 2H), 1.97-2.05 (m, 2H), 1.75-1.82 (m, 1H), 1.55-1.64 (m, 1H), 1.40-1.50 (m, 1H), 1.25-1.33 (m, 2H), 0.89 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 200.7, 144.2, 137.7, 92.8, 81.1, 72.9, 38.9, 37.0, 31.3, 28.3, 22.6, 22.3, 14.2.

Preparation of 1-methyl-6,7-dihydro-1H-isochromen-8(5H)-one (22A): Enynone 21A (1.60 g, 9.8 mmol) was reacted according to general procedure G in DCE, except that the cyclization was performed at rt for 24 h. Silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 1.07 g (67%) of 22A as a clear yellow oil which was homogeneous by TLC analysis [Rf (22A) = 0.38, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.63 (d, J = 5.4 Hz, 1H), 5.43 (q, J = 6.4 Hz, 1H), 5.21 (d, J = 5.4 Hz, 1H), 2.29-2.47 (m, 5H), 1.95-2.06 (m, 2H), 1.28 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 196.0, 150.7, 148.4, 122.5, 103.6, 69.9, 37.8, 28.3, 22.4, 18.8.

Preparation of 1-ethyl-6,7-dihydro-1H-isochromen-8(5H)-one (22B): Enynone 21B (1.30 g, 7.3 mmol) was reacted according to general procedure B in DCE, except that the cyclization was performed at rt for 24 h. Silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 1.0 g (51%) of 22B as a clear yellow oil which was homogeneous by TLC analysis [Rf (22B) = 0.38, 4:1 pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.65 (d, J = 5.4 Hz, 1H), 5.18-5.25 (m, 2H), 2.29-2.48 (m, 4H), 1.98-2.05 (m, 2H), 1.79-1.91 (m, 1H), 1.39-1.47 (m, 1H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 196.1, 150.9, 148.9, 121.6, 104.0, 74.8, 37.8, 28.4, 25.9, 22.4, 9.84.

Preparation of 1-isopropyl-6,7-dihydro-1H-isochromen-8(5H)-one (22C): Enynone 21C (1.10 g, 5.7 mmol) was reacted according to general procedure B in DCE, except that the cyclization was performed at rt for 24 h. Silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 760 mg (69%) of 22C as a clear yellow oil which was homogeneous by TLC analysis [Rf (22C) = 0.41, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.70 (d, J = 5.4 Hz, 1H), 5.19 (d, J = 5.4 Hz, 1H), 5.09 (d, J = 7.3 Hz, 1H), 2.26-2.57 (m, 4H), 1.91-2.17 (m, 3H), 1.01 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 196.5, 151.8, 149.4, 120.3, 104.1, 78.1, 37.9, 31.5, 28.7, 22.2, 18.4, 18.1.

Preparation of 1-butyl-6,7-dihydro-1H-isochromen-8(5H)-one (22D): Enynone 21D (1.30 g, 6.3 mmol) was reacted according to general procedure B in DCE, except that the cyclization was performed at rt for 24 h. Silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 900 mg (69%) of 22D as a clear yellow oil which was homogeneous by TLC analysis [Rf (22D) = 0.45, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.64 (d, J = 5.4 Hz, 1H), 5.21-5.33 (m, 1H), 5.21 (d, J = 5.4 Hz, 1H), 2.28-2.49 (m, 5H), 1.77-2.08 (m, 4H), 1.21-1.50 (m, 6H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 196.1, 150.8, 148.7, 121.8, 104.0, 73.6, 37.8, 32.4, 28.4, 27.5, 22.7, 22.4, 14.2.

Preparation of 1-methyl-1H-isochromen-8-ol (23A): Pyran 22A (523 mg, 3 mmol) was reacted according to general procedure C. Purification using silica gel chromatography (elution with pet ether/EtOAc = 6:1) gave 479 mg (93%) of 23A as a red oil which was homogeneous by TLC analysis [Rf (23A) = 0.36, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 7.04 (t, J = 7.8 Hz, 1H), 6.57 (t, J = 6.9 Hz, 2H), 6.45 (d, J = 5.7 Hz, 1H) 5.60-5.72 (m, 3H), 1.48 (d, J = 4.3 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 150.5, 143.7, 130.4, 128.5, 119.3, 116.3, 114.1, 103.8, 69.2, 19.7.

Preparation of 1-ethyl-1H-isochromen-8-ol (23B): Pyran 22B (379 mg, 2 mmol) was reacted according to general procedure C. Purification using silica gel chromatography (elution with pet ether/EtOAc = 6:1) gave 350 mg (93%) of 23B as a red oil which was homogeneous by TLC analysis [Rf (23B) = 0.42, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 7.05 (t, J = 7.7 Hz, 1H), 6.57 (m, 2H), 6.4 (d, J = 5.7 Hz, 1H), 5.71 (d, J = 5.7 Hz), 5.45 (dd, J = 9.2, 4.0 Hz, 1H), 5.07 (s, 1H), 1.99-2.07 (m, 1H), 1.55-1.66 (m, 1H), 1.05 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 150.6, 143.9, 130.9, 128.5, 118.4, 116.5, 114.1, 104.3, 74.3, 26.8, 10.4.

Preparation of 1-isopropyl-1H-isochromen-8-ol (23C): Pyran 22C (451 mg, 2 mmol) was reacted according to general procedure C. Purification using silica gel chromatography (elution with pet ether/EtOAc = 6:1) gave 415 mg (93%) of 23C as a red oil which was homogeneous by TLC analysis [Rf (23C) = 0.45, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 7.06 (t, J = 7.8 Hz, 1H), 6.57 (d, J = 7.8 Hz, 1H), 6.52 (d, J = 6.1 Hz, 1H), 5.70 (d, J = 5.7 Hz, 1H), 5.24 (d, J = 7.2 Hz, 1H), 5.19 (bs, 1H), 2.31 (sextet, J = 6.9 Hz, 1H), 1.09 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, CHCl3) δ 151.3, 144.7, 131.4, 128.6, 117.0, 116.4, 114.2, 104.7, 77.8, 32.3, 18.8, 18.7.

Preparation of 1-butyl-1H-isochromen-8-ol (23D): Pyran 22D (610 mg, 3 mmol) was reacted according to general procedure C. Purification using silica gel chromatography (elution with pet ether/EtOAc = 6:1) gave 550 mg (91%) of 23D as a red oil which was homogeneous by TLC analysis [Rf (23D) = 0.50, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 7.05 (t, J = 7.8 Hz, 1H), 6.59 (d, J = 6.7 Hz, 1H), 6.49 (d, J = 5.7 Hz, 1H), 5.74 (d, J = 5.78 Hz, 1H), 5.70 (bs, 1H), 5.57 (dd, J = 9.7, 2.6 Hz, 1H), 2.08-2.17 (m, 2H), 1.29-1.64 (m, 4H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 150.7, 143.6, 130.8, 128.5, 118.8, 116.4, 114.2, 104.6, 73.1, 32.2, 28.0, 22.7, 14.3.

General Procedure E (Alkylation at C−7): To a solution of 1,3-dioxin 10 (~25 mmol) in THF (50 mL) at -78 °C was added dropwise a solution of LDA (1.8M, 1.2 equiv., 30 mmol) over a 5-min period. The resulting solution was stirred at -78 °C for 30-min, at which time a corresponding alkylating agent (1.4, equiv., ~35 mmol) in THF (10 mL) was added dropwise over a 1-min period. The resulting solution was allowed to stir at -78 °C for 1 h, warmed to -30 °C over 30-min, then stirred at -30 °C for 1 h. The reaction was then quenched by the addition of saturated aqueous NH4Cl (10 mL). Standard extractive workup, followed by silica gel chromatography, gave the crude alkylation product.

Preparation of 6-methyl-7,8-dihydro-4H-benzo[d][1,3]dioxin-5(6H)-one (24A): Ketone 10 (4.10 g, 27 mmol) was reacted with iodomethane according to general procedure E. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 4.16 g (93%) of 24A as a yellow oil which was homogeneous by TLC analysis [Rf (24A) = 0.32, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 5.18 (d, J = 5.4 Hz, 1H), 5.07 (d, J = 5.4 Hz, 1H), 4.43 (dq, J = 14.8, 9.7 Hz, 2H), 2.27-2.55 (m, 3H), 1.98-2.09 (m, 1H), 1.66-1.79 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 198.7, 169.5, 111.1, 91.5, 63.1, 40.0, 28.8, 27.1, 15.3.

Preparation of 6-propyl-7,8-dihydro-4H-benzo[d][1,3]dioxin-5(6H)-one (24B): Ketone 10 (4.20 g, 27 mmol) was reacted with n-propyl iodide according to general procedure E, but the temperature was increased from -30 °C to rt until no further reaction was observed by TLC analysis. Silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 2.4 g (61% brsm, 73% conversion,) of 24B as a yellow oil which was homogeneous by TLC analysis [Rf (24B) = 0.47, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 5.16 (d, J = 5.4 Hz, 1H), 5.09 (d, J = 5.4 Hz, 1H), 4.43 (s, 2H), 2.33-2.48 (m, 2H), 2.16-2.27 (m, 1H), 2.04-2.13 (m, 1H), 1.71-1.82 (m, 2H), 1.30-1.39 (m, 3H), 0.92 (t, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 198.4, 169.2, 111.2, 91.4, 63.0, 44.7, 31.6, 26.6, 25.7, 20.3, 14.2.

Preparation of 6-benzyl-7,8-dihydro-4H-benzo[d][1,3]dioxin-5(6H)-one (24C): Ketone 10 (4.10 g, 27 mmol) was reacted with benzylbromide according to general procedure E. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 5.93 g (91%) of 24C as a yellow oil which was homogeneous by TLC analysis [Rf (24C) = 0.38, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 7.23-7.33 (m, 2H), 7.10-7.20 (m, 3H), 5.18 (d, J = 5.4 Hz, 1H), 5.08 (d, J = 5.4 Hz, 1H), 4.46 (dq, J = 14.6, 6.1 Hz, 2H), 3.37 (dq, J =9.6, 8.4 Hz, 1H), 2.40-2.52 (m, 2H), 2.34-2.43 (m, 2H), 1.87-1.99 (m, 1H), 1.59-1.70 (m, 1H); 13C NMR (100 MHz, CHCl3) δ 197.0, 169.7, 140.1, 129.6, 128.6, 126.3, 111.3, 91.6, 63.1, 46.9, 35.7, 27.0, 25.2.

Preparation of 6-allyl-7,8-dihydro-4H-benzo[d][1,3]dioxin-5(6H)-one (24D): Ketone 10 (4.20 g, 27 mmol) was reacted with allyl bromide according to general procedure E. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 4.91 g (93%) of 24D as a yellow oil which was homogeneous by TLC analysis [Rf (24D) = 0.44, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 5.76 (septet, J = 7.4, 1H), 5.18 (d, J = 5.4 Hz, 1H), 5.02-5.12 (m, 3H), 4.44 (dd, J = 15.0, 3.8 Hz, 2H), 2.60-2.71 (m, 1H), 2.41-2.49 (m, 2H), 2.22-2.35 (m, 1H), 2.05-2.16 (m, 2H), 1.68-1.81 (m, 1H); 13C NMR (100 MHz, CHCl3) δ 197.2, 169.6, 136.3, 116.9. 111.3, 91.5, 63.0, 44.5, 34.0, 26.9, 25.4.

Preparation of 6-(prop-2-yn-1-yl)-7,8-dihydro-4H-benzo[d][1,3]dioxin-5(6H)-one (24E): Ketone 10 (4.10 g, 27 mmol) was reacted with propargyl bromide according to general procedure E. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 4.68 g (90%) of 24E as a yellow oil which was homogeneous by TLC analysis [Rf (24E) = 0.32, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 5.21 (d, J = 5.4, 1H), 5.07 (d, J = 5.4, 1H), 4.43 (q, J = 17.4 Hz, 2H), 2.71-2.83 (m, 1H), 2.36-2.60 (m, 2H), 2.25-2.36 (m, 2H), 1.80-1.94 (m, 1H); 13C NMR (100 MHz, CHCl3) δ 195.5, 170.1, 111.2, 91.6, 82.3, 70.2, 62.9, 43.9, 27.3, 25.7, 19.1.

Preparation of 3-ethynyl-2-(hydroxymethyl)-4-methylcyclohex-2-en-1-one (25A): 1,3-Dioxin 24A (3.7 mg, 22 mmol) was reacted according to general procedure A. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 3.34 g (92%) of 25A as a clear colorless oil which was homogeneous by TLC analysis [Rf (25A) = 0.35, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 4.49 (d, J = 5.4, Hz, 2H), 3.83 (s, 1H), 2.90-3.02 (m, 1H), 2.50-2.65 (m, 2H) 2.37-2.48 (m, 1H), 2.10-2.21 (m, 1H), 1.69-1.79 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 199.8, 144.1, 141.4, 93.4, 80.1, 59.9, 35.8, 34.4, 29.8, 19.1.

Preparation of 3-ethynyl-2-(hydroxymethyl)-4-propylcyclohex-2-en-1-one (25B): 1,3-Dioxin 24B (2.80 g, 14 mmol) was reacted according to general procedure A. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 2.45 g (89%) of 25B as a clear colorless oil which was homogeneous by TLC analysis [Rf (25B) = 0.45, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 4.50 (s, 2H), 3.84 (s, 1H), 2.95 (bs, 1H), 2.44-2.53 (m, 2H), 2.34-2.41 (m, 1H), 2.06-2.15 (m, 1H), 1.79-1.88 (m, 2H), 1.43-1.50 (m, 2H), 1.30-1.39 (m, 1H), 0.93 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 200.0, 143.7, 141.7, 93.2, 80.4, 60.3, 39.2, 35.3, 34.6, 26.1, 20.6, 14.2.

Preparation of 4-benzyl-3-ethynyl-2-(hydroxymethyl)cyclohex-2-en-1-one (25C): 1,3-Dioxin 24C (4.15 g, 17 mmol) was reacted according to general procedure A. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 3.36 g (82%) of 25C as a clear colorless oil which was homogeneous by TLC analysis [Rf (25C) = 0.48, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 7.29-7.39 (m, 2H), 7.16-7.23 (m, 3H), 4.57 (d, J = 6.0 Hz, 2H), 3.93 (s, 1H), 3.39 (dd, J = 13.4, 3.0 Hz, 1H), 2.95 (bs, 1H), 2.69-2.81 (m, 1H), 2.49-2.70 (m, 2H), 2.30-2.39 (m, 1H), 1.92-2.02 (m, 1H), 1.69-1.78 (m, 1H); 13C NMR (100 MHz, CHCl3) δ 199.7, 142.4, 142.4, 139.3, 129.2, 128.8, 126.8, 93.8, 80.3, 60.2, 41.4, 38.7, 35.1, 25.5.

Preparation of 4-allyl-3-ethynyl-2-(hydroxymethyl)cyclohex-2-en-1-one (25D): 1,3-Dioxin 24D (3.30 g, 17 mmol) was reacted according to general procedure A. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 2.93 g (91%) of 25D as a clear colorless oil which was homogeneous by TLC analysis [Rf (25D) = 0.48, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 5.77 (sextet, J = 9.3 Hz, 1H), 5.09-5.16 (m, 2H), 4.50 (d, J = 14.6, 2H), 2.95 (t, J = 6.5 Hz, 1H), 2.57-2.64 (m, 1H), 2.50-2.61 (m, 2H), 2.33-2.41 (m, 1H), 2.22-2.31 (m, 1H), 2.06-2.13 (m, 1H), 1.80-1.89 (m, 1H); 13C NMR (100 MHz, CHCl3) δ 199.7, 142.5, 142.2, 135.5, 117.9, 93.7, 80.1, 59.9, 39.0, 37.0, 35.4, 25.9.

Preparation of 3-ethynyl-2-(hydroxymethyl)-4-(prop-2-yn-1-yl)cyclohex-2-en-1-one (25E): 1,3- Dioxin 24E (3.10 g, 16 mmol) was reacted according to general procedure A. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 2.6 g (85%) of 25E as a clear colorless oil which was homogeneous by TLC analysis [Rf (25E) = 0.35, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 4.52 (d, J = 5.8 Hz, 2H), 3.87 (s, 1H), 2.90 (bs, 1H), 2.73-2.81 (m, 1H), 2.58-2.73 (m, 2H), 2.39-2.56 (m, 2H), 2.23-2.32 (m, 1H), 2.02-2.10 (m, 1H); 13C NMR (100 MHz, CHCl3) δ 199.5, 142.9, 140.3, 93.9, 81.3, 79.4, 71.2, 60.3, 38.4, 35.9, 26.5, 22.9.

Preparation of 5-methyl-6,7-dihydro-1H-isochromen-8(5H)-one (26A): Enynone 25A (1.50 g, 9 mmol) was reacted according to general procedure B in DCE. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 1.16 g (78%) of 26A as a clear yellow oil which was homogeneous by TLC analysis [Rf (26A) = 0.36, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.80 (d, J = 5.5 Hz, 1H), 5.40 (d, J = 5.5 Hz, 1H), 4.84 (dd, J = 3.2, 16.3, Hz, 2H), 2.41-2.56 (m, 2H), 2.28-2.36 (m, 1H), 2.09-2.18 (m, 1H), 1.70-1.78 (m, 1H), 1.20 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 195.8, 153.3, 153.6, 116.7, 104.0, 63.3, 34.9, 31.7, 29.8, 18.3.

Preparation of 5-propyl-6,7-dihydro-1H-isochromen-8(5H)-one (26B): Enynone 25B (1.10 g, 6 mmol) was reacted according to general procedure B in DCE. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 910 mg (83%) of 26B as a clear yellow oil which was homogeneous by TLC analysis [Rf (26B) = 0.11, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.77 (d, J = 5.5 Hz, 1H), 5.37 (d, J = 5.5 Hz, 1H), 4.83 (s, 2H), 2.42-2.53 (m, 1H), 2.23-2.31 (m, 2H), 2.01-2.11 (m, 1H), 1.83-1.92 (m, 1H), 1.29-1.61 (m, 4H), 0.94 (t, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 195.8, 154.1, 153.3, 116.9, 104.6, 63.3, 36.6, 34.1, 34.0, 26.0, 20.9, 14.3.

Preparation of 5-benzyl-6,7-dihydro-1H-isochromen-8(5H)-one (26C): Enynone 25C (1.20 g, 5 mmol) was reacted according to general procedure B in DCE. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 1.01mg (85%) of 26C as a clear yellow oil which was homogeneous by TLC analysis [Rf (26C) = 0.42, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 7.29 (t, J = 7.3 Hz, 2H), 7.22 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 7.3 Hz, 2H), 6.76 (d, J = 5.4 Hz, 1H), 5.33 (d, J = 5.4 Hz, 1H), 4.84 (q, J = 10.8 Hz, 2H), 2.97 (dd, J = 4.1, 13.1 Hz, 1H), 2.39-2.69 (m, 3H), 2.27 (dt, J = 4.8, 17.4 Hz, 1H), 1.88-1.96 (m, 1H), 1.70-1.81 (m, 1H); 13C NMR (100 MHz, CHCl3) δ 195.5, 153.5, 153.0, 139.5, 129.2, 128.8, 126.8, 117.3, 104.6, 63.4, 38.7, 38.3, 33.8, 25.6.

Preparation of 5-allyl-6,7-dihydro-1H-isochromen-8(5H)-one (26D): Enynone 25D (1.6 mg, 7 mmol) was reacted according to general procedure B in DCE. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 1.42 g (90%) of 26D as a clear yellow oil which was homogeneous by TLC analysis [Rf (26D) = 0.12, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.80 (d, J = 6.8 Hz, 1H), 5.71-5.82 (m, 1H), 5.42 (d, J = 5.5 Hz, 1H), 5.13 (d, J = 8.2 Hz, 1H), 5.10 (s, 1H), 4.86 (s, 2H), 2.20-2.55 (m, 5H), 2.01-2.09 (m, 1H), 1.88-1.95 (m, 1H); 13C NMR (100 MHz, CHCl3) δ 192.7, 153.5, 152.9, 135.9, 117.7, 117.4, 104.3, 63.3, 36.5, 36.4, 34.2, 26.0.

Preparation of 5-(prop-2-yn-1-yl)-6,7-dihydro-1H-isochromen-8(5H)-one (26E): Enynone 25E (1.70 g, 7 mmol) was reacted according to general procedure B in DCE. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 1.54 g (91%) of 26E as a clear yellow oil which was homogeneous by TLC analysis [Rf (26E) = 0.36, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.82 (d, J = 5.2 Hz, 1H), 5.44 (d, J = 5.2 Hz, 1H), 4.84 (s, 2H), 2.20-2.64 (m, 4H), 1.93-2.24 (m, 3H); 13C NMR (100 MHz, CHCl3) δ 195.2, 153.8, 151.1, 117.7, 103.7, 81.7, 70.9, 63.3, 36.0, 34.4, 26.7, 22.0.

Preparation of 5-methyl-1H-isochromen-8-ol (27A): Pyran 26A (740 mg, 5 mmol) was reacted according to general procedure C. Purification using silica gel chromatography (elution with pet ether/EtOAc = 6:1) gave 670 mg (92%) of 27A as a red oil which was homogeneous by TLC analysis [Rf (27A) = 0.30, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.89 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 5.8 Hz, 1H), 6.50 (d, J = 8.2 Hz, 1H), 5.89 (d, J = 5.9 Hz, 1H), 5.24 (bs, 1H), 5.18 (s, 2H), 2.21 (s, 3H); 13C NMR (100 MHz, CHCl3) δ 148.7, 146.3, 129.9, 129.9, 123.4, 114.6, 113.9, 102.9, 63.2, 17.9.

Preparation of 5-propyl-1H-isochromen-8-ol (27B): Pyran 26B (440 mg, 2 mmol) was reacted according to general procedure C. Purification using silica gel chromatography (elution with pet ether/EtOAc = 6:1) gave 370 mg (85%) of 27B as a clear colorless oil which was homogeneous by TLC analysis [Rf (27B) = 0.36, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.88 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 5.9 Hz, 1H), 6.52 (d, J = 8.2 Hz, 1H), 5.89 (d, J = 5.9 Hz, 1H), 5.16 (s, 2H), 4.74 (bs, 1H), 2.50 (t, J = 7.9 Hz, 2H), 1.50-1.63 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 148.6, 146.4, 129.5, 129.3, 128.3, 114.8, 113.8, 102.6, 63.2, 34.0, 24.4, 14.2.

Preparation of 5-benzyl-1H-isochromen-8-ol (27C): Pyran 26C (490 mg, 2 mmol) was reacted according to general procedure C. Purification using silica gel chromatography (elution with pet ether/EtOAc = 6:1) gave 390 mg (80%) of 27C as a clear colorless oil which was homogeneous by TLC analysis [Rf (27C) = 0.42, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.90-7.15 (m, 5H), 6.66 (d, J = 8.0 Hz, 1H), 6.38 (d, J = 6.0 Hz, 1H), 6.34 (d, J = 8.4 Hz, 1H), 5.65 (d, J = 6.0 Hz, 1H), 4.98 (s, 2H), 3.73 (s, 2H); 13C NMR (100 MHz, CHCl3) δ 149.3, 146.8, 141.2, 131.1, 130.3, 128.8, 128.7, 128.6, 128.3, 126.2, 114.1, 102.7, 63.3, 37.7.

Preparation of 5-allyl-1H-isochromen-8-ol (27D): Pyran 26D (517 mg, 3 mmol) was reacted according to general procedure C. Purification using silica gel chromatography (elution with pet ether/EtOAc = 6:1) gave 510 mg (90%) of 27D as a clear colorless oil which was homogeneous by TLC analysis [Rf (27D) = 0.35, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.89 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 5.9 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 5.86-5.94 (m, 1H), 5.87 (d, J = 5.9 Hz, 1H), 5.16 (s, 2H), 5.05 (d, J = 10 Hz, 1H), 4.99 (d, J = 16.9 Hz, 1H), 4.89 (bs, 1H), 3.30 (d, J = 6.0 Hz, 2H); 13C NMR (100 MHz, CHCl3) δ 149.1, 146.7, 137.3, 130.0, 129.5, 125.3, 115.8, 114.8, 114.0, 102.5, 63.2, 36.2.

Preparation of 5-(prop-2-yn-1-yl)-1H-isochromen-8-ol (27E): Pyran 26E (600 mg, 3 mmol) was reacted according to general procedure C. Purification using silica gel chromatography (elution with pet ether/EtOAc = 6:1) gave 535 mg (92%) of 27E as a clear colorless oil which was homogeneous by TLC analysis [Rf (27E) = 0.25, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 7.13 (d, J = 8.2 Hz, 1H), 6.64 (d, J = 5.8 Hz, 1H), 6.55 (d, J = 8.2 Hz, 1H), 5.88 (d, J = 5.8 Hz, 1H), 5.16 (s, 2H), 5.09 (bs, 1H), 3.46 (s, 2H), 2.18 (s, 1H); 13C NMR (100 MHz, CHCl3) δ 149.6, 147.1, 129.6, 128.7, 121.3, 114.8, 114.0, 101.8, 82.2, 70.8, 63.1, 21.5.

Preparation of 3-(hex-1-yn-1-yl)-2-(hydroxymethyl)cyclohex-2-en-1-one (29A): To a solution of 1-hexyne (4.4 mL, 38 mmol) in 75 mL of THF at -78 °C was added n-butyllithium (13.1 mL, 2.5M, ~33 mmol) over a 2-min period. The resulting mixture was stirred at -78 °C for 30-min, and then warmed to 0 °C over a 30-min period. To the resulting solution was added a solution of 10 (4.20 g, 27 mmol) dissolved in 20 mL of THF via cannulation over a 5-min period. The resulting reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by the addition of water (20 mL), followed by the portion-wise addition of aqueous 6M HCl (50 mL). After warming the resulting solution to rt, and stirring for 30-min, the resulting solution was subjected to standard extractive workup. Silica gel chromatography (elution with pet ether/EtOAc = 2:1) gave 5.02 g (89%) of 29A as a yellow oil which was homogeneous by TLC analysis [Rf (29A) = 0.55, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 4.42 (s, 2H), 3.13 (bs, 1H), 2.35-2.43 (m, 6H), 1.90-1.99 (m, 2H), 1.43-1.52 (m, 2H), 1.32-1.40 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 200.0, 141.5, 139.8, 107.6, 78.9, 59.9, 38.0, 31.8, 30.5, 22.4, 21.1, 19.8, 13.7.

Preparation of 2-(hydroxymethyl)-3-(phenylethynyl)cyclohex-2-en-1-one (29B): To a solution of phenylacetylene (2.2 mL, 20 mmol) in 50 mL of THF at -78 °C was added n-butyllithium (6.9 mL, 2.5M, 17 mmol) over a 2-min period. The resulting mixture was stirred at -78 °C for 30-min, and then warmed to 0 °C over a 30-min period. To the resulting solution was added a solution of 10 (2.20 g, 14 mmol) dissolved in 10 mL of THF via cannulation over a 5-min period. The resulting reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by the addition of water (20 mL), followed by the portion-wise addition of aqueous 6M HCl (30 mL). After warming the resulting solution to rt, and stirring for 30-min, the resulting solution was subjected to standard extractive workup. Silica gel chromatography (elution with pet ether/EtOAc = 2:1) gave 2.37 g (73%) of 29B as a yellow oil which was homogeneous by TLC analysis [Rf (29B) = 0.57, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 7.43-7.52 (m, 2H), 7.30-7.41 (m, 3H), 4.62 (s, 2H), 3.03 (bs, 1H), 2.64 (t, J = 5.7 Hz, 2H), 2.52 (t, J = 6.5 Hz, 2H), 2.07 (pentet, J = 6.0 Hz, 2H); 13C NMR (100 MHz, CHCl3) δ 200.2, 140.3, 140.2, 132.1, 129.9, 128.8, 122.1, 104.9, 86.9, 60.5, 38.1, 31.5, 22.5.

Preparation of 3-butyl-6,7-dihydro-1H-isochromen-8(5H)-one (30A): Enynone 29A (1.40 g, 7 mmol) was reacted according to general procedure B in DCE, except that the cyclization was performed at rt for 24 h. Silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 284 mg (45% brsm, 55% conversion) of 30A as a clear colorless oil which was homogeneous by TLC analysis [Rf (30A) = 0.45, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 5.14 (s, 1H), 4.84 (s, 2H), 2.35 (t, J = 6.4 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 2.15 (t, J = 6.2 Hz, 2H), 1.95 (pentet, J = 7.6 Hz, 2H), 1.49 (pentet, J = 7.5 Hz, 2H), 1.32 (sextet, J = 7.5 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 195.5, 167.6, 152.5, 115.6, 101.6, 64.2, 37.6, 33.9, 29.2, 28.3, 22.5, 22.4, 14.0.

Preparation of 3-butyl-1H-isochromen-8-ol (31A): Pyran 30A (540 mg, 3 mmol) was reacted according to general procedure B. Purification using silica gel chromatography (elution with pet ether/EtOAc = 6:1) gave 470 mg (88%) of 31A as a clear colorless oil which was homogeneous by TLC analysis [Rf (31A) = 0.43, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 7.03 (t, J = 7.8 Hz, 1H), 6.52 (d, J = 7.6 Hz, 2H), 5.60 (s, 1H), 5.17 (s, 2H), 4.78 (bs, 1H), 2.19 (t, J = 7.6 Hz, 2H), 1.49-1.58 (m, 2H), 1.31-1.40 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 159.3, 150.4, 133.9, 128.6, 115.6, 113.6, 113.2, 100.6, 63.5, 33.6, 29.3, 22.5, 14.0.

General Procedure F (Dienone Formation from a Dioxin): To a solution of 1,3-dioxin (~13 mmol) in THF (50 mL) at 0 °C is added a solution of vinylmagnesium bromide (1.0M, 1.5 equiv., 20 mmol). The resulting reaction mixture is warmed to rt and stirred at rt for an additional 1 h. After cooling to 0 °C, H2O (20 mL) is added, followed by portionwise addition of 6M HCl (30 mL). The resulting solution is allowed to rise to rt and stirred for an additional 1 h. Standard extractive workup gave the crude enone.

Preparation of 2-(hydroxymethyl)-3-vinylcyclohex-2-en-1-one (33): 1,3-Dioxin 10 (2.50 g, 16 mmol) was reacted according to general procedure F. Purification using silica gel chromatography (elution with pet ether/EtOAc = 1:1) gave 2.05 g (82%) of 33 as a clear colorless oil which was homogeneous by TLC analysis [Rf (33) = 0.30, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 7.00 (dd, J = 17.3, 11.0 Hz, 1H), 5.76 (d, J = 17.4 Hz, 1H), 5.56 (d, J = 11.0 Hz, 1H), 4.49 (s, 2H), 2.73 (bs, 1H), 2.57 (t, J = 6.0 Hz, 2H), 2.48 (t, J = 6.0 Hz, 2H), 2.04 m, 2H); 13C NMR (100 MHz, CHCl3) δ 201.3, 153.4, 134.7, 133.9, 122.5, 55.6, 33.8, 25.8, 21.7.

General Procedure G (One-pot Isocoumarin Synthesis): To a solution of dienone (~5 mmol) in 1,4-dioxane (~10 mL) at rt was added DDQ (4 equiv., ~20 mmol) in one-portion. The resulting solution was stirred at 110 °C until the reaction was complete. The reaction mixture was then diluted with Et2O (50 mL) and the supernatant was decanted. The remaining solid was rinsed with Et2O (3 x 10 mL). The combined organic extractions were washed with H2O (5 x 5 mL), brine (5 mL), and dried over anhydrous Na2SO4. Concentration under reduced pressure gave the crude isocoumarin.

Preparation of 8-hydroxy-1H-isochromen-1-one (6): Dienone 33 (560 mg, 4 mmol) was reacted according to general procedure G. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 486 mg (81%) of 6 as a clear colorless oil which was homogeneous by TLC analysis [Rf (6) = 0.43, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, acetone) δ 11.0 (s, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 5.6 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 5.6 Hz, 1H); 13C NMR (100 MHz, acetone) δ 166.4, 161.9, 144.1, 137.6, 136.9, 110.1, 110.0, 108.6, 107.5.

Preparation of 2-(hydroxymethyl)-4-methyl-3-vinylcyclohex-2-en-1-one (41A): 1,3-Dioxin 24A (1.70 g, 10 mmol) was reacted according to general procedure G. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 1.57 g (93%) of 41A as a clear colorless oil which was homogeneous by TLC analysis [Rf (41A) = 0.36, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.84 (dd, J = 17.3, 11.0 Hz, 1H), 5.74(d, J = 17.4 Hz, 1H), 5.62 (d, J = 11.0 Hz, 1H), 4.44 (s, 2H), 2.95 (bs, 1H), 2.76 (bs, 1H), 2.56-2.65 (m, 1H), 2.39-2.48 (m, 1H), 2.09-2.19 (m, 1H), 1.82-1.90 (m, 1H), 1.25 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 200.6, 158.7, 133.7, 133.0, 126.7, 55.5, 32.7, 28.8, 28.5, 18.4.

Preparation of 2-(hydroxymethyl)-4-propyl-3-vinylcyclohex-2-en-1-one (41B): 1,3-Dioxin 24B (1.20 g, 6mmol) was reacted according to general procedure G. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 1.1 g (89%) of 41B as a clear colorless oil which was homogeneous by TLC analysis [Rf (41B) = 0.42, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.84 (dd, J = 17.3, 11.0 Hz, 1H), 5.72(d, J = 17.4 Hz, 1H), 5.57 (d, J = 11.0 Hz, 1H), 4.42 (s, 2H), 2.68-2.95 (m, 2H), 2.48-2.57 (m, 1H), 2.31-2.39 (m, 1H), 1.97-2.06 (m, 2H), 1.28-1.60 (m, 3H), 0.90-0.99 (m, 3H); 13C NMR (100 MHz, CHCl3) δ 200.0, 157.2, 132.7, 132.0, 121.3, 55.1, 32.7, 32.5, 31.7, 23.1, 20.5, 13.0.

Preparation of 2-(hydroxymethyl)-4-benzyl-3-vinylcyclohex-2-en-1-one (41C): 1,3-Dioxin 24C (1.50 g, 6 mmol) was reacted according to general procedure G. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 1.29 g (88%) of 41C as a clear colorless oil which was homogeneous by TLC analysis [Rf (41C) = 0.39, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 7.30-7.38 (m, 2H), 7.20-7.27 (m, 3H), 6.93 (dd, J = 17.3, 11.0 Hz, 1H), 5.91 (d, J = 17.4 Hz, 1H), 5.69 (d, J = 11.0 Hz, 1H), 4.42-4.52 (s, 2H), 2.97-3.08 (m, 2H), 2.66-2.73 (m, 3H), 2.39-2.48 (m, 1H), 1.57-2.00 (m, 2H); 13C NMR (100 MHz, CHCl3) δ 200.9, 156.9, 140.0, 134.6, 133.1, 128.9, 128.9, 126.8, 122.8, 37.7, 36.2, 32.8, 23.7, 21.2.

Preparation of 2-(hydroxymethyl)-4-allyl-3-vinylcyclohex-2-en-1-one (41D): 1,3-Dioxin 24D (1.60 g, 8 mmol) was reacted according to general procedure G. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 1.49 g (94%) of 41D as a clear colorless oil which was homogeneous by TLC analysis [Rf (41D) = 0.39, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.82 (dd, J = 17.3, 11.0 Hz, 1H), 5.70-5.78 (m, 1H), 5.69 (d, J = 17.4 Hz, 1H), 5.54 (d, J = 11.0 Hz, 1H), 5.05 (d, J = 8.0 Hz, 1H), 5.01 (s, 1H), 4.35 (s, 2H), 3.05 (bs, 1H), 2.72-2.80 (m, 1H), 2.43-2.52 (m, 1H), 2.28-2.35 (m, 2H), 2.15-2.23 (m, 1H), 1.94-2.02 (m, 3H); 13C NMR (100 MHz, CHCl3) δ 200.8, 157.2, 136.5, 134.4, 133.0, 122.7, 117.2, 55.9, 36.0, 33.9, 32.7, 24.2.

Preparation of 2-(hydroxymethyl)-4-(prop-2-yn-1-yl)-3-vinylcyclohex-2-en-1-one (41E): 1,3-Dioxin 24E (1.80 g, 9 mmol) was reacted according to general procedure G. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 1.46 g (82%) of 41E as a clear colorless oil which was homogeneous by TLC analysis [Rf (41E) = 0.36, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 6.84 (dd, J = 17.3, 11.0 Hz, 1H), 5.76 (d, J = 17.4 Hz, 1H), 5.62 (d, J = 11.0 Hz, 1H), 4.41 (s, 2H), 2.94-3.02 (m, 1H), 1.94-2.77 (m, 8H); 13C NMR (100 MHz, CHCl3) δ 200.3, 155.1, 134.9, 132.6, 122.9, 82.1, 70.9, 55.8, 33.6, 32.8, 24.9, 21.7.

Preparation of 2-(hydroxymethyl)-3-(prop-1-en-2-yl)cyclohex-2-en-1-one (34): To a suspension of magnesium metal (1.00 g, 40 mmol), 2-bromopropene (360 μL, 4 mmol) and an I2 crystal in THF (30 mL) was dropwise added a solution of 2-bromopropene (3.3 mL, 36 mmol) in THF (10 mL) at such a rate as to maintain a gentle reflux. Once the magnesium metal is consumed, the solution of propenylmagnesium bromide was cannulated to a solution of 10 (3.00 g, 19 mmol) in THF (10 mL) at 0 °C. The resulting reaction mixture is allowed to rise to rt and stirred at rt for an additional 1 h. After cooling to 0 °C, H2O is added, followed by 6M HCl (15 mL). The resulting solution is allowed to rise to rt and stirred for an additional 1 h. Standard extractive workup, followed by silica gel chromatography (elution with pet ether/EtOAc = 1:1), gave 2.3 g (71%) of 34 as a clear colorless oil which was homogeneous by TLC analysis [Rf (34) = 0.38, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 5.08 (s, 1H), 4.84 (s, 1H), 4.32 (s, 2H), 2.45 (t, J = 6.3 Hz, 4H), 1.97-2.06 (m, 2H), 1.91 (s, 3H); 13C NMR (100 MHz, CHCl3) δ 200.9, 162.4, 143.4, 132.9, 114.6, 57.8, 37.8, 29.9, 22.3, 21.7.

Preparation of 2-(hydroxymethyl)-3-(prop-1-en-1-yl)cyclohex-2-en-1-one (36): To a suspension of lithium metal (222 mg, 37 mmol), 1-bromopropene (310 μL, 4 mmol, ~1:1 E:Z mixture) and an I2 crystal in THF (30 mL) was dropwise added a solution of 1-bromopropene (2.8 mL, 33 mol) in THF (10 mL) at such a rate as to maintain a gentle reflux. Once the lithium metal is consumed, the solution of 1-propenyllithium was cannulated to a solution of 10 (2.70 g, 18 mmol) in THF (10 mL) at 0 °C. The resulting reaction mixture is allowed to rise to rt and stirred at rt for an additional 1 h. After cooling to 0 °C, H2O is added, followed by 6M HCl (15 mL). The resulting solution is allowed to rise to rt and stirred for an additional 1 h. Standard extractive workup, followed by silica gel chromatography (elution with pet ether/EtOAc = 1:1), gave 2.0 g (68%) of 36 as a clear colorless oil of two components (36-NP: nonpolar component; 36-P: polar component) by TLC analysis [Rf (36-NP) = 0.29, 1:1, pet ether/EtOAc, Rf (36-P) = 0.38, 1:1, pet ether/EtOAc]. 36-NP: 1H NMR (400 MHz, CHCl3) δ 6.02 (d, J = 11.7 Hz, 1H), 5.71-5.80 (m, 1H), 4.24 (s, 2H), 3.01-3.09 (m, 1H), 2.43 (t, J = 6.4 Hz, 2H), 2.37 (t, J = 6.4 Hz, 2H), 1.93-2.00 (m, 2H), 1.59 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 201.6, 156.0, 134.0, 130.1, 128.2, 59.1, 38.2, 31.1, 22.5, 15.4. 36-P: 1H NMR (400 MHz, CHCl3) δ 6.68 (d, J = 15.5Hz, 1H), 6.28 (m, 1H), 4.41 (s, 2H), 2.92-3.01 (m, 1H), 2.44-2.52 (m, 2H), 2.35-2.42 (m, 2H), 1.89-1.95 (m, 2H), 1.88 (d, J = 5.3 Hz, 3H); 13C NMR (100 MHz, CHCl3) δ 201.4, 153.8, 135.9, 132.9, 128.8, 56.0, 37.9, 26.5, 21.9, 19.6.

Preparation of 3-(but-2-en-2-yl)-2-(hydroxymethyl)cyclohex-2-en-1-one (39): To a suspension of lithium metal (205 mg, 34 mmol), 2-bromo-2-butene (350 μL, 3 mmol, ~3:1 E:Z mixture) and an I2 crystal in THF (30 mL) was dropwise added a solution of 2-bromo-2-butene (3.1 mL, 30 mmol) in THF (10 mL) at such a rate as to maintain a gentle reflux. Once the lithium metal is consumed, the solution of 2-butenyllithium was cannulated to a solution of dioxin 10 (2.50 g, 16 mol) in THF (10 mL) at 0 °C. The resulting reaction mixture is allowed to rise to rt and stirred at rt for an additional 1 h. After cooling to 0 °C, H2O is added, followed by 6M HCl (15 mL). The resulting solution is allowed to rise to rt and stirred for an additional 1 h. Standard extractive workup, followed by silica gel chromatography (elution with pet ether/EtOAc = 1:1), gave 2.2 g (75%) of 39 as a clear colorless oil which was homogeneous by TLC analysis but consisted of two components by 1H and 13C NMR analysis [Rf (39) = 0.44, 1:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 5.23-5.31 (m, 1H), 4.17 + 4.06 (s, 2H), 3.06 (bs, 1H), 2.28-2.42 (m, 4H), 1.87-1.99 (m, 2H), 1.73 + 1.68 (s, 2H), 1.59 (d, J = 6.7 Hz) + 1.36 (d, J = 6.6 Hz)(3H); 13C NMR (100 MHz, CHCl3) δ 201.4, 161.2, 135.2, 133.4, 121.5, 58.8, 38.1, 38.0, 29.7, 22.6, 22.4.

Preparation of 8-hydroxy-5-methyl-1H-isochromen-1-one (28A): Dienone 41A (606 mg, 4 mmol) was reacted according to general procedure G. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 277 mg (43%) of 28A as a clear colorless oil which was homogeneous by TLC analysis [Rf (28A) = 0.49, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 10.98 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 6.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 2.37 (s, 3H); 13C NMR (100 MHz, CHCl3) δ 166.7, 160.1, 143.7, 138.9, 134.7, 123.3, 115.6, 107.4, 105.6, 17.9.

Preparation of 8-hydroxy-5-benzyl-1H-isochromen-1-one (28C): Dienone 41C (710 mg, 3 mmol) was reacted according to general procedure G. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 248 mg (33%) of 29C as a clear colorless oil which was homogeneous by TLC analysis [Rf (29C) = 0.53, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 11.63 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.55 (t, J = 6.8 Hz, 1H), 7.42 (t, J = 6.8 Hz, 2H), 7.21 (d, J = 5.6 Hz, 1H), 7.10 (d, J = 6.0 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 3.63 (s, 2H); 13C NMR (100 MHz, CHCl3) δ 166.4, 164.6, 145.6, 140.2, 138.1, 137.7, 133.5, 130.3, 128.9, 124.8, 114.9, 108.1, 106.2, 67.3.

Preparation of 8-hydroxy-4-methyl-1H-isochromen-1-one (35): Dienone 34 (508 mg, 3 mmol) was reacted according to general procedure G. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 329 mg (61%) of 35 as a clear colorless oil which was homogeneous by TLC analysis [Rf (35) = 0.46, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 11.3 (s, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.10 (s, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 2.14 (s, 3H); 13C NMR (100 MHz, CHCl3) δ 166.8, 162.2, 140.5, 138.2, 137.5, 116.0, 114.6, 113.6, 106.8, 13.4.

Preparation of 8-hydroxy-3-methyl-1H-isochromen-1-one (37): Dienone 36 (690 mg, 4 mmol) was reacted according to general procedure G. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 402 mg (55%) of 37 as a clear colorless oil which was homogeneous by TLC analysis [Rf (37) = 0.49, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 11.0 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.27 (s, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, CHCl3) δ 166.4, 161.2, 153.5, 137.6, 136.9, 114.8, 114.2, 105.3, 104.3, 19.0.

Preparation of 8-hydroxy-3,4-dimethyl-1H-isochromen-1-one [oospolactone] (40): Dienone 39 (510 mg, 3 mmol) was reacted according to general procedure G. Purification using silica gel chromatography (elution with pet ether/EtOAc = 4:1) gave 411 mg (76%) of 40 as a clear colorless oil which was homogeneous by TLC analysis [Rf (40) = 0.49, 4:1, pet ether/EtOAc]: 1H NMR (400 MHz, CHCl3) δ 11.30 (s, 1H), 7.61 (t, J = 8.1 Hz, 1H), 6.92 (t, J = 7.6 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H); 13C NMR (100 MHz, CHCl3) δ 166.8, 162.1, 149.8, 139.3, 137.4, 114.6, 113.1, 109.4, 106.1, 17.3, 12.7.

ACKNOWLEDGEMENTS
We thank the National Science Foundation (CHE-0506486) for support of this research.

References

1. The preceding paper in this journal authored by G. Majetich and J. L. Grove and is entitled: “Synthesis of 6-Hydroxyisochromenes and 6-Hydroxycoumarins from 3-Ethoxycyclohex-2-en-1-one.”. CrossRef
2. (a) A. Ulubelen, Y. Aynehchi, M. Somogyi, A. Souri, and T. Mabry, J. Nat. Prod., 1984, 47, 170; CrossRef (b) A. Whyte, J. Gloer, J. Scott, and D. Malloch, J. Nat. Prod., 1996, 59, 765; CrossRef (c) D. S. Lim, Y. S. Kwak, J. H. Kim, S. H. Ko, W. H. Yoon, and C. H. Kim Chemotherapy, 2003, 49, 146; (d) A. Saeed, J. Heterocycl. Chem., 2004, 41, 975; CrossRef (e) M. Yoshikawa, E. Uchida, N. Chatani, H. Kobayashi, Y. Naitoh, Y. Okuno, H. Matsuda, J. Yamahara, and N. Murakami, Chem. Pharm. Bull., 1992, 40, 3352; (f) G. Qadeera, N. Ramaa, and S. Shahb, ARKIVOC, 2007, 14, 12; (g) G. Crosby and L. Beidler, Crit. Rev. Food Sci. Nutr., 1976, 7, 297; (h) J. Sonnenbichler, I. Sonnenbichler, and D. Schwarz, Phytochemistry, 1997, 44, 267; CrossRef (i) S. Nakajima, K. Kawai, S. Yamada, and Y. Sawai, Agr. Biol. Chem., 1976, 40, 811; CrossRef (j) L. Szlavik, A. Gyuris, J. Minarovits, P. Forgo, J. Molnar, and J. Hohmann, Planta Med., 2004, 70, 871. CrossRef
3. (a) R. Barry, Chem. Rev., 1964, 64, 229; CrossRef (b) N. Narasimhan and R. Mali, Synthesis, 1983, 957; CrossRef (c) R. Hill, Prog. Chem. Org. Nat. Prod., 1986, 49, 1; (d) E. Napolitano, Org. Prep. Proc. Int., 1997, 29, 631. CrossRef
4. (a) R. Larock, S. Varaprath, H. Lau, and C. Fellows, J. Am. Chem. Soc., 1984, 106, 5274; CrossRef (b) R. Larock and T. Hightower, J. Org. Chem., 1993, 58, 5298; CrossRef (c) R. Larock, M. Doty, and X. Han, J. Org. Chem., 1999, 64, 8770; CrossRef (d) S. Mehta, J. Waldo, and R. Larock, J. Org. Chem., 2009, 74, 1141; CrossRef (e) T. Yao and R. Larock, Tetrahedron Lett., 2002, 43, 7401; CrossRef (f) T. Yao and R. Larock, J. Org. Chem., 2003, 68, 5936; CrossRef (g) S. Roy, B. Neuenswander, D. Hill, and R. Larock, J. Comb. Chem., 2009, 11, 1128; CrossRef (h) D. Yue, N. Della Cà, and R. Larock, Org. Lett., 2004, 6, 1581; CrossRef (i) D. Yue, N. Della Cà, and R. Larock, J. Org. Chem., 2006, 71, 3381. CrossRef
5. (a) N. Asao, T. Nogami, K. Takahashi, and Y. Yamamoto, J. Am. Chem. Soc., 2002, 124, 764; CrossRef (b) N. Asao, C. Chan, K. Takahashi, and Y. Yamamoto, Tetrahedron, 2005, 61, 11322; CrossRef (c) S. Mondal, T. Nogami, N. Asao, and Y. Yamamoto, J. Org. Chem., 2003, 68, 9496; CrossRef (d) N. Patil and Y. Yamamoto, J. Org. Chem., 2004, 69, 5139. CrossRef
6. For the preparation of isochromenes from O-alkynyl benzoic acids, see: (a) R. G. F. Giles, I. R. Green, and C. P. Taylor, ARKIVOC, 2001, 7, 166; (b) R. Larock, S. Varaprath, H. Lau, and C. Fellows, J. Am. Chem. Soc., 1984, 106, 5274; CrossRef (c) R. Larock and T. Hightower, J. Org. Chem., 1993, 58, 5298. For the preparation of isochromenes from aryl alkynes; CrossRef (d) B. Gabriele, G. Salerno, A. Fazio, and R. Pittelli, Tetrahedron, 2003, 59, 6251; CrossRef (e) X. Li, A. Chianese, T. Vogel, and R. Crabtree, Org. Lett., 2005, 7, 5437; CrossRef (f) A. Varela-Fernandez, C. Gonzalez-Rodriguez, J. Varela, L. Castedo, and C. Saa, Org. Lett., 2009, 11, 5350; CrossRef (g) R. Mancuso, S. Mehta, B. Gabriele, G. Salerno, W. S. Jenks, and R. C. Larock, J. Org. Chem., 2009, 75, 897; CrossRef (h) D. Korte, L. Hegedus, and R. Wirth, J. Org. Chem., 1977, 42, 1329; CrossRef (i) G. Batu and R. Stevenson, J. Org. Chem., 1980, 45, 1532; CrossRef (j) H. Liao and C. Cheng, J. Org. Chem., 1995, 60, 3711. CrossRef
7. M. Bolte, W. Crow, and S. Yoshida, Aust. J. Chem., 1982, 1411. CrossRef
8. A. B. Smith, III, A. B. Dorsey, M. Ohba, A. Lupo, Jr., and M. Malamas, J. Org. Chem., 1988, 53, 4314. CrossRef
9. G. Stork and R. L. Danheiser, J. Org. Chem., 1973, 38, 1775. CrossRef
10. J. E. Baldwin, J. Chem. Soc., Chem. Commum., 1976, 734. CrossRef
11. H. Reich, J. Renga, and I. Reich, J. Am. Chem. Soc., 1975, 97, 5434. CrossRef
12. (a) L. Liu and P. Floreancig, Org. Lett., 2009, 11, 3152; CrossRef (b) W. Tu, L. Liu, and P. E. Floreancig, Angew. Chem. Int. Ed., 2008, 47, 4184; CrossRef (c) W. Tu and P. E. Floreancig, Angew. Chem. Int. Ed., 2009, 48, 4567. CrossRef
13. (a) Y.-C. Xu, E. Lebeau, J. W. Gillard, and G. Attardo, Tetrahedron Lett., 1993, 34, 3841; CrossRef (b) Y.-C. Xu, C. Roy, and E. Lebeau, Tetrahedron Lett., 1993, 34, 8189; CrossRef (c) Y.-C. Xu, E. Lebeau, P. L. Myers, and J. W. Gillard, J. Org. Chem., 1994, 59, 4868; CrossRef (d) W. Wang, T. Li, and G. Attardo, J. Org. Chem., 1997, 62, 6598. CrossRef
14. (a) D. Walker and J. D. Hiebert, Chem. Rev., 1963, 67, 153; CrossRef (b) J. N. Marx and Y.-S. P. Hahn, J. Org. Chem., 1988, 53, 2868; CrossRef (c) A. Begouin, S. Hesse, and G. Kirsch, ARKIVOC, 2008, 7, 84; (d) M. S. Islam, K. Ishigami, and H. Watanabe, Tetrahedron, 2007, 63, 1074; CrossRef (e) E.-C. Wang, Y.-S. Wein, and Y.-H. Kuo, Tetrahedron Lett., 2006, 47, 9195; CrossRef (f) V. K. Ahluwaliar, S. Jolly, and A. K. Tehim, Tetrahedron, 1982, 38, 3673; CrossRef (g) L. Y. Chen, S. R. Li, P. Y. Chen, H. C. Chang, T. P. Wang, I. L. Tsai, and E. C. Wanga, ARKIVOC, 2010, 11, 64.
15. Aromatizations of methylenecyclohexadienes, see: G. Majetich and S. Allen, ARKOVIC, 2010, 11, 104.
16. Aromatization of cyclohexenones using Pd/C, see: (a) E. Mosettig and H. M. Duvall, J. Am. Chem. Soc., 1937, 59, 367; CrossRef (b) E. C. Horning and M. G. Horning, J. Am. Chem. Soc., 1947, 69, 1359; CrossRef (c) E. C. Horning, M. G. Horning, and G. N. Walker, J. Am. Chem. Soc., 1949, 71, 169; CrossRef Aromatization of cyclohexenones using iodine, see: (d) A. S. Kotnis, Tetrahedron Lett., 1990, 31, 481. CrossRef
17. R. P. Thummel, W. E. Cravey, and D. B. Cantu, J. Org. Chem., 1980, 45, 1633. CrossRef
18. For related syntheses, see: (a) V. K. Ahluwalia, R. S. Jolly, and A. K. Tehim, Tetrahedron, 1982, 38, 3673; CrossRef (b) S. K. Ghosh, G. S. Buchanan, Q. A. Long, Y. Wei, Z. F. Al-Rashid, H. M. Sklenicka, and R. P. Hsung, Tetrahedron, 2007, 64, 883. CrossRef
19. For a recent synthesis, see: M. Islam, K. Ishigami, and H. Watanabe, Tetrahedron, 2007, 63, 1074. CrossRef