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Article Cite This: J. Org. Chem. 2018, 83, 5609−5618

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O‑Heterocycles from Unsaturated Carbonyls and Dimethoxycarbene Jean-Philippe Croisetière and Claude Spino* Département de Chimie, Université de Sherbrooke, 2500 Boulevard Université, Sherbrooke, Quebec J1K 2R1, Canada S Supporting Information *

ABSTRACT: The (4+1)-annulation of dimethoxycarbene with readily accessible α,β-unsaturated carbonyls gives cyclic orthoesters, which can then be converted in just a few steps to other O-heterocycles, including methoxyfurans, furanones, and furans.

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INTRODUCTION Dialkoxycarbenes1 are a nucleophilic species that participates in many reactions. Dimethoxycarbene 2 in particular has been reacted with carbonyls2 or thiocarbonyls to give α-hydroxyesters 8 or episulfurs 10, respectively.3 It was also reacted with alkenes,4 alkynes,5 or isocyanates,6 and its reaction with vinyl isocyanates 117 or silylated bis-ketenes 138 gave cyclopentadiones 14 or lactams 12, respectively (Scheme 1).

reactivity requires double activation of the alkene or a specific substitution of the unsaturated carbonyl, thus limiting the scope of these methods.11 On the other hand, dialkoxycarbenes are reactive1,12 and we surmised that they might be able to react with a larger spectrum of unsaturated carbonyls 5. If so, and given that enals and enones 5 of many substitution patterns (R1, R2, and R3) are easily accessible by a plethora of methods,13,14 useful O-heterocycles could be accessed by a short sequence of reactions via orthoesters 6 (Scheme 2). We

Scheme 1. Reactions of Dimethoxycarbene

Scheme 2. Proposed Conversion of Enones and Enals to Synthetically Useful O-Heterocycles

Dimethoxycarbene 2 is easily generated from the thermolysis of Warkentin’s oxadiazoline 1 in toluene at 110 or 150 °C.1 We have ourselves described the reaction of dialkoxycarbenes with electron-deficient dienes 3 to give (4+1)-cycloadducts 4.9 Surprisingly, reports of their reactions with α,β-unsaturated carbonyls 5 are scarce,10 and it was not clear at the outset if this transformation would be generally useful. While reactions of isonitriles or sulfur ylides with α,β-unsaturated carbonyls 5 have been used to make dihydrofurans and some furans, their low © 2018 American Chemical Society

herein report the successful implementation of this idea and the conversion of orthoesters 6 into useful furans 15 and 17 or butenolides 16 with excellent control over the degree and pattern of substitution (R1, R2, R3). Received: March 7, 2018 Published: April 23, 2018 5609

DOI: 10.1021/acs.joc.8b00613 J. Org. Chem. 2018, 83, 5609−5618

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The Journal of Organic Chemistry

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RESULTS AND DISCUSSION Figure 1 lists the α,β-unsaturated carbonyls 5a−p that were used for the study. Indeed many enones and enals 5a−k

We believe that oligomerization occurs when dimethoxycarbene undergoes a 1,2-addition instead of a 1,4-addition on the unsaturated system (Scheme 3). Naturally, aldehydes are Scheme 3. 1,4-Addition vs 1,2-Addition Hypothesis To Explain the Difference in Reactivity between Aldehydes and Ketones vis-à-vis Dimethoxycarbene 2

Figure 1. α,β-Unsaturated carbonyls 5 that were reacted with dimethoxycarbene 2.

more prone to 1,2-addition than ketones are, for steric reasons. In any case, there is no pathway leading to the desired product 6 that starts with a 1,2-addition of dimethoxycarbene. Of course, enolate E-19, resulting from a 1,4-addition, must isomerize to the enolate Z-19 before it can cyclize to product 6. Here, too, aldehydes would be inherently at a disadvantage due to the fact that the corresponding enolate 19 (R3 = H) would normally have a higher proportion of E enolate as compared to the corresponding ketone (19, R3 ≠ H). Intermediate 18, resulting from an initial 1,2-addition of dimethoxycarbene, could lead to oligomers and polymers in different ways. Warkentin has shown that epoxides like 20, can open homolytically to give a biradical such as 21 (Scheme 4).2b,3 Such biradical could easily initiate the polymerization of

reacted with dimethoxycarbene 2 to give the corresponding orthoesters 6a−6k (Figure 2). A silylether, an ester, and a

Scheme 4. Possible Mechanistic Pathways from Intermediate 18

Figure 2. Products from the reaction of enals and enones 5 with dimethoxycarbene 2. BRSM = based on recovered starting material.

primary bromide function proved compatible with this nucleophilic carbene. The orthoesters 6 were surprisingly stable despite the driving force of a potential aromatization by elimination of methanol as well as the presence of the acidsensitive orthoester and enolether functions. The yield of the reaction is decreased if there is steric hindrance (e.g., aldehyde 5h gave 34% of orthoester 6h) and/ or when the s-cis conformation of the unsaturated carbonyl is higher in energy (as is the case for ketone 5i). Ketone 5j, which is locked in the s-cis conformation, gave a high yield of orthoester 6j. Unhindered aldehyde 5b and ketone 6b gave the desired products 6b and 6c in 84% and 65% yields, respectively. However, aldehydes with only a R1 substituent were prone to oligomerization or polymerization and gave lower yields of the desired product 6. For example, aldehyde 5e gave 22% of 6e (Figure 2), while cinnamaldehyde 5n gave solely oligomeric materials (vide inf ra). The oligomers were not characterized, but they were identified by NMR and contained several methoxy signals as well as broad signals.

unsaturated aldehydes, although the epoxide 20 could react to give polymer-like products by other pathways. Radical scavengers, such as TEMPO and Cu(acac)2, reduced the yield of the reaction, while others, such as BHT, were clearly not compatible with the free dimethoxycarbene 2 and quickly reacted with it. Anionic traps like TMSCl led to myriad products (probably also incompatible with 2). While we cannot be certain that oligomerization is the result of an initial 1,2-addition, the hypothesis is clearly supported by comparing the results obtained from aldehyde 5e with those obtained from ketone 5f. The former gave 22% of the desired product 6e along with oligomers or polymers that contained methoxy groups, as judged by 1H NMR. In contrast, ketone 5f gave 82% of the desired orthoester 6f. The results obtained with aldehyde 5l offer yet further support to this hypothesis. In 5610

DOI: 10.1021/acs.joc.8b00613 J. Org. Chem. 2018, 83, 5609−5618

Article

The Journal of Organic Chemistry Scheme 5. Reaction of Dimethoxycarbene 2 with Cinnamaldehyde and Derivatives 5l−q

this case, a 65% yield of 24l was isolated (Scheme 5). Product 24l is not the expected orthoester 6l but an orthoester that arises from an initial 1,2-addition of dimethoxycarbene 2 on aldehyde 5l. The initial 1,2-addition of dimethoxycarbene to aldehyde 5l would lead to the epoxide 20l (Scheme 4). In this case, however, its heterolytic opening to Zwitterion 22l is accelerated by the presence of the methoxy group and results in the formation of a characterizable orthoester 24l, clearly identifiable as a 1,2-addition product. The corresponding ketone 5m underwent less 1,2-addition and more 1,4-addition and thus led to a higher yield (27%) of the desired orthoester 6m. It is not clear why the remainder (58%) transferred a methoxy group to give 23m instead of cyclizing to 24m, but either product is derived from an initial 1,2-addition in any case. It is also likely that 23m and 24m are in equilibrium at that temperature; we have not verified this possibility.15 The absence of an electron-donating group (aldehyde 5n, R1 = Ph, R3 = H) or the presence of an electron-withdrawing group on the aryl (aldehyde 5p, R1 = p-C6H4−CO2Me, R3 = H) slows the opening of the epoxides 20n and 20p to the corresponding intermediate 22 and thus leads to more polymerization. As shown in Scheme 5, their ketone derivatives 5o (R1 = Ph, R3 = Me) and 5q (R1 = p-C6H4−CO2Me, R3 = Me) gave higher yields of the desired cyclic orthoesters 6o (33%) and 6q (52%), presumably because of increased 1,4addition on these systems. In addition, the fact that R3 ≠ H, in these cases, increases the rate of ionic opening of the epoxide 20 to Zwitterion 22. One way to prevent oligomerization is to perform the corresponding intramolecular reaction whenever possible. Substrates 5r and 5s, similar in structure to 5e and 5f, respectively, afforded orthoesters 6r and 6s in high yields, presumably because of an increased rate of the desired 1,4addition (Scheme 6).9c We also briefly explored different carbenes, in particular, some we thought would be more prone to 1,4-additions, like alkoxythiocarbenes, dithiocarbenes, or methoxyphenoxycarbene 27 (Scheme 7). The first led to a different product, and the

Scheme 7. Reaction of Enals 5b and 5u with Methoxyphenoxy Carbene 27

second did not react with α,β-unsaturated carbonyls; however, the latter turned out to prevent oligomerization altogether when reacting with aldehydes 5b or 5u. Indeed, none of the characteristic signals of oligomers were present in the NMR spectra of the crude mixture. Unfortunately, another problem arose in this case. Carbene 27 is less reactive than dimethoxycarbene 2 and although its reaction with the nonhindered aldehyde 5b proceeds well at 110 °C, other aldehydes required higher temperatures. At such temperatures, methoxyfurans 15b and 15u are prematurely formed during the reaction by the elimination of phenol, a much better leaving group than methanol. As will be discussed later, these furan derivatives are sensitive and may react with the carbene itself, leading to a poor yield of product. Nonetheless, the results are promising and we are pursuing the search for a dialkoxycarbene that will give a high yield of orthoesters 6 with polymerizationprone aldehydes. Orthoesters 6 could be converted to several different useful products. We started by exploring ways to convert them to methoxyfurans 15 and furanones 16 by several procedures, all of them high yielding (Schemes 8 and 9). By far the easiest and most convenient method consists of treating the orthoester with a catalytic amount of camphorsulfonic acid in chloroform. Within minutes, the methoxyfuran 15b or 15c was formed and could be isolated cleanly (Scheme 8). Orthoesters 6a−c,f could also be converted efficiently to the corresponding methoxyfuran using trimethylaluminum in DCM at a low temperature. The weaker Lewis acid aluminum tris(tert-butoxide) was able to cleanly eliminate methanol from orthoesters 6a−c in toluene at 140 °C to afford similarly good yields of methoxyfurans 15a− c.16 Treating 6b with n-BuLi at −78 °C afforded a quantitative yield of methoxyfuran 15b, while DBU was basic enough to

Scheme 6. Intramolecular Reaction of Enals 5l and 5m

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DOI: 10.1021/acs.joc.8b00613 J. Org. Chem. 2018, 83, 5609−5618

Article

The Journal of Organic Chemistry Scheme 8. Ways to Convert Orthoesters 6 to Methoxyfurans 15

Scheme 10. Synthesis of Furans 17j and 17b

Scheme 9. Ways to Convert Orthoesters 6 to Furanones 16 Lastly, γ-ketoesters 28 are obtained in excellent yields either from orthoesters 6 or from methoxyfurans 15 (Scheme 11). Scheme 11. Conversion of Orthoesters 6 to Acyclic Products 28

eliminate methanol in the case of orthoester 6d. Methoxyfurans are sensitive to acid and oxygen and may degrade upon exposure to air. Furanones 16 could be accessed by mixing the orthoester 6 in the presence of concentrated HCl as shown by the conversion of orthoesters 6b and 6j to furanones 16b and 16j, respectively (Scheme 9). Furanone 16b was also obtained using a mild Lewis acid such as TMSCl in the presence of iodide in the reaction medium to dealkylate the methoxyloxonium ion. Starting with orthoester 6r and using TMSCl and NaI, dealkylation gave furanone 16r. Furanones 16 can be transformed to furans by known procedures, either by adding a hydride17 or by adding the Grignard reagent followed by an acidic workup.18,19 To showcase the efficiency of our sequence, starting from the readily available α,β-unsaturated carbonyl 5j, we procured the fully substituted furan 17j in three steps (Scheme 10). Functionalized furans are important building blocks in synthetic chemistry20 and have found multiple uses in materials chemistry,21 conducting polymers,22 as biofuels,23 and as pharmaceuticals.24 Monosubstituted furan 17b was obtained from an HCl treatment of orthoester 6b followed by DIBAL-H reduction at −40 °C (Scheme 10). This sequence also offers a solution to the preparation of some 2,5-unsubstituted furans, which may be difficult to access when the aldehyde precursor is prone to polymerization, such as enal 5u. One may thus use α,βunsaturated aldehyde 5b instead and obtain the same furan 17b, using the same sequence of reactions.

Possibly, methoxyfurans 15 are intermediates formed first from orthoesters 6 on the way to γ-ketoesters 28. Aqueous acetic acid was effective. γ-Ketoesters 28 are the product of the formal 1,4-addition of a methoxycarbonyl anion equivalent to the α,βunsaturated carbonyl. The same products may be obtained from hydrocyanation25 and methanolysis. The present method offers an alternative to the use of toxic cyanide.

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CONCLUSION In conclusion, we have devised a short and efficient sequence of reactions to convert simple α,β-unsaturated carbonyls into Oheterocycles with control over the degree of substitution and its pattern. Considering the ready availability of the starting α,βunsaturated carbonyls 5, the high yields of the reaction sequence, and the scope of this method, we believe it is an efficient and flexible way to make polysubstituted O-heterocycles.

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EXPERIMENTAL SECTION

General Considerations. All reactions were performed under an inert atmosphere of argon in oven-dried glassware. To make sure there was no acid or metal traces interfering with the intramolecular (4+1)-

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DOI: 10.1021/acs.joc.8b00613 J. Org. Chem. 2018, 83, 5609−5618

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The Journal of Organic Chemistry

(E)-7-(tert-Butyldimethylsilyloxy)hept-3-en-2-one (5f). To a solution of tert-butyldimethyl(4-penten-1-yloxy)silane29 (500 mg, 2.50 mmol, 1 equiv) and 3-buten-2-one (0.26 mL, 3.24 mmol, 1.3 equiv) in anhydrous DCM (10 mL) was added a solution of Grubb’s second generation catalyst (212 mg, 0.25 mmol, 10 mol %) in DCM (2.5 mL). The mixture was heated to reflux and stirred at that temperature for 18 h. The solution was then cooled to rt, and DMSO (0.12 mL, 1.75 mmol, 0.7 equiv) was added. The mixture was stirred for another 10 h. The solvent was evaporated under reduced pressure (mechanical pump), and the mixture was purified by flash chromatography on silica eluting with hexanes/ethyl acetate in a 9:1 ratio to afford (E)-7-(tertbutyldimethylsilyloxy)hept-3-en-2-one (5f) as a colorless oil (505 mg, 84%): 1H NMR (300 MHz, CDCl3) δ 6.86 (dt, 1H, J = 15.9, 6.9 Hz), 6.11 (dt, 1H, J = 15.9, 1.4 Hz), 3.66 (t, 2H, J = 6.1 Hz), 2.38−2.28 (m, 2H), 2.27 (s, 3H), 1.77−1.66 (m, 2H), 0.92 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 198.7 (s), 148.2 (d), 131.4 (d), 62.2 (t), 31.2 (t), 29.0 (t), 26.9 (q), 25.9 (q), 18.3 (s), −5.3 (q); IR (neat) ν (cm−1) 2934, 2852, 1680; HRMS (ESI-TOF) m/z [M + Na] calcd for C13H26O2SiNa 265.1600, found 265.1596. (E)-7-Bromohept-3-en-2-one (5g). 5-Bromo-1-pentene (1.90 g, 12.8 mmol, 1 equiv) was added to a dried flask along with eluting with DCM (5 mL). Grubbs’ second generation catalyst (0.22 g, 0.25 mmol, 0.02 equiv) was then added, followed by the addition of the methylvinylketone (4.6 mL, 51.00 mmol, 4 equiv). The mixture was stirred for 16 h and then heated to reflux for an additional 10 h. The mixture was filtered through a pad of silica and evaporated under reduced pressure. The crude product was then flashed on silica using petroleum ether and diethyl ether in a 90:10 ratio to afford enone 5g as a colorless oil (2.22 g, 91%): 1H NMR (300 MHz, CDCl3) δ 6.79 (dt, 1H, J = 15.9, 6.4 Hz), 6.16 (d, 1H, J = 15.9 Hz), 3.44 (t, 2H, J = 6.5 Hz), 2.48−2.38 (m, 2H), 2.27 (s, 3H), 2.11−2.01 (m, 2H). This characterization data corresponds with the one reported previously in the literature.30 (E)- and (Z)-2-Propylidenecyclohexanone (5h). Zinc chloride was charged into a flask under argon, and the flask was flamed-dried. Once the flask was cooled, EtOAc (2.0 mL) was added, followed by the diethylacetal of propionaldehyde (1.34 mL, 10.5 mmol, 1.05 equiv). The resulting solution was cooled to 0 °C, and cyclohexenyloxytrimethylsilane was slowly added over 20 min. After the addition, the solution was warmed to rt over a period of 20 h. The mixture was transferred into a separatory funnel and washed with H2O (4 mL). The aqueous layer was extracted with diethyl ether (2 mL), and the combined organic layers were washed with saturated aqueous NaHCO3 (4 × 2 mL), H2O (2 × 2 mL), and brine (2 and 1 mL), dried over anhydrous MgSO4, and evaporated under reduced pressure. The crude mixture was then diluted with toluene (100 mL), and silica (13.5 g) was added. The heterogeneous mixture was heated to reflux for 18 h using a Dean−Stark apparatus. After the reaction mixture cooled, the silica was filtered off and toluene was evaporated under reduced pressure. The crude mixture was purified by flash chromatography on silica using petroleum ether and diethyl ether using a 5−10% gradient of diethyl ether. Enone 5h as a colorless oil (0.77 g, 56%) was obtained: 1H NMR (400 MHz, CDCl3) δ 6.60 (ddd, 1H, J = 7.4, 4.7, 2.0 Hz), 2.47 (t, 2H, J = 6.3 Hz), 2.42 (t, 2H, J = 6.7 Hz), 2.11 (quint, 2H, J = 7.5 Hz), 1.89−1.80 (m, 2H), 1.78−1.69 (m, 2H), 1.04 (t, 3H, J = 7.5 Hz). The characterization data corresponds to the one previously reported.31 General Procedure for the Generation and Addition of Dimethoxycarbene to Enones and Enals. The α,β-unsaturated carbonyl 5 (1 equiv) was dissolved in anhydrous toluene (0.2 M) into an oven-dried sealed tube. 2,5-Dihydro-2,2-dimethoxy-5,5-dimethyl1,3,4-oxadiazoline (1) was then added, and the reaction mixture was heated to 140 °C for 16−20 h (time required to consume all of oxadiazoline 1). The solvent was then evaporated under reduced pressure, and the crude product was purified on silica saturated with trimethylamine eluting with ethyl acetate and hexanes or by distillation. In all cases, when using more than 1 equiv of oxadiazoline 1, the known tetramethoxyethylene 30 could be isolated as a side product from the dimerization of excess dimethoxycarbene: 1H NMR (300 MHz, CDCl3) δ 3.60 (s, 12H).

cycloaddition reactions, for those reactions, all glassware was washed with hexane, DCM, acetone, water, concentrated HCl, water, concentrated NH4OH, water, and finally anhydrous ethanol. The glassware was then dried overnight in an oven at 100 °C. Solvents were distilled from potassium/benzophenone (tetrahydrofuran), sodium/benzophenone (toluene, diethyl ether), calcium hydride (DCM, triethylamine), and ketyls prior to use. Proton nuclear magnetic (1H NMR) spectra were recorded on a 300 MHz spectrometer. NMR samples were dissolved in chloroform-d, and chemical shifts are reported in ppm from ppm relative to the residual undeuterated solvent. Data are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, dd = doublet of doublets, ddd = doublet of doublets of doublets, dddd = doublet of doublets of doublets of doublets, t = triplet, q = quartet, m = multiplet), coupling constant. Carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a 75.5 MHz spectrometer. NMR samples were dissolved in chloroform-d, and chemical shifts are reported in ppm relative to the solvent. LRMS analyses were performed on a GC system spectrometer (30 m length, 25 μ OD, DB-5 ms column) coupled with a mass spectrometer. High-resolution spectrometry was performed by electrospray time-of-flight. Reactions were monitored by thin-layer chromatography (TLC) on 0.25 mm silica gel coated glass plates visualized by UV 254, vanillin, KMnO4, PMA, or by 1H NMR. Silica gel (particule size 230−400 mesh) was used for flash chromatography. Melting points are uncorrected. 3-Methyleneheptan-2-one (5c). Methylmagnesium chloride (3 M) in THF (9.02 mL, 3 M in diethyl ether, 27.1 mmol, 1.2 equiv) was added to 20 mL of THF at 0 °C. To this solution was slowly added a 0.6 M solution of 2-butylacrolein (3.00 mL, 22.55 mmol, 1 equiv) dissolved in THF (40 mL) over 20 min. The reaction was then left to react letting the mixture warm to rt over a period of 45 min. The mixture was quenched with a saturated aqueous solution of NH4Cl (100 mL). The layers were separated, and the aqueous phase was washed with diethyl ether (3 × 75 mL). The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure, affording 3-methyleneheptan-2-ol as a colorless oil (2.80 g, 97%). The crude product 29 was pure enough to proceed to the next step without further purification: 1H NMR (300 MHz, CDCl3) δ 5.05 (s, 1H), 4.83 (s, 1H), 4.28 (q, 1H, J = 6.3 Hz), 2.19− 1.96 (m, 2H), 1.57−1.34 (m, 5H), 1.31 (d, 3H, J = 6.5 Hz), 0.94 (t, 3H, J = 7.2 Hz). The characterization data corresponds to the one reported previously in the literature.26 To a flask containing 3-methylene-2-heptanol (29) (2.70g, 21.1 mmol, 1 equiv) was added ethyl acetate (100 mL). IBX, made from a previously reported procedure,27 was then added all at once, and the heterogeneous solution was heated to reflux temperature for 5 h. The heterogeneous mixture was filtered on a Celite pad and washed with ethyl acetate. The solvent was evaporated under reduced pressure to afford 3-methylene-2-heptanone (5c) as a colorless oil (1.56 g, 59%): 1 H NMR (300 MHz, CDCl3) δ 6.01 (bs, 1H), 5.77 (bs, 1H), 2.35 (s, 3H), 2.31−2.24 (m, 2H), 1.47−1.26 (m, 4H), 0.92 (t, 3H, J = 7.1 Hz); 13 C NMR (75 MHz, CDCl3) δ 199.9 (s), 149.4 (s), 124.7 (t), 30.6 (t), 30.3 (t), 26.0 (q), 22.5 (t), 13.9 (q); HRMS (ESI-TOF) m/z [M + Na] calcd for C8H14ONa 149.0937, found 149.0933. (E)-6-(tert-Butyldimethylsilyloxy)hex-2-enal (5e). To a solution of tert-butyldimethyl(4-pentenyloxy)silane (350 mg, 1.75 mmol, 1 equiv), made from a previously reported method,28 and crotonaldehyde (0.25 mL, 2.97 mmol, 1.7 equiv) in anhydrous DCM (30.0 mL) was added a solution of Grubbs’ second generation catalyst (74 mg, 0.09 mmol, 5 mol %) in DCM (5 mL). The mixture was heated to reflux and stirred at that temperature for 18 h. The solution was then cooled to rt and evaporated under reduced pressure using the mechanical pump. The mixture was then purified by flash chromatography on silica gel using hexanes/diethyl ether in a 9:1 ratio, affording enone 5e as a colorless oil (204 mg, 51%): 1H NMR (300 MHz, CDCl3) δ 9.54 (d, 1H, J = 7.9 Hz), 6.91 (dt, 1H, J = 15.6, 6.8 Hz), 6.16 (dd, 1H, J = 15.6, 7.9 Hz), 3.68 (t, 2H, J = 6.1 Hz), 2.50−2.40 (m, 2H), 1.75 (dt, 2H, J = 13.3, 6.1 Hz), 0.92 (s, 9H), 0.07 (s, 6H). The characterization corresponds with the one reported previously in the literature.29 5613

DOI: 10.1021/acs.joc.8b00613 J. Org. Chem. 2018, 83, 5609−5618

Article

The Journal of Organic Chemistry 2,2-Dimethoxy-5-phenyl-2,3-dihydrofuran (6a). 1-Phenyl-2propen-1-one (5a) (202 mg, 1,53 mmol, 1 equiv), made from a previously reported method,32 was treated according to the general procedure with 1.5 equiv of oxadiazoline 1 to afford dihydrofuran 6a as a white solid (234 mg, 74%): 1H NMR (300 MHz, CDCl3) δ 7.62− 7.55 (m, 2H), 7.40−7.28 (m, 3H), 5.39 (t, 1H, J = 2.7 Hz), 3.44 (s, 6H), 2.89 (d, 2H, J = 2.7 Hz); 13C NMR (75 MHz, CDCl3) δ 153.6 (s), 130.7 (s), 128.8 (d), 128.6 (d), 125.2 (s), 124.6 (d), 95.0 (d), 50.6 (q), 38.0 (t); IR (neat) ν (cm−1) 2946, 2840, 1734; HRMS (ESITOF) m/z [M + Na] calcd for C12H14O3Na 229.0835, found 229.0838. 4-Butyl-2,2-dimethoxy-2,3-dihydrofuran (6b). 2-Butylacrolein (5b) (0.12 mL, 0.89 mmol, 1 equiv) was treated according to the general procedure with 2 equiv of oxadiazoline 1 to afford dihydrofuran 6b as a colorless oil (138 mg, 84%): 1H NMR (300 MHz, CDCl3) δ 6.07 (m, 1H), 3.34 (s, 6H), 2.58 (m, 2H), 2.01 (t, 2H, J = 6.9 Hz), 1.46−1.20 (m, 4H), 0.89 (t, 3H, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 137.0 (d), 124.3 (s), 114.8 (s), 50.0 (q), 38.9 (t), 29.9 (t), 26.1 (t), 22.4 (t), 13.9 (q); IR (neat) ν (cm−1) 2955, 1669, 1460; LRMS (m/z, relative intensity) 186 (MH+, 58), 155 (67), 143 (12) 112 (100); HRMS (ESI-TOF) m/z [M + Na] calcd for C10H18O3Na 209.1148, found 209.1156. 4-Butyl-2,2-dimethoxy-5-methyl-2,3-dihydrofuran (6c). 3-Methylene-2-heptanone (5c) (206 mg, 1.63 mmol, 1 equiv) was treated according to the general procedure with 3.5 equiv of oxadiazoline 1 to afford the desired product 6c as a clear oil (123 mg, 65%): 1H NMR (300 MHz, CDCl3) δ 3.33 (s, 6H), 2.59 (m, 2H), 2.00 (t, 2H, J = 6.9 Hz), 1.78−1.74 (m, 3H), 1.39−1.20 (m, 4H), 0.89 (t, 3H, J = 7.0 Hz); 13 C NMR (75 MHz, CDCl3) δ 145.1 (s), 122.3 (s), 107.1 (s), 49.8 (q), 39.7 (t), 30.5 (t), 25.7 (t), 22.3 (t), 13.9 (q), 11.1 (q); IR (neat) ν (cm−1) 2926, 1705, 1441; HRMS (ESI-TOF) m/z [M + Na] calcd for C11H20O3Na 223.1305, found 223.1303. Methyl 2,2-Dimethoxy-5-methyl-2,3-dihydrofuran-3-carboxylate (6d). Methyl (E)-4-oxo-2-pentenoate (5d) (150 mg, 1.17 mmol, 1 equiv) was treated according to the general procedure with 1.5 equiv of oxadiazoline 1 to afford dihydrofuran 6d as a colorless oil (214 mg, 93%): 1H NMR (300 MHz, CDCl3) δ 4.71 (bs, 1H), 3.87 (bs, 1H), 3.74 (s, 3H), 3.42 (s, 3H), 3.39 (s, 3H), 1.88 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.4 (s), 155.0 (s), 123.0 (s), 95.3 (d), 54.8 (d), 52.3 (q), 50.7 (q), 50.2 (q), 13.9 (q); IR (neat) ν (cm−1) 2954, 2847, 1736, 1437; HRMS (ESI-TOF) m/z [M + Na] calcd for C9H14O5Na 225.0733, found 225.0739. tert-Butyl-[3-(2,2-dimethoxy-3H-furan-3-yl)propoxy]-dimethyl-silane (6e). (E)-6-(tert-Butyldimethylsilyloxy)-2-hexenal (5e) (205 mg, 0.9 mmol, 1 equiv) was treated according to the general procedure with 3.5 equiv of oxadiazoline 1 to afford orthoester 6e as a colorless oil (15 mg, 22%) separated from a complex mixture of oligomers/ polymers (170 mg): 1H NMR (300 MHz, CDCl3) δ 6.31 (dd, 1H, J = 3.1, 2.4 Hz), 5.05−5.02 (m, 1H), 3.61 (t, 2H, J = 6.4 Hz), 3.40 (s, 3H), 3.31 (s, 3H), 2.89−2.81 (m, 1H), 1.72−1.51 (m, 3H), 1.40−1.29 (m, 1H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 142.2 (d), 124.2 (s), 105.5 (d), 63.3 (t), 50.1 (q), 50.0 (q), 46.3 (d), 31.0 (t), 26.0 (q), 25.9 (t), 18.4 (s), −5.3 (q); IR (neat) ν (cm−1) 2952, 2857, 1744, 1622, 1471; HRMS (ESI-TOF) m/z [M + Na] calcd for C15H30O4SiNa 325.1811, found 325.1806. tert-Butyl(3-(2,2-dimethoxy-5-methyl-2,3-dihydrofuran-3-yl)propoxy)dimethylsilane (6f). (E)-7-(tert-Butyldimethylsilyloxy)hept3-en-2-one (5f) (200 mg, 0.82 mmol, 1 equiv) was treated according to the general procedure with 3.5 equiv of oxadiazoline 1 to afford product 6f as a colorless oil (214 mg, 82%): 1H NMR (300 MHz, CDCl3) δ 4.69 (q, 1H, J = 1.3 Hz), 3.62 (t, 2H, J = 6.4 Hz), 3.42 (s, 3H), 3.33 (s, 3H), 2.91−2.82 (m, 1H), 1.83 (d, 3H, J = 1.3 Hz), 1.72− 1.46 (m, 3H), 1.41−1.27 (m, 1H), 0.91 (s, 9H), 0.06 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 151.6 (s), 124.2 (s), 100.7 (d), 63.7 (t), 50.3 (q), 50.1 (q), 48.0 (d), 31.4 (t), 26.5 (t), 26.3 (q), 18.7 (s), 14.2 (q), −4.9 (q); IR (neat) ν (cm−1) 2944, 2850, 1684, 1464; HRMS (ESI-TOF) m/z [M + Na] calcd for C16H32O4SiNa 339.1967, found 339.1953. 3-(3-Bromopropyl)-2,2-dimethoxy-5-methyl-2,3-dihydrofuran (6g). (E)-6-Bromo-3-hexen-2-one (5g) (1.0 g, 5.23 mmol, 1 equiv)

was treated according to the general procedure with 3.2 equiv of oxadiazoline 1 to afford orthoester 5g as a colorless oil (1.24 g, 90%): 1 H NMR (300 MHz, CDCl3) δ 4.66 (s, 1H), 3.43 (s, 3H), 3.33 (s, 3H), 3.36−3.29 (m, 2H), 2.95−2.84 (m, 1H), 1.98−1.86 (m, 2H), 1.86−1.83 (m, 3H), 1.82−1.65 (m, 1H), 1.54−1.41 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 151.8 (s), 123.7 (s), 99.8 (d), 50.0 (q), 49.9 (q), 47.1 (d), 33.9 (t), 31.0 (t), 28.6 (t), 13.9 (q); IR (neat) ν (cm−1) 2952, 2857, 1744, 1622, 1471; HRMS (ESI-TOF) m/z [M + Na] calcd for C10H17BrO3Na 287.0253, found 287.0256. 2,2-Dimethoxy-2,3,4,5,6,7a-hexahydrobenzofuran (6h). Cyclohex-1-enecarboxaldehyde (0.12 mL, 0.89 mmol, 1 equiv) was treated according to the general procedure with 3.5 equiv of oxadiazoline 1 to afford hexahydroisobenzofuran (6h) as a colorless oil (58 mg, 34%): 1 H NMR (300 MHz, CDCl3) δ 6.05 (t, J = 2.2 Hz, 1H), 3.42 (s, 3H), 3.33 (s, 3H), 2.71−2.58 (m, 1H), 2.42−2.31 (m, 1H), 2.02−1.72 (m, 3H), 1.51−1.08 (m, 3H); 13C NMR (76 MHz, CDCl3) δ 133.1 (d), 123.9 (s), 117.3 (s), 50.0 (q), 49.6 (q), 47.6 (d), 27.4 (t), 26.4 (t), 25.0 (t), 23.9 (t); IR (neat) ν (cm−1) 2930 (m), 1723 (m), 1449 (m), 1243−935 (br); HRMS (ESI-TOF) m/z [M + Na] calcd for C10H16O3Na 207.0992, found 207.0984. 2,2-Dimethoxy-3,4,5-trimethyl-2,3-dihydrofuran (6i). 3-Methyl-3penten-2-one (5i) (300 mg, 3.06 mmol, 1 equiv) was treated according to the general procedure with 5.0 equiv of oxadiazoline 1 to afford the desired orthoester 6i as a clear oil (205 mg, 39% (>90% corrected yield)): 1H NMR (300 MHz, CD3CN) δ 3.32 (s, 3H), 3.25 (s, 3H), 2.83−2.72 (m, 1H), 1.72 (bs, 3H), 1.56 (s, 3H), 1.01 (d, 3H, J = 7.2 Hz); 13C NMR (75 MHz, CD3CN) δ 143.21 (s), 122.21 (s), 108.13 (s), 49.09 (q), 48.89 (q), 45.73 (d), 12.22 (q), 10.14 (q), 8.62 (q); IR (neat) ν (cm−1) 2293, 1720, 1449; HRMS (ESI-TOF) m/z [M + Na] calcd for C9H16O3Na 195.0992, found 195.0999. 3-Ethyl-2,2-dimethoxy-2,3,4,5,6,7-hexahydrobenzofuran (6j). 2Propylidenecyclohexanone (5h) (305 mg, 2.21 mmol, 1 equiv) was treated according to the general procedure with 4.0 equiv of oxadiazoline 1 to afford orthoester 6j as a clear oil (406 mg, 87%): 1 H NMR (300 MHz, CD3CN) δ 3.35 (s, 3H), 3.26 (s, 3H), 2.73−2.63 (m, 1H), 2.10−2.00 (m, 3H), 1.79−1.42 (m, 7H), 0.95 (t, 3H, J = 7.4 Hz); 13C NMR (75 MHz, CDCl3) δ 148.0 (s), 123.6 (s), 109.7 (s), 50.8 (d), 49.8 (q), 49.8 (q), 22.7 (t), 22.6 (t), 22.5 (t), 22.2 (t), 21.0 (t), 12.2 (q); IR (neat) ν (cm−1) 2934, 2845, 1754, 1726, 1450; HRMS (ESI-TOF) m/z [M − CH4 + Na] calcd for C11H16O3Na 219.0992, found 219.0991. 2,2-Dimethoxy-3,5-diphenyl-2,3-dihydrofuran (6k). (E)-Chalcone (5k) (250 mg, 1.20 mmol, 1 equiv) was treated according to the general procedure with 3.0 equiv of oxadiazoline 1 to afford orthoester 6k as a clear oil (224 mg, 66%): 1H NMR (300 MHz, CDCl3) δ 7.66− 7.58 (m, 2H), 7.38−7.17 (m, 8H), 5.53 (d, 1H, J = 2.8 Hz), 4.21 (d, 1H, J = 2.8 Hz), 3.45 (s, 3H), 3.07 (s, 3H). The characterization corresponds with the one reported previously in the literature.33 2,2-Dimethoxy-3-(4-methoxyphenyl)-5-methyl-2,3-dihydrofuran (6m) and (E)-Methyl 2-Methoxy-4-(4-methoxyphenyl)-2-methylbut3-enoate (23m). (E)-4-(4-Methoxyphenyl)but-3-en-2-one (3n) (125 mg, 0.71 mmol, 1 equiv) was treated according to the general procedure with 3.5 equiv of oxadiazoline (1) to afford orthoester 6m as a white solid (31 mg, 17%) and (E)-methyl 2-methoxy-4-(4methoxyphenyl)-2-methylbut-3-enoate (23m) as a yellow oil (65 mg, 36%). The starting material was also recovered (48 mg, 38%). 6m: white solid, mp 38−40 °C; 1H NMR (300 MHz, CDCl3) δ 7.22−7.15 (m, 2H), 6.89−6.82 (m, 2H), 4.79 (dd, J = 2.3, 1.2 Hz, 1H), 4.04− 4.00 (m, 1H), 3.82 (s, 3H), 3.44 (s, 3H), 3.06 (s, 3H), 1.96 (dd, J = 1.8, 1.3 Hz, 3H); 13C NMR (76 MHz, CDCl3) δ 158.6 (s), 152.3 (s), 130.5 (s), 129.9 (d), 123.8 (s), 113.4 (d), 101.5 (d), 55.2 (q), 54.6 (d), 51.0 (q), 50.9 (q), 49.6 (q), 13.8 (q); IR (neat) ν (cm−1) 2933, 1680; HRMS (ESI-TOF) m/z [M + Na] calcd for C14H18O4Na 273.1103, found 273.1095. 23m: colorless oil; 1H NMR (300 MHz, CDCl3) δ 8.03−7.98 (m, 2H), 7.51−7.44 (m, 2H), 6.77 (d, J = 16.2 Hz, 1H), 6.47 (d, J = 16.2 Hz, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 3.38 (s, 3H), 1.64 (s, 3H); 13C NMR (76 MHz, CDCl3) δ 173.0 (s), 166.8 (s), 140.7 (s), 131.9 (d), 130.3 (d), 129.9 (d), 129.4 (s), 126.6 (d), 80.4 (s), 52.6 (q), 52.5 (q), 52.1 (q), 22.7 (q); IR (neat) ν (cm−1) 2957, 5614

DOI: 10.1021/acs.joc.8b00613 J. Org. Chem. 2018, 83, 5609−5618

Article

The Journal of Organic Chemistry 1731, 1505, 1435; HRMS (ESI-TOF) m/z [M + Na] calcd for C14H18O4Na 273.1103, found 273.1097. 2,2-Dimethoxy-5-methyl-3-phenyl-2,3-dihydrofuran (6o) and (E)-Methyl 2-Methoxy-2-methyl-4-phenylbut-3-enoate (23o). (E)4-Phenylbut-3-en-2-one (5o) (125 mg, 0.86 mmol, 1 equiv) was treated according to the general procedure with 3.5 equiv of oxadiazoline (1) to afford orthoester 6o as a white solid (44 mg, 33%) and (E)-methyl 2-methoxy-2-methyl-4-phenylbut-3-enoate (23o) as a yellow oil (58 mg, 42%). The starting material was also recovered (33 mg, 24%). 6o: white solid, mp 38−40 °C; 1H NMR (300 MHz, CDCl3) δ 7.40−7.20 (m, 5H), 4.83 (dd, J = 2.3, 1.2 Hz, 1H), 4.13−4.04 (m, 1H), 3.47 (s, 3H), 3.06 (s, 3H), 1.98 (dd, J = 1.8, 1.3 Hz, 3H); 13C NMR (76 MHz, CDCl3) δ 152.9 (s), 138.8 (s), 129.3 (d), 128.3 (d), 127.2 (d), 124.2 (s), 101.5 (d), 55.6 (d), 51.1 (q), 50.0 (q), 14.1 (q); IR (neat) ν (cm−1) 2957, 1680, 1461, 1316− 950; HRMS (ESI-TOF) m/z [M − CH4 + Na] calcd for C12H12O3Na 227.0684, found 227.0679. 23o: colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.46−7.40 (m, 2H), 7.38−7.23 (m, 3H), 6.73 (d, J = 16.3 Hz, 1H), 6.36 (d, J = 16.3 Hz, 1H), 3.81 (s, 3H), 3.37 (s, 3H), 1.64 (s, 3H); 13C NMR (76 MHz, CDCl3) δ 173.6 (s), 136.5 (s), 131.7 (d), 129.3 (d), 128.9 (d), 128.3 (d), 126.9 (d), 80.7 (s), 52.8 (q), 52.6 (q), 22.8 (q); IR (neat) ν (cm−1) 2947, 1735, 1440; HRMS (ESI-TOF) m/ z [M + Na] calcd for C13H16O3Na 243.0997, found 243.0997. Methyl 4-(2,2-Dimethoxy-5-methyl-2,3-dihydrofuran-3-yl)benzoate (6q) and (E)-Methyl 4-(3,4-dimethoxy-3-methyl-4-oxobut-1-enyl)benzoate (23q). (E)-Methyl 4-(3-oxobut-1-enyl)benzoate (5q) (150 mg, 0.73 mmol, 1 equiv) was treated according to the general procedure with 3.5 equiv of oxadiazoline (1) to afford the desired orthoester 6q as a white solid (91 mg, 52%) and (E)-methyl 4(3,4-dimethoxy-3-methyl-4-oxobut-1-enyl)benzoate (23q) as a colorless oil (42 mg, 25%). The starting material was also recovered (24 mg, 16%). 6q: white solid, mp 38−40 °C; 1H NMR (300 MHz, CDCl3) δ 8.01−7.94 (m, 2H), 7.37−7.30 (m, 2H), 4.80 (dd, J = 2.2, 1.1 Hz, 1H), 4.13−4.09 (m, 1H), 3.91 (s, 3H), 3.43 (s, 3H), 3.04 (s, 3H), 1.98−1.94 (m, 3H); 13C NMR (300 MHz, CDCl3) δ 167.0 (s), 153.3 (s), 144.0 (s), 129.2 (d), 129.0 (d), 128.8 (s), 123.8 (s), 100.5 (d), 55.1 (d), 52.0 (q), 50.8 (q), 49.8 (q), 13.8 (q); IR (neat) ν (cm−1) 2947, 1715, 1675, 1272, 1344−902; HRMS (ESI-TOF) m/z [M + Na] calcd for C15H18O5Na 301.1052, found 301.1045. 23q: colorless oil; 1 H NMR (300 MHz, CDCl3) δ 8.03−7.98 (m, 2H), 7.50−7.45 (m, 2H), 6.77 (d, J = 16.2 Hz, 1H), 6.47 (d, J = 16.2 Hz, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 3.38 (s, 3H), 1.64 (s, 3H); 13C NMR (76 MHz, CDCl3) δ 173.0 (s), 166.8 (s), 140.7 (s), 131.9 (d), 130.3 (d), 129.9 (d), 129.4 (s), 126.6 (d), 80.4 (s), 52.6 (q), 52.5 (q), 52.1 (q), 22.7 (q); IR (neat) ν (cm−1) 2943, 1721, 1605, 1425; HRMS (ESI-TOF) m/z [M + Na] calcd for C15H18O5Na 301.1052, found 301.1047. General Methods to Make 2-Methoxyfurans 15. General Method A. Orthoester 6 (1 equiv) was added to anhydrous DCM (0.1 M) into an oven-dried flask. The mixture was cooled to −42 °C using an acetonitrile/dry ice bath, and a 2 M solution of trimethylaluminum in hexanes (1.2 equiv) was added over the period indicated. The reaction was left to react for an additional 2 h at −42 °C, and then it was slowly warmed up to 0 °C over a period of 30 min. A 1 N aqueous NaOH solution was then added to the mixture, and the mixture was vigorously stirred for 10 min at 0 °C. The solution was extracted three times eluting with DCM, and the combined organic phases were dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The crude mixture was then purified on silica gel saturated with triethylamine eluting with DCM and hexanes in a 1:4 ratio. General Method B. In an oven-dried sealed tube was added orthoester 6 (1 equiv), and aluminum tert-butoxide (2 equiv) in toluene (0.5 M) was then added. The tube was sealed and heated to 140 °C for 4 h. The reaction was then cooled to rt and quenched with an aqueous solution of 10% NaOH, and then the aqueous layer was extracted three times with diethyl ether. The organic layer was dried over anhydrous MgSO4 and evaporated under reduced pressure. The crude product was then purified on silica gel saturated with triethylamine eluting with DCM and hexanes in a 1:4 ratio. General Method C. Orthoester 6 (1 equiv) was added to an ovendried flask under argon. Chloroform was then added (0.2 M) followed

by camphorsulfonic acid (5 mol %). After 5 min, the solution was washed once with saturated aqueous NaHCO3, then dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. Normally, the furan obtained needs no further purification. 2-Methoxy-5-phenylfuran (15a). 2,2-Dimethoxy-5-phenyl-2,3-dihydrofuran (6a) (70.0 mg, 0.34 mmol) was treated according to the general procedure B. Al(Ot-Bu)3 (167.2 mg, 0.68 mmol) and toluene (0.75 mL) afforded furan 15a as a colorless oil (52 mg, 87%): 1H NMR (300 MHz, CDCl3) δ 7.60−7.52 (m, 2H), 7.39−7.29 (m, 2H), 7.23−7.14 (m, 1H), 6.54 (d, 1H, J = 3.3 Hz), 5.25 (d, 1H, J = 3.3 Hz), 3.91 (s, 3H).13C NMR (75 MHz, CDCl3) δ 161.8 (s), 144.4 (s), 131.2 (s), 128.9 (d), 126.6 (d), 122.9 (d), 106.6 (d), 82.0 (d), 58.1 (q); IR (neat) ν (cm−1) 3128, 2935, 1599, 1368, 1265; HRMS (ESI-TOF) m/ z [M + Na] calcd for C11H10O3Na 213.0522, found 213.0531. 3-Butyl-5-methoxyfuran (15b). Butyl-2,2-dimethoxy-2,3-dihydrofuran (6b) (188.0 mg, 1.01 mmol) was treated according to the general procedure A. DCM (5 mL) and AlMe3 (2 M in hexanes, 0.71 mL, 1.41 mmol, 1.4 equiv, added over 2 min) afforded furan 15b as a colorless oil (105 mg, 68%): 1H NMR (300 MHz, CDCl3) δ 6.65 (bs, 1H), 5.04 (bs, 1H), 3.81 (s, 3H), 2.36−2.29 (m, 2H), 1.56−1.43 (m, 2H), 1.43−1.28 (m, 2H), 0.92 (t, 3H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 161.8 (s), 128.6 (d), 127.0 (s), 81.0 (d), 57.7 (q), 31.9 (t), 25.5 (t), 22.5 (t), 14.0 (q); IR (neat) ν (cm−1) 2931, 2860, 1757, 1613, 1573, 1439, 1398; HRMS (ESI-TOF) m/z [M + Na] calcd for C9H14O2Na 177.0886, found 177.0873. Alternatively, compound 15b was obtained by the following three methods: Butyl-2,2-dimethoxy-2,3-dihydrofuran (6b) (201.3 mg, 1.08 mmol) was treated according to the general procedure B. Al(Ot-Bu)3 (532 mg, 2.16 mmol) and toluene (2.4 mL) afforded furan 15b as a colorless oil (134 mg, 80%). Butyl-2,2-dimethoxy-2,3-dihydrofuran (6b) (50.0 mg, 0.25 mmol) was treated according to the general procedure C. Chloroform (1.5 mL) and camphorsulfonic acid (8.4 mg) afforded furan 15b as a colorless oil (44 mg, 99%). Butyl-2,2-dimethoxy-2,3-dihydrofuran (6b) (25.0 mg, 0.13 mmol) was dissolved in THF and cooled to −78 °C. n-BuLi (2.3 M in hexanes, 0.13 mL, 0.31 mmol) was slowly added, and the reaction mixture was stirred for 30 min at that temperature. Then, water was added, and the reaction was allowed to cool to room temperature. The phases were separated, and the aqueous phase was extracted three times with diethyl ether; the combined organic fractions were washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was used without further purification to afford furan 15b as a colorless oil (23 mg, quantitative). 3-Butyl-5-methoxy-2-methylfuran (15c). 4-Butyl-2,2-dimethoxy-5methyl-2,3-dihydrofuran (6c) (84.4 mg, 0.42 mmol) was treated according to the general procedure A. DCM (4 mL) and AlMe3 (0.25 mL, 0.51 mmol) afforded furan 15c as a colorless oil (67 mg, 95%): 1H NMR (300 MHz, CDCl3) δ 4.95 (s, 1H), 3.80 (s, 3H), 2.27 (t, 2H, J = 7.4 Hz), 2.13 (s, 3H), 1.55−1.42 (m, 2H), 1.42−1.26 (m, 2H), 0.94 (t, 3H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 159.6 (s), 136.6 (s), 119.8 (s), 80.8 (d), 57.5 (q), 32.4 (t), 24.9 (t), 22.3 (t), 13.9 (q), 10.9 (q); IR (neat) ν (cm−1) 2930, 1603, 1297; HRMS (ESI-TOF) m/z [M + Na] calcd for C10H16O3Na 207.0992, found 207.0994. Alternatively, compound 15c was obtained by the following two methods: 4-Butyl-2,2-dimethoxy-5-methyl-2,3-dihydrofuran (6c) (50.0 mg, 0.25 mmol) was treated according to the general procedure B. Al(OtBu)3 (123.0 mg, 0.5 mmol) and toluene (0.6 mL) afforded furan 15c as a colorless oil (32 mg, 77%). 4-Butyl-2,2-dimethoxy-5-methyl-2,3-dihydrofuran (6c) (112 mg, 0.56 mmol) was treated according to the general procedure C. Chloroform (3 mL) and camphorsulfonic acid (8.4 mg, 5 mol %) afforded furan 15c as a colorless oil (89 mg, 95%). Methyl 2-Methoxy-5-methylfuran-3-carboxylate (15d). To methyl 2,2-dimethoxy-5-methyl-2,3-dihydrofuran-3-carboxylate (6d) (95 mg, 0.47 mmol, 1 equiv) in dry DCM (2.35 mL) was quickly added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL, 0.94 mmol, 2 equiv). 5615

DOI: 10.1021/acs.joc.8b00613 J. Org. Chem. 2018, 83, 5609−5618

Article

The Journal of Organic Chemistry The reaction was heated to reflux for 2 h. It was then quenched with a 1 M HCl aqueous solution and extracted with DCM twice. The organic layer was dried over anhydrous MgSO4 and evaporated under reduced pressure. The crude material was then purified by flash chromatography on silica gel saturated with triethylamine eluting with hexane and ethyl acetate in a 9:1 ratio to afford furan 15d as a white solid (74 mg, 93%): mp 62−64 °C; 1H NMR (300 MHz, CDCl3) δ 6.16 (d, 1H, J = 1.2 Hz), 4.07 (s, 3H), 3.77 (s, 3H), 2.19 (d, 3H, J = 1.1 Hz); 13C NMR (75 MHz, CDCl3) δ 163.8 (s), 161.2 (s), 141.9 (s), 106.9 (d), 91.7 (s), 58.2 (q), 51.3 (q), 13.3 (q); IR (neat) ν (cm−1) 2956, 2359, 1707, 1597, 1447; HRMS (ESI-TOF) m/z [M + Na] calcd for C8H10O4Na 193.0471, found 193.0479. tert-Butyl(3-(2-methoxy-5-methylfuran-3-yl)propoxy)dimethylsilane (15f). tert-Butyl(3-(2,2-dimethoxy-5-methyl-2,3-dihydrofuran-3-yl)propoxy)dimethylsilane (6f) (150.0 mg, 0.47 mmol, 1 equiv) was treated according to the general procedure A. DCM (5 mL) and AlMe3 (0.28 mL, 0.57 mmol) afforded furan 15f as a colorless oil (134 mg, 100%): 1H NMR (300 MHz, CDCl3) δ 5.74 (s, 1H), 3.86 (s, 3H), 3.64 (t, 2H, J = 6.4 Hz), 2.34−2.27 (m, 2H), 2.19 (s, 3H), 1.77−1.65 (m, 3H), 0.92 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 154.7 (s), 141.9 (s), 107.8 (d), 99.7 (s), 62.6 (t), 60.4 (q), 33.2 (t), 26.0 (q), 19.6 (t), 18.3 (s), 13.6 (q), −5.3 (q); IR (neat) ν (cm−1) 2934, 1737, 1649, 1438, 1243; HRMS (ESI-TOF) m/z [M + Na] calcd for C15H28O4SiNa 323.1655, found 323.1643. 4-Butylfuran-2(5H)-one (16b). From treatment of 6b with HCl, 4butyl-2,2-dimethoxy-2,3-dihydrofuran (6b) (277 mg, 1.49 mmol, 1 equiv) was added to a separatory funnel containing CHCl3 (10 mL). Concentrated HCl (1.22 mL, 14.8 mmol, 10 equiv) was added, and the reaction was stirred for 30 s with vigorous agitation. Water was added, and the mixture was extracted three times using chloroform, dried over anhydrous MgSO4, and evaporated under reduced pressure to obtain furanone 16b as a colorless oil (206 mg, 99%). The product was used without further purification in the next step: 1H NMR (300 MHz, CDCl3) δ 5.85 (s, 1H), 4.76 (s, 2H), 2.43 (t, J = 7.6 Hz, 2H), 1.66−1.53 (m, 2H), 1.42 (dq, J = 14.3, 7.2 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.14 (s), 170.58 (s), 115.34 (d), 73.04 (t), 29.29 (t), 28.30 (t), 22.32 (t), 13.67 (q). The characterization data corresponds to the one previously reported in the literature.34 From treatment of 6b with TMSI, 4-butyl-2,2-dimethoxy-2,3dihydrofuran (6b) (15.0 mg, 0.08 mmol, 1 equiv) was added to a flask with acetonitrile (0.8 mL). TMSI (0.01 mL, 0.07 mmol, 0.85 equiv) was added, and the mixture was mixed for 5 min. The crude mixture showed 100% conversion to 4-butylfuran-2(5H)-one (16b), and the product could be used without further purification in the next step. 3-Ethyl-5,6,7,7a-tetrahydrobenzofuran-2(4H)-one (16j). 3-Ethyl2,2-dimethoxy-2,3,4,5,6,7-hexahydrobenzofuran (6j) (100 mg, 0.47 mmol, 1 equiv) was dissolved into CHCl3 (2.3 mL) directly into a separatory funnel. Then, concentrated HCl (0.59 mL) was added, and the mixture was shaken for 30 s. Water was added; the phases were separated, and the aqueous phase was extracted three times with chloroform. The combined organic phases were dried over anhydrous MgSO4 and evaporated under reduced pressure to give furanone 16j as a colorless oil. The product was used without further purification in the next step: 1H NMR (300 MHz, CDCl3) δ 4.56 (dd, 1H, J = 11.2, 6.2 Hz), 2.90−2.79 (m, 1H), 2.57−2.45 (m, 1H), 2.27 (q, 2H, J = 7.5 Hz), 2.14 (tt, 1H, J = 11.5, 5.8 Hz), 1.97 (dd, 2H, J = 34.1, 13.3 Hz), 1.47 (ddt, 1H, J = 26.9, 13.5, 3.0 Hz), 1.34−1.16 (m, 2H), 1.10 (t, 3H, J = 7.6 Hz); 13C NMR (75 MHz, CDCl3) δ 174.3 (s), 162.3 (s), 125.1 (s), 79.8 (d), 34.4 (t), 26.5 (t), 26.1 (t), 22.8 (t), 16.6 (t), 13.3 (q); HRMS (ESI-TOF) m/z [M + Na] calcd for C10H14O2Na 189.0886, found 189.0892. 3-(3-Iodopropyl)furan-2(5H)-one (16r). 7a-Methoxy-4,5,6,7a-tetrahydro-3aH-furo[2,3-b]pyran (6r)9c (81.0 mg, 0.52 mmol, 1 equiv) was added into an oven-dried flask, and then acetonitrile (5 mL) was added along with NaI (194 mg, 1.3 mmol, 2.5 equiv). Freshly distilled TMSCl (0.16 mL, 1.3 mmol, 2.5 equiv) was then added, and the mixture was stirred for 15 min. Water and diethyl ether (10 mL each) were then added to the mixture, and the aqueous phase was separated

and extracted three times with diethyl ether. The organic layers were combined and washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel using hexanes/ethyl acetate in a gradient from 95:5 to 80:20 to afford iodide 16r as a slightly yellow oil (46.8 mg, 36%): 1H NMR (300 MHz, CDCl3) δ 7.24−7.21 (m, 1H), 4.81 (bs, 2H), 3.21 (t, 2H, J = 6.7 Hz), 2.46 (m, 2H), 2.15−2.05 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 174.0 (s), 145.4 (d), 132.4 (s), 70.2 (t), 30.6 (t), 26.3 (t), 5.4 (t); HRMS (ESITOF) m/z [M + Na] calcd for C7H9IO2Na 274.9539, found 274.9542. 3-Butylfuran (17b). 4-Butylfuran-2(5H)-one (16b) (78 mg, 0.56 mmol, 1 equiv) was added into an oven-dried flask along with THF (5 mL). The mixture was put at −40 °C using an acetonitrile/dry ice bath. A 1 M solution of DIBAL-H in toluene (0.56 mL, 0.56 mmol, 1 equiv) was added, and the mixture was stirred for 2 h at −40 °C. A 10% solution of aqueous HCl was added, and the mixture was allowed to cool to rt and stirred for an additional 30 min. The mixture was then put into a separatory funne,l and 1 M HCl was added until the mixture became clear. It was extracted three times using diethyl ether, dried over anhydrous Na2SO4, and evaporated under reduced pressure. Furan 17b is volatile but a quantitative conversion was calculated based on NMR spectroscopy: 1H NMR (300 MHz, CDCl3) δ 7.38 (bt, J = 1.6 Hz, 1H), 7.17 (bs, 1H), 6.30 (bs, 1H), 1.64−1.52 (m, 1H), 1.39 (dq, J = 14.2, 7.1 Hz, 1H), 0.96 (t, J = 7.3 Hz, 1H). The characterization corresponds with the one reported previously in the literature.35 3-Ethyl-2-propyl-4,5,6,7-tetrahydrobenzofuran (17j). 3-Ethyl5,6,7,7a-tetrahydrobenzofuran-2(4H)-one (16j) (40.0 mg, 0.24 mmol, 1 equiv) was added into an oven-dried flask along with diethyl ether (0.6 mL). The mixture was heated to reflux while a solution of propylmagnesium chloride (0.2 mL, 1.41M, 1.2 equiv) was added over 1 h. After the addition, the mixture was refluxed for an additional 4 h. The mixture was cooled to rt, and a 10% HCl solution was added (0.6 mL); the mixture was stirred for 30 min. Diethyl ether was added (10 mL) along with water (10 mL), and the phases were separated. The aqueous layer was extracted three times with diethyl ether (3 × 5 mL). The organic layer was dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure to afford furan 17j as a colorless oil (45 mg, 96%): 1H NMR (300 MHz, CDCl3) δ 2.61−2.48 (m, 4H), 2.42−2.27 (m, 4H), 1.88−1.70 (m, 4H), 1.71−1.56 (m, 2H), 1.10 (t, 3H, J = 7.6 Hz), 0.97 (t, 3H, J = 7.4 Hz); 13C NMR (75 MHz, CDCl3) δ 148.4 (s), 147.8 (s), 120.0 (s), 117.4 (s), 28.2 (t), 23.2 (2 × CH2), 23.1 (t), 22.5 (t), 21.0 (t), 17.0 (t), 15.2 (q), 13.9 (q). This compound did not ionize under a number of methods. We suspect that it could not form a stable ionized complex. Methyl 4-Oxo-4-phenylbutanoate (28a). 2,2-Dimethoxy-5-phenyl2,3-dihydrofuran (6a) (52 mg, 0.25 mmol, 1 equiv) was added into a flask, and 6 N acetic acid (4.2 mL) was added; the reaction mixture was refluxed for 1 h. After cooling to rt, the mixture was carefully poured into a saturated aqueous solution of NaHCO3 (monitoring for pH). The aqueous phase was extracted with ethyl acetate twice, and the combined organic fractions were dried with anhydrous MgSO4, filtered, and evaporated under reduced pressure to give a quantitative yield of keto ester 28a. The crude NMR and GC trace of the mixture showed a clean product (>90%), with traces of the 2-methoxyfuran derivative 15a. 28a: 1H NMR (300 MHz, CDCl3) δ 8.02−7.96 (m, 2H), 7.62−7.53 (m, 1H), 7.51−7.43 (m, 2H), 3.71 (s, 3H), 3.33 (t, J = 6.6 Hz, 2H), 2.78 (t, J = 6.6 Hz, 2H). The characterization data corresponds to the one reported previously in the literature.36 Dimethyl 2-(2-Oxopropyl)malonate (28d). This compound was formed using the same procedure as per product 28a using methyl 2,2dimethoxy-5-methyl-2,3-dihydrofuran-3-carboxylate (6d) (193 mg, 0.96 mmol, 1 equiv) and 6 N acetic acid (30 mL). Purification by flash chromatography on silica gel using hexanes/EtOAc 9:1 yielded 145 mg (81%) of malonate derivative 28d: 1H NMR (300 MHz, CDCl3) δ 3.89 (t, J = 7.1 Hz, 1H), 3.75 (s, 6H), 3.07 (d, J = 7.2 Hz, 2H), 2.21 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 204.8 (s), 169.2 (s), 52.8 (q), 46.5 (d), 42.1 (t), 29.7 (q); IR (neat) ν (cm−1) 1740 (s), 1720 (s); HRMS (ESI-TOF) m/z [M + Na] calcd for C8H12O5Na 211.0582, found 211.0581. 5616

DOI: 10.1021/acs.joc.8b00613 J. Org. Chem. 2018, 83, 5609−5618

Article

The Journal of Organic Chemistry Methyl 5-(tert-Butyldimethylsilyloxy)-2-(2-oxopropyl)pentanoate (28f). This compound was formed using the same procedure as per product 28a using methyl tert-butyl(3-(2,2-dimethoxy-5-methyl-2,3dihydrofuran-3-yl)propoxy)dimethylsilane (6f) (33 mg, 0.10 mmol, 1 equiv) and 6 N acetic acid (5 mL). Purification by flash chromatography on silica gel using hexanes/EtOAc 9:1 yielded 22 mg (70%) of product 28f: 1H NMR (300 MHz, CDCl3) δ 3.67 (s, 3H), 3.59 (t, J = 6.0 Hz, 2H), 3.00−2.80 (m, 2H), 2.60−2.42 (m, 1H), 2.15 (s, 3H), 1.7−1.34 (m, 4H), 0.89 (d, J = 3.6 Hz, 9H), 0.04 (d, J = 4.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 206.7 (s), 175.8 (s), 62.6 (t), 51.8 (q), 45.1 (t), 39.7 (d), 30.2 (t), 30.0 (q), 28.3 (t), 25.9 (q), 18.3 (s), −5.33 (q); IR (neat) ν (cm−1) 1743 (s), 1719 (s); HRMS (ESI-TOF) m/z [M + Na] calcd for C15H30O4SiNa 325.1811, found 325.1813.

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the Presence of DMAD. Org. Lett. 2000, 2, 3501−3503. (d) Lu, X.; Warkentin, J. Ipso Aromatic Substitution from Reaction of a Carbene with DMAD. Tetrahedron Lett. 1999, 40, 1483−1486. (6) (a) Rigby, J. H.; Brouet, J.-C.; Burke, P. J.; Rohach, S.; Sidique, S.; Heeg, M. J. New Entry into β-Lactams via Reaction of Dimethoxycarbene with Isocyanates. Org. Lett. 2006, 8, 3121−3123. (b) Rigby, J. H.; Brouet, S. A. Metal-Mediated Reactions of Aryl Isocyanates with Dimethoxycarbene to Form Isatin Derivatives. Tetrahedron Lett. 2013, 54, 2542−2545. (7) (a) Rigby, J. H.; Cavezza, A.; Ahmed, G. Nucleophilic Carbenes in Organic Synthesis. Construction of Functionalized Hydroindolones Via a Novel Reaction Pathway of Dimethoxycarbene. J. Am. Chem. Soc. 1996, 118, 12848−12849. (b) Rigby, J. H.; Cavezza, A.; Heeg, M. J. Asymmetric Induction in [1 + 4] Cycloadditions of Vinyl Isocyanates with Chiral Nucleophilic Carbenes. Tetrahedron Lett. 1999, 40, 2473− 2476. (c) Rigby, J. H.; Cavezza, A.; Heeg, M. J. Total Synthesis of (±)-Tazettine. J. Am. Chem. Soc. 1998, 120, 3664−3670. (d) Rigby, J. H.; Laurent, S. Nucleophilic Carbenes in Synthesis. [1 + 4] Cycloaddition of Bis(alkylthio)carbenes with Vinyl Isocyanates. J. Org. Chem. 1999, 64, 1766−1767. (e) Rigby, J. H.; Wang, Z. Synthesis of Highly Substituted Cyclopentenones Via the [4 + 1] Cycloaddition of Nucleophilic Carbenes and Vinyl Ketenes. Org. Lett. 2003, 5, 263− 264. (8) Colomvakos, J. D.; Egle, I.; Ma, J.; Pole, D. L.; Tidwell, T. T.; Warkentin, J. [2 + 2], [4 + 1], and [4 + 2] Cycloaddition Reactions of Silylated Bisketenes. J. Org. Chem. 1996, 61, 9522−9527. (9) (a) Beaumier, F.; Dupuis, M.; Spino, C.; Legault, C. Y. Formal Intramolecular (4 + 1)-Cycloaddition of Dialkoxycarbenes: Control of the Stereoselectivity and a Mechanistic Portrait. J. Am. Chem. Soc. 2012, 134, 5938−5953. (b) Boisvert, L.; Beaumier, F.; Spino, C. Evidence for a Concerted [4 + 1]-Cycloaddition between ElectronRich Carbenes and Electron-Deficient Dienes. Org. Lett. 2007, 9, 5361−5363. (c) Spino, C.; Rezaei, H.; Dupont-Gaudet, K.; Bélanger, F. Inter- and Intramolecular [4 + 1]-Cycloadditions Between ElectronPoor Dienes and Electron-Rich Carbenes. J. Am. Chem. Soc. 2004, 126, 9926−9927. (10) (a) Nair, V.; Deepthi, A.; Poonoth, M.; Santhamma, B.; Vellalath, S.; Pattoorpady Babu, B.; Mohan, R.; Suresh, E. Reaction of Dimethoxycarbene-DMAD Zwitterion with 1,2-Diones and Anhydrides: A Novel Synthesis of Highly Substituted Dihydrofurans and Spirodihydrofurans. J. Org. Chem. 2006, 71, 2313−2319. (b) Nair, V.; Sreekumar, V.; Balagopal, L.; Bindu, S. Novel Dipolar Cycloaddition Reactions of Zwitterionic Species Generated from Dimethoxycarbene and Dimethyl Acetylenedicarboxylate with Carbonyl Compounds: Facile Synthesis of Dihydrofuran Derivatives. Synthesis 2003, 2003, 1446−1456. (c) Hoffmann, W. R.; Lilienblum, W.; Dittrich, B. Addition von Dimethoxycarben an CC-Mehrfachbindungen. Chem. Ber. 1974, 107, 3395−3407. See also ref 4. (11) (a) Kaur, T.; Wadhwa, P.; Bagchi, S.; Sharma, A. Isocyanide Based [4 + 1] Cycloaddition Reactions: an Indispensable Tool in Multi-Component Reactions (MCRs). Chem. Commun. 2016, 52, 6958−6976. (b) Zhu, C.; Ding, Y.; Ye, L.-W. Ylide Formal [4 + 1] Annulation. Org. Biomol. Chem. 2015, 13, 2530−2536. (12) (a) Kassam, K.; Pole, D. L.; El-Saidi, M.; Warkentin, J. New Convenient Source of Precursors of Dioxycarbenes. J. Am. Chem. Soc. 1994, 116, 1161−1162. (b) El-Saidi, M.; Kassam, K.; Pole, D. L.; Tadey, T.; Warkentin, J. 2,2-Dialkoxy-Δ3-1,3,4-oxadiazolines: Convenient Thermal Sources of Dialkoxycarbenes. J. Am. Chem. Soc. 1992, 114, 8751−8752. (c) Warkentin, J. Δ3-1,3,4-Oxadiazolines. Versatile Sources of Reactive Intermediates. J. Chem. Soc., Perkin Trans. 1 2000, 2161−2169. (13) For a recent review see: McNulty, J.; McLeod, D.; Das, P.; Zepeda-Velázquez, C. Wittig Reactions of Trialkylphosphine-Derived Ylides: New Directions and Applications in Organic Synthesis. Phosphorus, Sulfur Silicon Relat. Elem. 2015, 190, 619−632. (14) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; Meijere, de A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; Vols. 1, 2. (15) Similarly, an equilibrium existed at 160 °C between an orthoester and another compound. See Scheme 17 in ref 9a.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00613. Proton and carbon NMR for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Claude Spino: 0000-0001-6249-5908 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Both authors were funded by the Natural Sciences and Engineering Research Council of Canada (grant no. RGPIN2014-05189) and the Université de Sherbrooke. We thank them for their financial support.

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REFERENCES

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DOI: 10.1021/acs.joc.8b00613 J. Org. Chem. 2018, 83, 5609−5618