O-Heterocycles from Unsaturated Carbonyls and dimethoxycarbene

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O-Heterocycles from Unsaturated Carbonyls and dimethoxycarbene. Jean-Philippe Croisetière, and Claude Spino J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00613 • Publication Date (Web): 23 Apr 2018 Downloaded from http://pubs.acs.org on April 23, 2018

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The Journal of Organic Chemistry

1 O-Heterocycles from Unsaturated Carbonyls and dimethoxycarbene. Jean-Philippe Croisetière and Claude Spino* Université de Sherbrooke, Département de chimie, 2500 Boul. Université, Sherbrooke, QC, J1K 2R1, Canada [email protected] TOC MeO OMe N heat MeO O N Me Me

R1

O R2

OMe

R1 R2 R3

CSA or Lewis acid

HCl(aq) or TMSCl/NaI R1 R2

R4 O

R3

OMe OMe O

R3

R1

R4MgBr or R2 Dibal-H (R4 = H)

R1

O O

R2

R3

OMe O

R3

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 Oheterocycles, including methoxyfurans, furanones, and furans.

Introduction Dialkoxycarbenes1

are

nucleophilic

species

that

participate

in

many

reactions.

Dimethoxycarbene 2 in particular has been reacted with carbonyls 2 or thiocarbonyls to give αhydroxyesters 8 or episulfurs 10, respectively.3 It was also reacted with alkenes,4 alkynes,5 or

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2 isocyanates,6 and its reaction with vinyl isocyanates 117 or silylated bis-ketenes 138 gave cyclopentadiones 14 or lactams 12, respectively (Scheme 1). Dimethoxycarbene 2 is easily generated from the thermolysis of Warkentin’s oxadiazoline 1 in toluene at 110 or 150 ºC.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 scarce10 and it was not clear at the outset if this transformation would be generally useful. While reactions of isonitriles or sulfur ylids with α,β-unsaturated carbonyls 5 have been used to make dihydrofurans and some furans, their low 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. Scheme 1. Reactions of dimethoxycarbene.


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3 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 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).

Scheme 2. Proposed conversion of enones and enals to synthetically useful O-heterocycles.

MeO R

1

O 2

R

R

OMe 2

R1 R2

3

R3

5

6 HCl(aq) or TMSCl/NaI

R1 R2

R O

R3 17

4

R4MgBr or Dibal-H (R4 = H)

OMe OMe O

R1 R2

CSA or Lewis acid R1

O O

R3 16

R2

OMe O

R3 15

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 reacted with dimethoxycarbene 2 to give the corresponding orthoesters 6a-6k (Figure 2). A silylether, an ester, and a primary bromide function proved compatible with this nucleophilic carbene. The orthoesters 6 were surprisingly stable despite the driving force of



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4 a potential aromatisation by elimination of methanol as well as the presence of the acid-sensitive 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% yield, 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 infra). The oligomers were not characterised but they were identified by NMR and contained several methoxy signals as well as broad signals.

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


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5

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

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 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).



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6

Scheme 3. The 1,4- Vs 1,2-addition hypothesis to explain the difference in reactivity between aldehydes and ketones vis-à-vis dimethoxycarbene 2.

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 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).


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7 Scheme 4. Possible mechanistic pathways from intermediate 18.

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 of 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 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



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8 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 donor 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 lead to more polymerization. As shown in Scheme 5, their ketone derivative 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 1,4-addition 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


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9 Scheme 5. Reaction of dimethoxycarbene 2 with cinnamaldehyde and derivatives 5l-q.

MeO

O H

1, toluene MeO

reflux

+

O MeO 24l (65%)

6l (0%)

1, toluene O

X

MeO OMe O

reflux

3

5m (X = OMe, R3 = Me) 5n (X = R3 = H) 5o (X = H, R3 = Me) 5p (X = CO2Me, R3 = H) 5q (X = CO2Me, R3 = Me)

+

X

OMe CO2Me R3

R

R3

OMe OMe H

H

5l

X

MeO OMe O

6m (27%) 6n (0%) 6o (33%) 6p (0%) 6q (52%)

23m (58%) 23n (0%) 23o (42%) 23p (0%) 23q (25%)

Scheme 6. Intramolecular reaction of enals 5l and 5m.

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, the second did not react with α,β-unsaturated carbonyls but 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



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10 27 is less reactive than dimethoxycarbene 2 and although its reaction with the non-hindered aldehyde 5b proceeds well at 110 ºC, 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 poor yield of product. Nonetheless, the results are promising and we are pursuing the search for a dialkoxycarbene that will give high yield of orthoesters 6 with polymerization-prone aldehydes.

Scheme 7. Reaction of enals 5b and 5u with methoxyphenoxy carbene 27.

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


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11 minutes, the methoxyfurans 15b or 15c were formed and could be isolated cleanly (Scheme 8). Orthoesters 6a-c,f could also be converted efficiently to the corresponding methoxyfuran using trimethylaluminium in DCM at low temperature. The weaker Lewis acid aluminium tris(tbutoxide) was able to cleanly eliminate methanol from orthoesters 6a-c in toluene at 140 ºC to afford similarly good yields of methoxyfurans 15a-c.16 Treating 6b with n-BuLi at -78 ºC afforded a quantitative yield of methoxyfuran 15b while DBU was basic enough to eliminate methanol in the case of orthoester 6d. Methoxyfurans are sensitive to acid and oxygen and may degrade upon exposure to air.

Scheme 8. Ways to convert orthoesters 6 to methoxyfurans 15.

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 or 16j, respectively (Scheme 9). Furanone 16b was also obtained using a mild Lewis acid such as TMSCl in the



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12 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.

Scheme 9. Ways to convert orthoesters 6 to furanones 16.

Furanones 16 can be transformed to furans by known procedures, either by adding a hydride17 or Grignard reagent followed by an acidic work-up.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


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13 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,β-unsaturated aldehyde 5b instead and obtain the same furan 17b, using the same sequence of reactions.

Scheme 10. Synthesis of furans 17j and 17b.

Lastly, γ-ketoesters 28 are obtained in excellent yields either from the orthoesters 6 or from the methoxyfurans 15 (Scheme 11). Possibly, the 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,β-



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14 unsaturated carbonyl. The same products may be obtained from hydrocyanation25 and methanolysis. The present method offers an alternative to the use of toxic cyanide.

Scheme 11. Conversion of orthoesters 6 to acyclic products 28.

Conclusion In conclusion, we have devised a short and efficient sequence of reactions to convert simple α,βunsaturated carbonyls into O-heterocycles with control over the degree of substitution and its pattern. Considering the ready availability of the starting α,β-unsaturated carbonyls 5, the high


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15 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.

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)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 oven at 100 ºC. Solvents were distilled from potassium/benzophenone (tetrahydrofuran), sodium/benzophenone (toluene, diethyl ether), calcium hydride (DCM, triethylamine) ketyls prior to use. Proton nuclear magnetic (1H NMR) spectrums 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, 25µ OD, DB-5ms column) coupled with a mass spectrometer. High-resolution spectrometry was performed by electrospray time-of-fligh. Reactions were monitored by thin-



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16 layer chromatography (TLC) on 0.25 mm silica gel coated glass plate UV 254, vanillin, KMnO4, PMA, or by

1

H NMR. Silica gel (particule size: 230-400 mesh) was used for flash

chromatography. Melting points are uncorrected. 3-Methyleneheptan-2-one (5c). Methylmagnesium chloride 3M in THF (9.02 mL, 3M 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 x 75 mL). The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure, affording 3-methyleneheptan-2-ol as 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 heterogenous solution was heated to reflux temperature for 5 h. The heterogenous 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 colorless oil (1.56 g, 59%). 1H NMR (300 MHz, CDCl3) δ 6.01 (bs, 1H), 5.77 (bs, 1H), 2.35 (s, 3H), 2.31-2.24 (m, 2H), 1.471.26 (m, 4H), 0.92 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3) δ 199.9 (s), 149.4 (s), 124.7


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17 (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-(t-Butyldimethylsilyloxy)hex-2-enal

(5e).

To

a

solution

of

t-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 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 (E)-7-(t-Butyldimethylsilyloxy)hept-3-en-2-one (5f). To a solution of t-butyldimethyl(4penten-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-(tbutyldimethylsilyloxy) hept-3-en-2-one (5f) as 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),



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18 2.38-2.28 (m, 2H), 2.27 (s, 3H), 1.77-1.66 (m, 2H), 0.92 (s, 9H), 0.07 (s, 6H).

13

C 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 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 additionnal 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 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 down, 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 down 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), the combined organic layers were washed with saturated aqueous NaHCO3 (4 × 2 mL), H2O (2 × 2 mL), brine (2 and 1 mL), dried over anhydrous MgSO4, and evaporated under reduced pressure. The crude mixture was then diluted


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19 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 cooling down the reaction mixture, the silica was filtered off and the 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 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-dimethyl-1,3,4-oxadiazoline (1) was then added and the reaction mixture was heated to 140 °C for 16 to 20 h (time required to consume all the 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 one equivalent of the 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). 2,2-Dimethoxy-5-phenyl-2,3-dihydrofuran (6a). 1-Phenyl-2-propen-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 the 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).

13

C NMR (75 MHz, CDCl3) δ 153.6 (s), 130.7



Page 20 of 37

20 (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 (ESI-TOF) 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 the oxadiazoline 1 to afford dihydrofuran 6b as 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 the oxadiazoline 1 to afford the desired product 6c as 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). 13C 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-2pentenoate (5d) (150 mg, 1.17 mmol, 1 equiv.) was treated according to the general procedure with 1.5 equiv. of the oxadiazoline 1 to afford dihydrofuran 6d as colorless oil (214 mg, 93%). 1

H NMR (300 MHz, CDCl3) δ 4.71 (bs, 1H), 3.87 (bs, 1H), 3.74 (s, 3H), 3.42 (s, 3H), 3.39 (s,


Page 21 of 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


21 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 (ESITOF) m/z: [M + Na] Calcd for C9H14O5Na 225.0733; Found 225.0739. t-butyl-[3-(2,2-Dimethoxy-3H-furan-3-yl)propoxy]-dimethyl-silane

(6e).

(E)-6-(t-

Butyldimethylsilyloxy)-2-hexenal (5e) (205 mg, 0.9 mmol, 1 equiv.) was treated according to the general procedure with 3.5 equiv. of the oxadiazoline 1 to afford orthoester 6e as 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. t-Butyl(3-(2,2-dimethoxy-5-methyl-2,3-dihydrofuran-3-yl)propoxy)dimethylsilane (6f). (E)7-(t-Butyldimethylsilyloxy)hept-3-en-2-one (5f) (200 mg, 0.82 mmol, 1 equiv.) was treated according to the general procedure with 3.5 equiv. of the oxadiazoline 1 to afford product 6f as 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.



Page 22 of 37

22 3-(3-Bromopropyl)-2,2-dimethoxy-5-methyl-2,3-dihydrofuran (6g). (E)-6-Bromo-3-hexen-2one (5g) (1.0 g, 5.23 mmol, 1 equiv.) was treated according to the general procedure with 3.2 equiv. of the oxadiazoline 1 to afford orthoester 5g as colorless oil (1.24 g, 90%). 1H 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).

13

C 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 the oxadiazoline 1 to afford hexahydroisobenzofuran (6h) as colorless oil (58 mg, 34%) 1H 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-3-penten-2-one (5i) (300 mg, 3.06 mmol, 1 equiv.) was treated according to the general procedure with 5.0 equiv. of the oxadiazoline 1 to afford the desired orthoester 6i as 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.


Page 23 of 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


23 3-Ethyl-2,2-dimethoxy-2,3,4,5,6,7-hexahydrobenzofuran (6j). 2-Propylidenecyclohexanone (5h) (305 mg, 2.21 mmol, 1 equiv.) was treated according to the general procedure with 4.0 equiv. of the oxadiazoline 1 to afford orthoester 6j as clear oil (406 mg, 87%). 1H 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 the oxadiazoline 1 to afford orthoester 6k as 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 2methoxy-4-(4-methoxyphenyl)-2-methylbut-3-enoate (23m). (E)-4-(4-Methoxyphenyl)but-3en-2-one (3n) (125 mg, 0.71 mmol, 1 equiv.), was treated according to the general procedure with 3.5 equiv. of the oxadiazoline (1) to afford orthoester 6m as a white solid (31 mg, 17%) and (E)-methyl 2-methoxy-4-(4-methoxyphenyl)-2-methylbut-3-enoate (23m) as yellow oil (65 mg, 36%). Starting material was also recovered (48 mg, 38%). 6m : white solid, mp 38-40 °C. 1

H 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). 13

C 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.



Page 24 of 37

24 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, 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-2methyl-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 the oxadiazoline (1) to afford orthoester 6o as a white solid (44 mg, 33%) and (E)-methyl 2-methoxy-2-methyl-4phenylbut-3-enoate (23o) as a yellow oil (58 mg, 42%). 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-

Page 25 of 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


25 enyl)benzoate (5q) (150 mg, 0.73 mmol, 1 equiv.) was treated according to the general procedure with 3.5 equiv. of the 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 colorless oil (42 mg, 25%). Starting material was also recovered (24 mg, 16%). 6q: white solid, m.p. 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). 13

C 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. 1H 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 (cm1

) 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. The orthoester 6 (1 equiv.) is added to anhydrous DCM (0.1 M) into an oven dried flask. The mixture is cooled to 42 °C using an acetonitrile/dry ice bath and a 2 M solution of trimethylaluminum in hexanes (1.2 equiv.) is added over the period indicated. The reaction is left to react for an additional 2 h at 42°C, and then it is slowly warmed up to 0°C over a period of 30 min. A 1 N aqueous NaOH solution is then added to the mixture and vigorously stirred for 10 min at 0 °C. The solution is extracted three times eluting with DCM, the combined organic phases are dried over anhydrous



Page 26 of 37

26 MgSO4, filtered, and evaporated under reduced pressure. The crude mixture is then purified on silica gel saturated with triethylamine eluting eluting with DCM and hexanes in a 1:4 ratio. General Method B. In an oven-dried sealed tube is added the orthoester 6 (1 equiv.) and aluminum t-butoxide (2 equiv.) in Toluene (0.5 M) was then added. The tube is sealed and heated to 140°C for 4 h. The reaction is then cooled to rt, quenched with an aqueous solution of 10% NaOH and then the aqueous layer is extracted three times with diethyl ether. The organic layer is dried over anhydrous MgSO4 and evaporated under reduced pressure. The crude product is then purified on silica gel saturated with triethylamine eluting with DCM and hexanes in a 1:4 ratio. General Method C. The orthoester 6 (1 equiv.) is added to an oven-dried flask under argon. chloroform is then added (0.2 M) followed by camphorsulfonic acid (5 mol%). After 5 min, the solution is 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), toluene (0.75 mL) afforded furan 15a as 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.


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27 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), AlMe3 (2 M in hexanes, 0.71 mL, 1.41 mmol, 1.4 equiv., added over 2 min) afforded furan 15b as colorless oil (105 mg, 68%).1H NMR (300 MHz, CDCl3) δ 6.65 (bs, 1H), 5.04 (bs, 1H), 3.81 (s, 3H), 2.362.29 (m, 2H), 1.56-1.43 (m, 2H), 1.43-1.28 (m, 2H), 0.92 (t, 3H, J = 7.2 Hz).

13

C 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), toluene (2.4 mL) afforded furan 15b as 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), camphorsulfonic acid (8.4 mg) afforded furan 15b as 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 ºC. n-BuLi (2.3 M in hexanes, 0.13 mL, 0.31 mmol) was slowly added and the reaction mixture was stirred for 30 minutes at that temperature. Then, water was added and the reaction was allowed to cool down to room temperature. The phases were separated and the aqueous phase was extracted thrice with diethyl ether and the combined organic fractions washed with brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure.



Page 28 of 37

28 The residue was used without further purification to afford furan 15b as colorless oil (23 mg, quantitative). 3-Butyl-5-methoxy-2-methylfuran (15c). 4-Butyl-2,2-dimethoxy-5-methyl-2,3-dihydrofuran (6c) (84.4 mg, 0.42 mmol) was treated according to the general procedure A : (DCM, 4 mL) AlMe3 (0.25 mL, 0.51 mmol) afforded furan 15c as 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(Ot-Bu)3 (123.0 mg, 0.5mmol), toluene (0.6 mL) afforded furan 15c as 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), camphorsulfonic acid (8.4 mg, 5 mol%) afforded furan 15c as colorless oil (89 mg, 95%). Methyl 2-methoxy-5-methylfuran-3-carboxylate (15d). Methyl 2,2-dimethoxy-5-methyl-2,3dihydrofuran-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.). The reaction was heated to reflux for 2 h. It was then quenched with a 1M HCl aqueous solution and extracted with DCM twice. The organic layer was dried over anhydrous MgSO4 and evaporated under


Page 29 of 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


29 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%) m.p. 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).

13

C 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. t-Butyl(3-(2-methoxy-5-methylfuran-3-yl)propoxy)dimethylsilane

(15f).

t-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), AlMe3 (0.28 mL, 0.57mmol) afforded furan 15f as 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).

13

C 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 (cm1

) 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 : 4-butyl-2,2-dimethoxy-2,3dihydrofuran (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 seconds 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 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,



Page 30 of 37

30 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).

13

C 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-2,3-dihydrofuran (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 mixted 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-Ethyl-2,2-dimethoxy-2,3,4,5,6,7hexahydrobenzofuran (6j) (100 mg, 0.47 mmol, 1 equiv.) was dissolved into CHCl3 (2.3 mL) directly into a separatory funnel. Then, conc. HCl (0.59 mL) was added and the mixture was shaken for 30 seconds. 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 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


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31 mL) was added along 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) was then added to the mixture, 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 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), 2.152.05 (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 (ESI-TOF) 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, 0.56mmol, 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 down to rt and stirred for an additional 30 min. The mixture was then put into a separatory funnel and HCl 1M was added until the mixture became clear. It was extracted three times using diethyl ether, was 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



Page 32 of 37

32 3-Ethyl-2-propyl-4,5,6,7-tetrahydrobenzofuran (17j). 3-Ethyl-5,6,7,7a-tetrahydrobenzofuran2(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 propylmagnesiumchloride (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 down to rt and a 10% HCl solution was added (0.6 mL) and 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 x 5 mL). The organic layer was dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure to afford furan 17j as 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 (2xCH2), 23.1 (t), 22.5 (t), 21.0 (t), 17.0 (t), 15.2 (q), 13.9 (q). HRMS : this compound did not ionise 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-phenyl-2,3-dihydrofuran (6a) (52 mg, 0.25 mmol, 1 equiv.) was added into a flask and 6N acetic acid (4.2 mL) was added and the reaction mixture was refluxed for 1 hr. 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, 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 2methoxyfuran derivative 15a. 1H NMR (300 MHz, CDCl3) δ 8.02-7.96 (m, 2H), 7.62-7.53 (m,


Page 33 of 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


33 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). Same procedure as per product 28a using methyl 2,2-dimethoxy-5-methyl-2,3-dihydrofuran-3-carboxylate (6d) (193 mg, 0.96 mmol, 1 equiv.) and 6N 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 . Methyl 5-(t-butyldimethylsilyloxy)-2-(2-oxopropyl)pentanoate (28f). Same procedure as per product

28a

using

methyl

t-butyl(3-(2,2-dimethoxy-5-methyl-2,3-dihydrofuran-3-

yl)propoxy)dimethylsilane (6f) (33 mg, 0.10 mmol, 1 equiv.) and 6N 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.

Acknowledgement



Page 34 of 37

34 Both authors were funded by the Natural Sciences and Engineering Research Council of Canada (grant No. RGPIN-2014-05189) and the Université de Sherbrooke. We thank them for their financial support. ASSOCIATED CONTENT Supporting Information Proton and carbon NMR for all new compounds AUTHOR INFORMATION Corresponding author *E-Mail: [email protected] ORCID Claude Spino: 0000-0001-6249-5908 Notes The authors declare no competing financial interest

References and notes.

1

For a review on dialkoxycarbenes, see : Warkentin, J. 2,5-Dihydro-1,3,4-oxadiazoles and Bis(heteroatom-substituted)carbenes. Acc. Chem. Res. 2009, 42, 205–212. 2 (a) Lilienblum, W.; Hoffmann, R. H. Addition von Dimethoxycarben an Diene. Chem. Ber. 1977, 110, 3405–3409. (b) Venneri, P. C.; Warkentin, J. Reaction of Dimethoxycarbene with Strained Cyclic Carbonyl Compounds. Can. J. Chem. 2000, 78, 1194–1203. (c) Dawid, M.; Warkentin, J. Intramolecular Reactions of Dialkoxycarbenes with a Carbonyl Group. Can. J. Chem. 2003, 81, 598–606. (d) Pole, D. L.;


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35

Warkentin, J. Formation and Rearrangement of a 2,2-Dimethoxyoxirane from Dimethoxycarbene and Fluorenone. J. Org. Chem. 1997, 62, 4065–4067. 3 Dawid, M.; Mloston, G.; Warkentin, J. Relative Reactivities of Carbonyl and Thiocarbonyl Groups Toward Dimethoxycarbene: Two New Dimethoxythiiranes. Chem. Eur. J. 2002, 8, 2184–2187. 4 (a) Sliwinska, A.; Warkentin, J. Reactions of Dimethoxycarbene with Dimethyl 2,3-Dicyanomaleate and Fumarate. Org. Lett. 2007, 9, 2605–2607. (b) Zhou, H.; Mloston, G.; Warkentin, J. New Thermal Source of Dimethoxycarbene Leading to Zwitterionic Intermediates and 2:1 Stoichiometry in Reaction with Electrophilic Alkenes. Org. Lett. 2005, 7, 487–489. (c) Couture, P.; Pole D. L.; Warkentin, J. Reactions of Nucleophilic Carbenes with Enols. J. Chem. Soc., Perkin Trans. 2 1997, 1565–1570. 5 (a) Kassam, K.; Warkentin, J. Reactions of Dialkoxycarbenes with Tethered Triple Bonds to Form Heterocyclic Compounds. Can. J. Chem. 1997, 75, 120–128. (b) Kassam, K.; Venneri, P. C.; Warkentin, J. Reactions of Alkoxyaryloxycarbenes with Tethered Triple Bonds: A New Synthesis of Substituted Benzofurans. Can. J. Chem. 1997, 75, 1256–1263. (c) Lu, X.; Warkentin, J. Novel Products From Thermolysis of 5,5-Dimethyl-2,2-diphenoxy-∆3-1,3,4-oxadiazoline in 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 βLactams 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 Electron-Rich 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 Electron-Poor 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, B. V.; Balagopal, L. Novel Dipolar Cycloaddition Reactions of Zwitterionic Species Generated from Dimethoxycarbene and Dimethyl Acetylenedicarboxylate with Carbonyl Compounds: Facile Synthesis of Dihydrofuran Derivatives. Synthesis 2003, 1446–1456; (c) Hoffmann, W. R.; Lilienblum, W.; Dittrich, B. Addition von Dimethoxycarben an C—CMehrfachbindungen. 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.



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36

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-∆3-1,3,4-oxadiazolines: Convenient Thermal Sources of Dialkoxycarbenes. J. Am. Chem. Soc. 1992, 114, 8751–8752. (c) Warkentin, J. ∆3-1,3,4-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. Phosph. Sulf. Silic. 2015, 190, 619–632. 14 Metal-Catalyzed Cross-Coupling Reactions, Vol 1 & 2, de A. Meijere and F. Diederich, Eds., WileyVCH, 2nd ed., 2004, Weinheim. 15

Relatedly, an equilibrium existed at 160 ºC between an orthoester and another compound. See Scheme 17 in ref. 9a. 16

Graziano, M. L.; Iesce, M. R.; Scarpati, R. Reactions of Ketenes. XX. Phenylketene Dimethylacetal as Synthon for the Introduction of Functionalized Phenylethyl Units. J. Het. Chem. 1986, 23, 553–556. 17 (a) Minato, H.; Nagasaki, T. A New Method for the Synthesis of Furan Compounds. J. Chem. Soc. C 1966, 377–379. (b) Jefford, C. W.; Sledeski, A. W.; Rossier, J.-C.; Boukouvalas, T. A Short Route to Furanosesquiterpenes Using a New Siloxyfuran Building Block. The Synthesis of Freelingnite and Dehydrolasiosperman. Tetrahedron Lett. 1990, 31, 5741–5744. 18 Fournier, J.; Arseniyadis, S.; Cossy, J. A Modular and Scalable One-Pot Synthesis of Polysubstituted Furans. Angew. Chem. Int. Ed. 2012, 51, 7562–7566. 19 Iesce, M. R.; Graziano, M. L.; Cermola, F.; Montella, S.; Di Gioia, L. The First Nucleophilic Aromatic Substitution of Suitably Activated 2-Methoxyfurans with Grignard Reagents Tetrahedron Lett. 2003, 44, 5781–5784. 20 For reviews see (a) Lukevits, É.; Pudova, O. A. Furan Derivatives of Group I Elements. Chem. Het. Comp. 1995, 31, 377–411.(b) Lukevits, É.; Pudova, O. A. Furan Derivatives of Group II Elements. Chem. Het. Comp. 1995, 31, 412–431. 21 (a) Lee, C. F.; Yang, L. M.; Hwu, T. Y.; Feng, A. S.; Tseng, J. C.; Luh, T. Y. One-Pot Synthesis of Substituted Furans and Pyrroles From Propargylic Dithioacetals. New Annulation Route to Highly Photoluminescent Oligoaryls. J. Am. Chem. Soc. 2000, 122, 4992–4993, and references therein. (b) Liu, C. Y.; Luh, T. Y. Combining Furan Annulation, Heck Reaction, and Sonogashira Coupling for the Synthesis of Oligoaryls. Org. Lett. 2002, 4, 4305–4307. (c) Hucke A.; Cava, M. P. Synthesis of Mixed Thiophene/Furan Oligomers by Stille Coupling. J. Org. Chem. 1998, 63, 7413–7417. (d) Politis, J. K.; Nemes J. C.; Curtis, M. D. Synthesis and Characterization of Regiorandom and Regioregular Poly(3octylfuran). J. Am. Chem. Soc. 2001, 123, 2537–2547. (e) Pyo, S. M.; Kim, S. I.; Shim, T. J.; Park H. K.; Ree, M. Synthesis and Characterization of A New Blue-Light-Emitting Polyimide. Macromolecules 1998, 31, 4777–4781. 22 (a) Gidron, O.; Bendikov, M. α-Oligofurans: An Emerging Class of Conjugated Oligomers for Organic Electronics. Angew. Chem. Int. Ed. 2014, 53, 2546–2555. (b) Groenendaal, L.; Meijere, E. W.; Vekemans, J. A. J. M. Nitrogen-Containing Oligomers In Electronic Materials: The Oligomer Approach, Eds.: Müllen, K.; Wegner, G., Wiley-VCH, Weinheim, 1998, 235–272. (c) Handbook of Conducting Polymers, 2nd ed., Eds.: Skotheim, T. A.; Elsenbaumer, R. L. ; Reynolds J. R., Marcell Dekker, NewYork, 1998. 23 Li, H.; Zhang, Q.; Bhadury, P. S.; Yang, S. Furan-type Compounds From Carbohydrates via Heterogeneous Catalysis. Curr. Org. Chem. 2014, 18, 547–597 and references cited therein. 24 (a) See for examples : Nakanishi, K. Natural Products Chemistry, Kodansha, Ltd.: Tokyo, 1974. (b) Fuse, S.; Ohuchi, T.; Asawa, Y.; Sato, S.; Nakamura, S. Development of 1-Aryl-3-furanyl/Thienylimidazopyridine Templates for Inhibitors Against Hypoxia Inducible Factor (HIF)-1 Transcriptional Activity. Bioorg. Med. Chem. Lett. 2016, 26, 5887–5890. (c) Omelchuk, O. A.; Tikhomirov, A. S.; Shchekotikhin, A. E. Annelation of Furan Rings to Arenes. Russ. Chem. Rev. 2016, 85, 817–835.


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O-Heterocycles from Unsaturated Carbonyls and dimethoxycarbene

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