O-Heterocycles from Unsaturated Carbonyls and Dimethoxycarbene

Article abstract of DOI:10.1021/acs.joc.8b00613

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.

Full text of DOI:10.1021/acs.joc.8b00613

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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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O-Heterocycles from Unsaturated Carbonyls and dimethoxycarbene.
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Jean-Philippe Croisetière and Claude Spino*
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Université de Sherbrooke, Département de chimie, 2500 Boul. Université, Sherbrooke, QC, J1K
2R1, Canada
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Claude.Spino@USherbrooke.ca
TOC
R1
O
MeO
R1
OMe
OMe
OMe
R2
R3
N
N
MeO
heat
OMe
O
R2
O
Me
Me
R3
CSA or
HCl(aq) or
TMSCl/NaI
Lewis acid
R1
R1
R1
R4MgBr
or
R4
O
OMe
R2
R2
R2
O
O
O
Dibal-H
R3
(R4 = H)
R3
R3
Abstract: The (4+1)ꢀannulation of dimethoxycarbene with readily accessible α,βꢀunsaturated
carbonyls gives cyclic orthoesters, which can then be converted in just a few steps to other Oꢀ
heterocycles, including methoxyfurans, furanones, and furans.
Introduction
Dialkoxycarbenes1 are nucleophilic species that participate in many reactions.
2
Dimethoxycarbene 2 in particular has been reacted with carbonyls or thiocarbonyls to give αꢀ
hydroxyesters 8 or episulfurs 10, respectively.3 It was also reacted with alkenes,4 alkynes,5 or
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isocyanates,6 and its reaction with vinyl isocyanates 117 or silylated bisꢀketenes 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 electronꢀdeficient dienes 3 to
give (4+1)ꢀcycloadducts 4.9 Surprisingly, reports of their reactions with α,βꢀunsaturated
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,βꢀunsaturated 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.
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Scheme 1. Reactions of dimethoxycarbene.
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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,13ꢀ14 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).
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Scheme 2. Proposed conversion of enones and enals to synthetically useful Oꢀheterocycles.
MeO
OMe
R1
OMe
OMe
R1
O
2
R2
O
R2
R3
R3
5
6
CSA or
Lewis acid
HCl(aq) or
TMSCl/NaI
R4MgBr
or
R1
R1
R1
R4
O
OMe
R2
R2
R2
O
O
O
Dibal-H
(R4 = H)
R3
17
R3
16
R3
15
Results and Discussion
Figure 1 lists the α,βꢀunsaturated 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
6aꢀ6k (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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a potential aromatisation by elimination of methanol as well as the presence of the acidꢀsensitive
orthoester and enolether functions.
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. 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 sꢀcis conformation of the unsaturated carbonyl is higher in energy
(as is the case for ketone 5i). Ketone 5j, which is locked in the sꢀcis 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.
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Figure 1: α,βꢀUnsaturated carbonyls 5 that were reacted with dimethoxycarbene 2.
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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 1,2ꢀaddition
instead of a 1,4ꢀaddition on the unsaturated system (Scheme 3). Naturally, aldehydes are more
prone to 1,2ꢀaddition than ketones are, for steric reasons. In any case, there is no pathway leading
to the desired product 6 that starts with a 1,2ꢀaddition of dimethoxycarbene. Of course, enolate
E-19, resulting from a 1,4ꢀaddition, 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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Scheme 3. The 1,4ꢀ Vs 1,2ꢀaddition hypothesis to explain the difference in reactivity between
aldehydes and ketones visꢀàꢀvis dimethoxycarbene 2.
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Intermediate 18, resulting from an initial 1,2ꢀaddition 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
polymerꢀlike 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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Scheme 4. Possible mechanistic pathways from intermediate 18.
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While we cannot be certain that oligomerization is the result of an initial 1,2ꢀaddition, 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 1,2ꢀaddition of
dimethoxycarbene 2 on aldehyde 5l. The initial 1,2ꢀaddition 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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corresponding ketone 5m underwent less 1,2ꢀaddition and more 1,4ꢀaddition 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 1,2ꢀaddition in any case. It is also likely that 23m and 24m are in
equilibrium at that temperature, we have not verified this possibility.15
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The absence of an electron donor group (aldehyde 5n, R1 = Ph, R3 = H) or the presence of an
electronꢀwithdrawing group on the aryl (aldehyde 5p, R1 = pꢀC6H4–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
= pꢀC6H4–CO2Me, R3 = Me) gave higher yields of the desired cyclic orthoesters 6o (33%) and
6q (52%), presumably because of increased 1,4ꢀaddition 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 1,4ꢀ
addition (Scheme 6).9c
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Scheme 5. Reaction of dimethoxycarbene 2 with cinnamaldehyde and derivatives 5l-q.
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OMe
MeO
OMe
1
, toluene
reflux
O
MeO
O
H
OMe
O
+
MeO
MeO
H
H
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5l
6l
24l
(65%)
(0%)
OMe
O
MeO
1
, toluene
reflux
X
O
X
X
OMe
+
R3
CO2Me
R3
R3
3
5m
6m
23m (
58%)
(X = OMe, R = Me)
5n (X = R3 = H)
(X = H, R = Me)
5p (X = CO2Me, R3 = H)
(27%)
6n
23n
(0%)
6o (33%)
(0%)
23o (42%)
3
5o
6p
6q
23p
23q
(0%)
(52%)
(0%)
(25%)
3
5q
(X = CO2Me, R = Me)
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 1,4ꢀadditions, like alkoxythiocarbenes, dithiocarbenes, or methoxyphenoxycarbene 27
(Scheme 7). The first led to a different product, the second did not react with α,βꢀunsaturated
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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27 is less reactive than dimethoxycarbene 2 and although its reaction with the nonꢀhindered
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 polymerizationꢀprone aldehydes.
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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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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(tꢀ
butoxide) 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 nꢀBuLi 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.
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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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presence of iodide in the reaction medium to dealkylate the methoxyloxonium ion. Starting with
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orthoester 6r and using TMSCl and NaI, dealkylation gave furanone 16r.
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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 workꢀup.18,19 To showcase the efficiency of our
sequence, starting from the readily available α,βꢀunsaturated 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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Monosubstituted furan 17b was obtained from an HCl treatment of orthoester 6b followed by
DIBALꢀH reduction at ꢀ40°C (Scheme 10). This sequence also offers a solution to the
preparation of some 2,5ꢀunsubstituted furans which may be difficult to access when the aldehyde
precursor is prone to polymerization, such as enal 5u. One may thus use α,βꢀunsaturated
aldehyde 5b instead and obtain the same furan 17b, using the same sequence of reactions.
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Scheme 10. Synthesis of furans 17j and 17b.
Lastly, γꢀketoesters 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 γꢀketoesters 28. Aqueous acetic acid was effective. γꢀKetoesters
28 are the product of the formal 1,4ꢀaddition of a methoxycarbonyl anion equivalent to the α,βꢀ
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unsaturated 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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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,βꢀ
unsaturated carbonyls into Oꢀheterocycles with control over the degree of substitution and its
pattern. Considering the ready availability of the starting α,βꢀunsaturated carbonyls 5, the high
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yields of the reaction sequence, and the scope of this method, we believe it is an efficient and
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flexible way to make polysubstituted Oꢀheterocycles.
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EXPERIMENTAL SECTION:
General Considerations
All reactions were performed under an inert atmosphere of argon in ovenꢀdried 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
chloroformꢀd 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 chloroformꢀd 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, DBꢀ5ms column) coupled with a mass spectrometer. Highꢀresolution
spectrometry was performed by electrospray timeꢀofꢀfligh. Reactions were monitored by thinꢀ
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layer chromatography (TLC) on 0.25 mm silica gel coated glass plate UV 254, vanillin, KMnO4,
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PMA, or by H NMR. Silica gel (particule size: 230ꢀ400 mesh) was used for flash
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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 2ꢀbutylacrolein (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 3ꢀmethyleneheptanꢀ2ꢀol as colorless oil (2.80 g,
97%). The crude product 29 was pure enough to proceed to the next step without further
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purification. H NMR (300 MHz, CDCl3) δ 5.05 (s, 1H), 4.83 (s, 1H), 4.28 (q, 1H, J = 6.3 Hz),
2.19ꢀ1.96 (m, 2H), 1.57ꢀ1.34 (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 3ꢀmethyleneꢀ2ꢀheptanol (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 3ꢀmethyleneꢀ2ꢀheptanone (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), 2.31ꢀ2.24 (m, 2H), 1.47ꢀ
1.26 (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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(t), 30.6 (t), 30.3 (t), 26.0 (q), 22.5 (t), 13.9 (q). HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for
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C8H14ONa 149.0937; Found 149.0933.
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(E)-6-(t-Butyldimethylsilyloxy)hex-2-enal (5e). To
a
solution of tꢀbutyldimethyl(4ꢀ
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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), 2.50ꢀ2.40 (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 tꢀbutyldimethyl(4ꢀ
pentenꢀ1ꢀyloxy)silane29 (500 mg, 2.50 mmol, 1 equiv.) and 3ꢀbutenꢀ2ꢀone (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)ꢀ7ꢀ(tꢀ
butyldimethylsilyloxy) heptꢀ3ꢀenꢀ2ꢀone (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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2.38ꢀ2.28 (m, 2H), 2.27 (s, 3H), 1.77ꢀ1.66 (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 (cmꢀ1) 2934, 2852, 1680. HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for
C13H26O2SiNa 265.1600; Found 265.1596.
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(E)-7-Bromohept-3-en-2-one (5g). 5ꢀBromoꢀ1ꢀpentene (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
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a 90 : 10 ratio to afford enone 5g as colorless oil (2.22 g, 91%). H 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), 2.48ꢀ2.38 (m,
2H), 2.27 (s, 3H), 2.11ꢀ2.01 (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 flamedꢀdried. 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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with toluene (100 mL) and silica (13.5 g) was added. The heterogeneous mixture was heated to
reflux for 18 h using a DeanꢀStark 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 5ꢀ10%
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gradient of diethyl ether. Enone 5h as colorless oil (0.77 g, 56%) was obtained. H 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), 1.89ꢀ1.80 (m, 2H), 1.78ꢀ1.69 (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,βꢀunsaturated carbonyl 5 (1 equiv.) was dissolved in anhydrous toluene (0.2 M) into an
ovenꢀdried sealed tube. 2,5ꢀDihydroꢀ2,2ꢀdimethoxyꢀ5,5ꢀdimethylꢀ1,3,4ꢀoxadiazoline (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). 1ꢀPhenylꢀ2ꢀpropenꢀ1ꢀone (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 7.62ꢀ7.55 (m, 2H), 7.40ꢀ7.28 (m, 3H), 5.39 (t, 1H, J =
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2.7 Hz), 3.44 (s, 6H), 2.89 (d, 2H, J = 2.7 Hz). C NMR (75 MHz, CDCl3) δ 153.6 (s), 130.7
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(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 (cmꢀ1) 2946,
2840, 1734. HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for C12H14O3Na 229.0835; Found
229.0838.
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4-Butyl-2,2-dimethoxy-2,3-dihydrofuran (6b). 2ꢀButylacrolein (5b) (0.12 mL, 0.89 mmol, 1
equiv.) was treated according to the general procedure with 2 equiv. of the oxadiazoline 1 to
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afford dihydrofuran 6b as colorless oil (138 mg, 84%) H 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), 1.46ꢀ1.20 (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 (cmꢀ1) 2955, 1669, 1460. LRMS (m/z, relative intensity) 186
(MH+, 58), 155 (67), 143 (12) 112 (100). HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for
C10H18O3Na 209.1148; Found 209.1156.
4-Butyl-2,2-dimethoxy-5-methyl-2,3-dihydrofuran (6c). 3ꢀMethyleneꢀ2ꢀheptanone (5c) (206
mg, 1.63 mmol, 1 equiv.) was treated according to the general procedure with 3.5 equiv. of the
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oxadiazoline 1 to afford the desired product 6c as clear oil (123 mg, 65%). H NMR (300 MHz,
CDCl3) δ 3.33 (s, 6H), 2.59 (m, 2H), 2.00 (t, 2H, J = 6.9 Hz), 1.78ꢀ1.74 (m, 3H), 1.39ꢀ1.20 (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 (cmꢀ1) 2926, 1705, 1441.
HRMS (ESIꢀTOF) 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)ꢀ4ꢀoxoꢀ2ꢀ
pentenoate (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%).
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,
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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 (cmꢀ1) 2954, 2847, 1736, 1437. HRMS (ESIꢀ
TOF) m/z: [M + Na] Calcd for C9H14O5Na 225.0733; Found 225.0739.
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t-butyl-[3-(2,2-Dimethoxy-3H-furan-3-yl)propoxy]-dimethyl-silane
(6e).
(E)ꢀ6ꢀ(tꢀ
Butyldimethylsilyloxy)ꢀ2ꢀhexenal (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), 5.05ꢀ5.02 (m, 1H), 3.61 (t, 2H, J = 6.4 Hz),
3.40 (s, 3H), 3.31 (s, 3H), 2.89ꢀ2.81 (m, 1H), 1.72ꢀ1.51 (m, 3H), 1.40ꢀ1.29 (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 (cmꢀ1) 2952, 2857, 1744,
1622, 1471. HRMS (ESIꢀTOF) 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)ꢀ
7ꢀ(tꢀButyldimethylsilyloxy)heptꢀ3ꢀenꢀ2ꢀone (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), 2.91ꢀ2.82 (m, 1H), 1.83 (d, 3H, J = 1.3 Hz), 1.72ꢀ1.46 (m,
3H), 1.41ꢀ1.27 (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 (cmꢀ1) 2944, 2850, 1684, 1464. HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for
C16H32O4SiNa 339.1967; Found 339.1953.
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3-(3-Bromopropyl)-2,2-dimethoxy-5-methyl-2,3-dihydrofuran (6g). (E)ꢀ6ꢀBromoꢀ3ꢀhexenꢀ2ꢀ
one (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), 3.36ꢀ3.29 (m, 2H), 2.95ꢀ2.84 (m, 1H),
1.98ꢀ1.86 (m, 2H), 1.86ꢀ1.83 (m, 3H), 1.82ꢀ1.65 (m, 1H), 1.54ꢀ1.41 (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 (cmꢀ1) 2952, 2857, 1744, 1622, 1471. HRMS (ESIꢀTOF) m/z: [M + Na]
Calcd for C10H17BrO3Na 287.0253; Found 287.0256.
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2,2-Dimethoxy-2,3,4,5,6,7a-hexahydrobenzofuran (6h). Cyclohexꢀ1ꢀenecarboxaldehyde (0.12
mL, 0.89 mmol, 1 equiv.) was treated according to the general procedure with 3.5 equiv. of the
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oxadiazoline 1 to afford hexahydroisobenzofuran (6h) as colorless oil (58 mg, 34%) H NMR (300
MHz, CDCl3) δ 6.05 (t, J = 2.2 Hz, 1H), 3.42 (s, 3H), 3.33 (s, 3H), 2.71ꢀ2.58 (m, 1H), 2.42ꢀ2.31 (m,
1H), 2.02ꢀ1.72 (m, 3H), 1.51ꢀ1.08 (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 (cmꢀ1) 2930 (m), 1723
(m), 1449 (m), 1243ꢀ935 (br). HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for C10H16O3Na 207.0992;
Found: 207.0984.
2,2-Dimethoxy-3,4,5-trimethyl-2,3-dihydrofuran (6i). 3ꢀMethylꢀ3ꢀpentenꢀ2ꢀone (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
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yield)). H NMR (300 MHz, CD3CN) δ 3.32 (s, 3H), 3.25 (s, 3H), 2.83ꢀ2.72 (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 (cmꢀ1) 2293,
1720, 1449. HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for C9H16O3Na 195.0992; Found 195.0999.
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3-Ethyl-2,2-dimethoxy-2,3,4,5,6,7-hexahydrobenzofuran (6j). 2ꢀPropylidenecyclohexanone
(5h) (305 mg, 2.21 mmol, 1 equiv.) was treated according to the general procedure with 4.0
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MHz, CD3CN) δ 3.35 (s, 3H), 3.26 (s, 3H), 2.73ꢀ2.63 (m, 1H), 2.10ꢀ2.00 (m, 3H), 1.79ꢀ1.42 (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 (cmꢀ1)
2934, 2845, 1754, 1726, 1450. HRMS (ESIꢀTOF) m/z: [MꢀCH4 + 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
1
afford orthoester 6k as clear oil (224 mg, 66%). H NMR (300 MHz, CDCl3) δ 7.66ꢀ7.58 (m,
2H), 7.38ꢀ7.17 (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-methylbut-3-enoate (23m). (E)ꢀ4ꢀ(4ꢀMethoxyphenyl)butꢀ3ꢀ
enꢀ2ꢀone (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 2ꢀmethoxyꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀmethylbutꢀ3ꢀenoate (23m) as yellow oil (65
mg, 36%). Starting material was also recovered (48 mg, 38%). 6m : white solid, mp 38ꢀ40 °C.
1H NMR (300 MHz, CDCl3) δ 7.22ꢀ7.15 (m, 2H), 6.89ꢀ6.82 (m, 2H), 4.79 (dd, J = 2.3, 1.2 Hz,
1H), 4.04ꢀ4.00 (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 (cmꢀ1) 2933, 1680.
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HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for C14H18O4Na 273.1103; Found 273.1095. 23m :
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colorless oil. H NMR (300 MHz, CDCl3) δ 8.03ꢀ7.98 (m, 2H), 7.51ꢀ7.44 (m, 2H), 6.77 (d, J =
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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). C
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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 (cmꢀ1) 2957, 1731, 1505,
1435. HRMS (ESIꢀTOF) 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)ꢀ4ꢀPhenylbutꢀ3ꢀenꢀ2ꢀone (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 2ꢀmethoxyꢀ2ꢀmethylꢀ4ꢀ
phenylbutꢀ3ꢀenoate (23o) as a yellow oil (58 mg, 42%). Starting material was also recovered (33
mg, 24%). 6o: white solid, mp 38ꢀ40 °C. 1H NMR (300 MHz, CDCl3) δ 7.40ꢀ7.20 (m, 5H), 4.83
(dd, J = 2.3, 1.2 Hz, 1H), 4.13ꢀ4.04 (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 (cmꢀ1) 2957, 1680, 1461, 1316ꢀ950.
HRMS (ESIꢀTOF) m/z: [MꢀCH4 + Na] Calcd for C12H12O3Na 227.0684; Found 227.0679. 23o:
1
colorless oil. H NMR (300 MHz, CDCl3) δ 7.46ꢀ7.40 (m, 2H), 7.38ꢀ7.23 (m, 3H), 6.73 (d, J =
13
16.3 Hz, 1H), 6.36 (d, J = 16.3 Hz, 1H), 3.81 (s, 3H), 3.37 (s, 3H), 1.64 (s, 3H). C 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 (cmꢀ1) 2947, 1735, 1440. HRMS (ESIꢀTOF) 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 4ꢀ(3ꢀoxobutꢀ1ꢀ
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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 4ꢀ(3,4ꢀdimethoxyꢀ3ꢀmethylꢀ4ꢀoxobutꢀ1ꢀenyl)benzoate (23q) as
colorless oil (42 mg, 25%). Starting material was also recovered (24 mg, 16%). 6q: white solid,
m.p. 38ꢀ40 °C. 1H NMR (300 MHz, CDCl3) δ 8.01ꢀ7.94 (m, 2H), 7.37ꢀ7.30 (m, 2H), 4.80 (dd, J
= 2.2, 1.1 Hz, 1H), 4.13ꢀ4.09 (m, 1H), 3.91 (s, 3H), 3.43 (s, 3H), 3.04 (s,3H), 1.98ꢀ1.94 (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 (cmꢀ1) 2947, 1715,
1675, 1272, 1344ꢀ902. HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for C15H18O5Na 301.1052;
Found 301.1045. 23q: colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.03ꢀ7.98 (m, 2H), 7.50ꢀ7.45
(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,
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3H), 1.64 (s,3H). C 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 (cmꢀ
1) 2943, 1721, 1605, 1425. HRMS (ESIꢀTOF) 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
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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.
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General Method B. In an ovenꢀdried sealed tube is added the orthoester 6 (1 equiv.) and
aluminum tꢀbutoxide (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.
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General Method C. The orthoester 6 (1 equiv.) is added to an ovenꢀdried 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). 2,2ꢀDimethoxyꢀ5ꢀphenylꢀ2,3ꢀdihydrofuran (6a) (70.0 mg,
0.34 mmol) was treated according to the general procedure B : Al(OtꢀBu)3 (167.2 mg, 0.68
1
mmol), toluene (0.75 mL) afforded furan 15a as colorless oil (52 mg, 87%). H NMR (300
MHz, CDCl3) δ 7.60ꢀ7.52 (m, 2H), 7.39ꢀ7.29 (m, 2H), 7.23ꢀ7.14 (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 (cmꢀ1) 3128,
2935, 1599, 1368, 1265. HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for C11H10O3Na 213.0522;
Found 213.0531.
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3-Butyl-5-methoxyfuran (15b). Butylꢀ2,2ꢀdimethoxyꢀ2,3ꢀdihydrofuran (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), 2.36ꢀ
2.29 (m, 2H), 1.56ꢀ1.43 (m, 2H), 1.43ꢀ1.28 (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 (cmꢀ1) 2931, 2860, 1757, 1613, 1573, 1439, 1398. HRMS (ESIꢀTOF) m/z: [M +
Na] Calcd for C9H14O2Na 177.0886; Found 177.0873.
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Alternatively, compound 15b was obtained by the following three methods:
Butylꢀ2,2ꢀdimethoxyꢀ2,3ꢀdihydrofuran (6b) (201.3 mg, 1.08 mmol) was treated according to the
general procedure B : Al(OtꢀBu)3 (532 mg, 2.16 mmol), toluene (2.4 mL) afforded furan 15b as
colorless oil (134 mg, 80%).
Butylꢀ2,2ꢀdimethoxyꢀ2,3ꢀdihydrofuran (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%).
Butylꢀ2,2ꢀdimethoxyꢀ2,3ꢀdihydrofuran (6b) (25.0 mg, 0.13 mmol) was dissolved in THF and
cooled to ꢀ78 ºC. nꢀBuLi (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.
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The residue was used without further purification to afford furan 15b as colorless oil (23 mg,
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quantitative).
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3-Butyl-5-methoxy-2-methylfuran (15c). 4ꢀButylꢀ2,2ꢀdimethoxyꢀ5ꢀmethylꢀ2,3ꢀdihydrofuran
(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), 1.55ꢀ1.42 (m,
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2H), 1.42ꢀ1.26 (m, 2H), 0.94 (t, 3H, J = 7.2 Hz). C 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 (cmꢀ1)
2930, 1603, 1297. HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for C10H16O3Na 207.0992;
Found 207.0994.
Alternatively, compound 15c was obtained by the following two methods:
4ꢀButylꢀ2,2ꢀdimethoxyꢀ5ꢀmethylꢀ2,3ꢀdihydrofuran (6c) (50.0 mg, 0.25 mmol) was treated
according to the general procedure B : Al(OtꢀBu)3 (123.0 mg, 0.5mmol), toluene (0.6 mL)
afforded furan 15c as colorless oil (32 mg, 77%).
4ꢀButylꢀ2,2ꢀdimethoxyꢀ5ꢀmethylꢀ2,3ꢀdihydrofuran (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 2,2ꢀdimethoxyꢀ5ꢀmethylꢀ2,3ꢀ
dihydrofuranꢀ3ꢀcarboxylate (6d) (95 mg, 0.47 mmol, 1 equiv.) in dry DCM (2.35 mL) was
quickly added 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (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
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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
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15d as a white solid (74 mg, 93%) m.p. 62ꢀ64 °C. H NMR (300 MHz, CDCl3) δ 6.16 (d, 1H, J
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= 1.2 Hz), 4.07 (s, 3H), 3.77 (s, 3H), 2.19 (d, 3H, J = 1.1 Hz). 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 (cmꢀ1)
2956, 2359, 1707, 1597, 1447. HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for C8H10O4Na
193.0471; Found 193.0479.
t-Butyl(3-(2-methoxy-5-methylfuran-3-yl)propoxy)dimethylsilane (15f).
tꢀButyl(3ꢀ(2,2ꢀ
dimethoxyꢀ5ꢀmethylꢀ2,3ꢀdihydrofuranꢀ3ꢀyl)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,
1
0.57mmol) afforded furan 15f as colorless oil (134 mg, 100%). H NMR (300 MHz, CDCl3) δ
5.74 (s, 1H), 3.86 (s, 3H), 3.64 (t, 2H, J = 6.4 Hz), 2.34ꢀ2.27 (m, 2H), 2.19 (s, 3H), 1.77ꢀ1.65 (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 (cmꢀ
1) 2934, 1737, 1649, 1438, 1243.
C15H28O4SiNa 323.1655; Found 323.1643.
HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for
4-Butylfuran-2(5H)-one (16b). From treatment of 6b with HCl : 4ꢀbutylꢀ2,2ꢀdimethoxyꢀ2,3ꢀ
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 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,
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