Iodine-Catalyzed Synthesis of Substituted Furans and Pyrans: Reaction Scope and Mechanistic Insights

Article abstract of DOI:10.1021/acs.joc.1c00608

Substituted pyrans and furans are core structures found in a wide variety of natural products and biologically active compounds. Herein, we report a practical and mild catalytic method for the synthesis of substituted pyrans and furans using molecular iodine, a simple and inexpensive catalyst. The method described is performed under solvent-free conditions at an ambient temperature and atmosphere, thus offering a facile and practical alternative to currently available reaction protocols. A combination of experimental studies and density functional theory calculations revealed interesting mechanistic insights into this seemingly simple reaction.

Full text of DOI:10.1021/acs.joc.1c00608

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Iodine-Catalyzed Synthesis of Substituted Furans and Pyrans:
Reaction Scope and Mechanistic Insights
Domenic P. Pace, Raphaël Robidas, Uyen P. N. Tran, Claude Y. Legault,* and Thanh Vinh Nguyen*
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ABSTRACT: Substituted pyrans and furans are core structures found in a wide variety of natural products and biologically active
compounds. Herein, we report a practical and mild catalytic method for the synthesis of substituted pyrans and furans using
molecular iodine, a simple and inexpensive catalyst. The method described is performed under solvent-free conditions at an ambient
temperature and atmosphere, thus offering a facile and practical alternative to currently available reaction protocols. A combination
of experimental studies and density functional theory calculations revealed interesting mechanistic insights into this seemingly simple
reaction.
method involves cyclization or cycloaddition reactions of
unsaturated carbonyl compounds using transition metal
catalysts8e such as Hg,9 Au,10 Pd,11 Ag,12 Co,13 Zn,14 Cu,15
Rd,16 and Pt17 and other metals such as Ca,18 Ga,19 Sc,20 and
Bi.21
INTRODUCTION
■
Molecular iodine, an environmentally friendly and inexpensive
commodity chemical, has long been known not only as a
versatile reagent but also as an efficient catalyst to promote a
wide variety of chemical transformations.1 Being the largest
non-radioactive element in group 7 of the periodic table, iodine
is also the least electronegative and the most polarizable
halogen.1c,2 These properties lead to its several oxidation states
in several classes of synthetically valuable organoiodines.3 In
the elemental form, its ability to interact with oxygen-
containing functional groups has been exploited to design
efficient iodine-catalyzed organic reactions such as Michael,
aldol, esterification, and a range of cycloaddition reactions.1
Realization of the full catalytic potential of molecular iodine
has consistently been a topic of interest in the past decades.1d
Recently, we discovered the intriguing catalytic activity of
molecular iodine in promoting carbonyl−olefin metathesis.4
However, in the course of that study, we noticed an
unexpected 6-endo-trig cyclization reaction of a γ-alkenyl
ketone to produce a 3,4-dihydro-2H-pyran derivative (Scheme
1).
In 2008, Zhan and co-workers reported an interesting FeCl3-
catalyzed one-pot propargylation and cycloisomerization of
1,3-dicarbonyl compounds to form tetrasubstituted furans.22
Other iron catalysts were also found to promote different
synthetic approaches to furans and pyrans.23 Schindler and co-
workers subsequently identified FeCl3 as an efficient Lewis
acid-based catalyst for the formation of a range of 3,4-dihydro-
2H-pyrans24 and 3-carboxy-2,5-disubstituted furans.25 This
simple catalyst also proves to be an efficient promoter for the
intramolecular carbonyl−olefin metathesis reaction in a series
of elegant studies by the same group.26 The similarity in
catalytic activity between FeCl3 and iodine, demonstrated by
these studies and our earlier work (Scheme 1),4 prompted us
to investigate the possibility of using molecular iodine as a
Received: March 14, 2021
Published: May 28, 2021
Pyrans and furans are important structural elements of many
natural products5 and pharmaceuticals6 and valuable reaction
precursors or intermediates in organic synthesis.7 There are
several synthetic strategies which yield pyrans and furans
bearing different substitution patterns.5,7,8 One frequently used
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Scheme 1. Iodine-Catalyzed Reactions
a
catalyst for the synthesis of a broader scope of pyrans and
furans.
Table 1. Optimization Studies
Molecular iodine has been frequently used to mediate the
formation of heterocyclic compounds.27 In the context of this
work, I2 has been used previously in super-stoichiometric
amounts to obtain iodofurans via the iodoenoletherification of
2-alkenyl-substituted 1,3-dicarbonyl compounds or iodocycli-
zation of vinyl acetate.28 However, extraneous deiodination
and acid-catalyzed isomerization reactions were required to
obtain the non-iodinated furan products. Notably, an I2-PPh3
catalytic system was previously reported to promote the
synthesis of furan-type spiro enol ether derivatives from
unsaturated β-ketoesters.29 However, these examples are scarce
and non-systematic. Herein, we demonstrate that the I2 catalyst
can efficiently promote the cyclization of a broad range of α-
allylated or α-propargylated carbonyl substrates to form a wide
range of substituted pyrans and furans under mild reaction
conditions with excellent outcomes.
b
mol % I2
Solvents
DCM
DCE
toluene
THF
MeCN
MeOH
EtOAc
Et2O
conversion of 1a
yield 2a
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
10
10
5
71%
78%
79%
87%
50%
89%
62%
91%
67%
86%
100%
94%
63%
48%
0%
21%
20%
8%
traces
48%
traces
40%
traces
traces
traces
89%
78%
n.d.
9
EtOH
EtOH/H2O (1:1)
10
11
12
13
14
15
Neat
Neat
Neat
Neat
Neat
PYRAN FORMATION REACTIONS
■
2
1
0
We started our investigation by optimizing the serendipitous
reaction with substrate 1a to form product 2a (Table 1). The
reaction generally consumed most of the starting material;
however, the conversion to the cyclized product varied greatly
with solvents (entries 1−10, Table 1). Reactions in acetonitrile
or ethyl acetate (entries 5 and 7) seemed to give good
conversion to the product but proceeded sluggishly. Alcoholic
(MeOH and EtOH, entries 6 and 9) and ethereal solvents
(THF and Et2O, entries 4 and 8) showed consumption of 1a
without any noticeable formation of 2a. In the cases of
alcoholic solvents, we also observed some unwanted β-ester
n.d.
n.d.
a
Reaction conditions: 1a (0.5 mmol) and catalyst in the solvent at rt
b
for 24 h. Conversion determined by 1H NMR using 1,3,5-
triisopropylbenzene as an internal standard.
enol ethers.30 A further investigation revealed that the majority
of the product mixtures in these solvents contained
unidentifiable oligomers of the starting material. Interestingly,
further optimization studies (see page S2 in the experimental
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a
Table 2. Substrate Scope for 3,4-Dihydro-2H-pyrans
a
b
c
Reaction conditions: β-ketoester (0.5 mmol) and iodine (0.05 mmol) at rt for 24 h. Same conditions but at 50 °C in a heating mantle. Same
d
conditions but with 20 mol % I2. 0.5 mmol I2 was used. See the experimental Supporting Information for more details.
Supporting Information for more details)31 confirmed that the
reactions, without a solvent under an ambient atmosphere and
temperature, led to the formation of the target product in good
to high yields (entries 11−15, Table 1). The optimal setup
used 10 mol % I2 catalyst to afford product 2a in 89% yield
(entry 11). It should be noted here that the reaction mixture
was homogeneous under these conditions.
These optimal conditions were amenable to a range of other
α-prenylated aryl ketones (Table 2) to form the corresponding
3,4-dihydro-2H-pyrans in good to excellent yields. The
protocol tolerates a good range of functional groups, as
expected from the benign nature of iodine. Interestingly, the
reaction proceeded smoothly with electron-deficient aryl
groups (1b−d, Table 2), while only low yield of the desired
pyran product was observed with an electron-rich aryl group
(1e, entry 5). It is possible that an electrophilic aromatic
iodination side reaction rendered the iodine catalyst inactive,
as we did observe some iodination to the aromatic ring on 1e.
With diketone 1g (Table 2) where there are two carbonyl
groups competing for the reaction, it was interesting to see that
the cyclization preferred to occur on the aliphatic ketone.
When there was an aryl group also at the α-position (1h), the
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a
Scheme 2. Synthesis of (a) 3-Carboxy-2,5-disubstituted Furans and (b) 3-Carboxy-2,2,5-trisubstituted-4,5-dihydrofurans
a
Reaction conditions: 3 or 5 (0.5 mmol) and I2 (0.075 mmol) stirred at rt for 24 h. (*) = yield determined by 1H NMR using 1,3,5-
triisopropylbenzene as an internal standard due to the volatility of the products, see the Supporting Information for more details.
reaction led to a mixture of the desired pyran 2h (80%) and
the tetrahydronaphthalene derivative 2h′ (8%) as the minor
product. Compound 2h′ was presumably the outcome of the
Friedel−Crafts-type alkylation reaction on the side-chain
phenyl group, as was also previously observed with a FeCl3
catalyst by the Schindler group.26d A prolonged reaction time
of 48 h led to a product mixture of 62% 2h and 16% 2h′,
suggesting that there might be an equilibrium converting 2h to
2h′ via the reformation of 1h.26d Substrate 1i (Table 2), the
para-methoxy derivative of 1h, only led to poor yield of the
cyclized product 2i, and we were unable to identify the
Friedel−Crafts byproduct 2i′ from this reaction.
1, most likely due to unwanted side reactions owing to the
inherent reactivity of alkynes, as demonstrated later in the case
of non-terminal alkyne substrate 3f (product 4f) especially.
Notably, substrates with an electron-rich aryl group (3e) or
bulky alkyl group (3l) still reacted to give the products in good
yields. Given the poor reactivity of similar substrates (1e and
1m) in Table 1, this is rather surprising. We suspect that the
stability of the resulting aromatic furan systems gave sufficient
driving force for the reactions to happen on 3e and 3l. Non-
terminal alkyne substrates 3f and 3g also worked for this
iodine-catalyzed 5-exo cyclization reaction to give the products,
albeit in lower yields. A careful analysis of the reaction residue
for substrate 3f revealed adduct 4f′ as the major byproduct
apart from the target 4f. This unsurprising observation suggests
that the addition of molecular iodine to the C−C multiple
bond is always a competing process in our reactions. The
affinity of I2 to the C−C multiple bond, in addition to that of
the carbonyl moiety, likely plays a role in the mechanism of
this reaction, as discussed later in our computational studies.
Some members of this aryl-substituted furan family (4a−4g,
Scheme 2a) exhibit strong luminescence in liquid forms.
Photos of a representative sample of compound 4f under
visible light and 365 nm UV light were captured and are
included in Scheme 2a to illustrate this phenomenon.
Compound 4f is pale yellow under visible light but becomes
brightly green luminescent under 365 nm UV irradiation. This
is interesting considering the simple structure of such a phenyl-
furan system. Work to further advance the synthetic utility of
this method to produce more interesting photoactive furan
derivatives is ongoing in our laboratory and will be reported in
due course.
Alkyl ketoester substrates also worked smoothly under our
reaction conditions to form 3,4-dihydro-2H-pyran products in
moderate to high yields (2j−2m, Table 2). However, no
product formation was observed for the substrate with the tert-
butyl substituent (1n, Table 2), presumably due to its steric
hindrance. Surprisingly, the cyclopropyl group was not
tolerated in this reaction setup, as some of substrate 1o was
converted to the ring-opened product 2o′, which consumed
the iodine catalyst. When we subjected 1o to a stoichiometric
amount of I2, we were able to isolate 2o′ in 15% yield in
addition to the recovered 1o and some unidentified
byproducts. The reaction did not take place on the ester
carbonyl moiety of substrate 1p. Furthermore, when we
suppressed the substrates’ tendency to tautomerize to their
enol form, the reactivity was turned off, as demonstrated by
substrates 1q and 1r. These negative outcomes provide
insights into the mechanism of this iodine-catalyzed reaction
(vide infra).
FURAN FORMATION REACTIONS
Similar to reactions in Scheme 2a, the synthesis of 3-
carboxy-2,2,5-trisubstituted-4,5-dihydrofurans from analogous
alkenyl precursors also proceeded with good to excellent yields
(Scheme 2b). Curiously, there was a decrease in yields, in
comparison to other substrates, for the methoxyarene- and tert-
butyl-containing products 6d and 6i (Scheme 2b), which is
presumably related to the same trend in Table 1 where the
cyclization did not lead to an aromatic system either. Overall,
however, I2 proves to be an efficient catalyst for the cyclization
■
We then turned our attention to investigate the catalytic
activity of I2 in the synthesis of 3-carboxy-2,5-disubstituted
furans from the α-propargyl-β-ketoester substrates (Scheme
2a). Similar optimization studies proved that 15 mol % iodine
catalyst is the most efficient loading for this reaction.31 The
reaction worked relatively well on the 10 terminal alkyne
substrates we studied (products 4a−e and 4h−l). Overall,
yields were lower than those in the synthesis of pyrans in Table
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a
Table 3. Mechanistic Studies
a
b
Reaction conditions: 1a (0.2 mmol) and catalyst (0.02 mmol) at rt for 24 h. Entries 1−10 used 10 mol % I2; lab light means lighting conditions
c
inside the fumehood (4 × 13 W fluorescent lights); entries 11−20 used in an ambient atmosphere and lab light again. Yield of product 2a; messy
reaction means there were many unidentified products formed along with less than 10% conversion to 2a; n.r. means that no conversion to product
2a was observed. HI in MeCN solution was prepared from freshly produced gaseous HI; the concentration was determined via titration; and the
d
MeCN solvent volume was adjusted to 0.5 mL.
on the catalytic activity of I2 (entries 8−9). On the other hand, high-
energy photoirradiation, with the intention to trigger iodine radical
formation (entries 2−5, especially entry 4 where green light matched
the homolytic cleavage energy of the I−I bond33), significantly
reduced reaction efficiency. While these results seemed to contradict
each other, we encountered several literature examples where
TEMPO or BHT reacted directly with I2 in a range of oxidation or
substitution reactions,34 which might interfere with our cyclization
pathway. Moreover, it is also possible that BHT could trap the
carbocation intermediate to form HI as well to further complicate the
reaction. Thus, the negative outcomes from entries 8−9 should not be
interpreted as the evidence for a radical mechanism of this reaction in
particular; and TEMPO/BHT probably should not be used to study
reaction of alkenyl or alkynyl carbonyl substrates to produce
pyran and furan derivatives.
EXPERIMENTAL MECHANISTIC STUDIES
■
Based on our previous studies with iodine-catalyzed carbonyl−olefin
metathesis reaction4b,c and common knowledge in the field, we
suspected that this cyclization reaction could be catalyzed via one of
some possible pathways such as halogen bonding, Brønsted acid,
higher oxidation state iodine, iodonium ion, or free radical
catalysis.1d,32 We subsequently carried out a range of mechanistic
studies to learn more about this system (Table 3). Radical generators
such as TEMPO or radical traps such as BHT had diminishing effects
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the mechanism of I2-catalytic reactions in general. Collective
information from entries 2−9 suggests that a radical pathway is
mostly unlikely.
We first investigated the possible tautomers of 1j and their
coordinating adducts with molecular iodine (I2), as depicted in
Scheme 3.40 As could be expected for a β-ketoester derivative,
The reaction efficiency did not change much when we switched to
an inert environment (Table 3, entries 6−7), but oxidative
environments led to complicated reaction mixtures (entries 10−11).
Therefore, any pathways involving higher oxidation states of iodine,
including HOI, can be ruled out as unlikely. Spiking the reaction with
water or a variation of Brønsted acids had a negative effect on the
reaction outcomes (entries 12−16). The moderately successful
reaction profiles in the presence of TFA as a co-catalyst or sole
catalyst (entries 13−15) suggest that slightly acidic conditions might
help the reaction but are not the determining factor. Most notably, the
reaction performed in the presence of ∼10 mol % HI in acetonitrile
solution instead of an I2 catalyst led to much poorer yield of product
2a (22%) than the results of entry 5 in Table 1 (48%). From these
control experiments, it can be concluded that Brønsted acid catalysis
was not the driving force for this reaction.
Scheme 3. Possible 1j·I2 Adducts (Free Energy Values
Reported in kcal/mol)
On the other hand, KI did not mediate the reaction by itself (entry
17) but actually suppressed the catalytic activity of I2 (entry 18)
instead. The positive but non-efficient outcomes of entries 19−20 and
22 with NIS and ICl, all favorable conditions for the formation of I+
ions, indicate that iodonium can potentially activate the substrate for
the reaction. However, further control reactions when NIS and ICl as
I+ sources were combined with KI as the I− source (entries 21 and
24), which should generate I2 in situ, led to better reaction outcomes
than entries 19−20 and 22. These experiments hint that molecular
iodine is more likely to be the reaction promoter than the iodonium
ion. We also carried out a range of control experiments with some
Brønsted/Lewis base additives (NaOAc, PPh3, DMSO, DABCO, and
entries 25−28 Table 3), which are capable of coordinating to the
polarized iodine or iodonium ion. All of them led to negative results,
partly supporting our hypothesis at this point that halogen bonding is
the key element to promote the reaction. One of Huber’s bidentate
iodoazolium salt catalysts was moderately effective in promoting this
reaction (entry 29), also supporting the halogen-bonding activation
mode.2
We subsequently carried out kinetic studies of the reaction with
different catalyst loadings. The reaction order in the I2 catalyst was
determined to be the first order (see pages S3−S4 in the experimental
Supporting Information for further details). This clearly ruled out the
possibility of iodonium catalysis, as iodonium and its iodide
counterion often associate with iodine molecules, leading to a higher
empirical reaction order in I2.1d,32 All of these studies suggest that the
reaction mechanism might involve the intact but polarized molecular
iodine catalyst, activating the substrate through halogen-bonding
interactions.
the Z enol tautomer (1j′) is easily accessible at room
temperature (ΔG = +0.4 kcal/mol). The E enol tautomer
(1j″), while being much higher in energy, is still energetically
accessible. All of the substrate·I2-coordinating adducts are also
accessible at room temperature, with a preference for the
alkene·I2 (Int-B and Int-F). The diiodination of the alkene
(Int-D) is only slightly exergonic (ΔG = −0.8 kcal/mol) and
thus reversible.
Interestingly, complexation of molecular iodine to the alkene
moiety is even more favorable in the enol form than in the keto
form (Int-B vs Int-F). Analysis of the structures of Int-B and
Int-F suggests that this stabilization could be attributed to
additional favorable electrostatic Oδ−···Iδ+ interactions in Int-F,
as depicted in Figure 1. We noticed a shortening of the enol-
carbonyl hydrogen bond in Int-G (1.54 Å) with respect to that
of Int-F (1.57 Å).40 We postulated that the association of I2
significantly increases Oenol−H acidity. Indeed, we also
observed a H···alkene interaction in Int-C that would suggest
that the enol proton could act as a strong acid.
COMPUTATIONAL MECHANISTIC STUDIES
■
To be able to further elucidate the reaction mechanism, we
subsequently evaluated several different reaction pathways
using density functional theory (DFT) calculations. The
geometry optimizations were performed with the PBE0 density
functional,35 in combination with the Def2TZVP basis set36 for
all atoms except iodine, for which Def2TZVP(D) and the
corresponding ECP were used.37 Grimme’s D3 empirical
dispersion with Becke-Johnson damping was applied.38 The
reactions were carried out under neat conditions, but to
account for the overall effect of the reaction medium, the
calculations were performed using SMD implicit solvation
model for acetonitrile, which was also a working solvent for
this reaction.31 The recently corrected radius for the iodine
atom for SMD calculations was used.39 Substrate 1j (R1 = Me,
R2 = OMe) was selected for the study to reduce the degrees of
freedom and simplify analysis. The yield of the reaction with
this substrate was also representative of the general scope.
With this assumption in mind, we investigated a mechanism
in which this Oenol−H would be sufficiently acidic to protonate
the alkene side chain and lead to the formation of a
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Scheme 4. Plausible Catalytic Cycle Supported by DFT
Calculations (Free Energies Reported in kcal/mol)
The resulting carbocationic intermediate (Int-H) is
expected to react in mostly barrierless processes with the
various nucleophilic sites on the intermediate, leading to three
possible intermediates, Int-I, Int-J, and Int-K. Not surprisingly,
all three pathways are found to be exergonic, but a deeper look
into the thermodynamics provides interesting insights.
Collapse of the iodide anion onto the carbocation is exergonic
(−16.7 kcal/mol) and results in the formation of diiodoalkyl
intermediate Int-I. Attack of the ester group on the
carbocation, resulting in Int-J, is also exergonic by 18.1 kcal/
mol. The alternative ester cyclization product formation is
endergonic (+4.7 kcal/mol) with respect to the substrate and
is thus thermodynamically disfavored.
While the formation of this product is kinetically possible
under the reaction conditions, it is reversible, which explains
why it is not observed. These two processes are expected to be
reversible due to their respective exergonicities. In contrast,
cyclization of Int-H by attack of the ketone oxygen atom is
much more exergonic (−26.5 kcal/mol). Furthermore, the Int-
H to Int-K process appears to be completely barrierless
according to our exploration of the potential energy surface. It
should be noted that no transition state for the SN1-like SN2
reaction of Int-I to form Int-K was found. The calculations
thus support a SN1 mechanism from Int-H.
Figure 1. Structures of the selected intermediates and transition state
in Schemes 3 and 4 (bond lengths in Å).
carbocationic intermediate that would ultimately lead to the
desired product. It should be noted here that our control
experiments with Brønsted acid or base additives in Table 3
collectively suggest the possibility of this enolization pathway.
By taking away the enolization ability from the substrate (entry
30 Table 3), the reaction did not work at all, which further
supports this hypothesis. The results of the calculations are
illustrated in Scheme 4.
Gratifyingly, the transition state of intramolecular proton
transfer (TS-A) did indeed prove to be reasonable (ΔG⧧ =
21.9 kcal/mol from Int-F). Through this process, the carbon−
iodine bond shortens from 2.73 to 2.20 Å, indicating the
formation of a covalent C−I bond. Accordingly, the iodine−
iodine bond lengthens from 2.77 to 3.42 Å. With respect to the
most stable substrate·I2 adduct (Int-F), TS-A is considered to
be the highest transition state in our postulated mechanism on
the energy diagram, leading to the key carbocationic
intermediate Int-H. In this context, the computed energetic
span of the process (Int-F−TS-A, 21.9 kcal/mol) is in very
good agreement (deviation below 1 kcal/mol) with the
estimated experimental energetic span for substrate 1j.40
Furthermore, kinetic data are in accord with the kinetic
model describing the proposed mechanism (page S15−S17 in
the computational Supporting Information).36
Following cyclization, the I−I bond is regenerated in Int-K;
the latter can be considered to be a 2j·I2 adduct. As a final step,
to close the catalytic cycle, iodine must be transferred to a new
substrate molecule. This step was found to be exergonic with
respect to 1j′ (−1.0 kcal/mol) and 1j (−0.6 kcal/mol). It can
thus be concluded that there is no significant inhibition of the
reaction by the product. Product 2j is more stable by 6.5 kcal/
mol with respect to substrate 1j, confirming that the overall
reaction is exergonic.
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In this proposed mechanism, one could expect iodine
monochloride to be an even better catalyst, as polarization
along the I−Cl bond would make the iodine atom more Lewis
acidic. However, what is observed experimentally is a
significantly lower yield (31% vs 89% under otherwise identical
conditions). We computed the H-transfer transition structure
TS-B. As expected, with respect to 1j′ + ICl, we found it to be
lower in free energy than the analogous TS-A (Scheme 5).
Scheme 6. Key Intermediates of the Considered Reaction
Pathways of 3h (Free Energy Values Reported in kcal/mol)
Scheme 5. Key Intermediates in the ICl-Catalyzed Reaction
(Free Energies Reported in kcal/mol)
However, formation of Int-M from Int-L is much more
exergonic (−25.1 kcal/mol) than the corresponding formation
of Int-I from Int-H. This would result in a considerably slower
reaction and thus lower yields in the same reaction time.
Furthermore, the slower reaction/lower yield could also be
explained by the exergonicity of formation of the iodochlori-
nation intermediate Int-N. Interestingly, combination of
catalytic iodine monochloride and potassium iodide results in
a higher yield than iodine monochloride alone (Table 3, entry
24). One hypothesis is that iodine is formed in situ and acts as
the active catalyst.
We then investigated the reaction of α-propargyl-β-ketoester
substrates to form substituted furans using substrate 3h. A
mechanism analogous to the one in Scheme 4 would involve
an alkenyl carbocation, which is unlikely. Accordingly,
alternative pathways were considered. The key intermediates
and transition structures are illustrated in Scheme 6.40 First, we
envisioned that two substrate molecules (3h·3h) could be
involved in this process since the reaction is performed neat.
The reaction could then proceed with this substrate pair via a
concerted proton transfer and cyclization. The lowest-energy
transition state found for this process (TS-C, Scheme 6a) is
found to be at +25.1 kcal/mol with respect to 3h·3h. This
energy span is in good agreement with our observed reaction
rates.40 Alternatively, one could imagine an iodocyclization/
protodeiodination mechanism, as reported for a different
system by Saito and co-workers.41 The key intermediates and
transition structures provide facile reaction (Scheme 6b), with
the highest barrier being +10.0 kcal/mol going from 3h to TS-
AA. However, this mechanism raises the possibility that HI
could also be formed during the reaction, and an alternative
HI-catalyzed process could also be involved. Consequently, we
computed the key intermediates and transition structures for
this pathway and found it to be even more favorable, with the
highest activation barrier being +8.9 kcal/mol going from 3h to
TS-BA (Scheme 6b). To check the validity of this mechanistic
hypothesis, we performed a test reaction of compound 3h with
15 mol % HI and found that it provided 40% yield of the
desired product within the same reaction time, compared with
61% yield when performed with the same catalyst loading of I2.
These results suggest that a much slower process may be
limiting the rate of the HI-catalyzed reaction, which could be
the proton-transfer steps. Due to their complex and uncertain
nature, we did not compute these steps. However, we can
conclude that the reaction involving α-propargyl-β-ketoester
substrates is complicated and could involve parallel competing
mechanisms.
In conclusion, we have developed a new practical protocol
for the synthesis of 3,4-dihydro-2H-pyrans, 3-carboxy-2,2,5-
trisubstituted-4,5-dihydrofurans, and 3-carboxy-2,5-disubsti-
tuted furans using molecular iodine as a catalyst under mild
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mL). The combined organic layers were washed with brine (20 mL),
dried over Na2SO4, and then concentrated under reduced pressure.
Purification by flash column chromatography and eluting with
hexanes/EtOAc (100:1 to 50:1) provided 0.263 g of 1a (10%) as a
light-yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.03−7.95 (m, 2H),
7.62−7.54 (m, 1H), 7.52−7.41 (m, 2H), 5.16−5.06 (m, 1H), 4.29
(dd, J = 7.7, 6.9 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.80−2.57 (m,
2H), 1.65 (d, J = 1.3 Hz, 3H), 1.62 (d, J = 1.4 Hz, 3H), 1.16 (t, J = 7.1
Hz, 3H) ppm.
reaction conditions. The method tolerates a large range of
functional groups and offers an easy, green alternative to
currently available reaction protocols to access pyran and furan
derivatives. A combination of experimental studies and DFT
calculations revealed interesting mechanistic insights into this
reaction. They strongly support that the association of iodine
to the enol tautomer of the substrate enhances its acidity. This
key intermediate is a sufficiently strong Brønsted acid to
promote protonation of the alkene and formation of a key
carbocation, from which only the formation of the desired
product is thermodynamically favored.
Ethyl 2-(4-Bromobenzoyl)-5-methylhex-4-enoate (1b).24 The
alkylation of the ketoester starting material was performed according
to the general procedure on a 3.8 mmol scale. Purification by flash
column chromatography and eluting with hexanes/EtOAc (100:1 to
1
60:1) provided 0.51 g of 1b (40%) as a colorless oil. H NMR (400
EXPERIMENTAL SECTION
MHz, CDCl3): δ 7.88−7.80 (m, 2H), 7.65−7.57 (m, 2H), 5.08 (tp, J
= 7.3, 1.4 Hz, 1H), 4.22 (t, J = 7.3 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H),
2.77−2.58 (m, 2H), 1.65 (d, J = 1.3 Hz, 3H), 1.62 (d, J = 1.3 Hz,
3H), 1.17 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz,
CDCl3): δ 194.2, 169.6, 135.2, 135.0, 132.2, 130.2, 128.9, 120.0, 61.6,
54.7, 27.8, 25.9, 17.9, 14.1 ppm.
■
General Methods. Reactions, unless otherwise stated, were
conducted under a positive pressure of argon in oven-dried glassware.
Commercially available reagents were used as purchased unless
otherwise noted. Analytical thin-layer chromatography was performed
using aluminum plates precoated with silica gel 60 F254 (0.2 mm).
Flash chromatography was performed using 230−400-mesh silica gel.
Solvents used for chromatography are quoted as volume/volume
ratios.
Ethyl 5-Methyl-2-(4-nitrobenzoyl)hex-4-enoate (1c).24 The alky-
lation of the ketoester starting material was performed according to
the general procedure on a 5.0 mmol scale. Purification by flash
column chromatography and eluting with hexanes/EtOAc (100:1 to
NMR spectroscopy was performed at 298 K using an AVANCE III
1
1
HD 400 (400.1 MHz, H; 100.6 MHz, 13C; 376.5 MHz, 19F), an
20:1) provided 1.18 g of 1c (77%) as a yellow solid. H NMR (400
1
AVANCE III 300 (300 MHz, H; 75 MHz, 13C; 282.5 MHz, 19F) or
MHz, CDCl3): δ 8.33−8.28 (m, 2H), 8.14−8.09 (m, 2H), 5.11−5.02
(m, 1H), 4.28 (t, J = 7.3 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.78−2.62
(m, 2H), 1.64 (q, J = 1.3 Hz, 3H), 1.61 (d, J = 1.3 Hz, 3H), 1.16 (t, J
= 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 193.9,
169.1, 150.5, 141.0, 135.4, 129.7, 124.0, 119.6, 61.8, 55.1, 27.6, 25.8,
17.9, 14.1 ppm.
1
an AVANCE III 400 (400.1 MHz, H; 100.6 MHz, 13C; 376.5 MHz,
19F). Data are expressed in parts per million (ppm) downfield shift
from tetramethylsilane with the residual solvent as an internal
reference (δ 7.26 ppm for chloroform) and are reported as the
position (δ in ppm), multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, and m = multiplet), coupling constant (J in Hz), and
integration (number of protons). 13C NMR spectra were recorded at
298 K with complete proton decoupling. Data are expressed in parts
per million (ppm) downfield shift relative to the internal reference (δ
77.2 ppm for the central peak of deuterated chloroform).
Methyl 5-Methyl-2-(4-(trifluoromethyl)benzoyl)hex-4-enoate
(1d). The alkylation of the ketoester starting material was performed
according to the general procedure on a 5.0 mmol scale. Purification
by flash column chromatography and eluting with hexanes/EtOAc
1
(100:1 to 20:1) provided 0.36 g of 1d (23%) as a colorless oil. H
NMR (400 MHz, CDCl3): δ 8.10−8.04 (m, J = 7.9, 0.9 Hz, 2H),
7.76−7.70 (m, 2H), 5.10−5.03 (m, 1H), 4.32 (t, J = 7.3 Hz, 1H),
3.67 (s, 3H), 2.78−2.63 (m, 2H), 1.63 (d, J = 1.3 Hz, 3H), 1.61 (d, J
= 1.4 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 194.3,
169.8, 139.1, 135.3, 134.7 (q, J = 32.8 Hz), 129.0, 125.9 (q, J = 3.7
Hz), 123.6 (q, J = 272.5 Hz), 119.7, 54.6, 52.7, 27.8, 25.8, 17.8 ppm;
HRMS (ESI) m/z: [M + Na]+ calcd for C16H17F3O3Na, 337.1022;
found, 337.1022; FTIR (neat): 2955, 1736, 1692, 1580, 1509, 1435,
1409, 1379 cm−1.
Infrared spectra were obtained on a Cary 630 FT-IR ATR
spectrometer or a ThermoNicolet Avatar 370 FT-IR spectrometer
and are reported in wavenumbers (cm−1). HRMS was performed at
the Bioanalytical Mass Spectrometry Facility within the Mark
Wainwright Analytical Centre at the University of New South
Wales on an Orbitrap LTQ XL (Thermo Fisher Scientific, San Jose,
CA, USA) ion trap mass spectrometer.
General Procedure for the Synthesis of Cyclization
Precursors. Unless otherwise specified, the cyclization substrates
were synthesized as follows: to a mixture of K2CO3 (5.5 mmol, 1.1
equiv) and KI (0.5 mmol, 0.1 equiv) in DMF (6 mL) was added the
ketoester (5 mmol, 1.0 equiv) followed by dropwise addition of the
alkyl bromide (6 mmol, 1.2 equiv). The reaction was left to stir at
room temperature for 24−48 h. Water (10 mL) was subsequently
added to the reaction mixture, and the aqueous layer was extracted
with EtOAc (3 × 20 mL). The combined organic layers were washed
with brine (20 mL), dried over Na2SO4, and then concentrated under
reduced pressure. The crude material was then purified by flash
column chromatography (silica gel) to provide the products.
General Procedure for I2-Catalyzed Cyclization Reactions.
To a 4 mL vial charged with an iodine catalyst (0.05 mmol, 10 mol %
or 0.065 mmol, 15 mol %) and a stirrer bar was added starting
material 1 or 3 or 5 (0.5 mmol). The vial was closed with a cap, and
the mixture was stirred for 24 h at room temperature. The reaction
mixture was then directly purified by flash column chromatography
(silica gel) to provide the product 2 or 4 or 6, respectively.
Characterization Data of Cyclization Precursors. Ethyl 2-
Benzoyl-5-methylhex-4-enoate (1a).42 The ketoester starting ma-
terial (5.0 mmol, 1.0 equiv) was dissolved in THF (20 mL), and NaH
(6.0 mmol, 1.2 equiv) was added slowly under N2. After 15 min, a
solution of 3,3-dimethylallyl bromide (6 mmol, 1.2 equiv) in THF (20
mL) was added under N2. The reaction was left to stir at room
temperature for 24 h. Water (10 mL) was added to the reaction
mixture, and the aqueous layer was extracted with EtOAc (3 × 20
Ethyl 2-(4-Methoxybenzoyl)-5-methylhex-4-enoate (1e). The
ketoester starting material (2 mmol, 1.0 equiv) was slowly added to
a flask containing NaH (5 mmol, 2.5 equiv) and THF (15 mL) under
Ar. After 30 min, 3,3-dimethylallyl bromide (2 mmol, 1.0 equiv) was
added, and the reaction left to stir at room temperature for 24 h. The
reaction was cooled to 0 °C, and water (10 mL) was slowly added to
the reaction mixture. The aqueous layer was extracted with DCM (3
× 20 mL), and the combined organic layers were washed with brine
(20 mL), dried over Na2SO4, and concentrated under reduced
pressure. Purification by flash column chromatography and eluting
with hexanes/EtOAc (90:10) provided 0.37 g of 1e (63%) as a light-
yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.01−7.95 (m, 2H),
6.97−6.91 (m, 2H), 5.14−5.05 (m, 1H), 4.24 (dd, J = 7.9, 6.7 Hz,
1H), 4.13 (qd, J = 7.1, 0.8 Hz, 2H), 3.87 (s, 3H), 2.77−2.57 (m, 2H),
1.65 (d, J = 1.3 Hz, 3H), 1.62 (d, J = 1.3 Hz, 3H), 1.17 (t, J = 7.1 Hz,
3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 193.5, 170.1, 163.9,
134.6, 131.1, 129.5, 120.5, 114.0, 61.4, 55.6, 54.4, 27.9, 25.9, 17.9,
14.2 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C17H22O4Na,
313.1410; found, 313.1410; FTIR (neat): 2974, 2933, 2057, 1733,
1673, 1599, 1573, 1509, 1457, 1442, 1420, 1368 cm−1.
2-(3-Methylbut-2-en-1-yl)-1-phenylbutane-1,3-dione (1g).24 The
alkylation of the diketone starting material was performed according
to the general procedure on a 7.6 mmol scale. Purification by flash
column chromatography and eluting with hexanes/EtOAc (100:1)
1
provided 0.41 g of 1g (23%) as a yellow oil. H NMR (300 MHz,
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CDCl3): δ 8.01−7.94 (m, 2H), 7.64−7.54 (m, 1H), 7.52−7.43 (m,
2H), 5.08−4.99 (m, 1H), 4.44 (t, J = 7.2 Hz, 1H), 2.68 (t, J = 7.2 Hz,
1H), 2.14 (s, 3H), 1.64 (d, J = 1.4 Hz, 3H), 1.61 (d, J = 1.2 Hz, 3H)
ppm.
Ethyl 2-Butyryl-5-methylhex-4-enoate (1m). The alkylation of the
ketoester starting material was performed according to the general
procedure on a 3.8 mmol scale. Purification by flash column
chromatography and eluting with hexanes/EtOAc (20:1) provided
0.29 g of 1m (34%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ
4.95 (tdq, J = 7.3, 2.9, 1.3 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.37 (t, J
= 7.5 Hz, 1H), 2.51−2.33 (m, 4H), 1.59 (d, J = 1.3 Hz, 3H), 1.55 (d,
J = 1.4 Hz, 3H), 1.58−1.48 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H), 0.83 (t,
J = 7.4 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 205.1,
169.6, 134.5, 120.0, 61.2, 59.0, 44.1, 27.0, 25.7, 17.7, 16.9, 14.1, 13.5
ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C13H22O3Na, 249.1461;
found, 249.1461; FTIR (neat): 2966, 2933, 2877, 1736, 1714, 1446,
1368 cm−1.
5-Methyl-1,2-diphenylhex-4-en-1-one (1h).43 The ketoester start-
ing material (5.0 mmol, 1.0 equiv) was dissolved in THF (20 mL),
and NaH (6.0 mmol, 1.2 equiv) was added slowly under N2. After 15
min, a solution of 3,3-dimethylallyl bromide (6 mmol, 1.2 equiv) in
THF (20 mL) was added under N2. The reaction was left to stir at
room temperature for 24 h. Water (10 mL) was added to the reaction
mixture, and the aqueous layer was extracted with EtOAc (3 × 20
mL). The combined organic layers were washed with brine (20 mL),
dried over Na2SO4, and then concentrated under reduced pressure.
Purification by flash column chromatography and eluting with
hexanes/EtOAc (75:1 to 60:1) gave 0.81 g of 1h (60%) as a yellow
Ethyl 5-Methyl-2-pivaloylhex-4-enoate (1n). The alkylation of the
ketoester starting material was performed according to the general
procedure on a 3.8 mmol scale. Purification by flash column
chromatography and eluting with hexanes/EtOAc (100:1 to 50:1)
1
oil. H NMR (400 MHz, CDCl3): δ 8.06−8.00 (m, 2H), 7.50−7.44
(m, 1H), 7.43−7.35 (m, 4H), 7.35−7.29 (m, 2H), 7.25−7.19 (m,
1H), 5.14−5.01 (m, 1H), 4.63 (t, J = 7.3 Hz, 1H), 3.02−2.91 (m,
1H), 2.66−2.55 (m, 1H), 1.68 (d, J = 1.4 Hz, 3H), 1.61 (d, J = 1.4
Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 199.7, 139.6,
136.9, 133.6, 132.7, 128.8, 128.7, 128.5, 128.2, 127.0, 121.6, 54.0,
32.8, 25.7, 17.7 ppm.
1
provided 0.13 g of 1n (10%) as a colorless oil. H NMR (400 MHz,
CDCl3): δ 5.00 (m, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.86 (t, J = 7.3 Hz,
1H), 2.57−2.39 (m, 2H), 1.63 (q, J = 1.2 Hz, 3H), 1.59 (d, J = 1.7
Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H), 1.12 (s, 9H) ppm; 13C{1H} NMR
(101 MHz, CDCl3): δ 210.0, 169.6, 134.5, 120.6, 61.2, 52.7, 45.4,
28.8, 26.2, 25.8, 17.8, 14.1 ppm; HRMS (ESI) m/z: [M + Na]+ calcd
for C14H24O3Na, 263.1618; found, 263.1618; FTIR (neat): 2970,
2933, 2873, 1736, 1703, 1476, 1464, 1368 cm−1.
1-(4-Methoxyphenyl)-5-methyl-2-phenylhex-4-en-1-one (1i).43
4-Methoxydeoxybenzoin (2.6 mmol, 1.0 equiv) was added to a flask
containing NaH (6.5 mmol, 2.5 equiv) and dry THF (20 mL) under
Ar. After 15 min, 3,3-dimethylallyl bromide (2.7 mmol, 1.0 equiv) was
added. The reaction was heated to reflux in a sand bath and left to stir
for 24 h. The reaction was then cooled to 0 °C, and water (10 mL)
was slowly added to the reaction mixture. The aqueous layer was
extracted with DCM (3 × 20 mL), and the combined organic layers
were washed with brine (20 mL), dried over Na2SO4, and
concentrated under reduced pressure. Purification by flash column
chromatography and eluting with hexanes/EtOAc (80:20) provided
0.50 g of 1i (65%) as a viscous light-yellow oil. 1H NMR (400 MHz,
CDCl3): δ 7.99−7.90 (m, 2H), 7.34−7.24 (m, 4H), 7.22−7.16 (m,
1H), 6.90−6.82 (m, 2H), 5.02−5.10 (m, 1H), 4.49 (t, J = 7.3 Hz,
1H), 3.81 (s, 3H), 2.92−2.77 (m, 1H), 2.57−2.43 (m, 1H), 1.62 (d, J
= 1.4 Hz, 3H), 1.54 (d, J = 1.4 Hz, 3H) ppm; 13C{1H} NMR (101
MHz, CDCl3): δ 198.4, 163.4, 140.1, 133.6, 131.1, 130.1, 128.9,
128.3, 127.0, 121.9, 113.8, 55.5, 53.8, 32.9, 25.9, 17.9 ppm.
Ethyl 2-(Cyclopropanecarbonyl)-5-methylhex-4-enoate (1o).24
The alkylation of the ketoester starting material was performed
according to the general procedure on a 3.8 mmol scale. Purification
by flash column chromatography and eluting with hexanes/EtOAc
1
(100:1 to 50:1) provided 0.3941 g of 1o (46%) as a yellow oil. H
NMR (300 MHz, CDCl3): δ 5.10−4.98 (m, 1H), 4.19 (q, J = 7.2 Hz,
2H), 3.55 (t, J = 7.5 Hz, 1H), 2.68−2.49 (m, 2H), 2.13−1.99 (m,
1H), 1.67 (d, J = 1.3 Hz, 3H), 1.63 (d, J = 1.4 Hz, 3H), 1.26 (t, J = 7.1
Hz, 3H), 1.14−1.03 (m, 2H), 0.97−0.84 (m, 2H) ppm; 13C{1H}
NMR (76 MHz, CDCl3): δ 205.3, 169.9, 134.6, 120.1, 61.3, 60.2,
27.1, 25.9, 19.9, 17.9, 14.3, 11.9, 11.6 ppm.
Ethyl 2-Benzoylpent-4-ynoate (3a).9 The alkylation of the
ketoester starting material was performed according to the general
procedure on a 5.0 mmol scale. Purification by flash column
chromatography and eluting with hexanes/EtOAc (20:1) provided
0.48 g of 3a (42%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ
8.06−8.01 (m, 2H), 7.64−7.58 (m, 1H), 7.53−7.46 (m, 2H), 4.57 (t,
J = 7.4 Hz, 1H), 4.16 (qd, J = 7.1, 1.4 Hz, 2H), 2.90 (qdd, J = 17.0,
7.4, 2.7 Hz, 2H), 1.99 (t, J = 2.7 Hz, 1H), 1.17 (t, J = 7.1 Hz, 3H)
ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 193.4, 168.3, 136.0,
133.9, 128.9, 128.8, 80.7, 70.5, 61.9, 53.3, 18.4, 14.0 ppm.
Methyl 2-Acetyl-5-methylhex-4-enoate (1j).24 The alkylation of
the ketoester starting material was performed according to the general
procedure on a 5.0 mmol scale. Purification by flash column
chromatography and eluting with hexanes/EtOAc (20:1) provided
1
0.59 g of 1j (64%) as a yellow oil. H NMR (400 MHz, CDCl3): δ
Ethyl 2-(4-Bromobenzoyl)pent-4-ynoate (3b).44 The alkylation of
the ketoester starting material was performed according to the general
procedure on a 5.0 mmol scale. Purification by flash column
chromatography and eluting with hexanes/Et2O (20:1) provided
0.35 g of 3b (23%) as a light-yellow oil. 1H NMR (400 MHz,
CDCl3): δ 7.90 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H), 4.50 (t, J
= 7.4 Hz, 1H), 4.16 (qd, J = 7.1, 1.3 Hz, 2H), 2.97−2.80 (m, 2H),
1.98 (t, J = 2.7 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR
(101 MHz, CDCl3): δ 192.5, 168.1, 134.8, 132.2, 130.5, 129.3, 80.5,
70.6, 62.1, 53.3, 18.4, 14.1 ppm.
5.05−4.92 (m, 1H), 3.70 (s, 3H), 3.43 (t, J = 7.5 Hz, 1H), 2.52 (t, J =
7.2 Hz, 2H), 2.20 (s, 3H), 1.65 (s, 3H), 1.60 (s, 3H) ppm; 13C{1H}
NMR (101 MHz, CDCl3): δ 203.1, 170.1, 135.0, 119.8, 59.7, 52.4,
29.2, 27.1, 25.8, 17.8 ppm.
Ethyl 2-Acetyl-5-methylhex-4-enoate (1k).42 The alkylation of the
ketoester starting material was performed according to the general
procedure on a 7.6 mmol scale. Purification by flash column
chromatography and eluting with hexanes/EtOAc (20:1) provided
0.65 g of 1k (43%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ
4.90−4.82 (m, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.27 (t, J = 7.5 Hz, 1H),
2.40−2.31 (m, 2H), 2.05 (s, 3H), 1.50 (d, J = 1.4 Hz, 3H), 1.46 (d, J
= 1.4 Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101
MHz, CDCl3): δ 202.6, 169.3, 134.3, 119.7, 60.9, 59.5, 28.7, 26.7,
25.4, 17.4, 13.8 ppm.
Ethyl 2-(4-Nitrobenzoyl)pent-4-ynoate (3c).45 The alkylation of
the ketoester starting material was performed according to the general
procedure on a 5.0 mmol scale. Purification by flash column
chromatography and eluting with hexanes/Et2O (20:1) provided
Benzyl 2-Acetyl-5-methylhex-4-enoate (1l).24 The alkylation of
the ketoester starting material was performed according to the general
procedure on a 7.0 mmol scale. Purification by flash column
chromatography and eluting with hexanes/EtOAc (100:1) provided
0.64 g of 1l (36%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ
7.41−7.27 (m, 5H), 5.16 (s, 2H), 5.05−4.96 (m, 1H), 3.48 (t, J = 7.5
Hz, 1H), 2.60−2.50 (m, 2H), 2.17 (s, 3H), 1.65 (d, J = 1.4 Hz, 3H),
1.60 (d, J = 1.4 Hz, 3H) ppm; 13C{1H} NMR (76 MHz, CDCl3): δ
202.9, 169.6, 135.5, 135.0, 128.7, 128.5, 128.4, 119.7, 67.1, 59.9, 29.2,
27.1, 25.8, 17.9 ppm.
1
0.69 g of 3c (50%) as a yellow oil. H NMR (400 MHz, CDCl3): δ
8.37−8.32 (m, 2H), 8.22−8.17 (m, 2H), 4.57 (t, J = 7.4 Hz, 1H),
4.17 (qd, J = 7.1, 0.8 Hz, 2H), 2.93 (dt, J = 7.6, 2.6 Hz, 2H), 1.99 (s,
1H), 1.18 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz,
CDCl3): δ 192.3, 167.5, 150.5, 140.4, 129.8, 123.9, 80.1, 70.8, 62.2,
53.4, 18.1, 13.9 ppm.
Methyl 2-(4-(Trifluoromethyl)benzoyl)pent-4-ynoate (3d). The
alkylation of the ketoester starting material was performed according
to the general procedure on a 5.1 mmol scale. Purification by flash
column chromatography and eluting with hexanes/Et2O (20:1)
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1
provided 0.87 g of 3d (62%) as a clear oil. H NMR (400 MHz,
CDCl3): δ 8.12−8.07 (m, 2H), 7.73−7.68 (m, 2H), 4.60 (t, J = 7.4
Hz, 1H), 3.64 (s, 3H), 2.93−2.78 (m, 2H), 1.96 (t, J = 2.6 Hz, 1H)
ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 192.6, 168.3, 138.6, 134.9
(q, J = 32.9 Hz), 129.2, 125.8 (q, J = 3.7 Hz), 123.4 (q, J = 272.4 Hz),
80.2, 70.7, 53.1, 52.9, 18.3 ppm; HRMS (ESI) m/z: [M + Na]+ calcd
for C14H11F3O3Na, 307.0552; found, 307.0552; FTIR (neat): 3290,
2959, 1740, 1692, 1580, 1513, 1435, 1409, 1319 cm−1.
Benzyl 2-Acetylpent-4-ynoate (3j). The alkylation of the ketoester
starting material was performed according to the general procedure
on a 5.0 mmol scale. Purification by flash column chromatography
and eluting with hexanes/EtOAc (10:1) provided 0.23 g of 3j (19%)
as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.42−7.29 (m, 5H),
5.20 (s, 2H), 3.74 (t, J = 7.5 Hz, 1H), 2.79−2.68 (m, 2H), 2.25 (s,
3H), 1.99 (t, J = 2.7 Hz, 1H) ppm; 13C{1H} NMR (101 MHz,
CDCl3): δ 200.9, 168.0, 135.2, 128.8, 128.7, 128.5, 80.4, 70.5, 67.6,
58.3, 29.7, 17.5 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C14H14O3Na, 253.0835; found, 253.0835; FTIR (neat): 2978, 2933,
2875, 1742, 1701, 1482, 1460, 1372 cm−1.
Ethyl 2-(4-Methoxybenzoyl)pent-4-ynoate (3e).44 The alkylation
of the ketoester starting material was performed according to the
general procedure on a 5.0 mmol scale. Purification by flash column
chromatography and eluting with hexanes/Et2O (10:1) provided 0.33
Ethyl 3-Oxo-2-(prop-2-yn-1-yl)hexanoate (3k).49 The alkylation
of the ketoester starting material was performed according to the
general procedure on a 5 mmol scale. Purification by flash column
chromatography and eluting with hexanes/Et2O (100:1 to 10:1)
1
g of 3e (26%) as a light-yellow oil. H NMR (400 MHz, CDCl3): δ
7.91 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 4.45 (t, J = 7.4 Hz,
1H), 4.03 (qd, J = 7.1, 1.5 Hz, 2H), 3.74 (s, 3H), 2.86−2.65 (m, 2H),
1.92 (t, J = 2.7 Hz, 1H), 1.06 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR
(101 MHz, CDCl3): δ 191.3, 168.2, 163.9, 131.0, 128.6, 113.7, 80.6,
70.2, 61.4, 55.3, 52.5, 18.1, 13.7 ppm.
1
provided 0.36 g of 3k (36%) as a colorless oil. H NMR (400 MHz,
CDCl3): δ 4.21 (qd, J = 7.1, 1.3 Hz, 2H), 3.69 (t, J = 7.5 Hz, 1H),
2.79−2.67 (m, 2H), 2.67−2.48 (m, 2H), 1.98 (t, J = 2.7 Hz, 1H),
1.64 (h, J = 7.3 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.4 Hz,
3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 203.4, 168.2, 80.6,
70.3, 61.8, 57.6, 44.6, 17.5, 16.9, 14.1, 13.6 ppm.
Ethyl 2-Benzoylhex-4-ynoate (3f).46 The ketoester precursor (2
mmol, 1.0 equiv) was slowly added to a flask containing NaH (5
mmol, 2.5 equiv) and dry THF (20 mL) under Ar. After 20 min, 1-
bromo-2-propyne (2 mmol, 1.0 equiv) was added. The reaction was
heated to reflux in a sand bath and left to stir for 24 h. The reaction
was then cooled to 0 °C, and water (10 mL) was slowly added to the
reaction mixture. The aqueous layer was extracted with DCM (3 × 20
mL), and the combined organic layers were washed with brine (20
mL), dried over Na2SO4, and concentrated under reduced pressure.
Purification by flash column chromatography and eluting with
hexanes/DCM (70:30 to 30:70) provided 0.20 g of 3f (41%) as a
light-yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.06−8.00 (m, 2H),
7.63−7.56 (m, 1H), 7.53−7.45 (m, 2H), 4.51 (t, J = 7.4 Hz, 1H),
4.16 (qd, J = 7.2, 0.7 Hz, 2H), 2.83 (m, 2H), 1.70 (t, J = 2.5 Hz, 3H),
1.17 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ
194.0, 168.8, 136.2, 133.8, 129.0, 128.8, 78.0, 75.4, 61.8, 53.9, 18.9,
14.1, 3.6 ppm.
Ethyl 2-Pivaloylpent-4-ynoate (3l).44 The alkylation of the
ketoester starting material was performed according to the general
procedure on a 5 mmol scale. Purification by flash column
chromatography and eluting with hexanes/Et2O (50:1) provided
0.65 g of 3l (53%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ
4.22−4.11 (m, 3H), 2.81−2.62 (m, 2H), 1.97 (t, J = 2.7 Hz, 1H),
1.25 (t, J = 7.1 Hz, 3H), 1.21 (s, 9H) ppm; 13C{1H} NMR (101
MHz, CDCl3): δ 208.5, 168.1, 80.9, 70.2, 61.6, 51.3, 45.1, 26.2, 19.2,
14.0 ppm.
Ethyl 2-Benzoyl-4-methylpent-4-enoate (5a).20 The alkylation of
the ketoester starting material was performed according to the general
procedure on a 3.8 mmol scale. Purification by flash column
chromatography and eluting with hexanes/Et2O (40:1) provided
1
0.82 g of 5a (88%) as a yellow oil. H NMR (400 MHz, CDCl3): δ
7.93−7.86 (m, 2H), 7.46−7.38 (m, 1H), 7.36−7.28 (m, 2H), 4.67−
4.62 (m, 1H), 4.62−4.58 (m, 1H), 4.48 (dd, J = 8.0, 6.7 Hz, 1H), 3.98
(qd, J = 7.1, 1.0 Hz, 2H), 2.61 (qdd, J = 15.3, 7.5, 1.2 Hz, 2H), 1.62
(s, 3H), 1.00 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz,
CDCl3): δ 194.1, 169.0, 141.8, 135.9, 133.2, 128.4, 128.3, 111.9, 60.9,
52.3, 36.2, 22.2, 13.6 ppm.
Ethyl 2-Benzoylhept-4-ynoate (3g).45 The ketoester precursor (3
mmol, 1.0 equiv) was slowly added to a flask containing NaH (7.5
mmol, 2.5 equiv) and THF (15 mL). After 30 min, 1-bromo-2-
pentyne (3 mmol, 1.0 equiv) was added, and the reaction was left to
stir at room temperature for 24 h. The reaction was cooled to 0 °C,
and water (10 mL) was slowly added to the reaction mixture. The
aqueous layer was extracted with DCM (3 × 20 mL), and the
combined organic layers were washed with brine (20 mL), dried over
Na2SO4, and concentrated under reduced pressure. Purification by
flash column chromatography and eluting with hexanes/DCM (50:50
to 40:60) provided 0.39 g of 3g (50%) as a light-yellow oil. 1H NMR
(400 MHz, CDCl3): δ 8.01−7.95 (m, 2H), 7.57−7.50 (m, 1H),
7.46−7.38 (m, 2H), 4.49 (t, J = 7.5 Hz, 1H), 4.18−4.01 (m, 2H),
2.89−2.68 (m, 2H), 2.06−1.94 (m, 2H), 1.12 (t, J = 7.1 Hz, 3H),
0.94 (t, J = 7.5 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ
194.0, 168.6, 136.2, 133.6, 128.8, 128.6, 83.9, 75.4, 61.5, 53.6, 18.8,
13.9, 13.9, 12.2 ppm.
Ethyl 2-(4-Bromobenzoyl)-4-methylpent-4-enoate (5b). The
alkylation of the ketoester starting material was performed according
to the general procedure on a 3.8 mmol scale. Purification by flash
column chromatography and eluting with hexanes/Et2O (100:1)
1
provided 0.36 g of 5b (29%) as a colorless oil. H NMR (400 MHz,
CDCl3): δ 7.91−7.85 (m, 2H), 7.65−7.59 (m, 2H), 4.77 (qt, J = 1.5,
0.8 Hz, 1H), 4.69 (qd, J = 1.5, 1.0 Hz, 1H), 4.48 (dd, J = 7.8, 6.9 Hz,
1H), 4.13 (qd, J = 7.2, 0.8 Hz, 2H), 2.79−2.64 (m, 2H), 1.76 (d, J =
0.6 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz,
CDCl3): δ 193.7, 169.3, 142.0, 135.1, 132.2, 130.3, 129.0, 112.4, 61.7,
52.9, 36.5, 22.8, 14.1 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C15H1779BrO3Na, 347.0254 and C15H1781BrO3Na, 349.0233; found,
347.0256 and 349.0232; FTIR (neat): 3078, 2977, 2936, 1733, 1684,
1584, 1226 cm−1.
Methyl 2-Acetylpent-4-ynoate (3h).47 The alkylation of the
ketoester starting material was performed according to the general
procedure on a 5.0 mmol scale. Purification by flash column
chromatography and eluting with hexanes/Et2O (20:3) provided
0.11 g of 3h (10%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ
3.77 (s, 3H), 3.71 (t, J = 7.5 Hz, 1H), 2.72 (ddd, J = 7.5, 2.7, 1.5 Hz,
2H), 2.30 (s, 3H), 2.00 (t, J = 2.7 Hz, 1H) ppm; 13C{1H} NMR (76
MHz, CDCl3): δ 201.1, 168.7, 80.4, 70.5, 58.2, 52.9, 29.8, 17.6 ppm.
Ethyl 2-Acetylpent-4-ynoate (3i).48 The alkylation of the ketoester
starting material was performed according to the general procedure
on a 7.0 mmol scale. Purification by flash column chromatography
and eluting with hexanes/EtOAc (50:1 to 10:1) provided 0.40 g of 3i
(34%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 4.23 (q, J =
7.0 Hz, 2H), 3.69 (t, J = 7.5 Hz, 1H), 2.72 (ddd, J = 7.5, 2.7, 1.4 Hz,
2H), 2.31 (s, 3H), 1.99 (t, J = 2.7 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H)
ppm; 13C{1H} NMR (76 MHz, CDCl3): δ 201.2, 168.2, 80.5, 70.4,
62.0, 58.4, 29.7, 17.6, 14.2 ppm.
Ethyl 4-Methyl-2-(4-nitrobenzoyl)pent-4-enoate (5c). The alky-
lation of the ketoester starting material was performed according to
the general procedure on a 5.0 mmol scale. Purification by flash
column chromatography and eluting with hexanes/Et2O (100:1 to
1
20:1) provided 0.63 g of 5c (43%) as a yellow solid. H NMR (400
MHz, CDCl3): δ 8.34−8.28 (m, 2H), 8.19−8.12 (m, 2H), 4.81−4.75
(m, 1H), 4.71−4.64 (m, 1H), 4.53 (t, J = 7.3 Hz, 1H), 4.14 (q, J = 7.1
Hz, 2H), 2.84−2.66 (m, 2H), 1.75 (t, J = 1.1 Hz, 3H), 1.17 (t, J = 7.1
Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 193.4, 168.9,
150.6, 141.7, 140.9, 129.7, 124.1, 112.7, 62.0, 53.4, 36.4, 22.7, 14.1
ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C15H17NO5Na,
314.0999; found, 314.0996; FTIR (neat): 3112, 3082, 3052, 2970,
2936, 2873, 1718, 1692, 1647, 1602, 1524 cm−1.
Ethyl 2-(4-Methoxybenzoyl)-4-methylpent-4-enoate (5d). The
alkylation of the ketoester starting material was performed according
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to the general procedure on a 3.8 mmol scale. Purification by flash
mmol scale with 10 mol % I2 in 24 h at room temperature.
Purification by flash column chromatography and eluting with
hexanes/EtOAc (100:1 to 50:1) provided 51.4 mg of 2b (74%) as
column chromatography and eluting with hexanes/Et2O (100:1)
1
provided 0.17 g of 5d (16%) as a colorless oil. H NMR (400 MHz,
1
CDCl3): δ 8.04−7.98 (m, 2H), 6.98−6.92 (m, 2H), 4.77 (s, 1H), 4.71
(s, 1H), 4.50 (dd, J = 8.1, 6.5 Hz, 1H), 4.13 (qd, J = 7.1, 1.3 Hz, 2H),
3.88 (s, 3H), 2.82−2.63 (m, 2H), 1.76 (dd, J = 1.4, 0.8 Hz, 3H), 1.18
(t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 193.1,
169.9, 164.0, 142.4, 131.2, 129.3, 114.1, 112.2, 61.5, 55.7, 52.6, 36.7,
22.8, 14.2 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C16H20O4Na,
299.1254; found, 299.1255; FTIR (neat): 3078, 2977, 2936, 2131,
1733, 1684, 1651, 1584 cm−1.
a yellow oil. H NMR (400 MHz, CDCl3): δ 7.49−7.43 (m, 2H),
7.21−7.16 (m, 2H), 3.95 (q, J = 7.1 Hz, 2H), 2.47 (t, J = 6.7 Hz, 2H),
1.75 (t, J = 6.7 Hz, 2H), 1.35 (s, 6H), 0.99 (t, J = 7.1 Hz, 3H) ppm;
13C{1H} NMR (76 MHz, CDCl3): δ 168.5, 161.1, 136.7, 130.9, 130.4,
123.0, 102.5, 76.6, 59.9, 32.3, 26.5, 20.3, 14.0 ppm.
Ethyl 2,2-Dimethyl-6-(4-nitrophenyl)-3,4-dihydro-2H-pyran-5-
carboxylate (2c).24 The cyclization of 1c was performed on a 0.5
mmol scale with 10 mol % I2 in 24 h at room temperature. As the
starting material was solid, two drops of DCE were added to aid
mixing. Purification by flash column chromatography and eluting with
hexanes/EtOAc (20:1) provided 105 mg of 2c (69%) as a yellow
solid. 1H NMR (400 MHz, CDCl3): δ 8.21−8.16 (m, 2H), 7.49−7.42
(m, 2H), 3.94 (q, J = 7.1 Hz, 2H), 2.50 (t, J = 6.7 Hz, 2H), 1.77 (t, J =
6.7 Hz, 2H), 1.36 (s, 6H), 0.98 (t, J = 7.1 Hz, 3H) ppm; 13C{1H}
NMR (101 MHz, CDCl3): δ 167.7, 159.8, 147.8, 144.3, 129.7, 122.9,
103.6, 77.1, 60.1, 32.1, 26.4, 20.1, 13.9 ppm.
Methyl 2-Acetyl-4-methylpent-4-enoate (5e).50 The alkylation of
the ketoester starting material was performed according to the general
procedure on a 7.0 mmol scale. Purification by flash column
chromatography and eluting with hexanes/Et2O (100:1) provided
0.48 g of 5e (40%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ
4.79 (s, 1H), 4.69 (s, 1H), 3.73 (s, 3H), 3.69 (t, J = 7.6 Hz, 1H),
2.64−2.50 (m, 2H), 2.24 (s, 3H), 1.73 (t, J = 1.1 Hz, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3): δ 202.5, 170.0, 141.9, 112.3, 58.1,
52.5, 35.9, 28.9, 22.4 ppm.
Methyl 2,2-Dimethyl-6-(4-(trifluoromethyl)phenyl)-3,4-dihydro-
2H-pyran-5-carboxylate (2d). The cyclization of 1d was performed
on a 0.5 mmol scale with 10 mol % I2 in 24 h at room temperature.
Purification by flash column chromatography and eluting with
hexanes/EtOAc (100:1 to 20:1) provided 120.3 mg of 2d (73%) as
Ethyl 2-Acetyl-4-methylpent-4-enoate (5f).51 The alkylation of
the ketoester starting material was performed according to the general
procedure on a 7.0 mmol scale. Purification by flash column
chromatography and eluting with hexanes/Et2O (20:1) provided
0.81 g of 5f (63%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ
4.57 (s, 1H), 4.49 (s, 1H), 3.98 (q, J = 7.1 Hz, 2H), 3.49 (t, J = 7.6
Hz, 1H), 2.35 (d, J = 7.6 Hz, 2H), 2.03 (s, 3H), 1.53 (s, 3H), 1.06 (t,
J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 201.9,
169.0, 141.6, 111.8, 60.9, 57.8, 35.5, 28.4, 22.0, 13.7 ppm.
1
a colorless oil. H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.1 Hz,
2H), 7.43 (d, J = 7.9 Hz, 2H), 3.50 (s, 3H), 2.51 (t, J = 6.7 Hz, 2H),
1.78 (t, J = 6.7 Hz, 2H), 1.37 (s, 6H) ppm; 13C{1H} NMR (101
MHz, CDCl3): δ 168.50, 161.06, 141.20 (d, J = 1.5 Hz), 130.66 (q, J
= 32.4 Hz), 129.04, 124.75 (q, J = 3.8 Hz), 124.20 (q, J = 272.2 Hz),
102.60, 76.87, 51.17, 32.20, 26.40, 20.22 ppm; HRMS (ESI) m/z: [M
+ Na]+ calcd for C16H17F3O3Na, 337.1022; found, 337.1023; FTIR
(neat): 2977, 2948, 2854, 1714, 1695, 1632, 1610, 1323, 1297 cm−1.
Ethyl 6-(4-Methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyran-
5-carboxylate (2e). The cyclization of 1e was performed on a 1
mmol scale with 10 mol % I2 in 24 h at room temperature. As the
product has the same Rf as that of the starting material and could not
be separated in all eluent systems attempted (hexanes/EtOAc,
hexanes/DCM, and hexanes/Et2O), the reaction yield was
determined to be approximately 38% from a combination of column
Benzyl 2-Acetyl-4-methylpent-4-enoate (5g).20 The alkylation of
the ketoester starting material was performed according to the general
procedure on a 7 mmol scale. Purification by flash column
chromatography and eluting with hexanes/Et2O (100:1) provided
1.06 g of 5g (62%) as a light-yellow oil. 1H NMR (400 MHz, CDCl3):
δ 7.31−7.19 (m, 5H), 5.08 (s, 2H), 4.70 (s, 1H), 4.62 (s, 1H), 3.68
(dd, J = 8.0, 7.2 Hz, 1H), 2.59−2.45 (m, 2H), 2.09 (s, 3H), 1.64 (t, J
= 1.2 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 201.7,
168.9, 141.5, 135.2, 128.3, 128.1, 128.0, 112.0, 66.7, 57.8, 35.5, 28.4,
22.0 ppm.
1
Ethyl 2-(2-Methylallyl)-3-oxohexanoate (5h).51 The alkylation of
the ketoester starting material was performed according to the general
procedure on a 7.0 mmol scale. Purification by flash column
chromatography and eluting with hexanes/Et2O (100:1 to 50:1)
fractions via H NMR, using 1,3,5-triisopropylbenzene as an internal
standard. To allow characterization of the product, a small amount of
the almost pure compound 2e was able to be obtained after column
chromatography with hexanes/DCM (10:90); however, a trace
amount of the uncyclized starting material (compound 1e) is still
visible in the spectra. 1H NMR (400 MHz, CDCl3): δ 7.29−7.23 (m,
2H), 6.88−6.82 (m, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 2.48
(t, J = 6.8 Hz, 2H), 1.74 (t, J = 6.8 Hz, 2H), 1.35 (s, 6H), 1.00 (t, J =
7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 169.0, 161.9,
160.2, 130.2, 130.1, 113.1, 101.4, 76.2, 59.8, 55.4, 32.4, 26.5, 20.5,
14.1 ppm; HRMS (ESI) m/z: [M + H]+ calcd for C17H23O4,
291.1591; found, 291.1589; FTIR (neat): 2976, 2934, 1681, 1603,
1509, 1459, 1369, 1295, 1245 cm−1.
1
provided 0.37 g of 5h (25%) as a colorless oil. H NMR (400 MHz,
CDCl3): δ 4.70 (s, 1H), 4.61 (s, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.60
(t, J = 7.6 Hz, 1H), 2.56−2.33 (m, 4H), 1.66 (s, 3H), 1.54 (h, J = 7.3
Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3): δ 204.5, 169.4, 142.0, 112.1, 61.3,
57.5, 43.7, 35.7, 22.4, 16.8, 14.1, 13.5 ppm.
Ethyl 4-Methyl-2-pivaloylpent-4-enoate (5i).20 The alkylation of
the ketoester starting material was performed according to the general
procedure on a 3.8 mmol scale. Purification by flash column
chromatography and eluting with hexanes/Et2O (50:1) provided
0.58 g of 5i (68%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ
4.75 (s, 1H), 4.69 (s, 1H), 4.17−4.06 (m, 3H), 2.65−2.53 (m, 1H),
2.46−2.34 (m, 1H), 1.73 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.16 (s,
9H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 209.4, 169.4, 142.2,
112.7, 61.4, 51.3, 45.5, 37.5, 26.3, 22.6, 14.2 ppm.
2,2-Dimethyl-3,4-dihydroindeno[1,2-b]pyran-5(2H)-one (2f).52
The cyclization of 1f was performed on a 0.5 mmol scale with 10
mol % I2 in 24 h at 50 °C in a heating mantle. Purification by flash
column chromatography and eluting with hexanes/EtOAc (50:1 to
25:1) provided 87.7 mg of 2f (82%) as a colorless oil. 1H NMR (300
MHz, CDCl3): δ 7.38−7.32 (m, 1H), 7.30−7.16 (m, 2H), 7.10−7.04
(m, 1H), 2.30 (t, J = 6.4 Hz, 2H), 1.76 (t, J = 6.4 Hz, 2H), 1.42 (s,
6H) ppm; 13C{1H} NMR (76 MHz, CDCl3): δ 193.4, 173.8, 138.6,
133.9, 131.8, 129.7, 120.8, 117.5, 106.4, 81.1, 32.7, 26.7, 14.4 ppm.
1-(2,2-Dimethyl-6-phenyl-3,4-dihydro-2H-pyran-5-yl)ethan-1-
one (2g) and Phenyl(2,2,6-trimethyl-3,4-dihydro-2H-pyran-5-yl)-
methanone (2g′).24 The cyclization of 1g was performed on a 1
mmol scale with 15 mol % I2 in 24 h at 50 °C in a heating mantle.
Purification by flash column chromatography and eluting with
hexanes/EtOAc (75:1) provided 64 mg of 2g (26%) and 102 mg
of 2g′ (44%) as light-yellow oils. 2g: 1H NMR (300 MHz, CDCl3): δ
7.44−7.32 (m, 5H), 2.48 (t, J = 6.8 Hz, 2H), 1.74 (t, J = 6.8 Hz, 2H),
1.67 (s, 3H), 1.36 (s, 6H) ppm; 13C{1H} NMR (76 MHz, CDCl3): δ
Characterization Data of Cyclized Products. Ethyl 2,2-
Dimethyl-6-phenyl-3,4-dihydro-2H-pyran-5-carboxylate (2a).24
The cyclization of 1a was performed on a 1 mmol scale with 10
mol % I2 in 24 h at room temperature. Purification by flash column
chromatography and eluting with hexanes/EtOAc (100:1 to 50:1)
1
provided 231 mg of 2a (89%) as a yellow oil. H NMR (300 MHz,
CDCl3): δ 7.37−7.27 (m, 5H), 3.92 (q, J = 7.1 Hz, 2H), 2.49 (t, J =
6.7 Hz, 2H), 1.76 (t, J = 6.7 Hz, 2H), 1.36 (s, 6H), 0.91 (t, J = 7.1 Hz,
3H) ppm; 13C{1H} NMR (76 MHz, CDCl3): δ 168.9, 162.2, 137.9,
128.7, 128.6, 127.7, 102.0, 76.3, 59.8, 32.4, 26.5, 20.4, 13.8 ppm.
Ethyl 6-(4-Bromophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyran-5-
carboxylate (2b).24 The cyclization of 1b was performed on a 0.5
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200.5, 163.5, 137.6, 129.9, 129.4, 128.5, 114.1, 76.6, 32.5, 30.6, 26.3,
scale with 10 mol % I2 in 24 h at room temperature. Purification by
flash column chromatography and eluting with hexanes/EtOAc
(100:1 to 50:1) provided 32 mg of 2m (68%) as a yellow oil. H
1
20.2 ppm. 2g′: H NMR (300 MHz, CDCl3): δ 7.66−7.60 (m, 2H),
1
7.51−7.35 (m, 3H), 2.39 (tt, J = 6.6, 1.5 Hz, 2H), 1.73 (t, J = 1.5 Hz,
3H), 1.68 (t, J = 6.6 Hz, 2H), 1.33 (s, 6H) ppm; 13C NMR (76 MHz,
CDCl3): δ 198.8, 160.7, 141.2, 131.5, 128.5, 128.5, 108.9, 75.5, 32.5,
26.8, 21.3, 21.2 ppm.
NMR (400 MHz, CDCl3): δ 4.14 (q, J = 7.1 Hz, 2H), 2.59 (ddt, J =
8.7, 6.8, 0.9 Hz, 2H), 2.30 (tt, J = 6.7, 0.9 Hz, 2H), 1.59 (t, J = 6.7 Hz,
2H), 1.57−1.50 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H), 1.23 (s, 6H), 0.92
(t, J = 7.4 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 168.8,
167.4, 99.3, 75.1, 59.6, 35.5, 32.4, 26.6, 21.3, 19.7, 14.5, 14.1 ppm;
HRMS (ESI) m/z: [M + Na]+ calcd for C13H22O3Na, 249.1461;
found, 249.1462; FTIR (neat): 2974, 2933, 2873, 1703, 1610, 1453,
1368, 1289 cm−1.
Ethyl 6-(3-Iodopropyl)-2,2-dimethyl-3,4-dihydro-2H-pyran-5-
carboxylate (2o′). The reaction of 1o with the catalytic amount of
I2 did not lead to any significant amounts of identifiable products.
Once the reaction was performed on a 0.5 mmol scale with the
stoichiometric amount of I2, it was possible to isolate some products
from the reaction mixture. Purification by flash column chromatog-
raphy and eluting with hexanes/DCM (50:50) provided 26 mg of 2o′
(15%) as a brown oil along with some other unidentifiable products.
1H NMR (400 MHz, CDCl3): δ 4.15 (q, J = 7.1 Hz, 2H), 3.19 (t, J =
7.4 Hz, 2H), 2.71 (ddt, J = 8.5, 6.3, 0.9 Hz, 2H), 2.30 (tt, J = 6.7, 0.9
Hz, 2H), 2.08 (p, J = 7.4 Hz, 2H), 1.60 (t, J = 6.7 Hz, 2H), 1.28 (t, J =
7.1 Hz, 3H), 1.23 (s, 6H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ
168.5, 165.2, 100.2, 75.5, 59.8, 34.6, 32.3, 32.1, 26.6, 19.7, 14.6, 6.0
ppm; HRMS (ESI) m/z: [M + H]+ calcd for C13H22IO3, 353.0609;
found, 353.0605 (minor ∼15%); FTIR (neat): 2975, 2936, 1699,
1610, 1448, 1367, 1274, 1226 cm−1.
2,2-Dimethyl-5,6-diphenyl-3,4-dihydro-2H-pyran (2h) and (4,4-
Dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)(phenyl)methanone
(2h′).26d The cyclization of 1h was performed on a 1 mmol scale with
15 mol % I2 in 24 h at room temperature. Purification by flash column
chromatography and eluting with hexanes/EtOAc (75:1 to 50:1)
provided 208.0 mg of 2h (80%) and 21.0 mg of 2h′ (8%) as yellow
1
oils. 2h: H NMR (400 MHz, CDCl3): δ 7.22−7.04 (m, 10H), 2.50
(t, J = 6.8 Hz, 2H), 1.88 (t, J = 6.8 Hz, 2H), 1.42 (s, 6H) ppm;
13C{1H} NMR (101 MHz, CDCl3): δ 148.0, 142.2, 137.4, 130.4,
129.7, 129.6, 128.8, 128.2, 128.1, 128.0, 127.6, 127.5, 127.3, 127.2,
1
125.7, 110.4, 73.7, 33.8, 26.5, 25.9 ppm. 2h′: H NMR (300 MHz,
CDCl3): δ 8.07−7.99 (m, 2H), 7.64−7.55 (m, 1H), 7.55−7.47 (m,
2H), 7.47−7.41 (m, 1H), 7.30−7.20 (m, 1H), 7.14−7.03 (m, 1H),
6.96−6.87 (m, 1H), 4.84 (t, J = 6.4 Hz, 1H), 2.28−2.05 (m, 2H),
1.89−1.76 (m, 1H), 1.72−1.60 (m, 1H), 1.41 (s, 3H), 1.35 (s, 3H)
ppm; 13C{1H} NMR (76 MHz, CDCl3): δ 202.5, 146.5, 136.7, 133.8,
133.1, 129.4, 128.8, 128.8, 127.1, 126.9, 125.7, 48.4, 36.1, 33.8, 31.9,
31.6, 24.0 ppm.
6-(4-Methoxyphenyl)-2,2-dimethyl-5-phenyl-3,4-dihydro-2H-
pyran (2i). The cyclization of 1i was performed on a 0.5 mmol scale
with 10 mol % I2 in 24 h at room temperature. Purification by flash
column chromatography and eluting with hexanes/DCM (60:40)
provided 34.3 mg of 2i (20%) as a yellow oil. The Friedel−Crafts-type
byproduct 2i′ was not identified from the reaction mixture. 1H NMR
(400 MHz, CDCl3): δ 7.22−7.02 (m, 7H), 6.73−6.61 (m, 2H), 3.73
(s, 3H), 2.48 (t, J = 6.8 Hz, 2H), 1.87 (t, J = 6.8 Hz, 2H), 1.41 (s, 6H)
ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 158.9, 147.7, 142.5,
130.8, 129.9, 129.7, 128.1, 125.5, 113.1, 109.3, 73.6, 55.3, 33.8, 26.5,
25.9 ppm; HRMS (ESI) m/z: [M + H]+ calcd for C20H23O2,
295.1693; found, 295.1693; FTIR (neat): 2971, 2930, 2838, 1672,
1601, 1510, 1248 cm−1.
Ethyl 5-Methyl-2-phenylfuran-3-carboxylate (4a).9 The cycliza-
tion of 3a was performed on a 0.5 mmol scale with 10 mol % I2 in 24
h at room temperature. Purification by flash column chromatography
and eluting with hexanes/Et2O (50:1 to 20:1) provided 102 mg of 4a
(78%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.99−7.93 (m,
2H), 7.45−7.33 (m, 3H), 6.44 (q, J = 1.0 Hz, 1H), 4.28 (q, J = 7.1
Hz, 2H), 2.35 (d, J = 1.0 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3): δ 163.9, 156.1, 151.2, 130.2,
129.0, 128.3, 128.1, 114.6, 108.9, 60.5, 14.4, 13.5 ppm.
Ethyl 2-(4-Bromophenyl)-5-methylfuran-3-carboxylate (4b).44
The cyclization of 3b was performed on a 0.5 mmol scale with 15
mol % I2 in 24 h at room temperature. Purification by flash column
chromatography and eluting with hexanes/Et2O (20:1) provided 110
mg of 4b (63%) as a light-yellow solid. 1H NMR (400 MHz, CDCl3):
δ 7.88 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 6.43 (q, J = 1.1
Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.34 (d, J = 1.1 Hz, 3H), 1.33 (t, J
= 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 163.7,
154.8, 151.5, 131.3, 129.7, 129.0, 123.2, 115.1, 109.1, 60.6, 14.4, 13.4
ppm.
Methyl 2,2,6-Trimethyl-3,4-dihydro-2H-pyran-5-carboxylate
(2j).24 The cyclization of 1j was performed on a 0.5 mmol scale
with 10 mol % I2 in 24 h at room temperature. Because 2j is quite
1
volatile, the yield of this reaction was determined to be 87% by H
NMR using 1,3,5-triisopropylbenzene as an internal standard.
Purification by flash column chromatography and eluting with
hexanes/EtOAc (40:1) provided 2j as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ 3.67 (s, 3H), 2.28 (td, J = 6.7, 1.5 Hz, 2H),
2.19 (t, J = 1.5 Hz, 3H), 1.59 (t, J = 6.7 Hz, 2H), 1.22 (s, 6H) ppm;
13C{1H} NMR (76 MHz, CDCl3): δ 169.3, 164.1, 99.3, 75.6, 51.0,
Ethyl 5-Methyl-2-(4-nitrophenyl)furan-3-carboxylate (4c).53 The
cyclization of 3c was performed on a 0.5 mmol scale with 15 mol % I2
in 24 h at room temperature. Purification by flash column
chromatography and eluting with hexanes/EtOAc (20:1) provided
32.4, 26.6, 20.9, 19.5 ppm.
Ethyl 2,2,6-Trimethyl-3,4-dihydro-2H-pyran-5-carboxylate
(2k).29 The cyclization of 1k was performed on a 0.5 mmol scale
with 10 mol % I2 in 24 h at room temperature. Because 2k is quite
1
86 mg of 4c (58%) as a light-yellow solid. H NMR (400 MHz,
1
CDCl3): δ 8.28−8.19 (m, 4H), 6.51 (d, J = 1.2 Hz, 1H), 4.31 (q, J =
7.1 Hz, 2H), 2.39 (d, J = 1.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3): δ 163.4, 153.1, 152.8, 147.4,
volatile, the yield of this reaction was determined to be 91% by H
NMR using 1,3,5-triisopropylbenzene as an internal standard.
Purification by flash column chromatography and eluting with
hexanes/EtOAc (40:1) provided 2k as a colorless oil. 1H NMR
(400 MHz, CDCl3): δ 4.14 (q, J = 7.1 Hz, 2H), 2.33−2.25 (m, 2H),
2.20 (t, J = 1.5 Hz, 3H), 1.59 (t, J = 6.7 Hz, 2H), 1.26 (t, J = 7.1 Hz,
3H), 1.23 (s, 6H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 168.9,
163.8, 99.5, 75.5, 59.6, 32.4, 26.6, 20.9, 19.6, 14.6 ppm.
135.8, 128.5, 123.5, 117.7, 110.0, 61.0, 14.3, 13.5 ppm.
Methyl 5-Methyl-2-(4-(trifluoromethyl)phenyl)furan-3-carboxy-
late (4d). The cyclization of 3d was performed on a 0.5 mmol
scale with 15 mol % I2 in 24 h at room temperature. Purification by
flash column chromatography and eluting with hexanes/EtOAc
1
(100:1) provided 98 mg of 4d (69%) as a colorless oil. H NMR
Benzyl 2,2,6-Trimethyl-3,4-dihydro-2H-pyran-5-carboxylate
(2l).24 The cyclization of 1l was performed on a 0.5 mmol scale
with 10 mol % I2 in 24 h at room temperature. Purification by flash
column chromatography and eluting with hexanes/EtOAc (50:1 to
(400 MHz, CDCl3): δ 8.12 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.3 Hz,
2H), 6.46 (q, J = 1.0 Hz, 1H), 3.83 (s, 3H), 2.37 (d, J = 1.1 Hz, 3H)
ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 164.1, 154.3, 152.3,
133.3, 130.5 (q, J = 32 Hz), 128.3, 125.2 (q, J = 3.8 Hz), 124.2 (q, J =
271.4 Hz), 115.8, 109.3, 51.8, 13.5 ppm; 19F{1H} NMR (376 MHz,
CDCl3): δ −62.8 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C14H11F3O3Na, 307.0553; found, 307.0553; FTIR (neat): 2955, 1722,
1688, 1610, 1558, 1323, 1274 cm−1.
1
25:1) provided 71 mg of 2l (51%) as a colorless oil. H NMR (300
MHz, CDCl3): δ 7.43−7.27 (m, 5H), 5.16 (s, 2H), 2.36 (tq, J = 6.7,
1.5 Hz, 2H), 2.24 (q, J = 1.5 Hz, 3H), 1.62 (t, J = 6.7 Hz, 2H), 1.25
(s, 6H) ppm; 13C{1H} NMR (76 MHz, CDCl3): δ 168.6, 164.6,
137.1, 128.6, 128.0, 127.9, 99.2, 75.7, 65.5, 32.4, 26.7, 21.0, 19.6 ppm.
Ethyl 2,2-Dimethyl-6-propyl-3,4-dihydro-2H-pyran-5-carboxy-
late (2m). The cyclization of 1m was performed on a 0.2 mmol
Ethyl 2-(4-Methoxyphenyl)-5-methylfuran-3-carboxylate (4e).
The cyclization of 3e was performed on a 0.5 mmol scale with 15
8166
https://doi.org/10.1021/acs.joc.1c00608
J. Org. Chem. 2021, 86, 8154−8171

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
mol % I2 in 24 h at room temperature. Purification by flash column
chromatography and eluting with hexanes/EtOAc (50:1 to 20:1)
provided 104 mg of 4e (71%) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ 7.97−7.91 (m, 2H), 6.97−6.90 (m, 2H), 6.41 (q, J = 1.1
Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 2.33 (d, J = 1.1 Hz,
3H), 1.32 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz,
CDCl3): δ 164.0, 160.2, 156.3, 150.4, 129.8, 122.9, 113.5, 113.3,
108.7, 60.3, 55.4, 14.4, 13.4 ppm; HRMS (ESI) m/z: [M + Na]+ calcd
for C15H16O4Na, 283.0941; found, 283.0942; FTIR (neat): 2977,
2929, 2836, 1710, 1606, 1502, 1252 cm−1.
Ethyl 5-Ethyl-2-phenylfuran-3-carboxylate (4f) and 4f′ Adduct.
The cyclization of 3f was performed on a 0.5 mmol scale with 15 mol
% I2 in 24 h at room temperature. Purification by flash column
chromatography and eluting with hexanes/DCM (1:1) provided 42
mg of 4f (34%) as a colorless oil. Another byproduct (4f′) was also
isolated from the reaction mixture in ∼18% yield, which was most
likely the adduct of iodine to 3f. 4f: 1H NMR (400 MHz, CDCl3): δ
8.00−7.93 (m, 2H), 7.47−7.32 (m, 3H), 6.45 (t, J = 1.1 Hz, 1H),
4.29 (q, J = 7.1 Hz, 2H), 2.70 (qd, J = 7.5, 1.1 Hz, 2H), 1.37−1.24
(m, 6H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 164.0, 156.8,
155.9, 130.3, 129.0, 128.3, 128.1, 114.5, 107.4, 60.5, 21.3, 14.4, 12.0
ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C15H16NaO3, 267.0992;
found, 267.0990; FTIR (neat): 2975, 1713, 1555, 1490, 1378, 1229
cm−1. 4f′: 1H NMR (400 MHz, CDCl3): δ 8.07−7.98 (m, 2H), 7.64−
7.56 (m, 1H), 7.53−7.44 (m, 2H), 4.78 (dd, J = 7.9, 6.3 Hz, 1H), 4.15
(qd, J = 7.1, 4.2 Hz, 2H), 3.53−3.26 (m, 2H), 2.58 (d, J = 1.0 Hz,
3H), 1.16 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz,
CDCl3): δ 193.7, 168.6, 136.2, 133.8, 128.9, 128.9, 98.3, 96.7, 61.9,
53.8, 49.1, 40.9, 14.1 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C15H16I2NaO3, 520.9082; found, 520.9078; FTIR (neat): 2979, 1736,
1686, 1596, 1447, 1369, 1234 cm−1.
h at room temperature. Purification by flash column chromatography
and eluting with hexanes/Et2O (20:1) provided 75 mg of 4k (78%) as
a light-yellow oil. H NMR (400 MHz, CDCl3): δ 6.24−6.17 (m,
1H), 4.25 (q, J = 7.1 Hz, 2H), 2.90 (t, J = 7.5 Hz, 2H), 2.24 (d, J = 1.1
Hz, 3H), 1.68 (h, J = 7.4 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H), 0.94 (t, J =
7.4 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 164.4, 161.7,
150.0, 113.9, 106.3, 60.0, 29.7, 21.7, 14.5, 13.9, 13.4 ppm.
1
Ethyl 2-(tert-Butyl)-5-methylfuran-3-carboxylate (4l).44 The
cyclization of 3l was performed on a 0.5 mmol scale with 15 mol %
I2 in 24 h at room temperature. Purification by flash column
chromatography and eluting with hexanes/Et2O (20:1) provided 74
mg of 4l (64%) as a light-yellow oil. 1H NMR (400 MHz, CDCl3): δ
6.26 (d, J = 1.1 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 2.23 (d, J = 1.1 Hz,
3H), 1.40 (s, 9H), 1.33 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101
MHz, CDCl3): δ 166.9, 164.2, 148.0, 112.7, 108.3, 60.1, 34.5, 28.4,
14.4, 13.2 ppm.
Ethyl 5,5-Dimethyl-2-phenyl-4,5-dihydrofuran-3-carboxylate
(6a).20 The cyclization of 5a was performed on a 0.5 mmol scale
with 15 mol % I2 in 24 h at room temperature. Purification by flash
column chromatography and eluting with hexanes/EtOAc (100:1 to
1
10:1) provided 91 mg of 6a (74%) as a colorless oil. H NMR (400
MHz, CDCl3): δ 7.78−7.70 (m, 2H), 7.43−7.32 (m, 3H), 4.12 (q, J =
7.1 Hz, 2H), 2.93 (s, 2H), 1.49 (s, 6H), 1.20 (t, J = 7.1 Hz, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3): δ 165.8, 164.1, 130.7, 130.2,
129.4, 127.7, 101.8, 85.6, 59.7, 44.4, 28.3, 14.4 ppm.
Ethyl 2-(4-Bromophenyl)-5,5-dimethyl-4,5-dihydrofuran-3-car-
boxylate (6b). The cyclization of 5b was performed on a 0.5 mmol
scale with 15 mol % I2 in 24 h at room temperature. Purification by
flash column chromatography and eluting with hexanes/EtOAc
(100:1) provided 113 mg of 6b (70%) as a light-yellow oil. 1H
NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.7
Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 2.91 (s, 2H), 1.48 (s, 6H), 1.22 (t,
J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 165.6,
162.8, 131.0, 130.9, 129.5, 124.6, 102.3, 85.8, 59.8, 44.4, 28.3, 14.4
ppm; HRMS (ESI) m/z: [M + H]+ calcd for C15H1779BrO3H,
325.0434 and C15H1781BrO3H 327.0414; found, 325.0435 and
327.0414; FTIR (neat): 2974, 2929, 2866, 1688, 1617, 1483, 1256
cm−1.
Ethyl 2-Phenyl-5-propylfuran-3-carboxylate (4g).45 The cycliza-
tion of 3g was performed on a 0.5 mmol scale with 15 mol % I2 in 24
h at room temperature. Purification by flash column chromatography
and eluting with hexanes/DCM (1:1) provided 54.2 mg of 4g (41%)
as an orange oil. 1H NMR (400 MHz, CDCl3): δ 8.01−7.93 (m, 2H),
7.46−7.34 (m, 3H), 6.46 (d, J = 0.9 Hz, 1H), 4.29 (q, J = 7.1 Hz,
2H), 2.65 (td, J = 7.4, 0.9 Hz, 2H), 1.73 (h, J = 7.4 Hz, 2H), 1.33 (t, J
= 7.1 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H) ppm; 13C{1H} NMR (101
MHz, CDCl3): δ 164.0, 155.9, 155.4, 130.3, 129.0, 128.3, 128.1,
114.4, 108.2, 60.5, 29.9, 21.3, 14.4, 13.8 ppm.
Ethyl 5,5-Dimethyl-2-(4-nitrophenyl)-4,5-dihydrofuran-3-car-
boxylate (6c). The cyclization of 5c was performed on a 0.5 mmol
scale with 15 mol % I2 in 24 h at room temperature, with 2 drops of
DCE added to aid mixing. Purification by flash column chromatog-
raphy and eluting with hexanes/EtOAc (50:1 to 10:1) provided 118
Methyl 2,5-Dimethylfuran-3-carboxylate (4h).54 The cyclization
of 3h was performed on a 0.5 mmol scale with 15 mol % I2 in 24 h at
room temperature. Purification by flash column chromatography and
eluting with hexanes/EtOAc (20:1) provided 48 mg of 4h (61%) as a
1
mg of 6c (82%) as a yellow solid. H NMR (400 MHz, CDCl3): δ
8.22−8.17 (m, 2H), 7.97−7.92 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H),
2.95 (s, 2H), 1.49 (s, 6H), 1.21 (t, J = 7.1 Hz, 3H) ppm; 13C{1H}
NMR (101 MHz, CDCl3): δ 165.1, 161.1, 148.4, 136.8, 130.5, 122.8,
104.6, 86.5, 60.1, 44.4, 28.2, 14.3 ppm; HRMS (ESI) m/z: [M + Na]+
calcd for C15H17NO5Na, 314.0999; found, 314.0999; FTIR (neat):
3119, 2970, 2933, 2866, 1692, 1584, 1513, 1341, 1260 cm−1.
Ethyl 2-(4-Methoxyphenyl)-5,5-dimethyl-4,5-dihydrofuran-3-
carboxylate (6d). The cyclization of 5d was performed on a 0.5
mmol scale with 15 mol % I2 in 24 h at room temperature.
Purification by flash column chromatography and eluting with
hexanes/EtOAc (100:1 to 20:1) provided 75 mg of X (58%) as a
light-yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.81−7.75 (m, 2H),
6.91−6.86 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 2.91 (s,
2H), 1.47 (s, 6H), 1.23 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101
MHz, CDCl3): δ 166.0, 164.0, 161.2, 131.1, 123.0, 113.0, 100.4, 85.1,
59.6, 55.4, 44.5, 28.3, 14.5 ppm; HRMS (ESI) m/z: [M + H]+ calcd
for C16H20O4H, 277.1435; found, 277.1436; FTIR (neat): 2974,
2936, 2843, 1692, 1606, 1509, 1245 cm−1.
1
light-yellow oil. H NMR (300 MHz, CDCl3): δ 6.19 (q, J = 1.2 Hz,
1H), 3.79 (s, 3H), 2.51 (s, 3H), 2.23 (d, J = 1.1 Hz, 3H) ppm;
13C{1H} NMR (76 MHz, CDCl3): δ 164.9, 157.9, 150.1, 113.8, 106.2,
51.3, 13.8, 13.3 ppm.
Ethyl 2,5-Dimethylfuran-3-carboxylate (4i).10b The cyclization of
3i was performed on a 0.5 mmol scale with 15 mol % I2 in 24 h at
room temperature. Purification by flash column chromatography and
eluting with hexanes/EtOAc (95:5) provided 68 mg of 4i (70%) as a
1
light-yellow oil. H NMR (400 MHz, CDCl3): δ 6.21 (d, J = 1.2 Hz,
1H), 4.26 (q, J = 7.1 Hz, 2H), 2.52 (s, 3H), 2.23 (d, J = 0.6 Hz, 3H),
1.33 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ
164.5, 157.7, 150.0, 114.1, 106.3, 60.0, 14.5, 13.8, 13.3 ppm.
Benzyl 2,5-Dimethylfuran-3-carboxylate (4j). The cyclization of
3j was performed on a 1 mmol scale with 15 mol % I2 in 24 h at room
temperature. Purification by flash column chromatography and eluting
with hexanes/Et2O (20:1) provided 77 mg of 4j (65%) as a light-
yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.43−7.28 (m, 5H), 6.24
(q, J = 1.2 Hz, 1H), 5.26 (s, 2H), 2.53 (s, 3H), 2.23 (d, J = 1.3 Hz,
3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 164.2, 158.1, 150.1,
136.5, 128.7, 128.2, 128.1, 113.8, 106.4, 65.8, 13.9, 13.3 ppm; HRMS
(ESI) m/z: [M + Na]+ calcd for C14H14O3Na, 253.0836; found,
253.0836; FTIR (neat): 3033, 2951, 2921, 1710, 1587, 1498, 1397,
1360, 1278 cm−1.
Methyl 2,5,5-Trimethyl-4,5-dihydrofuran-3-carboxylate (6e).56
The cyclization of 5e was performed on a 0.5 mmol scale with 15
mol % I2 in 24 h at room temperature. Because 6e is quite volatile, the
1
yield of this reaction was determined to be 84% by H NMR using
1,3,5-triisopropylbenzene as an internal standard. Purification by flash
column chromatography and eluting with hexanes/EtOAc (50:1)
provided 6e as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.69 (s,
3H), 2.67 (q, J = 1.6 Hz, 2H), 2.16 (t, J = 1.6 Hz, 3H), 1.37 (s, 6H)
Ethyl 5-Methyl-2-propylfuran-3-carboxylate (4k).55 The cycliza-
tion of 3k was performed on a 0.5 mmol scale with 15 mol % I2 in 24
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Article
ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 167.2, 167.1, 100.9, 86.3,
50.9, 42.7, 28.4, 14.6 ppm.
Raphaël Robidas − Department of Chemistry, Centre in Green
Chemistry and Catalysis, Université de Sherbrooke, Québec
J1K 2R1, Canada
Uyen P. N. Tran − School of Chemistry, University of New
South Wales, Sydney, New South Wales 2052, Australia;
Van Hien University, Ho Chi Minh City, Vietnam
Ethyl 2,5,5-Trimethyl-4,5-dihydrofuran-3-carboxylate (6f).57 The
cyclization of 5f was performed on a 0.5 mmol scale with 15 mol % I2
in 24 h at room temperature. Because 6f is quite volatile, the yield of
1
this reaction was determined to be 88% by H NMR using 1,3,5-
triisopropylbenzene as an internal standard. Purification by flash
column chromatography and eluting with hexanes/EtOAc (20:1)
provided 6f as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 4.15 (q,
J = 7.1 Hz, 2H), 2.67 (q, J = 1.6 Hz, 2H), 2.16 (t, J = 1.6 Hz, 3H),
1.37 (s, 6H), 1.26 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101
MHz, CDCl3): δ 166.8, 166.7, 101.2, 86.1, 59.4, 42.8, 28.4, 14.6, 14.6
ppm.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00608
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Benzyl 2,5,5-Trimethyl-4,5-dihydrofuran-3-carboxylate (6g).20
The cyclization of 5g was performed on a 0.5 mmol scale with 15
mol % I2 in 24 h at room temperature. Purification by flash column
chromatography and eluting with hexanes/Et2O (50:1) provided 80
mg of 6g (65%) as a light-yellow oil. 1H NMR (400 MHz, CDCl3): δ
7.42−7.27 (m, 5H), 5.16 (s, 2H), 2.71 (q, J = 1.6 Hz, 2H), 2.18 (t, J =
1.6 Hz, 3H), 1.38 (s, 6H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ
167.5, 166.4, 137.0, 128.6, 128.0, 128.0, 100.9, 86.4, 65.3, 42.7, 28.4,
14.7 ppm.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Australian Research Council (grants
FT180100260 and DP200100063 to T.V.N.) for financial
support. D.P.P. is grateful for his RTP Ph.D. scholarship.
Computational resources were provided by Calcul Québec and
Compute Canada. R.R. is grateful to NSERC for a Canada
Graduate Scholarship (CGS M).
Ethyl 5,5-Dimethyl-2-propyl-4,5-dihydrofuran-3-carboxylate
(6h). The cyclization of 5h was performed on a 0.5 mmol scale
with 15 mol % I2 in 24 h at room temperature. Purification by flash
column chromatography and eluting with hexanes/Et2O (100:1 to
1
50:1) provided 106 mg of 6h (89%) as a light-yellow oil. H NMR
(400 MHz, CDCl3): δ 4.15 (q, J = 7.1 Hz, 2H), 2.68 (t, J = 1.1 Hz,
2H), 2.58 (ddt, J = 8.5, 7.4, 1.0 Hz, 2H), 1.64−1.51 (m, 3H), 1.37 (s,
6H), 1.27 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H) ppm; 13C{1H}
NMR (101 MHz, CDCl3): δ 170.4, 166.5, 100.8, 85.8, 59.3, 42.8,
29.9, 28.3, 20.4, 14.5, 13.8 ppm; HRMS (ESI) m/z: [M + Na]+ calcd
for C12H20O3Na, 235.1305; found, 235.1306; FTIR (neat): 2970,
2933, 2873, 1695, 1636, 1371, 1263 cm−1.
REFERENCES
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Ethyl 2-(tert-Butyl)-5,5-dimethyl-4,5-dihydrofuran-3-carboxylate
(6i).20 The cyclization of 5i was performed on a 0.5 mmol scale with
15 mol % I2 in 24 h at room temperature. Purification by flash column
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1
provided 49 mg of 6i (42%) as a colorless oil. H NMR (400 MHz,
CDCl3): δ 4.12 (q, J = 7.1 Hz, 2H), 2.71 (s, 2H), 1.33 (s, 6H), 1.27
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ppm.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00608.
■
sı
Experimental details and spectroscopic data for all
products, full Gaussian reference, Cartesian coordinates,
and electronic and free energies (PDF)
Computational details (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Claude Y. Legault − Department of Chemistry, Centre in
Green Chemistry and Catalysis, Université de Sherbrooke,
Québec J1K 2R1, Canada; orcid.org/0000-0002-0730-
0263; Email: claude.legault@usherbrooke.ca
Thanh Vinh Nguyen − School of Chemistry, University of
New South Wales, Sydney, New South Wales 2052,
Australia; orcid.org/0000-0002-0757-9970;
Email: t.v.nguyen@unsw.edu.au
Authors
Domenic P. Pace − School of Chemistry, University of New
South Wales, Sydney, New South Wales 2052, Australia
8168
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