Regiocontrolled Synthesis of γ-Hydroxybutenolides via Singlet Oxygen-Mediated Oxidation of 2-Thiophenyl Furans

Article abstract of DOI:10.1021/acs.joc.6b00660

Photooxygenation of 2-thiophenyl-substituted furans in ethanol leads to the rapid, regiocontrolled, and quantitative synthesis of γ-hydroxybutenolides. The carbonyl group in butenolide holds the position of thiophenyl moiety in reacting furans. Decomposit

Full text of DOI:10.1021/acs.joc.6b00660

Note
pubs.acs.org/joc
Regiocontrolled Synthesis of γ‑Hydroxybutenolides via Singlet
Oxygen-Mediated Oxidation of 2‑Thiophenyl Furans
Vasiliki Kotzabasaki, Georgios Vassilikogiannakis, and Manolis Stratakis*
Department of Chemistry, University of Crete, 71003 Voutes, Iraklion, Greece
S
* Supporting Information
ABSTRACT: Photooxygenation of 2-thiophenyl-substituted furans in ethanol leads to
the rapid, regiocontrolled, and quantitative synthesis of γ-hydroxybutenolides. The
carbonyl group in butenolide holds the position of thiophenyl moiety in reacting
furans. Decomposition of the initially formed [4 + 2] endoperoxide into products
through a radical chain mechanism is proposed, as the fate of thiophenyl moiety is its
transformation into ethyl phenylsulfenate (PhS-OEt) and diphenyldisulfide. Under the reaction conditions, the sulfenate is fast
oxidized into the corresponding sulfinate.
he γ-hydroxybutenolide moiety [5-hydroxyfuran-2(5H)-
ones] appears as an essential unit in a vast variety of
undergoes ring opening rearrangement followed by hydrolysis;
and (3) photooxygenation of furans bearing at the ortho-
position a hydroxyalkyl group, an aldehyde, or a carboxylate.17
In this manuscript, we present a new and highly efficient
protocol for the synthesis of γ-hydroxybutenolides, using the
easily synthesized 2-thiophenyl-substituted furans as precursors
(Table 1). Methylene Blue-sensitized photooxygenation of
these compounds in ethanol as solvent at 0 °C provides after
2−3 min of irradiation (0.2−0.3 mmol scale) their clean and
quantitative transformation into γ-hydroxybutenolides (Scheme
2). A protic solvent, such as ethanol or methanol, is essential as
T
bioactive natural products and other substances of biomedical
significance. They can be either unsubstituted (hydrogen) at
the γ-position (e.g., dysidiolide,1 manoalide,2 cacospongiono-
lides,3 etc.) or substituted (e.g., PD 156707,4 caribenol A,5
annomolon A,6 etc.). As a consequence, several methodologies
for the construction of this class of compounds have been
developed, including acid-catalyzed inter or intramolecular
condensation,7 Knoevenagel condensation,8 selective reduction
of substituted maleic anhydrides,9 carbonylative oxidative
cycloaddition among aldehydes and alkynes,10 and acid-
catalyzed annulation of alkynes with α-keto acids.11 Yet, the
most common and straightforward approach relies on suitable
furan oxidation by various means (Scheme 1), such as
Scheme 2. Photooxygenation of 2-Thiophenyl Furans in
Ethanol
Scheme 1. Protocols for the Synthesis of γ-
Hydroxybutenolides Using Furans as Precursors and a
Suitable Oxidant
will be analyzed in the following mechanistic discussion. In
nonprotic solvents (DCM, chloroform), a mixture of products
is formed. The fate of thiophenyl moiety in reacting furans is its
final transformation into ethyl phenylsulfinate [PhS(O)-OEt]
and diphenyldisulfide (PhSSPh) in a relative ratio sulfinate/
disulfide ∼4/1 to 3/1 for all substrates examined. The side
products were isolated and characterized by comparison with
an authentic sample for disulfide and to the known
spectroscopic data of the sulfinate esters (methyl or ethyl,
depending on the solvent used).18 Note that in contrast to our
photooxygenation results of 2-substituted thiofurans, the
treatment of 2-trialkylsilyloxyfurans with dimethyldioxirane,12
NaClO2-mediated oxidation of simple furans,13 oxidation with
K2Cr2O7,14 and by using singlet molecular oxygen (1O2) as a
green oxidant. The known protocols for the synthesis of γ-
1
hydroxybutenolides utilizing O2 are (1) photooxygenation of
furans having at least one nonsubstituted ortho-position, in the
presence of a hindered base,15 where the initially formed [4 +
2] endoperoxide (ozonide) yields product(s) via a Kornblum-
DeLaMare rearrangement; (2) photooxygenation of 2-
trialkylsilylfurans,16 where the [4 + 2] silyl endoperoxide
Received: March 28, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b00660
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
reaction of singlet oxygen with 2,5-bis-thiophenylfuran
derivatives in methanol affords O-methyl-S-phenyl thioma-
leates.19
Table 1. Synthesis of γ-Hydroxybutenolides via
Photooxygenation of 2-Thiophenyl Furans in Ethanol
In Table 1, we present the scope and generality of this
method for the synthesis of a series of γ-hydroxybutenolides,
using suitably substituted 2-thiophenylfurans whose syntheses
is presented in Scheme 3. Substrates 1−4 were obtained by
Scheme 3. Synthesis of the 2-Thiophenyl-Substituted Furans
Used in This Study
direct lithiation of the corresponding furans with n-BuLi
followed by quenching with PhSSPh in ∼60−75% yield.20
Substrates 5−8 were synthesized as follows: ortho-bromination
of 2-(phenylthio)furan, 16, with 1 equiv of NBS in dry DCM at
0 °C for 1 h afforded 2-bromo-5-(phenylthio)furan (17) in
75% yield. The bromofuran 17 was treated with n-BuLi (−78
°C, 30 min, THF) and then quenched with benzyl bromide (to
produce 5, 67% yield), with butyraldehyde (to produce 6, 81%
yield), with ethyl chloroformate (to produce 7, 58% yield), and
with paraformaldehyde to produce (5-(phenylthio)furan-2-
yl)methanol (18) in 70% yield. Subsequently, 18 was acetylated
with Ac2O to form 8 in 95% yield. Substrates 9−15 were
synthesized as follows: bromination of 1 with 1 equiv of NBS in
dry DCM at 0 °C for 1 h, afforded bromofuran 920 in 73%
a
b
Mixture of diastereomers (∼50/50). Mixture of diastereomers
(∼55/45).
B
DOI: 10.1021/acs.joc.6b00660
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The Journal of Organic Chemistry
Note
yield. The bromofuran was transmetalated with n-BuLi (−78
°C, 30 min, THF) and then quenched with CH3I to produce
10 (65% yield), with PhSSPh to produce 12 (73% yield), with
PhMe2SiCl to produce 15 (89% yield), and with dodecanal to
produce 13 (77% yield). Reduction of 13 with BF3/Et3SiH
afforded 11 in 64% yield. Finally, furan 14 was prepared in 68%
overall yield by quenching transmetalated 9 with butyraldehyde
to form 19,20 followed by esterification with p-bromobenzoyl
chroride (Et3N, 4-DMAP, DCM).
phenylsulfenate (PhSOEt) and diphenyldisulfide (PhSSPh).
Oxidation of PhSOEt under the reaction conditions by singlet
oxygen generates ethyl phenylsulfinate.22 Note that PhS-OEt or
PhS(O)-OEt do not arise from PhSSPh under the reaction
conditions, as verified by an independent experiment. In our
1
hands, diphenyldisulfide was inert against O2, as already well
established in the literature.23 The possibility that persulfenate
ester III is formed, through a mechanism analogous to the
photooxygenation of silylfurans,16a followed by radical scission
of the O−S bond (initiation) and subsequent propagation steps
cannot be excluded. A complete ionic mechanism (ethanol
attack on sulfur of intermediate I to form ethyl phenylsulfenate
accompanied by peroxide opening to form hydroxybutenolide)
is less likely to occur, as formation of side product
diphenyldisulfide cannot be justified. In addition, thiophenol
(formed by any ionic pathway) was excluded as precursor of
diphenyldisulfide, as in separate experiment (methylene-blue
sensitized photooxygenation of thiophenol in ethanol for 5
min) no such transformation was noticed.
After photooxygenation, the desired γ-hydroxybutenolides
were purified by column chromatography and the isolated
yields ranged between 62 and 75%. The reaction tolerates as
series of functionalities in furan side chains such as alcohol,
esters, thioether, halide, or silyl group. Although the photo-
oxygenation of 2-thiophenylfurans is quantitative and clean, the
lower isolated yields of products probably reflects the partial
tendency of cyclic butenolides to isomerize into trans-keto acids
while in silica gel. The current protocol has the advantage that
not only the directing thiophenyl moiety can be easily
introduced at the ortho position of the furan ring, but it also
directs bromination of furans, so it is feasible to achieve the
regiocontrolled synthesis of a series of γ-hydroxybutenolides,
such as 9a−15a.
In conclusion, we have shown herein a novel and quite
simple method for the quantitative formation of γ-hydro-
butenolides via photooxygenation of 2-thiophenylfurans in
ethanol. A radical-chain decomposition of the initially formed
[4 + 2] endoperoxide is proposed as the most rational
mechanism. The reacting furans can be easily synthesized from
simple precursors. Our protocol adds a new and useful
application of furan photooxygenation in synthetic organic
chemistry.24
A useful observation in terms of mechanistic discussion was
that after ∼1 min of photooxygenation of the model compound
1 (Table 1) in ethanol, the sulfenate ester PhS-OEt21 can be
1
detected by H NMR (see Supporting Information) in 1:2 to
1:3 relative ratio compared with ethyl phenylsulfinate, but after
an additional 1−2 min of irradiation, it had been completely
oxidized into the corresponding sulfinate, which as noted above
is the final fate of the thiophenyl moiety of all reacting furans in
our studies, along with diphenyldisulfide. Therefore, we
consider ethyl phenylsulfenate (PhSOEt) as a primary reaction
product. The formation of byproduct PhSSPh dictates a free
radical decomposition pathway of the initially formed
endoperoxide I, shown in Scheme 4. After cleavage of C−S
and O−O bonds in I, the resulting butenyloxy radical II
abstracts a hydrogen atom from the protic solvent to generate
the γ-hydroxybutenolide. The ethoxy as well as the thiophenyl
radicals lead to II through the depicted propagation steps
(Scheme 2) and to the observed side products ethyl
EXPERIMENTAL SECTION
■
General. The reactions were monitored by thin-layer chromatog-
raphy (TLC) carried out on silica gel plates (60F-254). Flash column
chromatography was carried out on SiO2 (silica gel 60, particle size
0.040−0.063 mm). NMR spectra were recorded on 300 and 500 MHz
instruments. High resolution mass spectra (HRMS) were recorded
using ESI-Orbitrap and TOF-ESI techniques.
Spectroscopic Data of Synthesized Furans. 2-Methyl-5-
(phenylthio)furan (1):20 Colorless oil (1.82 g, 75% yield). H NMR
1
(500 MHz, CDCl3): 7.27−7.22 (m, 2H), 7.19−7.13 (m, 3H), 6.67 (d,
J = 3.0 Hz, 1H), 6.08 (dq, J1 = 3.0 Hz, J2 = 1.0 Hz, 1H), 2.33 (d, J = 1.0
Hz, 3H). 13C NMR (125 MHz, CDCl3): 156.8, 140.2, 137.0, 129.0
(2C), 127.0 (2C), 126.0, 121.2, 108.1, 14.1.
2-Ethyl-5-(phenylthio)furan (2). Colorless oil (0.34 g, 73% yield).
1H NMR (500 MHz, CDCl3): 7.25−7.22 (m, 2H), 7.18−7.13 (m,
3H), 6.68 (d, J = 3.0 Hz, 1H), 6.09 (d, J = 3.0 Hz, 1H), 2.68 (q, J = 7.5
Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3):
162.4, 140.0, 137.2, 129.0 (2C), 126.9 (2C), 126.0, 121.0, 106.5, 21.8,
11.9. HRMS (ESI-Orbit trap) m/z: [M + H]+ Calcd for C12H12OS +
H, 205.0687; found, 205.0679.
Scheme 4. Possible Mechanisms for the Formation of γ-
Hydroxybutenolide via Photooxygenation of a 2-
Thiophenyl-Substituted Furan in Ethanol
2,3-Dimethyl-5-(phenylthio)furan (3). Colorless oil (0.26 g, 72%
1
yield). H NMR (500 MHz, CDCl3): 7.26−7.21 (m, 2H), 7.19−7.12
(m, 3H), 6.55 (br s, 1H), 2.24 (br s, 3H), 1.96 (br s, 3H). 13C NMR
(125 MHz, CDCl3): 152.3, 138.5, 137.2, 128.9 (2C), 126.9 (2C),
125.9, 123.3, 116.5, 11.8, 9.8. HRMS (ESI-Orbit trap) m/z: [M + H]+
Calcd for C12H12OS + H, 205.0687; found, 205.0679.
(R)-3,6-Dimethyl-2-(phenylthio)-4,5,6,7-tetrahydrobenzofuran
1
(4). Colorless oil (0.065 g, 60% yield). H NMR (500 MHz, CDCl3):
7.26−7.21 (m, 2H), 7.14−7.08 (m, 3H), 2.69 (dd, J1 = 17.5 Hz, J2 =
5.5 Hz, 1H), 2.46−2.32 (m, 2H), 2.19 (dd, J1 = 17.5 Hz, J2 = 9.5 Hz,
1H), 2.02 (s, 3H), 1.98−1.91 (m, 1H), 1.89−1.82 (m, 1H), 1.44−1.34
(m, 1H), 1.08 (d, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3):
154.2, 137.8, 135.7, 129.5, 128.9 (2C), 126.4 (2C), 125.6, 119.2, 31.5,
31.0, 29.4, 21.4, 20.2, 9.3. HRMS (ESI-Orbit trap) m/z: [M + H]+
Calcd for C16H18OS + H, 259.1157; found, 259.1149.
2-(Phenylthio)furan (16):25 Colorless oil (1.15 g, 80% yield). H
1
NMR (500 MHz, CDCl3): 7.59 (m, 1H), 7.28−7.17 (m, 5H), 6.76
C
DOI: 10.1021/acs.joc.6b00660
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Note
(m, 1H), 6.49 (m, 1H). 13C NMR (125 MHz, CDCl3): 146.5, 142.9,
136.3, 129.0 (2C), 127.4 (2C), 126.3, 119.5, 111.8.
1H), 1.35−1.16 (m, 18H), 0.89 (t, J = 7.0 Hz, 3H). 13C NMR (125
MHz, CDCl3): 156.5, 137.6, 137.0, 136.6, 129.0 (2C), 126.9 (2C),
126.1, 106.3, 67.1, 37.5, 31.9, 29.6, 29.6, 29.5, 29.5, 29.4, 29.3, 25.6,
22.7, 14.1, 14.1. HRMS (TOF-ESI) m/z: [M + H]+ Calcd for
C23H34O2S + H − H2O, 357.2252; found, 357.2260.
2-Bromo-5-(phenylthio)furan (17). Colorless oil (0.95 g, 75%
yield). 1H NMR (500 MHz, CDCl3): 7.30−7.19 (m, 5H), 6.72 (d, J =
3.0 Hz, 1H), 6.40 (d, J = 3.0 Hz, 1H). 13C NMR (125 MHz, CDCl3):
145.2, 135.5, 129.2 (2C), 127.8 (2C), 126.7, 125.3, 122.3, 113.7. MS
(EI): 256 (M+, 22%), 254 (M+, 22%), 175 (42%), 147 (100%).
2-Benzyl-5-(phenylthio)furan (5). Colorless oil (0.090 g, 67%
1-(5-Methyl-2-(phenylthio)furan-3-yl)butan-1-ol (19).20 Colorless
oil (0.135 g, 79% yield). 1H NMR (300 MHz, CDCl3): 7.26−7.10 (m,
5H), 6.18 (s, 1H), 4.78 (t, J = 7.0 Hz, 1H), 2.32 (s, 3H), 1.82−1.54
(m, 2H), 1.40−1.30 (m, 2H), 0.87 (t, J = 7.5 Hz, 3H). 13C NMR (75
MHz, CDCl3): 156.5, 137.6, 136.9, 136.5, 129.1 (2C), 126.8 (2C),
126.1, 106.3, 66.8, 39.6, 18.8, 14.1, 13.8.
1
yield). H NMR (500 MHz, CDCl3): 7.38−7.33 (m, 2H), 7.30−7.26
(m, 5H), 7.22−7.18 (m, 3H), 6.71 (br s, 1H), 6.10 (br s, 1H), 4.03 (s,
2H). 13C NMR (125 MHz, CDCl3): 159.2, 141.1, 137.3, 136.8, 128.9
(2C), 128.7 (2C), 128.5 (2C), 127.0 (2C), 126.6, 126.0, 120.9, 108.7,
34.9. HRMS (ESI-Orbit trap) m/z: [M + H]+ Calcd for C17H14OS +
H, 267.0844; found, 267.0836.
1-(5-Methyl-2-(phenylthio)furan-3-yl)butyl 4-Bromobenzoate
(14). White solid (0.068 g, 58% yield). 1H NMR (300 MHz,
CDCl3): 7.84 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.24−7.07
(m, 5H), 6.19 (s, 1H), 6.08 (t, J = 7.0 Hz, 1H), 2.31 (s, 3H), 2.04−
1.94 (m, 1H), 1.82−1.72 (m, 1H), 1.40−1.25 (m, 2H), 0.89 (t, J = 7.5
Hz, 3H). 13C NMR (75 MHz, CDCl3): 164.9, 156.4, 138.0, 136.4,
133.4, 131.6 (2C), 131.1 (2C), 129.3, 128.9 (2C), 127.9, 127.2 (2C),
126.1, 106.9, 70.1, 37.2, 18.6, 14.1, 13.7. HRMS (ESI-Orbit trap) m/z:
[M + H]+ Calcd for C21H19BrO3S + H − p-bromobenzoic acid,
245.1000; found, 245.0997.
1-(5-(Phenylthio)furan-2-yl)butan-1-ol (6). Colorless oil (0.104 g,
1
81% yield). H NMR (300 MHz, CDCl3): 7.29−7.13 (m, 5H), 6.70
(d, J = 3.5 Hz, 1H), 6.31 (d, J = 3.5 Hz, 1H), 4.67 (t, J = 7.0 Hz, 1H),
1.85−1.77 (m, 2H), 1.52−1.28 (m, 2H), 0.93 (t, J = 7.0 Hz, 3H). 13C
NMR (75 MHz, CDCl3): 161.3, 141.9, 136.4, 129.0 (2C), 127.2 (2C),
126.2, 120.5, 107.8, 67.7, 37.5, 18.6, 13.8. HRMS (ESI-Orbit trap) m/
z: [M + H]+ Calcd for C14H16O2S + H − H2O, 231.0844; found,
231.0845.
Dimethyl(5-methyl-2-(phenylthio)furan-3-yl)(phenyl)silane (15).
1
Colorless oil (0.078 g, 89% yield). H NMR (300 MHz, CDCl3):
Ethyl 5-(Phenylthio)furan-2-carboxylate (7). Colorless oil (0.072
g, 58% yield). 1H NMR (500 MHz, CDCl3): 7.29−7.21 (m, 5H), 7.17
(d, J = 3.5 Hz, 1H), 6.66 (d, J = 3.5 Hz, 1H), 4.35 (q, J = 7.0 Hz, 2H),
1.36 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): 158.0, 149.4,
147.2, 133.7, 129.3 (2C), 129.2 (2C), 127.3, 119.0, 118.9, 61.1, 14.2.
HRMS (ESI-Orbit trap) m/z: [M + H]+ Calcd for C13H12O3S + H,
249.0585; found, 249.0580.
7.53−7.50 (m, 2H), 7.35−7.30 (m, 3H), 7.23−7.12 (m, 3H), 7.05−
7.01 (m, 2H), 5.99 (d, J = 1.5 Hz, 1H), 2.29 (s, 3H), 0.51 (s, 6H). 13C
NMR (75 MHz, CDCl3): 156.3, 145.2, 137.9, 137.3, 133.9 (2C),
129.0, 128.9 (2C), 128.6, 127.7 (2C), 126.8 (2C), 125.8, 113.1, 13.7,
−2.1. HRMS (ESI-Orbit trap) m/z: [M + H]+ Calcd for C19H20OSSi
+ H, 325.1082; found, 325.1087.
(5-(Phenylthio)furan-2-yl)methanol (18).26 Colorless oil (0.090 g,
Photooxygenation of 2-Thiophenyl Furans. In a vial the
appropriate 2-thiophenylfuran (∼0.2 mmol) is dissolved in ethanol
(1 mL). Methylene blue is added (concentration ∼10−3 to 10−4 M)
and the solution is irradiated with visible light using a 300 W xenon
lamp, under a constant flow (bubbling) of oxygen gas. After substrate
consumption (typically 2−3 min), the solvent is evaporated and the
residue is chromatographed to provide the γ-hydroxybutenolides. The
byproducts (diphenyldisulfide and ethyl phenylsulfinate) can also be
isolated.
1
70% yield). H NMR (500 MHz, CDCl3): 7.28−7.13 (m, 5H), 6.71
(d, J = 3.5 Hz, 1H), 6.38 (d, J = 3.5 Hz, 1H), 4.61 (s, 2H). 13C NMR
(125 MHz, CDCl3): 158.1, 143.0, 136.0, 129.1 (2C), 127.6 (2C),
126.4, 120.5, 109.7, 57.7.
(5-(Phenylthio)furan-2-yl)methyl Acetate (8). Colorless oil (0.103
g, 95% yield). 1H NMR (500 MHz, CDCl3): 7.27−7.14 (m, 5H), 6.70
(d, J = 3.5 Hz, 1H), 6.47 (d, J = 3.5 Hz, 1H), 5.04 (s, 2H), 2.08 (s,
3H). 13C NMR (125 MHz, CDCl3): 170.5, 153.4, 144.1, 135.7, 129.1
(2C), 127.9 (2C), 126.5, 120.2, 112.2, 58.1, 20.8. HRMS (ESI-Orbit
trap) m/z: [M + H]+ Calcd for C13H12O3S + H, 249.0585; found,
249.0580.
Ethyl Phenylsulfinate.18a 1H NMR (500 MHz, CDCl3): 7.73−7.70
(m, 2H), 7.56−7.52 (m, 3H), 4.12 (dq, J1 = 11.5 Hz, J2 = 7.0 Hz, 1H),
3.73 (dq, J1 = 11.5 Hz, J2 = 7.0 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H). 13
C
3-Bromo-5-methyl-2-(phenylthio)furan (9):20 Colorless oil (1.22
NMR (125 MHz, CDCl3): 144.8, 132.0, 129.0 (2C), 125.2 (2C), 61.0,
1
15.5.
g, 73% yield). H NMR (500 MHz, CDCl3): 7.58−7.54 (m, 2H),
Methyl Phenylsulfinate.18b Formed if methanol is used as solvent.
1H NMR (500 MHz, CDCl3): 7.73−7.70 (m, 2H), 7.56−7.52 (m,
7.48−7.44 (m, 3H), 6.22 (s, 1H), 1.66 (s, 3H). 13C NMR (125 MHz,
CDCl3): 156.7, 140.0, 135.3, 129.1 (2C), 127.8 (2C), 126.6, 111.8,
111.7, 14.2.
3H), 3.48 (s, 3H). 13C NMR (125 MHz, CDCl3): 143.9, 132.2, 129.1
(2C), 125.4 (2C), 49.6.
3,5-Dimethyl-2-(phenylthio)furan (10). Colorless oil (0.074 g, 65%
1
yield). H NMR (500 MHz, CDCl3): 7.25−7.08 (m, 5H), 6.04 (br s,
Spectroscopic Data of γ-Hydroxybutenolides. 5-Hydroxy-5-
methylfuran-2(5H)-one (1a):17a Colorless oil (0.024 g, 75% yield).
1H NMR (500 MHz, CDCl3): 7.26 (d, J = 5.5 Hz, 1H), 6.08 (d, J = 5.5
1H), 2.32 (br s, 3H), 2.11 (br s, 3H). 13C NMR (125 MHz, CDCl3):
155.6, 137.5, 136.2, 131.0, 128.9 (2C), 126.3 (2C), 125.6, 110.2, 14.0,
11.1. HRMS (ESI-Orbit trap) m/z: [M + H]+ Calcd for C12H12OS +
H, 205.0687; found, 205.0679.
Hz, 1H), 1.71 (s, 3H). 13C NMR (125 MHz, CDCl3): 170.9, 155.3,
122.4, 106.6, 24.4.
3-Dodecyl-5-methyl-2-(phenylthio)furan (11). Colorless oil (0.058
5-Ethyl-5-hydroxyfuran-2(5H)-one (2a).27 Colorless oil (0.016 g,
1
1
g, 64% yield from 13). H NMR (500 MHz, CDCl3): 7.25−7.21 (m,
72% yield). H NMR (500 MHz, CDCl3): 7.22 (d, J = 5.5 Hz, 1H),
2H), 7.14−7.07 (m, 3H), 6.03 (br s, 1H), 2.46 (t, J = 7.5 Hz, 2H),
2.30 (br s, 3H), 1.52−1.46 (m, 2H), 1.32−1.18 (m, 18H), 0.89 (t, J =
7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): 155.7, 137.8, 135.9, 135.8,
128.9 (2C), 126.3 (2C), 125.6, 109.0, 31.9, 30.0, 29.7, 29.7, 29.6, 29.5,
29.4, 29.3, 29.2, 25.7, 22.7, 14.1, 14.1. HRMS (ESI-Orbit trap) m/z:
[M + H]+ Calcd for C23H34OS + H, 359.2409; found, 359.2412.
5-Methyl-2,3-bis(phenylthio)furan (12). White solid (0.076 g, 73%
yield). 1H NMR (500 MHz, CDCl3): 7.31−7.17 (m, 10H), 6.08 (br s,
1H), 2.31 (br s, 3H). 13C NMR (125 MHz, CDCl3): 156.6, 143.0,
135.6, 129.1 (2C), 129.0 (2C), 128.9 (2C), 128.2 (2C), 128.2, 126.5,
126.4, 125.6, 111.7, 14.1. HRMS (ESI-Orbit trap) m/z: [M + H]+
Calcd for C17H14OS2 + H, 299.0564; found, 299.0555.
6.11 (d, J = 5.5 Hz, 1H), 2.04−1.93 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H).
13C NMR (125 MHz, CDCl3): 170.9, 154.2, 123.3, 108.8, 30.6, 7.6.
5-Hydroxy-4,5-dimethylfuran-2(5H)-one (3a):7b Colorless oil
1
(0.012 g, 74% yield). H NMR (300 MHz, CDCl3): 5.75 (q, J = 1.5
Hz, 1H), 2.09 (d, J = 1.5 Hz, 3H), 1.63 (s, 3H). 13C NMR (75 MHz,
CDCl3): 170.7, 168.0, 117.1, 106.7, 23.3, 12.4.
(6R,7aR)-7a-Hydroxy-3,6-dimethyl-5,6,7,7a-tetrahydrobenzofur-
an-2(4H)-one (4a):28 Colorless oil (0.012 g, 65% yield). H NMR
1
(500 MHz, CDCl3): 2.70−2.65 (m, 1H), 2.40−2.32 (m, 2H), 2.02−
1.94 (m, 2H), 1.80 (d, J = 1.0 Hz, 3H), 1.29−1.23 (m, 1H), 1.06−0.98
(m, 1H), 0.97 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3):
172.2, 160.3, 121.4, 103.4, 45.9, 35.0, 29.1, 24.3, 21.1, 8.2.
1-(5-Methyl-2-(phenylthio)furan-3-yl)dodecan-1-ol (13). Color-
5-Benzyl-5-hydroxyfuran-2(5H)-one (5a). Colorless oil (0.012 g,
1
1
less oil (0.195 g, 77% yield). H NMR (500 MHz, CDCl3): 7.26−
7.22 (m, 2H), 7.16−7.11 (m, 3H), 6.18 (br s, 1H), 4.77 (t, J = 7.0 Hz,
1H), 2.32 (d, J = 1.0 Hz, 3H), 1.82−1.75 (m, 1H), 1.64−1.58 (m,
68% yield). H NMR (500 MHz, CDCl3): 7.36−7.26 (m, 5H), 7.20
(d, J = 5.5 Hz, 1H), 6.06 (d, J = 5.5 Hz, 1H), 3.26 (d, J = 14.0 Hz,
1H), 3.21 (d, J = 14.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): 170.0,
D
DOI: 10.1021/acs.joc.6b00660
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The Journal of Organic Chemistry
Note
153.8, 132.8, 130.5 (2C), 128.7 (2C), 127.8, 123.7, 106.8, 44.2. HRMS
(ESI-Orbit trap) m/z: [M + H]+ Calcd for C11H10O3 + H, 191.0708;
found, 191.0712.
5-Hydroxy-5-(1-hydroxybutyl)furan-2(5H)-one (6a, Equimolar
Mixture of Two Diastereomers). Colorless oil (0.013 g, 73% yield).
1H NMR (500 MHz, CDCl3): 7.25 (d, J = 5.5 Hz, 1H of first
diastereomer), 7.24 (d, J = 5.5 Hz, 1H of second diastereomer), 6.20
(d, J = 5.5 Hz, 1H of first diastereomer), 6.19 (d, J = 5.5 Hz, 1H of
second diastereomer), 3.79 (m, 1H from each diastereomer), 1.65−
1.36 (m, 4H from each diastereomer), 0.93 (t, J = 7.5 Hz, 3H from
each diastereomer). 13C NMR (125 MHz, CDCl3): 170.7 and 170.3
(two diastereomers), 152.2 and 151.9 (two diastereomers), 125.0 and
124.7 (two diastereomers), 108.7 and 108.2 (two diastereomers), 74.5
and 74.2 (two diastereomers), 33.1 and 33.0 (two diastereomers), 19.0
and 18.8 (two diastereomers), 13.8 and 13.8 (two diastereomers).
HRMS (ESI-Orbit trap) m/z: [M + H]+ Calcd for C8H12O4 + H −
H2O, 155.0708; found, 155.0707.
1-(5-Hydroxy-5-methyl-2-oxo-2,5-dihydrofuran-3-yl)butyl 4-Bro-
mobenzoate (14a, Mixture of Two Diastereomers in 55/45 Relative
Ratio). Colorless oil (0.021 g, 68% yield). 1H NMR (500 MHz,
CDCl3): 7.93 (d, J = 8.5 Hz, 2H of first diastereomer), 7.91 (d, J = 8.5
Hz, 2H of second diastereomer), 7.61 (d, J = 8.5 Hz, 2H from each
diastereomer), 7.00 (br s, 1H of first diastereomer), 6.96 (br s, 1H of
second diastereomer), 5.80−5.76 (m, 1H from each diastereomer),
2.02−1.91 (m, 2H from each diastereomer), 1.70 (s, 3H from each
diastereomer), 1.48−1.40 (m, 2H from each diastereomer), 0.97 (t, J =
7.5 Hz, 3H of first diastereomer), 0.96 (t, J = 7.5 Hz, 3H of second
diastereomer). 13C NMR (125 MHz, CDCl3): 168.4 and 168.2 (two
diastereomers), 165.1 and 164.9 (two diastereomers), 147.9 and 147.7
(two diastereomers), 135.1 and 135.0 (two diastereomers), 132.0 and
131.9 (2C of two diastereomers), 131.2 (2C of two ovelapping
diastereomers), 128.8 and 128.7 (two diastereomers), 128.4 and 128.3
(two diastereomers), 104.5 and 104.2 (two diastereomers), 69.6 and
69.2 (two diastereomers), 34.9 and 34.8 (two diastereomers), 24.8 and
24.5 (two diastereomers), 18.4 and 18.4 (two diastereomers), 13.7 and
13.7 (two diastereomers). HRMS (ESI-Orbit trap) m/z: [M + H]+
Calcd for C16H17BrO5 + H, 369.0338; found, 369.0331.
Ethyl 2-Hydroxy-5-oxo-2,5-dihydrofuran-2-carboxylate (7a). Col-
orless oil (0.010 g, 62% yield). 1H NMR (500 MHz, CDCl3): 7.19 (d,
J = 5.5 Hz, 1H), 6.33 (d, J = 5.5 Hz, 1H), 4.33 (q, J = 7.5 Hz, 2H),
1.31 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): 169.6, 167.0,
149.7, 125.4, 100.6, 64.3, 13.9. HRMS (TOF-ESI) m/z: [M − H]−
Calcd for C7H8O5 − H, 171.0294; found, 171.0302.
3-(Dimethyl(phenyl)silyl)-5-hydroxy-5-methylfuran-2(5H)-one
(15a). Colorless oil (0.028 g, 74% yield). 1H NMR (300 MHz,
CDCl3): 7.60−7.56 (m, 2H), 7.42−7.38 (m, 3H), 7.17 (s, 1H), 1.64
(s, 3H), 0.55 (s, 6H). 13C NMR (75 MHz, CDCl3): 172.8, 163.5,
135.3, 135.0, 134.0 (2C), 129.9, 128.1 (2C), 105.8, 24.3, −3.6, −3.7.
HRMS (ESI-Orbit trap) m/z: [M + H]+ Calcd for C13H16SiO3 + H −
H2O, 231.0841; found, 231.0845.
(2-Hydroxy-5-oxo-2,5-dihydrofuran-2-yl)methyl Acetate (8a):17a
Colorless oil (0.012 g, 69% yield). 1H NMR (500 MHz, CDCl3): 7.25
(d, J = 5.5 Hz, 1H), 6.22 (d, J = 5.5 Hz, 1H), 4.52 (d, J = 11.5 Hz,
1H), 4.22 (d, J = 11.5 Hz, 1H), 2.11 (s, 3H). 13C NMR (125 MHz,
CDCl3): 170.7, 169.5, 151.7, 124.7, 104.7, 65.1, 20.6.
ASSOCIATED CONTENT
* Supporting Information
■
3-Bromo-5-hydroxy-5-methylfuran-2(5H)-one (9a). Colorless oil
(0.014 g, 71% yield). 1H NMR (300 MHz, CDCl3): 7.34 (s, 1H), 1.75
(s, 3H). 13C NMR (75 MHz, CDCl3): 166.0, 151.5, 115.9, 105.9, 24.7.
HRMS (ESI-Orbit trap) m/z: [M + H]+ Calcd for C5H5BrO3 + H,
192.9500; found, 192.9505.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00660.
1
Copies of H and 13C NMR of all compounds (PDF)
5-Hydroxy-3,5-dimethylfuran-2(5H)-one (10a):7b Colorless oil
1
(0.012 g, 72% yield). H NMR (500 MHz, CDCl3): 6.86 (q, J = 1.5
Hz, 1H), 1.91 (d, J = 1.5 Hz, 3H), 1.68 (s, 3H). 13C NMR (125 MHz,
CDCl3): 171.8, 147.6, 131.7, 104.2, 24.7, 10.3.
AUTHOR INFORMATION
Corresponding Author
*E-mail: stratakis@uoc.gr
■
3-Dodecyl-5-hydroxy-5-methylfuran-2(5H)-one (11a). White
1
solid (0.026 g, 71% yield). H NMR (500 MHz, CDCl3): 6.81 (t, J
Notes
= 1.5 Hz, 1H), 2.31 (td, J1 = 7.5 Hz, J2= 1.5 Hz, 2H), 1.67 (s, 3H),
1.55−1.50 (m, 2H), 1.36−1.22 (m, 18H), 0.86 (t, J = 7.5 Hz, 3H). 13C
NMR (125 MHz, CDCl3): 171.8, 146.9, 136.1, 104.5, 31.9, 29.6, 29.6,
29.6, 29.5, 29.3, 29.3, 29.2, 27.1, 24.8, 24.8, 22.7, 14.1. HRMS (ESI-
Orbit trap) m/z: [M + H]+ Calcd for C17H30O3 + H, 283.2273; found,
283.2275.
5-Hydroxy-5-methyl-3-(phenylthio)furan-2(5H)-one (12a). Color-
less oil (0.015 g, 66% yield). 1H NMR (500 MHz, CDCl3): 7.58−7.55
(m, 2H), 7.47−7.43 (m, 3H), 6.23 (s, 1H), 1.66 (s, 3H). 13C NMR
(125 MHz, CDCl3): 167.4, 140.8, 136.2, 134.4 (2C), 130.0 (2C),
129.9, 128.8, 105.7, 25.0. HRMS (TOF-ESI) m/z: [M + H]+ Calcd for
C11H10O3S + H, 223.0429; found, 223.0425.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge co-funding of this research by the
European Regional Development Fund of the EU and national
funds - Greek Ministry of Education and Religious Affairs,
Sport and Culture/GGET − EYDE-ETAK, through the
Operational Program Competitiveness and Entrepreneurship
(OPC II), NSRF 2007-2013, Action “SYNERGASIA 2011”
Project: THERA-CAN - No. 11ΣYN_1_485. We thank ProFI
(ITE, Iraklion, Greece) for obtaining the HRMS spectra.
5-Hydroxy-3-(1-hydroxydodecyl)-5-methylfuran-2(5H)-one (13a,
Mixture of Two Diastereomers in 55/45 Relative Ratio). Colorless oil
1
REFERENCES
(0.026 g, 70% yield). H NMR (500 MHz, CDCl3): 7.02 (d, J = 1.5
■
Hz, 1H of major diastereomer), 6.98 (d, J = 1.5 Hz, 1H of minor
diastereomer), 4.43 (m, 1H from each diastereomer), 1.78−1.62 (m,
2H from each diastereomer), 1.69 (s, 3H of minor diastereomer), 1.68
(s, 3H of major diastereomer), 1.35−1.20 (m, 18H from each
diastereomer), 0.87 (t, J = 7.0 Hz, 3H from each diastereomer). 13C
NMR (125 MHz, CDCl3): 170.9 and 170.5 (two diastereomers),
147.8 and 147.8 (two diastereomers), 137.7 and 137.0 (two
diastereomers), 105.4 and 105.1 (two diastereomers), 67.1 and 65.9
(two diastereomers), 35.2 and 34.9 (two diastereomers), 31.9 (two
overlapping diastereomers), 29.7, 29.6, 29.6, 29.6, 29.5, 29.3, 29.3, 29.3
(overlapping peaks from each and the two diastereomers), 25.4 and
25.2 (two diastereomers), 24.5 and 24.3 (two diastereomers), 22.7
(two overlapping diastereomers), 14.1 (two overlapping diaster-
eomers). HRMS (TOF-ESI) m/z: [M + H]+ Calcd for C17H30O4 +
H − H2O, 281.2117; found, 281.2109.
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