A New Powerful Approach to Multi-Substituted 3(2H)-Furanones via Br?nsted Acid-Catalyzed Reactions of 4-Diazodihydrofuran-3-ones

Article abstract of DOI:10.1055/s-0036-1588304

The interaction of 5,5-dialkyl(diaryl)-substituted 4-diazo-3(2H)furanones with Br?nsted acids (TFA, TsOH, etc.) causes elimination of nitrogen accompanied by 1,2-nucleophilic rearrangement, giving rise to exclusive formation of 4,5-dialkyl(diaryl)-substit

Full text of DOI:10.1055/s-0036-1588304

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
J. J. Medvedev et al.
Paper
Synthesis
A New Powerful Approach to Multi-Substituted 3(2H)-Furanones
via Brønsted Acid-Catalyzed Reactions of 4-Diazodihydrofuran-3-
ones
Jury J. Medvedev
Dmitrii V. Semenok
Xenia V. Azarova
Liudmila L. Rodina
Valerij A. Nikolaev*
R3
O
N2
R3
R4
R3
O
O
R1
R2
R1
R1
R2
acid
– N2
acid
– N2
R4
R4
O
O
R2
O
acids: TFA, TfOH, TsOH, etc.;
R1, R2, R3, R4 = alkyl, aryl
R1–R2, R3–R4 = cycloalkyl, cycloaryl
4,5-alkyl(aryl)
3(2H)-furanones
up to 99%
ring-fused spiro-
3(2H)-furanones
75–91%
3 examples
19 examples
Saint-Petersburg State University, Institute of Chemistry,
Universitetskii pr. 26, Petrodvorets, St. Petersburg 198504,
Russian Federation
vnikola@VN6646.spb.edu
Received: 03.07.2016
Accepted after revision: 02.08.2016
Published online: 14.09.2016
O
O
O
Ar
selective COX-2 inhibitors
C6H4-4-SO2Me
DOI: 10.1055/s-0036-1588304; Art ID: ss-2016-t0478-op
O
Abstract The interaction of 5,5-dialkyl(diaryl)-substituted 4-diazo-
3(2H)furanones with Brønsted acids (TFA, TsOH, etc.) causes elimina-
tion of nitrogen accompanied by 1,2-nucleophilic rearrangement, giv-
ing rise to exclusive formation of 4,5-dialkyl(diaryl)-substituted 3(2Н)-
furanones, ring-fused 3(2H)-furanones, and phenanthro[9,10-b]furan-
3(2H)-ones in yields of up to 99%. The reaction is a new highly efficient
way for the synthesis of multisubstituted 3(2Н)furanones.
O
H
H
H
O
O
O
R
O
OH
O
jatrophone
eremantholide
R = i-Pr, s-Bu, CMe=CH2
Key words diazo compounds, Brønsted acids, catalysis, rearrange-
ment, carbocation
Figure 1 Examples of naturally occurring and biologically active 3(2H)-
furanones
Highly functionalized 3(2H)-furanones exhibit a wide
range of biological activities1 and in recent years have at-
tracted much attention of different specialists. Thus, 4,5-di-
aryl-substituted 3(2Н)-furanones were found to be selec-
tive inhibitors of СОХ-2,1a,b and a series of furanones display
cytotoxic activity.1c–e It is also known that a wealth of
3(2H)-furanones possess antiallergic, antibacterial, and an-
tifungal activities.1c,f Many natural compounds contain
structural elements of 3(2Н)-furanones,1c,f as for instance
Jatrophone, isolated from Jatropha gossypiifolia L and Erm-
antholides, which are shown in Figure 1.1h
In spite of a considerable body of known approaches for
the structure of substituted 3(2Н)-furanones,1h,2 the syn-
thesis of their multi-substituted derivatives continue to be
a challenging task in synthetic organic chemistry.1a–c,2a,3,4
One of the recent examples in this field represents a power-
ful one-pot synthesis of multi-substituted 3(2Н)-furanones
from cyanopropargylic alcohols and carboxylic acids, which
furnishes a variety of 4-CN-substituted 3(2H)-furanones at-
tractive for subsequent functionalizations.4 Another in-
stance for the efficient preparation of furanones is a one-
pot synthesis of 4,5-diaryl-substituted 3(2H)-furanones
from 1,2-diarylethanones and 2-bromoisobutyryl cya-
nide.3b
It was shown previously that a great body of O-contain-
ing heterocycles, such as 3(2H)-furanones, dihydrofuran-
3(2H)-ones, phenanthro[9,10-b]furan-3(2H)-ones, oxetane-
carboxylic acids, and so on,5,6 are basically available using
thermal5 or photochemical6 reactions of diazoketones of
the tetrahydrofuran series. However 3(2Н)-furanones are
usually formed in these processes as a mixture with other
reaction products.5,6 In this connection, we tried to employ
for this purpose Brønsted acids catalyzed reactions of 4-di-
azodihydrofuran-3(2Н)-ones 1, instead of photochemically
or thermally activated processes. Herein we present the
principal results of this study.
During preliminary experiments it was established that
4-diazodihydrofuran-3(2Н)-ones 17 were completely stable
in the presence of acetic and formic acids and did not de-
compose even on heating their solutions in chloroform up
to 60–62 °С. At the same time, employment of more strong
Brønsted acids, such as trifluoroacetic acid (TFA), trifluoro-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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J. J. Medvedev et al.
Paper
Synthesis
methanesulfonic acid (TfOH), etc. produced a notable de-
composition of these diazoketones at room temperature.
Furthermore, unlike photochemical6 and thermal5 process-
es, reactions with acids occurred very selectively yielding
essentially only the corresponding 3(2Н)-furanones 2.
Initially, reactions of diazoketones 1a–j, bearing two
identical substituents at the carbon atom С5 of heterocycle,
with Brønsted acids were studied. It was shown that de-
composition of these diazoketones using trifluoroacetic
acid afforded the appropriate 3(2Н)-furanones 2a–j in
yields of 73–98% (Table 1).
FC6H4) significantly slowed down the process and it took up
to six hours for complete decomposition of diazo com-
pound 1h in the same reaction conditions.
One would expect that in the case of diazoketones 1k–
m, bearing spirocyclic substituents at the С5 atom of het-
erocycle, a similar reaction (1,2-alkyl shift) will lead to the
formation of ring-fused systems, which would be a useful
method for the synthesis of these structures (Scheme 1). It
was actually found that decomposition of diazoketones 1k,l
with spirocyclopentyl and -cyclohexyl substituents [(CH2)4
and (CH2)5, respectively] easily occurred even at room tem-
perature producing in high yields (75–91%) annulated
3(2Н)-furanones 3k,l. Related Brønsted acid catalyzed
transformation of diazoketone 1m with fluorenyl substitu-
ent gave phenanthro[9,10-b]furan-3(2H)-one 3m in a yield
of 85%. However, this reaction proceeded only at more dras-
tic conditions (+60 °С), than with spiro analogues 1k,l (r.t.),
and required application of TfOH as a catalyst for the pro-
cess.
Table 1 Scope of 3(2H)-Furanones Prepared from Diazo Ketones 1a–j
R3
O
O
N2
R3
R4
TFA
CHCl3, reflux
R1
R2
R1
R2
R4
O
O
– N2
1a–j
2a–j
Entry Diazoketone R1
R2
R3, R4
Time
Yield (%)
(min)
of 2
R3
R4
O
O
N2
R3
R4
H+
R1
R2
R1
R2
1a
2a
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
Me
Me
Me
Ph
60
60
82
87
82
98
83
73
98
93
98
97
– N2
O
O
Ph
Ph
1k–m
3k–m
3a
4-FC6H4
PMP
Ph
4-FC6H4
PMP
Me
360
50
4a
O
O
5b
6b
7b
8a
O
O
60
p-Tol
Me
Me
60
O
O
1g
1h
1i
Me
50
3k, 91%a
3l, 75%a
Me
Me
4-FC6H4
4-ClC6H4
PMP
360
300
30
3m, 85%b
9b
10b
Me
Me
Scheme 1 Scope of ring-fused 3(2H)-furanones. a Reagents and condi-
tions: diazoketone 1 (1 equiv), TFA (1–1.4 equiv), CH2Cl2, r.t., 1 h. b Re-
agents and conditions: diazoketone 1 (1 equiv), TfOH (1 equiv), CHCl3,
reflux, 2 h.
1j
Me
Me
a Two equivalents of TFA were used.
b Six equivalents of TFA were used.
The decomposition rate of diazoketones 1a,b,d–f with
two methyl groups at the С5 atom, regardless of the nature
of substituents at atom С2, looked much the same and
these reactions (using 2 equiv of TFA) were completed in
one hour producing 4,5-dimethyl-substituted 3(2Н)-fura-
nones 2a,b,d–f. The only exception in this case was found to
be diazoketone 1с with a 4-FC6H4 group on atom С2, de-
composition of which took around six hours.
Reactions of diazoketones 1g–j with both aryl groups on
atom С5 of the heterocycle occurred at more rigorous con-
ditions. It took approximately 6 equivalents of TFA to carry
out the reaction at a notable rate. More than that, the dura-
tion of these reactions, unlike the decomposition of di-
azoketones 1a–f, was strongly dependent on the electronic
effects of substituents on the aryl rings. Thus, incorporation
of electron-donating MeO group in the aryl ring (R3, R4 =
PMP) markedly accelerated decomposition of diazoketone
1j and its full conversion was observed already in half an
hour, while an electron-withdrawing group (R3, R4 = 4-
When employing diazoketones 1 with nonequivalent
substituents R3, R4 at atom С5 in similar reactions, one
would expect the appearance of two regioisomeric 3(2Н)-
furanones owing to a different migratory aptitude of non-
equivalent R3, R4 groups. To elucidate the most workable
conditions for these reactions, a series of different acid cat-
alysts and solvents of variable polarity were tested on the
example of diazoketone 1n having in the structure Ph and
4-MeSС6H4 groups at C5 atom of the heterocycle (Tables 2
and 3).
On catalytic decomposition of diazoketone 1n with two
nonequivalent substituents R3, R4, two regioisomeric 3(2Н)-
furanones 4n and 5n were obtained. It was established in
this case that yields of reaction products were to some ex-
tent controlled by the nature of employed acid. The best re-
sults were obtained with trifluoroacetic acid as the catalyst
(Table 2, entry 1; yield 99%, ratio 4n:5n = 1:3.2). Rather
moderate yields of regioisomers 4n, 5n (65–74%) were
gained by using stronger acids as, for example, TfOH or
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J. J. Medvedev et al.
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Synthesis
Table 3 Effect of Solvent Polarity on the Ratio of Regioisomers 4:5a
H2SO4 (entries 5, 6). This was most likely caused by side re-
actions of furan heterocycle cleavage in the initial 1n and/or
final reaction products 4n, 5n, induced by these acids.
O
O
O
Ph
R
N2
TFA
– N2
R
+
R
Ph
O
O
Ph
O
Table 2 Search for the Best Acid Catalysts for Decomposition of Di-
azoketone 1n (CHCl3, Reflux)
1n R = 4-MeSC6H4
4n,p
5n,p
1p R = 4-MeSO2C6H4
O
N2
Ph
O
Ar
O
Ph
acid
– N2
Entry
Solvent
Ratiob 4n/5n
Ratiob 4p/5p
+
Ph
Ar
O
O
Ar
O
1
2
3
4
5
benzene
CHCl3
1:3.8
1:3.2
1:3
6.1:1
5.9:1
4.5:1
2.7:1
2.4:1
1n: Ar = 4-MeSC6H4
4n
5n
hexane
TFA
Entry Acid
Time (min)
Yield (%) 4n + 5n Ratio 4n:5n
1:2.6
1:2.3
1
2
3
4
5
6
TFA (6 equiv)
80
80
99
98
99
98
74
65
1:3.2
1:2.7
1:1.3
1:3
acetone
TsOH (1 equiv)
a Reaction conditions: refluxing with 6 equiv of TFA for up to 24 h.
b Ratio determined by 1H NMR spectroscopy.
a
HClO4
360
360
360
< 10
HCl (gas)b
c
H2SO4
1:2.1
1:3
due to a very high dielectric permeability of HClO4
(ε = 115).
TfOH (1 equiv)
a Decomposition of diazoketone 1n in a mixture of 70% aq solution of
HClO4 with CH2Cl2 (1:1).
Hence it was established by these studies that the most
useful conditions for the preparation of 3(2Н)-furanones
from diazoketones 1 with two different substituents R3, R4
at the С5 atom of heterocycle were the use of TFA as a de-
composition catalyst and a reaction temperature of 60 °С in
chloroform solution. These conditions were used in the
subsequent reactions with diazoketones 1n–v, which re-
sulted in the formation of 3(2Н)-furanones 4n–v and 5n–v
in total yields of 84–99% for two regioisomers (Table 4).
b HCl (gas) was bubbled through a boiling CHCl3 solution of 1n during 3 h.
c Mixture of 1 equiv of 98% H2SO4 with 3 mL of CHCl3.
As to the regioselectivity of the process, it did not de-
pend on the nature of the acid in most of the cases and
ranged around a ratio of 1:3 (4n/5n; Table 2, entries 1, 2, 4,
6). Thus, as one would expect8 the predominant migration
of the aryl group with the electron-donating substituent (4-
MeSС6H4) was established. A notable decrease in regiose-
lectivity was observed only when using HClO4 and H2SO4
(entries 3,5; ratio 4n/5n = up to 1:2.1), which was probably
associated with a high polarity of the medium during de-
composition of diazoketone 1n.
To clarify the effect of the nature of the solvent on the
efficiency and regioselectivity of the process, decomposi-
tion of diazoketones 1n and 1p was studied in nonpolar or
weakly polar solvents (benzene, chloroform, hexane; Table
3, entries 1–3) and polar solvents (entry 5, acetone) as well
for in the pure trifluoroacetic acid (entry 4).
During these experiments it was ascertained that the
sole reaction products in all cases were 3(2Н)-furanones,
which were formed in 98–99% yields (1Н NMR analysis).
However, the ratio of regioisomers 4:5 was substantially
dependent on the solvent polarity.
The most regioselective reactions proceeded in nonpo-
lar or weakly polar solvents (Table 3, entries 1–3), whereas
carrying out the process in acetone or acid solutions nota-
bly diminished the regioselectivity of the process (entries 4,
5). A limiting case appears to be the reaction in a two phase
system with 70% HClO4/CH2Cl2 where essentially full loss of
selectivity occurred with the ratio of reaction products be-
ing 1:1.3 (Table 2, entry 3 for 1n). This effect is most likely
Table 4 Scope of 3(2H)-Furanones 4 and 5a
O
N2
R3
R4
O
R3
R4
O
R4
R3
acid
– N2
+
O
O
O
1n–v
4n–v
5n–v
Entry
1n–v; R3, R4
Yield (%) of 4 + 5 Ratio of 4/5
1
2
3
4
5
6
7
8
9
1n; Ph, 4-MeSC6H4
1o; Ph, 4-MeSOC6H4
1p; Ph, 4-MeSO2C6H4
1q; 4-MeSC6H4, 4-FC6H4
1r; 4-MeSC6H4, 4-ClC6H4
1s; 4-MeSC6H4, 3-ClC6H4
1t; Me, Ph
99
98
98
99
86
94
94
84
97
1:3.3
4.4:1
6.1:1
3.3:1
3.1:1
5.3:1
1:2
1u; Me, 4-MeC6H4
1:3.4
1.3:1
1v; Me, 4-CF3C6H4
a Reaction conditions: 6.5 equiv of TFA, СHCl3, reflux, 2–6 h.
The regioselectivity of the process in this case was again
found to be dependent on the nature of substituents on the
aryl rings.9 A preferable migration was observed for aryl
groups with electron-donating substituents (4-MeSC6H4,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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J. J. Medvedev et al.
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Synthesis
Ph), whereas an EWG (in 4-XC6H4, X = MeSO, MeSO2, CF3)
hindered migration and these groups mostly remained at
the atom С5 of the heterocycle (Table 4). Accordingly, the
greater the difference in migratory aptitudes of aryl groups
at C5 atom, the higher the regioselectivity of the process.
These results, together with the effect of solvent polari-
ty, open a good opportunity to manage the process and use
it for the preparation of different regioisomers. In nonpolar
solvents, predominantly one of the isomers can be ob-
tained, while carrying out the decomposition process in
HClO4 solution provides a way for the synthesis of another
(minor) regioisomer in a yield of around 50%.
As for the pathway for the formation of 3(2Н)-furanones
2 from diazoketones 1, the most plausible scheme for this
process, based on the known literature data,10 is given be-
low for the example of diazoketone А with two nonidenti-
cal substituents (Ph and Ar) at the carbon atom C5 (Scheme
2).
observed in our experiments. Thus, the 4-MeSC6H4 group
demonstrated considerably higher migratory aptitude than
Ph, 4-FC6H4, 4-ClC6H4, or 3-ClC6H4 group (Table 4, entries 1,
4–6), preferably giving rise to a regioisomer with electron-
donating group at the atom С4 of heterocycle (selectivity up
to 5.3:1). Aryl groups with electron-withdrawing substitu-
ents migrated much worse than phenyl group, resulting in
predominant formation of regioisomer with Ph group at the
atom С4 (entries 2, 3; selectivity up to 6:1). The migratory
aptitude of CH3 group in these reactions proved to be much
lower than for aryl counterparts, even relative to the aryl
rings with a strong EWG. In these cases, methyl group re-
mained predominantly on the spot at atom C5 of the het-
erocycle (entries 7, 8; selectivity up to 3.4:1).
Summing up, we have established that on interaction of
5,5-dialkyl(diaryl)-substituted 4-diazodihydrofuran-3(2H)-
ones with Brønsted acids (TFA, TsOH, TfOH, HClO4, etc.) the
elimination of a nitrogen molecule occurred, which is at-
tended by simultaneous 1,2-nucleophilic rearrangement to
produce the associated 4,5-dialkyl(diaryl)-substituted
3(2Н)-furanones in yields of up to 99%. The reaction is like-
wise a new powerful way for the synthesis of ring-fused
3(2H)-furanones and phenanthro[9,10-b]furan-3(2H)-ones
from the appropriate diazoketones of tetrahydrofuran se-
ries in yields of 75–91%.
R
N2
H
N2
Ar
O
O
H
O
N2
O
+ H+
– H+
Ar
Ph
O
Ph
O
Ph
A
A1
TS1
+ H+
N2
– H+
HO
– N2
Ar
H
O
Ar
O
All reactions were carried out under an argon atmosphere in solvents
dried and purified before use by common methods. Monitoring of the
reaction course was accomplished by TLC on precoated silica gel SIL
G/UV254 plates (Macherey-Nagel & Co.). Flash chromatography was
performed using Merck silica gel 60, 230–400 mesh (eluent: hex-
ane/CH2Cl2). IR spectra of the compounds were measured in CCl4
solution by means of compact size FTIR spectrometer TENSOR 37
(Bruker). 1Н, 13C, and 19F NMR spectra were recorded on a Bruker 400
Avance NMR spectrometer. Chemical shifts are reported in ppm, and
coupling constants are given in Hz. All signals in NMR spectra were
normalized relative to signals of CDCl3 (δ = 7.26 for 1H NMR and δ =
77.0 for 13C NMR spectra). Spectral parameters for all known com-
pounds corresponded to the literature data.
Ar
Ph
– H+
Ph
Ph
O
O
O
B1
C
D
Scheme 2 The assumed scheme for the formation of 3(2Н)-furanones
C
Initially, diazoketone А is reversibly protonated by
Brønsted acid at the diazocarbon atom С4 with the forma-
tion of diazonium intermediate А1.11 On the next reaction
steps, a concerted elimination10 of nitrogen molecule (N2)
and simultaneous migration of one of aryl groups from car-
bon atom С5 to С4 take place via transition state TS1 afford-
ing the protonated form of the final product B1. Stabiliza-
tion of this intermediate by way of proton elimination re-
sults in the formation of 3(2H)furanone С.
Melting points are uncorrected. All the ESI/HR mass spectra were re-
corded on a «MaXis» (Bruker Daltonik GmbH). All diazo compounds
1a–u were prepared using previously described protocols.7
3(2H)-Furanones; General Procedure
Another alternative for the first step of this process is
the О-protonation of the diazoketone carbonyl group pro-
ducing diazoniun ion D (Scheme 2). However, in this case
elimination of nitrogen apparently does not occur.11 It is
very likely that just this step is realized in the case of weak
acetic and formic acids, whereas for С-protonation of the
diazo group much stronger acid like TFA or TfOH is re-
quired.
To a solution of diazoketone 1a–v (0.6 mmol) in anhydrous solvent
(mostly CHCl3, 5 mL) was added dropwise up to 0.3 mL (3.8 mmol, 6.5
equiv) of TFA. After refluxing for 2–6 h (until completion of the reac-
tion according to TLC), the mixture was washed with aq NaHCO3, and
the aqueous fractions were extracted with CH2Cl2 (3 × 15 mL). The
combined organic fractions were dried over K2CO3. After removal of
the solvent, pure 3(2H)-furanones 2–5 were obtained as a single com-
pound (2a–j, 3a–c) or as a mixture of isomers (4n–v and 5n–v). Iso-
mers were separated by flash chromatography or preparative TLC.
Following the foregoing scheme, electron-donating
groups in aryl rings should stabilize transition state TS1 in-
creasing the migration aptitude of an aryl (Ar) as compared
to the phenyl (Ph) group (Scheme 2), which was actually
In some cases (see Table 2), instead of TFA for decomposition of 0.6
mmol of starting diazoketone 1n other Brønsted acids were used: 0.6
mmol TsOH; 5 mL of 70% HClO4; 0.3 mmol of HCl (gas); 0.6 mmol of
98% H2SO4; 0.6 mmol TfOH.
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J. J. Medvedev et al.
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2
2,2,4,5-Tetramethylfuran-3(2H)-one (2a)5
13C NMR (75 MHz, CDCl3): δ = 23.3, 87.2, 112.5, 115.8 (d, JC,F = 21.9
Hz), 125.9 (d, 3JC,F = 18.9 Hz), 130.7 (d, 3JC,F = 9.0 Hz), 131.2 (d, 3JC,F = 8.3
Hz), 162.3 (d, 1JC,F = 247.5 Hz), 164.7 (d, 1JC,F = 256.6 Hz), 177.0, 205.1.
Colorless liquid; yield: 69 mg (82%).
1H NMR (300 MHz, CDCl3): δ = 1.34 (s, 6 H), 1.67 (s, 3 H), 2.18 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 6.0, 15.8, 23.1, 88.7, 109.2, 188.5, 210.8.
4,5-Bis(4-chlorophenyl)-2,2-dimethylfuran-3(2H)-one (2i)
Colorless oil; yield: 196 mg (98%).
1H NMR (300 MHz, CDCl3): δ = 1.58 (s, 6 H), 7.26 (d, J = 8.4 Hz, 2 H),
7.33–7.44 (m, 4 H), 7.60 (d, J = 8.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 23.3, 87.4, 112.7, 128.1, 128.9, 129.0,
129.7, 130.7, 133.6, 138.2, 177.0, 204.9.
4,5-Dimethyl-2,2-diphenylfuran-3(2H)-one (2b)5
Colorless solid; yield: 138 mg (87%); mp 110–111 °C.
1H NMR (300 MHz, CDCl3): δ = 1.71 (s, 3 H), 2.31 (s, 3 H), 7.21–7.59
(m, 10 H).
13C NMR (75 MHz, CDCl3): δ = 6.3, 15.5, 91.3, 110.2, 126.9, 128.6,
128.8, 139.1, 183.9, 203.1.
HRMS (ESI): m/z [M + Na]+ calcd for C18H14Cl2O2Na: 355.0269; found:
355.0265.
2,2-Bis(4-fluorophenyl)-4,5-dimethylfuran-3(2H)-one (2c)5
4,5-Bis(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2j)5
Colorless solid; yield: 148 mg (82%); mp 70–71 °C.
1H NMR (400 MHz, CDCl3): δ = 1.72 (s, 3 H), 2.32 (s, 3 H),6.98–7.44 (m,
8 H).
13C NMR (100 MHz, CDCl3): δ = 5.9, 15.1, 89.8, 109.8, 115.4 (d, JC,F
21.0 Hz), 128.4 (d, 3JC,F = 8 Hz), 134.4 (d, 4JC,F = 3.0 Hz), 162.6 (d, 1JC,F
246.0 Hz), 183.8, 202.5.
Colorless solid; yield: 189 mg (97%); mp 127–128 °C.
1H NMR (300 MHz,CDCl3): δ = 1.55 (s, 6 H), 3.84 (s, 6 H), 6.85 (d, J = 9.0
Hz, 2 H), 6.92 (d, J = 9.0 Hz, 2 H), 7.25 (d, J = 9.0 Hz, 2 H), 7.64 (d, J = 9.0
Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 55.2, 55.4, 86.5, 112.0, 113.7, 114.1,
122.4, 122.6, 130.1, 130.8, 158.9, 162.3, 177.4, 205.4.
2
=
=
2,2-Bis(4-methoxyphenyl)-4,5-dimethylfuran-3(2H)-one (2d)5
4,5,6,7-Tetrahydro-3H-spiro[benzofuran-2,1′-cyclopentan]-3-one
(3k)
Colorless oil; yield: 191 mg (98%).
1H NMR (300 MHz, CDCl3): δ = 1.72 (s, 3 H), 2.31 (s, 3 H), 3.78 (s, 6 H),
6.85 (d, J = 9.0 Hz, 4 H), 7.34 (d, J = 9.0 Hz, 4 H).
13C NMR (75 MHz, CDCl3): δ = 5.9, 15.1, 55.3, 91.1, 109.7, 113.7, 128.0,
130.9, 159.5, 184.0, 203.7.
Colorless oil; yield: 105 mg (91%).
1H NMR (300 MHz, CDCl3): δ = 1.55-2.06 (m, 12 H), 2.19 (t, J = 6.0 Hz,
2 H), 2.41 (t, J = 6.2 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 18.3, 21.8, 25.5, 26.1, 36.9, 98.2, 111.9,
187.5, 205.1.
2,4,5-Trimethyl-2-phenylfuran-3(2H)-one (2e)
HRMS (ESI): m/z [M + Na]+ calcd for C12H16O2Na: 215.1048; found:
215.1045.
Colorless oil; yield: 101 mg (83%).
1H NMR (300 MHz, CDCl3): δ = 1.68 (s, 3 H), 1.72 (s, 3 H), 2.30 (s, 3 H),
7.19–7.40 (m, 3 H), 7.49 (d, J = 7.0 Hz, 2 H).
5,6,7,8-Tetrahydrospiro[cyclohepta[b]furan-2,1′-cyclohexan]-
3(4H)-one (3l)
13C NMR (75 MHz, CDCl3): δ = 5.8, 15.0, 24.5, 88.6, 108.7, 124.6, 128.0,
128.4, 138.3, 184.3, 205.6.
HRMS (ESI): m/z [M + Na]+ calcd for C13H14O2Na: 225.0891; found:
225.0889.
Colorless solid; yield: 99 mg (75%); mp 83–85 °С.
1H NMR (400 MHz, CDCl3): δ = 1.25–1.40 (m, 1 H), 1.42–1.85 (m, 15
H), 2.09–2.33 (m, 2 H), 2.55–2.65 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 20.4, 21.8, 24.4, 25.0, 27.5, 30.1, 31.7,
32.2, 89.1, 114.6, 190.0, 206.8.
2,4,5-Trimethyl-2-(p-tolyl)furan-3(2H)-one (2f)
Colorless oil; yield: 95 mg (73%).
1H NMR (300 MHz, CDCl3): δ = 1.67 (s, 3 H), 1.69 (s, 3 H), 2.28 (s, 3 H),
2.32 (s, 3 H), 7.15 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.1 Hz, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C14H20O2Na: 243.1361; found:
243.1366.
13C NMR (75 MHz, CDCl3): δ = 5.8, 15.0, 21.0, 24.5, 88.4, 108.6, 124.5,
2,2-Dimethylphenanthro[9,10-b]furan-3(2H)-one (3m)
129.1, 135.6, 137.7, 183.4, 205.3.
HRMS (ESI): m/z [M + Na]+ calcd for C14H16O2Na: 17.1238; found:
217.1229.
Bright-yellow oil; yield: 134 mg (85%).
1H NMR (400 MHz, CDCl3): δ = 1.63 (s, 6 H), 7.54–7.63 (m, 1 H), 7.69
(td, J = 7.8, 0.9 Hz, 2 H), 7.85–7.90 (m, 1 H), 8.36 (dd, J = 8.0, 0.9 Hz, 1
H), 8.57 (d, J = 8.2 Hz, 1 H), 8.67 (d, J = 8.4 Hz, 1 H), 8.86 (dd, J = 8.0, 1
Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 23.3 , 89.6, 108.2, 122.0, 122.8, 123.4,
123.5, 123.8, 125.6, 126.7, 127.1, 127.6, 128.7, 131.5, 135.8, 172.8,
203.5.
2,2-Dimethyl-4,5-diphenylfuran-3(2H)-one (2g)5
Colorless solid; yield: 155 mg (98%); mp 81–82 °C.
1H NMR (300 MHz, CDCl3): δ = 1.58 (s, 6 H), 7.28–7.68 (m, 10 H).
13С NMR (75 MHz, CDCl3): δ = 23.8, 87.4, 114.0, 127.9, 128.8, 129.0,
129.9, 130.4, 132.2, 178.4, 205.8.
HRMS (ESI): m/z [M + Na]+ calcd for C18H14O2Na: 285.0891; found:
285.0882.
4,5-Bis(4-fluorophenyl)-2,2-dimethylfuran-3(2H)-one (2h)5
2,2-Dimethyl-5-[4-(methylthio)phenyl]-4-phenylfuran-3(2H)-one
Colorless solid; yield: 167 mg (93%); mp 109–110 °C.
1H NMR (300 MHz, CDCl3): δ = 1.55 (s, 6 H), 7.03–7.30 (m, 6 H), 7.63–
7.68 (dd, J = 9.0, JH,F = 6.0 Hz, 2 H).
(4n)12
Colorless oil; yield: 44 mg (24%).
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J. J. Medvedev et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 1.55 (s, 6 H), 2.48 (s, 3 Н), 7.15–7.17
(m, 1 H), 7.25 (d, J = 7.6 Hz, 2 H), 7.30–7.40 (m, 4 H), 7.56 (d, J = 7.4 Hz,
2 H).
13C NMR (101 MHz, CDCl3): δ = 23.3, 43.5, 87.9, 111.7, 127.6, 128.4,
128.7, 129.2, 130.1, 132.4, 136.2, 139.0, 179.8, 204.4.
HRMS (ESI): m/z [M + Na]+ calcd for C19H18O4SNa: 365.0823; found:
365.0823.
13C NMR (101 MHz, CDCl3): δ = 15.7, 23.4, 86.9, 113.1, 125.0, 128.6,
128.6, 129.6, 131.8, 144.3, 177.6, 205.2.
HRMS (ESI): m/z [M + H]+ calcd for C19H18O2SH: 311.1106; found:
311.1113.
2,2-Dimethyl-4-(4′-fluorophenyl)-5-[4′-(methylthio)phenyl]fu-
ran-3(2H)-one (5q)
Bright yellow oil; yield: 150 mg (76%).
1H NMR (400 MHz, CDCl3): δ = 1.54 (s, 6 H), 2.48 (s, 3 H), 7.00–7.15
(m, 2 H), 7.20–7.25 (m, 2 H), 7.40 (d, J = 8.1 Hz, 1 H), 7.54 (d, J = 8.5 Hz,
2 H), 7.84 (d, J = 8.3 Hz, 1 H).
2,2-Dimethyl-4-[4-(methylthio)phenyl]-5-phenylfuran-3(2H)-one
(5n)
Bright yellow crystals; yield: 140 mg (75%); mp 120–121 °C.
1H NMR (400 MHz, CDCl3): δ = 1.55 (s, 6 H), 2.49 (s, 3 Н), 7.24–7.25
(m, 4 H), 7.36 (d, J = 7.6 Hz, 2 H), 7.45–7.49 (m, 1 H), 7.66 (d, J = 7.4 Hz,
2 H).
13C NMR (101 MHz, CDCl3): δ = 14.7, 21.7, 86.9, 112.0, 115.6 (d, J =
21.4 Hz), 126.09, 126.12, 127.5, 130.2, 131.2 (d, J = 8.0 Hz), 146.1,
164.6 (d, J = 254.0 Hz), 177.6, 205.0.
13C NMR (101 MHz, CDCl3): δ = 15.7, 23.4, 87.0, 113.0, 126.6, 128.4,
19F NMR (376 MHz, CDCl3): δ = –114.2.
128.4, 129.8, 131.8, 137.8, 178.1, 205.4.
HRMS (ESI): m/z [M + H]+ calcd for C19H18O2SH: 311.1106; found:
HRMS (ESI): m/z [M + Na]+ calcd for C19H17FO2SNa: 351.0831; found:
351.0836.
311.1107.
2,2-Dimethyl-4-[4′-(methylthio)phenyl]-5-(4′-fluorophenyl)fu-
ran-3(2H)-one (4q)
2,2-Dimethyl-5-[4-(methylsulfinyl)phenyl]-4-phenylfuran-3(2H)-
one (4o)
Bright yellow oil; yield: 45 mg (23%).
Colorless crystals; yield: 157 mg (80%); mp 178–179 °С.
1H NMR (400 MHz, CDCl3): δ = 1.57 (s, 6 H), 2.74 (s, 3 H), 7.28–7.39
(m, 5 H), 7.64 (d, J = 8.3 Hz, 2 H), 7.78 (d, J = 8.2 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = 23.4, 43.8, 87.3, 114.7, 123.6, 127.9,
128.8, 129.2, 129.4, 132.6, 149.5, 176.2, 205.3.
1H NMR (400 MHz, CDCl3): δ = 1.54 (s, 6 H), 2.49 (s, 3 H), 7.00–7.19
(m, 2 H), 7.20–7.25 (m, 4 H), 7.68 (dd, J = 8.9, 5.4 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = 15.6, 23.4, 87.1, 112.8, 115.7 (d, J =
21.9 Hz), 126.4, 126.6, 128.5, 129.8, 130.7 (d, J = 8.9 Hz), 138.0, 164.7
(d, J = 254.0 Hz), 176.8, 205.2.
HRMS (ESI): m/z [M + Na]+ calcd for C19H18O3SNa: 349.0874; found:
19F NMR (376 MHz, CDCl3): δ = –106.3.
349.0874.
HRMS (ESI): m/z [M + H]+ calcd for C19H17FO2SH: 329.1012; found:
329.1007.
2,2-Dimethyl-4-[4-(methylsulfinyl)phenyl]-5-phenylfuran-3(2H)-
one (5o)
2,2-Dimethyl-4-(4′-chlorophenyl)-5-[4′-(methylthio)phenyl]fu-
ran-3(2H)-one (5r)
Colorless oil; yield: 35 mg (18%).
1H NMR (400 MHz, CDCl3): δ = 1.58 (s, 6 H), 2.74 (s, 3 H), 7.27–7.42
Bright yellow oil; yield: 43 mg (21%).
(m, 2 H), 7.49–7.51 (m, 3 H), 7.55–7.68 (m, 4 H).
13C NMR (101 MHz, CDCl3): δ = 23.3, 23.4, 43.9, 87.6, 112.4, 123.9,
127.8, 128.5, 128.7, 129.6, 130.4, 132.3, 144.6, 179.2, 204.9.
1H NMR (400 MHz, CDCl3): δ = 1.54 (s, 6 H), 2.49 (s, 3 H), 7.18 (d, J =
8.6 Hz, 2 H), 7.33 (d, J = 8.6 Hz, 2 H), 7.26 (d, J = 8.1 Hz, 2 H), 7.33 (d,
J = 8.6 Hz, 2 H), 7.54 (d, J = 8.6 Hz, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C19H18O3SNa: 349.0874; found:
13C NMR (101 MHz, CDCl3): δ = 14.8, 23.3, 87.1, 111.8, 125.1, 125.7,
349.0876.
126.2, 128.4, 128.6, 128.7, 133.3, 144.7, 177.9, 204.8.
HRMS (ESI): m/z [M + Na]+ calcd for C19H17ClO2SNa: 367.0535; found:
367.0536.
2,2-Dimethyl-5-[4-(methylsulfonyl)phenyl]-4-phenylfuran-3(2H)-
one (4p)
Colorless crystals; yield: 172 mg (84%); mp 201–202 °С.
1H NMR (400 MHz, CDCl3): δ = 1.58 (s, 6 H), 3.06 (s, 3 H), 7.26–7.40
(m, 5 H), 7.73 (d, J = 8.5 Hz, 2 H), 8.03 (d, J = 8.4 Hz, 2 H).
2,2-Dimethyl-4-[4′-(methylthio)phenyl]-5-(4′-chlorophenyl)fu-
ran-3(2H)-one (4r)
Bright yellow oil; yield: 135 mg (65%).
13C NMR (101 MHz, CDCl3): δ = 23.3, 43.3, 87.5, 115.6, 127.4, 128.2,
128.9, 129.2, 129.4, 135.1, 142.8, 175.2, 205.2.
1H NMR (400 MHz, CDCl3): δ = 1.54 (s, 6 H), 2.49 (s, 3 H), 7.20–7.24
(m, 4 H), 7.33 (d, J = 8.6 Hz, 2 H), 7.60 (d, J = 8.6 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C19H18O4SH: 343.1004; found:
13C NMR (101 MHz, CDCl3): δ = 15.6, 23.3, 87.1, 113.3, 126.6, 128.8,
343.0996.
128.9, 129.7, 129.8, 130.8, 138.0, 138.2, 176.6, 205.2.
HRMS (ESI): m/z [M + H]+ calcd for C19H17ClO2SH: 345.0716; found:
345.0720.
2,2-Dimethyl-4-[4-(methylsulfonyl)phenyl]-5-phenylfuran-3(2H)-
one (5p)
Colorless crystals; yield: 29 mg (14%); mp 181–182 °С.
2,2-Dimethyl-4-(3′-chlorophenyl)-5-[4′-(methylthio)phenyl]fu-
ran-3(2H)-one (5s)
1H NMR (400 MHz, CDCl3): δ = 1.58 (s, 6 H), 3.05 (s, 3 H), 7.39 (t, J = 7.7
Hz, 2 H), 7.50–7.55 (m, 3 H), 7.60 (d, J = 8.5 Hz, 2 H), 7.90 (d, J = 8.4 Hz,
2 H).
Bright yellow oil; yield: 31 mg (15%).
1H NMR (400 MHz, CDCl3): δ = 1.55 (s, 6 H), 2.47 (s, 3 H), 7.17–7.28
(m, 4 H), 7.55 (d, J = 8.6 Hz, 2 H), 7.84 (d, J = 8.3 Hz, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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J. J. Medvedev et al.
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Synthesis
13C NMR (101 MHz, CDCl3): δ = 14.7, 23.3, 87.2, 111.8, 125.0, 125.5,
2,2,4-Trimethyl-5-[4-(trifluoromethyl)phenyl]furan-3(2H)-one
125.9, 127.6, 127.7, 128.6, 129.5, 129.9, 132.1, 134.4, 178.0, 204.6.
(4v)
HRMS (ESI): m/z [M + Na]+ calcd for C19H17ClO2SNa: 367.0535; found:
Colorless oil; yield: 89 mg (55%).
1H NMR (400 MHz, CDCl3): δ = 1.46 (s, 6 H), 2.01 (s, 3 H), 7.76 (d, J =
8.3 Hz, 2 H), 7.94 (d, J = 8.2 Hz, 2 H).
367.0536.
2,2-Dimethyl-4-[4′-(methylthio)phenyl]-5-(3′-chlorophenyl)fu-
ran-3(2H)-one (4s)
13C NMR (101 MHz, CDCl3): δ = 7.4, 23.2, 86.3, 109.5, 125.6 (q, J = 3.8
Hz), 128.2, 134.0, 175.7, 208.1.
Bright yellow oil; yield: 164 mg (79%).
HRMS (ESI): m/z [M + H]+ calcd for C14H13F3O2H: 271.0946; found:
271.0948.
1H NMR (400 MHz, CDCl3): δ = 1.55 (s, 6 H), 2.49 (s, 3 H), 7.21–7.26
(m, 4 H), 7.36 (s, 1 H), 7.43 (d, J = 9.1 Hz, 1 H), 7.48 (d, J = 7.8 Hz, 1 H),
7.72 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 15.6 , 23.3, 87.2, 113.7, 126.6, 126.7,
128.0, 128.3, 129.7, 129.8, 131.7, 131.8, 134.7, 138.2, 176.1, 205.3.
Acknowledgment
The authors express their gratitude to the SPbSU resource centers:
‘Center for Magnetic Resonance’, ‘Chemical Analysis and Materials Re-
search Centre’ and ‘Resource Education Center’. The authors grateful-
ly acknowledge generous financial support from ‘Russian Foundation
for Basic Research’ (RFBR, mol_a No. 16-33-00059) and ‘Foundation
for Assistance to Small Innovative Enterprises in Science and Technol-
ogy’ (contract No. 10093GU2/2015). D. Semenok acknowledges
F.A.S.I.E. foundation (contract No. 1074GC1/21867) for the financial
support.
HRMS (ESI): m/z [M + Na]+ calcd for C19H17ClO2SNa: 345.0716, found:
345.0718.
2,2,4-Trimethyl-5-phenylfuran-3(2H)-one (4t)13
Colorless oil; yield: 38 mg (31%).
1H NMR (300 MHz, CDCl3): δ = 1.43 (s, 6 H), 1.97 (s, 3 H), 7.35–7.50
(m, 3 Н), 7.68–7.88 (m, 2 Н).
2,2,5-Trimethyl-4-phenylfuran-3(2H)-one (5t)
Colorless oil; yield: 76 mg (63%).
1H NMR (300 MHz, CDCl3): δ = 1.48 (s, 6 H), 2.40 (s, 3 H), 7.21–7.3 (m,
Supporting Information
Supporting information for this article is available online at
1 H), 7.38–7.45 (m, 4 H).
http://dx.doi.org/10.1055/s-0036-1588304.
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13C NMR (101 MHz, CDCl3): δ = 16.3, 23.1, 87.2, 114.1, 127.0, 128.4,
128.5, 129.8, 183.3, 204.7.
HRMS (ESI): m/z [M + Na]+ calcd for C13H14O2Na: 225.0891; found:
225.0885.
References
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7.21 (d, J = 8.0 Hz, 2 H), 7.28 (d, J = 8.2 Hz, 2 H).
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(5v)
Colorless oil; yield: 68 mg (42%).
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8.1 Hz, 2 H), 7.65 (d, J = 8.2 Hz, 2 H).
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271.0951.
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