Copper(II) bromide-catalyzed conjugate addition of furans to α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1007/s10593-018-2206-1

[Figure not available: see fulltext.] A simple method for the synthesis of 2-(3-oxoalkyl)furan derivatives based on conjugate addition of 2-substituted furans to various α,β-unsaturated carbonyl compounds in the presence of copper(II) bromide as catalyst was developed.

Full text of DOI:10.1007/s10593-018-2206-1

DOI 10.1007/s10593-018-2206-1
Chemistry of Heterocyclic Compounds 2017, 53(12), 1286–1293
Copper(II) bromide-catalyzed conjugate
addition of furans to α,β-unsaturated
carbonyl compounds
Alexander A. Fadeev1, Maxim G. Uchuskin1,2,
Igor V. Trushkov2,3, Anton S. Makarov1*
1 Perm State National Research University,
15 Bukirev St., Perm 614990, Russia; e-mail; antony.s.makarov@psu.ru
2 RUDN University, 6 Miklukho-Maklaya St., Moscow 117198, Russia; e-mail: mu@psu.ru
3 Dmitry Rogachev National Research Center of Pediatric Hematology,
Oncology and Immunology,
1 Samory Mashela St., Moscow 117997, Russia; e-mail: itrushkov@mail.ru
Submitted September 28, 2017
Accepted November 14, 2017
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2017, 53(12), 1286–1293
A simple method for the synthesis of 2-(3-oxoalkyl)furan derivatives based on conjugate addition of 2-substituted furans to various
α,β-unsaturated carbonyl compounds in the presence of copper(II) bromide as catalyst was developed.
Keywords: copper(II) bromide, furan, α,β-unsaturated carbonyl compounds, conjugate addition.
Significantly increasing interest toward furan derivatives
has been noted over the recent decades. Apparently, it is
stimulated by the existence of large number of natural
compounds1 and biologically active molecules containing a
furan ring,2 as well as motivated by the applications of
furan derivatives for the synthesis of advanced materials.3
The importance of this heterocycle is also raised by the
availability of simple furans by the biomass processing.4
Besides that, the diverse reactivity of furans, readily
participating in dearomatization reactions with ring
preservation or cleavage allows to use substituted furans in
the synthesis of other types of organic compounds.5 On the
other hand, the pronounced lability of furan ring
significantly limits the scope of methods available for its
functionalization, to some degree creating obstacles to
active development of furan chemistry.
From this point of view, the most promising synthetic
methods are based on catalytic C–H bond functionalization.7
As a result, new approaches as well as modifications of
classical methods that rely on electrophilic8 and radical
substitution9 or reactions proceeding via the formation of
transition metal complexes10 are being developed.
The conjugate addition (Michael addition) is of
particular importance among the methods for furan ring
functionalization, that provides a versatile tool for effective
and environmentally benign formation of chemical bonds.11
The practical value of conjugate addition is based on the
availability and broad structural diversity of electrophilic
components that are able to react with furans. At the same
time, conjugate addition reactions do not require preli-
minary introduction of additional functional groups into the
structure of Michael acceptors. Finally, this reaction is not
accompanied by the formation of any by-products.
The latest developments of methods for the synthesis of
substituted furans have been guided by the principles of
green chemistry,6 focusing on atom economy and reducing
the number of synthetic steps, in particular. Such emphasis
allowed to minimize the formation of waste and thus to
improve the environmental aspects of the chemical process.
A range of catalytic systems are currently known that
can be used with various degrees of effectiveness for the
preparation of conjugate addition products from furans and
α,β-unsaturated ketones. The earliest examples of the
discussed reaction relied on the use of mineral acids and
0009-3122/17/53(12)-1286©2017 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2017, 53(12), 1286–1293
Table 1. Optimization of reaction conditions for the addition of
some hard Lewis acids as catalysts,12 but such options are
2-methylfuran (1а) to chalcone 2а*
not currently favored due to the lability of furan ring in the
presence of acids. On the other hand, catalysis by transition
metal compounds has broader applicability in terms of
searching for the optimal reaction conditions.13 Various
transition metal compounds are known to be effective cata-
lysts for the conjugate addition of furans to α,β-unsaturated
ketones.14 However, the currently developed catalytic
methods for performing this reaction are characterized by
one substantial drawback – their effectiveness has been de-
monstrated only for a small number of substrates, which is in-
sufficient for evaluating their range of practical applicabi-
lity. Besides that, the need for costly catalysts requiring
special storage conditions limits the economic significance
of such methods. We have recently observed that copper(II)
bromide is an effective catalyst for conjugate addition of
furans to various chalcones.15 Herein, we describe a simple
method for the preparation of 2-(3-oxoalkyl)furan
derivatives by conjugate addition reactions of 2-substituted
furans to α,β-unsaturated carbonyl compounds in the
presence of CuBr2, a stable and inexpensive catalyst.
We studied readily available copper compounds as
catalysts for Michael addition of furans to α,β-unsaturated
carbonyl compounds.16 The reaction conditions were
optimized on a model reaction of 2-methylfuran (1a) with
the unsubstituted chalcone 2a. The examined copper(I) com-
pounds (Table 1, entries 1–4) showed virtually no catalytic
activity. Using a series of copper(II) compounds, such as
CuO, Cu(SO4)2·5H2O, Cu(NO3)2·6H2O, Cu(OAc)2·H2O,
and Cu(OTf)2 (entries 5–9), the target product 3а was
formed in trace amounts. In a continuation of our search for
an effective catalyst for the studied transformation among
copper(II) salts, we found that CuCl2 was moderately
active as a catalyst: the yield of product 3а in this case
reached 48% (entry 10). The highest yield of the target
product 3а (79%) was achieved when the reaction was
performed in the presence of 2.5 mol % CuBr2 (entry 11).
By varying the ratio of starting materials we found that the
yield of product 3а can be increased to 91% when the ratio
of reagents 1а and 2а was equal to 1.5:1 (entry 12). It is
important to note that increasing the catalyst load did not
improve the yield of product 3а (entry 13), while smaller
amounts of the catalyst gave lower yields of product 3а
(entry 14). The use of alternative solvents such as ethyl
acetate, 1,4-dioxane, DMF, ethanol, or toluene in this
reaction did not improve the yield.
Amount of
Yield of
Entry
Catalyst
catalyst,
mol %
product 3а**, %
1
2
Cu2O
CuCl
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
No conversion
No conversion
No conversion
No conversion
No conversion
Trace
3
CuBr
4
CuI
5
CuO
6
CuSO4·5H2O
Cu(NO3)2·6H2O
Cu(OAc)2·H2O
Cu(OTf)2
CuCl2
7
Trace
8
Trace
9
Trace
10
11
12
48
CuBr2
79
91 (1а:2а = 1.5:1)
84 (1а:2а = 1.5:1)***
86 (1а:2а = 1.5:1)*4
CuBr2
13
14
15
CuBr2
CuBr2
5
1
91 (1а:2а = 1.5:1)
76 (1а:2а = 1.5:1)
79
CuBr2
(reaction time 3 h)
2.5
16
17
CuBr2
(reaction time 6 h)
2.5
2.5
91
37
46% HBr/H2O
(reaction time 40 h)
18
19
BF3·Et2O/Et2O
2.5
2.5
10
11
concd H2SO4
* The ratio of furan 1а and ketone 2а was 1:1.
** The yield was determined by GC/MS method using n-pentadecane as
internal standard.
*** The yield of compound 3а after column chromatography when using
0.5 mmol of chalcone 2а.
*4 The yield of compound 3а after column chromatography when using
5 mmol of chalcone 2а.
In order to verify the catalytic importance of copper ions
in CuBr2, instead of it acting only as a source of acid, we
investigated whether the studied reaction can be catalyzed
by the addition of HBr in the amount of 2.5 mol %, which
would correspond to the amount of CuBr2 used. Product 3а
in that case was formed only in 37% yield (Table 1, entry 17).
It should be noted that the catalysts previously used for con-
jugate addition of furans to α,β-unsaturated carbonyl com-
pounds, such as boron trifluoride etherate12b and sulfuric
acid,12c were found to be ineffective in the studied reaction
(entries 18, 19).
chalcone 2a were achieved by stirring the reaction mixture
in dichloromethane at room temperature for 4 h in the
presence of 2.5 mol % CuBr2 at 1.5:1 ratio of the starting
materials 1а and 2а. Such reaction conditions allowed to
perform the process on a preparative scale: the use of
0.5 mmol of the starting chalcone 2a resulted in 84%
isolated yield of product 3a, while performing the reaction
on 5 mmol-scale gave an 86% yield (Table 1, entry 12).
Next, we studied the scope of the reaction and the
influence of different substituents in the structure of
starting materials on the reaction outcome (Table 2). It was
found that chalcones containing both electron-donating and
electron-withdrawing substituents in the styrene moiety
Thus, the optimum reaction conditions for conjugate
addition of 2-methylfuran (1a) to the unsubstituted
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Chemistry of Heterocyclic Compounds 2017, 53(12), 1286–1293
Table 2. The range of applicability for the conjugate addition of
reacted with 2-methylfuran (1а), forming the
furans 1 to unsaturated ketones 2*
corresponding products 3a–f in 73–86% yields. The
reaction of 2-methylfuran (1а) with chalcone 2с containing
a para-methoxy group required more forcing conditions,
namely, heating in DCE at 40°C in the presence of 5 mol %
CuBr2. The product yields from conjugate addition of
2-methylfuran (1а) to chalcones containing electron-
donating and electron-withdrawing substituents at the para
position of benzoyl ring (compounds 2g–j) were also
comparable to the yield of product 3а (70–81%). Thus, we
did not observe a significant effect due to the substituents
in the structure of monosubstituted chalcones on the target
product yields.
Yield**,
%
Furan
R1
Ketone
R2
R3
Product
Me
Me
Ph
Ph
Ph
4-MeC6H4
4-MeOC6H4
4-BrC6H4
4-F3CC6H4
2-FC6H4
Ph
84
73
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
Me
Ph
75***
85
The reaction of 2-methylfuran (1а) with chalcone 2k
containing a nitro group at the para position of benzoyl
ring and a methoxy group at the para position of styrene
moiety led to the formation of adduct 3k in 81% yield. On
the other hand, product 3l containing a nitro group at the
para position of styrene moiety and a methoxy group at the
para position of benzoyl ring was formed in 53% yield. In
the latter case, a partial resinification of the reaction
mixture was observed, while the conversion of the starting
chalcone 2l was incomplete even after 6 h. Increasing the
reaction duration, the amount of starting furan, or the
catalyst load only caused a higher degree of resinification
instead of increasing the yield of target product 3l.
The major product from the reaction of 2-methylfuran
(1а) with dibenzylideneacetone 2m was monoadduct 3m
having been isolated in 55% yield. Besides the main
reaction product, we observed the formation of a mixture of
compounds, apparently containing the bis-adduct of
conjugate addition as a mixture of diastereomers, even
though we could not isolate this compound as an individual
sample.
The reaction of 2-ethylfuran (1b) with chalcone 2а led
to the formation of product 3n in 88% yield. However,
when the substituent at the С-2 atom of the starting furan
was replaced with a tert-butyl group (compound 1c) or a
4-chlorophenyl group (compound 1d), the respective
products were formed in low yields. Increasing the catalyst
load up to 10 mol % did not improve the yield of products
3o,p significantly, despite the complete conversion of the
starting furans. Products 3o,p were obtained as mixtures
with the starting chalcone 2а that were difficult to separate.
No product from the reaction of chalcone 2а with
unsubstituted furan was observed; stirring the reaction
mixture for 20 h only gave insignificant conversion of the
starting chalcone.
When performing the reaction of 2-methylfuran (1а)
with benzylideneacetone (2n), the target product 3q was
obtained in 63% yield (Table 3). A comparable yield of the
Michael adduct 3s was also observed in the case of methyl
vinyl ketone (2p). The moderate yields of the target
products 3q,s in these cases were explained by the
occurrence of side reactions, but we were unable to isolate
and characterize any by-products. It is important to note
that the reaction of 2-methylfuran (1а) with 4-(4-chloro-
phenyl)but-3-en-2-one (2o), in contrast to the reaction with
benzylideneacetone (2n), provided a high yield of the
Me
Ph
Me
Ph
86
Me
Ph
77
Me
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
70
2g
2h
2i
3g
3h
3i
Me
Ph
71
Me
Ph
79
Me
Ph
81
2j
3j
Me
4-O2NC6H4 4-MeOC6H4
4-MeOC6H4 4-O2NC6H4
81***
53*4
55
2k
2l
3k
3l
Me
Me
PhCH=CH
Ph
Ph
Ph
Ph
2m
2a
2a
2a
3m
3n
3o
3p
Et
Ph
Ph
Ph
88
t-Bu
4-ClC6H4
10*5
40*5
* Scale of reaction – 0.5 mmol, ratio of reagents 1:2 = 1.5:1.
** Yield after column chromatography step.
*** In DCE at 40°С in the presence of 5 mol % CuBr2, reaction time 5 h.
*4 Reaction time 6 h.
*5 The catalyst was 10 % CuBr2. The yield was determined by Н NMR
1
spectroscopy using CH2Br2 as internal standard.
Table 3. The yields of conjugate addition products 3q–u*
R1
O
CuBr2 (2.5 mol %)
CH2Cl2, rt, 4 h
O
R2
Me
O
+
R1
1a,c,d
O
R2
Me
2n–p
3q–u
Furan
R1
Ketone
R2
Product
Yield**, %
Me
Me
Me
Ph
63***
88
1a
1a
1a
1c
1d
2n
2o
2p
2p
2p
3q
3r
3s
3t
4-ClC6H4
H
H
H
65***
81
t-Bu
4-ClC6H4
84
3u
* Reaction scale – 0.5 mmol, ratio of reagents 1:2 = 1:1.
** Yield after column chromatography.
*** Reaction time 2 h. A mixture of by-products was formed besides the
target furanylbutanone 3.
1288

Chemistry of Heterocyclic Compounds 2017, 53(12), 1286–1293
respective product. Remarkably, the reactions of methyl
Experimental
vinyl ketone 2p with furans 1c,d led to the formation of the
respective products in yields above 80%.
1Н and 13С NMR spectra were acquired on a Bruker
Avance III HD 400 spectrometer (400 and 100 MHz,
respectively) at room temperature in DMSO-d6 (compound
6b) or CDCl3 (the rest of the compounds). The chemical
shifts were measured relative to the residual solvent signals
(for 1H nuclei: CDCl3 – 7.26 ppm, DMSO-d6 – 2.50 ppm; for
13С nuclei: CDCl3 – 77.16 ppm, DMSO-d6 – 39.52 ppm).
High-resolution mass spectra were recorded on a Bruker
microTOF-Q ESI-TOF mass spectrometer. Analytical gas
chromatography was performed on an Agilent 5977A
GC/MSD instrument. Melting points were determined on a
Stuart SMP 30 apparatus. TLC analyses were performed on
Sorbfil plates. The reaction mixtures were purified by using
Macherey Nagel silica gel (40–63 μm).
The reaction of 2-methylfuran (1а) with acrolein (2q) in
the presence of CuBr2 gave compound 4, which was
formed by condensation of the conjugate addition product
with two additional molecules of 2-methylfuran (1a). This
result can be explained by the stronger electrophilic
properties of aldehyde carbonyl group compared to
analogous ketones (Scheme 1).17 The optimization of this
reaction showed that the highest yield of compound 4
(75%) was achieved by using 5 equiv of 2-methylfuran
(1а) relative to 1 equiv of acrolein. Still, the reaction
mixture contained multiple unidentified minor products
besides compound 4.
Compounds 1c,19a 1d,19b 2b–i,19c 2j,l,m,19d and 2o19e
were obtained according to published procedures, with the
physicochemical characteristics of the obtained compounds
matching the literature data. Compounds 1a,b, 2a,p,q were
commercially available.
Scheme 1
Me
O
Preparation of compounds 3a,b,d–j,l–p (General
method). CuBr2 (2.8 mg, 2.5 mol %) was added to a
solution of ketone 2 (0.5 mmol) and furan 1 (0.75 mmol) in
dichloromethane (1.25 ml). The reaction mixture was
stirred for 4 h at room temperature while controlling the
reaction progress by TLC. Upon comletion, the mixture
was concentrated at reduced pressure. The product was
isolated by column chromatography (eluent petroleum
ether – CH2Cl2, gradient from 19:1 to 1:1). Products 3o,p
were not isolated as individual compounds.
Preparation of compounds 3c,k (General method).
CuBr2 (5.6 mg, 5 mol %) was added to a solution of ketone
2 (0.5 mmol) and furan 1a (68 μl, 0.75 mmol) in 1,2-di-
chloroethane (1.25 ml). The reaction mixture was stirred
for 5 h at 40°С while controlling the reaction progress by
TLC. Upon comletion, the mixture was concentrated at
reduced pressure. The product was isolated by column
chromatography (eluent petroleum ether – CH2Cl2, gradient
from 19:1 to 1:1).
O
CuBr2 (2.5 mol %)
H2C
Me
H
O
CH2Cl2, rt, 4 h
75%
O
O
+
1a
2q
Me
Me
4
The developed catalytic conditions can be applied also
for the functionalization of other electron-rich heterocyclic
systems. Thus, indole (5a) and 2-methylindole (5b)
participated in conjugate addition reactions with methyl
vinyl ketone (2p), resulting in the formation of 4-(indol-
3-yl)butan-2-ones 6a,b in 82 and 71% yields, respectively
(Scheme 2). It is necessary to note that 1.5 mol % of
catalyst was sufficient for achieving this transformation.
Scheme 2
Preparation of compounds 3q–u (General method).
CuBr2 (2.8 mg, 2.5 mol %) was added to a solution of
ketone 2 (0.5 mmol) and furan 1 (0.5 mmol) in
dichloromethane (1.25 ml). The reaction mixture was
stirred for 4 h at room temperature while controlling the
reaction progress by TLC. Upon comletion, the mixture
was concentrated at reduced pressure. The product was
isolated by column chromatography (eluent petroleum
ether – CH2Cl2, gradient from 19:1 to 1:1).
Obviously, CuBr2 acted as a Lewis acid in this process
and the studied reaction proceeded according to the well-
known conjugate addition mechanism.18
3-(5-Methylfuran-2-yl)-1,3-diphenylpropan-1-one (3a).
1
Thus, we have developed a simple method for the
synthesis of 2-(3-oxoalkyl)furan derivatives by conjugate
addition of 2-substituted furans to α,β-unsaturated carbonyl
compounds in the presence of CuBr2. The method is
characterized by low catalyst loads, mild reaction
conditions, high yields of the target products, and broad
scope. It was shown that the developed method can be used
for functionalization of other electron-rich heterocyclic
compounds.
Yield 122 mg (84%), light-yellow oil. H NMR spectrum,
δ, ppm (J, Hz): 2.23 (3Н, s, CH3); 3.54 (1H, dd, 2J = 16.9,
2
3
3J = 7.2, CH2); 3.80 (1H, dd, J = 16.9, J = 7.2, CH2);
4.80 (1H, t, 3J = 7.2, СН); 5.85 (1H, d, J = 2.8, H furan);
5.91 (1H, d, J = 2.8, H furan); 7.20–7.25 (1H, m, H Ph);
3
3
7.28–7.36 (4H, m, H Ph); 7.42–7.47 (2H, m, H Ph); 7.53–
7.57 (1Н, m, H Ph); 7.94–7.96 (2Н, m, H Ph). 13C NMR
spectrum, δ, ppm: 13.6; 40.6; 43.9; 106.1; 106.6; 126.8;
128.0 (2С); 128.2 (2С); 128.6 (2С); 128.7 (2С); 133.1;
1289

Chemistry of Heterocyclic Compounds 2017, 53(12), 1286–1293
137.3; 142.4; 151.2; 155.0; 197.8. Found, m/z: 291.1379
7.44–7.50 (2Н, m, H Ar); 7.58–7.60 (1Н, m, H Ar); 7.99–
8.01 (2Н, m, H Ar). 13C NMR spectrum, δ, ppm (J, Hz):
13.5; 34.2 (d, 3JCF = 2.7); 42.5 (d, 4JCF = 1.5); 106.2; 106.9;
[M+H]+. C20H19O2. Calculated, m/z: 291.1380.
3-(5-Methylfuran-2-yl)-3-(4-methylphenyl)-1-phenyl-
propan-1-one (3b). Yield 111 mg (73%), light-yellow oil.
1H NMR spectrum, δ, ppm (J, Hz): 2.22 (3Н, s, CH3); 2.32
2
4
115.7 (d, JCF = 22.4); 124.2 (d, JCF = 3.5); 128.1 (2C);
3
2
128.4 (d, JCF = 8.3); 128.6 (2C); 129.2 (d, JCF = 14.0);
2
3
3
(3Н, s, CH3); 3.52 (1Н, dd, J = 16.9, J = 7.2, CH2); 3.78
129.6 (d, JCF = 4.3); 133.1; 137.0; 151.2; 153.6; 160.7 (d,
2
3
3
(1Н, dd, J = 16.9, J = 7.2, CH2); 4.76 (1Н, t, J = 7.2,
СН); 5.83 (1Н, br. s, H furan); 5.90 (1Н, br. s, H furan);
7.11–7.18 (2Н, m, H Ar); 7.23–7.26 (2Н, m, H Ph); 7.42–
7.48 (2Н, m, H Ar); 7.53–7.57 (1Н, m, H Ph); 7.94–7.96
(2Н, m, H Ph). 13C NMR spectrum, δ, ppm: 13.6, 21.1;
40.3, 44.0; 106.1; 106.5; 127.9 (2С); 128.2 (2С); 128.7
(2С); 129.3 (2С); 133.1; 136.3; 137.3; 139.4; 151.1; 155.3;
197.9. Found, m/z: 305.1544 [M+H]+. C21H21O2.
Calculated, m/z: 305.1536.
1JCF = 246.4); 197.4. Found, m/z: 309.1274 [M+H]+.
C20H18FO2. Calculated, m/z: 309.1285.
3-(5-Methylfuran-2-yl)-1-(4-methylphenyl)-3-phenyl-
propan-1-one (3g). Yield 106 mg (70%), light-yellow oil.
1H NMR spectrum, δ, ppm (J, Hz): 2.24 (3Н, s, CH3); 2.42
2
3
(3Н, s, CH3); 3.52 (1Н, dd, J = 16.9, J = 7.2, CH2); 3.77
2
3
3
(1Н, dd, J = 16.9, J = 7.2, CH2); 4.79 (1Н, t, J = 7.2,
СН); 5.85 (1Н, br. s, H furan); 5.91 (1Н, br. s, H furan);
7.20–7.36 (7Н, m, H Ar); 7.86–7.88 (2Н, m, H Ar);
13C NMR spectrum, δ, ppm: 13.7, 21.7; 40.6, 43.7; 106.1;
106.5; 126.8; 128.0 (2С); 128.4 (2С); 128.6 (2С); 129.4
(2С); 134.7; 142.5; 144.0; 151.2; 155.1; 197.4. Found, m/z:
305.1543 [M+H]+. C21H21O2. Calculated, m/z: 305.1536.
1-(4-Methoxyphenyl)-3-(5-methylfuran-2-yl)-3-phenyl-
propan-1-one (3h). Yield 114 mg (71%), light-yellow oil.
1H NMR spectrum, δ, ppm (J, Hz): 2.24 (3Н, s, СН3); 3.49
(1H, dd, 2J = 16.7, 3J = 7.2, CH2); 3.75 (1H, dd, 2J = 16.7,
3-(4-Methoxyphenyl)-3-(5-methylfuran-2-yl)-1-phenyl-
propan-1-one (3c). Yield 120 mg (75%), light-yellow oil.
1H NMR spectrum, δ, ppm (J, Hz): 2.22 (3Н, s, СН3); 3.51
(1H, dd, 2J = 16.8, 3J = 7.5, CH2); 3.75 (1H, dd, 2J = 16.8,
3
3J = 7.5, CH2); 3.77 (3Н, s, ОСН3); 4.73 (1Н, t, J = 7.5,
СН); 5.84 (1Н, br. s, H furan); 5.88 (1Н, br. s, H furan);
6.84 (2Н, d, J = 8.0, H Ar); 7.24 (2Н, d, J = 8.0, H Ar);
7.41–7.47 (2Н, m, H Ph); 7.52–7.58 (1Н, m, H Ph); 7.93–
7.95 (2Н, m, H Ph). 13C NMR spectrum, δ, ppm: 13.7;
39.8; 44.0; 55.3; 106.1; 106.4; 114.1 (2C); 128.2 (2C);
128.7 (2C); 129.0 (2C); 133.1; 134.4; 137.2; 151.1; 155.4;
158.5; 198.0. Found, m/z: 321.1494 [M+H]+. C21H21O3.
Calculated, m/z: 321.1485.
3
3J = 7.2, CH2); 3.88 (3Н, s, ОСН3); 4.79 (1Н, t, J = 7.2,
СН); 5.85 (1Н, br. s, H furan); 5.91 (1Н, br. s, H furan);
6.94 (2Н, d, J = 8.8, H Ar); 7.19–7.25 (1Н, m, H Ph); 7.27–
7.35 (4Н, m, H Ph); 7.95 (2Н, d, J = 8.8, H Ar). 13C NMR
spectrum, δ, ppm: 13.7; 40.7; 43.5; 55.6; 106.1; 106.5;
113.8 (2C); 126.8; 128.0 (2C); 128.6 (2C); 130.3; 130.5
(2C); 142.6; 151.1; 155.2; 163.6; 196.3. Found, m/z:
321.1478 [M+H]+. C21H21O3. Calculated, m/z: 321.1485.
1-(4-Chlorophenyl)-3-(5-methylfuran-2-yl)-3-phenyl-
propan-1-one (3i). Yield 128 mg (79%), light-yellow oil.
1H NMR spectrum, δ, ppm (J, Hz): 2.22 (3Н, s, CH3); 3.50
(1Н, dd, 2J = 16.9, 3J = 7.2, CH2); 3.75 (1Н, dd, 2J = 16.9,
3-(4-Bromophenyl)-3-(5-methylfuran-2-yl)-1-phenyl-
propan-1-one (3d). Yield 157 mg (85%), orange oil.
1H NMR spectrum, δ, ppm (J, Hz): 2.24 (3Н, s, CH3); 3.55
(1Н, dd, 2J = 17.2, 3J = 7.7, CH2); 3.78 (1Н, dd, 2J = 17.2,
3
3J = 7.7, CH2); 4.78 (1Н, t, J = 7.7, СН); 5.87 (1Н, br. s,
H furan); 5.93 (1Н, br. s, H furan); 7.21–7.25 (2Н, m,
H Ar); 7.39–7.49 (4Н, m, H Ph and Ar); 7.53–7.58 (1Н, m,
H Ph); 7.95–7.97 (2Н, m, H Ph). 13C NMR spectrum,
δ, ppm: 13.6; 39.9; 43.5; 106.1; 106.7; 120.6; 128.1 (2С);
128.7 (2С); 129.8 (2С); 131.6 (2С); 133.2; 136.9; 141.3;
151.3; 154.3; 197.3. Found, m/z: 369.0501 [M+H]+.
C20H18BrO2. Calculated, m/z: 369.0485.
3
3J = 7.2, CH2); 4.77 (1Н, t, J = 7.2, СН); 5.85 (1Н, br. s,
H furan); 5.89 (1Н, br. s, H furan); 7.19–7.25 (1Н, m,
H Ph); 7.28–7.34 (4Н, m, H Ph); 7.41 (2Н, d, J = 8.0, H Ar);
7.87 (2Н, d, J = 8.0, H Ar). 13C NMR spectrum, δ, ppm: 13.6;
40.7; 43.8; 106.2; 106.7; 126.9; 128.0 (2С); 128.7 (2С);
129.0 (2С); 129.6 (2С); 135.6; 139.6; 142.2; 151.2; 154.8;
196.6. Found, m/z: 325.0998 [M+H]+. C20H18ClO2.
Calculated, m/z: 325.0990.
3-(5-Methylfuran-2-yl)-1-phenyl-3-[4-(trifluoromethyl)-
phenyl]propan-1-one (3e). Yield 154 mg (86%), light-
yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 2.24 (3Н, s,
CH3); 3.58 (1H, dd, 2J = 17.3, 3J = 7.8, CH2); 3.80 (1Н, dd,
2J = 17.3, 3J = 7.8, CH2); 4.86 (1Н, t, 3J = 7.8, СН); 5.86 (1Н,
br. s, H furan); 5.93 (1Н, br. s, H furan); 7.42–7.48 (4Н, m,
H Ar); 7.54–7.57 (3Н, m, H Ar); 7.94–7.96 (2Н, m, H Ar).
13C NMR spectrum, δ, ppm (J, Hz): 13.6; 40.4; 43.5; 106.3;
107.0; 124.4 (q, 1JCF = 271.9), 125.6 (q, 3JCF = 3.7, 2C); 128.2
3-(5-Methylfuran-2-yl)-1-(4-nitrophenyl)-3-phenylpro-
1
pan-1-one (3j). Yield 136 mg (81%), yellow oil. H NMR
spectrum, δ, ppm (J, Hz): 2.21 (3Н, s, CH3); 3.55 (1Н, dd,
2J = 16.9, 3J = 7.2, CH2); 3.82 (1Н, dd, 2J = 16.9, 3J = 7.2,
CH2); 4.74 (1Н, t, 3J = 7.2, СН); 5.84 (1Н, br. s, H furan);
5.88 (1Н, br. s, H furan); 7.20–7.25 (1Н, m, H Ph); 7.27–
2
3
(2С); 128.5 (2С); 128.8 (2С); 129.2 (q, JCF = 32.4); 133.4;
7.33 (4Н, m, H Ph); 8.05 (2Н, d, J = 8.7, H Ar); 8.28 (2Н,
3
137.0; 146.5; 151.6; 154.1; 197.2. Found, m/z: 359.1254
d, J = 8.7, H Ar). 13C NMR spectrum, δ, ppm: 13.7; 40.7;
[M+H]+. C21H18F3O2. Calculated, m/z: 359.1253.
44.4; 106.2; 106.9; 123.9 (2C); 127.1; 127.9 (2С); 128.8
(2С); 129.2 (2С); 141.6; 141.8; 150.5; 151.4; 154.4; 196.6.
Found, m/z: 336.1236 [M+H]+. C20H18NO4. Calculated, m/z
336.1230.
3-(2-Fluorophenyl)-3-(5-methylfuran-2-yl)-1-phenyl-
propan-1-one (3f). Yield 119 mg (77%), light-yellow oil.
1H NMR spectrum, δ, ppm (J, Hz): 2.25 (3Н, s, CH3); 3.63
(1H, dd, 2J = 17.1, 3J = 7.1, CH2); 3.85 (1Н, dd, 2J = 17.1,
3-(4-Methoxyphenyl)-3-(5-methylfuran-2-yl)-1-(4-nitro-
phenyl)propan-1-one (3k). Yield 148 mg (81%), orange
3
3J = 7.1, CH2); 5.14 (1Н, t, J = 7.1, СН); 5.89 (1Н, br. s,
1
H furan); 5.98 (1Н, br. s, H furan); 7.05–7.14 (2Н, m,
H Ar); 7.19–7.26 (1Н, m, H Ar); 7.30–7.36 (1Н, m, H Ar);
oil. H NMR spectrum, δ, ppm (J, Hz): 2.21 (3Н, s, CH3);
2
3
3.53 (1H, dd, J = 16.9, J = 7.5, CH2); 3.77 (3Н, s,
1290

Chemistry of Heterocyclic Compounds 2017, 53(12), 1286–1293
3
ОCH3); 3.79 (1H, dd, 2J = 16.9, 3J = 7.5, CH2); 4.69 (1Н, t,
2J = 16.3, J = 5.5, СН2); 3.45–3.56 (1Н, m, СН); 5.82
(1Н, br. s, H furan); 5.88 (1Н, br. s, H furan); 7.41 (2Н, d,
3J = 7.5, СН); 5.83–5.86 (2Н, m, H furan); 6.83 (2Н, d,
3J = 8.6, H Ar); 7.23 (2Н, d, J = 8.6, H Ar); 8.05 (2Н, d,
3J = 8.8, H Ar); 7.88 (2Н, d, J = 8.8, H Ar). 13C NMR
3
3
3
3J = 8.8, H Ar); 8.27 (2Н, d, J = 8.8, H Ar). 13C NMR
spectrum, δ, ppm: 13.5; 19.1; 29.6; 44.6; 104.7; 105.9;
129.0 (2С); 129.7 (2С); 135.8; 139.5; 150.6; 157.3; 197.7.
Found, m/z: 263.0842 [M+H]+. C15H16ClO2. Calculated, m/z:
263.0833.
spectrum, δ, ppm: 13.6; 39.9; 44.5; 55.3; 106.2; 106.7;
114.2 (2C); 123.9 (2C); 128.9 (2C); 129.2 (2C); 133.8;
141.6; 150.4; 151.3; 154.8; 158.7; 196.7. Found, m/z:
366.1351 [M+H]+. C21H20NO5. Calculated, m/z: 366.1336.
1-(4-Methoxyphenyl)-3-(5-methylfuran-2-yl)-3-(4-nitro-
phenyl)propan-1-one (3l). Yield 97 mg (53%), orange oil.
1H NMR spectrum, δ, ppm (J, Hz): 2.21 (3Н, s, CH3); 3.56
(1H, dd, 2J = 17.2, 3J = 7.5, CH2); 3.73 (1H, dd, 2J = 17.2,
4-(5-Methylfuran-2-yl)butan-2-one (3s).21 Yield 49 mg
(65%), light-yellow oil. 1H NMR spectrum, δ, ppm (J, Hz):
2.13 (3H, s, CH3); 2.21 (3H, s, CH3); 2.73 (2Н, t, 3J = 7.2,
3
СН2); 2.83 (2Н, t, J = 7.2, СН2); 5.81–5.83 (2H, m,
H furan). 13C NMR spectrum, δ, ppm: 13.5; 22.3; 29.9;
41.9; 105.8; 106.0; 150.6; 152.7; 207.4. Found, m/z:
153.0914 [M+H]+. C9H13O2. Calculated, m/z: 153.0910.
4-(5-tert-Butylfuran-2-yl)butan-2-one (3t). Yield 79 mg
(81%), light-yellow oil. 1H NMR spectrum, δ, ppm (J, Hz):
1.25 (9H, s, C(CH3)3); 2.15 (3H, s, CH3); 2.75 (2Н, t,
3
3J = 7.5, CH2); 3.84 (3Н, s, ОCH3); 4.86 (1Н, t, J = 7.5,
СН); 5.86 (1Н, br. s, H furan); 5.96 (1Н, br. s, H furan);
3
3
6.91 (2Н, d, J = 8.8, H Ar); 7.47 (2Н, d, J = 8.7, H Ar);
3
7.91 (2Н, d, J = 8.8, H Ar); 8.11 (2Н, d, J = 8.7, H Ar).
13C NMR spectrum, δ, ppm: 13.6; 40.3; 42.7; 55.5; 106.3;
107.1; 113.9 (2C); 123.8 (2C); 129.0 (2C); 129.7; 130.4
(2C); 146.8; 150.0; 151.8; 153.4; 163.8; 195.3. Found, m/z:
366.1326 [M+H]+. C21H20NO5. Calculated, m/z 366.1336.
(E)-5-(5-Methylfuran-2-yl)-1,5-diphenylpent-1-en-3-one
(3m). Yield 87 mg (55%), light-yellow oil. 1H NMR
spectrum, δ, ppm (J, Hz): 2.25 (3Н, s, СН3); 3.24 (1Н, dd,
2J = 16.2, 3J = 7.3, СН2); 3.48 (1Н, dd, 2J = 16.2, 3J = 7.3,
СН2); 4.69 (1Н, t, 3J = 7.3, СН); 5.87 (1Н, br. s, H furan);
5.93 (1Н, br. s, H furan); 6.71 (1H, d, J = 16.2, CH); 7.22–
7.33 (5Н, m, H Ph); 7.40–7.41 (3Н, m, H Ph); 7.52–7.56
(3Н, m, CH and H Ph). 13C NMR spectrum, δ, ppm: 13.7;
40.9; 46.1; 106.2; 106.7; 126.5; 126.9; 128.0 (2C); 128.4
(2C); 128.7 (2C); 129.1 (2C); 130.6; 134.7; 142.4; 142.9;
151.2; 155.5; 197.8. Found, m/z: 317.1537 [M+H]+.
C22H21O2. Calculated, m/z: 317.1536.
3J = 7.4, СН2); 2.88 (2Н, t, J = 7.4, СН2); 5.80–5.84 (2H,
3
m, H furan). 13C NMR spectrum, δ, ppm: 22.7; 29.2 (3С);
30.0; 32.7; 42.0; 102.3; 105.4; 152.4; 163.1; 207.6. Found,
m/z: 195.1388 [M+H]+. C12H19O2. Calculated, m/z:
195.1380.
4-[5-(4-Chlorophenyl)furan-2-yl]butan-2-one
(3u).
1
Yield 104 mg (84%), light-yellow oil. H NMR spectrum,
3
δ, ppm (J, Hz): 2.19 (3Н, s, СН3); 2.83 (2Н, t, J = 7.2,
СН2); 2.98 (2Н, t, 3J = 7.2, СН2); 6.08 (1Н, br. s, H furan);
3
6.52 (1Н, br. s, H furan); 7.32 (2Н, d, J = 8.1, H Ar); 7.53
(2Н, d, J = 8.1, H Ar). 13C NMR spectrum, δ, ppm: 22.6;
3
30.0; 41.9; 106.4; 107.8; 124.8 (2С); 129.0 (2С); 129.7;
132.7; 151.7; 154.9; 207.0. Found, m/z: 249.0682 [M+H]+.
C14H14ClO2. Calculated, m/z: 249.0677.
2,2',2''-Propane-1,1,3-triyltris(5-methylfuran) (4).17a
CuBr2 (2.8 mg, 2.5 mol %) was added to a solution of
acrolein (2q) (33 μl, 0.5 mmol) and 2-methylfuran (1a)
(225 μl, 2.5 mmol, 5 equiv) in dichloromethane (1.25 ml).
The reaction mixture was stirred for 4 h at room
temperature while controlling the reaction progress by TLC
method. After the reaction was complete, the mixture was
concentrated at reduced pressure. The product was isolated
by column chromatography (eluent petroleum ether – CH2Cl2,
3-(5-Ethylfuran-2-yl)-1,3-diphenylpropan-1-one (3n).
1
Yield 134 mg (88%), light-yellow oil. H NMR spectrum,
3
δ, ppm (J, Hz): 1.21 (3Н, t, J = 7.5, CH3); 2.61 (2Н, q,
2
3
3J = 7.5, СН2); 3.56 (1Н, dd, J = 16.8, J = 7.2, СН2);
3.84 (1Н, dd, 2J = 16.8, 3J = 7.2, СН2); 4.85 (1Н, t, 3J = 7.2,
СН); 5.88 (1Н, d, 3J = 2.8, H furan); 5.93 (1Н, d, 3J = 2.8,
H furan); 7.21–7.26 (1Н, m, H Ph); 7.30–7.39 (4Н, m,
H Ph); 7.42–7.48 (2Н, m, H Ph); 7.52–7.57 (1Н, m, H Ph);
7.97–7.99 (2Н, m, H Ph). 13C NMR spectrum, δ, ppm:
12.1; 21.4; 40.7; 43.9; 104.5; 106.4; 126.8; 128.0 (2C);
128.2 (2C); 128.6 (2C); 128.7 (2C) 133.1; 137.3; 142.4;
154.9; 156.9; 197.8. Found, m/z: 305.1549 [M+H]+.
C21H21O2. Calculated, m/z: 305.1536.
1
10:1). Yield 107 mg (75%), light-yellow oil. H NMR
spectrum, δ, ppm (J, Hz): 2.25–2.30 (11Н, m, 3CH3 and
CH2); 2.58 (2Н, t, 3J = 7.6, СН2); 3.99 (1Н, t, 3J = 7.6, СН);
5.84–5.98 (6Н, m, H furan). 13C NMR spectrum, δ, ppm:
13.6; 13.7 (2C); 26.1; 31.4; 38.5; 105.8; 105.9; 106.1 (2C);
106.6 (2C); 150.4; 151.0 (2C); 153.6 (2C); 153.8. Found,
m/z: 285.1489 [M+H]+. C18H21O3. Calculated, m/z:
285.1485.
4-(5-Methylfuran-2-yl)-4-phenylbutan-2-one (3q).20
1
Yield 72 mg (63%), light-yellow oil. H NMR spectrum,
δ, ppm (J, Hz): 2.11 (3H, s, CH3); 2.26 (3Н, s, CH3); 3.01
(1Н, dd, 2J = 16.5, 3J = 7.4, CH2); 3.23 (1Н, dd, 2J = 16.5,
Preparation of compounds 6a,b. CuBr2 (1.7 mg,
1.5 mol %) was added to a solution of methyl vinyl ketone
(2p) (41 μl, 0.5 mmol) and indole 5 (0.5 mmol) in
dichloromethane (1.25 ml). The mixture was stirred for 4 h
at room temperature while controlling the reaction prograss
by TLC. Upon comletion, the mixture was concentrated at
reduced pressure. The product was isolated by column
chromatography (eluent petroleum ether – CH2Cl2, 10:1).
4-(1Н-Indol-3-yl)butan-2-one (6a).22 Yield 77 mg
(82%), white crystalline powder, mp 91–92°C (petroleum
ether – CH2Cl2) (mp 92–93°C20). 1H NMR spectrum, δ, ppm
3
3J = 7.4, CH2); 4.58 (1Н, t, J = 7.4, СН); 5.88–5.90 (2Н,
m, H furan); 7.19–7.24 (1Н, m, H Ph); 7.25–7.35 (4Н, m,
H Ph). 13C NMR spectrum, δ, ppm: 13.6; 30.4; 40.6; 48.7;
106.1; 106.5; 126.9; 127.9 (2С); 128.6 (2С); 142.1; 151.2;
154.8; 206.2. Found, m/z: 229.1221 [M+H]+. C15H17O2.
Calculated, m/z: 229.1223.
4-(4-Chlorophenyl)-4-(5-methylfuran-2-yl)butan-2-one
1
(3r). Yield 115 mg (88%), orange oil. H NMR spectrum,
3
δ, ppm (J, Hz): 1.31 (3H, d, J = 6.9, СН3); 2.22 (3Н, s,
СН3); 3.01 (1Н, dd, 2J = 16.3, J = 5.5, СН2); 3.36 (1Н, dd,
1291

Chemistry of Heterocyclic Compounds 2017, 53(12), 1286–1293
(J, Hz): 2.14 (3Н, s, СН3); 2.85 (2Н, t, 3J = 7.4, СН2); 3.07
Soedin. 2016, 52, 359.] (c) Abaev, V. T.; Trushkov, I. V.;
Uchuskin, M. G. Chem. Heterocycl. Compd. 2016, 52, 973.
[Khim. Geterotsikl. Soedin. 2016, 52, 973.]
3
(2Н, t, J = 7.4, СН2); 6.98 (1Н, s, H indole); 7.10–7.15
(1Н, m, H indole); 7.17–7.22 (1Н, m, H indole); 7.32–7.36
(1Н, m, H indole); 7.59–7.61 (1Н, m, H indole); 7.96 (1Н,
br. s, NH). 13C NMR spectrum, δ, ppm: 19.6; 30.1; 44.3;
111.3; 115.5; 118.8; 119.5; 121.6; 122.2; 127.4; 136.6; 206.7.
4-(2-Methyl-1Н-indol-3-yl)butan-2-one (6b).22 Yield
71 mg (71%), yellow oil. 1H NMR spectrum, δ, ppm (J, Hz):
2.06 (3Н, s, СН3); 2.33 (3Н, s, СН3); 2.69 (2Н, t, 3J = 7.2,
6. (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press, 1998, р. 30. (b) Beach, E. S.;
Cui, Z.; Anastas, P. T. Energy Environ. Sci. 2009, 2, 1038.
(c) Anastas, P.; Eghbali, N. Chem. Soc. Rev. 2010, 39, 301.
7. (a) Schnurch, M.; Dastbaravardeh, N.; Ghobrial, M.; Mrozek, B.;
Mihovilovic, M. D. Curr. Org. Chem. 2011, 15, 2694.
(b) Sharma, A.; Vacchani, D.; Van der Eycken, E. Chem.–
Eur. J. 2013, 19, 1158. (c) Wei, Y.; Hu, P.; Zhang, M.; Su, W.
Chem. Rev. 2017, 117, 8864.
3
СН2); 2.84 (2Н, t, J = 7.2, СН2); 6.90–7.00 (2Н, m,
H indole); 7.23–7.25 (1Н, m, H indole); 7.40–7.42 (1Н, m,
H indole); 10.65 (1Н, br. s, NH). 13C NMR spectrum, δ, ppm:
11.2; 18.1; 29.7; 43.8; 109.1; 110.3; 117.3; 118.0; 119.9;
127.9; 131.4; 135.2; 208.3.
8. (a) Uchuskin, M. G.; Makarov, A. S.; Butin, A. V. Chem.
Heterocycl. Compd. 2014, 50, 791. [Khim. Geterotsikl.
Soedin. 2014, 860.] (b) Santos, F. M.; Batista, J. H. C.;
Vessecchi, R.; Clososki, G. C. Synlett 2015, 2795.
9. (a) Wetzel, A.; Pratsch, G.; Kolb, R.; Heinrich, M. R. Chem.–
Eur. J. 2010, 16, 2547. (b) Pratsch, G.; Anger, C. A.; Ritter, K.;
Heinrich, M. R. Chem.–Eur. J. 2011, 17, 4104. (c) Chalikidi, P. N.;
Nevolina, T. A.; Uchuskin, M. G.; Abaev, V. T.; Butin, A. V.
Chem. Heterocycl. Compd. 2015, 51, 621. [Khim. Geterotsikl.
Soedin. 2015, 51, 621.]
10. (a) Zhao, J.; Huang, L.; Cheng, K.; Zhang, Y. Tetrahedron
Lett. 2009, 50, 2758. (b) Zhang, Y.; Li, Z.; Liu, Z. Q. Org.
Lett. 2012, 14, 226. (c) Pei, K.; Jie, X.; Zhao, H.; Su, W.
Eur. J. Org. Chem. 2014, 20, 4230. (d) Bheeter, C. B.; Chen, L.;
Soulé, J.-F.; Doucet, H. Catal. Sci. Technol. 2016, 6,
2005.
1
A Supporting information file containing Н and 13С
NMR spectra of all synthesized compounds is available at
the journal website at http://link.springer.com/journal/10593.
This work was supported by the Russian Foundation for
Basic Research (grant 16-33-00101 mol_a) and the
Ministry of Education and Science of the Russian
Federation (contract No. 02.a03.0008).
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