Copper-Catalyzed Regioselective Synthesis of Multisubstituted Furans by Coupling between Ketones and Aromatic Olefins

Article abstract of DOI:10.1021/acs.joc.7b00476

A regioselective synthesis of multisubstituted furan derivatives has been developed via Cu(II)-catalyzed intermolecular annulation of aryl ketones with a wide range of aromatic olefins under ambient air in good yields. This protocol is applicable to both cyclic and acyclic aryl ketones.

Full text of DOI:10.1021/acs.joc.7b00476

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Article
Copper-Catalyzed Regioselective Synthesis of Multisubstituted
Furans by Coupling between Ketones and Aromatic Olefins
Amrita Dey, Md Ashif Ali, Sourav Jana, and Alakananda Hajra
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00476 • Publication Date (Web): 12 Apr 2017
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Copper-Catalyzed Regioselective Synthesis of Multisubstituted Furans
by Coupling between Ketones and Aromatic Olefins
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Amrita Dey, Md Ashif Ali, Sourav Jana, and Alakananda Hajra*
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Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India
Abstract:
A regioselective synthesis of multi-substituted furan derivatives has been developed via Cu(II)-
catalyzed intermolecular annulation of aryl ketones with a wide range of aromatic olefins under
ambient air in good yields. This protocol is applicable to both cyclic and acyclic aryl ketones.
Introduction:
Among the five-membered heterocyclic derivatives polysubstituted furan is one of the most
important motifs present in a number of pharmaceuticals and biologically active compounds and
natural products.1 Furthermore, they are the basic scaffolds of numerous therapeutic agents,
optoelectronic materials and also used as building blocks in organic synthesis.
The versatile pharmacological and biological activities of furan derivatives is resulting in
development of various methods for construction of polysubstituted furan derivatives.2 Despite
considerable synthetic routes for their preparation, construction of furan molecules from readily
available starting materials under mild conditions till now attracts the interest of organic
chemists. As for examples, the Paal−Knorr and Feist−Benary cyclocondensations from
dicarbonyl compounds provide direct access to substituted furans.3 In addition, several
methodologies from prefunctionalized alkynyl, allenyl, or cyclopropyl ketone precursors
involving alkyne- or allene-assisted cyclizations have been developed for the synthesis of
furans.4
Although a number of methods have been extensively utilized for the furan synthesis, most of
these approaches require either prefunctionalized substrates or multistep procedures. To the best
of our knowledge the use of commercially available simple aryl ketones and olefins as precursors
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has been less explored.5 Very recently, Maiti et al. reported an efficient method of 2,3-
dihydrofuran synthesis from aryl ketones and aromatic olefins by using stoichiometric amount of
Cu(OAc)2.5b On the basis of our experience in copper catalysis,6 we envisaged that furan might
be synthesized via annulation of ketones with aromatic olefins by using catalytic amount of
copper salt in ambient air.7 Transition-metal-catalyzed organic transformations have become one
of the most powerful tools to prepare functionalized furan molecules during the past few years.8
The most versatile and widely used transition-metal for the synthesis of furan derivatives are Pd,
Cu, Au, Ag and Ru.9 In general direct regioselective synthesis of substituted heterocycles from
readily available and cheap chemicals as reactants is a great challenge. Recently, our group has
reported a copper-catalyzed regioselective synthesis of multisubstituted furan derivatives
employing ketones and nitroalkenes as the coupling partners.10 This discovery encouraged us to
search suitable conditions for synthesis of furan derivatives using simple alkene as coupling
partner. Herein we report a regioselective synthesis of 2,3,5-trisubstituted furans from aryl
ketones and olefins (Scheme 1).
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Scheme 1. Synthesis of Multisubstituted Furans from Olefins
Results and Discussion:
In our initial study, we focused on the reaction of styrene with propiophenone varring different
copper salts, additives and solvents to standardize reaction conditions. The 3-methyl-2,5-
diphenylfuran was obtained as single regioisomer in 30% yield when we used Cu(OAc)2·H2O
(20 mol %) in DMF at 120 °C (Table 1, entry 1). The addition of perchloric acid greatly
enhanced the yield of desired product (Table 1, entry 2). Other acids like trifluoroacetic acid and
hydrochloric acid were effective but acetic acid was less efficient. The use of potassium acetate
as an additive was not successful providing only trace amount of the product. Next we examined
different copper salt and the most effective result came out when the reaction was performed
with copper(II) chloride. The reaction yielded 95% of the desired product without any additives.
Other copper salt like copper(I) chloride, copper(II) bromide and copper(II) triflate were also
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effective but not as copper(II) chloride. The solvents like xylene, NMP and DMAc were less
effective than DMF. The reaction did not work well under argon atmosphere and at 80 ºC
providing only 20% and trace amount of desired product respectively (Table 1, entry 14). The
reaction did not proceed in water as well as under solvent-free conditions (Table 1, entries 16
and 17). Use of organic bases is not also effective for this transformation (Table 1, entry 18).
There is no reaction in the absence of Cu-catalyst (Table 1, entry 19).
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Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
additive
solvent
temp. (°C)
yield (%)
(20 mol%)
(3 equiv.)
1
2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
CuCl2
-
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Xylene
NMP
DMAc
DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
120
30
80
HClO4
3
TFA
50
4
HCl
85
5
AcOH
30
6
KOAc
Trace
95
7
-
-
-
-
-
-
-
-
8
CuCl
60
9
CuBr2
85
10
11
12
13
14
Cu(OTf)2
CuCl2
85
81
CuCl2
90
CuCl2
84
CuCl2
20b
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CuCl2
CuCl2
CuCl2
CuCl2
-
-
DMF
H2O
-
80
trace
N.R.
N.R.
-
100
120
120
120
-
DBU
-
DMF
DMF
N.R. (15c, 58d)
N.R.
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aReaction conditions: 0.5 mmol of 1a and 0.5 mmol of 2a in the presence of 20 mol % catalyst in 2 mL
DMF at mentioned temperature for 16 h. bUnder argon atmosphere. cUsing DABCO. dUsing Et3N.
Scheme 2. Substrates Scope with Different Styrenesa
aReaction conditions: 0.5 mmol of 1a and 0.5 mmol of 2a-h in the presence of 20 mol % CuCl2 in 2
mL DMF at 120 °C for 16 h.
Having optimized reaction conditions in hand, we began to explore the substrate scope for the
annulation of propiophenone with various substituted styrenes (Scheme 2). 3-Substituted
styrenes such as 3-methyl and 2-substituted styrenes such as 2-chloro as well as 4-substituted
styrenes like 4-methoxy, 4-chloro, and 4-bromo worked well providing very high yield of the
desired products (3ab-3af). Multi-substituted styrenes such as 2,4-dimethyl and 2,4,6-
trimethyl styrenes worked resulting in good yield of the expected products 3ag and 3ah
respectively. The styrene containing strong electron withdrawing groups like -NO2 and -F did
not give any desired products under the standard reaction conditions.
Scheme 3. Substrates Scope with Different Aryl Ketones and Styrenesa
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aReaction conditions: 0.5 mmol of 1 and 0.5 mmol of 2 in the presence of 20 mol % CuCl2 in 2 mL DMF
at 120 °C for 16 h.
Next, to generalise the reaction conditions, we have performed the reaction with different aryl
ketones derivatives and styrenes (Scheme 3). 4-Methyl and 4-methoxy acetophenone reacted
with styrene to give the desired furan 3ba and 3ca 51 and 50% yield respectively. Likewise,
reaction of 4-methyl, 4-methoxy, and 4-chloro propiophenones with styrene were also
compatible and the desired furans 3da, 3ea, and 3fa were formed in excellent yield. The reaction
of substituted aryl ketones and substituted styrenes were also successful. For examples, 4-
methoxy, and 4-chloro propiophenone reacted with 4-methoxy, 4-chloro, and 4-bromostyrene
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and afforded corresponding furans 3ed, 3fe, 3ef with excellent regioselectivity and good yield.
Other aryl ketones like butyrophenone and 2-phenylacetophenone were also effective and
provided the corresponding furans 3ga and 3ha with styrene. Trans-stilbene is also suitable
candidate and was converted to the product 3di with good yield. Moreover, α-tetralone was
found to be effective under the reaction conditions and reacted efficiently with styrene and 3-
methylstyrene to give the product 3ia and 3ib respectively.
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Scheme 4. Synthesis of 2,3,4,5-Tetrasubstituted Furansa
R1
Me
O
Cu(OTf)2 (20 mol %)
Me
+
R1
DMF, 120 oC
16 h, air
O
R2
R2
4
5
1
Me
Me
Me
O
O
O
Me
MeO
5da, 70%
5ea, 88%
5aa, 92%
Me
Et
Me
Me
5ab, 67%
O
O
O
Cl
5ga, 80%
5fa,84%
aReaction conditions: 0.5 mmol of 1 and 0.5 mmol of 4 in the presence of 20 mol % Cu(OTf)2 in 2 mL
DMF at 120 °C for 16 h.
Although, the stilbene worked well under the standard conditions but α-substituted styrene like
α-phenylstyrene did not work with copper(II) chloride. This failure led us to investigate further.
Interestingly, 2,3,4,5-tetrasubstituted furans were obtained through 1,2-phenyl migration when
the catalyst was changed from copper(II) chloride to copper(II) triflate under the same conditions
(Scheme 4). Hence, we explored the substrate scopes with different α-substituted styrenes. For
examples, α-phenylstyrene was treated with different aryl ketone such as propiophenone, 4-
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methylpropiophenone, 4-methoxypropiophenone, 4-chloropropiophenone and butyrophenone to
get the expected tetra-substituted furans 5aa, 5da, 5ea, 5fa and 5ga respectively in good yield.
Similarly, α-methylstyrene reacted well with propiophenone resulting in 67% yield of the
product 5ab. But α-methylstyrene did not respond well with the other substituted aryl ketones.
While performing these reactions, we observed that some substrates did not give the tetra-
substituted furans instead the reaction stopped at dihydrofurans (Scheme 5). The 2-
phenylacetophenone gave the 2,2,4,5-tetraphenyl-2,3-dihydrofuran 6ha in 93% yield while
reacting with α-phenylstyrene. Similar product was obtained when butyrophenone was treated
with α-methylstyrene (6gb, 63%). α-Tetralone was treated with α-phenylstyrene and α-
methylstyrene to produce naphthodihydrofurans (6ia, 84% and 6ib, 90% respectively). But the
aliphatic ketones like ethylmethyl ketone, 4-phenylbutan-2-one and cyclohexanone as well as the
aliphatic olefin like oct-1-ene did work at all under the present reaction conditions. The structure
of 3-methyl-4,5-diphenyl-2-(p-tolyl)furan (5da) was further confirmed by the X-ray
crystallography.12
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Scheme 5. Synthesis of 2,2,4,5-Tetrasubstituted-2,3-dihydrofuransa
aReaction conditions: 0.5 mmol of 1 and 0.5 mmol of 4 in the presence of 20 mol % Cu(OTf)2 in 2 mL
DMF at 120 °C for 16 h.
To understand the possible mechanism of this reaction, some controlled experiments were
carried out and the results have been summarized in Scheme 6. The reactions were nearly or
totally stopped upon treatment with a radical scavenger such as TEMPO (1.5 equiv.), BHT (1.5
equiv.) and BQ (1.5 equiv.). These results are the possible indication of a radical formation
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pathway. Furthermore, two reaction intermediates (6da and 6fa) have been isolated after 2 h
(Scheme 6, eq B) which are transformed to the corresponding furans (5da and 5fa) in the
presence of air only.
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Scheme 6. Control Experimentsa,b
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aReaction conditions for eq A: 0.5 mmol of 1a, 0.5 mmol of 2a and 0.75 mmol scavenger in the presence
b
of 20 mol % CuCl2 in 2 mL DMF at 120 °C for 16 h. Reaction conditions for eq B: 0.5 mmol of 1 and
0.5 mmol of 4 in the presence of 20 mol % Cu(OTf)2 in 2 mL DMF at 120 °C for 2 h. cDMF, 120 °C, 12
h.
Scheme 7. Proposed Mechanism
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O
3aa
Me
Ph
R = H
[O]
1a
Cu(II)
Ph
Me
Ph
O
Me
Ph
H2O
R
Me
Me
Ph
O
Ph
Ph
Ph
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5
A
O
R
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R
E
Ph
Ph
O
R
-H
Ph
F
Ph
2a/4
O2
-H
Me
Ph
Me
Ph
Me
Me
Ph
Ph
R
R
O
G
O
R
R
O
Ph
O
F'
1,2-Ph shift
B
D
Ph
Me
SET [O]
O
R
C
Ph
A plausible reaction mechanism has been outlined in Scheme 7 on the basis of the controlled
experiments and literature reports.5b-c,10,11 The propiophenone can be converted to a carbon-
centered radical A in the presence of copper catalysts5b-c and air oxygen. Intermediate A attacks
the styrene to form another carbon-centered radical B which is further transformed to
intermediate C via single-electron transfer. After cyclization and tautomerization, the
intermediate C can form the intermediate E which has been isolated in some cases (see Scheme
5). Upon oxidation, intermediate E is either converted to product 3aa or intermediate F
depending on the styrene derivatives. The intermediate F is transformed to intermediate G after
1,2-phenyl shift.13 The intermediate G directly forms tetra-substituted furans after the removal
of a proton.
Conclusion:
In conclusion, we have demonstrated the copper-catalysed annulation via an oxidative free-
radical process from aryl ketones and aromatic olefins without using any external oxidant. These
reactions provide a novel synthetic route to 2,3,5-tri-, 2,3,4,5- tetrasubstituted furan and 2,2,4,5-
tetrasubstituted dihydrofurans from readily available starting materials. Complete
regioselectivity, broad substrates scope and wide availablability of starting materials make this
protocol synthetically useful to create a library of furan derivatives.
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EXPERIMENTAL SECTION:
3
4
1
General Information: H NMR spectra were determined on a 400 MHz spectrometer as
solutions in CDCl3. Chemical shifts are expressed in parts per million (δ) and are referenced to
tetramethylsilane (TMS) as internal standard and the signals were reported as s (singlet), d
(doublet), t (triplet), dd (doublet of doublet), m (multiplet) and coupling constants J were given
in Hz. Proton-decoupled 13C{1H} NMR spectra were recorded at 100 MHz in CDCl3 solution.
TLC was monitored with aluminium backed silica gel 60 (HF254) plates (0.25 mm) using various
organic solvent mixtures. Silica gel (60-120 mesh) was used for column chromatography.
Petroleum ether (PET) refers to the fraction boiling in the range of 60-80ºC unless otherwise
mentioned. All solvents were dried and distilled before use. Commercially available substrates
were freshly distilled before the reaction. All reactions involving moisture sensitive reactants
were executed using oven dried glassware. X-ray single crystal data were collected using MoKα
(λ = 0.71073 Å) radiation with CCD area detector.
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General Experimental Procedure for the Synthesis of Multisubstituted Furan (Scheme 2,
Scheme 3): A mixture of 1 (0.5 mmol), styrenes (0.5 mmol), and CuCl2 (0.1 mmol, 14 mg) in
DMF (2 mL) was placed in a reaction tube. Then the reaction mixture was stirred at 120 °C for
16 h under ambient air. After completion of the reaction (TLC), the reaction mixture was cooled
to room temperature and extracted with ethyl acetate. The organic phase was dried over
anhydrous Na2SO4. The crude residue was obtained after evaporation of the solvent in vacuum
and was purified by column chromatography on silica gel (60−120 mesh) using petroleum ether
as the eluent to afford pure product.
3-Methyl-2,5-diphenylfuran (3aa):10 White solid (95%, 115 mg), Rf 0.8 (PET), mp 46−47 °C
1
(lit. mp 47−48 °C); H NMR (400 MHz, CDCl3): δ 7.69 (d, J =7.6 Hz, 4H), 7.42-7.33 (m, 4H),
7.24-7.20 (m, 2H), 6.56 (s, 1H), 2.29 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 151.7, 148.3,
131.8, 130.9, 128.7, 128.6, 127.3, 126.7, 125.3, 123.7, 118.7, 110.9, 12.2.
3-Methyl-2-phenyl-5-(m-tolyl)furan (3ab):5c Gummy colorless liquid (94%, 116 mg), Rf 0.8
1
(PET); H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.0 Hz, 2H), 7.67-7.64 (m, 2H), 7.56 (t, J =
8.0 Hz, 2H), 7.43-7.38 (m, 2H), 7.20 (d, J = 7.2 Hz, 1H), 6.72 (s, 1H), 2.53 (s, 3H), 2.46 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 151.9, 148.2, 138.3, 131.9, 130.8, 128.7, 128.6, 128.1,
126.7, 125.3, 124.4, 121.0, 118.7, 110.8, 21.6, 12.2.
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(2-Chlorophenyl)-3-methyl-2-phenylfuran (3ac):7a Gummy liquid (81% yield, 108 mg), Rf 0.7
1
(PET); H NMR (400 MHz, CDCl3): δ 7.96 (dd, J = 8.0, 1.6 Hz, 1H), 7.74-7.71 (m, 2H), 7.47-
13
7.42 (m, 3H), 7.35-7.29 (m, 2H), 7.21-7.16 (m, 1H), 7.11 (s, 1H), 2.36 (s, 3H); C{1H} NMR
(100 MHz, CDCl3): δ 148.4, 148.0, 131.6, 130.8, 130.0, 129.2, 128.7, 127.9, 127.7, 127.09,
127.00, 125.5, 118.7, 116.8, 12.2.
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5-(4-Methoxyphenyl)-3-methyl-2-phenylfuran (3ad):10 White solid (88%, 116 mg), Rf 0.6
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(PET : EtOAc = 98 :2), mp 95−96 °C (lit. mp 96−97 °C); H NMR (400 MHz, CDCl3): δ 7.72-
7.69 (m, 2H), 7.67-7.63 (m, 2H), 7.45-7.40 (m, 2H), 7.28-7.24 (m, 1H), 6.96-6.91 (m, 2H), 6.48
(s, 1H), 3.85 (s, 3H), 2.33 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.1, 151.9, 147.6,
132.0, 128.6, 126.5, 125.27, 125.21, 124.0, 118.7, 114.3, 109.4, 55.4, 12.2.
5-(4-Chlorophenyl)-3-methyl-2-phenylfuran (3ae):7a White solid (82 % yield, 110 mg), Rf 0.7
(PET), mp 80–82 °C (lit. 81–82 °C); 1H NMR (400 MHz, CDCl3): δ 7.75-7.72 (m, 2H), 7.67-
7.64 (m, 2H), 7.50-7.45 (m, 2H), 7.40-7.36 (m, 2H), 7.34-7.30 (m, 1H), 6.62 (s, 1H), 2.36 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 150.7, 148.6, 132.8, 131.6, 129.3, 128.9, 128.7, 126.9,
125.3, 124.9, 118.8, 111.3, 12.2.
5-(4-Bromophenyl)-3-methyl-2-phenylfuran (3af):7a White solid (85 % yield, 133 mg), Rf 0.7
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(PET), mp 85–86 °C (lit. 84–85 °C); H NMR (400 MHz, CDCl3): δ 7.72-7.69 (m, 2H), 7.58-
7.55 (m, 2H), 7.52-7.49 (m, 2H), 7.46-7.42 (m, 2H), 7.31-7.27 (m, 1H), 6.61 (s, 1H), 2.33 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 150.7, 148.7, 131.9, 131.6, 129.8, 128.7, 127.0, 125.4,
125.3, 125.2, 123.8, 121.0, 118.9, 111.4, 12.2.
5-(2,4-Dimethylphenyl)-3-methyl-2-phenylfuran (3ag): Liquid (78%, 102 mg), Rf 0.8 (PET);
1H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 7.6 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 8.0
Hz, 2H), 7.29-7.25 (m, 1H), 7.08 (d, J = 6.8 Hz, 2H), 6.47 (s, 1H), 2.54 (s, 3H), 2.36 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3): δ 151.8, 147.6, 137.2, 134.4, 132.1, 132.0, 128.6, 127.5,
126.9, 126.8, 126.6, 125.2, 118.3, 113.8, 22.1, 21.2, 12.2; Anal. Calcd for C19H18O: C, 86.99; H,
6.92; Found: C, 86.77; H, 7.01%.
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5-Mesityl-3-methyl-2-phenylfuran (3ah): Colorless liquid (76%, 105 mg), Rf 0.7 (PET); H
NMR (400 MHz, CDCl3): δ 7.69 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.26 (t, J = 7.6 Hz,
1H), 6.97 (s, 2H), 6.23 (s, 1H), 2.38 (s, 3H), 2.35 (s, 3H), 2.30 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 150.4, 147.7, 138.3, 138.2, 132.2, 128.6, 128.5, 128.2, 126.4, 125.1, 117.3, 115.2,
21.2, 20.9, 12.3; Anal. Calcd for C20H20O: C, 86.92; H, 7.29%; Found: C, 87.13; H, 7.18%.
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2H), 6.73 (d, J = 3.2 Hz, 1H), 6.68 (d, J = 3.6 Hz, 1H), 2.38 (s, 3H); C{1H} NMR (100 MHz,
CDCl3): δ 129.5, 128.8, 128.7, 128.6, 128.3, 127.5, 127.3, 125.4, 123.87, 123.81, 107.3, 106.6,
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2-(4-Methoxyphenyl)-5-phenylfuran (3ca): Gummy mass (50%, 62 mg), Rf 0.8 (PET : EtOAc
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= 98:2); H NMR (400 MHz, CDCl3): δ 7.74-7.67 (m, 4H), 7.41-7.37 (m, 2H), 7.27-7.25 (m,
1H), 6.96-6.93 (m, 2H), 6.72 (d, J = 3.6 Hz, 1H), 6.60 (d, J = 3.2 Hz, 1H), 3.85 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 159.2, 152.8, 131.0, 128.8, 128.4, 127.2, 126.7, 125.3, 123.6, 114.3,
107.3, 105.7, 55.4; Anal. Calcd for C17H14O2: C, 81.58; H, 5.64%; Found: C, 81.31; H, 5.71%.
3-Methyl-5-phenyl-2-(p-tolyl)furan (3da):10 White solid (85%, 105 mg), Rf 0.8 (PET), mp
94−95 °C (lit. 95–96 °C); 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 7.6 Hz, 2H), 7.50 (d, J =
8.0 Hz, 2H), 7.27 (t, J = 7.6 Hz, 2H), 7.14-7.12 (m, 3H), 6.48 (s, 1H),2.28 (s, 3H), 2.20 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 151.4, 148.5, 136.5, 131.0, 129.3, 129.1, 128.7, 127.1,
125.3, 123.7, 118.0, 110.8, 21.3, 12.1.
2-(4-Methoxyphenyl)-3-methyl-5-phenylfuran (3ea):5c White solid, (90%, 119 mg), Rf 0.6
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(PET : EtOAc = 98 :2), mp 92-93 °C (lit. 92–93 °C); H NMR (400 MHz, CDCl3): δ 7.72-7.69
(m, 2H), 7.67-7.63 (m, 2H), 7.39 (t, J = 8.0 Hz, 2H), 7.26-7.22 (m, 1H), 7.00-6.97 (m, 2H), 6.60
(s, 1H), 3.86 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 158.6, 151.2, 148.4,
131.0, 128.7, 127.0, 126.8, 124.9, 123.6, 117.1, 114.2, 110.7, 55.4, 12.0.
2-(4-Chlorophenyl)-3-methyl-5-phenylfuran (3fa): White solid (91%, 122 mg), Rf 0.8 (PET),
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mp 77–78 °C; H NMR (400 MHz, CDCl3): δ 7.73-7.70 (m, 2H), 7.66-7.62 (m, 2H), 7.43-7.38
(m, 4H), 7.30-7.26 (m, 1H), 6.61 (s, 1H), 2.31 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
152.0, 147.2, 132.3, 130.6, 130.3, 128.87, 128.82, 127.5, 126.3, 123.8, 119.2, 111.0, 12.2; Anal.
Calcd for C17H13ClO: C, 75.98; H, 4.88%; Found: C, 76.10; H, 4.76%.
2,5-Bis(4-methoxyphenyl)-3-methylfuran (3ed): White solid (81%, 119 mg), Rf 0.6 (PET :
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EtOAc = 97:3), mp 82–84 °C; H NMR (400 MHz, CDCl3): δ 7.55-7.52 (m, 4H), 6.90-6.81 (m,
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4H), 6.36 (s, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 2.18 (s, 3H); C{1H} NMR (100 MHz, CDCl3): δ
158.9, 158.4, 151.3, 147.7, 128.3, 127.3, 126.7, 125.1, 125.0, 124.2, 117.0, 114.2, 114.1, 109.2,
55.4, 12.0; Anal. Calcd for C19H18O3: C, 77.53; H, 6.16%; Found: C, 77.31; H, 6.04%.
2,5-Bis(4-chlorophenyl)-3-methylfuran (3fe): Liquid (69%, 104 mg), Rf 0.8 (PET : EtOAc =
99:1); 1H NMR (400 MHz, CDCl3): δ 7.62-7.59 (m, 4H), 7.40-7.38 (m, 2H), 7.36-7.34 (m, 2H),
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6.58 (s, 1H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 151.0, 147.6, 133.1, 132.6,
130.1, 129.1, 129.0, 128.9, 126.4, 125.0, 119.3, 111.4, 12.2; Anal. Calcd for C17H12Cl2O: C,
67.35; H, 3.99%; Found: C, 67.56; H, 3.85%.
5-(4-Bromophenyl)-2-(4-methoxyphenyl)-3-methylfuran (3ef): White solid (71%, 122 mg), Rf
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0.6 (PET : EtOAc = 97:3), mp 82–83 °C; H NMR (400 MHz, CDCl3): δ 7.64-7.60 (m, 2H),
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7.56-7.53 (m, 2H), 7.50-7.47 (m, 2H), 7.00-6.96 (m, 2H), 6.58 (s, 1H), 3.86 (s, 3H), 2.28 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 158.8, 150.1, 148.9, 131.9, 129.9, 126.9, 125.1, 124.6,
120.7, 117.2, 114.2, 111.3, 55.4, 12.0; Anal. Calcd for C18H15BrO2: C, 62.99; H, 4.41%; Found:
C, 63.13; H, 4.32%.
3-Ethyl-2,5-diphenylfuran (3ga):10 Colorless oil (83% yield, 103 mg,), Rf 0.8 (PET); 1H NMR
(400 MHz, CDCl3): δ 7.77-7.72 (m, 4H), 7.49-7.40 (m, 4H), 7.33-7.25 (m, 2H), 6.72 (s, 1H),
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2.78 (q, J = 7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 152.1,
147.7, 131.8, 130.9, 128.7, 128.6, 127.3, 126.9, 125.6, 125.5, 123.7, 108.7, 19.4, 14.5.
2,3,5-Triphenylfuran (3ha):5c White solid (87 % yield, 129 mg), Rf 0.8 (PET), mp 99–101 °C
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(lit. 93–94 °C); H NMR (400 MHz, CDCl3): δ 7.75-7.72 (m, 2H), 7.60-7.56 (m, 2H), 7.45-7.42
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(m, 2H), 7.39-7.35 (m, 3H), 7.34-7.31 (m, 1H), 7.30-7.19 (m, 5H), 6.78 (s, 1H); C{1H} NMR
(100 MHz, CDCl3): δ 152.6, 148.0, 134.4, 131.2, 130.6, 128.87, 128.84, 128.80, 128.5, 127.66,
127.63, 127.4, 126.2, 124.6, 123.9, 109.6.
3-Methyl-4,5-diphenyl-2-(p-tolyl)furan (3di): White solid (86%, 139 mg), Rf 0.8 (PET), mp
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147–149 °C; H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 8.0 Hz, 2H), 7.40-7.33 (m, 4H), 7.31-
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7.25 (m, 3H), 7.18-7.12 (m, 4H), 7.07 (t, J = 7.6 Hz, 1H), 2.31 (s, 3H), 2.03 (s, 3H); C{1H}
NMR (100 MHz, CDCl3): δ 147.9, 146.8, 136.7, 134.0, 131.1, 130.2, 129.3, 128.9, 128.8, 128.3,
127.4, 126.9, 126.0, 125.5, 125.4, 118.1, 21.3, 10.4; Anal. Calcd for C24H20O: C, 88.85; H,
6.21%; Found: C, 89.13; H, 6.16%.
2-Phenyl-4,5-dihydronaphtho[1,2-b]furan (3ia):7a Colourless liquid (73% yield, 90 mg,), Rf
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0.8 (PET); H NMR (400 MHz, CDCl3): δ 7.85-7.81 (m, 2H), 7.70-7.67 (m, 1H), 7.52-7.46 (m,
2H), 7.38-7.34 (m, 2H), 7.30 (d, J = 7.2 Hz, 1H), 7.25-7.21 (m, 1H), 6.73 (s, 1H), 3.10 (t, J = 8.0
Hz, 2H), 2.88 (t, J = 8.4 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 153.3, 149.8, 134.8,
128.9, 128.8, 128.5, 128.1, 128.0, 127.2, 126.8, 126.4, 124.8, 123.7, 121.6, 119.2, 106.6, 29.1,
21.1.
2-(m-Tolyl)-4,5-dihydronaphtho[1,2-b]furan (3ib): Colorless oil (78%, 101 mg), Rf 0.8 (PET);
1H NMR (400 MHz, CDCl3): δ 7.73-7.65 (m, 3H), 7.44-7.36 (m, 2H), 7.33-7.30 (m, 1H), 7.27-
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7.23 (m, 1H), 7.21 (d, J = 6.8 Hz, 1H), 6.74 (s, 1H), 3.12 (t, J = 8.0 Hz, 2H), 2.90 (t, J = 8.4 Hz,
2H), 2.54 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.7, 153.5, 149.6, 138.3, 134.7, 131.0,
128.7, 128.1, 126.8, 126.4, 125.3, 125.1, 124.3, 121.5, 120.9, 120.1, 119.2, 106.5, 29.1, 21.6,
21.1; Anal. Calcd for C19H16O: C, 87.66; H, 6.20%; Found: C, 87.58; H, 6.14%.
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General Experimental Procedure for the Synthesis of Multisubstituted Furan (Scheme 4,
Scheme 5): A mixture of 1 (0.5 mmol), styrenes (4) (0.5 mmol), and Cu(OTf)2 (0.1 mmol, 36
mg) in DMF (2 mL) was placed in a reaction tube. Then the reaction mixture was stirred at 120
°C for 16 h under ambient air. After completion of the reaction (TLC), the reaction mixture was
cooled to room temperature and extracted with ethyl acetate. The organic phase was dried over
anhydrous Na2SO4. The crude residue was obtained after evaporation of the solvent in vacuum
and was purified by column chromatography on silica gel (60−120 mesh) using petroleum ether
as the eluent to afford pure product.
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3-Methyl-2,4,5-triphenylfuran (5aa): White solid (92%, 142 mg), Rf 0.8 (PET), mp 99–100 °C;
1H NMR (400 MHz, CDCl3): δ 7.69-7.67 (m, 2H), 7.40-7.33 (m, 6H), 7.31-7.29 (m, 1H), 7.27-
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7.25 (m, 2H), 7.22-7.18 (m, 1H), 7.16-7.12 (m, 2H), 7.10-7.05 (m, 1H), 2.05 (s, 3H); C{1H}
NMR (100 MHz, CDCl3): δ 147.8, 147.3, 134.0, 131.8, 131.1, 130.3, 128.9, 128.7, 128.4, 127.5,
127.1, 127.0, 126.1, 125.6, 125.5, 118.9, 10.5; Anal. Calcd for C23H18O: C, 89.00; H, 5.85%;
Found: C, 89.28; H, 5.76%.
3-Methyl-4,5-diphenyl-2-(p-tolyl)furan (5da): White solid (70%, 113 mg), Rf 0.8 (PET), mp
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147–149 °C; H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.4 Hz, 2H), 7.50-7.44 (m, 4H), 7.42-
7.39 (m, 1H), 7.38-7.35 (m, 2H), 7.29-7.22 (m, 4H), 7.20-7.15 (m, 1H), 2.42 (s, 3H), 2.14 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 148.0, 146.9, 136.8, 134.1, 131.2, 130.3, 129.4, 129.0,
128.9, 128.4, 127.5, 127.0, 126.0, 125.6, 125.5, 118.2, 21.4, 10.5; Anal. Calcd for C24H20O: C,
88.85; H, 6.21%; Found: C, 88.77; H, 6.29%.
2-(4-Methoxyphenyl)-3-methyl-4,5-diphenylfuran (5ea): White solid (88%, 150 mg), Rf 0.6
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(PET : EtOAc = 98:2), mp 132–133 °C; H NMR (400 MHz, CDCl3): δ 7.60-7.57 (m, 2H), 7.38-
7.31 (m, 5H), 7.25-7.22 (m, 3H), 7.13-7.09 (m, 2H), 6.90-6.87 (m, 2H), 3.73 (s, 3H), 2.00 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 158.7, 147.9, 146.6, 137.6, 134.1, 132.5, 131.2, 130.3,
128.8, 128.3, 127.4, 127.1, 125.4, 124.7, 117.3, 114.1, 55.4, 10.4; Anal. Calcd for C24H20O2: C,
84.68; H, 5.92%; Found: C, 84.48; H, 6.06%.
2-(4-Chlorophenyl)-3-methyl-4,5-diphenylfuran (5fa): White solid (84%, 145 mg), Rf 0.7
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(PET), mp 137–139 °C; H NMR (400 MHz, CDCl3): δ 7.62-7.58 (m, 2H), 7.38-7.35 (m, 3H),
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7.34-7.28 (m, 4H), 7.25-7.23 (m, 2H), 7.16-7.12 (m, 2H), 7.10-7.06 (m, 1H), 2.03 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 147.5, 146.7, 133.7, 132.6, 130.9, 130.3, 130.2, 128.97,
128.92, 128.4, 128.2, 127.6, 127.3, 126.7, 126.2, 125.6, 119.4, 10.6 ; Anal. Calcd for C23H17ClO:
C, 80.11; H, 4.97%; Found: C, 80.32; H, 4.89%.
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1H NMR (400 MHz, CDCl3): δ 7.69-7.66 (m, 2H), 7.38-7.30 (m, 7H), 7.29-7.25 (m, 2H), 7.23-
7.19 (m, 1H), 7.14-7.10 (m, 2H), 7.08-7.04 (m, 1H), 2.49 (q, J = 7.6 Hz, 2H), 0.98 (t, J = 7.6 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.35, 147.31, 134.2, 131.7, 131.1, 130.3, 128.9,
128.7, 128.4, 127.6, 127.1, 127.0, 125.7, 125.6, 125.4, 17.5, 14.7; Anal. Calcd for C24H20O: C,
88.85; H, 6.21%; Found: C, 88.61; H, 6.08%.
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2,4-Dimethyl-3,5-diphenylfuran (5ab): White solid (67%, 83 mg), Rf 0.8 (PET), mp 59–61 °C;
1H NMR (400 MHz, CDCl3): δ 7.67-7.64 (m, 2H), 7.45-7.39 (m, 4H), 7.34-7.29 (m, 3H), 7.27-
7.23 (m, 1H), 2.36 (s, 3H), 2.20 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.3, 147.0,
133.7, 132.0, 129.8, 128.6, 128.5, 126.8, 126.5, 125.4, 124.9, 116.5, 12.5, 10.9; Anal. Calcd for
C18H16O: C, 87.06; H, 6.49%; Found: C, 86.87; H, 6.52%.
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2,2,4,5-Tetraphenyl-2,3-dihydrofuran (6ha): Colorless oil (93%, 174 mg), Rf 0.7 (PET); H
NMR (400 MHz, CDCl3): δ 7.73-7.71 (m, 2H), 7.66-7.64 (m, 4H), 7.45-7.38 (m, 7H), 7.36-7.27
(m, 6H), 7.23-7.20 (m, 1H), 4.00 (d, J = 1.2 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ
149.0, 146.4, 135.6, 131.8, 128.8, 128.4, 128.3, 128.2, 127.5, 127.3, 126.2, 126.0, 109.6, 88.5,
50.0; Anal. Calcd for C28H22O: C, 89.81; H, 5.92%; Found: C, 90.13; H, 5.78%.
4-Ethyl-2-methyl-2,5-diphenyl-2,3-dihydrofuran (6gb): Colorless oil (63%, 83 mg), Rf 0.7
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(PET); H NMR (400 MHz, CDCl3): δ 7.58-7.56 (m, 2H), 7.49-7.46 (m, 2H), 7.38-7.25 (m, 5H),
7.24-7.20 (m, 1H), 2.98 (q, J = 15.6 Hz, 2H), 2.38-2.24 (m, 2H), 1.70 (s, 3H), 1.05 (t, J = 7.6 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 148.5, 146.5, 132.4, 128.3, 128.2, 127.8, 127.2, 126.7,
124.6, 110.8, 84.3, 49.3, 29.6, 20.3, 13.2; Anal. Calcd for C19H20O: C, 86.32; H, 7.63%; Found:
C, 86.55; H, 7.73%.
2,2-Diphenyl-2,3-dihydronaphtho[1,2-b]furan (6ia): Colorless oil (84%, 135mg), Rf 0.7 (PET);
1H NMR (400 MHz, CDCl3): δ 8.25 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.62-7.59 (m,
4H), 7.54-7.52 (m, 1H), 7.50-7.46 (m, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.38-7.33 (m, 5H), 7.31-
7.26 (m, 2H), 4.14 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 153.9, 145.7, 134.2, 128.4,
128.0, 127.5, 126.1, 125.8, 125.5, 122.8, 121.6, 120.69, 120.62, 119.2, 93.3, 45.6; Anal. Calcd
for C24H18O: C, 89.41; H, 5.63%; Found: C, 89.62; H, 5.55%.
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2-Methyl-2-phenyl-2,3-dihydronaphtho[1,2-b]furan (6ib): Colorless oil (90%, 117 mg), Rf 0.7
1
(PET); H NMR (400 MHz, CDCl3): δ 8.27 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.67-
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7.65 (m, 2H), 7.62-7.53 (m, 2H), 7.51-7.43 (m, 3H), 7.39-7.34 (m, 2H), 3.66 (q, J = 15.2 Hz,
2H), 1.98 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 154.2, 147.2, 134.2, 128.5, 128.0, 127.1,
125.7, 125.3, 124.6, 123.1, 121.7, 120.7, 120.2, 119.2, 90.0, 45.8, 29.5; Anal. Calcd for C19H16O:
C, 87.66; H, 6.20%; Found: C, 87.82; H, 6.12%.
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4-Methyl-2,2-diphenyl-5-(p-tolyl)-2,3-dihydrofuran (6da): Colorless oil (55%, 55 mg), Rf 0.6
(PET); 1H NMR (400 MHz, CDCl3): δ 7.49 (d, J = 8.4 Hz, 2H), 7.43-7.40 (m, 4H), 7.24-7.20 (m,
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4H), 7.15-7.11 (m, 4H), 3.41 (d, J = 1.2 Hz, 2H), 2.29 (s, 3H), 1.82 (s, 3H); C{1H} NMR (100
MHz, CDCl3): δ 147.1, 137.6, 129.2, 128.9, 128.2, 127.0, 126.1, 125.9, 104.1, 87.5, 52.1, 21.4,
12.9; Anal. Calcd for C24H22O: C, 88.31; H, 6.79%; Found: C, 88.07; H, 6.67%.
5-(4-Chlorophenyl)-4-methyl-2,2-diphenyl-2,3-dihydrofuran (6fa): Colorless oil (42%, 73
1
mg), Rf 0.6 (PET); H NMR (400 MHz, CDCl3): δ 7.52-7.47 (m, 2H), 7.39 (d, J = 7.6 Hz, 3H),
7.27-7.19 (m, 9H), 3.41 (s, 2H), 1.81 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 146.7, 133.4,
130.5, 128.6, 128.55, 128.50, 128.34, 128.30, 128.2, 127.2, 125.8, 105.7, 87.8, 52.1, 12.9; Anal.
Calcd for C23H19ClO: C, 79.65; H, 5.52%; Found: C, 79.52; H, 5.64%.
AUTHOR INFORMATION
Corresponding Author
E-mail: alakananda.hajra@visva-bharati.ac.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
A.H. acknowledges the financial support from SERB-DST, New Delhi (File No.
EMR/2016/001643). A.D. thanks CSIR thanks for fellowship.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:.
Scanned copies of 1H and 13C{1H} NMR spectra of the
synthesized compounds (PDF)
Crystallographic data for compound 5da (CIF)
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