An Unexpected C-C Bond Cleavage of Acetophenones: Synthesis of Bis(heteroaryl)arylmethanes and Triarylmethanes via SeO2/Lanthanide Chloride Catalyzed Friedel-Crafts Arylation

Article abstract of DOI:10.1055/s-0035-1560808

A novel synthesis of bisheteroarylaryl methanes and triarylmethanes is described by the selective C-C bond cleavage of acetophenones in the presence of SeO₂/lanthanide chlorides. The present strategy provides an in situ generation of aldehydes from acetophenones followed by a double Friedel-Crafts reaction of electron-rich arenes. Natural product 1,1,1-tris(3-indolyl)methane is synthesized in a single step following the same protocol.

Full text of DOI:10.1055/s-0035-1560808

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, A–I
letter
A
G. S. Kumar et al.
Letter
Synlett
An Unexpected C–C Bond Cleavage of Acetophenones: Synthesis
of Bis(heteroaryl)arylmethanes and Triarylmethanes via
SeO2/Lanthanide Chloride Catalyzed Friedel–Crafts Arylation
G. Santosh Kumar
A. Sanjeeva Kumar
A. Swetha
B. Madhu Babu
H. M. Meshram*
Medicinal Chemistry and Pharmacology Division, CSIR-Indian
Institute of Chemical Technology, Uppal Road, Tarnaka,
Hyderabad, Telangana 500007, India
hmmeshram@yahoo.com
Received: 15.06.2015
Accepted after revision: 28.09.2015
Published online: 30.11.2015
NaHSO4,20 silica-sulfuric acid,21 perfluorinated sulfonic acid
resin (Nafion-H),22 and ionic liquids23 have also been used
for the synthesis of diheteroarylalkane derivatives.
DOI: 10.1055/s-0035-1560808; Art ID: st-2015-b0446-l
Abstract A novel synthesis of bisheteroarylaryl methanes and triaryl-
methanes is described by the selective C–C bond cleavage of acetophe-
nones in the presence of SeO2/lanthanide chlorides. The present strate-
gy provides an in situ generation of aldehydes from acetophenones
followed by a double Friedel–Crafts reaction of electron-rich arenes.
Natural product 1,1,1-tris(3-indolyl)methane is synthesized in a single
step following the same protocol.
HN
NH
H
N
NH
OH
OH
N
HIV-1-integrase
inhibitor
arcindoline A
Key words acetophenones, C–C bond cleavage, double Friedel–Crafts
reaction
HN
N
N
NH
Bis(heteroaryl)arylmethane (BHAAM) and triarylmeth-
ane (TRAM) scaffolds containing molecules were found to
exhibit important biological activities such as antitubercu-
lar, anticancer, analgesic, antimicrobial, antiviral, and anti-
hyperglycemic properties (Figure 1).1 Many BHAAM deriva-
tives have a wide application in dyes, medicines, copy engi-
neering,2 agriculture chemistry,3 food industry,4 materials,
and photochromic agents.5 Moreover, tetraoxaquaterenes6
and macromolecules which are used as metal-ion carriers
have been synthesized from bis(furyl)methanes.7 As a re-
sult of this prevalence and prominence of BHAAM and
TRAM derivatives, various methods have been reported for
their synthesis using Lewis and Brønsted acids, solid-sup-
ported catalysts, and superacidic systems. For example,
Yb(OTf)3,8 AuCl3,9 molecular iodine,10 TMSCl,11 FeCl3,12 and
Cu(OTf)213 have been utilized as Lewis acids for these types
of reactions. Subsequently, Brønsted acids such as TfOH,14
TFA,15 PTSA,16 BF3·H2O,17 and o-benzenedisulfonimide18
have also been used predominately. In addition to this poly-
styrene-supported sulfonic acid,19 silica gel supported
O
Cl
O
streptindole
IKCa1 inhibitor
H2N
O
OH
MeO
Cl
S
IKCa17043
immune regulator
anti-tuberculosis agent
Figure 1 BHAAM- and TRAM-containing drugs
Though the reported methods are satisfactory for the
synthesis of BHAAM and TRAM, they have some drawbacks
like low yield, high catalyst loadings, and environmental in-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–I

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G. S. Kumar et al.
Letter
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compatibility. In this regard it is desirable to develop gener-
al and catalytic method for the synthesis of BHAAM and
TRAM (Scheme 1).
and 2-methylfuran (2) as the starting substrates (Table 1).
We performed the reaction of 1a with 2 in the presence of
SeO2/YCl3 (0.3 mmol) in DMSO–H2O (9:1, 3 mL) at 100 °C.
As expected, the above reaction gave the desired product
5,5′-[(4-chlorophenyl)methylene]bis(2-methylfuran) (4f) in
reasonable yield (75%, Table 1, entry 1). The structure of the
well known
H1Ar
Ar1H
O
1
Ar1H
product was confirmed by H NMR, 13C NMR, and IR spec-
H
troscopic and MS spectrometric analysis. It was presumed
that the formation of the desired product occurred may be
via C–C bond cleavage followed by double Friedel–Crafts re-
action. However, the reaction did not proceed in the ab-
sence of catalyst (Table 1, entry 2). Thus, a sequence of cata-
lysts, such as SeO2/YbCl3, SeO2/GdCl3, SeO2/SmCl3, SeO2/
NdCl3, SeO2/ErCl3, and SeO2/LaCl3 were tested for the reac-
tion (Table 1, entries 3–8). Among the screened catalysts,
YbCl3 was found the most suitable for maximum conversion
(80% yield, Table 1, entry 3).
R1
R1
this work
H1Ar
Ar1H
O
Ar1H
R1
R1
Scheme 1 Friedel–Crafts reactions of electron-rich arenes
Table 1 Optimization of the Reaction Conditions for the Synthesis of
5,5′-[(4-Chlorophenyl)methylene]bis(2-methylfuran) (4f)a
The selective cleavage of C–C bond can be a challenging,
yet offers one of the most powerful and efficient synthetic
strategies for chemical transformations.24 In addition to
this, metal-catalyzed C–C bond-cleavage reactions have be-
come the subject of intensive studies.25 On the other hand,
Friedel–Crafts reaction has attracted much attention and
emerged as well-accepted method in organic synthesis for
C–C bond formation.26 Till date various electron-rich
arenes/heteroarenes are used so far in the Friedel–Crafts re-
action with diverse carbonyl compounds. Lanthanide chlo-
rides are used as catalysts for various organic transforma-
tions27 because of certain advantages, like easy availability,
water-tolerant and nontoxic nature. Moreover, these cata-
lysts can be recovered and reused without loss of efficien-
cy.28
To the best of our knowledge the oxidative coupling of
acetophenones with electron-rich arenes to BHAAM and
TRAM remain unexplored. In the continuation of our work
related to green chemistry29a–d and double Friedel–Crafts
reactions,29e–i herein we wish to report for the first time
C–C bond cleavage of acetophenones in the presence of lan-
thanide chlorides for in situ generation of aldehydes and
subsequent Friedel–Crafts reaction with electron-rich
arenes/heteroarenes (Scheme 2).
Entry
Catalyst
Solvent
Yield (%)b
1
2
SeO2/YCl3
–
DMSO–H2O (9:1)
DMSO–H2O (9:1)
DMSO–H2O (9:1)
DMSO–H2O (9:1)
DMSO–H2O (9:1)
DMSO–H2O (9:1)
DMSO–H2O (9:1)
DMSO–H2O (9:1)
DMF–H2O (9:1)
toluene–H2O (9:1)
1,4-dioxane–H2O (9:1)
DMSO
75
n.r.
80
68
66
60
57
42
70
65
60
n.r.
n.r.
n.r.
n.r.
3
SeO2/YbCl3
SeO2/GdCl3
SeO2/SmCl3
SeO2/NdCl3
SeO2/ErCl3
SeO2/LaCl3
SeO2/YbCl3
SeO2/YbCl3
SeO2/YbCl3
SeO2/YbCl3
SeO2/YbCl3
SeO2
4
5
6
7
8
9
10
11
12
13
14
15
H2O
DMSO–H2O (9:1)
DMSO–H2O (9:1)
YbCl3
a Reaction conditions: 1-(4-chlorophenyl)ethanone (1e, 1 mmol), 2-methyl-
furan (2, 2 mmol), and lanthanide chloride (0.3 mmol) in solvent (3 mL) at
110 °C and 70 °C within 15 h and 10 min.
b Isolated yield.
Later, various solvent systems such as DMF–H2O, tolu-
ene–H2O, and 1,4-dioxane–H2O were examined, and the
DMSO–H2O system was found as solvent of choice in terms
of yield (Table 1, entries 9–11). The reaction failed to initi-
ate either in pure DMSO or in pure H2O (Table 1, entries 12
and 13), indicating that the mixture of solvent was essential
for the reaction to proceed. It is noteworthy to mention that
the reaction did not proceed with either SeO2 or YbCl3
alone (Table 1, entries 14 and 15).
Scheme 2 YbCl3-catalyzed C–C bond cleavage followed by Friedel–
Crafts reaction
In order to determine the credibility of our protocol in
the initial exploring experiments, we investigated different
reaction conditions using 1-(4-chlorophenyl)ethanone (1e)
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G. S. Kumar et al.
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With the optimal reaction conditions33 in hand, the
scope of this SeO2/lanthanide chloride catalyzed protocol
was extended to a variety of substituted acetophenones
with 2-methylfuran/thiophene, and the results are outlined
in the Scheme 3. Acetophenone bearing electron-donating
(OH, Me, OMe), or electron-withdrawing (CO2H, NO2, F, Cl)
groups reacted smoothly under the optimized conditions
and gave the desired products in good to high yields
(Scheme 3, 4a,c,d,f–i, 5a,c,e–j). In addition to this, both elec-
tron-donating and electron-deficient (2-HO-3,5-Cl and
2-HO-5-O2N) groups containing phenyl ring of acetophe-
nones also underwent smooth reaction and afforded high
yield of the corresponding products (Scheme 3, 4b,e, 5b,d).
To expand the scope of the substrates, acetophenones 1
with indoles 6 was examined in optimized conditions. To
our delight, the reaction proceeded easily to furnish bisin-
dolylmethanes 7. The results demonstrated that the elec-
tronic nature of the acetophenones had little influence on
X
X
SeO2 (2 mmol)
O
or
YbCl3 (0.3 mmol)
S
O
R1
DMSO–H2O (9:1)
110 °C, 15 h
2 or 3
70 °C, 10 min
1
R1
4 or 5
O
O
O
O
O
O
O
O
O
O
CO2H
OH
OH
OH
Cl
OH
O2N
OMe
Cl
OH
4d 75%
4a 77%
4b 78%
4c 75%
4e 72%
O
O
O
O
O
O
S
O
O
S
OH
OMe
OMe
Cl
OMe
F
4f 80%
4g 78%
4h 73%
4i 70%
5a 73%
S
S
S
S
S
S
S
S
S
S
OH
OH
Cl
Cl
NO2
OH
O2N
OH
OH
5c 70%
5b 72%
5d 67%
5e 69%
5f 72%
S
S
S
S
S
S
S
S
OMe
F
OMe
5j 64%
Cl
5g 73%
5h 72%
5i 67%
Scheme 3 YbCl3-catalyzed synthesis of bisheteroarylaryl methanes. Reagents and conditions: acetophenones 1 (1 mmol), 2-methylfuran/thiophene 2/3
(2 mmol), SeO2 (2 mmol), and YbCl3 (0.3 mmol) in DMSO–H2O (9:1, 3 mL) at 110 °C and 70 °C within 15 h and 10 min. Isolated yields are given.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–I

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G. S. Kumar et al.
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the reaction efficiency, as all the desired products with sub-
stituents were obtained in moderate to good yields
(Scheme 4, 7a,f).
phenyl)methylene] bis(2-methylfuran) (4f) was observed in
82% yield. Furthermore, aldehyde B with 2-methylfuran
could be converted into 4f under the same reaction condi-
tions. These results clearly confirmed the intermediacy of
phenylglyoxal A and aldehyde B in the transformation.
A putative mechanism for this SeO2/YbCl3-catalyzed
C–C bond cleavage followed by double Friedel–Crafts reac-
tion is proposed based on previous reports32 and illustrated
in Scheme 8. Initially, acetophenone was converted into
arylglyoxal A in the presence of SeO2, which reacts with wa-
ter, and reacted to hydrated α,α-bis(hydroxy)acetophenone
B by grasping one molecule of water. Compound B further
transformed into intermediate C in the presence of YbCl3 by
a 1,2-hydrate shift from methyl hydrogen atom to carbonyl
carbon in a Cannizaro-type reaction.33 Subsequently, cleav-
age of the C–C bond from int-C furnishes aldehyde D along
with the release of formic acid. Next, the aldehyde is coordi-
nated by YbCl3 to yield the more electrophilic carbonyl car-
bon of intermediate D. The nucleophilic carbon of arene/he-
teroarene attacks on the carbonyl carbon of D via Friedel–
Crafts reaction leading to the formation of the complex E,
which further converts into the highly stabilized carboca-
tion intermediate F by leaving a hydroxyl group. Finally, a
second molecule of arene/heteroarene reacts with F via
Friedel–Crafts reaction to afford the desired BHAAM and
TRAM products.
To further expand the substrate scope, we performed
the reactions of acetophenones 1 with different electron-
rich arenes 8, such as 1,3-dimethoxybenzene, 1,3,4-trime-
thoxybenzene, and 1,3,5-trimethoxybenzene, and they
were well tolerated to produce TRAM 9 in good yields
(Scheme 5). During the experiments we observed the reac-
tivity profile of electron-rich arenes/heteroarenes is as fol-
lows 2-methylfuran > indoles > 2-methylthiophene >
arenes.
The developed protocol was successfully applied to the
rapid and straightforward synthesis of natural product
1,1,1-tris(3-indolyl)methane.30 When we treated 1-(1H-in-
dol-3-yl)ethanone 1r with indole under the optimized reac-
tion conditions,31 we directly obtained the 1,1,1-tris(3-in-
dolyl)methane 7f in 50% yield (Scheme 6).
In order to address the mechanism of the present proto-
col, we carried out a few control experiments. 1-(4-chloro-
phenyl)ethanone (1f) was converted into 2-(4-chlorophe-
nyl)-2-oxoacetaldehyde A in 75% yield using the SeO2
(Scheme 7). Further the reaction of glyoxal A with YbCl3
gave 4-chlorobenzaldehyde B in 84% yield by the C–C bond
cleavage. Subsequently, glyoxal A was subjected to 2-meth-
ylfuran (2) in the presence of YbCl3, product 5,5′-[(4-chloro-
R2
HN
NH
SeO2 (2 mmol)
O
N
YbCl3 (0.3 mmol)
H
6
R2
R2
R1
DMSO–H2O (9:1)
70 °C, 10 min
110 °C, 15 h
1
R1
7
HN
HN
NH
NH
O2N
Br
7a 72%
7b 78%
H
HN
NH
N
NH
HN
NH
Br
Br
NC
Cl
OMe
CN
OMe
7c 72%
7d 65%
7e 76%
Scheme 4 YbCl3-catalyzed synthesis of bisindolylmethanes. Reagents and conditions: acetophenones 1 (1 mmol), indoles 6 (2 mmol), SeO2 (2 mmol),
and YbCl3 (0.3 mmol) in DMSO–H2O (9:1, 3 mL) at 110 °C and 70 °C within 15 h and 10 min. Isolated yields are given.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–I

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(MeO)n
(OMe)n
SeO2 (2 mmol)
YbCl3 (0.3 mmol)
O
(MeO)n
8
R1
DMSO–H2O (9:1)
110 °C 15 h
70 °C 10 min
1
R1
MeO
9
MeO
OMe
MeO
OMe
OMe
MeO
MeO
OMe
OMe
MeO
OMe
MeO
MeO
OMe
OMe
OMe
OMe
MeO
CN
9c 75%
OH
9b 65%
9a 70%
OMe
OMe
MeO
OMe
MeO
OMe
MeO
OMe
MeO
OMe
S
9d 65%
9e 62%
Scheme 5 YbCl3-catalyzed synthesis of triarylmethanes. Reagents and conditions: acetophenones 1 (1 mmol), arenes 8 (2 mmol), SeO2 (2 mmol), and
YbCl3 (0.3 mmol) in DMSO–H2O (9:1, 3 mL) at 110 °C and 70 °C within 15 h and 10 min. Isolated yields are given.
The recovery and reusability of the YbCl3 catalyst was
studied for four model products, such as 4f, 5a, 7b, and 9c.
After completion of the reaction, the reaction mixture was
filtered through a short pad of Celite®. Excess SeO2 and oth-
er selenium-containing byproducts were removed by ad-
sorption on Celite.
Water was added to the filtrate, and the mixture was ex-
tracted with dichloromethane. The catalyst was recovered
from the aqueous layer by removing water and then sub-
jected to the next run. The reuse of YbCl3 up to three cycles
gave consistent yield of product without any substantial
loss in the catalytic activity. These results are summarized
in Figure 2. The ease of recovery and reusability of this reac-
tion media may contribute to the development of green
strategy for the preparation of BHAAMs and TRAMs.
We believe that the present method may serve as an al-
ternative method for the synthesis of bisheteroarylmeth-
anes/tryarylmethanes, via in situ generation of aldehyde by
C–C bond cleavage. Moreover, the present method provides
access to bis(heteroaryl)methanes that were not prepared
earlier (Scheme 3, 4c–e, 5a–f,h,j).
In summary, we have developed a lanthanide chlorides
catalyzed novel one-pot synthesis of BHAAMs and TRAMs
by the Friedel–Crafts reaction of acetophenones with elec-
tron-rich arenes. Our method describes the use of ace-
tophenes for the first time in a one-pot reaction for the syn-
thesis of BHAAMs and TRAMs. The reaction involves an un-
HN
NH
O
N
H
6
SeO2/YbCl3
DMSO–H2O (9:1)
70 °C, 20 min
NH
110 °C, 15 h
NH
1r
50%
1,1,1-tris(3-indolyl)methane (7f)
Scheme 6 Synthesis of 1,1,1-tris(3-indolyl)methane 7f
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–I

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G. S. Kumar et al.
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O
O
O
O
SeO2
YbCl3
H
DMSO–H2O (9:1)
110 °C
DMSO–H2O (9:1)
110 °C
Cl
Cl
Cl
75%
84%
1f
A
B
O
O
O
O
O
YbCl3
2
O
H
DMSO–H2O (9:1)
110 °C
70 °C
Cl
Cl
A
B
Cl
4f
82%
O
O
O
YbCl3
H
+
O
DMSO–H2O (9:1)
70 °C
Cl
2
4f
B
Cl
90%
Scheme 7 Control experiments
SeO2
O
O
O
Ar1H
Ar
Ar
Ar1
1
H
H2O
Ar
Ar1
A
Ar1
F
Ar
O
OH
3
Ar
OH
B
H
YbCl3
Ar1
O
Ar
E
OH
H
1,2-hydride
shift
H
OH
+
Ar
Ar
O
+
OH
Ar1H
HO
YbCl3
YbCl3
H
O
YbCl3
O
Ar
D
OH
O
Ar
HCOOH
H
OH
C
Scheme 8 Plausible mechanistic pathway for the formation of BHAAMs and TRAMs
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G. S. Kumar et al.
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expected cleavage of the C–C bond of acetophenones that
yields aldehydes which further participated in a Friedel–
Crafts reaction. This is the first report regarding the C–C
bond cleavage in the presence of YbCl3. The present method
is rapid, convenient, and practical to provide BHAAMs and
TRAMs. Moreover, the recovery and reusability of the cata-
lyst makes the procedure environmental friendly.
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Figure 2 Reusability data for YbCl3
Acknowledgment
G S K, A S K, A S and B M B thank CSIR for the award of a fellowship
and to Dr. Ahmed Kamal, Director IICT, for his support and encourage-
ment.
The authors also thank CSIR, New Delhi for financial support as part
of XII Five Year plan programme under title ORIGIN (CSC-0108).
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Supporting Information
Supporting information for this article is available online at
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http://dx.doi.org/10.1055/s-0035-1560808.
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Letter
Synlett
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added to the filtrate, and the mixture was extracted with
CH2Cl2. The combined organic layers were dried over anhydrous
Na2SO4, concentrated in vacuo, and purified by chromatography
on silica gel to afford required products 4 or 5. The recovered
catalyst was obtained from the aqueous layer after removing
water.
1H NMR, 13C NMR, MS, and IR spectral data for the new products
are given below.
2-[Bis(5-methylfuran-2-yl)methyl]-6-methoxyphenol
Scheme 3)
(4c,
Dark-brown viscous oil. 1H NMR (300 MHz, CDCl3): δ = 2.23 (s, 6
H), 3.86 (s, 3 H), 4.01 (s, 1 H), 5.86 (s, 4 H), 6.73–6.83 (m, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 13.6, 37.6, 55.9, 105.9,
107.9, 109.1, 119.2, 121.3, 123.3, 125.6, 142.9, 146.3, 151.1,
152.4, ppm. IR (KBr): ν = 731, 790, 1023, 1232 1290, 1481,
1608, 3521 cm–1. ESI-MS: m/z = 321 [M + Na]+. ESI-HRMS: m/z
calcd for C18H18O4Na [M + Na]+: 321.1098; found: 321.1092.
4-[Bis(5-methylfuran-2-yl)methyl]benzene-1,2-diol
Scheme 3)
(4d,
Dark-brown viscous oil. 1H NMR (300 MHz, CDCl3): δ = 2.24 (s, 6
H), 5.21 (s, 1 H), 5.83–5.88 (m, 4 H), 6.68 (dd, J = 1.88, 8.12 Hz, 1
H), 6.75 (d, J = 1.88 Hz, 1 H), 6.80 (d, J = 8.30 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 13.5, 44.3, 106.0, 107.9, 115.2,
115.4, 120.9, 132.9, 142.5, 143.3, 151.3, 152.9 ppm. IR (KBr): ν =
750, 801, 1107, 1269, 1519, 1603, 3387cm–1. ESI-MS: m/z = 307
[M + Na]+. ESI-HRMS: m/z calcd for C17H16O4Na [M + Na]+:
307.0945; found: 307.0939.
2-[Bis(5-methylfuran-2-yl)methyl]-4,6-dichlorophenol (4e,
Scheme 3)
Dark-brown viscous oil. 1H NMR (300 MHz, CDCl3): δ = 2.24 (s, 6
H), 5.73–5.76 (m, 1 H), 5.87–5.93 (m, 4 H), 7.01–7.04 (m, 1 H),
7.22 (d, J = 2.13 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
13.5, 38.4, 106.1, 108.6, 120.4, 125.2, 127.1, 128.3, 128.9, 147.6,
150.8, 151.7 ppm. IR (KBr): ν = 735, 811, 1051, 1182, 1240,
1321, 1465, 1679, 3509 cm–1. ESI-MS: m/z = 360 [M + Na]+. ESI-
HRMS: m/z calcd for C17H14Cl2O3Na [M + Na]+: 360.0214; found:
360.0210.
(27) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W. L. Chem.
Rev. 2002, 102, 2227.
(28) Xu, F.; Luo, Y.; Wu, J.; Shen, Q.; Chen, H. Heteroat. Chem. 2006,
17, 389.
(29) (a) Santosh Kumar, G.; Pushpa Ragini, S.; Sanjeeva Kumar, S.;
Meshram, H. M. RSC Adv. 2015, 5, 51576. (b) Madhu Babu, B.;
Santosh Kumar, G.; Thakur, P. B.; Bangade, V. M. Tetrahedron
Lett. 2014, 55, 3473. (c) Santosh Kumar, G.; Pushpa Ragini, S.;
Meshram, H. M. Tetrahedron Lett. 2013, 54, 5974. (d) Meshram,
H. M.; Ramesh, P.; Santosh Kumar, G.; Reddy, B. C. K. Tetrahe-
dron Lett. 2010, 51, 4313. (e) Raghavender Reddy, M.;
Nageswara Rao, N.; Ramakrishna, K.; Meshram, H. M. Tetrahe-
dron Lett. 2014, 55, 1898. (f) Nageswara Rao, N.; Raghavende
Reddy, M.; Ramakrishna, K.; Meshram, H. M. Helv. Chim. Acta
2014, 97, 744. (g) Swetha, A.; Kumar, G. S.; Kumar, A. S.;
Meshram, H. M. Tetrahedron Lett. 2014, 55, 4705. (h) Madhu
Babu, B.; Thakur, P. B.; Rao, N. N.; Kumar, G. S.; Meshram, H. M.
Tetrahedron Lett. 2014, 55, 1868. (i) Madhu Babu, B.; Thakur, P.
B.; Bangade, V. M. Tetrahedron Lett. 2014, 55, 766.
2-[Bis(5-methylthiophen-2-yl)methyl]phenol (5a, Scheme 3)
Dark-brown viscous oil. 1H NMR (300 MHz, CDCl3): δ = 2.40 (s, 6
H), 5.94 (s, 1 H), 6.56–6.58 (m, 2 H), 6.63 (d, J = 3.35 Hz, 2 H),
6.77 (dd, J = 1.22, 8.54 Hz, 1 H), 6.88 (td, J = 1.22, 7.47 Hz, 1 H),
7.12–7.16 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.3,
41.6, 116.2, 120.8, 124.6, 125.8, 128.3, 129.3, 130.1, 139.3,
143.7, 153.0 ppm. IR (KBr): ν = 754, 810, 1042, 1227, 1270,
1455, 1593, 3504 cm–1. ESI-MS: m/z = 301 [M + H]+. ESI-HRMS:
m/z calcd for C17H17OS2 [M + H]+: 301.0719; found: 301.0714.
2-[Bis(5-methylthiophen-2-yl)methyl]-4-nitrophenol
Scheme 3)
(5b,
White solid; mp 196–198 °C. 1H NMR (300 MHz, CDCl3): δ =
2.44 (s, 6 H), 5.94 (s, 1 H), 6.61 (dd, J = 0.94, 3.39 Hz, 2 H), 6.65
(d, J = 3.39 Hz, 2 H), 6.90 (q, J = 6.04 Hz, 1 H), 8.07–8.12 (m, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 15.3, 41.6, 116.5, 124.7,
124.9, 125.5, 126.4, 131.0, 140.2, 141.7, 158.8 ppm. IR (KBr): ν =
639, 1071, 1278, 1327, 1486, 1588, 3317 cm–1. ESI-MS: m/z =
368 [M + Na]+. ESI-HRMS: m/z calcd for C17H16NO3S2 [M + Na]+:
368.0390; found: 368.0387.
(30) Ravikanth, V.; Imelda, O.; Irene, W.; Hartmut, L. J. Nat. Prod.
2003, 66, 1520.
(31) General Procedure for the Synthesis of Compounds 4 or 5
A solution of acetophenone 1 (1 mmol), SeO2 (2 mmol), and
YbCl3 (0.3 mmol) in DMSO–H2O (9:1, 3 mL) was well stirred at
110 °C for 15 h. Then the 2-methylfuran (2) or 2-methylthio-
phene (3) was added to the reaction mixture at r.t. and stirred
again for 10 min at 70 °C. After completion of the reaction, the
reaction mixture brought to r.t., and it was filtered through a
short pad of Celite, excess SeO2, and other selenium-containing
byproducts were removed by adsorption on Celite. Water was
4-[Bis(5-methylthiophen-2-yl)methyl]benzene-1,2-diol (5c,
Scheme 3)
Dark-brown viscous oil. 1H NMR (300 MHz, CDCl3): δ = 2.40 (s, 6
H), 5.55 (s, 1 H), 6.53–6.60 (m, 4 H), 6.72–6.82 (m, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 15.3, 47.0, 115.1, 115.4, 120.9,
124.4, 125.5, 136.9, 138.9, 142.4, 143.2, 145.3 ppm. IR (KBr): ν =
765, 806, 1111, 1282, 1518, 1607, 3392 cm–1. ESI-MS: m/z = 317
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–I

I
G. S. Kumar et al.
Letter
Synlett
[M + H]+. ESI-HRMS: m/z calcd for C17H17O2S2 [M + H]+:
317.0668; found: 317.0666.
MS: m/z = 301 [M + H]+. ESI-HRMS: m/z calcd for C17H17O2S2 [M
+ H]+: 301.0717; found: 301.0712.
2-[Bis(5-methylthiophen-2-yl)methyl]-4,6-dichlorophenol
(5d, Scheme 3)
5,5′-[(4-Fluorophenyl)methylene]bis(2-methylthiophene)
(5h, Scheme 3)
Dark-brown viscous oil. 1H NMR (300 MHz, CDCl3): δ = 2.42 (s, 6
H), 5.71 (s, 1 H), 6.04 (br s, 1 H), 6.57 (s, 4 H), 7.09 (d, J = 2.45 Hz,
1 H), 7.24 (d, J = 2.45 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 15.3, 40.7, 120.4, 124.6, 125.2, 126.0, 127.1, 128.0, 133.0,
139.3, 142.9, 147.2 ppm. IR (KBr): ν = 757, 800, 1039, 1161,
1227, 1321, 1460, 1667, 3521 cm–1. ESI-MS: m/z = 370 [M + H]+.
ESI-HRMS: m/z calcd for C17H18Cl2OS2 [M + H]+: 370.3362;
found: 370.3358.
Dark-brown viscous oil. 1H NMR (300 MHz, CDCl3): δ = 2.40 (s, 6
H), 5.64 (s, 1 H), 6.56 (s, 4 H), 6.97 (t, J = 3.50 Hz, 2 H), 7.22–7.28
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.0, 46.8, 115.1,
124.4, 125.5, 129.6, 138.9, 144.8, 159.9, 163.1 ppm. IR (KBr): ν =
537, 803, 842, 1158, 1227, 1505, 1603 cm–1. ESI-MS: m/z = 303
[M + H]+. ESI-HRMS: m/z calcd for C17H16FS2 [M + H]+: 303.0673;
found: 303.0670.
5,5′-[(3,4-Dimethoxyphenyl)methylene]bis(2-methylthio-
phene) (5j, Scheme 3)
5,5′-[(3-Nitrophenyl)methylene]bis(2-methylthiophene) (5e,
Scheme 3)
Brown solid; mp 112–114 °C. 1H NMR (300 MHz, CDCl3): δ =
2.40 (s, 6 H), 3.81 (s, 3 H), 3.84 (s, 3 H), 5.61 (s, 1 H), 6.55 (dd, J =
0.94, 3.39 Hz, 2 H), 6.59 (d, J = 3.21 Hz, 2 H), 6.80–6.86 (m, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 15.2, 47.3, 55.7, 110.8,
111.6, 120.2, 124.3, 125.4, 136.3, 138.8, 145.4, 147.9, 148.7
ppm. IR (KBr): ν = 721, 759, 1038, 1251, 1302, 1491, 1572, 1692
cm–1. ESI-MS: m/z = 367 [M + Na]+. ESI-HRMS: m/z calcd for
Dark-brown viscous oil. 1H NMR (300 MHz, CDCl3): δ = 2.40 (s, 6
H), 5.77 (s, 1 H), 6.54–6.62 (m, 4 H), 7.44 (t, J = 8.30 Hz, 1 H),
7.64 (d, J = 7.55 Hz, 1 H), 8.08 (d, J = 8.30 Hz, 1 H), 8.16 (s, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 15.1, 47.0, 121.9, 123.0,
124.6, 126.0, 129.1, 134.2, 139.6, 143.2, 145.7, 148.1 ppm. IR
(KBr): ν = 730, 800, 1229, 1350, 1530 cm–1. ESI-MS: m/z = 352
[M + Na]+. ESI-HRMS: m/z calcd for C17H15NO2S2Na [M + Na]+:
352.0347; found: 352.0342.
C
19H20O2S2Na [M + H]+: 367.0899; found: 367.0894.
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Angew. Chem. Int. Ed. 2013, 52, 11303. (b) Koito, Y.; Nakajima,
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A. J. Org. Chem. 1996, 61, 6100.
3-[Bis(5-methylthiophen-2-yl)methyl]phenol (5f, Scheme 3)
Dark-brown viscous oil. 1H NMR (300 MHz, CDCl3): δ = 2.39 (s, 6
H), 5.25 (br s, 1 H), 5.60 (s, 1 H), 6.49–6.61 (m, 4 H), 6.63–6.77
(m, 2 H), 6.82–6.89 (m, 1 H), 7.09–7.18 (m, 1 H) ppm. IR (KBr): ν
= 703, 754, 803, 1040, 1227, 1263, 1451, 1598, 3393 cm–1. ESI-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–I