I2-Catalyzed divergent regioselective addition of methoxybenzenes with ethenylbenzenes under microwave irradiation

Article abstract of DOI:10.1002/hlca.201300333

A highly efficient synthesis of 1,2,2-triarylethanones has been developed from simple and commercially available electron-rich arenes and styrenes (ethenylbenzenes). Copyright

Full text of DOI:10.1002/hlca.201300333

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Helvetica Chimica Acta – Vol. 97 (2014)
I2-Catalyzed Divergent Regioselective Addition of Methoxybenzenes with
Ethenylbenzenes under Microwave Irradiation
by Nalajala Nageswara Rao, Maddi Raghavender Reddy, Konakalla Ramakrishna,
and Harshadas Mitaram Meshram*
Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500 007, India
(phone: þ 91-40-27191640; fax: þ 91-40-27160512; e-mail: hmmeshram@yahoo.com)
A highly efficient synthesis of 1,2,2-triarylethanones has been developed from simple and
commercially available electron-rich arenes and styrenes (ethenylbenzenes).
Introduction. – The synthesis of diarylmethanes have attracted considerable
attention due to their importance as the core structure in a multitude of biologically
active compounds and pharmaceuticals such as anastrozol, avrainvilleol, beclobrate,
letrozole, piritrexim, trimethoprim, and papaverine [1]. Diarylmethanes are key
intermediates in the synthesis of such natural products and biologically relevant small
molecules. In spite of their diverse medicinal features including antitubercular,
anticancer, and antiproliferative activities, an efficient and general protocol for the
synthesis of diarylmethanes is still highly desirable [2]. Consequently, several elegant
methods have been reported for the synthesis of diarylmethane derivatives, which were
mainly focused on FriedelꢀCrafts alkylation of electron-rich arenes with carbonyl
compounds and their imines using a Lewis or a protic acid [3]. Various Pd-catalyzed
coupling methods have also been developed for the synthesis of diarylmethanes from
aryl methyl ketones [4]. Myrboh and co-workers also proposed a regioselective
diarylation of aromatic ketones in the presence of SeO2 and BF3 · Et2O [5]. Recently,
A.-X. Wu and co-workers reported excellent methods for the oxidation aryl methyl
ketones or terminal alkenyl-arenes to a-oxoaldehydes and subsequent reactions with
various nucleophiles [6]. On the basis of these reports, we found that a wide range of
terminal ethenyl-arenes could easily be converted to a-iodoacetophenone in the
presence of I2/2-iodoxybenzoic acid (IBX) in DMSO [7] and a-iodoacetophenone was
easily converted to a-oxoaldehyde in DMSO via Kornblum oxidation [8].
In view of this and in continuation of our work on microwave-promoted reactions
[9], we herein report on a protocol under microwave irradiation (MWI) for the
diarylation of aromatic arenes with electron-rich arenes such as 1,3-dimethoxybenzene
1,3,5-trimethoxybenzene, and 1,2,4-trimethoxybenzene to afford 1,2,2-triarylethanones
1 (Scheme 1).
Results and Discussion. – The initial reaction of styrene with 1,3-dimethoxybenzene
was examined under MWI with different oxidants and I2 in DMSO. Surprisingly, all of
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Helvetica Chimica Acta – Vol. 97 (2014)
745
Scheme 1. Synthesis of 1,2,2-Triarylethanones from Methoxybenzenes and Styrenes
the oxidants including oxone, PhI(OAc)2, DMP, TBHP, TEMPO, DDQ, and mCPBA
were ineffective. Gratifyingly, the reaction proceeded in good yield by using 2-
iodoxybenzoic acid (IBX) as an oxidant and I2 as an additive in DMSO under MWI.
Different temperatures were also tested to improve the yield, and 908 was found to be
the most optimal temperature for the domino reaction. Finally, from the above results,
the optimal reaction conditions for the domino reaction turned out to be styrene
(ethenylbenzene; R3 ¼ H; 0.5 mmol) and 1,3-dimethoxybenzene (R1 ¼ R2 ¼ H;
1.2 mmol), at 908 with I2/IBX (0.8 mmol/0.6 mmol) in DMSO (3 ml) under MWI.
With the optimized reaction conditions in hand, the scope of the reaction was
investigated (Table). Both electron-donating and electron-withdrawing groups (R3; see
Scheme 1) attached to etheyl-arenes were all suitable for this protocol. Ethenyl-arenes
with different substituents, such as Br, Cl, NO2, and OH could all provide the
corresponding products with yields in the range of 50 – 75% (i.e., 1b, 1c, 1d, 1h, 1i, 1j,
1k, and 1l). Simple styrenes also gave good yields with electron-rich arenes (Table; 1a,
1f, and 1j). In addition, 4-phenylstyrene also reacted with 1,3-dimethoxybenzene (R1 ¼
R2 ¼ H) to give the desired products 1e in 65% yield. Then, we turned our attention to
the methoxybenzenes, and found all the electron-rich arenes gave good yields (i.e., 1a –
1l). There had been no steric influence of different electron-rich arenes on the reaction.
Next, an attempt was undertaken to examine the reactivity of 1,2-, 1,4-dimethox-
ybenzene and catechols. They, however, failed to give the desired products. All the
compounds were characterized by their IR, 1H- and 13C-NMR, and MS data.
A possible reaction mechanism is shown in Scheme 2. Initially, the substrate styrene
is converted into phenacyl iodide, A, by I2/IBX. Subsequently, phenylglyoxal is formed
via Kornblum oxidation in the presence of DMSO. The a-keto aldehyde B is attacked
by 1,3-dimethoxybenzene in the presence of formed HI, which then undergoes a
FriedelꢀCrafts-like alkylation with the diarylmethanes (Scheme 2).
Conclusion. – We have developed a highly efficient, microwave-assisted synthesis
of diarylmethanes by domino oxidative FriedelꢀCrafts reaction of styrenes with
methoxybenzenes.
The authors thank CSIR, New Delhi, for financial support as part of XII. Five Year Plan Program
under the title ORIGIN (CSC-0108) and to Dr. A. Kamal, an outstanding scientist and Head of MCP
Division, for his support and encouragement. N. N. Rao, M. R. Reddy, and K. Ramakrishna thank UGC
for the award of a fellowship.

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Helvetica Chimica Acta – Vol. 97 (2014)
Table. Synthesis of Diarylmethanes from Methoxybenzenes and Styrenes with I2/IBX in DMSO under
Microwave Irradiation
Entry
R1
R2
R3
Product
Yield [%]
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
NO2
OH
Ph
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
65
75
50
60
65
65
70
50
55
65
70
70
H
MeO
MeO
MeO
MeO
H
Br
NO2
OH
H
Cl
Br
H
10
11
12
MeO
MeO
MeO
1j
1k
1l
H
H
Scheme 2. A Plausible Mechanism of the Reaction Leading to 1,2,2-Triarylethanones

Helvetica Chimica Acta – Vol. 97 (2014)
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Experimental Part
General. The chemicals, I2, styrenes (Aldrich), IBX (prepared), and all the solvents were obtained
from local suppliers. Column chromatography (CC): silica gel (SiO2; 60 – 120 mesh). M.p.: Mettler-Temp
apparatus; uncorrected. IR Spectra: PerkinElmer-1600 FT-IR spectrometer; in KBr; ˜n in cmꢀ1. 1H- and
13C-NMR spectra: Bruker-Avance-300 spectrometer; in CDCl3 ; d in ppm rel. to Me4Si as internal
standard; J in Hz. ESI-MS: VG Micromass 7070 H spectrometer with a direct inlet system; in m/z (rel.
%), and Agilent 6510 Q-TOF LC/MS instrument. Microwave irradiation (MWI): CEMTM Discover
Microwave instrument.
General Procedure: Freshly prepared IBX (0.6 mmol) and I2 (0.8 mmol) were added to a well-stirred
soln. of styrene (0.5 mmol) and 1,3-dimethoxybenzene (1.2 mmol) in anh. DMSO (3 ml). The mixture
was stirred for 5 – 10 min at r.t., then placed in the cavity of a MW reactor, and irradiated for 15 – 20 min,
at 908 (temp. monitored by built-in infrared sensor) with a power of 150 W. After cooling to r.t. by an air-
flow, the tube was removed from the rotor. The mixture was diluted with H2O and extracted with AcOEt.
The combined extracts were then dried (Na2SO4), and, after removal of the solvent, the mixture was
purified by CC (SiO2, 60 – 120 mesh; hexane/AcOEt 4 :1) to give the pure product 1a.
2,2-Bis(2,4-dimethoxyphenyl)-1-phenylethanone (1a). White solid. M.p. 145 – 1468. IR: 2959, 2836,
1680, 1610, 1212, 1038. 1H-NMR: 7.99 (d, J ¼ 7.9, 2 H); 7.46 (t, J ¼ 7.4, 1 H); 7.37 (t, J ¼ 7.4, 2 H); 6.87 (d,
J ¼ 8.3, 2 H); 6.49 (d, J ¼ 2.4, 2 H); 6.48 (s, 1 H); 6.41 (d, J ¼ 2.4, 1 H); 6.39 (d, J ¼ 2.4, 1 H); 3.78 (s, 6 H);
3.75 (s, 6 H). 13C-NMR: 199.6; 159.9; 157.6; 137.0; 132.2; 130.2; 128.4; 128.2; 119.4; 103.8; 98.7; 55.5; 55.2;
45.0. ESI-MS: 393 ([M þ H]þ).
1-(4-Bromophenyl)-2,2-bis(2,4-dimethoxyphenyl)ethanone (1b). Pale-orange color solid. M.p. 110 –
1128. IR: 3155, 2961, 2835, 1720, 1610, 1587, 1503, 1466, 1271, 1210, 1135, 810. 1H-NMR: 7.86 (d, J ¼ 8.5,
2 H); 7.50 (d, J ¼ 8.5, 2 H); 7.50 (d, J ¼ 8.5, 2 H); 6.85 (d, J ¼ 8.5, 2 H); 6.49 (d, J ¼ 2.4, 2 H); 6.41 (d, J ¼
2.4, 2 H); 6.40 (s, 1 H); 3.78 (s, 6 H); 3.75 (s, 6 H). 13C-NMR: 198.4; 160.0; 157.5; 135.8; 131.5; 130.2;
129.9; 127.2; 119.0; 104.0; 98.7; 55.4; 55.2; 45.0. ESI-MS: 471 ([M þ H]þ).
2,2-Bis(2,4-dimethoxyphenyl)-1-(4-nitrophenyl)ethanone (1c). Pale-yellow solid. M.p. 179 – 1808. IR:
2930, 2833, 1694, 1592, 1530, 1505, 1344, 1210, 834. 1H-NMR: 8.22 (d, J ¼ 9.0, 2 H); 8.12 (d, J ¼ 9.0, 2 H);
6.86 (d, J ¼ 8.5, 2 H); 6.50 (d, J ¼ 2.4, 2 H); 6.43 (d, J ¼ 2.4, 1 H); 6.42 (s, 1 H); 6.41 (d, J ¼ 2.4, 1 H); 3.78
(s, 6 H); 3.76 (s, 6 H). 13C-NMR: 198.0; 159.5; 157.7; 153.1; 145.8; 130.1; 129.5; 123.2; 122.9; 103.5; 98.5;
55.3; 55.0; 42.3. ESI-MS: 438 ([M þ H]þ).
2,2-Bis(2,4-dimethoxyphenyl)-1-(4-hydroxyphenyl)ethanone (1d). Ash-colored solid. M.p. 147 –
1
1488. IR: 3269, 2930, 2827, 1640, 1599, 1472, 1222, 1121, 810. H-NMR: 7.93 (d, J ¼ 8.8, 2 H); 6.87 (d,
J ¼ 8.5, 2 H); 6.79 (d, J ¼ 8.6, 2 H); 6.48 (d, J ¼ 2.4, 2 H); 6.42 (s, 1 H); 6.40 (d, J ¼ 2.4, 1 H); 6.38 (d, J ¼
2.4, 1 H); 6.32 (s, 1 H); 3.77 (s, 6 H); 3.74 (s, 6 H); 13C-NMR: 198.1; 159.0; 157.9; 153.3; 136.5; 132.2;
130.1; 125.6; 114.7; 103.4; 98.7; 55.6; 55.2; 41.2. ESI-MS: 409 ([M þ H]þ).
1-(1,1’-Biphenyl-4-yl)-2,2-bis(2,4-dimethoxyphenyl)ethanone (1e). Pale yellow solid. M.p. 140 – 1428.
1
IR: 3034, 3100, 2924, 1697, 1602, 1487, 1198, 1125, 824. H-NMR: 8.68 (d, J ¼ 8.4, 2 H); 7.56 – 7.61 (m,
4 H); 7.40 – 7.46 (m, 2 H); 6.90 (d, J ¼ 8.3, 2 H); 6.52 (s, 1 H); 6.50 (d, J ¼ 2.2, 2 H); 6.43 (d, J ¼ 2.4, 1 H);
6.40 (d, J ¼ 2.2, 1 H); 3.78 (s, 6 H); 3.77 (s, 6 H). 13C-NMR: 199.0; 159.9; 157.6; 144.7; 139.9; 135.7; 130.2;
129.6; 128.9; 128.8; 128.7; 127.8; 127.1; 127.0; 126.8; 119.4; 103.9; 98.7; 55.4; 55.1; 45.0. ESI-MS: 469 ([M þ
H]þ).
1-Phenyl-2,2-bis(2,4,6-trimethoxyphenyl)ethanone (1f). Sandy-brown colored solid. M.p. 75 – 778.
1
IR: 2996, 2936, 1693, 1593, 1461, 1225, 1205, 1120, 813. H-NMR: 7.86 (d, J ¼ 8.5, 2 H); 7.38 (t, J ¼ 7.4,
2 H); 7.30 (d, J ¼ 7.8, 2 H); 6.29 (s, 1 H); 6.07 (s, 4 H); 3.75 (s, 6 H); 3.55 (s, 12 H). 13C-NMR: 198.0; 159.5;
158.9; 137.7; 131.1; 127.7; 127.4; 110.7; 91.2; 55.8; 55.0; 41.4. ESI-MS: 453 ([M þ H]þ).
1-(4-Bromophenyl)-2,2-bis(2,4,6-trimethoxyphenyl)ethanone (1g). Light-brown solid. M.p. 111 –
1
1138. IR: 3055, 2972, 2824, 1730, 1605, 1499, 1309, 1133, 823. H-NMR: 7.71 (d, J ¼ 8.4, 2 H); 7.42 (d,
J ¼ 7.4, 2 H); 6.22 (s, 1 H); 6.07 (s, 4 H); 3.77 (s, 6 H); 3.56 (s, 12 H). 13C-NMR: 197.1; 159.7; 158.8; 136.6;
131.7; 131.0; 130.9; 129.0; 125.8; 110.2; 91.1; 55.8; 55.0; 41.5. ESI-MS: 531 ([M þ H]þ).
1-(4-Nitrophenyl)-2,2-bis(2,4,6-trimethoxyphenyl)ethanone (1h). Burly wood-colored solid. M.p.
153 – 1558. IR: 2929, 2833, 1694, 1612, 1532, 1345, 1211, 834. 1H-NMR: 8.15 (d, J ¼ 8.8, 2 H); 7.98 (d, J ¼

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Helvetica Chimica Acta – Vol. 97 (2014)
8.6, 2 H); 6.28 (s, 1 H); 6.07 (s, 4 H); 3.77 (s, 6 H); 3.58 (s, 12 H). 13C-NMR: 197.9; 160.2; 157.5; 130.2;
129.2; 128.2; 123.4; 118.2; 104.0; 98.7; 55.7; 55.4; 55.2; 45.6. ESI-MS: 498 ([M þ H]þ).
1-(4-Hydroxyphenyl)-2,2-bis(2,4,6-trimethoxyphenyl)ethanone (1i). Burly wood-colored solid. M.p.
210 – 2118. IR: 3259, 2934, 2839, 1669, 1603, 1458, 1225, 1115, 813. 1H-NMR: 7.75 (d, J ¼ 8.8, 2 H); 6.68 (s,
2 H); 6.25 (s, 1 H); 6.06 (s, 4 H); 3.76 (s, 6 H); 3.54 (s, 12 H). 13C-NMR: 198.2; 159.6; 159.0; 132.1; 129.8;
116.3; 115.5; 114.7; 114.6; 91.3; 55.8; 55.6; 55.1; 42.3. ESI-MS: 469 ([M þ H]þ).
1-Phenyl-2,2-bis(2,4,5-trimethoxyphenyl)ethanone (1j). Pale-orange solid. M.p. 128 – 1298. IR: 2934,
2832, 1680, 1517, 1205, 1033. 1H-NMR: 8.02 (d, J ¼ 7.1, 2 H); 7.48 (d, J ¼ 7.1, 1 H); 7.39 (d, J ¼ 7.1, 2 H ) ;
6.59 (d, J ¼ 10, 4 H); 6.54 (s, 1 H); 3.89 (s, 6 H); 3.75 (s, 6 H); 3.75 (s, 6 H). 13C-NMR: 199.3; 150.7; 148.4;
142.2; 136.6; 132.0; 127.9; 117.9; 113.5; 97.3; 56.1; 55.9; 55.5; 44.9. ESI-MS: 453 ([M þ H]þ).
1-(4-Chlorophenyl)-2,2-bis(2,4,5-trimethoxyphenyl)ethanone (1k). Brick-red solid. M.p. 129 – 1308.
1
IR: 3032, 2839, 1670, 1601, 1452, 1235, 1123, 817. H-NMR: 7.96 (d, J ¼ 8.5, 2 H); 7.36 (d, J ¼ 8.5, 2 H);
6.57 (s, 4 H); 6.46 (s, 1 H); 3.88 (s, 6 H); 3.75 (s, 6 H); 3.69 (s, 6 H). 13C-NMR: 198.5; 151.1; 148.8; 142.9;
138.7; 135.3; 129.8; 128.6; 118.0; 113.8; 97.7; 56.5; 56.4; 56.0; 45.3. ESI-MS: 487 ([M þ H]þ).
1-(4-Bromophenyl)-2,2-bis(2,4,5-trimethoxyphenyl)ethanone (1l). White solid. M.p. 112 – 1148.
1
IR: 3055, 2945, 2830, 1745, 1609, 1588, 1500, 1210, 1135, 810. H-NMR: 7.88(d, J ¼ 8.6, 2 H); 7.52 (d,
J ¼ 8.6, 2 H); 6.57 (d, J ¼ 8.2, 2 H); 6.45 (s, 1 H); 3.88 (s, 6 H); 3.74 (s, 6 H); 3.68 (s, 6 H). 13C-NMR:
198.6; 151.0; 148.8; 142.9; 135.7; 131.5; 129.9; 127.4; 117.9; 113.8; 97.7; 56.5; 56.4; 56.0; 45.2. ESI-MS: 531
([M þ H]þ).
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Received September 5, 2013