An improved synthesis of 1,2-diarylethanols under conventional heating and ultrasound irradiation

Article abstract of DOI:10.3390/molecules170910708

A simple and efficient synthesis of 1,2-diarylethanols has been developed. The procedure involved the reaction between a variety of toluene derivatives and aryl aldehydes under conventional heating and ultrasound irradiation. This procedure possesses seve

Full text of DOI:10.3390/molecules170910708

Molecules 2012, 17, 10708-10715; doi:10.3390/molecules170910708
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
An Improved Synthesis of 1,2-Diarylethanols under
Conventional Heating and Ultrasound Irradiation
Dong-Mei Gao, Wei-Li Ma, Tian-Rui Li, Liang-Zhu Huang and Zhen-Ting Du *
College of Science, Northwest A&F University, Yangling 712100, Shaanxi, China
* Author to whom correspondence should be addressed; E-Mail: duzt@nwsuaf.edu.cn;
Tel./Fax: +86-29-8709-2226.
Received: 7 August 2012; in revised form: 28 August 2012 / Accepted: 3 September 2012 /
Published: 7 September 2012
Abstract: A simple and efficient synthesis of 1,2-diarylethanols has been developed. The
procedure involved the reaction between a variety of toluene derivatives and aryl aldehydes
under conventional heating and ultrasound irradiation. This procedure possesses several
advantages such as operational simplicity, high yield, safety and environment benignancy.
Ultrasound was proved to be very helpful to the reaction, markedly improving the yield and
the reaction rate.
Keywords: 1,2-diarylethanols; ultrasonic-assisted organic synthesis; 2-nitrotoulene
1. Introduction
1,2-diarylethanols are important intermediates in organic synthesis and can be used in a variety of
natural and biological products such as the well-known resveratrol and derivatives [1], combrestastatins [2],
isocombretastatins [3]. As a representative, combrestastatin (Figure 1), which was separated from
African plants, inhibits growth of the murine P388 lymphocytic leukemia cell line (PS system)
significantly, reverses the differentiation of AC glioma cells into astrocytes and inhibits tubulin
polymerization [4,5].

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Figure 1. Representative structures of 1,2-diarylethanols.
The traditional formation of 1,2-diarylethanols need highly reactive agents such as titanium [6], the
Barbier reaction or Grignard reagents. The method suffered some drawbacks such as harsh reaction
conditions (high temperature and basic conditions), unpredictable yields, use of expensive metals and
limited applicability. Murata reported a method for the synthesis of 1,2-diarylethanols in only 44% yield
by refluxing a mixture of 2-nitrotoulene, sodium ethoxide and aldehyde for 2 days [7]. Therefore, there
is still a need for general methods for the preparation of 1,2-diarylethanols.
Ultrasound can accelerate chemical reactions to provide improved yields, shortened reaction times
and increased selectivity, therefore ultrasound irradiation has been recognized as an efficient technique
in organic synthesis over the last two decades [8–14]. Typically, ultrasound works by the phenomenon
of cavitation; which involves the growth, oscillation, and collapse of bubbles under the action of an
acoustic field. There are three different theories about cavitation: the hotspot, the electrical and the
plasma theory; and the most popular one is the hot spot theory. It has been experimentally shown that,
the cavitational collapse creates drastic conditions inside the medium for an extremely short time and
temperatures of 2,000–5,000 K, pressures up to 1,800 atmosphere pressure. Inside the collapsing cavity
have been produced under sonic conditions [14,15]. The collapse causes a couple of strong physical
effects outside the bubble such as-shear forces, jets and shock waves. These cavitation-induced effects
can cause physical, chemical, and biological transformations more effectively. Thus, ultrasound has
found applications in synthetic chemistry, in materials science, in life sciences, as well as in medicinal
chemistry [16].
As mentioned above, we were interested in a practical technique for the synthesis of
1,2-diarylethanols. To best of our knowledge, the ultrasound-assisted methodology has not yet been
explored in the formation of 1,2-diarylethanols. Herein, we wish to report our studies toward the
coupling of 2-nitrotoluenes with aldehydes in the presence of sodium ethoxide as the base to produce
diverse 1,2-diarylethanols under conventional and ultrasound irradiation conditions.
2. Results and Discussion
To begin with, we intend to screen the most suitable base and solvent for this model reaction in which
2-nitrotoulene and benzaldehyde were chosen as substrates under ultrasound irradiation. At 40 °C,
K2CO3 and NaOH give low yields in ethanol, however, when organic bases such as DBU and NaOEt
were used, the yields were improved slightly. When DMSO was used as solvent, although the TLC
showed promising results, the distillation workup would produce byproducts due to elimination.
Eventually, a mixed solvent (EtOH–DMSO = 6:1) was used to overcome this drawback; apparently, it is
helpful to improve the yield (Table 1, entries 6–9). Finally, we investigated the influence of temperature
(such as at 40 °C, 50 °C, 60 °C and 70 °C) on the reaction, and we found that the reaction temperature

Molecules 2012, 17
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played a key role. For example, a higher temperature may give better yield (Table 1, entries 6–7), but if
the temperature was increased to 60 °C, the side reaction would prevail. Unfortunately, this side reaction
affected the yield immensely at 70 °C. Finally, we set up the optimized reaction conditions that are
NaOEt as base, the mixed solvent (EtOH–DMSO = 6:1), at 50 °C (Table 1, entry 7).
Table 1. Screening the solvent, base and temperature for synthesis of 2-(2-nitro-
phenyl)-1-phenylethanol where the molar ratio of 2-nitrotoulene:benzaldehyde is 2:1.
Temperature
Time
Entry
Base
Solvent
Yield (%) a
°C
40
40
40
40
40
40
50
60
70
h
5
5
5
5
5
8
8
8
8
1
2
3
4
5
6
7
8
9
K2CO3
NaOH
DBU
EtOH
EtOH
0
5
EtOH
8
NaOEt
NaOEt
NaOEt
NaOEt
NaOEt
NaOEt
EtOH
22
44
53
62
56
28
DMSO
EtOH:DMSO (6:1)
EtOH:DMSO (6:1)
EtOH:DMSO (6:1)
EtOH:DMSO (6:1)
a Isolated yields.
Under these optimized reaction conditions, we next examined the scope of ultrasound
irradiation-promoted synthesis of 2-(2-nitrophenyl)-1-phenylethanol using 2-nitrotoulenes and
benzaldehydes. The results are summarized in Table 2. 2-Nitrotoulene and 2,4-dinitrotoulene and a
wide range of aryl aldehydes (Table 2), bearing chloro (Table 2, entries d, e and j), bromo (entry c) and
methoxy group (entry b) substituents were subjected to this protocol to give the corresponding
1,2-diarylethanols in good yields. Meanwhile, the reaction time was reduced significantly compared
with the conventional thermal method (2 days). For example, 2-nitrotoulene was coupled with
benzaldehyde to provide the expected 1-phenyl-2-(2'-nitro)phenyl ethanol in 62% yield after only 8 h
under sonication at 50 °C. It should be pointed out that two activitated groups didn't show a promising
effects in this reaction (entries e, j), for instance, 2,4-dinitrotoulene reacted with 2-chlorobenzaldehyde
in low yield (entry j, 35%) compared with 2-nitrotoulene (entry e, 58%). Moreover, as we all know
furaldehyde is unstable under harsh conditions, but it could provide the corresponding 1,2-diarylethanol
through our protocol in 53% yield. All the products in our reactions listed in Table 2 were easily
characterized on the basis of physical and spectral data and also by comparison with authentic samples.

Molecules 2012, 17
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Table 2. Ultrasound-assisted synthesis of 1,2-arylethanols using nitrotoluenes and arylaldehydes.
Entry Compound 1 Compound 2
Product 3
Time (h) Yield (%) a
a
8
8
62
65
b
c
d
e
12
12
12
60
49
58
f
12
8
46
44
Cl
Cl
NO2
Cl
Cl
g
OHC
OH
h
i
12
8
45
44
j
8
8
35
53
k
a: isolated yield.
3. Experimental
3.1. General
Sonication was performed in a Ningbo SB-3200DT ultrasonic cleaner (Xi’an, China) with a
frequency of 40 KHz and an output power of 180 W. the temperature of the water was maintained
through an outside cooling loop system. The materials were used as purchased if not noted otherwise
and DMSO was used directly without any additional purification. Melting points were uncorrected.

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1H-NMR and 13C-NMR spectra were recorded on a Bruker Avance DMX 500 MHz instrument
(Xi’an, China) using TMS as internal standard and CDCl3 as solvent. MS were carried out with a
Thermo DSQ GC/MS instrument.
3.2. General Procedure
The mixture of the appropriate nitrotoluenes (1, 10 mmol), the aldehydes (2, 5 mmol), and freshly
prepared NaOEt (20 mmol) in DMSO (6 mL) in EtOH (36 mL) in a shaken flask was reacted using
sonication at 50 °C under argon. The reaction progress was monitored by TLC, after completion, the
reaction mixtures were poured into ice water, acidified to pH 2–3, and extracted with ethyl acetate
(3 × 30 mL). The combined organic phase was washed by brine (40 mL), dried over anhydrous MgSO4,
concentrated in vacuo and purified by preparative column chromatography to give the pure
1,2-diaryl-ethanols. All compounds were characterized by 1H-NMR, MS and m.p. The yields are listed
in Table 2.
1-Phenyl-2-(2-nitrophenyl)ethanol (3a). White solid, m.p. 74–75 °C, Lit [17] 70–72 °C; 1H-NMR (CDCl3):
3.23 (dd, 1H, J = 4.7 Hz, J = 13.5 Hz), 3.39 (dd, 1H, J = 3.8 Hz, J = 13.6 Hz), 5.03 (dd, 1H, J = 3.8 Hz,
13
J = 12.1 Hz), 7.28–7.40 (m, 7H), 7.51 (t, 1H, J = 7.5 Hz), 7.94 (d, 1H, J = 8.2 Hz); C-NMR (CDCl3):
42.8, 74.3, 124.8, 125.7, 127.7, 127.9, 128.6, 132.7, 133.4, 133.6, 143.8, 149.9.
1
1-(4-Methoxyphenyl)-2-(2-nitrophenyl)ethanol (3b). Orange solid, m.p. 91–92 °C; H-NMR (CDCl3):
3.23 (dd, 1H, J = 9.0 Hz, J = 14.0 Hz), 3.32 (dd, 1H, J = 4.0 Hz, J = 13.5 Hz), 3.80 (s, 3H), 4.96 (dd, 1H,
J = 4.0 Hz, J = 8.0 Hz), 6.88 (d, 2H, J = 8.6 Hz), 7.28–7.31 (m, 3H), 7.38 (t, 1H, J = 5.1 Hz), 7.50 (t, 1H,
J = 4.7 Hz), 7.92 (d, 1H, J = 7.9 Hz); 13C-NMR (CDCl3): 42.8, 55.3, 73.9, 113.9, 124.8, 126.9, 127.6,
132.7, 133.5, 133.6, 136.0, 149.9, 159.2.
1-(4-Bromophenyl)-2-(2-nitrophenyl)ethanol (3c). White solid, m.p. 71–72 °C; 1H-NMR (CDCl3): 3.17
(dd, 1H, J = 8.8 Hz, J = 13.6 Hz), 3.35 (dd, 1H, J = 4.0 Hz, J = 13.6 Hz), 5.01 (dd, 1H, J = 4.3 Hz,
J = 8.7 Hz), 7.28 (d, 1H, J = 8.3 Hz), 7.30 (d, 1H, J = 8.7 Hz), 7.41 (t, 2H, J = 7.7 Hz), 7.48 (d, 1H,
J = 8.3 Hz), 7.52 (t, 2H, J = 7.5 Hz), 7.96 (d, 1H, J = 8.1 Hz); 13C-NMR (CDCl3): 42.9, 73.7, 121.6,
124.9, 127.4, 127.9, 131.6, 132.9, 133.0, 133.6, 142.8, 149.8.
1-(4-Chlorophenyl)-2-(2-nitrophenyl)ethanol (3d). White solid, m.p. 89–91 °C; 1H-NMR (CDCl3): 3.17
(dd, 1H, J = 9.1 Hz, J = 12.8 Hz), 3.34 (dd, 1H, J = 2.0 Hz, J = 13.5 Hz), 3.47 (s, 1H), 5.03 (dd, 1H,
J = 3.5 Hz, J = 8.5 Hz), 7.29–7.33 (m, 5H), 7.41 (t, 1H, J = 7.6 Hz), 7.52 (t, 1H, J = 7.3 Hz), 7.96 (d, 1H,
J = 8.1 Hz); 13C-NMR (CDCl3): 43.0, 73.6, 124.9, 127.1, 127.1, 128.7, 132.9, 133.0, 133.5, 133.6,
142.3, 149.8.
1-(2-Chlorophenyl)-2-(2-nitrophenyl)ethanol (3e). Pale yellow solid, m.p. 93–94 °C, Lit [18] 59–60 °C;
1H-NMR (CDCl3): 3.35 (d, 2H, J = 5.9 Hz), 5.40 (t, 1H, J = 5.8 Hz), 7.23 (d, 1H, J = 7.6 Hz), 7.27
(t, 1H, J = 6.5 Hz), 7.31 (d, 1H, J = 6.5 Hz), 7.38 (t, 2H, J = 7.7 Hz), 7.50 (t, 1H, J = 9.0 Hz), 7.53
(d, 2H, J = 7.0 Hz), 7.87 (d, 1H, J = 8.1 Hz); 13C-NMR (CDCl3): 39.9, 71.3, 124.6, 127.3, 127.3, 127.7,
128.9, 129.4, 131.7, 132.7, 132.7, 133.0, 140.8, 150.5.

Molecules 2012, 17
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1-(3-Nitrophenyl)-2-(2-nitrophenyl)ethanol (3f). White solid, m.p. 98–99 °C; 1H-NMR (CDCl3): 3.17 (dd,
1H, J = 8.9 Hz, J = 13.6 Hz), 3.44 (dd, 1H, J = 3.6 Hz, J = 13.6 Hz), 5.19 (dd, 1H, J = 3.1 Hz, J = 8.7 Hz),
7.34 (d, 1H, J = 7.6 Hz), 7.45 (t, 1H, J = 7.8 Hz), 7.55 (q, 2H, J = 7.7 Hz), 7.75 (d, 1H, J = 7.6 Hz), 7.99
(d, 1H, J = 8.2 Hz), 8.15 (d, 1H, J = 8.1 Hz), 8.30 (s, 1H); 13C-NMR (CDCl3): 43.1, 73.2, 120.7, 122.7,
125.1, 128.2, 129.5, 132.0, 132.5, 133.1, 133.7, 146.0, 148.4, 149.7.
1
1-(2,4-Dichlorophenyl)-2-(2-nitrophenyl)ethanol (3g). Pale yellow solid, m.p. 88–89 °C; H-NMR
(CDCl3): 3.29 (dd, 1H, J = 6.1 Hz, J = 13.9 Hz), 3.34 (dd, 1H, J = 4.8 Hz, J = 13.9 Hz), 5.37 (dd, 1H,
J = 5.0 Hz, J = 7.5 Hz), 7.25–7.34 (m. 3H), 7.40 (t, 1H, J = 7.7 Hz), 7.47 (d, 1H, J = 8.5 Hz), 7.51
(t, 1H, J = 7.5 Hz), 7.88 (d, 1H, J = 8.1 Hz); 13C-NMR (CDCl3): 39.8, 70.8, 124.7, 127.6, 127.9, 128.4,
129.1, 132.2, 132.3, 132.8, 133.0, 133.9, 139.5, 150.5.
1
1-(3-Nitrophenyl)-2-(2,4-dinitrophenyl)ethanol (3h). Yellow solid, m.p. 116–117 °C; H-NMR
(CDCl3): 3.30 (dd, 1H, J = 9.4 Hz, J = 12.7 Hz), 3.54 (d, 1H, J = 12.9 Hz), 5.23 (dd, 1H, J = 4.1 Hz,
J = 8.3 Hz), 7.58 (t, 1H, J = 7.7 Hz), 7.67 (d, 1H, J = 8.4 Hz), 7.78 (d, 1H, J = 7.3 Hz), 8.18 (d, 1H,
J = 7.6 Hz), 8.31 (s, 1H); 8.40 (d, 1H, J = 7.9 Hz), 8.82 (s, 1H); 13C-NMR (CDCl3): 42.6, 72.8, 120.4,
120.5, 123.1, 126.8, 129.8, 131.8, 135.3, 139.6, 145.4, 147.0, 148.5, 149.7.
1-(4-Nitrophenyl)-2-(2,4-dinitrophenyl)ethanol (3i). Yellow solid, m.p. 159–160 °C; 1H-NMR
(CDCl3): 3.28 (dd, 1H, J = 8.8 Hz, J = 13.1 Hz), 3.52 (dd, 1H, J = 3.2 Hz, J = 13.4 Hz), 5.12 (dd, 1H,
J = 3.1 Hz, J = 8.2 Hz), 7.61 (d, 2H, J = 8.1 Hz), 7.68 (d, 1H, J = 8.3 Hz), 8.23 (d, 2H, J = 8.2 Hz),
8.40 (d, 1H, J = 8.1 Hz), 8.81 (s, 1H); 13C-NMR (CDCl3): 44.6, 74.1, 122.0, 122.2, 125.7, 128.6, 137.4,
142.2,148.8, 149.3, 151.7, 153.7.
1
1-(2-Chlorophenyl)-2-(2,4-dinitrophenyl)ethanol (3j). Yellow solid, m.p. 134–135 °C; H-NMR
(CDCl3): 3.28 (dd, 1H, J = 8.6 Hz, J = 13.6 Hz), 3.46 (dd, 1H, J = 7.5 Hz, J = 13.4 Hz), 5.00 (dd, 1H,
J = 7.4 Hz, J = 13.4 Hz), 7.28–7.51 (m, 3H), 7.50 (d, 1H, J = 7.6 Hz), 7.57 (d, 1H, J = 8.2 Hz), 8.35
(d, 1H, J = 8.1 Hz), 8.80 (s, 1H); 13C-NMR (CDCl3): 42.6, 72.9, 120.2, 122.0, 126.5, 127.3, 131.8,
135.2, 140.2, 142.4, 146.9, 149.9.
1-(Furan-2-yl)-2-(2-nitrophenyl)ethanol (3k). colorless liquid; 1H-NMR (CDCl3): 3.41 (dd, 1H, J = 8.2 Hz,
J = 13.6 Hz), 3.46 (dd, 1H, J = 5.2 Hz, J = 13.6 Hz), 5.03 (dd, 1H, J = 5.0 Hz, J = 8.6 Hz), 6.22 (d, 1H,
J = 3.1 Hz), 6.32 (dd, 1H, J = 1.7 Hz, J = 3.0 Hz), 7.31 (d, 1H, J = 7.6 Hz), 7.36–7.52 (m, 3H), 7.92
13
(d, 1H, J = 8.2 Hz); C-NMR (CDCl3): 39.0, 67.9, 106.6, 110.3, 124.8, 127.8, 132.7, 132.9, 133.3,
142.2, 149.9, 155.4.
4. Conclusions
In summary, we have applied ultrasound methodology to promote the synthesis of
1,2-diarylethanols in moderate to good yields in the presence of sodium ethoxide. The merits of this
protocol such as easy operation and workup, and good to moderate yields make it an attractive approach
to such kinds of compounds.

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Acknowledgments
The financial support from the Fundamental Research Funds for the Central Universities
in NWSUAF (QN2009048) and the National Natural Science Foundation of China (20802058) is
greatly appreciated.
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Sample Availability: Samples of the compounds 3a–k are available from the authors.
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