Stereoselective and regioselective synthesis of N-substituted methyl 2-((azolyl)methyl)-3-arylacrylates from Baylis–Hillman acetates

Article abstract of DOI:10.3906/kim-1607-35

N -Substituted methyl 2-((azolyl)methyl)-3-arylacrylates were synthesized stereo- and regioselectively with one-pot reaction between Baylis–Hillman acetates and a suitable acylazole in the presence of K₂ CO₃ as a base catalyst. The t

Full text of DOI:10.3906/kim-1607-35

Turk J Chem
Turkish Journal of Chemistry
(2017) 41: 323 – 334
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http://journals.tubitak.gov.tr/chem/
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c
⃝ TUBITAK
doi:10.3906/kim-1607-35
Research Article
Stereoselective and regioselective synthesis of N -substituted methyl
2-((azolyl)methyl)-3-arylacrylates from Baylis–Hillman acetates
∗
¨
Ay¸sen KOSECELI OZENC¸ , Ilhami C¸ ELIK , S¸ule KOKTEN
˙ ¨
˙
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Department of Chemistry, Faculty of Science, Anadolu University, Eski¸sehir, Turkey
Received: 17.07.2016
•
Accepted/Published Online: 25.10.2016
•
Final Version: 16.06.2017
Abstract: N -Substituted methyl 2-((azolyl)methyl)-3-arylacrylates were synthesized stereo- and regioselectively with
one-pot reaction between Baylis–Hillman acetates and a suitable acylazole in the presence of K2 CO3 as a base catalyst.
The targeted N -substituted azole acrylates were efficiently obtained in good yields (39%–89%).
Key words: Imidazole, benzimidazole, benzotriazole, Baylis–Hillman acetates, N -substituted azole acrylates
1. Introduction
Heterocyclic compounds containing imidazole, benzimidazole, and benzotriazole skeletons are usually found as
important core structures in a wide number of natural products and biologically active pharmaceuticals1,2
.
Some examples of clinically employed drugs such as ketoconazole,3 omeprazole,4 and alizapride5 respectively
have imidazole, benzimidazole, and benzotriazole rings (Figure 1). It is also known that many N -substituted
derivatives of these azole rings play an important role in the medical field with many pharmacological activities
including antimicrobial, antiviral, antidiabetic, and anticancer.6−8 Heterocyclics bearing these ring systems are
not only used to design medicinally important drugs. They are also used as corrosion inhibitors to protect metal
and alloy surfaces9 and as catalysts10
.
Baylis–Hillman reaction involving the coupling of an activated alkene with an electrophile in the presence
of a tertiary amine base catalyst is one of the most powerful and useful carbon–carbon bond-forming processes
and often yields a variety of multifunctional products, so-called Baylis–Hillman adducts. Because of the
simplicity of this reaction in the easy construction of the C-C bond and its ability to accommodate a wide range
of electrophiles, activated alkenes, and catalysts, many acyclic and cyclic compounds can be synthesized using
these adducts.11 N -Substituted azole acrylates derived from Baylis–Hillman adducts are also useful compounds
containing azole units. They were used as an intermediate to prepare poly-fused heterocycles12 and as a
substrate to synthesize ionic liquids.13 A few methods have been developed for their preparation. In these
literature methods, N -substituted azole acrylates were either prepared from an intermediate that was obtained
through bromination or acetylation of Baylis–Hillman adducts in two steps14,15 or they were directly prepared
from Baylis–Hillman adducts in a single step using carbonyldiimidazole (CDI)13 (Figure 2). Although it is
possible to access a wide range of azole derivatives using these methods, they still have some drawbacks, such as
the use of highly reactive and toxic reagents to prepare starting compounds17 or the need for previous activation
of the OH group in Baylis–Hillman adducts.14,15
∗Correspondence: ilcelik@anadolu.edu.tr
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Figure 1. Some medicines bearing azole moiety.
Figure 2. Literature methods for the synthesis of N -substituted azole acrylates.
N -Acylazoles, which are effective acylating agents, are among the useful synthetic auxiliaries derived from
these ring systems. They show great potential in organic synthesis as activated carboxylic acid derivatives to
prepare amides,18,19 esters,18,20,21 thioesters,18,21 ketones,22,23 and some useful heterocycles.24,25 Because
there are few methods for the synthesis of N -substituted azole acrylates and the present methods have
some drawbacks, herein we aimed to develop a more general method to synthesize N -substituted derivatives
of imidazole, benzimidazole, and benzotriazole from the reaction between N -acylazoles and Baylis–Hillman
adducts.
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2. Results and discussion
We first prepared Baylis–Hillman adducts 1a–1i by treating a suitable aldehyde with methyl acrylate in the
presence of DABCO according to the literature procedures26,27 (Scheme 1). Next, N -acetylazoles 7a–7c were
prepared by modifying the method developed in the literature.18
Scheme 1. Synthesis of Baylis–Hillman adducts.
N -substituted azole acrylates were then obtained by the reaction of Baylis–Hillman adducts with N -
acylazoles. Treatment of N -acetylimidazole with Baylis–Hillman acetates in DMF in the presence of K2 CO3
at room temperature afforded the corresponding N -substituted-2-((imidazolyl)methyl)-3-acrylates in 39%–84%
yields (Table 1).
Table 1. Synthesis of N -substituted-2-((imidazolyl)methyl)-3-acrylates.
Entry
R
Ph
Yield (%)
8a, 58
8b, 73
8c, 39
8d, 84
8e, 50
8f, 42
1
2
3
4
5
6
7
8
9
4-Me-Ph
4-MeO-Ph
2-NO2-Ph
4-F-Ph
3-Cl-Ph
2-py
8g, 57
8h, 40
2-furanyl
2-(3-Me-thiophenyl) 8i, 42
As an extension of this reaction, N -substituted-2-((benzimidazolyl)methyl)-3-acrylates were prepared
using N -acetylbenzimidazole with 33%–65% yields under the same conditions (Table 2). In the literature
method, necessary reaction conditions were more vigorous to synthesize benzimidazole acrylate derivatives and
in some cases the obtained products had both E and Z isomers.16 With the method used here only products
having the E configuration were obtained.
We also examined the same reaction conditions while treating N -acetylbenzotriazole with Baylis–Hillman
acetates to give N -substituted-2-((benzotriazolyl)methyl)-3-acrylates in 45%–89% yields (Table 3). At the end
of the reaction, it was observed that two different products had formed. It was concluded that these two
products were N-1 (Bt1) and N-2 (Bt2) isomers of benzotriazole according to their 13 C NMR spectra. In the
13 C NMR spectra, six C signals were observed for Bt1 compounds. On the other hand, three C signals were
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observed for Bt2 compounds because of the symmetry in the molecules. Comparing the formation of the Bt1
isomer to the Bt2 isomer, the yields of Bt1 are much higher than that of Bt2 compounds. This shows that the
reaction is regioselective.
Table 2. Synthesis of N -substituted-2-((benzimidazolyl)methyl)-3-acrylates.
Entry
R
Ph
Yield (%)
9a, 44
9b, 43
9c, 44
9d, 65
9e, 42
9f, 42
1
2
3
4
5
6
7
8
9
4-Me-Ph
4-MeO-Ph
2-NO2-Ph
4-F-Ph
3-Cl-Ph
2-py
9g, 41
9h, 46
2-furanyl
2-(3-Me-thiophenyl) 9i, 33
Table 3. Synthesis of N -substituted-2-((benzotriazolyl)methyl)-3-acrylates.
Entry
R
Ph
% Overall yield % Yield of Bt1 % Yield of Bt2
1
2
3
4
5
6
7
8
9
85
54
80
89
77
80
64
45
10a, 67
10b, 54
10c, 63
10d, 70
10e, 60
10f, 68
10g, 53
10h, 35
10i, 48
11a, 18
11b, 0
4-Me-Ph
4-MeO-Ph
2-NO2-Ph
4-F-Ph
3-Cl-Ph
2-py
11c, 17
11d, 19
11e, 17
11f, 12
11g, 11
11h, 10
11i, 21
2-furanyl
3-Me-2-thiophenyl 69
All the synthesized products were purified by column chromatography and their structures were identified
by 1 H and 13 C NMR spectra. The obtained results were supported by elemental analysis and high-resolution
mass spectrum (HRMS) data. The overall yields seemed to be satisfactory and the double bond configurations
of these compounds were assigned on the basis of 1 H NMR spectra and by comparing data available in the
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literature.13,14,28 According to the literature, while the chemical shift value of the olefinic proton in the E-isomer
is observed obviously downfield of the aromatic ring proton, the corresponding olefinic proton of the Z-isomer
appears upfield.28,29 When we went through the 1 H NMR spectra, we observed a chemical shift of a proton
as a singlet appeared obviously downfield of the aromatic ring protons around 7.97–8.77 ppm for almost all
compounds synthesized. In addition, the 1 H NMR spectra showed that there was no formation of the Z-isomer.
As the chemical shift values of olefinic protons in 1 H NMR spectra and the data obtained from the literature
are in accordance with each other, it was thought that all synthesized compounds had E configuration.
The proposed mechanism shown in Scheme 2 is a one-pot reaction that is first initiated by acylation of
the hydroxyl group in Baylis–Hillman adducts. This follows Michael addition of the azole anion to alkene, which
leads to the elimination of the acetyl group to afford the desired N -substituted azole acrylates.
Scheme 2. Proposed mechanism for the synthesis of N -substituted azole acrylates.
In conclusion, we have developed an efficient protocol for the stereo- and regioselective synthesis of N -
substituted azole acrylates. With the use of readily available acylazoles, the methodology described here offers
an alternative way to get N -substituted azole acrylates in a single step directly from Baylis–Hillman adducts.
3. Experimental
3.1. General procedure
All chemicals were purchased from commercial suppliers and used without further purification. Reactions were
monitored by thin-layer chromatography and visualized under UV light. Melting points were recorded on a
Mettler Toledo MP90 apparatus and are uncorrected. 1 H and 13 C NMR spectra were recorded on a Bruker
Advance 500 DPX spectrometer and an Agilent DD2 NMR (400 MHz) spectrometer in CDCl3 . HRMS data
were recorded on a Shimadzu hybrid LC-MS-IT-TOF spectrometer. Elemental analyses were carried out on a
VarioEL III instrument.
3.2. Synthesis of N -substituted-2-((imidazolyl)methyl)-3-acrylates (8a–8i)
To a solution of N -acetylimidazole 7a (1 mmol) and a suitable Baylis–Hillman acetate 1 (1 mmol) in DMF (1
mL), K2 CO3 (1 mmol) was added and the resulting mixture was stirred at room temperature until complete
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consumption of N -acetylimidazole 7a. The reaction mixture was then diluted with water (20 mL) and extracted
with ethylacetate (3 × 20 mL). The combined organic layers were washed with brine and dried over anhydrous
Na2 SO4 . After removal of the solvent under reduced pressure, the residue was purified by flash chromatography
over silica gel with EtOAc and hexane (1:1).
(E)-Methyl 2-((1-imidazolyl)methyl)-3-phenylacrylate (8a)
Yellow oil; yield (141 mg, 58%); 1 H NMR (500 MHz, CDCl3): 8.03 (s, 1H), 7.48 (s, 1H), 7.42 (d, J =
7.4 Hz, 3H), 7.31 (d, J = 6.8 Hz, 2H), 7.01 (s, 1H), 6.85 (s, 1H), 4.96 (s, 2H), 3.79 (s, 3H); 13 C NMR (125
MHz, CDCl3): 166.9, 144.9, 137.0, 133.9, 129.7, 129.1, 129.0, 128.8, 127.0, 118.8, 52.5, 43.0; HRMS (IT-TOF);
Anal. Calcd. for C14 H14 N2 O2 : m/z 243.1128; Found [M+H]+ : m/z 243.1126.
(E)-Methyl 2-((1-imidazolyl)methyl)-3-(p-tolyl)acrylate (8b)
Yellow oil; yield (188 mg, 73%); 1 H NMR (500 MHz, CDCl3): 8.03 (s, 1H), 7.51 (s, 2H), 7.25 (s, 3H),
7.03 (s, 1H), 6.90 (s, 1H), 5.01 (s, 2H), 3.82 (s, 3H), 2.40 (s, 3H); 13 C NMR (125 MHz, CDCl3): 167.1, 145.0,
140.2, 137.0, 131.1, 129.8, 129.3, 129.0, 126.0, 118.8, 52.5, 43.1, 21.4; HRMS (IT-TOF); Anal. Calcd. for
C15 H16 N2 O2 : m/z 257.1285; Found [M+H]+ : m/z 257.1284.
(E)-Methyl 2-((1-imidazolyl)methyl)-3-(4-methoxyphenyl)acrylate (8c)
Yellow solid; yield (106 mg, 39%); mp 88.0–89.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.02 (s, 1H), 7.54
(s, 1H), 7.32 (d, J = 10.0 Hz, 2H), 7.06 (s, 1H), 6.96 (d, J = 10.0 Hz, 2H), 6.93 (s, 1H), 5.03 (s, 2H), 3.86 (s,
3H), 3.82 (s, 3H); 13 C NMR (125 MHz, CDCl3): 167.4, 161.0, 144.9, 136.9, 131.1, 129.3, 126.2, 124.3, 118.7,
114.6, 55.4, 52.5, 43.2; Anal. Calcd for C15 H16 N2 O3 (272.30): C, 66.16; H, 5.92; N, 10.29; Found: C, 66.08;
H, 6.05; N, 10.21.
(E)-Methyl 2-((1-imidazolyl)methyl)-3-(2-nitrophenyl)acrylate (8d)
Light yellow solid; yield (242 mg, 84%); mp 85.0–87.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.29 (s, 1H),
8.26 (d, J = 10.0 Hz, 1H), 7.74 (t, J = 5.0 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.36 (s, 1H), 7.25 (d, J =
10.0 Hz, 1H), 7.00 (s, 1H), 6.80 (s, 1H), 4.79 (s, 2H), 3.88 (s, 3H); 13 C NMR (125 MHz, CDCl3): 166.1, 147.2,
141.8, 137.1, 134.1, 130.5, 130.3, 130.1, 129.5, 128.3, 125.5, 118.7, 52.8, 43.1; HRMS (IT-TOF); Anal. Calcd.
for C14 H13 N3 O4 : m/z 288.0979; Found [M+H]+ : m/z 288.0970.
(E)-Methyl 2-((1-imidazolyl)methyl)-3-(4-fluorophenyl)acrylate (8e)
White solid; yield (131 mg, 50%); mp 101.0–102.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.03 (s, 1H), 7.50
(s, 1H), 7.35–7.32 (m, 2H), 7.16 (t, J = 7.5 Hz, 2H), 7.07 (s, 1H), 6.89 (s, 1H), 4.99 (s, 2H), 3.84 (s, 3H); 13 C
NMR (125 MHz, CDCl3): 166.9, 143.8, 137.0, 131.0, 130.9, 129.6, 126.9, 118.7, 116.4, 116.2, 52.6, 42.9; HRMS
(IT-TOF); Anal. Calcd. for C14 H13 FN2 O2 : m/z 261.1034; Found [M+H]+ : m/z 261.1030.
(E)-Methyl 2-((1-imidazolyl)methyl)-3-(3-chlorophenyl)acrylate (8f)
Light yellow solid; yield (116 mg, 42%); mp 80.0–81.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 7.97 (s, 1H),
7.47 (s, 1H), 7.43–7.39 (m, 2H), 7.32 (s, 1H), 7.20 (d, J = 10.0 Hz, 1H), 7.04 (s, 1H), 6.86 (s, 1H), 4.96 (s, 2H),
3.84 (s, 3H); 13 C NMR (125 MHz, CDCl3): 166.6, 143.0, 137.1, 135.7, 135.1, 130.4, 129.7, 129.5, 128.8, 128.6,
126.7, 118.7, 52.7, 42.8; HRMS (IT-TOF); Anal. Calcd. for C14 H13 ClN2 O2 : m/z 277.0738; Found [M+H]+ :
m/z 277.0732.
(E)-Methyl 2-((1-imidazolyl)methyl)-3-(2-pyridinyl)acrylate (8g)
Brown solid; yield (138 mg, 57%); mp 96.0–97.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.77 (s, 1H), 7.82–7.76
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(m, 3H), 7.43 (d, J = 10.0 Hz, 1H), 7.35 (t, J = 5.0 Hz, 1H), 7.18 (s, 1H), 6.99 (s, 1H), 5.70 (s, 2H), 3.86 (s,
3H); 13 C NMR (125 MHz, CDCl3): 167.4, 153.1, 149.8, 139.9, 138.1, 137.0, 130.5, 128.5, 127.7, 124.2, 119.7,
52.6, 41.8; HRMS (IT-TOF); Anal. Calcd. for C13 H13 N3 O2 : m/z 244.1081; Found [M+H]+ : m/z 244.1081.
(E)-Methyl 2-((1-imidazolyl)methyl)-3-(2-furanyl)acrylate (8h)
Light brown solid; yield (93 mg, 40%); mp 92.0–93.0 ◦ C; 1 H NMR (400 MHz, CDCl3): 7.62 (d, J = 9.6
Hz, 2H), 7.54 (s, 1H), 6.98 (d, J = 10.4 Hz, 2H), 6.75 (d, J = 3.2 Hz, 1H), 6.56 (t, J = 1.4 Hz, 1H), 5.27 (s,
2H), 3.79 (s, 3H); 13 C NMR (100 MHz, CDCl3): 167.4, 150.1, 145.9, 137.5, 128.9, 128.8, 122.1, 119.3, 119.2,
112.7, 52.5, 42.8; Anal. Calcd for C12 H12 N2 O3 (232.24): C, 62.06; H, 5.21; N, 12.06; Found: C, 61.91; H,
5.17; N, 12.03.
(E)-Methyl 2-((1-imidazolyl)methyl)-3-(2-(3-methyl)thiophenyl)acrylate (8i)
Yellow solid; yield (109 mg, 42%); mp 99.0–100.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.17 (s, 1H), 7.62
(s, 1H), 7.48 (d, J = 5.0 Hz, 1H), 7.03 (s, 2H), 7.02 (d, J = 5.0 Hz, 1H), 5.23 (s, 2H), 3.83 (s, 3H), 2.43 (s, 3H);
13 C NMR (125 MHz, CDCl3): 167.5, 144.5, 137.3, 134.5, 130.9, 130.0, 129.2, 129.1, 121.2, 118.9, 52.5, 43.2,
14.8; Anal. Calcd for C13 H14 N2 O2 S (262.33): C, 59.52; H, 5.38; N, 10.68; Found: C, 59.42; H, 5.39; N, 10.58.
3.3. Synthesis of N -substituted-2-((benzimidazolyl)methyl)-3-acrylates (9a–9i)
To a solution of N -acetylbenzimidazole 7b (1 mmol) and a suitable Baylis–Hillman acetate 1 (1 mmol) in
DMF (1 mL), K2 CO3 (1 mmol) was added and the resulting mixture was stirred at room temperature until
complete consumption of N -acetylbenzimidazole. The reaction mixture was then diluted with water (20 mL)
and extracted with ethylacetate (3 × 20 mL). The combined organic layers were washed with brine and dried
over anhydrous Na2 SO4 . After removal of the solvent under reduced pressure, the residue was purified by flash
chromatography over silica gel with EtOAc and hexane (1:1).
(E)-Methyl 2-((1-benzimidazolyl)methyl)-3-phenylacrylate (9a)
Colorless oil; yield (128 mg, 44%); 1 H NMR (400 MHz, CDCl3): 8.08 (s, 1H), 7.90 (s, 1H), 7.74 (d, J =
8.4 Hz, 1H), 7.45–7.42 (m, 3H), 7.35–7.33 (m, 2H), 7.21 (t, J = 7.8 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.94 (d,
J = 8.0 Hz, 1H), 5.20 (s, 2H), 3.75 (s, 3H); 13 C NMR (100 MHz, CDCl3): 166.8, 144.8, 143.6, 143.0, 140.3,
134.0, 133.6, 129.8, 129.1, 126.5, 122.8, 122.1, 120.2, 109.8, 52.5, 41.0; Anal. Calcd for C18 H16 N2 O2 (292.33):
C, 73.95; H, 5.52; N, 9.58; Found: C, 74.25; H, 5.60; N, 9.69.
(E)-Methyl 2-((1-benzimidazolyl)methyl)-3-(p-tolyl)acrylate (9b)
Yellow oil; yield (132 mg, 43%); 1 H NMR (500 MHz, CDCl3): 8.11 (s, 1H), 7.95 (s, 1H), 7.80 (d, J =
10.0 Hz, 1H), 7.33–7.27 (m, 3H), 7.25–7.20 (m, 3H), 7.07 (d, J = 5.0 Hz, 1H), 5.25 (s, 2H), 3.79 (s, 3H), 2.43 (s,
3H); 13 C NMR (125 MHz, CDCl3): 167.0, 145.1, 143.8, 143.0, 140.3, 133.8, 131.1, 129.9, 129.3, 125.5, 122.8,
122.1, 120.3, 109.8, 52.5, 41.2, 21.5; HRMS (IT-TOF); Anal. Calcd. for C19 H18 N2 O2 : m/z 307.1441; Found
[M+H]+ : m/z 307.1444.
(E)-Methyl 2-((1-benzimidazolyl)methyl)-3-(4-methoxyphenyl)acrylate (9c)
Light yellow oil; yield (142 mg, 44%); 1 H NMR (500 MHz, CDCl3): 8.10 (s, 1H), 7.95 (s, 1H), 7.81 (d, J
= 10.0 Hz, 1H), 7.35 (d, J = 10.0 Hz, 3H), 7.29–7.24 (m, 1H), 7.14 (d, J = 5.0 Hz, 1H), 6.97 (d, J = 10.0 Hz,
2H), 5.26 (s, 2H), 3.87 (s, 3H), 3.79 (s, 3H); 13 C NMR (125 MHz, CDCl3): 167.2, 161.1, 144.9, 143.8, 142.8,
133.8, 131.3, 126.3, 123.7, 122.9, 122.2, 120.3, 114.6, 109.8, 55.5, 52.4, 41.4; HRMS (IT-TOF); Anal. Calcd. for
C19 H18 N2 O3 : m/z 323.1390; Found [M+H]+ : m/z 323.1390.
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(E)-Methyl 2-((1-benzoimidazolyl)methyl)-3-(2-nitrophenyl)acrylate (9d)
Light yellow solid; yield (218 mg, 65%); mp 126.0–128.0 ◦ C; 1 H NMR (400 MHz, CDCl3): 8.26 (s, 1H),
8.18 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.61–7.53 (m, 2H), 7.21–7.12 (m, 3H), 6.93
(d, J = 8.0 Hz, 1H), 5.03 (s, 2H), 3.82 (s, 3H); 13 C NMR (100 MHz, CDCl3): 166.2, 147.0, 143.3, 142.9,
141.6, 133.9, 133.3, 130.3, 130.2, 129.9, 127.7, 125.4, 122.9, 122.2, 120.3, 109.4, 52.8, 41.3; Anal. Calcd for
C18 H15 N3 O4 (337.33): C, 64.09; H, 4.48; N, 12.46; Found: C, 64.14; H, 4.54; N, 12.54.
(E)-Methyl 2-((1-benzimidazolyl)methyl)-3-(4-fluorophenyl)acrylate (9e)
White solid; yield (130 mg, 42%); mp 83.0–85.0 ◦ C; 1 H NMR (400 MHz, CDCl3): 8.04 (s, 1H), 7.90 (s,
1H), 7.76 (d, J = 8.0 Hz, 1H), 7.34–7.31 (m, 2H), 7.25–7.23 (m, 1H), 7.21–7.16 (m, 1H), 7.14–7.10 (m, 2H),
6.97 (d, J = 8.0 Hz, 1H), 5.17 (s, 2H), 3.75 (s, 3H); 13 C NMR (100 MHz, CDCl3): 166.7, 163.4, 143.7, 142.8,
133.6, 131.2, 130.0, 126.2, 122.9, 122.2, 120.4, 116.5, 116.3, 109.6, 52.6, 41.0; Anal. Calcd for C18 H15 FN2 O2
(310.32): C, 69.67; H, 4.87; N, 9.03; Found: C, 69.64; H, 4.95; N, 9.05.
(E)-Methyl 2-((1-benzimidazolyl)methyl)-3-(3-chlorophenyl)acrylate (9f)
White solid; yield (136 mg, 42%); mp 83.5–84.5 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.03 (s, 1H), 7.94 (s,
1H), 7.80 (d, J = 5.0 Hz, 1H), 7.47–7.40 (m, 2H), 7.38 (s, 1H), 7.27–7.22 (m, 3H), 6.98 (d, J = 5.0 Hz, 1H),
5.22 (s, 2H), 3.80 (s, 3H); 13 C NMR (125 MHz, CDCl3): 166.5, 143.7, 143.1, 142.9, 135.8, 135.2, 133.6, 130.4,
129.8, 129.0, 128.1, 126.9, 123.0, 122.2, 120.4, 109.6, 52.7, 40.9; Anal. Calcd for C18 H15 ClN2 O2 (326.78): C,
66.16; H, 4.63; N, 8.57; Found: C, 66.45; H, 4.59; N, 8.68.
(E)-Methyl 2-((1-benzimidazolyl)methyl)-3-(2-pyridinyl)acrylate (9g)
Brown solid; yield (120 mg, 41%); mp 97.5–100.0 ◦ C; 1 H NMR (400 MHz, CDCl3): 8.74 (d, J = 4.2
Hz, 1H), 8.16 (s, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.79 (dd, J = 7.6, 2.0 Hz, 1H), 7.73 (dd, J = 6.6, 1.8 Hz,
1H), 7.44 (d, J = 8.0 Hz, 1H), 7.40–7.38 (m, 1H), 7.35–7.32 (m, 1H), 7.22–7.14 (m, 2H), 5.95 (s, 2H), 3.75 (s,
3H); 13 C NMR (100 MHz, CDCl3): 167.3, 153.2, 149.8, 144.2, 143.4, 140.0, 137.1, 134.2, 130.1, 127.8, 124.3,
122.5, 121.7, 120.0, 110.5, 52.5, 40.2; HRMS (IT-TOF); Anal. Calcd. for C17 H15 N3 O2 : m/z 294.1237; Found
[M+H]+ : m/z 294.1243.
(E)-Methyl 2-((1-benzimidazolyl)methyl)-3-(2-furanyl)acrylate (9h)
Brown solid; yield (130 mg, 46%); mp 115.5–116.5 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.04 (s, 1H), 7.79
(s, 1H), 7.67 (s, 2H), 7.41 (s, 1H), 7.26 (t, J = 5.0 Hz, 2H), 6.84 (d, J = 5.0 Hz, 1H), 6.62 (d, J = 5.0 Hz,
1H), 5.57 (s, 2H), 3.77 (s, 3H); 13 C NMR (125 MHz, CDCl3): 167.3, 150.1, 146.0, 143.6, 143.5, 134.1, 129.2,
122.8, 121.9, 121.4, 120.2, 119.5, 112.8, 110.2, 52.5, 41.5; Anal. Calcd for C16 H14 N2 O3 (282.29): C, 68.07; H,
5.00; N, 9.92; Found: C, 67.73; H, 5.05; N, 9.61.
(E)-Methyl 2-((1-benzoimidazolyl)methyl)-3-(2-(3-methyl)thiophenyl)acrylate (9i)
White solid; yield (102 mg, 33%); mp 131.5–132.5 ◦ C; 1 H NMR (400 MHz, CDCl3): 8.23 (s, 1H), 7.88
(s, 1H), 7.78–7.75 (m, 1H), 7.40 (d, J = 5.2 Hz, 1H), 7.37–7.34 (m, 1H), 7.27–7.22 (m, 2H), 6.97 (d, J = 5.2
Hz, 1H), 5.37 (s, 2H), 3.74 (s, 3H), 2.42 (s, 3H); 13 C NMR (100 MHz, CDCl3): 167.3, 144.5, 143.8, 142.6, 135.1,
133.9, 130.9, 129.9, 129.5, 122.8, 122.1, 122.0, 120.3, 110.0, 52.5, 41.7, 14.8; Anal. Calcd for C17 H16 N2 O2 S
(312.39): C, 65.36; H, 5.16; N, 8.97; Found: C, 65.25; H, 5.18; N, 8.85.
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3.4. Synthesis of N -substituted-2-((1- and 2-benzotriazolyl)methyl)-3-acrylates (10a–10i and 11a–
11i)
To a solution of N -acetylbenzotriazole 7c (1 mmol) and a suitable Baylis–Hillman acetate 1 (1 mmol) in
DMF (1 mL), K2 CO3 (1 mmol) was added and the resulting mixture was stirred at room temperature until
complete consumption of N -acetylbenzotriazole. The reaction mixture was then diluted with water (20 mL)
and extracted with ethylacetate (3 × 20 mL). The combined organic layers were washed with brine and dried
over anhydrous Na2 SO4 . After removal of the solvent under reduced pressure, the residue was purified by flash
chromatography over silica gel with EtOAc and hexane (1:4).
(E)-Methyl 2-((1-benzotriazolyl)methyl)-3-phenylacrylate (10a)
White solid; yield (196 mg, 67%); mp 89.0–90.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.18 (s, 1H), 8.08
(dd, J = 8.4, 0.8 Hz, 1H), 7.75–7.74 (m, 2H), 7.64 (dd, J = 8.4, 0.8 Hz, 1H), 7.53–7.39 (m, 5H), 5.62 (s, 2H),
3.74 (s, 3H); 13 C NMR (125 MHz, CDCl3): 167.0, 145.8, 145.4, 134.0, 133.5, 129.7, 129.4, 128.9, 127.3, 125.7,
123.8, 119.9, 110.1, 52.4, 44.7; Anal. Calcd for C17 H15 N3 O2 (293.32): C, 69.61; H, 5.15; N, 14.33; Found: C,
69.81; H, 5.15; N, 14.36.
(E)-Methyl 2-((2-benzotriazolyl)methyl)-3-phenylacrylate (11a)
White solid; yield (53 mg, 18%); mp 102.5–103.5 ◦ C; 1 H NMR (400 MHz, CDCl3): 8.18 (s, 1H), 7.88
(dd, J = 6.8, 3.2 Hz, 2H), 7.55–7.53 (m, 2H), 7.40–7.36 (m, 5H), 5.74 (s, 2H), 3.77 (s, 3H); 13 C NMR (100
MHz, CDCl3): 167.0, 145.5, 144.4, 134.0, 129.7, 129.3, 128.9, 126.2, 125.0, 118.2, 53.0, 52.5; Anal. Calcd for
C17 H15 N3 O2 (293.32): C, 69.61; H, 5.15; N, 14.33; Found: C, 69.71; H, 5.19; N, 14.32.
(E)-Methyl 2-((1-benzotriazolyl)methyl)-3-(p-tolyl)acrylate (10b)
White solid; yield (167 mg, 54%); mp 83.0–85.0 ◦ C; 1 H NMR (400 MHz, CDCl3): 8.10 (s, 1H), 8.04 (dd,
J = 7.2, 0.8 Hz, 1H), 7.61–7.58 (m, 3H), 7.46 (td, J = 7.6, 1.2 Hz, 1H), 7.34 (td, J = 7.6, 1.2 Hz, 1H), 7.22 (s,
1H), 5.60 (s, 2H), 3.69 (s, 3H), 2.37 (s, 3H); 13 C NMR (100 MHz, CDCl3): 167.1, 145.7, 145.5, 140.1, 133.5,
131.1, 129.6, 129.5, 127.2, 124.7, 123.8, 119.9, 110.1, 52.3, 44.8, 21.4; Anal. Calcd for C18 H17 N3 O2 (307.35):
C, 70.34; H, 5.58; N, 13.67; Found: C, 70.48; H, 5.60; N, 13.68.
(E)-Methyl 2-((1-benzotriazolyl)methyl)-3-(4-methoyphenyl)acrylate (10c)
White solid; yield (205 mg, 63%); mp 90.0–91.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.12 (s, 1H), 8.08 (d,
J = 8.5 Hz, 1H), 7.76 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.39 (t, J =
7.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 2H), 5.66 (s, 2H), 3.87 (s, 3H), 3.75 (s, 3H); 13 C NMR (125 MHz, CDCl3):
167.4, 161.0, 145.8, 145.3, 133.5, 131.7, 127.3, 126.4, 123.8, 123.2, 119.9, 114.4, 110.3, 55.4, 52.3, 45.0; Anal.
Calcd for C18 H17 N3 O3 (323.35): C, 66.86; H, 5.30; N, 13.00; Found: C, 66.67; H, 5.28; N, 12.93.
(E)-Methyl 2-((2-benzotriazolyl)methyl)-3-(4-methoxyphenyl)acrylate (11c)
White solid; yield (55 mg, 17%); mp 89.0–90.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.17 (s, 1H), 7.93 (dd,
J = 6.5, 3.0 Hz, 2H), 7.56 (d, J = 9.0 Hz, 2H), 7.41 (dd, J = 6.5, 3.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H),
5.81 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H); 13 C NMR (125 MHz, CDCl3): 167.4, 161.0, 145.4, 144.4, 131.5, 126.6,
126.2, 122.7, 118.2, 114.4, 55.4, 53.2, 52.4; Anal. Calcd for C18 H17 N3 O3 (323.35): C, 66.86; H, 5.30; N, 13.00;
Found: C, 66.79; H, 5.24; N, 12.98.
(E)-Methyl 2-((1-benzotriazolyl)methyl)-3-(2-nitrophenyl)acrylate (10d)
Yellow solid; yield (236 mg, 70%); mp 107.0–108.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.37 (s, 1H), 8.22
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(d, J = 10.0 Hz, 1H), 8.08 (d, J = 10.0 Hz, 1H), 8.03 (d, J = 10.0 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.66
(d, J = 5.0 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.38, (t, J = 7.5 Hz, 1H), 5.42 (s,
2H), 3.78 (s, 3H); 13 C NMR (125 MHz, CDCl3): 166.1, 147.1, 145.6, 142.1, 134.3, 133.4, 131.3, 130.0, 130.0,
127.5, 126.8, 125.0, 124.0, 119.8, 110.0, 52.7, 44.7; Anal. Calcd for C17 H14 N4 O4 (338.32): C, 60.35; H, 4.17;
N, 16.56; Found: C, 60.49; H, 4.13; N, 16.69.
(E)-Methyl 2-((2-benzotriazolyl)methyl)-3-(2-nitrophenyl)acrylate (11d)
Yellow solid; yield (65 mg, 19%); mp 110.5–111.5 ◦ C; 1 H NMR (400 MHz, CDCl3): 8.40 (s, 1H), 8.18
(d, J = 8.0 Hz, 1H), 7.83 (dd, J = 6.6, 3.0 Hz, 2H), 7.77 (d, J = 7.2 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H),
7.52 (t, J = 8.2 Hz, 1H), 7.35 (dd, J = 6.8, 3.2 Hz, 2H), 5.51 (s, 2H), 3.79 (s, 3H); 13 C NMR (100 MHz,
CDCl3): 165.9, 144.3, 142.4, 134.1, 130.6, 130.2, 130.0, 126.4, 126.3, 125.1, 118.1, 109.4, 52.8, 52.7; Anal. Calcd
for C17 H14 N4 O4 (338.32): C, 60.35; H, 4.17; N, 16.56; Found: C, 60.40; H, 4.22; N, 16.25.
(E)-Methyl 2-((1-benzotriazol-1-yl)methyl)-3-(4-fluorophenyl)acrylate (10e)
White solid; yield (188 mg, 60%); mp 112.0–113.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.12 (s, 1H), 8.09
(d, J = 10.0 Hz, 1H), 7.82–7.79 (m, 2H), 7.69 (d, J = 5.0 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.40 (t, J =
10.0 Hz, 1H), 7.17 (t, J = 10.0 Hz, 2H), 5.59 (s, 2H), 3.75 (s, 3H); 13 C NMR (125 MHz, CDCl3): 166.9,
163.5, 145.7, 144.2, 133.6, 131.6, 130.0, 127.4, 125.6, 123.9, 119.9, 116.1, 110.1, 52.5, 44.6; Anal. Calcd for
C17 H14 FN3 O2 (311.31): C, 65.59; H, 4.53; N, 13.50; Found: C, 65.34; H, 4.71; N, 13.48.
(E)-Methyl 2-((2-benzotriazolyl)methyl)-3-(4-fluorophenyl)acrylate (11e)
White solid; yield (53 mg, 17%); mp 114.0–115.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.17 (s, 1H), 7.93–
7.91 (m, 2H), 7.63–7.60 (m, 2H), 7.43–7.41 (m, 2H), 7.13 (t, J = 7.5 Hz, 2H), 5.76 (s, 2H), 3.82 (s, 3H); 13 C
NMR (125 MHz, CDCl3): 166.9, 163.5, 144.5, 144.4, 131.5, 130.2, 126.4, 124.9, 118.2, 116.1, 52.9, 52.6; Anal.
Calcd for C17 H14 FN3 O2 (311.31): C, 65.59; H, 4.53; N, 13.50; Found: C, 65.87; H, 4.62; N, 13.49.
(E)-Methyl 2-((1-benzotriazolyl)methyl)-3-(3-chlorophenyl)acrylate (10f)
White solid; yield (223 mg, 68%); mp 87.0–88.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.09 (d, J = 8.4 Hz,
1H), 7.64 (d, J = 8.4 Hz, 1H), 7.53 (td, J = 7.7, 0.9 Hz, 1H), 7.40 (td, J = 7.6, 0.9 Hz, 1H), 7.29–7.23 (m,
3H), 7.14–7.12 (m, 1H), 6.85 (s, 1H), 5.62 (s, 2H), 3.61 (s, 3H); 13 C NMR (125 MHz, CDCl3): 166.7, 146.1,
138.3, 136.3, 134.1, 133.0, 129.4, 128.8, 128.6, 128.5, 127.8, 126.8, 124.2, 120.1, 109.7, 52.1, 50.9; Anal. Calcd
for C17 H14 ClN3 O2 (327.76): C, 62.30; H, 4.31; N, 12.82; Found: C, 62.51; H, 4.35; N, 12.87.
(E)-Methyl 2-((2-benzotriazolyl)methyl)-3-(3-chlorophenyl)acrylate (11f)
White solid; yield (40 mg, 12%); mp 104.0–105.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.13 (s, 1H), 7.92
(dd, J = 6.3, 3.0 Hz, 2H), 7.60 (s, 1H), 7.50 (s, 1H), 7.43–7.36 (m, 4H), 5.74 (s, 2H), 3.81 (s, 3H); 13 C NMR
(125 MHz, CDCl3): 166.6, 144.4, 143.8, 135.8, 134.9, 130.2, 129.7, 129.3, 127.1, 126.5, 126.4, 118.2, 52.7, 52.6;
HRMS (IT-TOF); Anal. Calcd. for C17 H14 ClN3 O2 : m/z 328.0847; Found [M+H]+ : m/z 328.0840.
(E)-Methyl 2-((1-benzotriazolyl)methyl)-3-(2-pyridinyl)acrylate (10g)
Light brown solid; yield (156 mg, 53%); mp 114.0–116.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.68 (d, J
= 4.5 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.93 (s, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.64 (d, J = 8.5 Hz,
1H), 7.59 (d, J = 7.5 Hz, 1H), 7.44 (td, J = 7.5, 1.0 Hz, 1H), 7.35–7.29 (m, 2H), 6.43 (s, 2H), 3.75 (s, 3H);
13 C NMR (125 MHz, CDCl3): 167.1, 153.3, 149.7, 145.7, 140.9, 137.0, 133.5, 129.0, 127.6, 126.9, 124.1, 123.6,
119.7, 110.5, 52.5, 44.0; HRMS (IT-TOF); Anal. Calcd. for C16 H14 N4 O2 : m/z 295.1190; Found [M+H]+:
m/z 295.1192.
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(E)-Methyl 2-((2-benzotriazolyl)methyl)-3-(2-pyridinyl)acrylate (11g)
Light brown solid; yield (32 mg, 11%); mp 138.0–140.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 7.38 (d, J =
4.5 Hz, 1H), 6.74 (s, 1H), 6.60 (dd, J = 6.5, 3.0 Hz, 2H), 6.47 (dd, J = 7.8, 1.8 Hz, 1H), 6.27 (d, J = 8.0
Hz, 1H), 6.08 (dd, J = 6.5, 3.0 Hz, 2H), 6.01–5.98 (m, 1H), 5.27 (s, 2H), 2.61 (s, 3H); 13 C NMR (125 MHz,
CDCl3): 162.4, 148.5, 145.1, 139.5, 136.6, 132.0, 123.4, 122.6, 121.2, 119.2, 113.3, 47.8, 47.2; HRMS (IT-TOF);
Anal. Calcd. for C16 H14 N4 O2 : m/z 295.1190; Found [M+H]+: m/z 295.1190.
(E)-Methyl 2-((1-benzotriazolyl)methyl)-3-(2-furanyl)acrylate (10h)
Light yellow solid; yield (100 mg, 35%); mp 128.0–130.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.03 (d, J
= 8.3 Hz, 1H), 7.75 (s, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.44 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H),
6.95 (d, J = 3.2 Hz, 1H), 6.56–6.55 (m, 1H), 5.98 (s, 2H), 3.73 (s, 3H); 13 C NMR (125 MHz, CDCl3): 168.3,
151.0, 147.0, 146.7, 134.0, 131.1, 127.9, 124.4, 121.1, 120.5, 120.0, 113.3, 110.8, 52.7, 45.2; Anal. Calcd for
C15 H13 N3 O3 (283.28): C, 63.60; H, 4.63; N, 14.83; Found: C, 63.78; H, 4.70; N, 14.86.
(E)-Methyl 2-((2-benzotriazolyl)methyl)-3-(2-furanyl)acrylate (11h)
Yellow solid; yield (28 mg, 10%); mp 76–78 ◦ C; 1 H NMR (400 MHz, CDCl3): 7.82 (dd, J = 6.4, 3.2
Hz, 2H), 7.78 (s, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.31 (dd, J = 6.6, 3.2 Hz, 2H), 6.81 (d, J = 3.6 Hz, 1H), 6.47
(dd, J = 3.0, 1.6 Hz, 1H), 6.05 (s, 2H), 3.75 (s, 3H); 13 C NMR (100 MHz, CDCl3): 167.3, 150.1, 146.0, 144.2,
130.6, 126.0, 119.8, 118.8, 118.1, 112.5, 52.7, 52.5; Anal. Calcd for C15 H13 N3 O3 (283.28): C, 63.60; H, 4.63;
N, 14.83; Found: C, 63.40; H, 4.82; N, 14.72.
(E)-Methyl 2-((1-benzotriazolyl)methyl)-3-(2-(3-methyl)thiophenyl)acrylate (10i)
White solid; yield (151 mg, 48%); mp 134.0–135.0 ◦ C; 1 H NMR (500 MHz, CDCl3): 8.14 (s, 1H), 8.05
(d, J = 8.3 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.49–7.44 (m, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.15 (s, 1H), 5.81
(s, 2H), 3.74 (s, 3H), 2.28 (s, 3H); 13 C NMR (125 MHz, CDCl3): 168.3, 146.8, 139.7, 138.4, 137.2, 137.1, 134.1,
128.0, 127.8, 124.5, 121.5, 120.6, 110.9, 52.7, 45.3, 15.6; Anal. Calcd for C16 H15 N3 O2 S (313.37): C, 61.32; H,
4.82; N, 13.41; Found: C, 61.17; H, 4.83; N, 13.31.
(E)-Methyl 2-((2-benzotriazolyl)methyl)-3-(2-(3-methyl)thiophenyl)acrylate (11i)
White solid; yield (66 mg, 21%); mp 137.0–138.0 ◦ C; 1 H NMR (500 MHz, DMSO-d6): 8.40 (s, 1H), 7.89
(dd, J = 6.6, 3.1 Hz, 2H), 7.40–7.36 (m, 3H), 6.96 (d, J = 5.1 Hz, 1H), 6.03 (s, 2H), 3.83 (s, 3H), 2.45 (s, 3H);
13 C NMR (125 MHz, DMSO-d6): 168.6, 145.3, 145.0, 136.7, 131.4, 131.3, 130.5, 126.9, 120.0, 118.9, 53.1, 52.8,
14.9; Anal. Calcd for C16 H15 N3 O2 S (313.37): C, 61.32; H, 4.82; N, 13.41; Found: C, 61.53; H, 4.77; N, 13.32.
Acknowledgment
It is gratefully acknowledged that this work was supported financially by Anadolu University (Project No:
1110F163).
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