An efficient water-mediated synthetic route for the alkylation of heteroarenes

Article abstract of DOI:10.3906/kim-1802-18

An efficient synthetic route has been described for the alkylation of 1H-indole, 1H-benzimidazole, and 1H-benzotriazole. This approach features the alkylation of heteroaromatics through in situ generated enones from ketonic Mannich bases under metal-free conditions. A series of alkylated heteroaromatics have been synthesized via the K10 catalyzed alkylation reactions of these heteroaromatics with a variety of ketonic Mannich bases. Environmentally benign K10 catalyst, water-mediated mild reaction conditions, and the efficient synthesis of alkylated products are the advantages of this alkylation method.

Full text of DOI:10.3906/kim-1802-18

Turk J Chem
Turkish Journal of Chemistry
(2018) 42: 1598 – 1610
© TÜBİTAK
http://journals.tubitak.gov.tr/chem/
doi:10.3906/kim-1802-18
Research Article
An efficient water-mediated synthetic route for the alkylation of heteroarenes
Pınar SEYİTDANLIOĞLU,, Essam Hamied Ahmed HANASHALSHAHABY,,
Canan ÜNALEROĞLU∗,
Department of Chemistry, Faculty of Science, Hacettepe University, Ankara, Turkey
Received: 08.02.2018
•
Accepted/Published Online: 22.07.2018
•
Final Version: 06.12.2018
Abstract: An efficient synthetic route has been described for the alkylation of 1H -indole, 1H -benzimidazole, and
1H -benzotriazole. This approach features the alkylation of heteroaromatics through in situ generated enones from
ketonic Mannich bases under metal-free conditions. A series of alkylated heteroaromatics have been synthesized via the
K10 catalyzed alkylation reactions of these heteroaromatics with a variety of ketonic Mannich bases. Environmentally
benign K10 catalyst, water-mediated mild reaction conditions, and the efficient synthesis of alkylated products are the
advantages of this alkylation method.
Key words: Mannich base, alkylation reaction of 1H -indole 1H -benzimidazole and 1H -benzotriazole, K10, environ-
mentally friendly synthesis
1. Introduction
Indole, benzimidazole, and benzotriazole derivatives appear in a wide range of biologically active compounds
on both the synthetic and the natural basis. These heteroaromatics exhibit biological activities such as
1
2
3
4
antiparasitic, antimicrobial, antiviral, antiserotonergic, antiadrenergic, antihistaminic, and analgesic.
Omeprazole, lansoprazole, rabeprazole, and pantoprazole as proton pump inhibitors or H2 receptor blockers
5
6
are market drugs of benzimidazole derivatives, and nonsteroidal aromatase inhibitor vorozole and antiemetic
drug alizapride are examples of commercially used benzotriazole derivatives. Moreover, alkyl functionalized
indole, benzimidazole, and benzotriazole derivatives show such bioactivities.
7
8−10
Given the importance of these
functionalized heteroaromatics in medicinal chemistry, development of an environmentally friendly synthetic
route to these heteroaromatics is of high importance.
To date, various synthetic methods have been applied to the alkylation of these heteroaromatics; however,
very limited studies have been reported on the synthesis of carbonyl functionality bearing alkyl substituted
indoles, benzimidazoles, and benzotriazoles. Acid catalyzed Mannich reaction of 1H -benzimidazole with
9
8
acetophenone and formaldehyde or substitution reaction of alkyl halides with 1H -benzimidazole in organic
solvents is used for the alkylation of benzimidazole. Another approach for the alkylation of heteroaromatics
11
was reported by Roman with the use of Mannich bases to reach alkyl substituted benzimidazoles, in which
Mannich bases provide a good opportunity to form new C-C and C-N bonds through the substitution or
12
elimination-addition reactions. Recently, syntheses of alkyl substituted benzotriazoles have been reported via
13
Mannich-type coupling of ketones and benzotriazoles in the presence of Selectfluor catalyst in DMSO or from
14
the reaction of enones in the presence of Sc(OTf)3 . Alkylated indole syntheses were handled from the reaction
∗Correspondence: canan@hacettepe.edu.tr
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SEYİTDANLIOĞLU et al/Turk J Chem
15
of indoles with quite expensive and unstable enones in various organic solvents by using Br2 or different metal
16−20
catalysts such as Al(III), Pd(II)/Sn(II), Fe(II), Cu(II), and Ru(I)/Ag(I).
In the present work, it is aimed to achieve the metal-free alkylation of 1H -indole, 1H -benzimidazole, and
1H -benzotriazole from the reaction of these heteroaromatics with Mannich bases in water. In this approach,
Mannich base 1 serves as an enone precursor for 2 as given in Scheme 1.
Scheme 1. Retrosynthetic strategy of alkylated heteroaromatics.
2. Results and discussion
Vinyl ketones are generally unstable and high-cost starting materials; therefore, we previously used Mannich
21
bases as enone precursors. Here, our strategy began with the reaction of 1H -indole (3) with Mannich base 1a
in water (Scheme 2). The reaction furnished target molecule 4a with quite a high yield (50%) under catalyst-free
conditions.
Scheme 2. Alkylation of 1H -indole.
To improve the product yield, reaction conditions were optimized on the model reaction given in Scheme
2. In catalyst-free conditions, the highest yield was obtained in water (Table 1, entries 1–3.) We next tested a
variety of catalysts to improve the yield but Cu(OTf)2 , Ce(OTf)3 , CAN, and KSF gave the product with lower
yields (20%–40%) (Table 1, entries 5–8). When the reaction was performed with K10, the yield of 4a increased
from 50% to 75% (Table 1, entry 4). We then screened the effect of ratios of 1H -indole to Mannich base as
shown in Table 1, entries 9–11. The same result was obtained with the optimum ratio of 1:1.5 (Table 1, entry
10). Compound 4a has been previously obtained from the reaction of 1H -indole (3) with 1-phenylprop-2-en-
16−20
1-one (2a) in the presence of different metal catalysts in yields between 72% and 95% in organic solvents.
With this strategy, we achieved a water-mediated environmentally friendly K10 catalyzed reaction starting from
a Mannich base instead of unstable enones and compound 4a was obtained with yields comparable to metal
catalyst reaction systems.
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Table 1. Screening of the reaction conditions.
a
Entry
Solvent 1H-Indole:mannich base Catalyst
Yield (%)
1
2
3
4
5
6
7
8
H2O
EtOH
AcOH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
-
-
-
50
32
10
75
K-10
Cu(OTf)2 25
Ce(OTf)3 20
CAN
KSF
K-10
K-10
K-10
20
40
45
75
75
9
10
11
1:1.2
1:1.5
1:2
a
Isolated yields.
To extend the scope of the alkylation reactions of 1H -indole (3), we next used the synthesized Mannich
bases 1a–1g shown in the Figure in the optimized reaction condition.
Figure. Mannich bases.
Reactions of 1H -indole with Mannich bases 1d and 1e formed products 4d and 4e with low yields
(20% and 42%, respectively) (Table 2, entries 4 and 5). 4e was previously obtained by condensation of N ,N -
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SEYİTDANLIOĞLU et al/Turk J Chem
22
dimethylacrylamide/trifluoromethanesulfonic anhydride complex with indole in a lower yield. Mannich bases
1b and 1c, respectively, yielded corresponding alkylated products 4b and 4c with moderate yields (72%, 65%)
(Table 2, entries 2 and 3). The novel alkylated indole 4g was obtained with high yield (85%) (Table 2, entry 7)
and the highest yield (90%) was obtained for alkylated product 4f from the reaction of Mannich base 4f and
1H -indole (3) (Table 2, entry 6).
Table 2. Synthesis of alkylated indoles.
Entry
1
Mannich Base
1a
Product
Time (h) Yield (%)a
12
9
75
72
2
1b
3
4
1c
1d
8
65
20
16
5
1e
12
42b
6
7
1f
9
90
85
1g
12
aIsolated yields bAt reflux
With the optimum conditions in hand, we next expanded the reaction to the alkylation of 1H -benzimidazole
(5) and 1H -benzotriazole (7). K10 catalyzed reactions of 1H -benzimidazole with Mannich bases 1a–1d, 1f–1g
were generated in water and the corresponding 3-alkylated benzimidazoles 6a–6d, 6f–6g were obtained with
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SEYİTDANLIOĞLU et al/Turk J Chem
moderate to high yields (Table 3, entries 1–4, 6, 7). 3-Alkylated benzimidazoles 6a and 6c have been previously
11
obtained with 61% and 77% yields, respectively, in ethanol/water. K10 catalyzed reactions of 1H - benzim-
idazole with Mannich bases 1a, 1c, and 1f formed the corresponding products 6a (89%), 6c (80%), and 6f
(80%). Moreover, reactions with Mannich bases 1b, 1d, and 1g yielded the novel products 6b, 6d, and 6g with
moderate to high yields (67%–80%). The results indicate that this environmentally friendly reaction protocol
is very applicable for the alkylation of 1H -benzimidazole. 3-Alkylated benzimidazole 6e formed; however, the
isolation of the product failed due to the low solubility of this product in organic solvents. Formation of 6e was
proved by mass analysis (Table 3, entry 5).
Table 3. Synthesis of alkylated benzimidazoles.
Entry Mannich Base Product
Time (h) Yield (%)a
1
2
3
4
1a
1b
1c
1d
6
6
6
6
89
78
80
67
b
5
1e
6
-
6
7
1f
3
3
80
80
1g
aIsolated yields bNot isolated
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SEYİTDANLIOĞLU et al/Turk J Chem
In the next step, the K10 catalyzed reactions of 1H -benzotriazole (7) with Mannich bases 1a–1g were
investigated. The reaction of 1H -benzotriazole with Mannich base 1a was carried out and the reaction
resulted in the formation of 3-alkylated benzotriazole 8a as the major product with 65% yield and 2-alkylated
benzotriazole 9a as a minor product with 8% yield due to the two resonance forms of benzotriazole (Table 4,
entry 1). 3-Alkylated benzotriazoles 8b, 8c, and 8f were obtained with moderate to high yields (55%–79%) and
2-alkylated benzotriazoles 9b, 9c, and 9f formed with low yields (3%–20%) from the reactions of benzotriazole
and Mannich bases 1b, 1c, and 1f, respectively (Table 4, entries 2, 3, and 6). From the reaction of Mannich
base 1g, 3-alkylated benzotriazole 8g was obtained with 65% yield as the only product (Table 4, entry 7).
Compounds 8d, 9d, 8e, and 9e were formed; however, they could not be isolated due to their low solubility
in organic solvents. Formation of 8d, 9d, 8e, and 9e was proved by mass analysis (Table 4, entries 4 and 5).
With these results, hitherto unknown compounds 8b, 8f, 8g, 9b, 9c, and 9f were described in this study. All
1
13
the synthesized compounds were characterized by H NMR, C NMR, and HRMS-TOF-MS techniques.
To investigate the reaction mechanism, we performed a series of reactions of 1H -indole (3) and Mannich
base 1a. When the reactions were performed at 50 °C and room temperature, product yields decreased from
75% to 42% and 2%, respectively. These results showed that the formation of essential enone intermediate is
highly temperature-dependent.
Independently isolated key structure enone 2a was used in a separate reaction of 1H -indole (3), and
the product was obtained in 80% yield, similar to the prior result (75%). In light of the foregoing findings, we
suggest the reaction mechanism in Scheme 3. In this mechanism, Mannich base 1a in situ forms enone 2a at
80 °C and the addition of 1H -indole (3) to enone 2a forms intermediate A, and the following aromatization
gives target molecule 4a.
Scheme 3. Proposed reaction mechanism.
In conclusion, an environmentally friendly and simple method has been established to alkylate 1H -
indole, 1H -benzimidazole, and 1H -benzotriazole. All alkylation reactions were performed under metal-free
conditions in water. In this strategy, target molecules were efficiently obtained with moderate to highest yields
via environmentally friendly K10 catalyzed reactions of ketonic Mannich bases, as enone precursors, with 1H -
indole, 1H -benzimidazole, or 1H -benzotriazole. Our method exemplifies the fact that the Mannich bases
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SEYİTDANLIOĞLU et al/Turk J Chem
Table 4. Synthesis of alkylated benzotriazoles.
Mannich
Base
Yield
(%)a
Yield Time
(%)a
Entry
3-Alkylated Benzotriazole
2-Alkylated Benzotriazole
(h)
1
1a
65
8
8
2
3
4
5
1b
1c
1d
1e
55
71
5
3
6
7
8
8
b
b
-
-
b
b
-
-
6
7
1f
79
65
20
5
5
1g
-
aIsolated yields bNot isolated
are effective reagents in alkylation reactions of these heterocyclic systems. This study provides a beneficial
method for the further alkylation reactions of such heteroaromatics in water-mediated environmentally friendly
moderate reaction conditions.
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SEYİTDANLIOĞLU et al/Turk J Chem
3. Experimental
All reagents were purchased from Acros Organics, Sigma-Aldrich, or Fischer Scientific and were used without
further purification. Reactions were monitored by TLC using precoated silica plates (Kieselgel 60, F254, Merck)
and visualized by an UV lamp. Flash column chromatography was performed using silica gel (0.05–0.63 nm,
1
13
230–400 mesh ASTM, Merck). H NMR (400 MHz) and C NMR (100 MHz) data were recorded on a Bruker
DPX-400-Ultra Shield FT-NMR spectrometer using SiMe4 as an internal reference. Coupling constants are
expressed as J values in hertz (s = singlet, d = doublet, t = triplet, bs = broad singlet, m = multiplet).
Melting points were determined with a Gallenkamp electrothermal digital melting point apparatus and are
uncorrected. High-resolution mass spectra (HRMS) were recorded with an Agilent 1200/6210 high resolution
mass time-of-flight (TOF) LC/MS spectrometer.
3.1. General procedure for synthesis of Mannich bases
23
Mannich bases were synthesized according to the given literature procedure. A mixture of paraformaldehyde
(1.80 g, 1.2 eq., 60.0 mmol), ketone (1.0 eq., 50.0 mmol), morpholine (4.35 g, 1.0 eq., 50.0 mmol), and
hydrochloric acid (1.0 eq., 50.0 mmol) in ethanol was stirred at reflux. The reaction was monitored by TLC.
After the completion of the reaction, crude product was filtered and recrystallized in ethanol.
3-Morpholino-1-phenylpropan-1-one hydrochloride (1a): White solid; mp 177–178 °C (lit. 175–
24
178 °C); yield: 75%.
1-(Furan-2-yl)-3-morpholinopropan-1-one hydrochloride (1b): White solid; mp 191–192 °C (lit.
25
191–192 °C); yield: 60%.
3-Morpholino-1-(thiophen-2-yl)propan-1-one hydrochloride (1c): White solid; mp 193–194 °C
26
(lit. 194 °C); yield: 70%.
3-Morpholino-1-(1H-pyrrol-2-yl)propan-1-one hydrochloride (1d): Light brown solid; mp 206–
27
207 °C (lit. 206–207 °C); yield: 20%.
1-(1H-Indol-3-yl)-3-morpholinopropan-1-one hydrochloride (1e): Pink solid; mp 229–230 °C;
21
yield: 50%.
(E)-5-Morpholino-1-phenylpent-1-en-3-one hydrochloride (1f): White solid; mp 158–159 °C (lit.
28
158–159 °C); yield: 40%.
(E)-1-(4-Hydroxyphenyl)-5-morpholinopent-1-en-3-one hydrochloride (1g): Yellow solid; mp
28
195–196 °C (lit. 195–196 °C); yield: 65%.
3.2. General procedure for the alkylation of 1H-indole, 1H-benzimidazole, and 1H-benzotriazole
A mixture of 1H -indole, 1H -benzimidazole, or 1H -benzotriazole (1.0 eq., 0.49 mmol), ketonic Mannich base
(1.5 eq., 0.75 mmol), and montmorillonite K10 (0.15 eq., 75 mg) in 2 mL of water was heated to 80 °C. The
reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room
temperature and extracted with EtOAc (3 ×10 mL) and then dried over MgSO4 . Solvent was removed under
reduced pressure and the crude product was purified by column chromatography (EtOAc:hexane, 1:3; EtOAc).
29
3-(1H-Indol-3-yl)-1-phenylpropan-1-one (4a): White solid; mp 127–128 °C (lit. 126–127 °C);
1
yield 75%; Rf = 0.34 (EtOAc-hexane, 1:3); H NMR (400 MHz, DMSO) δ 3.04 (t, J = 7.4 Hz, 2H), 3.42 (t,
1605

SEYİTDANLIOĞLU et al/Turk J Chem
J = 7.4 Hz, 2H), 6.97 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 7.0 Hz, 1H), 7.16 (bs, 1H), 7.32 (d, J = 8.0 Hz, 1H),
13
7.49–7.56 (m, 3H), 7.63 (t, J = 6.8 Hz, 1H), 8.00 (d, J = 7.8 Hz, 2H), 10.78 (s, 1H); C NMR (100 MHz,
DMSO) δ = 19.9, 39.2, 111.8, 114.1, 118.7, 118.8, 121.4, 122.8, 127.5, 128.4, 129.2, 133.5, 136.7, 137.2, 200.2;
+
HRMS (ESI): m/z calculated for C17 H16 NO [M+H] : 250.1226; found: 250.1235.
1-(Furan-2-yl)-3-(1H-indol-3-yl)propan-1-one (4b): White solid; mp 105–106 °C; yield 72%; Rf
=
1
0.40 (EtOAc-hexane, 1:3); H NMR (400 MHz, DMSO) δ 3.01 (t, J = 7.4 Hz, 2H), 3.19 (t, J = 7.4 Hz, 2H),
6.67 (bs, 1H), 6.96 (t, J = 7.4 Hz, 1H), 7.05 (t, J = 7.1 Hz, 1H), 7.12 (bs, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.45
13
(d, J = 3.5 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.95 (bs, 1H), 10.77 (bs, 1H); C NMR (100 MHz, DMSO)
δ = 19.8, 38.9, 111.8, 112.9, 113.8, 118.7, 118.8, 121.4, 122.9, 127.4, 136.7, 148.0, 152.4, 188.7; HRMS (ESI):
+
m/z calculated for C15 H14 NO2 [M+H] : 240.1019; found: 240.1026.
30
3-(1H-Indol-3-yl)-1-(thiophen-2-yl)propan-1-one (4c): White solid; mp 104–105 °C (lit. 105 °C);
1
yield 65%; Rf = 0.20 (EtOAc-hexane, 1:3); H NMR (400 MHz, DMSO) δ 3.09 (t, J = 7.4 Hz, 2H), 3.38 (t,
J = 7.4 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.19 (bs, 1H) 7.25 (t, J = 4.3 Hz, 1H),
13
7.37 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.99 (bs, 1H), 8.01 (bs, 1H), 10.82 (s, 1H, NH); C NMR
(100 MHz, DMSO) δ = 20.1, 40.6, 111.8, 113.9, 118.7, 118.8, 121.4, 122.9, 127.5, 129.2, 133.6, 135.0, 136.7,
+
144.4, 193.3; HRMS (ESI): m/z calculated for C15 H14 NOS [M+H] : 256.0791; found: 256.0809.
3-(1H-Indol-3-yl)-1-(1H-pyrrol-2-yl)propan-1-one (4d): White solid; mp 167.5–168.0 °C; yield
1
20%; Rf = 0.27 (EtOAc-hexane, 1:3); H NMR (400 MHz, DMSO) δ 3.05 (t, J = 7.4 Hz, 2H), 3.15 (t, J =
7.4 Hz, 2H), 6.16–6.23 (m, 1H), 6.68–7.02 (m, 2H), 7.05–7.13 (m, 2H), 7.16 (bs, 1H), 7.35 (d, J = 8.0 Hz, 1H),
13
7.57 (d, J = 7.8 Hz, 1H), 10.79 (s, 1H), 11.81 (s, 1H); C NMR (100 MHz, DMSO) δ = 20.6, 38.5, 110.1,
111.8, 114.2, 116.8, 118.7, 118.8, 121.4, 122.8, 125.6, 127.4, 132.2, 136.6, 189.7; HRMS (ESI): m/z calculated
+
for C15 H15 N2 O [M+H] : 239.1179; found: 239.1193.
1,3-Di(1H-indol-3-yl)propan-1-one (4e): Pink solid; mp 200–201 °C; yield 42%; Rf = 0.30 (EtOAc-
1
hexane, 1:3); H NMR (400 MHz, DMSO) δ 3.09 (t, J = 7.5 Hz, 2H), 3.27 (t, J = 7.5 Hz, 2H), 6.99 (t, J =
7.3 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 7.14–7.25 (m, 3H), 7.34 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 6.9 Hz, 1H),
13
7.59 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 7.4 Hz, 1H), 8.35 (bs, 1H), 10.77 (bs, 1H), 11.91 (gt, 1H); C NMR
(100 MHz, DMSO) δ = 20.6, 111.8, 112.5, 114.6, 116.9, 118.6, 118.8, 121.3, 121.9, 122.1, 122.8, 123.2, 125.9,
+
127.6, 134.3, 136.7, 137.1, 195.4; HRMS (ESI): m/z calculated for C19 H17 N2 O [M+H] : 289.1385; found:
289.13512.
31
(E)-5-(1H-Indol-3-yl)-1-phenylpent-1-en-3-one (4f): White solid; mp 126–127 °C (lit. 127 °C);
yield 90%; Rf = 0.37 (EtOAc-hexane, 1:3); H NMR (400 MHz, DMSO) δ 3.09 (t, J = 7.6 Hz, 2H), 3.17 (t,
1
J = 7.6 Hz, 2H), 7.00 (d, J = 16.3 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.22 (bs, 1H),
7.42 (d, J = 8.0 Hz, 1H), 7.45–7.52 (m, 3H), 7.64 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 16.3 Hz, 1H), 7.73–7.79 (m,
13
2H), 10.86 (bs, 1H); C NMR (100 MHz, DMSO) δ = 19.9, 41.2, 111.8, 114.1, 118.7, 118.8, 121.4, 122.8, 127.0,
+
127.5, 128.9, 129.4, 130.8, 135.0, 136.8, 142.5, 200.2; HRMS (ESI): m/z calculated for C19 H18 NO: [M+H] :
276.1383; found: 276.1372.
(E)-1-(4-Hydroxyphenyl)-5-(1H-indol-3-yl)pent-1-en-3-one (4g): Yellow solid; mp 198–199 °C;
1
yield 85%; Rf = 0.14 (EtOAc-hexane, 1:3); H NMR (400 MHz, DMSO) δ 2.97–3.02 (m, 4H), 6.70 (d, J =
16.2 Hz, 1H), 6.77 (d, J = 7.8 Hz, 2H), 6.96 (t, J = 7.4 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 7.09 (bs, 1H), 7.31
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SEYİTDANLIOĞLU et al/Turk J Chem
13
(d, J = 8.0 Hz, 1H), 7.49–7.54 (m, 4H), 9.99 (bs, 1H), 10.73 (bs, 1H); C NMR (100 MHz, DMSO) δ = 20.0,
40.9, 111.8, 114.2, 116.3, 118.6, 118.8, 121.3, 122.7, 123.7, 125.9, 127.5, 130.8, 136.8, 142.8, 160.3, 199.9; HRMS
+
(ESI): m/z calculated for C19 H18 NO2 : [M+H] : 292.1332; found: 292.1325.
9
3-(1H-Benzo[d]imidazol-1-yl)-1-phenylpropan-1-one (6a): White solid; mp 80–81 °C (lit. 80–
1
81 °C); yield 89%; Rf = 0.29 (EtOAc); H NMR (400 MHz, acetone) δ 3.74 (t, J = 6.7 Hz, 2H), 4.73 (t, J =
13
6.7 Hz, 2H), 7.24–7.30 (m, 2H), 7.48–7.53 (m, 2H), 7.59–7.67 (m, 3H), 8.00–8.03 (m, 2H), 8.16 (bs, 1H);
C
NMR (100 MHz, DMSO) δ = 38.5, 42.8, 111.0, 119.8, 121.9, 122,7, 128.4, 129.2, 134.0, 134.2, 136.6, 143.8,
+
144.7, 198.3; HRMS (ESI): m/z calculated for C16 H15 N2 O [M+H] : 251.1179; found: 251.1179.
3-(1H-Benzo[d]imidazol-1-yl)-1-(furan-2-yl)propan-1-one (6b): White solid; mp 84.5–85.5 °C;
1
yield 78%; Rf = 0.26 (EtOAc); H NMR (400 MHz, DMSO) δ 3.46 (t, J = 6.7 Hz, 2H), 4.58 (t, J = 6.7 Hz,
2H), 6.68 (bs, 1H), 7.19 (t, J = 7.0 Hz, 1H), 7.25 (t, J = 7.0 Hz, 1H), 7.47 (bs, 1H), 7.57–7.72 (m, 2H), 7.97
13
(bs, 1H), 8.20 (bs, 1H); C NMR (100 MHz, DMSO) δ = 38.2, 111.0, 113.0, 119.5, 119.8, 121.9, 122.8, 134.1,
+
143.8, 144.7, 148.5, 152.0, 186.4; HRMS (ESI): m/z calculated for C14 H13 N2 O2 [M+H] : 241.0971; found:
241.0969.
3-(1H-Benzo[d]imidazol-1-yl)-1-(thiophen-2-yl)propan-1-one (6c): Colorless viscous oil; yield
1
80%; Rf = 0.28 (EtOAc); H NMR (400 MHz, acetone) δ 3.62 (t, J = 6.7 Hz, 2H), 4.60 (t, J = 6.7 Hz, 2H),
13
7.16–7.23 (m, 2H), 7.25 (t, J = 7.1, 1H), 7.62–7.68 (m, 2H), 7.91–8.03 (m, 2H), 8.24 (bs, 1H); C NMR (100
MHz, DMSO) δ 38.9, 111.0, 119.8, 122.0, 122.8, 129.3, 134.1, 134.3, 135.7, 143.7, 143.8, 144.7, 191.2; HRMS
+
(ESI): m/z calculated for C14 H13 N2 OS [M+H] : 257.0743; found: 257.0744.
11
Spectroscopic data are in agreement with literature values.
3-(1H-Benzo[d]imidazol-1-yl)-1-(1H-pyrrol-2-yl)propan-1-one (6d): White solid; mp 164–165
1
°C; yield 67%; Rf = 0.22 (EtOAc); H NMR (400 MHz, acetone) δ 4.58 (t, J = 6.0 Hz, 2H, CH2), 6.14 (bs,
1H), 6.97 (bs, 1H), 7.06 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.60–7.67 (m, 2H), 8.20
13
(bs, 1H), 11.86 (bs, 1H); C NMR (100 MHz, DMSO) δ = 37.6, 110.4, 110.9, 117.6, 119.8, 122.1, 122.6, 126.2,
+
131.9, 133.9, 143.5, 144.7, 187.1; HRMS (ESI): m/z calculated for C14 H14 N3 O [M+H] : 240.1131; found:
240.1125.
3-(1H-Benzo[d]imidazol-1-yl)-1-(1H-indol-3-yl)propan-1-one (6e): HRMS (ESI): m/z calcu-
+
lated for C18 H16 N3 O [M+H] : 290.1288; found: 290.1267.
(E)-5-(1H-Benzo[d]imidazol-1-yl)-1-phenylpent-1-en-3-one (6f): White solid; mp 153–154 °C;
1
yield 80%; Rf = 0.65 (EtOAc) ; H NMR (400 MHz, acetone) δ 4.55 (t, J = 6.8 Hz, 2H), 6.88 (d, J = 16.4
Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.38–7.45 (m, 3H), 7.57–7.72 (m, 5H), 8.22 (s,
13
1H); C NMR (100 MHz, DMSO) δ = 40.6, 111.0, 119.8, 121.9, 122.7, 126.7, 129.0, 129.4, 131.1, 134.7, 143.5,
+
143.8, 144.7, 198.3; HRMS (ESI): m/z calculated for C18 H17 N2 O [M+H] : 277.1335; found: 277.1315.
(E)-5-(1H-Benzo[d]imidazol-1-yl)-1-(4-hydroxyphenyl)pent-1-en-3-one (6g): White solid; mp
1
214–215 °C; yield 80%; Rf = 0.9 (EtOAc); H NMR (400 MHz, DMSO) δ 3.29 (t, J = 6.8 Hz, 2H), 4.53 (t,
J = 6.8 Hz, 2H), 6.66 (d, J = 16.0 Hz, 1H), 6.79 (d, J = 8.5 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H), 7.26 (t, J =
13
7.5 Hz, 1H), 7.51–7.56 (m, 3H), 7.62–7.67 (m, 2H), 8.21 (s, 1H), 10.10 (s, 1H); C NMR (100 MHz, DMSO)
δ = 40.6, 111.0, 116.3, 119.8, 121.9, 122.7, 123.4, 125.7, 125.8, 131.0, 134.1, 143.9, 144.6, 160.5, 197.8; HRMS
+
(ESI): m/z calculated for C18 H17 N2 O: [M+H] : 293.1285; found: 293.1282.
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SEYİTDANLIOĞLU et al/Turk J Chem
9
3-(1H-Benzo[d][1,2,3]triazol-1-yl)-1-phenylpropan-1-one (8a): White solid; mp 62–63 °C (lit.
1
62–63 °C); yield 65%; H NMR (400 MHz, DMSO) δ 3.88 (t, J = 6.6 Hz, 2H), 5.05 (t, J = 6.6 Hz, 2H),
7.38–7.43 (m, 1H), 7.50–7.65 (m, 4H), 7.90–8.10 (m, 4H); C NMR (100 MHz, DMSO) δ = 37.8, 42.8, 111.5,
13
119.1, 124.2, 127.4, 128.3, 129.2, 133.1, 133.7, 136.3, 145.4, 197.7; HRMS (ESI): m/z calculated for C15 H14 N3 O
+
[M+H] : 252.1131; found: 252.1143.
3-(2H-Benzo[d][1,2,3]triazol-2-yl)-1-phenylpropan-1-one (9a): White solid; mp 114–115 °C; yield
1
8%; H (400 Hz, DMSO) δ 3.98 (t, J = 6.6 Hz, 2H), 5.12 (t, J = 6.6 Hz, 2H), 7.39–7.44 (m, 2H), 7.55 (t, J =
13
8.0 Hz, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.87–7.92 (m, 2H), 8.02 (d,J = 8.0 Hz, 2H); C (100 MHz, DMSO) δ
37.5, 51.4, 118.2, 126.0, 128.5, 129.3, 134.0, 136.5, 144.0, 197.3; HRMS (ESI): m/z calculated for C15 H14 N3 O
+
[M+H] : 252.1131; found: 252.1141.
3-(1H-Benzo[d][1,2,3]triazol-1-yl)-1-(furan-2-yl)propan-1-one (8b): Colorless viscous oil; yield
1
55%; H NMR (400 MHz, acetone) δ 3.67 (t, J = 6.5 Hz, 2H), 5.06 (t, J = 6.5 Hz, 2H), 6.62–6.67 (m, 1H),
7.37–7.44 (m, 2H), 7.56 (t, J = 8.0 Hz, 1H), 7.83 (bs, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 8.4 Hz,
13
1H); C NMR (100 MHz, acetone) δ = 37.6, 42.3, 110.4, 112.3, 117.7, 119.2, 123.6, 127.0, 133.3, 145.8, 147.3,
+
152.3, 185.1; HRMS (ESI): m/z calculated for C13 H12 N3 O [M+H] : 242.0924; found: 242.0924.
3-(2H-benzo[d][1,2,3]triazol-2-yl)-1-(furan-2-yl)propan-1-one (9b): Colorless viscous oil; yield
1
5%; H (400 Hz, DMSO) δ 3.74 (t, J = 6.6 Hz, 2H), 5.09 (t, J = 6.6 Hz, 2H), 6.74 (bs, 1H), 7.37–7.48 (m,
13
2H), 7.56 (bs, 1H), 7.88–7.91 (m, 2H), 8.02 (bs, 1H); C (100 MHz, DMSO) δ 37.2, 51.1, 113.1, 118.2, 119.5,
+
126.8, 144.0, 148.5, 185.4; HRMS (ESI): m/z calculated for C13 H12 N3 O [M+H] : 242.0924; found: 242.0920.
3-(1H-Benzo[d][1,2,3]triazol-1-yl)-1-(thiophen-2-yl)propan-1-one (8c): White solid; mp 97–98
32
1
°C (lit. 94–95 °C); yield 71%; Rf = 0.12 (EtOAc-hexane, 1:2); H NMR (400 MHz, DMSO) δ 3.79 (t, J =
6.4 Hz, 2H), 5.03 (t, J = 6.4 Hz, 2H), 7.21 (bs, 1H), 7.39 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.95
13
(d, J = 8.1 Hz, 1H), 7.99–8.03 (m, 3H); C NMR (100 MHz, DMSO) δ = 38.4, 43.2, 111.4, 119.5, 124.4,
127.6, 129.3, 133.4, 134.4, 135.7, 143.6, 145.6, 190.7; HRMS (ESI): m/z calculated for C13 H12 N3 OS: [M+H] :
+
258.0696; found: 258.0688.
3-(2H-Benzo[d][1,2,3]triazol-2-yl)-1-(thiophen-2-yl)propan-1-one (9c): Colorless viscous oil;
1
yield 3%; Rf = 0.14 (EtOAc-hexane, 1:2); H (400 Hz, DMSO) δ 3.89 (t, J = 6.6 Hz, 2H), 5.09 (t, J = 6.6
13
Hz, 2H), 7.25 (t, J = 4 Hz, 1H), 7.40–7.43 (m, 2H), 7.87–7.90 (m, 2H), 8.02–8.07 (m, 2H); C (100 Hz, DMSO)
δ = 37.9, 51.3, 118.2, 126.8, 129.3, 134.3, 135.7, 144.1, 190.3; HRMS (ESI): m/z calculated for C13 H12 N3 OS
+
[M+H] : 258.0696; found: 258.0683.
3-(1H-Benzo[d][1,2,3]triazol-1-yl)-1-(1H-pyrrol-2-yl)propan-1-one (8d) /
3-(2H-benzo[d][1,2,3]triazol-2-yl)-1-(1H-pyrrol-2-yl)propan-1-one (9d):
+
HRMS (ESI): m/z calculated for C13 H13 N4 O [M+H] : 241.1084; found: 241.1073.
3-(2H-Benzo[d][1,2,3]triazol-2-yl)-1-(1H-indol-3-yl)propan-1-one (8e) /
3-(2H-benzo[d][1,2,3]triazol-2-yl)-1-(1H-indol-3-yl)propan-1-one (9e):
+
HRMS (ESI): m/z calculated for C17 H15 N4 O [M+H] : 291.1240; found: 291.1241.
(E)-5-(1H-Benzo[d][1,2,3]triazol-1-yl)-1-phenylpent-1-en-3-one (8f): Colorless viscous oil; yield
1
79%; Rf = 0.59 (EtOAc-hexane, 1:1); H (400 MHz, DMSO) δ 3.63 (t, J = 6.5 Hz, 2H), 5.05 (t, 6.5 Hz,
2H), 6.95 (d, J = 16.4 Hz, 1H), 7.35–7.46 (m, 4H), 7.57(t, J = 8.0, 1H), 7.59–7.76 (m, 3H), 7.97 (d, J =
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SEYİTDANLIOĞLU et al/Turk J Chem
13
8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H); C (100 MHz, DMSO) δ = 43.2, 111.4, 119.5, 124.4, 126.6, 127.6,
+
129.0, 129.4, 131.1, 133.4, 134.7, 143.5, 145.6, 197.7; HRMS (ESI): m/z calculated for C17 H16 N3 O [M+H] :
278.1288; found: 278.1271.
(E)-5-(2H-Benzo[d][1,2,3]triazol-2-yl)-1-phenylpent-1-en-3-one (9f): Colorless viscous oil; yield
1
20%; Rf = 0.75 (EtOAc-hexane, 1:1); H (400 Hz, DMSO) δ 3.63 (t, J = 6.6 Hz, 2H), 5.05 (t, J = 6.6 Hz,
13
2H), 6.95 (d, J = 16.0 Hz, 1H), 7.41–7.44 (m, 5H), 7.67–7.71 (m, 3H), 7.88–7.91 (m, 2H); C (100 Hz, DMSO)
δ = 51.4, 118.2, 126.5, 126.6, 129.1, 129.5, 131.1, 134.8, 143.4, 144.0, 197.2; HRMS (ESI): m/z calculated for
+
C17 H16 N3 O: found [M+H] : 278.1288; found: 278.1288.
(E)-5-(1H-Benzo[d][1,2,3]triazol-1-yl)-1-(4-hydroxyphenyl)pent-1-en-3-one (8g): Brown solid;
1
mp 183–184 °C; yield 65%; H NMR (400 MHz, acetone) δ 3.48 (t, J = 6.6 Hz, 2H), 4.97 (t, J = 6.6 Hz, 2H),
6.70 (d, J = 16.3 Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 7.48–7.62 (m, 4H), 7.96 (d,
13
J = 8.1 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 10.90 (bs, 1H, OH); C (100 MHz, acetone) δ = 39.2, 42.8, 110.6,
115.8, 119.2, 123.1, 123.6, 126.2, 126.9, 130.4, 133.3, 143.2, 145.9, 159.9, 196.2; HRMS (ESI): m/z calculated
+
for C17 H16 N3 O2 [M+H] : 294.1237; found: 294.1233.
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