1-(2-Chlorobenzyloxy)-3-[1,2,3]triazol-1-yl-propan-2-ol Derivatives: Synthesis, Characterization, and DFT-Based Descriptors Analysis

Article abstract of DOI:10.1155/2017/4783608

A novel series of 1-(2-chlorobenzyloxy)-3-[1,2,3]triazol-1-yl-propan-2-ol derivatives was designed and synthesized using copper catalyzed alkyne-azide cycloaddition in the key step. Theoretical investigation of molecular and electronic properties by means

Full text of DOI:10.1155/2017/4783608

Hindawi
Journal of Chemistry
Volume 2017, Article ID 4783608, 9 pages
https://doi.org/10.1155/2017/4783608
Research Article
1-(2-Chlorobenzyloxy)-3-[1,2,3]triazol-1-yl-propan-2-ol
Derivatives: Synthesis, Characterization, and DFT-Based
Descriptors Analysis
Eloisa Román-Maldonado,1 Horacio Reyes,2 Miguel A. Sanchez-Carmona,1
Nelly González-Rivas,1 and Erick Cuevas-Yañez1
1
´
´
´
´
Centro Conjunto de Investigacion en Quımica Sustentable UAEM-UNAM, Universidad Autonoma del Estado de Mexico,
Carretera Toluca-Atlacomulco Km 14.5, 50200 Toluca, MEX, Mexico
2
´
´
´
´
Division de Ingenierıa Quımica, Instituto de Estudios Superiores de Jocotitlan, Carretera Toluca-Atlacomulco Km 44.8,
Ejido de San Juan y San Agustin, Jocotitlan, MEX, Mexico
´
Correspondence should be addressed to Erick Cuevas-Yan˜ez; ecuevasy@uaemex.mx
Received 14 December 2016; Accepted 13 February 2017; Published 13 March 2017
Academic Editor: Anton Kokalj
Copyright © 2017 Eloisa Roma´n-Maldonado et al. is is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
A novel series of 1-(2-chlorobenzyloxy)-3-[1,2,3]triazol-1-yl-propan-2-ol derivatives was designed and synthesized using copper
catalyzed alkyne-azide cycloaddition in the key step. eoretical investigation of molecular and electronic properties by means
of global and local reactivity indexes of the synthetized compounds was carried out, using DFT (Density Functional eory) at
PBEPBE/6-31++G∗∗ level.
1. Introduction
molecules in order to improve the above-mentioned prop-
erties. However, a synthetic challenge in the preparation of
this molecule is the tetrahydropyridine moiety prepared from
4-piperidone analogs, which in turn are obtained through
several reaction steps [10, 11]. In this regard, we propose
a synthesis of a novel family of compounds 2 analogs to
molecule 1 based on a substitution of tetrahydropyridine
ring by 1,2,3-triazole which is easily synthesized by copper
catalyzed alkyne-azide cycloaddition (CuAAC), the most
powerful click reaction (Scheme 1).
On the other hand, DFT-based methods have already
proven to be useful in determining molecular structure of
organic compounds, as well as in elucidating their electronic
structure and reactivity [12]. ere are two kinds of DFT-
based reactivity indexes: global and local quantities. e
global parameters measure the electronic features of the
molecules as a whole and the local quantity reflects the
reactivity of particular regions or atoms. e properties
calculated in this study have been successfully applied in to
explain the reactivity of organic and inorganic molecules,
proteins, solids, and others [13].
Depression and similar psychological disorders affect about
350 million people worldwide and represent one of the
leading causes of disability and a major contributor to the
burden of suicide and ischemic heart diseases [1, 2]. is
illness is associated with a decreased production of serotonin
in conjunction with a decreased sensitivity of postsynaptic
receptors to available serotonin [3]. erefore, one of the most
extended current therapies for this kind of diseases involve
the use of commercially available drugs which work as selec-
tive serotonin reuptake inhibitors (SSRI) such as fluoxetine
among other analogous compounds [4, 5]. Although all these
compounds are effective as antidepressants, some side effects
are observed during their use. is reason has motivated the
design and development of diverse molecules, which display
good reuptake inhibiting activity [6–8].
A particular molecule that has attracted us is a deriva-
tive from chlorobenzyloxy-3,6-dihydropyridinyl propan-2-
ol named DJLDU-3-79, 1 [9]. is compound was designed
from a hybridization of two active reuptake inhibitory

2
Journal of Chemistry
temperature below 25∘C. e resulting mixture was heated
at 50∘C during 1.5 h. e solvent was removed in vacuo, and
water (20 mL) was added; the mixture was acidified with
diluted HCl (10%) to pH = 5. e product was extracted with
CH Cl (3 × 15 mL), the organic phases were joined and dried
O
NH
Cl
N
HO
2
2
over Na SO , and the solvent was removed in vacuo to yield a
2
4
1
white solid (1.27 g, 90%), which was used without additional
1
purification, m.p. 50∘C; H NMR (300 MHz, CDCl ) ꢅ 7. 49
3
(dd, J = 7.3, 2.0 Hz, 1H), 7.37 (dd, J = 7.5, 1.8 Hz, 1H), 7.32–7.20
(m, 2H), 4.79 (d, J = 6.0 Hz, 1H), 1.69 (s, 1H); 13C NMR
O
N
N
N
(75 MHz, CDCl ) ꢅ 137.1, 131.6, 128.2, 127.7, 127.6, 125.9, 61.7;
R
3
Cl
IR (ATR, cm−1): 3302, 3216, 2912, 2859, 1439; MS [EI+] m/z
HO
(%): 142 [M]+ (1), 107 [C H O]+ (35), 77 [C H ]+ (100), 51
7
7
6
5
[C H ]+ (91).
2
4
3
Scheme 1: Structure of DJLDU-3-79 (1) and general structure for
molecules 2 proposed in this work.
2.1.2. 2-(2-Chloro-benzyloxymethyl)-oxirane (5). A mixture
of 40% aqueous solution of NaOH (6.5 mL) (2-chloro-
phenyl)-methanol 4 (0.71 g, 5 mmol) and tetrabutylammo-
nium iodide (0.09 g, 0.25 mmol) was vigorously stirred at
room temperature for 24 h. e mixture was cooled to 0∘C
and epichlorohydrin (1.55 mL, 1.83 g, and 19.9 mmol) was
added dropwise. Afer completion, the reaction mixture was
stirred at 0∘C for 30 minutes and at room temperature
overnight. e mixture was poured into ice cold water
(20 mL). e product was extracted with CH Cl (3 × 15 mL),
Several studies have confirmed closed relationships
between the biological performance of a family of com-
pounds and their chemical reactivity. e pharmacokinetic
and pharmacodynamic properties of SSRI molecules are
strongly influenced by their interactions to the body proteins
[9]. erefore, the electron transfer properties in protein-
ligand binding could be studied by using DFT reactivity
indexes. To accomplish this goal, the use of global chemical
reactivity parameters, chemical potential (ꢀ), electron affinity
(ꢁ), chemical potential (ꢂ), sofness (ꢃ), and electrophilicity
(ꢄ), could aid the understanding of the interaction process
between SSRI and biological molecules. Also, the local
parameters could give some light about which molecular
moieties are most involved in the binding structure
2
2
the organic phases were joined and dried over Na SO , and
2
4
the solvent was removed in vacuo to yield a pale yellow oil
(1.27 g, 90%), which was used without additional purification;
1H NMR (300 MHz, CDCl ) ꢅ 7. 5 0 (dd, J = 7.4, 2.1 Hz, 1H),
3
7. 35 (dd, J = 7.4, 1.8 Hz, 1H), 7.31–7.19 (m, 2H), 4.68 (d, J =
3.9 Hz, 2H), 3.49–3.87 (dd, J = 11.4, 5.8 Hz, 2H), 3.27–3.18 (m,
1H), 2.65–2.82 (dd, J = 5.0, 2.7 Hz, 2H); 13C NMR (75 MHz,
CDCl ) ꢅ 135.4, 132.6, 129.0, 128.7, 128.5, 126.5, 71.1, 69.9, 50.5,
is report summarizes our most recent findings in
the click chemistry area aiming to search and develop
new molecules with high SSRI activity; also the theoreti-
cal characterization of the obtained molecules was carried
out.
3
43.9; IR (ATR, cm−1): 3061, 2998, 2923, 2864, 1250, 1096; MS
[EI+] m/z (%): 198 [M]+ (5), 56 [C H O]+ (100). HRMS (EI):
3
5
calcd. For C H ClO : 198.0448; found: 198.0442.
10 11
2
2.1.3. 1-Azido-3-(2-chloro-benzyloxy)-propan-2-ol (6). 2-(2-
Chloro-benzyloxymethyl)-oxirane 5 (0.965 g, 4.86 mmol),
NH Cl (0.529 g, 9.89 mmol), and NaN (2.652 g, 40.8 mmol)
2. Experimental Section
4
3
2.1. Synthesis. e starting materials were purchased from
Aldrich Chemical Co. and were used without further purifi-
cation. Solvents were distilled before use. Silica plates of
0.20 mm thickness were used for thin layer chromatography.
Melting points were determined with a Kru¨ss Optronic
were added successively to a mixture of MeOH (8 mL) and
H O (1 mL) and the reaction mixture was stirred at room
2
temperature for 24 h. e solvent was removed in vacuo
and the product was extracted with AcOEt (3 × 15 mL);
the organic phases were joined and dried over Na SO and
2
4
1
melting point apparatus and they are uncorrected. H and
the solvent was removed in vacuo to yield a pale yellow
13C NMR spectra were recorded using a Bruker AVANCE
300; the chemical shifs (ꢅ) are given in ppm relative to TMS
as internal standard (0.00). For analytical purposes the mass
spectra were recorded on a Shimadzu GCMS-QP2010 Plus
in the EI mode, 70 eV, 200∘C via direct inlet probe. Only the
molecular and parent ions (m/z) are reported. IR spectra were
recorded on a Bruker TENSOR 27 FT instrument.
oil (1.2981 g, 74.12%), which was used without additional
purification; 1H NMR (300 MHz, CDCl ) ꢅ 7. 4 0 (dd, J
3
= 7.2, 2.2 Hz, 1H), 7.35–7.30 (m, 1H), 7.29–7.16 (m, 2H),
4.60 (s, 2H), 3.94 (ddd, J = 10.8, 5.9, 4.9 Hz, 2H), 3.54
(s, broad, 1H), 3.52–3.34 (ddd, J = 5.4, 2.3, 1.3 Hz, 2H),
3.22 (s, 1H); 13C NMR (75 MHz, CDCl ) ꢅ 135.3, 133.2,
3
129.4, 129.4, 129.1, 126.9, 71.85, 70.6, 69.6, 53.5; IR (ATR,
cm−1): 3426, 2097, 1092, 751; MS [EI+] m/z (%): 241 [M]+
(5), 149 [M-C H ClO]+ (100), 125 [M-C H Cl]+ (90), 107
2.1.1. 2-Chlorophenyl-methanol (4). A solution of 2-chlorob-
enzaldehyde (1.125 mL, 1.40 g, 10.03 mmol) in ethanol (15 mL)
was added to a suspension of sodium borohydride (0.189 g,
4.97 mmol) in absolute ethanol (6 mL) maintaining the
7
6
7
6
[M- C H N O]+ (90), 89 [M-C H N O]+ (60), 43 [M-N ]+
3
6
3
2
4
3
3
(65). HRMS (EI): calcd. For C H ClN O : 241.0618; found:
10 12
3
2
241.0622.

Journal of Chemistry
3
2.2. General Procedure for the Synthesis of 1-(2-Chloro-
benzyloxy)-3-[1,2,3]triazol-1-yl-propan-2-oles. e appropri-
ate alkyne (1 mol) was added in one portion to a solution
of 1-azido-3-(2-chloro-benzyloxy)-propan-2-ol 6 (0.241 g,
1 mmol), CuI (0.009 g, 0.05 mmol), and DIPEA (0.17 mL,
0.129 g, 1 mmol) in CH Cl (15 mL). e resulting mixture
NMR (75 MHz, CDCl ) ꢅ 155.1, 143.0, 134.7, 134.22, 132.3,
3
129.5, 128.5, 128.8, 127.9, 125.8, 123.4, 113.8, 70.6, 69.5, 68.1,
60.9, 52.1, 19.5; IR (ATR, cm−1): 3392, 2918, 2865, 1442, 1107;
MS [EI+] m/z (%): 357 [M]+ (5), 125 [C H Cl]+ (100). HRMS
7
6
(EI): calcd. For C H ClN O : 357.1244; found: 357.1247.
19 20
3
2
2
2
was stirred at room temperature for 24 h. An aqueous
solution of 2% EDTA (30 mL) was added and the stirring was
continued for additional 24 h. e product was extracted with
CH Cl (3 × 15 mL), the organic phases were joined and dried
2.2.5. 2-{1-[3-(2-Chlorobenzyloxy)-2-hydroxy-propyl]-1H-[1,2,
3]triazol-4-ylmethyl}-2-methyl-cyclopentane-1,3-dione (11).
Colorless oil; yield: 66%; 1H NMR (300 MHz, CDCl ) ꢅ 7. 4 4
3
2
2
(s, 1H), 7.48–7.41 (m, 1H), 7.36–7.31 (m, 1H), 7.26–7.19 (m, 2H),
4.60 (s, 2H), 4.46–4.29 (dddd, J = 14.0, 13.9, 7.3, 3.6 Hz, 2H),
4.14 (dq, J = 9.4, 5.3 Hz, 1H), 3.50 (d, J = 5.2 Hz, 2H), 3.05 (s,
2H), 2.80 (d, J = 3.2 Hz, 4H), 2.01 (s, broad, 1H), 1.17 (s, 3H);
over Na SO , the solvent was removed in vacuo, and the final
2
4
product was purified by crystallization.
13C NMR (75 MHz, CDCl ) ꢅ 212.2, 202.7, 137.5, 130.5, 128.0,
2.2.1. 1-(2-Chlorobenzyloxy)-3-(4-phenyl-[1,2,3]triazol-1-yl)-
3
propan-2-ol (7). White solid; yield: 85%; mp 58∘C; 1H NMR
124.5, 124.4, 124.1, 122.02, 118.20, 66.9, 65.6, 64.1, 50.3, 48.1,
30.1, 26.0, 25.9, 25.3; IR (ATR, cm−1): 3304, 2925, 2869, 1442,
1361, 1219; MS [EI+] m/z (%): 391 [M]+ (10), 125 [C H Cl]+
(300 MHz, CDCl ) ꢅ 7.86 (s, 1H), 7.78–7.65 (m, 2H), 7.47–7.30
3
(m, 5H), 7.32 (s, 1H), 7.30–7.20 (m, 2H), 4.65 (s, 2H), 4.64–4.57
(m), 4.49 (dd, J = 8.7, 7.0 Hz, 1H), 4.48–4.36 (m, 1H), 3.59–3.52
(m, 1H), 3.44–3.37 (m, 1H), 2.62 (s, broad, 1H); 13C NMR
7
6
(100). HRMS (EI): calcd. For C H ClN O : 391.1299; found:
19 22
3
4
391.1303.
(75 MHz, CDCl ) ꢅ 135.3, 133.2, 129.4, 129.4, 129.1, 126.9, 71.8,
3
70.6, 69.6, 53.5; IR (ATR, cm−1): 3227, 3061, 2866, 1440, 750;
2.2.6. 3-{1-[3-(2-Chlorobenzyloxy)-2-hydroxy-propyl]-[1,2,3]
MS [EI+] m/z (%): 343 [M]+ (5), 125 [C H Cl]+ (100). HRMS
1
7
6
triazol-4-yl}-propan-1-ol (12). Colorless oil; yield: 84%; H
(EI): calcd. For C H ClN O : 343.1088; found: 343.1091.
18 18
3
2
NMR (300 MHz, CDCl ) ꢅ 7.44 (s, 1H), 7.43–7.35 (m, 1H),
3
7.30–7.21 (m, 3H), 4.78 (s, broad, 1H), 4.64 (s, 2H), 4.53–4.38
(dddd, J = 14.0, 14.0, 7.1, 3.6 Hz), 4.28–4.20 (m, 1H), 3.66 (t, J =
6.4 Hz, 2H), 3.58–3.51 (dddd, J = 9.7, 9.7, 5.5, 5.0 Hz, 2H), 2.79
(t, J = 7.4 Hz, 2H), 2.17 (s, broad, 1H), 1.89 (p, J = 6.6 Hz, 2H);
2.2.2. 1-(2-Chlorobenzyloxy)-3-(4-p-tolyloxymethyl-[1,2,3]tri-
azol-1-yl)-propan-2-ol (8). White solid; yield: 99%; mp 25∘C;
1H NMR (300 MHz, CDCl ) ꢅ 7.70 (s, 1H), 7.46 (dd, J = 7.6,
3
1.7 Hz, 1H), 7.41 (dd, J = 3.8, 1.7 Hz, 1H), 7.27 (dd, J = 12.2,
1.8 Hz, 1H), 7.20–7.13 (m, 1H), 7.05 (d, J = 8.5 Hz, 2H), 6.87 (d,
J = 2.3 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 5.08 (s, 2H), 4.57 (s,
2H), 4.52–4.36 (dddd, J = 13.9, 14.0, 3.8, 7.1 Hz, 2H), 4.20 (dd,
J = 9.2, 5.2 Hz, 1H), 3.53–3.46 (ddd, J = 9.7, 5.4, 4.9 Hz, 2H),
13C NMR (75 MHz, CDCl ) ꢅ 147.0, 134.8, 133.1, 129.3, 129.2,
3
126.6, 122.3, 71.2, 70.5, 68.8, 61.3, 52.6, 31.5, 21.7; IR (ATR,
cm−1): 3487, 2912, 2862, 1716, 1446, 1219; MS [EI+] m/z (%):
325 [M]+ (10), 126 [C H N O]+ (100). HRMS (EI): calcd. For
5
8
3
C H ClN O : 325.1193; found: 325.1195.
15 20
3
3
2.49 (s, broad, 1H), 2.25 (s, 3H); 13C NMR (75 MHz, CDCl )
3
ꢅ 155.1, 143.0, 134.7, 134.2, 132.3, 129.5, 128.5, 128.5, 127.9, 125.8,
123.4, 113.8, 70.6, 69.5, 68.1, 60.93, 52.1, 19.5; IR (ATR, cm−1):
3312, 2925, 2860, 1269, 1120; MS [EI+] m/z (%): 387 [M]+ (5),
125 [C H Cl]+ (100). HRMS (EI): calcd. For C H ClN O :
2.2.7. 1-(2-Chlorobenzyloxy)-3-[4-(4-nitro-phenoxymethyl)-[1,
2,3]triazol-1-yl]-propan-2-ol (13). White solid; yield: 55%; mp
85∘C; 1H NMR (300 MHz, CDCl ) ꢅ 8.20 (d, J = 8.2 Hz, 2H),
3
7
6
20 22
3
3
8.17 (d, ꢆ = 2.1 Hz, 2H), 7.81 (s, 1H), 7.43–7.23 (m, 4H), 7.08
387.1350; found: 387.1351.
(m, 2H), 4.63 (d, J = 1.1 Hz, 2H), 4.62 (dddd, ꢆ = 14.1,
14.0 7.1, 4.6 Hz, 2H), 4.30 (m, 1H), 3.64–3.49 (dddd, ꢆ =
9.7, 9.7, 5.0, 4.7 Hz, 2H), 2.16 (s, 1H); 13C NMR (75 MHz,
2.2.3. 1-(2-Chlorobenzyloxy)-3-[4-(4-methoxy-phenoxymeth-
yl)-[1,2,3]triazol-1-yl]-propan-2-ol (9). White solid; yield:
CDCl ) ꢅ 162.7, 142.1, 141.4, 134.6, 132.9, 129.2, 129.2, 128.9,
3
1
46%; mp 76∘C; H NMR (300 MHz, CDCl ) ꢅ 7.78 (s, 1H),
126.5, 125.5, 124.4, 114.5, 71.0, 70.4, 68.75, 52.7; IR (ATR, cm−1):
3253, 2878, 2856, 1336; MS [EI+] m/z (%): 418 [M]+ (5),
125 [C H Cl]+ (100). HRMS (EI): calcd. For C H ClN O :
3
7. 75–7. 68 (m, 2H), 7. 39 (dd, J = 10.7, 4.2 Hz, 2H), 7.31–7.20 (m,
2H), 6.95 (d, J = 8.4 Hz, 2H), 4.65 (s, 1H), 4.60–4.46 (dddd, J
= 14.2, 3.6, 14.0, 6.8 Hz, 2H), 4.36–4.26 (m, 1H), 3.84 (s, 3H),
3.63–3.53 (ddd J = 9.8, 4.9, 9.7, 5.7 Hz, 2H), 2.04 (s, broad, 1H);
7
6
19 19
4
5
418.1044; found: 418.1048.
13C NMR (75 MHz, CDCl ) ꢅ 159.6, 147.5, 135.0, 133.5 de C3,
2.2.8. 1-(2-Chlorobenzyloxy)-3-[4-(4-chlorophenoxymethyl)-[1,
3
129.6, 129.6, 129.3, 126.9, 126.9, 126.9, 120.4, 114.2, 71.3, 70.8,
69.3, 55.3, 52.9; IR (ATR, cm−1): 3256, 3141, 2958, 2924, 2854,
1360, 1249; MS [EI+] m/z (%): 403 [M]+ (28), 125 [C H Cl]+
2,3]triazol-1-yl]-propan-2-ol (14). White solid; yield: 89%;
mp 67-68∘C; H NMR (300 MHz, CDCl ) ꢅ 7.73 (s, 1H),
1
3
7
6
7. 41 (dd, J = 9.6, 4.8 Hz, 1H), 7.30–7.20 (m, 5H), 6.94–6.89
(m, 2H), 5.16 (s, 2H), 4.63 (s, 2H), 4.60–4.40 (m, 2H), 4.29
(dd, J = 4.5, 3.7 Hz, 1H), 3.62–3.46 (m, 2H), 2.95 (s, broad,
(100).
1H); 13C NMR (75 MHz, CDCl ) ꢅ 156.1, 143.0, 134.3, 132.8,
2.2.4. 1-(2-Chlorobenzyloxy)-3-(4-p-tolyl-[1,2,3]triazol-1-yl)-
3
propan-2-ol (10). White solid; yield: 51%; mp 120∘C; 1H
128.9, 128.9, 128.8, 128.7, 128.7, 126.2, 123.6, 115.4, 70.5, 70.1,
68.5, 61.5, 52.2; IR (ATR, cm−1): 3168, 2921, 2869, 1489, 1237;
MS [EI+] m/z (%): 407 [M]+ (2), 185 [C H ClO]+ (80), 127
NMR (300 MHz, CDCl ) ꢅ 7.81 (s, 1H), 7.64–7.55 (m, 2H),
3
7. 42 (dd, J = 6.4, 2.9 Hz, 1H), 7.29–7.14 (m, 5H), 4.64 (s, 2H),
4.58–4.45 (dddd, J = 14.0, 7.2, 3.8, 4.8 Hz, 2H), 4.44–4.38 (m,
1H), 3.61–3.57 (m, 2H), 2.36 (s, 3H), 1.26 (s, broad, 1H); 13C
9
10
[C H ClO]+ (100). HRMS (EI): calcd. For C H Cl N O :
6
4
19 19
2
3
3
407.0803; found: 407.0808.

4
Journal of Chemistry
N3
O
O
(b)
OH
(c)
O
(a)
O
OH
Cl
Cl
Cl
Cl
6
5
3
4
Scheme 2: Reagents and conditions: (a) NaBH and MeOH. (b) Epichlorohydrin, NaOH, and N-Bu NBr. (c) NaN , NH Cl, and MeOH-H O.
4
4
3
4
2
Ph
N
O
N3
O
N
N
Copper (I)
source
OH
OH
Cl
Cl
Ph
7
6
Scheme 3: Reaction of azido alcohol 6 with phenylacetylene.
2.2.9. 1-(2-Chlorobenzyloxy)-3-[4-(6-methoxynaphthalen-2-
2.2.12. 1-(2-Chlorobenzyloxy)-3-[4-(2-trifluoromethylphenyl)-
yl)-[1,2,3]triazol-1-yl]-propan-2-ol (15). White solid; yield:
[1,2,3]triazol-1-yl]-propan-2-ol (18). Colorless oil; yield: 68%;
94%; mp 100∘C; 1H NMR (300 MHz, CDCl ) ꢅ 8.10 (s,
1H NMR (300 MHz, CDCl ) ꢅ 7.91 (s, 1H), 7.90 (d, J = 6.9 Hz,
3
3
1H), 7.90 (s, 1H), 7.79 (dt, J = 8.5, 1.8 Hz, 1H), 7.72 (s, 1H),
7. 68 (dd, J = 8.8, 1.8 Hz, 1H), 7.40 (dd, J = 17.1, 9.3 Hz),
7.29–7.20 (m, 3H), 7.16–7.09 (m, 2H), 4.66 (s, 2H), 4.60–4.46
(ddd, J = 3.5, 13.9, 6.7 Hz, 2H), 4.36 (s, 1H), 3.92 (s, 3H),
3.65–3.57 (dddd, J = 9.7, 4.9, 9.7, 5.5 Hz, 2H), 2.16 (s, broad,
1H), 7.73 (dd, J = 8.0, 1.4 Hz, 1H), 7.47 (dd, J = 7.9, 1.5 Hz, 1H),
7.42 (ddd, J = 6.9, 3.7, 1.6 Hz, 1H), 7.37–7.32 (m, 1H), 7.23 (td, J =
6.5, 5.7, 3.7 Hz, 2H), 4.63 (d, J = 1.2 Hz, 2H), 4.63–4.50 (dddd,
J = 14.1, 14.0, 6.8, 3.9 Hz, 2H), 4.30 (dq, J = 9.8, 5.3 Hz, 1H),
3.60–3.51 (dddd, J = 9.8, 9.7, 5.6, 4.9 Hz, 2H), 1.26 (s, broad,
1H); 13C NMR (75 MHz, CDCl ) ꢅ 157.9, 147.6, 135.1, 134.3,
1H); 13C NMR (75 MHz, CDCl ) ꢅ 163.4, 160.1, 139.6, 134.9,
3
3
133.4, 129.7, 129.6, 129.5, 129.2, 128.8, 127.3, 126.9, 125.5, 124.9,
121.2, 119.2, 105.7, 71.5, 70.8, 69.2, 55.3, 53.3; IR (ATR, cm−1):
3391, 3131, 2921, 2852, 1606, 1216; MS [EI+] m/z (%): 423
[M]+ (10), 226 [C H N O]+ (80), 185 [C H ClO]+ (35),
134.3, 132.6, 128.8, 128.5, 126.1, 123.21, 114.2, 111.1, 103.6, 70.74,
70.1, 68.5, 52.4; IR (ATR, cm−1): 3344, 1354, 1168.86, 1107; MS
[EI+] m/z (%): 411 [M]+ (5), 125 [C H Cl]+ (100). HRMS (EI):
7
6
calcd. For C H ClF N O : 411.0961; found: 411.0965.
13 10
3
9
10
19 17
3
3
2
125 [C H Cl]+ (100). HRMS (EI): calcd. For C H ClN O :
7
6
23 22
3
3
2.3. eoretical Calculations. All the electronic structure
computations were carried out with NWChem package [14].
A frequency analysis was applied to the optimized geometries
to verify the corresponding stability criterion. e PBEPBE
[15] exchange and correlation functional was used with the 6-
311++g∗∗ Pople’s basis set. All the reactivity parameters were
computed from a finite differences approach.
423.1350; found: 423.1356.
2.2.10. 1-(2-Chlorobenzyloxy)-3-[4-(4-fluorophenyl)-[1,2,3]tri-
azol-1-yl]-propan-2-ol (16). Colorless oil; yield: 66%; 1H
NMR (300 MHz, CDCl ) ꢅ 7.82 (s, 1H), 7.77–7.70 (m, 2H), 7.53
3
(dd, J = 5.7, 3.3 Hz, 1H), 7.38 (td, J = 7.4, 2.2 Hz, 1H), 7.26 (ddt,
J = 7.6, 2.2, 1.1 Hz, 1H), 7.30–7.21 (m, 2H), 7.09 (t, ꢆ = 7.4 Hz,
1H), 4.65 (d, ꢆ = 0.8 Hz, 2H), 4.61–4.46 (dd, J = 14.0, 7.0 Hz,
2H), 4.31 (p, ꢆ = 153.2 Hz, 1H), 3.64–3.54 (dd, J = 9.7, 5.7 Hz,
3. Results and Discussion
2H), 2.17 (s, 1H); C NMR (75 MHz, CDCl ) ꢅ 164.1, 160.8,
3
146.5, 134.8, 133.2, 129.5, 129.4, 129.1, 127.2, 127.1, 126.7, 126.4,
120.8, 115.7, 115.5, 71.2, 70.6, 69.0, 52.9; IR (ATR, cm−1): 3365,
2922, 2864, 1497, 1224; MS [EI+] m/z (%): 361 [M]+ (25), 164
[C H FN ]+ (100). HRMS (EI): calcd. For C H ClFN O :
3.1. Chemistry. e first experiments were carried out
with the objective to prepare 1-azido-3-(2-chloro-benzyl-ox-
y)-propan-2-ol, 6 (Scheme 2). Initially, 2-chlorophenyl meth-
anol 4 prepared from reduction of 4-chlorobenzaldehyde 3
was reacted with epichlorohydrin to give the aryl epoxide 5
[9, 15] which was opened with sodium azide to afford azido
alcohol 6 in a 62% global yield from 4-chlorobenzaldehyde 3.
Azido alcohol 6 was the starting material for the following
CuAAC experiments. In a model reaction, compound 6 was
treated with phenylacetylene in presence of diverse Cu(I)
catalytic sources according to that described by Rostovtsev et
al. [16], Tornøe et al. [17] and our group [18, 19] (Scheme 3),
obtaining compound 7 as only reaction product. From these
experiments presented in Table 1, we selected CuI-DIPEA
for CuAAC reaction because a best yield (85%) was reached
using this catalytic system.
8
7
3
18 17
3
2
361.0993; found: 361.0997.
2.2.11. 1-(2-Chlorobenzyloxy)-3-[4-(2,4-difluorophenyl)-[1,2,3]
triazol-1-yl]-propan-2-ol (17). White solid; yield: 67%; mp
77∘C; 1H NMR (300 MHz, CDCl ) ꢅ 8.31–8.15 (m, 1H),
3
8.00 (s, 1H), 7.47–7.33 (m, 2H), 7.26 (dd, J = 5.9, 3.5 Hz,
2H), 6.99 (td, J = 8.4, 2.6 Hz, 1H), 6.88 (ddd, J = 11.1, 8.9,
2.6 Hz, 1H), 4.66 (s, 2H), 4.61–4.49 (ddd, J = 14.1, 6.9, 3.7 Hz,
2H), 4.37–4.27 (m, 1H), 3.65–3.55 (dddd, J = 9.7, 9.6, 5.6,
4.6 Hz, 2H), 1.65 (s, broad, 1H); 13C NMR (75 MHz, CDCl )
3
ꢅ 163.4, 160.1, 139.6, 134.9, 134.3, 132.6, 128.8, 128.5, 126.1,
123.21, 114.2, 111.1, 103.6, 70.74, 70.1, 68.5, 52.4; IR (ATR,
cm−1): 3194, 3151, 2908, 1361; MS [EI+] m/z (%): 379 [M]+
(10), 239 [C H F N O]+ (100). HRMS (EI): calcd. For
Taking these optimized conditions, a synthetic procedure
was developed and a series of (2-chlorobenzyloxy)-1,2,3-
triazolyl-propan-2-ol derivatives was prepared from azido
10 11
2
3
C H ClF N O : 379.0889; found: 379.0891.
18 16
2
3
2

Journal of Chemistry
5
Table 1: Effect of catalyst, reducing agent, base, and solvent.
Entry
7
8
9
10
11
Copper salt
Reducing agent
Glucose
Sodium ascorbate
None
Base
NaOH
none
NaOH
DIPEA
DIPEA
Solvent
% yield
CuSO
CuSO
CuI
CuI
CuI
MeOH-H O
34
28
40
35
85
4
2
tBuOH-H O
4
2
MeOH-H O
2
None
None
MeOH
CH Cl
2
2
N
R
O
N3
O
N
N
CuI/CH2Cl2
OH
OH
Cl
Cl
R
6
Scheme 4
Table 2: 1,2,3-Triazoles prepared via CuAAC.
results, the molecule 12 showed the highest ionization poten-
tial value, and the molecule 15 has the closest value to 1,
showing that electron-rich aromatic rings are necessary to
mimic the properties of molecule 1. On the other hand,
the presence of electron attracting groups in the aromatics
increases the value of ꢀ; the aliphatic moieties have the same
effect.
Compound
R1
Ph
% yield
85
7
8
9
10
CH O(4-CH )C H
99
46
51
2
3
6
4
CH O(4-OCH )C H
2
3
6
4
4-CH C H
3
6
4
Electron affinity (EA) measures the ability of a molecule
to accept electrons and form anions. ere are some EA neg-
ative in the obtained values, because the molecules released
energy in the process of electron acceptance. In a general
view, only the half of the molecules has positive EA values
like one. Nevertheless, the computed values are different
compared with 1, with the molecules 16 with a behavior
closest to 1.
O
11
66
CH2
O
12
13
14
(CH ) OH
84
55
89
2
3
Chemical potential (ꢂ) measures the escaping tendency of
an electronic cloud in the ground state system. e obtained
results shown that molecule 1 has higher value (less negative)
than synthesized triazolyl derivatives, making compound 1 a
better electron donor than obtained compounds. Neverthe-
less, almost all the compounds have pretty close values to 1,
except for compound 7 and in minor degree 12.
Chemical sofness (S) is related to polarizability. e
values S for compounds 14 and 18 are remarkably close to the
value of compound 1, suggesting a similar facility to charge
transfer; other compounds with similar values are 15–17,
respectively. As matter of fact, the trifluorobenzyl group in
compound 18 shows similar characteristics to indolyl moiety
in compound 1.
CH O(4-NO )C H
2
2
6
4
CH O(4-Cl)C H
2
6
4
15
94
OCH3
16
17
18
4-FC H
66
67
68
6
4
2,4-FC H
6
3
2-CF C H
3
6
4
alcohol 6 with different alkynes. e results in Table 2 show
that this process occurs with high efficiency and functional
group tolerance; see Scheme 4.
Electrophilicity (ꢄ) gives an idea of the stabilization
energy when the system acquires electrons from the envi-
ronment up to saturation. Since the electrophilicity power is
2
3.2. DFT Characterization. In order to compare triazoles
7–18 with compound 1 and to establish possible SSRI candi-
dates, a theoretical study was carried out. e global reactivity
indexes of studied compounds are presented in Table 3,
computed through (ꢂ /2ꢇꢈ, the differences in electrophilic-
ity power (ꢄ) between the compounds are mainly due to
differences in their chemical potential. In this regard, the
results suggest that triazole moiety is a better nucleophile
electronic affinity (ꢁ), ionization potential (ꢀ), chemical
potential (ꢂ), chemical sofness (S), and electrophilicity (ꢄ).
e obtained results are gathered in Table 3.
for compounds 7–18 than tetrahydropyridine system in
compound 1. In a general way all the parameters obtained by
DFT calculations show the necessity of having an electron-
rich aromatic bond to mimic the indolyl moiety in compound
1.
Ionization potential (ꢀ) is defined as the energy needed to
remove an electron from a molecule. According to obtained

6
Journal of Chemistry
Table 3: Global reactivity indexes in eV.
A
0.113
I
ꢂ
ꢃ
ꢄ
1
7
8
9
10
12
13
14
15
16
6.546
7.717
7.593
7.250
7.510
8.362
8.253
7.312
6.619
7.397
−3.216
0.155
0.056
0.128
0.135
0.804
2.219
0.969
0.922
−1.042
−8.879
−0.162
−3.878
−0.129
−3.689
−0.105
−3.808
0.131
0.117
0.136
0.143
0.164
0.140
0.952
1.065
0.917
0.870
0.761
0.890
−0.158
−4.260
0.911
−3.671
0.347
−3.482
0.526
−3.044
0.271
−3.562
17
18
0.371
0.568
7.537
7.688
−3.583
0.139
0.140
0.895
0.889
−3.559
2
ꢀ = 1/2(ꢁꢂ + ꢁꢃ); ꢄ = ꢁꢃ − ꢁꢂ; ꢅ = 1/; ꢆ = ꢀ /2ꢄ.
Table 4: Local reactivity indexes for selec−ted atoms.
+
+
−
Compound
ꢉ
ꢉ
ꢊ
ꢊ
N1
0.01
0.02
0.02
0.00
0.01
0.02
0.00
0.02
0.01
0.01
0.02
0.02
0.00
0.01
0.01
0.01
0.02
0.00
0.02
0.05
0.03
0.01
0.03
0.02
0.02
0.02
0.03
0.00
0.02
0.02
0.02
0.02
0.03
0.04
0.08
0.04
0.02
0.03
0.01
0.04
0.08
0.04
0.04
0.08
0.03
0.03
0.10
0.04
0.03
0.06
0.03
0.01
0.03
0.02
0.03
0.05
0.03
0.02
0.03
0.04
0.04
0.07
0.04
0.02
0.04
0.03
0.01
0.06
0.12
0.06
0.07
0.10
0.03
0.14
0.29
0.14
0.14
0.28
0.10
0.11
7
N2
N3
N1
N2
N3
N1
N2
N3
N1
N2
N3
N1
N2
N3
N1
N2
N3
N1
N2
N3
N1
N2
N3
N1
N2
N3
N1
N2
N3
N1
N2
N3
0.03
0.03
0.00
0.03
0.07
0.00
0.07
0.03
0.03
0.07
0.07
0.00
0.03
0.03
0.04
0.08
0.00
0.08
0.22
0.13
0.04
0.11
0.07
0.07
0.07
0.11
0.00
0.07
0.07
0.08
0.08
0.12
8
9
10
12
13
14
15
16
17
18
0.37
0.14
0.12
0.23
0.12
0.13
0.27
0.13
0.11
0.19
0.11
0.07
0.11
0.15
0.15
0.27
0.17
0.08
0.16
0.12

Journal of Chemistry
7
1
7
9
8
10
12
13
14
15
16
18
17
Figure 1: Dual descriptor ꢉ for the molecules studied in this work.
e local properties of synthesized compounds are hard
to analyze due to the diverse nature of substituent groups
used in this study. For this reason, the three nitrogen atoms
in triazole ring were used as a probe for the local properties
in the prepared molecules. As shown in Table 4, the highest
values of ꢉ can be observed for N2 atom in all molecules,
indicating that this atom is the most susceptible to a nucle-
ophilic attack. In addition, a visible tendency for the case of
+
ꢉ was not found. e local sofness (s) followed the same
tendencies as Fukui functions; nevertheless, this function
could be comparable between molecules, being higher in
compounds 14–18 on N2 atom.
−

8
Journal of Chemistry
Other important index is known as dual descriptor ꢉ
of psychiatric disorders,” European Neuropsychopharmacology,
vol. 9, supplement 3, pp. S81–S86, 1999.
which contains information about the chemical philicity
(electrophilicity/nucleophilicity). In this case, the graphic
maps are generally sufficient for rationalizing the chemical
reactivity. e maps of dual descriptor for the set of molecules
studied in this work are represented in Figure 1, displaying the
most probable sites for a possible nucleophilic-electrophilic
attack. In a general way, the most electrophilic sites are found
on the chlorobenzyl moiety, while the most nucleophilic sites
are located on the opposite side of the molecule independent
of the electronic nature of substituent group. ese elements
reveal some similarities between compound 1 and synthe-
sized compounds with nearest values for compounds 14–18.
e calculated parameters also allow establishing interaction
sites in these molecules.
[6] O. M. Ghoneim, D. A. Ibrahim, I. M. El-Deeb, S. H. Lee, and
R. G. Booth, “A novel potential therapeutic avenue for autism:
design, synthesis and pharmacophore generation of SSRIs with
dual action,” Bioorganic and Medicinal Chemistry Letters, vol. 21,
no. 22, pp. 6714–6723, 2011.
[7] J. I. Andre´s, J. Alca´zar, J. M. Alonso et al., “Synthesis of
7-amino-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazole
derivatives displaying combined ꢋ2-adrenoceptor antagonistic
and 5-HT reuptake inhibiting activities,” Bioorganic and
Medicinal Chemistry, vol. 14, no. 13, pp. 4361–4372, 2006.
[8] J. M. Dorsey, M. G. Miranda, N. V. Cozzi, and K. G. Pinney,
“Synthesis and biological evaluation of 2-(4-fluorophenoxy)-
2-phenyl-ethyl piperazines as serotonin-selective reuptake
inhibitors with a potentially improved adverse reaction profile,”
Bioorganic and Medicinal Chemistry, vol. 12, no. 6, pp. 1483–
1491, 2004.
4. Conclusions
[9] T. L. Nolan, D. J. Lapinsky, J. N. Talbot et al., “Identification
of a novel selective serotonin reuptake inhibitor by coupling
monoamine transporter-based virtual screening and rational
molecular hybridization,” ACS Chemical Neuroscience, vol. 2,
no. 9, pp. 544–552, 2011.
[10] J. Barluenga, F. Aznar, C. Valde´s, and M.-P. Cabal, “Stereoselec-
tive synthesis of 4-piperidone and 4-aminotetrahydropyridine
derivatives by the imino Diels-Alder reaction of 2-amino-1,3-
butadienes,” Journal of Organic Chemistry, vol. 58, no. 12, pp.
3391–3396, 1993.
A new class of derivatives of chlorobenzyloxy triazolyl-
propan-2-ol was obtained from CuAAC reaction using
commercially available raw materials through simple and
efficient methods. eoretical calculations indicate that a
high similarity can be found between these products and the
leading molecule 1; consequently, a good SSRI ability would
be expected for these compounds, suggesting more studies
about this topic. Also, DFT descriptors show that the presence
of an electron-rich aromatic ring is necessary to mimic the
indolyl moiety present in compound 1.
[11] M. M. Faul, M. E. Kobierski, and M. E. Kopach, “Green chem-
istry approach to the synthesis of N-substituted piperidones,”
Journal of Organic Chemistry, vol. 68, no. 14, pp. 5739–5741,
2003.
Conflicts of Interest
e authors declare that they have no conflicts of interest.
[12] P. Geerlings, F. De Prof, and W. Langenaeker, “Conceptual
density functional theory,” Chemical Reviews, vol. 103, no. 5, pp.
1793–1873, 2003.
[13] F. Aparicio, N. Gonza´lez-Rivas, J. Ireta et al., “Sof-Sof inter-
actions in the protein-protein recognition process: the K+
channel-charybdotoxin case,” International Journal of Quantum
Chemistry, vol. 112, no. 22, pp. 3618–3623, 2012.
[14] E. Apra, T. L. Windus, T. P. Straatsma et al., NWChem,
A Computational Chemistry Package for Parallel Computers,
Version 5.1, Pacific Northwest National Laboratory, Richland,
Wash, USA, 2005.
[15] C. Adamo and V. Barone, “Toward reliable density functional
methods without adjustable parameters: the PBE0 model,”
Journal of Chemical Physics, vol. 110, no. 13, pp. 6158–6170, 1999.
Acknowledgments
Financial support from CONACYT (Project no. 135053) is
gratefully acknowledged. e authors would like to thank
Signa S. A. de C. V. for some graciously donated solvents and
reagents and to N. Zavala, A. Nun˜ez, and L. Triana for the
technical support.
References
[1] M. Reddy, “Depression: the disorder and the burden,” Indian
Journal of Psychological Medicine, vol. 32, no. 1, pp. 1–2, 2010.
[16] V. V. Rostovtsev, L. G. Green, V. V. Fokin, and K. B. Sharpless,
“A stepwise huisgen cycloaddition process: copper(I)-catalyzed
regioselective ‘ligation’ of azides and terminal alkynes,” Ange-
wandte Chemie - International Edition, vol. 41, no. 14, pp. 2596–
2599, 2002.
[2] M. Marcus, M. T. Yasamy, M. Ommeren, D. Chisholm, and
S. Saxena, Depression: A Global Public Health Concern, World
Health Organization, 2012, http://www.who.int/mental health/
management/depression/who paper depression wfmh 2012
.pdf.
[3] K. Sangkuhl, T. Klein, and R. Altman, “Selective Serotonin
Reuptake Inhibitors (SSRI) pathway,” Pharmacogenetics Ge-
nomics, vol. 19, no. 11, pp. 907–909, 2009.
[4] M. Vaswani, F. K. Linda, and S. Ramesh, “Role of selective
serotonin reuptake inhibitors in psychiatric disorders: a com-
prehensive review,” Progress in Neuro-Psychopharmacology and
Biological Psychiatry, vol. 27, no. 1, pp. 85–102, 2003.
[17] C. W. Tornøe, C. Christensen, and M. Meldal, “Peptidotriazoles
on solid phase: [1,2,3]-Triazoles by regiospecific copper(I)-
catalyzed 1,3-dipolar cycloadditions of terminal alkynes to
azides,” Journal of Organic Chemistry, vol. 67, no. 9, pp. 3057–
3064, 2002.
[18] M. A. Garc´ıa, Z. G. R´ıos, J. Gonza´lez et al., “e use of glucose
as alternative reducing agent in copper-catalyzed alkyne-azide
cycloaddition,” Letters in Organic Chemistry, vol. 8, no. 10, pp.
701–706, 2011.
[5] D. J. Nutt, S. Forshall, C. Bell et al., “Mechanisms of action
of selective serotonin reuptake inhibitors in the treatment

Journal of Chemistry
9
[19] J. Gonza´lez, V. M. Pe´rez, D. O. Jime´nez, G. Lopez-Valdez, D.
Corona, and E. Cuevas-Yan˜ez, “Effect of temperature on triazole
and bistriazole formation through copper-catalyzed alkyne-
azide cycloaddition,” Tetrahedron Letters, vol. 52, no. 27, pp.
3514–3517, 2011.

International Journal of
Advances in
Organic Chemistry
International
International Journal of
International Journal of
Photoenergy
Medicinal Chemistry
Analytical Chemistry
Physical Chemistry
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
Volume 2014
International Journal of
Carbohydrate
Chemistry
Journal of
Quantum Chemistry
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
http://www.hindawi.com
Volume 2014
Volume 2014
Submit your manuscripts at
https://www.hindawi.com
Journal of
The Scientific
Analytical Methods
in Chemistry
World Journal
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
http://www.hindawi.com
Volume 2014
Volume 2014
International Journal of
Journal of
Journal of
International Journal of
Bioinorganic Chemistry
Spectroscopy
Inorganic Chemistry
Electrochemistry
Applied Chemistry
and Applications
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
Journal of
Journal of
International Journal of
Chromatography
Journal of
Theoretical Chemistry
Research International
Catalysts
Chemistry
Spectroscopy
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
Volume 2014
Volume 2014
Volume 2014