Application of Huisgen (3 + 2) cycloaddition reaction: Synthesis of 1-(2,3-dihydrobenzofuran-2-yl-methyl [1,2,3]-triazoles and their antitubercular evaluations

Article abstract of DOI:10.1016/j.ejmech.2009.09.036

1,4-Disubstituted-1,2,3-triazoles (3-27) have been synthesized by [3+2] cycloaddition of different 2-(azidomethyl)-dihydronaptho(benzo)furans (2a, 2b, 2c and 2d) with different alkynes. All the compounds were screened for antitubercular activity against M

Full text of DOI:10.1016/j.ejmech.2009.09.036

European Journal of Medicinal Chemistry 45 (2010) 142–148
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Application of Huisgen (3 þ 2) cycloaddition reaction: Synthesis
of 1-(2,3-dihydrobenzofuran-2-yl-methyl [1,2,3]-triazoles
and their antitubercular evaluations
,
a
a
a
b
Rama P. Tripathi a , Amit Kumar Yadav , Arya Ajay , Surendra Singh Bisht , Vinita Chaturvedi ,
*
Sudhir Kumar Sinha b
a Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226001, UP, India
b Division of Drug Target Discovery and Development, Central Drug Research Institute, Lucknow 226001, CSIR, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
1,4-Disubstituted-1,2,3-triazoles (3–27) have been synthesized by [3þ2] cycloaddition of different
2-(azidomethyl)-dihydronaptho(benzo)furans (2a, 2b, 2c and 2d) with different alkynes. All the compounds
were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv. Compounds 2a, 7, 9,12
Received 29 May 2009
Received in revised form
18 September 2009
Accepted 25 September 2009
Available online 30 September 2009
and 14 exhibited antitubercular activities with MIC ranging from 12.5 to 3.12 mg/ml.
Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords:
1,2,3-Triazoles
[3 þ 2] cycloaddition
Cuprous iodide
Antitubercular agents
1. Introduction
1,4-disubstituted triazole moieties have displayed a number of
chemotherapeutic properties such as antifungal [17], anticancer
The rediscovery of ‘‘old’’ reactions invented in the middle of the
last century has encouraged the researchers to develop new chem-
istry in terms of atom economy, eco-friendly nature, yields and
simplicity. The reaction between an azide (1,3-dipole) and acety-
lenes (dipolarophiles) belonging to a concerted (one step) [1,2] 3 þ 2
cycloaddition reaction was systematically studied in early 1960s by
Huigsen as 1,3-dipolar addition reactions [3–6]. The Huisgen (3 þ 2)
cycloaddition reaction using azides and alkynes is an important
method for the atom economic synthesis of 1,2,3-triazoles [7]. The
advantages of 100% atom economy and simple purification method
of the resulting products have led to explorations of different
catalysts and conditions for this reaction in accessing compound
libraries. This reaction has a high status in synthetic organic chem-
istry as various pharmaceuticals, agrochemicals, polymers, bio-
chemicals, and functional materials [8–11] have been prepared via
this reaction. In particular, 1,4-disubstituted triazoles have been
usedas metalbinding compounds, ligand linkers, andtriazole-based
monophosphine ligands [12–16]. Further, compounds with
[18], growth factor b1 type receptor inhibitory [19] and antituber-
cular activities [20]. However, the major limitations of the original
reaction are the requirement of high reaction temperatures and low
regioselectivity. To achieve regioselectivity, high yields and energy
efficiency different variables of Cu(I) species have been adopted by
Meldal and co-workers, Sharpless and co-workers and many other
groups [21]. Keeping in mind the antitubercular activities of
triazoles [20] and recent reports that benzofuran and dihy-
drobenzofuran derivatives are natural product leads to develop new
antitubercular agents [22,23] we were interested to synthesize
a hybrid molecule consisting of benzofuran and triazole moieties.
Our method consists of 3 þ 2 cycloaddition reaction of
2-(azidomethyl)-benzofurans with different acetylenes in the
presence of CuSO4$5H2O (1 mol%) at moderate temperatures to
give respective 1-(2,3)-dihydrobnzofuran-2-yl-methyl [1,2,3]-tri-
azoles in good yields. All the compounds were evaluated for their
antitubercular activity against Mycobacterium tuberculosis H37Rv.
2. Chemistry
2-(Iodomethyl)-dihydronaphthofuran (1a) and 2-(iodomethyl)-
dihydrobenzofuran derivatives (1b–d) were prepared in good
* Corresponding author. Tel.: þ91 522 2612412; fax: þ91 522 2623405.
E-mail address: rpt.cdri@gmail.com (R.P. Tripathi).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.09.036

R.P. Tripathi et al. / European Journal of Medicinal Chemistry 45 (2010) 142–148
143
N
N
I
N3
N
R1
O
O
O
OH
R1
a
Ref-24
b
1a,
68.6 %
3-8
2a
Scheme 1. Synthesis of 1,4-disubstituted 1,2,3-triazoles (3–8). Reaction conditions: (a) NaN3, Cu-powder, 90 ꢀC, DMF; (b) Na-ascorbate (5 mol%), t-BuOH:H2O, 2:1, CuSO4$5H2O
(1 mol%), 90 ꢀC, 4 h.
yields by oxidative cyclization following earlier reported method
[24]. The reaction of these iodomethyl-dihydronaphtho (or benzo)-
furans 1a, 1b, 1c and 1d with sodium azide in the presence of Cu-
powder (as catalyst) at 90 ꢀC in N,N-dimethylformamide yielded the
respective 2-(azidomethyl)- dihydronapthofuran (2a) and 2-(azi-
domethyl)-dihydrobenzofuran derivatives 2b, 2c, and 2d in good
yields. The (3 þ 2) cycloaddition of the 2-azidomethyldihydronaph-
tho (or benzo)furans (2a–d) with different alkynes viz. 1-octyne,
1-heptyne, 3-butyn-1-ol, 1-octyn-3-ol, phenylaceytylene, 3-phenyl-
1-propyne, propargyl alcohol (Schemes 1 and 2) in the presence
of Na-ascorbate (5 mol%), t-BuOH:H2O (2:1), and CuSO4$5H2O
(1 mol%), at 90 ꢀC afforded the corresponding 1,4-disubstuted-1,2,3-
triazole compounds 3–27 in good yields (Tables 1 and 2).
d
112.4–157.0 ppm. Almost similar 1H NMR and 13C NMR spectral
patterns were noticed for compounds 2b–d.
Similarly the structures of compounds 3–27 were established
on the basis of their spectroscopic data. In IR spectra of the
above compounds the absorption peak corresponding to azido
group was not observed around 2100 cmꢁ1. In the 1H NMR
spectrum of compound 3 the vinylic proton of C-5 on triazole
ring was merged with two aromatic protons and appeared as
multiplet at around
proton was observed as multiplet at around
three aromatic protons of naphthyl ring were observed as three
distinct doublets at 7.75 ppm, 7.66 ppm, and 7.07 ppm with
d
7.49–7.33 ppm while the one aromatic
d
7.30–7.23 ppm. The
d
d
d
coupling constant of 8.1 Hz, 8.8 Hz, and 8.7 Hz, respectively. The
methylene protons of C-3 on dihydronapthofuran ring appeared
as multiplet at around
protons were observed as two discrete double doublet at
3.63 ppm with J1 ¼15.7 Hz, J2 ¼ 9.8 Hz and at 3.25 ppm with
J1 ¼15.7 Hz, J2 ¼ 7.12 Hz. The six protons of hexyl chain appeared
as multiplet at around 1.24–1.20 ppm and the remaining seven
protons of hexyl chain were observed as three distinct triplet at
d 4.73–4.51 ppm while two methylene
3. Biology
d
d
The newly synthesized compounds were screened for their
antimycobacterial activity against M. tuberculosis H37Rv employing
agar microdilution method [25]. Isoniazid (INH) and ethambutol
were used as standard drugs.
d
d
2.63 ppm, J ¼ 7.3 Hz (2H);
d
1.55 ppm, J ¼ 6.9 Hz (2H); and
d
0.84 ppm, J ¼ 6.1 Hz (3H). In 13C NMR spectrum of compound 3,
4. Results and discussions
five methylene carbons of hexyl chain were observed
d 22.9, 26.0,
29.2, 29.7, 31.9 ppm while one methylene carbon in between the
triazole and benzofuran moieties appeared at 53.9 ppm and
methylene carbon the dihydronapthofuran ring (C-3) at
32.0 ppm. The vinylic carbon (C-2) was observed at 81.7 ppm.
4.1. Chemistry
d
The structures of compounds 2a–d were in accordance with
their spectroscopic data. The IR spectra of the compounds in
general exhibited the absorption band at around 2100–2110 cmꢁ1
indicating that the azido group was present in the compounds. The
ES mass spectra of the compounds showed their respective
[M þ H]þ peaks. In the 1H NMR spectrum of the compound 2a
the one methine proton of C-2 appeared as multiplet at around
d
d
All aromatic carbons were observed at their usual chemical shifts.
4.2. Biology
All the newly synthesized compounds including 2-azidome-
thyldihydronaphtho (benzo)furans and 1-(2,3-dihydro naphtha-
(benzo)-furan-2-yl-methyl) [1,2,3]-triazoles were screened against M.
tuberculosis H37Rv. As evident from Table 3 one of the compounds
2-azidomethyldihydronaphthofurans 2a proved to be potent antitu-
d
5.17–5.04 ppm, while the methylene protons of C-3 merged with
multiplet of one of the methylene proton of azidomethyl group
appeared at around 3.71–3.49 ppm. The other methylene proton
of azidomethyl group was observed as double doublet at
3.29 ppm with J1 ¼15.6 Hz, J2 ¼ 6.7 Hz. All aromatic protons were
observed at their usual chemical shift
7.83–7.16 ppm. In the 13C
NMR spectrum one methylene carbon of azidomethyl group
d
d
bercular with MIC 3.12 mg/ml comparable to the standard drug
d
ethambutol. The cycloaddition products 1-(2,3-dihydronaph-
thofuran-2-yl-methyl)[1,2,3]triazoles of compound 2a with different
alkynes in general were less active than compound 2a. Among 1-(2,3-
dihydronaphthofuran-2-yl-methyl)[1,2,3]triazoles only compound 7
with n-pentyl substituent exhibited mild antitubercular activity with
appearedat
ring (C-3) at
d
55.0 ppmandmethylenecarbonofdihydronapthofuran
32.2 ppmwhile C-2 carbonwas observed at 82.1 ppm.
d
d
All the aromatic carbons were observed in a chemical shift range of
N
N
N3
I
N
R1
O
O
R1
O
OH
a
Ref-24
b
R
R
R
R
1b,
1c,
78 %
80 %
2b,2c,2d
9-27
1d, 71 %
Scheme 2. Synthesis of 1,4-disubstituted 1,2,3-triazoles (9–27). Reaction conditions: (a) NaN3, Cu-powder, 90 ꢀC, DMF; (b) Na-ascorbate (5 mol%), t-BuOH þ H2O, 2:1, CuSO4$5H2O
(1 mol%), 90 ꢀC, 4 h.

144
R.P. Tripathi et al. / European Journal of Medicinal Chemistry 45 (2010) 142–148
Table 1
Table 3
Synthesis of 2-(azidomethyl)dihydronapthofuran (2a) and 1,4-disubstituted-1,2,3-
triazoles (3–8).
In vitro antitubercular activity of 2-(azidomethyl)dihydronapthofuran, 2-(azido-
methyl) dihydrobenzofuran derivatives (2a–2d) and 1,4-disubstituted-1,2,3-tri-
azoles (3–27).
Entry
Compound no.
R1
Yield (%)
Compd no.
cLog Pa
MIC (
3.12
>12.5
m
g/mL) M. tuberculosis H37Rv
1
2
3
4
5
6
7
2a
3
4
5
6
–
89
86
95
86
91
89
64
–(CH2)5CH3
–C6H5
–CH2OH
–CH2C6H5
–(CH2)4CH3
–CH2CH2OH
2a
2b
2.96
1.47
2.41
2.38
5.63
4.74
2.48
4.83
5.17
2.82
3.25
4.12
3.34
1.93
4.28
1.33
4.19
4.62
4.25
2.27
3.37
3.46
4.26
3.80
1.45
1.11
4.36
0.30
2.62
0.668
0.1188
2c
2d
3
4
5
6
7
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
12.5
7
8
MIC 12.5
mg/ml, other compounds of the series were inactive as their
8
9
>12.5
12.5
MIC was >12.5
mg/ml.
Among all the 2-azidomethyldihydrobenzofurans none of them
showed significant inhibition of the mycobacterial growth.
However, among 1-(2,3-dihydrobenzofuran-2-yl-methyl)[1,2,3]-
triazoles, compounds 9 and 12 with 4-n-pentyl and n-hexyl
substituent, respectively, in the triazole moiety and compound 14
with 4-hydroxymethyl substituent exhibited mild in vitro antitu-
10
11
>12.5
>12.5
12
6.25
13
14
>12.5
12.5
15
16
17
18
19
20
21
22
23
24
25
26
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>25.0
>25.0
bercular activity with MIC 12.5
strain. Other compounds of the series were inactive as their MIC
values were >12.5 g/ml. No definite SAR could be established in
mg/ml against M. tuberculosis H37Rv
m
this series of compounds. One of the possible reasons for the
inactivity of few of the compounds may be that the compounds are
unable to reach the growing mycobacterial cell; however, detailed
biological studies are needed to find out definite reasons for their
inactivity.
27
Isoniazid
Ethambutol
0.75
3.25
5. Conclusions
a
cLogP was determined by OSIRIS Property Explorer Programme available at
http://www.organic-chemistry.org/prog/peo.
In summary, we have synthesized a new class of hybrid mole-
cules 1-(2,3-dihydronaphtho(benzo)furan-2-yl-methyl) 4-alkyl/
aryl-1,2,3-triazoles employing an old chemistry of 3 þ 2 cycload-
dition of azides and acetylenes in good to very good yields. One of
the intermediates 2-azidomethyldihydronaphthofuran exhibited
potent antitubercular activity comparable to standard drug
ethambutol. The hybrid molecules did show only mild antituber-
cular activities. The synthetic methodology and the compounds
developed may open a new door towards the synthesis of inter-
esting biologically active compounds.
6. Experimental
6.1. Chemistry
Commercially available reagent grade chemicals were used as
received. All reactions were followed by TLC on E. Merck Kieselgel
60 F254, with detection by UV light, spraying a 20% KMnO4 aq.
solution. Column chromatography was performed on silica gel
(60–120 mesh E. Merck). IR spectra were recorded as thin films
(KBr) or neat CHCl3 solution with a Perkin Elmer Spectrum RX-1
(4000–450 cmꢁ1) spectrophotometer. 1H and 13C NMR spectra
were recorded on a Brucker DRX-200 MHz and 50 MHz, respec-
tively, in CDCl3, and DMSO. Chemical shift values are reported in
ppm relative to TMS (tetramethylsilane) as internal reference,
unless otherwise stated; bs (broad singlet), s (singlet), d (doublet),
t (triplet), m (multiplet); J in hertz. ESI mass spectra were per-
formed using Quattro II (Micromass). Melting points were deter-
mined by open capillary method and uncorrected. Elemental
analyses were performed on a Perkin–Elmer 2400 II elemental
analyzer.
Table 2
Synthesis of 2-(azidomethyl)-dihydrobenzofuran derivatives (2b–2d) and 1,4-
disubstituted-1,2,3-triazoles (9–27).
Entry
Compound no.
R
R1
Yield (%)
1
2
3
4
5
6
7
8
2b
2c
2d
9
-4-CHO
-2,5-Di-Me
-4-CN
–
–
–
64
75
74
94
73
92
90
95
86
95
90
91
86
74
87
94
59
87
78
75
77
85
-4-CHO
-4-CHO
-4-CHO
-4-CHO
-4-CHO
-2,5-Di-Me
-2,5-Di-Me
-2,5-Di-Me
-2,5-Di-Me
-2,5-Di-Me
-2,5-Di-Me
-2,5-Di-Me
-4-CN
-4-CN
-4-CN
-4-CN
-4-CN
-4-CN
-4-CN
–(CH2)4CH3
–CH2OH
–C6H5
–(CH2)5CH3
–CH2C6H5
–CH2OH
–CH2C6H5
–(CH2)5CH3
–C6H5
–(CH2)4CH3
–CH(OH)–(CH2)4CH3
–CH2CH2OH
–C6H5
–CH2C6H5
–(CH2)5CH3
–(CH2)4CH3
–CH2CH2OH
–CH2OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
9
10
11
12
13
14
15
16
17
18
19
20
21
22
6.1.1. General experimental procedure for preparation of
2-(azidomethyl)-1,2-dihydronaphtho[2,1-b] furan and
2-(azidomethyl)-1,2-dihybenzo[2,1-b] furan derivatives (2a–d)
To a magnetically stirred solution of the 2-(idomethyl)-1,2-dihy-
dronaphtho[2,1-b] furan (1a) or 2-(idomethyl)-1,2-dihybenzo[2,1-b]
furan derivatives (1b–d) (1 equivalent) in DMF, NaN3 (1.2 equivalent)
andCu-powder(catalyst,10 mol%)wascautiouslyaddedandreaction
mixture was stirred for 6–8 h at 90 ꢀC. Reaction progress was moni-
tored by TLC. The reaction mixture was diluted with water and
–CH(OH)–(CH2)4CH3

R.P. Tripathi et al. / European Journal of Medicinal Chemistry 45 (2010) 142–148
145
extracted by ethylacetate; organic layer was washed by water
(3 ꢂ 200 mL), dried (anhyd. Na2SO4) and evaporated under reduced
pressure to get crude mass. The latter was chromatographed over
silica gel (60–120 mesh) using a gradient of hexane–ethylacetate as
eluent to give desired products.
6.1.2.1. 1-((1,2-Dihydronaphtho[2,1-b]furan-2-yl) methyl)-4-hexyl-
1H-1,2,3-triazole (3). White solid, mp 108–110 ꢀC, yield (86%); IR
(KBr) cmꢁ1: 2923 (C–H stretching), 1633 (C]C–), 1255 (C–O–C
stretching); ESIMS: 336 (M þ H)þ; 1H NMR (200 MHz, CDCl3 þ
CCl4):
d
7.75 (d, J ¼ 8.1 Hz, 1H, Ar–H), 7.66 (d, J ¼ 8.8 Hz, 1H, Ar–H),
7.37–7.49 (m, 3H, Ar–H, triazole ring proton), 7.23–7.30 (m, 1H,
Ar–H), 7.07 (d, J ¼ 8.7 Hz, 1H, Ar–H), 5.23–5.30 (m, 1H, CH of
dihydrofuran ring), 4.51–4.73 (m, 2H, CH2), 3.63 (dd, J1 ¼15.7 Hz,
J2 ¼ 9.6 Hz, 1H, H-3a), 3.25 (dd, J1 ¼15.7 Hz, J2 ¼ 9.6 Hz, 1H, H-3b),
2.63 (t, J ¼ 7.3 Hz, 2H, CH2 of hexyl chain),1.57 (m, 2H, CH2),1.24 (bs,
6H, 3CH2) 0.84 (bs, 3H, CH3), 13C NMR (50 MHz, CDCl3 þ CCl4):
6.1.1.1. 2-(Azidomethyl)-1,2-dihydronaphtho[2,1-b] furan (2a). Reddish
liquid, yield (89%); IR (Neat) cmꢁ1: 2102 (N3), 1244 (C–O–C); ESIMS:
226 (M þ H)þ; 1H NMR (200 MHz, CDCl3 þ CCl4):
7.83 (d, J ¼ 8.1 Hz,
d
1H, Ar–H), 7.71 (d, J ¼ 8.8 Hz, 1H, Ar–H), 7.43–7.56 (m, 2H, Ar–H),
7.26–7.36 (m, 1H, Ar–H), 7.16 (d, J ¼ 8.7, 1H, Ar–H), 5.04–5.17 (m, 1H,
CH of dihydrofuran ring), 3.71–3.49 (m, 3H, 1H, H-3a of dihydrofuran
ring, CH2 of azidomethyl), 3.29 (dd, J1 ¼6.7 Hz, J2 ¼ 6.7 Hz,1H, H-3b of
d
156.5, 148.7, 131.0, 129.8, 129.0, 127.3, 123.6, 123.0, 121.9, 117.7,
112.0, 81.7, 53.9, 32.0, 31.9, 29.7, 29.2, 26.0, 22.9, 14.6. Anal. Calcd for
C21H25N3O: C, 75.19; H, 7.51; N, 12.53%. Found: C, 75.23; H, 7.48; N,
12.50%.
dihydrofuran ring); 13C NMR (50 MHz, CDCl3 þ CCl4):
d 157.0, 131.1,
129.9, 129.8, 129.2, 127.2, 123.5, 123.0, 117.7, 112.4, 82.1, 55.0, 32.2.
Anal. Calcd for C13H11N3O: C, 69.32; H, 4.92; N, 18.66%. Found: C,
69.34; H, 4.90; N, 18.65%.
6.1.2.2. 1-[(1,2-Dihydronaphtho[2,1-b]furan-2-yl)methyl]-4-phenyl-
1H-1,2,3-triazole (4). White solid, mp 166 ꢀC, yield (95%); IR (KBr)
cmꢁ1: 2922 (C–H stretching), 1629 (C]C), 1252 (C–O–C); ESIMS:
6.1.1.2. 2-(Azidomethyl)-2,3-dihydrobenzofuran-5-carbaldehyde(2b).
Yellowish liquid, yield (64%); IR (Neat) cmꢁ1: 2104 (N3), 1685
(C]O), 1247 (C–O–C); ESIMS: 204 (M þ H)þ; 1H NMR (200 MHz,
328 (M þ H)þ; 1H NMR (200 MHz, CDCl3 þ DMSO-d6):
d 8.51 (s, 1H,
triazole ring proton), 7.83–7.77 (m, 2H, Ar–H), 7.71 (d, J ¼ 8.8 Hz,1H,
Ar–H), 7.61 (d, J ¼ 8.1 Hz, 1H, Ar–H), 7.24–7.49 (m, 6H, ArH), 7.13 (d,
J ¼ 8.7 Hz, 1H, ArH), 5.41–5.48 (m, 1H, CH of dihydrofuran ring),
4.76–4.80 (m, 2H, –NCH2), 3.72 (dd, J1 ¼15.9, J2 ¼ 9.7 Hz, 1H, H-3a),
3.39 (dd, J1 ¼15.8 Hz, J2 ¼ 6.8 Hz, 1H, H-3b); 13C NMR (50 MHz,
CDCl3 þ CCl4):
d 9.76 (s, 1H, CHO), 7.60–7.66 (m, 2H, Ar–H), 6.87 (d,
J ¼ 8.1 Hz, 1H, Ar–H), 5.02–5.04 (m, 1H, CH of dihydrofuran ring),
3.27–3.58 (m, 3H, 1H, H-3a of dihydrofuran ring, CH2 azido), 3.11
(dd, J1 ¼6.6 Hz, J2 ¼ 6.6 Hz,1H, H-3b of dihydrofuran ring); 13C NMR
(50 MHz, CDCl3 þ CCl4):
d
189.8, 164.6, 133.4, 131.4, 127.7, 126.1,
CDCl3 þ DMSO-d6):
d 161.5, 152.0, 136.2, 135.9, 134.5, 134.2, 134.0,
110.1, 82.9, 54.6, 32.2. Anal. Calcd for C10H9N3O2: C, 59.11; H, 4.46;
N, 20.68%. Found: C, 59.13; H, 4.45; N, 20.67%.
133.2, 132.2, 130.7, 128.5, 128.2, 127.4, 123.2, 117.3, 86.6, 58.9, 36.7,
34.6. Anal. Calcd for C21H17N3O: C, 77.04; H, 5.23; N, 12.84%. Found:
C, 77.10; H, 5.20; N, 12.88%.
6.1.1.3. 2-(Azidomethyl)-4,7-dimethyl-2,3-dihydrobenzofuran (2c).
Reddish liquid, yield (75%); IR (Neat) cmꢁ1: 2104 (N3); ESIMS: 218
6.1.2.3. (1-[(1,2-Dihydronaphtho[2,1-b] furan-2-yl) methyl]-1H-
1,2,3-triazol-4-yl) methanol (5). Yellowish solid, mp 114 ꢀC, yield
(86%), IR (KBr) cmꢁ1: 3356 (OH); ESIMS: 282 (M þ H)þ; 1H NMR
(M þ CH3); 1H NMR (200 MHz, CDCl3 þ CCl4):
d
6.88 (d, J ¼ 7.6 Hz,
1H, Ar–H), 6.61 (d, J ¼ 7.6 Hz,1H, Ar–H), 5.02–4.94 (m,1H, m,1H, CH
of dihydrofuran ring), 3.46–3.43 (m, 2H, CH2 azidomethyl), 3.31 (dd,
J1 ¼15.6 Hz, J2 ¼ 6.6 Hz, 1H, H-3a), 3.02 (dd, J1 ¼15.6 Hz, J2 ¼ 6.5 Hz,
1H, H-3b), 2.22 (s, 3H, Ar–CH3), 2.16 (s, 3H, Ar–CH3); 13C NMR
(200 MHz, CDCl3 þ CCl4):
d 7.76 (s, 1H, triazol ring proton), 7.72
(d, J ¼ 8.1 Hz, 1H, Ar–H), 7.61 (d, J ¼ 8.8 Hz, 1H, Ar–H), 7.49
(d, J ¼ 8.0 Hz, 1H, Ar–H), 7.33–7.41 (m, 1H, Ar–H), 7.18–7.26 (m, 1H,
Ar–H), 7.03 (d, J ¼ 8.7 Hz, 1H, Ar–H), 5.20–5.34 (m, 1H, CH of
dihydrofuran ring), 4.52–4.72 (m, 4H, –OCH2, –NCH2), 3.61 (dd,
J1 ¼15.7 Hz, J2 ¼ 9.6, 1H, H-3a), 3.25 (dd, J1 ¼15.7 Hz, J2 ¼ 7.1, 1H,
(50 MHz, CDCl3 þ CCl4):
d 157.7, 139.8, 135.1, 132.1 (C-8), 129.9 (C-7),
125.4 (C-9), 81.6 (C-2), 54.8 (C-6), 33.8 (C-3),19.0 (C-12),15.3 (C-11).
Anal. Calcd for C11H13N3O: C, 65.01; H, 6.45; N, 20.68%. Found: C,
65.30; H, 6.40; N, 20.60%.
H-3b), 13C NMR (50 MHz, CDCl3 þ CCl4):
d 161.4, 135.8, 134.5, 134.4,
133.8, 132.0, 128.3, 127.9, 122.7, 117.1, 86.5, 61.0, 58.6, 36.7. Anal.
Calcd for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94%. Found: C, 68.28;
H, 5.39; N, 14.98%.
6.1.1.4. 2-(Azidomethyl)-2,3-dihydrobenzofuran-5-carbonitrile (2d).
Yellowish liquid, yield (74%); IR (Neat) cmꢁ1: 3020 (C–H), 2220
(CN), 2107 (N3); ESIMS: 224 (M þ Na)þ; 1H NMR (200 MHz,
CDCl3 þ CCl4):
d
7.42–7.39 (m, 2H, Ar–H), 6.83 (d, J ¼ 6.0 Hz, 1H,
6.1.2.4. 4-Benzyl-1-[(1,2-dihydronaphtho[2,1-b]furan-2-yl)methyl]-
Ar–H), 5.08–4.96 (m, 1H, 1H, CH of dihydrofuran ring), 3.61–3.26
1H-1,2,3- triazole (6). White solid, mp 118 ꢀC, yield (91%); IR (KBr)
(m, 3H, CH2 of azidomethyl, H-3a), 3.11 (dd, J1 ¼16.1 Hz, J2 ¼ 6.8 Hz,
cmꢁ1
: 2919 (C–H), 1631 (C]C), 1253 (C–O–C); ESIMS: 342
1H, H-3b); 13C NMR (50 MHz, CDCl3 þ CCl4):
d
162.9, 133.9, 129.1,
(M þ H)þ; 1H NMR (200 MHz, CDCl3 þ DMSO-d6):
d 7.74 (d,
128.0, 119.1, 110.8, 104.9, 82.7, 54.5, 32.3. Anal. Calcd for C10H8N4O:
C, 59.99; H, 4.03; N, 27.99%. Found: C, 59.96; H, 4.20; N, 27.91%.
J ¼ 8.1 Hz,1H, Ar–H), 7.62 (d, J ¼ 8.8 Hz,1H, Ar–H), 7.28–7.50 (m, 3H,
triazol ring proton þ 2ꢂAr–H), 6.97–7.24 (m, 7H, Ar–H), 5.27–5.30
(m, 1H, CH of dihydrofuran ring), 4.59–4.63 (m, 2H, –NCH2), 3.93 (s,
2H, CH2), 3.61 (dd, J1 ¼15.8 Hz, J2 ¼ 9.9 Hz, 1H, H-3a), 3.25 (dd,
J1 ¼15.8 Hz, J2 ¼ 6.9, 1H, H-3b); 13C NMR (50 MHz, CDCl3 þ CCl4):
6.1.2. General experimental procedure for preparation
of 1,2,3-triazole (3–27)
The mixture of 2-(azidomethyl)-1,2-dihydronaphtho[2,1-b]
furan (1 mmol) or 2-(azidomethyl)-1,2-dihydrobenzo[2,1-b] furan
derivatives (1 mmol) and alkyne (1.2 mmol) were suspended in
a 2:1 mixture of tert-butyl alcohol and water. Sodium ascorbate
(5 mol% freshly prepared solution in water) was added followed by
addition of CuSO4$5H2O (1 mol%, freshly prepared solution in of
water). The heterogeneous mixture was stirred vigorously for 6 h,
the reaction mixture was diluted with ice cold water and precipi-
tate thus obtained was collected by filtration and washed with ice
cold water and dried under vacuum to give a crude mass which was
purified by a short column of silica gel (60–120) using hex-
ane:EtOAc as eluent to give desired products (3–27).
d 161.4, 151.9, 144.4, 135.8, 134.5, 134.4, 133.8, 133.7, 133.6, 132.0,
131.8, 131.4, 131.1, 128.3, 128.1, 128.0, 122.8, 117.0, 86.4, 58.7, 37.1,
36.6, 34.8. Anal. Calcd for C22H19N3O: C, 77.40; H, 5.61; N, 12.31%.
Found: C, 77.35; H, 5.90; N, 12.34%.
6.1.2.5. 1-((1,2-Dihydronaphtho[2,1-b]furan-2-yl) methyl)-4-pentyl-
1H-1,2,3-triazole (7). Brown solid, mp 100 ꢀC, yield (89%); IR (KBr)
cmꢁ1
: 2926 (C–H), 1632 (C]C), 1252 (C–O–C); ESIMS: 322
(M þ H)þ; 1H NMR (200 MHz, CDCl3 þ CCl4):
7.74 (d, J ¼ 8.0 Hz,1H,
d
Ar–H), 7.65 (d, J ¼ 8.8 Hz, 1H, Ar–H), 7.35–7.48 (m, 3H, 2 Ar–H,
triazole ring proton), 7.20–7.29 (m,1H, Ar–H), 7.06 (d, J ¼ 8.7 Hz,1H,
Ar–H), 5.18–5.32 (m, 1H, CH of dihydrofuran ring), 4.49–4.72 (m,

146
R.P. Tripathi et al. / European Journal of Medicinal Chemistry 45 (2010) 142–148
2H, –NCH2), 3.61 (J1 ¼15.7 Hz, J2 ¼ 9.7 Hz, 1H, H-3a), 3.23 (dd,
J1 ¼15.7 Hz, J2 ¼ 7.1 , 1H, H-3b), 2.63 (t, J ¼ 7.3 Hz, 2H, pentyl chain
CH2), 1.65 (m, 2H, CH2), 1.26 (bs, 4H, 2ꢂCH2) 0.84 (t, J ¼ 6.5 Hz, 3H,
5.24–5.26 (m, 1H, CH of dihydrofuran ring), 4.72–4.64
(m, 2H, –NCH2), 3.38 (dd, J1 ¼9.2 Hz, J2 ¼15.8 Hz,1H, H-3a), 3.12 (dd,
J1 ¼6.5 Hz, J2 ¼ 15.8 Hz, 1H, H-3b), 2.62 (t, 2H, CH2), 1.56 (m, 2H,
CH2), 1.24 (m, 6H, 3CH2), 0.84 (t, 3H, –CH3); 13C NMR (50 MHz,
CH3), 13C NMR (50 MHz, CDCl3 þ CCl4):
d 156.5, 148.6, 131.0, 129.8,
129.1, 126.9, 123.6, 123.0, 120.6, 117.7, 112.0, 81.7, 53.9, 31.9, 31.7,
29.4, 26.0, 24.0, 22.8, 14.4. Anal. Calcd for C20H23N3O: C, 74.74; H,
7.21; N, 13.07%. Found: C, 74.72; H, 7.22; N, 13.30%.
CDCl3 þ CCl4):
d 190.3, 164.2, 133.1, 131.5, 127.5, 126.6, 110.1, 82.4,
53.7, 31.9, 29.6, 29.2, 25.9, 22.9, 14.5. Anal. Calcd for C18H23N3O2: C,
68.98; H, 7.40; N, 13.41%. Found: C, 68.93; H, 7.35; N, 13.35%.
6.1.2.6. 2-(1-((1,2-Dihydronaphtho[2,1-b] furan-2-yl) methyl)-1H-
1,2,3-triazol-4-yl) ethanol (8). Brown solid, mp 111 ꢀC, yield (64%);
IR (KBr) cmꢁ1: 3020 (C–H), 1216 (C–O–C); ESIMS: 296 (M þ H)þ; 1H
6.1.2.11. 2-[(4-Benzyl-1H-1,2,3-triazol-1-yl) methyl]-2,3-dihy-
drobenzofuran-5-carbaldehyde (13). White solid, mp 136 ꢀC, yield
(95%); IR (KBr) cmꢁ1: 1684 (C]O), 1608 (C]C), 1249 (C–O–C);
NMR (200 MHz, CDCl3 þ CCl4):
d
6.71–6.86 (m, 3H, Ar–H), 6.52-6.61
ESIMS: 320 (M þ H)þ; 1H NMR (200 MHz, CDCl3 þ CCl4):
d 9.79 (s,
(m, 2H, triazole ring proton þ Ar–H), 6.33–6.41 (m, 1H, Ar–H), 6.16
(d, J ¼ 8.76 Hz, 1H, Ar–H), 4.35–4.40 (m, 1H, CH of dihydrofuran
ring), 3.59–3.81 (m, 2H, NCH2), 3.27 (bs, 3H, CH2, OH), 2.74 (dd,
J1 ¼15.7 Hz, J2 ¼ 9.7 Hz, 1H,H-3a), 2.36 (dd, J1 ¼15.7 Hz, J2 ¼ 6.8, 1H,
1H, CHO), 7.65–7.62 (m, 2H, Ar–H, triazole ring proton), 7.29–7.10
(m, 6H, Ar–H), 6.84 (d, J ¼ 8.7 Hz, 1H, Ar–H), 5.27–5.24 (m, 1H, CH
dihydrofuran ring), 4.64–4.58 (m, 2H, –NCH2), 4.01 (s, 2H, CH2Ph),
3.46 (dd, J1 ¼16.2, J1 ¼9.6 Hz, 1H, H-3a), 3.12 (dd, J1 ¼16.2,
H-3b), 1.96 (bs, 2H, CH2); 13C NMR (50 MHz, CDCl3 þ CCl4):
d
156.4,
J1 ¼6.8 Hz,, 1H, H-3b); 13C NMR (50 MHz, CDCl3 þ CCl4):
d 190.7,
130.9, 129.9, 129.8, 129.0, 126.9, 123.6, 122.9, 117.6, 112.4, 81.4, 61.3,
54.2, 32.0, 29.0. Anal. Calcd for C17H17N3O2: C, 69.14; H, 5.80; N,
14.23%. Found: C, 69.17; H, 5.85; N, 14.20%.
164.2, 148.2, 139.2, 133.1, 131.4, 129.0, 127.4, 126.9, 126.7, 123.1, 110.2,
82.3, 53.8, 32.5, 31.8. Anal. Calcd for C19H17N3O2: C, 71.46; H, 5.37;
N, 13.16%. Found: C, 71.39; H, 5.40; N, 13.13%.
6.1.2.7. 2-((4-Pentyl-1H-1,2,3-triazol-1-yl)methyl)-2,3-dihydrobenzo-
furan-5-carbaldehyde (9). Greenish solid, mp 115 ꢀC, yield (91%); IR
(KBr) cmꢁ1: 2928 (C–H), 1685 (C]O), 1218 (C–O–C); ESIMS: 300
6.1.2.12. 1-[(4,7-Dimethyl-2,3-dihydrobenzofuran-2-yl)methyl]-1H-
1,2,3-triazol-4-yl methanol (14). Yellowish liquid, yield (86%); IR
(Neat) cmꢁ1: 3367 (O–H), 2924 (C–H), 1590 (C]C); ESIMS: 260
(M þ H)þ; 1H NMR (200 MHz, CDCl3 þ CCl4):
d
9.76 (s, 1H, CHO),
(M þ H)þ; 1H NMR (200 MHz, CDCl3 þ CCl4):
d 7.74 (s, 1H, OH), 7.34
7.65–7.62 (m, 3H, 2ꢂAr–H, triazole ring proton), 6.87 (d, J ¼ 8.6 Hz,
1H, Ar–H), 5.26 (bs, 1H, CH of dihydrofuran ring), 4.73–4.66 (m, 2H),
3.46 (dd, J1 ¼15.9 Hz, J2 ¼ 9.1 Hz, 1H, H-3a), 3.12 (dd, J1 ¼16.0 Hz,
J2 ¼ 6.0 Hz, 1H, H-3b), 2.62 (bs, 2H, CH2), 1.57 (bs, 2H, CH2), 1.25 (bs,
4H, 2CH2), 0.87 (t, J ¼ 6.5 Hz, 3H, CH3); 13C NMR (50 MHz,
(s, 1H, triazole ring proton), 6.80 (d, J ¼ 7.6 Hz, 1H, Ar–H), 6.54 (d,
J ¼ 7.6 Hz, 1H, Ar–H), 5.07 (bs, 1H, CH dihydrofuran ring), 4.68–4.60
(m, 4H, OCH2, NCH2), 3.30 (dd, J1 ¼15.5, J2 ¼ 8.6 Hz, 1H, H-3a), 2.88
(dd, J1 ¼15.0, J2 ¼ 7.0 Hz, 1H, H-3b), 2.15 (s, 3H, Ar–CH3), 2.14 (s, 3H,
Ar–CH3); 13C NMR (50 MHz, CDCl3 þ CCl4):
d 157.2, 139.8, 135.3,
CDCl3 þ CCl4):
d
190.2, 164.2, 133.1, 131.5, 127.5, 126.6, 110.1, 82.3,
132.2, 129.9, 125.1, 123.8, 122.3, 80.7, 54.4, 33.7, 32.5, 19.0,14.9. Anal.
Calcd for C14H17N3O2: C, 64.85; H, 6.61; N, 16.20%. Found: C, 64.80;
H, 6.67; N, 16.18%.
32.0, 31.7, 29.2, 25.9, 22.7, 14.4. Anal. Calcd for C17H21N3O2: C, 68.20;
H, 7.07; N, 14.04%. Found: C, 68.18; H, 7.15; N, 14.00%.
6.1.2.8. 2-[(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl]-2,3-
dihydrobenzofuran-5-carbaldehyde (10). White solid, mp 165 ꢀC,
yield (73%); IR (KBr) cmꢁ1: 3448 (O–H), 1677 (C]O), 1603 (C]C);
6.1.2.13. 4-Benzyl-1-[(4,7-dimethyl-2,3-dihydrobenzofuran-2-yl)-
methyl]-1H-1,2,3-triazole (15). Yellowish liquid, yield (95%); IR
(Neat) cmꢁ1: 3020 (C–H), 1216 (C–O–C); ESIMS: 320 (M þ H)þ; 1H
ESIMS: 260 (M þ H)þ; 1H NMR (200 MHz, CDCl3 þ CD3OD):
d
9.77
NMR (200 MHz, CDCl3 þ CCl4):
d 7.34–7.12 (m, 7H, Ar–H, triazole ring
(s, 1H, CHO), 7.80 (s, 1H, triazole ring proton), 7.71–7.67 (m, 2H,
2ꢂAr–H), 6.92 (d, J ¼ 8.54 Hz, 1H, Ar–H), 5.33–5.30 (bs, 1H, CH of
dihydrofuran ring), 4.81–4.59 (m, 4H, –OCH2, –NCH2), 3.53 (dd,
J1 ¼16.2 Hz, J2 ¼ 9.4 Hz, 1H, H-3a), 3.17 (dd, J1 ¼16.1 Hz, J2 ¼ 7.1 Hz,
proton), 6.83 (d, J ¼ 7.6 Hz, 1H, Ar–H), 6.57 (d, J ¼ 7.6 Hz, 1H, Ar–H),
5.11–5.04 (m, 1H, CH dihydrofuranring), 4.67–4.41 (m, 2H, –NCH2),
4.04 (s, 2H, –CH2Ph), 3.30 (dd, J1 ¼15.8 Hz, J2 ¼ 9.3 Hz, 1H), 2.93
(dd, J1 ¼15.8 Hz, J2 ¼ 9.2 Hz, 1H), 2.15 (s, 3H, Ar–CH3), 2.07 (s, 3H,
1H, H-3b); 13C NMR (50 MHz, CDCl3 þ CD3OD):
d
195.3, 168.5, 137.5,
Ar–CH3); 13C NMR(50 MHz, CDCl3 þ CCl4):
d 156.8,148.1,139.3,132.3,
135.2, 131.6, 130.6, 129.9, 127.8, 114.3 86.3, 59.8, 57.9, 35.9. Anal.
Calcd for C13H13N3O3: C, 60.22; H, 5.05; N, 16.21%. Found: C, 60.25;
H, 5.60; N, 16.15%.
129.8, 129.1, 129.0, 128.9, 126.8, 123.9, 123.3, 119.6, 116.9, 80.6, 54.1,
32.6, 32.2, 19.0, 15.2. Anal. Calcd for C20H21N3O: C, 75.21; H, 6.63; N,
13.16%. Found: C, 75.15; H, 6.69; N, 13.10%.
6.1.2.9. 2-[(4-Phenyl-1H-1,2,3-triazol-1-yl)methyl]-2,3-dihydrobenzo-
furan-5-carbaldehyde (11). White solid, mp 174 ꢀC, yield (92%); IR
(KBr) cmꢁ1: 1684 (C]O), 1606 (C]C), 1252 (C–O–C); ESIMS: 306
6.1.2.14. 1-[(4,7-Dimethyl-2,3-dihydrobenzofuran-2-yl)methyl]-4-
hexyl-1H-1,2,3-triazole (16). Orange liquid, yield (90%); IR (Neat)
cmꢁ1: 2927 (C–H),1592 (C]C),1259 (C–O–C); ESIMS: 314 (M þ H)þ
,
(M þ H)þ; 1H NMR (200 MHz, DMSO-d6):
d
9.78 (s, 1H, CHO), 8.59 (s,
1H NMR (200 MHz, CDCl3 þ CCl4):
d 7.34 (s,1H, triazole ring proton),
1H, Ar–H), 7.83–7.68 (m, 4H, Ar–Hx4), 7.46–7.31 (m, 3H, Ar–Hx2,
triazole ring proton), 6.98 (d, J ¼ 8.1 Hz, 1H, Ar–H), 5.42 (bs, 1H, CH
dihydrofuran ring), 4.86–4.67 (m, 2H, –NCH2), 3.54–3.37(m, 1H, H-
3a), 3.19–3.07 (dd, 1H, J1 ¼6.5 Hz, J2 ¼ 16.4 Hz); 13C NMR (50 MHz,
6.80 (d, J ¼ 7.6 Hz, 1H, Ar–H), 6.53 (d, J ¼ 7.62 Hz, 1H, Ar–H),
5.11–5.04 (m, 1H, CH dihydrofuran ring), 4.67–4.51 (m, 2H, –NCH2),
3.29 (dd, J1 ¼15.7 Hz, J2 ¼ 9.2 Hz, 1H, H-3a), 2.92 (dd, J1 ¼15.4 Hz,
J2 ¼ 6.7 Hz, 1H, H-3b), 2.69 (t, J ¼ 7.4 Hz, 2H, CH2), 2.20 (s, 3H,
Ar–CH3), 2.15 (s, 3H, Ar–CH3), 1.63–1.56 (m, 2H, CH2), 1.29–1.25
(m, 6H, 3CH2), 0.91 (t, J ¼ 6.4 Hz, 3H, CH3); 13C NMR (50 MHz,
CDCl3 þ DMSO-d6):
d 196.4, 169.4, 152, 138.0, 136.2, 136.0, 134.4,
133.5, 133.4, 131.6, 130.7, 127.7, 115.0, 58.5, 36.8. Anal. Calcd for
C18H15N3O2: C, 70.81; H, 4.95; N, 13.76%. Found: C, 70.77; H, 4.99; N,
13.73%.
CDCl3 þ CCl4):
d 157.3, 148.6, 139.8, 135.3, 132.2, 129.8, 123.9, 121.8,
80.9, 54.0, 32.0, 29.7, 29.2, 25.9, 24.7, 22.9,19.0,15.3,14.5. Anal. Calcd
for C19H27N3O: C, 72.81; H, 8.68; N, 13.41%. Found: C, 72.75; H, 8.72;
N, 13.39%.
6.1.2.10. 2-[(4-Hexyl-1H-1,2,3-triazol-1-yl)methyl]-2,3-dihydrobenzo-
furan-5-carbaldehyde (12). White solid, mp 108 ꢀC, yield (90%); IR
(KBr) cmꢁ1: 2926 (C–H), 1683 (C]O), 1606 (C]C); ESIMS: 314
6.1.2.15. 1-[(4,7-Dimethyl-2,3-dihydrobenzofuran-2-yl)methyl]-4-
phenyl-1H-1,2,3-triazole (17). White solid, mp 122–124 ꢀC, yield
(91%); IR (KBr) cmꢁ1: 3020 (C–H), 1216 (C–O–C); ESIMS: 306
(M þ H)þ; 1H NMR (200 MHz, CDCl3 þ CCl4):
d 9.77 (s, 1H, CHO), 7.63
(s, 2H, Ar–H), 7.36 (s,1H, triazole ring proton), 6.87 (d, J ¼ 8.1 Hz,1H),

R.P. Tripathi et al. / European Journal of Medicinal Chemistry 45 (2010) 142–148
147
(M þ H)þ; 1H NMR (200 MHz, CDCl3 þ CCl4):
d
7.88–7.76 (m, 3H,
ESIMS: 317 (M þ H)þ; 1H NMR (200 MHz, CDCl3 þ CCl4):
d
7.37 (s,
Ar–H), 7.43–7.24(m,3H, Ar–H, triazoleringproton), 6.85(d, J ¼ 7.6 Hz,
1H, Ar–H), 6.58 (d, J ¼ 7.6 Hz, 1H, Ar–H), 5.17–5.09 (m, 1H, CH
dihydrofuran ring), 4.76–4.51 (m, 2H, –NCH2), 3.33 (dd, J1 ¼15.7 Hz,
J2 ¼ 8.7 Hz, 1H, H-3a), 2.96 (dd, J1 ¼15.7 Hz, J2 ¼ 6.8 Hz, 1H, H-3b),
2.22 (s, 3H, Ar–CH3), 2.16 (s, 3H, Ar–CH3); 13C NMR (50 MHz,
1H), 7.33 (s, 1H), 7.28–7.06 (m, 6H, Ar–H), 6.74 (d, J ¼ 8.18 Hz, 1H,
Ar–H), 5.28–5.16 (m, 1H, CH dihydrofuran ring), 4.68–4.49 (m, 2H,
–NCH2), 3.98 (s, 2H, –CH2Ph), 3.42 (dd, J1 ¼16.4 Hz, J2 ¼ 9.6 Hz, 1H,
H-3a), 3.12 (dd, J1 ¼16.4 Hz, J2 ¼ 6.8 Hz, 1H, H-3b); 13C NMR
(50 MHz, CDCl3 þ CCl4):
d 162.3, 139.1, 133.9, 129.3, 128.9, 128.8,
CDCl3 þ CCl4):
d
157.3, 148.3, 139.9, 135.5, 132.4, 131.0, 130.9, 130.0,
127.5, 126.9, 118.8, 110.5, 105.4, 81.9, 53.5, 32.5, 30.1. Anal. Calcd for
C19H16N4O: C, 72.13; H, 5.10; N, 17.71%. Found: C, 72.10; H, 5.20; N,
17.65%.
129.2, 128.5, 128.4, 126.1,125.2, 122.4, 80.9, 54.3, 33.7, 19.0, 15.4.
Anal. Calcd for C19H19N3O: C, 74.73; H, 6.27; N, 13.76%. Found: C,
74.70; H, 6.30; N, 13.72%.
6.1.2.21. 2-((4-Hexyl-1H-1,2,3-triazol-1-yl)methyl)-2,3-dihydro-
benzofuran-5-carbonitrile (23). White solid, mp 148 ꢀC, yield (87%);
IR (KBr) cmꢁ1: 2221 (CN), 1612 (C]C), 1253 (C–O); ESIMS: 311
6.1.2.16. 1-[(4,7-Dimethyl-2,3-dihydrobenzofuran-2-yl)methyl]-4-
pentyl-1H-1,2,3-triazole (18). Yellowish liquid, yield (86%); IR
(Neat) cmꢁ1: 2930 (C–H), 1216 (C–O–C); ESIMS: 300 (M þ H)þ; 1H
(M þ H)þ; 1H NMR (300 MHz, CDCl3 þ CCl4):
d 7.44–7.28 (m, 3H,
NMR (200 MHz, CDCl3 þ CCl4):
d
7.34 (s, 1H, triazole ring proton),
Ar–H, triazole ring proton), 6.84 (d, J ¼ 8.28 Hz, 1H, Ar–H),
5.28–5.23 (m, 1H, CH dihydrofuran ring), 4.78–4.58 (m, 2H, –NCH2),
3.39 (dd, J1 ¼16.0 Hz, J2 ¼ 6.3 Hz, 1H, H-3a), 3.13 (dd, J1 ¼16.0 Hz,
J2 ¼ 4.5 Hz, 1H, H-3a), 2.65 (bs, 2H, CH2), 1.60 (bs, 2H,CH2), 1.28 (bs,
6H, 3CH2), 0.90 (t, J ¼ 5.94 Hz, 3H, CH3); 13C NMR (50 MHz,
6.80 (d, J ¼ 7.6 Hz,1H, Ar–H), 6.54 (d, J ¼ 7.6 Hz,1H, Ar–H), 5.12–5.04
(m, 1H, CH dihydrofuran ring), 4.68–4.45 (m, 2H, –NCH2), 3.30–3.18
(m, 1H, H-3a), 3.00–2.81 (m, 1H, H-3b), 2.69 (t, J ¼ 7.3 Hz, 2H),
2.21–2.15 (m, 6H, 2Ar–CH3),1.68–1.54 (m, 2H, CH2),1.37–1.19 (m, 4H,
2CH2), 0.92 (t, 3H, J ¼ 6.5 Hz, CH3); 13C NMR (50 MHz, CDCl3 þ CCl4):
CDCl3 þ CCl4):
d 162.5, 134.0, 129.4, 127.7, 119.1, 110.2, 105.2, 82.2,
53.5, 32.1, 31.9, 29.6, 29.1, 22.9, 14.4. Anal. Calcd for C18H22N4O: C,
69.65; H, 7.14; N, 18.05%. Found: C, 69.50; H, 7.17; N, 18.25%.
d
157.3, 139.8, 135.3, 132.2, 129.8, 125.1, 123.9, 116.8, 80.9, 54.0, 32.3,
31.7, 29.4, 25.9, 24.7, 19.0, 15.3, 14.4. Anal. Calcd for C18H25N3O: C,
72.21; H, 8.42; N, 14.03%. Found: C, 72.10; H, 8.48; N, 14.21%.
6.1.2.22. 2-((4-Pentyl-1H-1,2,3-triazol-1-yl)methyl)-2,3-dihydro-
benzofuran-5-carbonitrile (24). White solid, mp 134 ꢀC, yield (78%);
IR (KBr) cmꢁ1: 2221 (CN), 1611 (C]C), 1253 (C–O–C); ESIMS: 297
6.1.2.17. 1-(1-((4,7-Dimethyl-2,3-dihydrobenzofuran-2-yl)methyl)-
1H-1,2,3-triazol-4-yl)hexan-1-ol (19). White semi solid, yield (74%);
IR (KBr) cmꢁ1 3381(O–H), 3018 (C–H), 1593(C]C), 1216 (C–O–C);
(M þ H)þ; 1H NMR (300 MHz, CDCl3 þ CCl4):
d 7.43–7.38 (m, 3H, Ar–
ESIMS: 330 (M þ H)þ; 1H NMR (200 MHz, CDCl3 þ CCl4):
d
7.35 (s,
H, triazole ring proton), 6.83 (d, J ¼ 8.3 Hz, 1H, Ar–H), 5.26–5.25 (m,
1H, triazole ring proton), 6.83 (d, J ¼ 7.6 Hz, 1H, Ar–H), 6.56 (d,
J ¼ 7.5 Hz, 1H, Ar–H), 5.11 (bs, 1H, CH dihydrofuran ring), 4.70 (m,
3H, -NCH2, CHOH), 3.32–3.20 (m, 1H, H-3a), 2.94–2.83 (m, 1H, H-
3b), 2.22–2.15 (m, 6H, 2Ar–CH3), 1.83 (bs, 2H, CH2), 1.30 (bs, 6H,
3CH2), 0.90 (bs, 3H, CH3); 13C NMR (50 MHz, CDCl3 þ CCl4):157.2,
139.8, 135.4, 132.4, 129.9, 123.9, 122.3, 80.6, 80.1, 37.8, 33.7, 32.4,
32.0, 22.9, 19.0, 15.3, 14.4. Anal. Calcd for C19H27N3O2: C, 69.27; H,
8.26; N, 12.76%. Found: C, 69.34; H, 8.35; N, 12.90%.
1H, dihydrofuran ring proton), 4.71–4.57 (m, 1H, –NCH2), 3.44 (dd, ,
J1 ¼15.9 Hz, J2 ¼ 9.3 HZ, 1H, H-3a), 3.14 (dd,
,
J1 ¼15.9 Hz,
J2 ¼ 4.5 Hz, 1H, H-3b), 2.64 (bs, 2H, CH2), 1.60 (bs, 2H, CH2), 1.30–
1.26 (m, 6H, 3CH2), 0.91 (t, J ¼ 6.6 Hz, 3H, CH3); 13C NMR (50 MHz,
CDCl3 þ CCl4):
d 162.4, 133.9, 129.3, 129.1, 127.7, 118.8, 110.6, 105.4,
82.6, 53.4, 32.3, 32.1, 31.7, 29.4, 22.7,14.4. Anal. Calcd for C17H20N4O:
C, 68.89; H, 6.80; N, 18.90%. Found: C, 68.85; H, 6.86; N, 18.87%.
6.1.2.23. 2-((4-(2-Hydroxyethyl)-1H-1,2,3-triazol-1-yl)methyl)-2,3-
dihydrobenzofuran-5-carbonitrile (25). White solid, mp 132 ꢀC,
yield (75%); IR (KBr) cmꢁ1: 3410 (O–H), 2221 (N3), 1251 (C–O–C);
6.1.2.18. 2-(1-((4,7-Dimethyl-2,3-dihydrobenzofuran-2-yl)methyl)-
1H-1,2,3-triazol-4-yl)ethanol (20). White solid, mp 110 ꢀC, yield
(87%); IR (KBr) cmꢁ1: 3409 (O–H), 3018 (C–H),1591 (C]C), 1216(C–
O–C); ESIMS: 274 (M þ H)þ; 1H NMR (200 MHz, CDCl3 þ CCl4):
ESIMS: 271 (M þ H)þ; 1H NMR (300 MHz, CDCl3 þ CCl4):
d 7.56 (s,
1H), 7.47–7.35 (m, 3H, Ar–H, triazole ring proton), 6.87 (d,
J ¼ 8.3 Hz, 1H, Ar–H), 5.33–5.24 (m, 1H, CH dihydrofuran ring),
4.74–4.58 (m, 2H, –NCH2), 3.94 (bs, 2H, –OCH2), 3.47 (dd,
J1 ¼16.2 Hz, J2 ¼ 9.4 Hz, 1H, H-3a), 3.14 (dd, J1 ¼16.2 Hz, J2 ¼ 7.0 Hz,
1H, H-3b), 2.91 (t, J ¼ 6.33 Hz, 2H, CH2); 13C NMR (50 MHz,
d
7.48 (s, 1H, triazole ring proton), 6.76 (d, J ¼ 7.5 Hz, 1H, Ar–H), 6.50
(d, J ¼ 7.5 Hz, 1H, Ar–H), 5.03–5.00 (m, 1H, CH dihydrofuran ring),
4.61–4.41 (m, 2H, –NCH2), 3.81 (bs, 1H, OH), 3.24–3.11 (m, 1H,
H-3a), 2.89–2.75 (m, 3H, H-3b, CH2), 2.14–2.03 (m, 8H, -CH2,
Ar–CH3ꢂ2); 13C NMR (50 MHz, CDCl3 þ CCl4):
d
157.3, 139.8, 135.4,
CDCl3 þ CCl4):
d 167.5, 138.7, 134.1, 132.9, 124.1, 115.6, 109.3, 87.1,
66.0, 58.2, 37.0, 34.3. Anal. Calcd for C14H14N4O2: C, 62.21; H, 5.22;
N, 20.73%. Found: C, 62.13; H, 5.25; N, 11.82%.
132.4, 129.8, 125.1, 123.9, 122.3, 61.8, 54.3, 32.4, 29.1, 18.9, 15.3. Anal.
Calcd for C15H19N3O2: C, 65.91; H, 7.01; N, 15.37%. Found: C, 65.85;
H, 7.10; N, 15.30%.
6.1.2.24. 2-((4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-2,3-
dihydrobenzofuran-5-carbonitrile (26). White solid, mp 152 ꢀC,
yield (77%); IR (KBr) cmꢁ1: 3426 (O–H), 1251 (C–O–C); ESIMS: 257
6.1.2.19. 2-((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)-2,3-dihydro-
benzofuran-5-carbonitrile (21). White solid, mp 182 ꢀC, yield (94%);
IR (KBr) cmꢁ1: 2925 (C–H), 2223(CN), 1609 (C]C), 1246 (C–O–C);
(M þ H)þ; 1H NMR (300 MHz, CDCl3 þ CCl4):
d 7.71 (s, 1H, Ar–H),
ESIMS: 303 (M þ H)þ; 1H NMR (200 MHz, CDCl3 þ CCl4):
d
7.82 (s,1H,
7.42–7.35 (m, 2H, Ar–H, triazole ring proton), 6.83 (d, J ¼ 8.6 Hz, 1H,
Ar–H), 5.30–5.22 (m, 1H, CH dihydrofuran ring), 4.73–4.56
(m, 4H, –NCH2, –OCH2), 3.44-3.35 (m, 2H, H-3a, OH), 3.11
(dd, J1 ¼16.2 Hz, J2 ¼ 7.0 Hz, 1H, H-3b); 13C NMR (50 MHz,
Ar–H), 7.67 (d, J ¼ 6.8 Hz, 2H, Ar–H), 7.33–7.18 (m, 5H, Ar–H, triazole
ring proton), 6.76 (d, J ¼ 8.8 Hz, 1H, Ar–H), 5.25–5.18 (m, 1H, CH
dihydrofuran ring), 4.70–4.58 (m, 2H, –NCH2), 3.39 (dd, J1 ¼16.4 Hz,
J2 ¼ 9.4 Hz, 1H, H-3a), 3.08 (dd, J1 ¼16.4 Hz, J2 ¼ 7.2, 1H, H-3b); 13C
CDCl3 þ CCl4):
d 162.5, 133.9, 129.3, 128.9, 127.8, 119.3, 110.8, 104.5,
82.1, 56.3, 53.4, 32.1. Anal. Calcd for C13H12N4O2: C, 60.93; H, 4.72;
N, 21.86%. Found: C, 60.89; H, 4.80; N, 21.84%.
NMR (50 MHz, CDCl3 þ CCl4):
d
134.0,129.3,129.1,128.5,127.7,126.0,
121.2,119.1,110.8,105.0, 63.0, 53.5, 32.1. Anal. Calcd for C18H14N4O: C,
71.51; H, 4.67; N, 18.53%. Found: C, 71.40; H, 4.73; N, 18.45%.
6.1.2.25. 2-((4-(1-Hydroxyhexyl)-1H-1,2,3-triazol-1-yl)methyl)-2,3-
dihydrobenzofuran-5-carbonitrile (27). White solid, mp 112 ꢀC,
yield (85%); IR (KBr) cmꢁ1: 3387 (O–H), 2928 (C–H), 2224 (CN),
1610 (C]C), 1248 (C–O–C); ESIMS: 327 (M þ H)þ; 1H NMR
6.1.2.20. 2-((4-Benzyl-1H-1,2,3-triazol-1-yl)methyl)-2,3-dihydro-
benzofuran-5-carbonitrile (22). White solid, mp 142 ꢀC, yield (59%);
IR (KBr) cmꢁ1: 3019 (C–H), 2226 (CN), 1607 (C]O), 1217 (C–O–C);

148
R.P. Tripathi et al. / European Journal of Medicinal Chemistry 45 (2010) 142–148
(300 MHz, CDCl3 þ CCl4):
d
7.57 (s, 1H, Ar–H), 7.45 (d, J ¼ 8.4 Hz, 1H,
Financial assistance from DRDO and DBT New Delhi is also grate-
fully acknowledged.
Ar–H), 7.39 (s, 1H triazole ring proton), 6.85 (d, J ¼ 8.31 Hz, 1H,
Ar–H), 5.32–5.23 (m, 1H, CH dihydrofuran ring), 4.83–4.58 (m,
3H,–NCH2, –CH(OH)–), 3.46 (dd, J1 ¼16.3 Hz, J2 ¼ 9.5 Hz, 1H, H-3a),
3.14 (dd, J1 ¼16.3 Hz, J2 ¼ 6.9 Hz, 1H, H-3b), 2.71 (bs, 1H, OH),
1.79–175 (m, 2H,CH2), 1.30–1.26 (m, 6H, 3CH2), 0.91 (t, J ¼ 6.0 Hz,
Appendix A. Supplementary data
3H, CH3); 13C NMR (50 MHz, CDCl3 þ CCl4):
d 162.4, 134.1, 129.4,
General procedure and scan spectral data of compounds are
available online at www.sciencedirect.com. Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.ejmech.2009.09.036.
127.6, 119.1, 110.8, 105.2, 82.0, 67.3, 53.7, 37.7, 32.2, 32.1, 22.9, 14.4.
Anal. Calcd for C18H22N4O2: C, 66.24; H, 6.79; N, 17.17%. Found: C,
66.20; H, 6.82; N, 17.20%.
7. Biological activity
References
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Authors are thankful to UGC and CSIR New Delhi for the award
of JRF and SRF, respectively. We sincerely thank SAIF CDRI for
providing spectroscopic data and microanalyses of the compounds.