Synthesis of sterically congested 1,5-disubstituted-1,2,3-Triazoles using chloromagnesium acetylides and hindered 1-naphthyl azides

Article abstract of DOI:10.1016/j.tet.2020.131916

Sterically congested 1-(2-methoxy-1-naphthyl)-5-substituted-1,2,3-triazoles can be prepared from sterically hindered 2-methoxy-1-azidonaphthalene and chloromagnesium acetylides, including 2-substituted phenylacetylides. Catalytic methods using Cp?RuCl(PPh

Full text of DOI:10.1016/j.tet.2020.131916

Tetrahedron 81 (2021) 131916
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of sterically congested 1,5-disubstituted-1,2,3-Triazoles
using chloromagnesium acetylides and hindered 1-naphthyl azides
Muni Kumar Mahadari, Andrew J. Tague, Paul A. Keller**, Stephen G. Pyne*
School of Chemistry and Molecular Bioscience, University of Wollongong, Illawarra Health and Medical Research Institute, Wollongong NSW, 2522, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Sterically congested 1-(2-methoxy-1-naphthyl)-5-substituted-1,2,3-triazoles can be prepared from ste-
rically hindered 2-methoxy-1-azidonaphthalene and chloromagnesium acetylides, including 2-
substituted phenylacetylides. Catalytic methods using Cp*RuCl(PPh3)2 or Cp2Ni/Xanphos were not
successful.
Received 17 November 2020
Received in revised form
21 December 2020
Accepted 27 December 2020
Available online 31 December 2020
© 2020 Elsevier Ltd. All rights reserved.
Dedicated to the memory of our friend and
mentor Prof. Lewis N. Mander
Keywords:
Triazole
1-Naphthyl
Click reaction
Magnesium acetylide
1. Introduction
acetylenes and stoichiometric quantities of base, e.g. KOH or
Me4NOH in DMSO [13] (Scheme 1). Potassium acetylides, formed in
1,2,3-Triazoles are valuable heterocycles in many branches of
chemistry [1]. In medicinal chemistry, they serve as more stable
bioisosteres for amides [2] and cis-alkenes [3], as well as serving as
bioactive chemical scaffolds and pharmacophore linkers [4]. They
also have found applications as chiral ligands [5] in metal-catalyzed
transformations, as organocatalysts [6], and are recognized as
important linker groups in chemical biology [7]. The increasing
popularity and utility of these heterocycles, especially 1,4-
disubstituted-1,2,3-triazoles, is due to the development of the
Cu(I)-catalyzed cycloaddition reaction (“click reaction”) between
terminal alkynes and azide derivatives which reliably, efficiently,
and regioselectively provide these important heterocycles under
mild reaction conditions (Scheme 1) [8].
situ from vinyl bromides [14] or 2-arylethanol derivatives [15], have
also been used to produce 1,5-disubstituted-1,2,3-triazoles from
azides. Ln[N(SiMe3)2]3-catalyzed cycloadditions of terminal acety-
lenes to azides also provides 1,5-disubstituted-1,2,3-triazoles [16].
While the scope for the production of 1,5-disubstituted-1,2,3-
triazoles is varied, the synthesis of sterically hindered derivatives
in the substrate scope for these methods is largely ignored, or if
attempted, give rise to, at best, modest yields [17]. Therefore, there
is a need for general methods for the synthesis of sterically hin-
dered 1,5-disubstituted-1,2,3-triazoles with better outcomes for
hindered products.
2. Results and discussion
Access to 1,5-disubstituted-1,2,3-triazoles, in a regioselective
manner, is also possible using other transition metal catalysts [1],
e.g. Ru [9], Ni [10], stoichiometric amounts of terminal metal ace-
tylides (RC≡CM, e.g. M ¼ Mg [11], In Ref. [12]), or from terminal
As part of an ongoing medicinal chemistry project aimed at
developing hydrophobic di- and tri-cationic peptide derivatives as
antibacterial agents to target pathogenic bacteria [18], we required
the synthesis of the relatively sterically hindered 1-(1-naphthyl)-5-
isopentyl-1,2,3-triazole 2a (Scheme 2).
We initially examined the Ru-catalyzed cycloaddition method
developed by Fokin et al. using Cp*RuCl(PPh3)2 as the catalyst. This
was reported to work well for both aliphatic and aromatic azides
* Corresponding author.
** Corresponding author.
E-mail addresses: keller@uow.edu.au (P.A. Keller), spyne@uow.edu.au
(S.G. Pyne).
https://doi.org/10.1016/j.tet.2020.131916
0040-4020/© 2020 Elsevier Ltd. All rights reserved.

M.K. Mahadari, A.J. Tague, P.A. Keller et al.
Tetrahedron 81 (2021) 131916
resulted in the isolation of only amines 3a and 3b, respectively. The
reaction of 1c and the sterically more crowded 2-
methoxyphenyacetylene resulted in isolation of only amine 3c in
19% yield. These results indicated that the 2-substituted-1-
azidonaphthalenes 1a,b are too hindered to be substrates for the
Cp*RuCl(PPh3)2
catalyzed
azide-alkyne
cycloaddition
methodology.
In contrast, the less sterically demanding, but also ortho-
substituted, 2-methoxyphenylazide gave the desired 1-(2-
4
Scheme 1. Synthesis of 1,4-disubstituted and 1,5-disubstituted 1,2,3-triazoles.
methoxyphenyl)-5-substituted-1,2,3-triazoles 5a and 5b in 87%
and 78% yields, respectively, after heating with terminal acetylenes
(RC≡CH, R ¼ i-pentyl or cyclohexyl) 70 ꢀC for 12 h (Scheme 3). The
reaction of
4
with the more sterically demanding 2-
methoxyphenylacetylene required an extended reaction time
(36 h) to obtain the corresponding 1-(2-methoxyphenyl)-5-
substituted-1,2,3-triazole 5c in 58% yield. The analogous reaction
with the more highly sterically demanding 1-
naphthylacetylene required heating at 70 ꢀC for 48 h to produce
5d in only 7% yield (TLC analysis of the crude reaction mixture
indicated unreacted 4 and other more polar products had also
formed). The yields and reaction times for the above mentioned
reactions correlate well with the steric demands of the acetylene
component.
We also examined the reaction of the azide 1a and 5-methyl-1-
hexyne under the conditions reported by Hong using Cp2Ni/Xant-
phos/Cs2CO3 in toluene or water as solvent [10]. None of the desired
1,2,3-triazole product 2a was produced, however this method was
reported
not
to
work
with
benzylazide
and
2-
Scheme 2. Attempted synthesis of 1-(1-naphthyl)-5-isopentyl-1,2,3-triazoles 2a and
2b and synthesis of 2c.
methoxyphenylacetylene and thus our result using the more hin-
dered azide 1a may be expected. Additional attempts using tetra-
methylammonium hydroxide in DMSO [13] with substrates 1a and
5-methyl-1-hexyne were also unsuccessful in producing 2a, despite
these conditions being reported to work for ortho-substituted
phenylazides (1-naphthylazides were not studied, although one
successful example using the less hindered 6- methoxy-2-
naphthylazide was reported).
We thus turned our attention to the paper of Kransinski, Fokin
and Sharpless for the synthesis of 1,5-disubstituted-1,2,3-triazoles
using chloromagnesium acetylides, reported to work with both
para- and meta-substituted phenylazides [11]. The results of our
study are reported in Scheme 4. 1-(2-Methoxynaphthyl)-5-
substituted-1,2,3-triazole products 2a-2i were successfully syn-
thesized from the azide 1a even in the presence of relatively hin-
dered, ortho-substituted phenylacetylides (e.g. 2f, 2g and 2i),
including 2,4,6-trimethylphenylacetylide, which gave triazole 2i in
52% yield. In contrast, the reaction involving 2,6-
dimethoxyphenylacetylide gave none of the desired triazole
product 2j. While 3-fluorophenylacetylide gave the triazole 2h in
86% yield, its isomeric acetylide, derived from 4-
[9], however, this manuscript only reported relatively unhindered
para-substituted phenylazides. In our hands, treatment of a solu-
tion of azide 1a and 5-methyl-1-hexyne, under the reported con-
ditions, 10 mol% Cp*RuCl(PPh3)2 in 1,4-dioxane at 70 ꢀC for 12 h
under a nitrogen atmosphere, surprisingly gave none of the desired
1-(1-naphthyl)-5-isopentyl-1,2,3-triazole 2a and only the naph-
thylamine 3a in 16% yield, formed from formal reduction of the
sterically hindered azide 1a (Scheme 2). The same amine 3a was
produced in 16% yield when the reaction of 1a was repeated in the
absence of the alkyne component. A recent study showed that
under similar reaction conditions, other sterically hindered alky-
lazides give the unexpected 1,4-disubstituted-1,2,3-triazole prod-
ucts, often in low yields (16e44%) [17]. Some reactions gave
mixtures of the 1,4-disubstituted and 1,5-disubstituted-1,2,3-
triazole products [17]. However amine products from overall
reduction of the azide, as we observed (Scheme 2), were not re-
ported [17]. Our study also revealed similar results in the reaction of
5-methyl-1-hexyne with the related ortho-substituted azide, 2-
methyl-1-naphthylazide 1b at 70 ꢀC for 12 h. 1-Amino-2-
methylnaphthalene 3b was isolated in 14% yield (Scheme 2).
These results suggested that as a result of the hindered nature of
azides 1a and 1b, they may be undergoing a Staudinger reaction
[19] with the PPh3 derived from the Ru catalyst rather than un-
dergoing the desired cycloaddition reactions. Subsequently, the
intermediate iminophosphoranes underwent hydrolysis to their
corresponding amines 3a,b with adventitious water in the reaction
mixture or upon work up and column chromatography. Consistent
with this premise was the result of the Ru-catalyzed reaction of the
less hindered 1-naphthylazide 1c with 5-methyl-1-hexyne which
gave the 1-(1-naphthyl)-5-isopentyl-1,2,3-triazole 2c in 63% yield
along with 12% of 1-aminonaphthalene 3c (Scheme 2). The Ru-
catalyzed reactions of 1a and 1b with other terminal acetylenes
(RC≡CH, R ¼ c-C6H11, 2-MeO-phenyl or 1-naphthyl) at 70 ꢀC for 12 h
Scheme 3. Synthesis of 1-(2-methoxyphenyl)-5-substituted-1,2,3-triazoles 5a-5d.
2

M.K. Mahadari, A.J. Tague, P.A. Keller et al.
Tetrahedron 81 (2021) 131916
Scheme 5. Synthesis of 1-(1-naphthyl)-4-substituted-1,2,3-triazoles 6 using copper
catalysis.
Scheme 6. Synthesis of 1-(2-methoxyphenyl)-4-substituted-1,2,3-triazoles
7 using
copper catalysis.
Scheme 4. Synthesis of 1-(1-naphthyl)-5-substituted-1,2,3-triazoles 2 using magne-
sium acetylides.
while 4-fluorophenyl- and 4-nitrophenyl-acetylene gave 6d and 6e,
respectively, in good yields.
A comparison of the NMR spectra of compounds 2a, 2d and 2f
with those of 6a, 6b and 6c, respectively indicated their regioiso-
meric relationships. A similar comparison indicated that 5a, 5b and
5c were regioisomeric with 7a, 7b and 7c, respectively. These
structural assignments were further established by HMBC experi-
ments, with the spectra of 6a and 7a showing 3-bond correlations
between the triazole proton and C-1 of the N-aryl group while in
those of 2a and 5a this correlation was absent. These differences in
regiochemical outcomes between the Cu-catalyzed1(d) and Mg-
promoted versions [11] of these reactions are consistent with
previous reports and the accepted mechanistic differences for these
processes.
fluorophenylacetylene, failed to give triazole 2k. Likewise the re-
actions involving 3-nitro- and 4-nitrophenylacetylene failed to
produce triazoles 2l and 2m. The addition of EtMgCl to these
acetylenes gave black coloured solutions indicating that undesired
reactions were occurring due to the presence of the nitro group.
The starting azide 1a was recovered in these unsuccessful reactions.
Unsurprisingly, the reaction involving the highly hindered chlor-
omagesium 1-naphthylacetylide failed to produce the triazole 2n.
In contrast, the reactions of azide 1b with three different chloro
magnesium acetylides failed to produce the triazole products 2o-
2q (Scheme 4). These negative results are consistent with the much
larger steric demand of the 2-methyl group in azide 1b compared to
the methoxy group in azide 1a. Consistent with this argument were
the results of the reactions of the less sterically demanding 1-
naphthylazide 1c with chloromagnesium acetylides which gave
triazoles 2r and 2s, both in yields of 88%. The more hindered
3. Conclusions
In conclusion, sterically congested 1-(2-methoxy-1-naphthyl)-
5-substituted-1,2,3-triazoles can be prepared from sterically hin-
dered 2-methoxy-1-azidonaphthalene using chloromagnesium
acetylides, including ortho-substitutedphenylacetylenes, in cir-
cumstances where catalytic methods, e.g. Cp*RuCl(PPh3)2 or Cp2Ni/
Xantphos, were not successful. These results open the possibility
for the use of chloromagnesium acetylides as the preferred “click
chemistry” strategy for the synthesis of sterically hindered 1,5-
disubstituted-1,2,3-triazoles.
chloromagnesium
acetylides
formed
from
2-
methoxyphenylacetylene and 1-naphthylacetylene were less pro-
ductive giving 2t and 2u in yields of 10 and 0%, respectively. The
former result is in contrast to that of the reaction of chlor-
omagnesium 2-methoxyphenylacetylide with 1a that gave 2f in
89% yield, possibly due to the methoxy group in 1a having a posi-
tive coordinating effect with the magnesium reagent.
To secure the regiochemical assignments of our products we
have prepared, in some cases, the regioisomeric 1-(1-naphthyl)-4-
substituted-1,2,3-triazoles 6a-g (Scheme 5) and the 1-(2-
methoxyphenyl)-4-substituted-1,2,3-triazoles 7a-c (Scheme 6) us-
ing copper catalyzed “click” chemistry. In those examined in-
stances, all reactions worked efficiently. The reaction of 1a with the
sterically encumbered 1-naphthylacetylene gave 6f in 91% yield
4. Experimental
4.1. Synthesis of azides and alkynes
The known azides, 1a [20], 1b [21] and 1c [22] were prepared
from their corresponding 1-naphthylamines as described by Hu
3

M.K. Mahadari, A.J. Tague, P.A. Keller et al.
Tetrahedron 81 (2021) 131916
H400), 6.99e6.96 (m, 1H, H300), 3.87 (s, 3H, OMe), 2.45e2.34 (m, 2H,
H1’), 1.47e1.35 (m, 3H, H2’ and H3’), 0.74 (d, J ¼ 7.8 Hz, 3H, H4’ or
H5’), 0.71 (d, J ¼ 7.8 Hz, 3H, H5’ or H4’); 13C NMR (101 MHz, CDCl3)
et al. [23] All alkynes were commercially sourced expect for 1-
ethynylnaphthalene [24], 1-ethynyl-4-nitrobenzene [25], and 2-
ethynyl-1,3,5-trimethylbenzene [26] which were prepared by
literature methods. The signals in the 1H NMR and 13C NMR spectra
of each compound were assigned with support of 2D NMR
techniques.
d
152.7 (C200), 140.7 (C5), 132.0 (C8a’’), 131.6 (C4), 131.4 (C4a’’), 128.7
(C400), 128.3 (C500), 127.9 (C700), 124.6 (C800), 121.2 (C600), 117.9 (C300),
113.1 (C100), 56.5 (OMe), 36.7 (C2’), 27.2 (C3’), 22.09 (C4’ or C5’),
22.08 (C5’ or C4’), 20.8 (C1’); IR (neat) nmax 2954, 2868, 1630, 1599,
1507, 1457, 1275, 1255, 1064,1040, 809, 748 cmꢂ1; MS (ESI þ ve) m/z
296 ([MþH]þ); HRMS (ESI þ ve TOF) calcd for C18H22N3O 296.1763,
found 296.1750 ([MþH]þ).
4.2. General procedure A: magnesium-promoted click reaction
To a dried flask containing a solution of EtMgCl (2 M in diethyl
ether, 0.3 mmol, 1.2 eq) in dry THF (1 mL) under a nitrogen atmo-
sphere at room temperature, was added dropwise the alkyne
(0.27 mmol, 1.1 eq) and stirring was continued for 30 min. The
solution was cooled to room temperature and a solution of the
azide (0.25 mmol, 1.0 eq) in dry THF (2 mL) was added dropwise
over a period of 5 min at room temperature. After a further 10 min,
the reaction mixture was stirred and heated at 50 ꢀC for 3e5 h.
Aqueous saturated NH4Cl solution (0.5 mL), then water (25 mL) was
added and the mixture was extracted with EtOAc (2 ꢁ 25 mL). The
combined extracts were washed with water (2 ꢁ 25 mL), brine
(2 ꢁ 25 mL) and dried (MgSO4). The solution was filtered,
concentrated under vacuum and the residue was subjected to silica
gel column chromatography to give the product.
4.6. 5-Isopentyl-1-(naphthalen-1-yl)-1H-1,2,3-triazole (2c)
This compound was prepared according to the general proced-
ure B using 1-azidonaphthalene (50 mg, 0.29 mmol), 5-methyl-1-
hexyne (31 mg, 0.32 mmol) and a 12 h reaction time to give 2c
(50 mg, 63%) as a brown oil after purification by column chroma-
tography over SiO2 gel (EtOAc/n-hexane - 20:80 / 100:0). Naph-
thalen-1-amine 3c was also isolated (5 mg, 12%). 2c: TLC (EtOAc/n-
hexane 1:4): Rf ¼ 0.4; 1H NMR (500 MHz, CDCl3)
d 8.04 (d,
J ¼ 10.4 Hz, 1H, H8"), 7.95 (d, J ¼ 10.2 Hz, 1H, H5"), 7.70 (s, 1H, H4),
7.62e7.54 (m, 2H, H6" and H7"), 7.51e7.47 (m, 2H, H3" and H4"),
7.16 (dd, J ¼ 8.5, 0.8 Hz, 1H, H2"), 2.45e2.42 (m, 2H, H1’), 1.43e1.36
(m, 3H, H2’ and H3’), 0.72 (d, J ¼ 7.8 Hz, 6H, H4’ and H5’); 13C NMR
(126 MHz, CDCl3) d 140.2 (C5), 134.1 (C8a"), 132.6 (C4a"), 131.7 (C4),
4.3. General procedure B: ruthenium-catalyzed click reaction
130.6 (C8"), 129.9 (C5"), 128.2 (C4"), 127.8 (C6"), 127.0 (C7"), 125.0
(C3"), 125.0 (C1"), 122.3 (C2"), 37.1 (C2’), 27.3 (C3’), 22.1 (C4’ and
C5’), 21.2 (C1’); IR (neat) nmax 2956, 2928, 1598, 1471, 1437, 1247,
1078, 960, 802, 773, 661 cmꢂ1; MS (ESI þ ve) m/z 266 ([MþH])þ;
HRMS (ESI þ ve TOF) calcd for C17H20N3 266.1657, found 266.1667
([MþH]þ).
To a stirred solution of azide (0.33 mmol, 1.0 eq) in dry 1,4-
dioxane (2 mL) was added the alkyne (0.37 mmol, 1.1 eq), fol-
lowed by pentamethylcyclopentadienyl-bis(triphenylphosphine)
ruthenium(II) chloride (0.033 mmol, 0.1 eq) at room temperature
and the reaction was allowed to stir at 70 ꢀC for 12 h. The reaction
was cooled to room temperature and quenched with saturated
aqueous NH4Cl solution (1 mL), then water (25 mL) was added and
the mixture was extracted with EtOAc (2 ꢁ 25 mL). The combined
extracts were washed with water (2 ꢁ 25 mL), brine (2 ꢁ 25 mL)
and dried (MgSO4). The solution was filtered, concentrated under
vacuum and the residue was subjected to silica gel column chro-
matography to give the product.
4.7. 5-Cyclohexyl-1-(2-methoxynaphthalen-1-yl)-1H-1,2,3-triazole
(2d)
This compound was prepared according to the general proced-
ure A using 1-azido-2-methoxynaphthalene (50 mg, 0.25 mmol),
ethynylcyclohexane (30 mg, 0.27 mmol) and a 5 h reaction time to
give 2d (60 mg, 78%) as a cream white solid after purification by
column chromatography over SiO2 gel (EtOAc/n-hexane
-
4.4. General procedure C: copper-catalyzed click reaction
30:70 / 100:0). M.P: 104e106 ꢀC; TLC (EtOAc/n-hexane 1:4):
Rf ¼ 0.1; 1H NMR (500 MHz, CDCl3)
d
8.03 (d, J ¼ 9.1 Hz, 1H, H8"),
To a stirred solution of azide (0.25 mmol, 1 eq) and alkyne
(0.50 mmol, 2.0 eq) in tert-butanol/water (2 mL : 0.5 mL) was added
CuSO4.5H2O (0.05 mmol, 0.20 eq), followed by sodium ascorbate
(0.1 mmol, 0.4 eq) at room temperature and the reaction was stirred
at room temperature for 12 h. Then the reaction was quenched with
NH4Cl solution (1 mL), then water (25 mL) was added and the
mixture was extracted with EtOAc (2 ꢁ 25 mL). The combined ex-
tracts were washed with water (2 ꢁ 25 mL), brine (2 ꢁ 25 mL) and
dried (MgSO4). The solution was filtered, concentrated under vac-
uum and the residue was subjected to silica gel column chroma-
tography to give the product.
7.87e7.85 (m, 1H, H5"), 7.71 (s, 1H, H4), 7.44e7.38 (m, 3H, H6", H7"
and H4"), 6.95 (dd, J ¼ 8.2, 1.2 Hz, 1H, H3"), 3.87 (s, 3H, OMe),
2.31e2.24 (m, 1H, H1’), 1.91e1.88 (m, 1H, H5’), 1.74e1.70 (m, 1H,
H6’), 1.60e1.56 (m, 3H, H2’, H3’ and H4’), 1.43e1.40 (m, 1H, H5’),
1.32e1.29 (m, 1H, H6’), 1.19e1.10 (m, 2H, H2’ and H4’), 1.01e0.97 (m,
1H, H3’); 13C NMR (126 MHz, CDCl3)
d 152.7 (C2"), 145.8 (C5), 132.0
(C8a"), 131.8 (C4), 130.1 (C4"), 128.7 (C4a"), 128.3 (C5"), 127.9 (C7"),
124.6 (C8"), 121.3 (C6"), 118.1 (C3"), 113.1 (C1"), 56.6 (OMe), 33.3
(C2’), 32.9 (C3’), 32.4 (C1’), 25.9 (C6’), 25.8 (C5’), 25.6 (C4’); IR (neat)
nmax 2927, 2852, 1628, 1599, 1510, 1482, 1276, 1245, 1151, 1067, 818,
751 cmꢂ1; MS (ESI þ ve) m/z 308 ([MþH]þ); HRMS (ESI þ ve TOF)
calcd for C19H22N3O 308.1763, found 308.1750 ([MþH]þ).
4.5. 5-Isopentyl-1-(2-methoxynaphthalen-1-yl)-1H-1,2,3-triazole
(2a)
4.8. 1-(2-Methoxynaphthalen-1-yl)-5-(4-methoxyphenyl)-1H-
This compound was prepared according to the general proced-
ure A using 1-azido-2-methoxynaphthalene (50 mg, 0.25 mmol), 5-
methyl-1-hexyne (27 mg, 0.27 mmol) and a 3 h reaction time to
give 2a (60 mg, 81%) as a pale brown waxy solid after purification
by column chromatography over SiO2 gel (EtOAc/n-hexane -
20:80 / 100:0). TLC (EtOAc/n-hexane 1:4): Rf ¼ 0.2; 1H NMR
1,2,3-triazole (2e)
This compound was prepared according to the general proced-
ure A using 1-azido-2-methoxynaphthalene (50 mg, 0.25 mmol), 1-
ethynyl-4-methoxybenzene (37 mg, 0.27 mmol) and a 4 h reaction
time to give 2e (72 mg, 86%) as a waxy solid after purification by
(400 MHz, CDCl3)
d
8.03 (d, J ¼ 9.1 Hz, 1H, H800), 7.85 (dd, J ¼ 2.0,
column chromatography over SiO2 gel (EtOAc/n-hexane
-
7.4 Hz, 1H, H500), 7.71 (s, 1H, H4), 7.45e7.37 (m, 3H, H600, H700 and
40:60 / 100:0). TLC (EtOAc/n-hexane 1:4): Rf ¼ 0.2; 1H NMR
4

M.K. Mahadari, A.J. Tague, P.A. Keller et al.
Tetrahedron 81 (2021) 131916
(500 MHz, CDCl3)
d
7.97 (s, 1H, H4), 7.96 (d, J ¼ 9.6 Hz, 1H, H8"), 7.81
by column chromatography over SiO2 gel (EtOAc/n-hexane -
40:60 / 100:0). M.P: 148e150 ꢀC. TLC (EtOAc/n-hexane 1:4):
(d, J ¼ 8.0 Hz, 1H, H5"), 7.43e7.35 (m, 2H, H6" and H7"), 7.28 (d,
J ¼ 9.1 Hz, 1H, H4"), 7.16 (d, J ¼ 8.3 Hz, 1H, H3"), 7.09e7.06 (m, 2H,
H2’ and H6’), 6.69e6.66 (m, 2H, H30 and H50), 3.69 (s, 3H, OMe),
Rf ¼ 0.3; 1H NMR (500 MHz, CDCl3)
d 8.05 (s, 1H, H4), 8.00 (d,
J ¼ 9.1 Hz, 1H, H8"), 7.84 (d, J ¼ 8.1 Hz, 1H, H5"), 7.46e7.43 (m, 1H,
H6"), 7.41e7.37 (m, 1H, H7"), 7.30 (d, J ¼ 9.1 Hz, 1H, H4"), 7.16e7.11
(m, 2H, H3" and H2’), 6.95e6.86 (m, 3H, H4’, H5’ and H6’), 3.72 (s,
3.66 (s, 3H, H7’); 13C NMR (126 MHz, CDCl3)
d 160.0 (C4’), 152.6
(C2"), 140.2 (C8a"), 132.0 (C4), 131.6 (C4"), 131.6 (C4a"), 128.7 (C2’
and C6’), 128.4 (C5"), 127.9 (C7"), 127.8 (C8"), 124.6 (C6"), 121.3
(C3"), 119.2 (C5), 118.6 (C1’), 114.0 (C30 and C50), 113.2 (C1"), 56.5
(OMe), 55.1 (C7’); IR (neat) nmax 2940, 2839, 1616, 1558, 1507, 1495,
1457, 1276, 1249, 1179, 1067, 1020, 810, 750 cmꢂ1; MS (ESI þ ve) m/z
332 ([MþH]þ); HRMS (ESI þ ve TOF) calcd for C20H18N3O2 332.1399,
found 332.1386 ([MþH]þ).
3H, OMe); 13C NMR (126 MHz, CDCl3)
d
162.4 (d, 1JC-F ¼ 198.3 Hz,
C3’), 152.6 (C200), 139.2 (C8a’’), 132.5 (C4a’’), 132.5 (C4), 131.6 (C800),
130.4 (d, 2JC-F ¼ 7.0, C1’), 129.0 (d, 3JC-F ¼ 10.1, C5’), 128.8 (C400), 128.7
(C500), 128.2 (C300), 124.7 (C600), 123.1 (C700), 121.1 (C6’), 118.2 (C5),
4
5
116.0 (d, JC-F ¼ 16.9 Hz, C2’), 114.4 (d, JC-F ¼ 18.6 Hz, C4’), 113.0
(C100), 56.5 (OMe); IR (neat) nmax 2937, 2842, 1558, 1507, 1457, 1273,
1149, 1110, 1069, 862, 807, 798, 690 cmꢂ1; MS (ESI þ ve) m/z 320
([MþH]þ); HRMS (ESI þ ve TOF) calcd for C19H15FN3O 320.1199,
found 320.1205 ([MþH]þ).
4.9. 1-(2-Methoxynaphthalen-1-yl)-5-(2-methoxyphenyl)-1H-
1,2,3-triazole (2f)
This compound was prepared according to the general proced-
ure A using 1-azido-2-methoxynaphthalene (50 mg, 0.25 mmol), 1-
ethynyl-2-methoxybenzene (36 mg, 0.27 mmol) and a 4 h reaction
time to give 2f (74 mg, 89%) as an off-white waxy solid after puri-
fication by column chromatography over SiO2 gel (EtOAc/n-hexane
- 40:60 / 100:0). TLC (EtOAc/n-hexane 2:3): Rf ¼ 0.1; 1H NMR
4.12. 5-Mesityl-1-(2-methoxynaphthalen-1-yl)-1H-1,2,3-triazole
(2i)
This compound was prepared according to the general proced-
ure A using 1-azido-2-methoxynaphthalene (50 mg, 0.25 mmol), 2-
ethynyl-1,3,5-trimethylbenzene (40 mg, 0.27 mmol) and a 6 h re-
action time to give 2i (45 mg, 52%) as a brown waxy solid after
purification by column chromatography over SiO2 gel (EtOAc/n-
hexane - 40:60 / 100:0). TLC (EtOAc/n-hexane 2:3): Rf ¼ 0.1; 1H
(500 MHz, CDCl3)
d
8.01 (s, 1H, H4), 7.89 (d, J ¼ 9.1 Hz, 1H, H6’), 7.79
(d, J ¼ 8.1 Hz, 1H, H8"), 7.46e7.43 (m, 1H, H5"), 7.39e7.35 (m, 2H,
H6" and H7"), 7.21e7.17 (m, 2H, H4’ and H5’), 7.06 (dd, J ¼ 7.6,1.7 Hz,
1H, H4"), 6.75 (t, J ¼ 7.5 Hz, 1H, H3’), 6.70 (d, J ¼ 8.3 Hz, 1H, H3"),
3.59 (s, 3H, OMe), 3.26 (s, 3H, H7’); 13C NMR (126 MHz, CDCl3)
NMR (500 MHz, CDCl3)
d
7.85 (d, J ¼ 7.3 Hz, 1H, H8"), 7.83 (s, 1H,
H4), 7.77 (d, J ¼ 7.3 Hz, 1H, H5"), 7.50e7.44 (m, 2H, H6" and H4"),
7.38e7.35 (m, 1H, H7"), 7.12e7.10 (m,1H, H3"), 6.89 (s,1H, H5’), 6.57
(s, 1H, H3’), 3.57 (s, 3H, OMe), 2.25 (s, 3H, H9’), 2.18 (s, 3H, H7’), 1.57
d
156.6 (C2’), 151.9 (C2"), 137.2 (C8a"), 133.7 (C4), 131.4 (C6’), 131.4
(C4"), 130.5 (C4’), 130.3 (C4a"), 128.7 (C5"), 127.8 (C7"), 127.6 (C8"),
124.3 (C6"), 122.3 (C5’), 120.1 (C5), 119.3 (C3"), 116.2 (C1’), 113.0
(C1"), 110.7 (C3’), 56.3 (C7’), 54.7 (OMe); IR (neat) nmax 2938, 2840,
1507, 1486, 1465, 1264, 1150, 1104, 1067, 1020, 806, 749 cmꢂ1; MS
(ESI þ ve) m/z 332 ([MþH]þ); HRMS (ESI þ ve TOF) calcd for
(s, 3H, H8’); 13C NMR (126 MHz, CDCl3)
d 151.4 (C2"), 138.7 (C8a"),
138.6 (C4’), 138.6 (C2’), 137.6 (C6’), 134.3 (C4), 131.7 (C5"), 130.8
(C4a"), 128.9 (C4"), 128.3 (C3’), 128.1 (C5’), 128.0 (C7"), 127.9 (C8"),
124.3 (C6"), 123.2 (C1’), 122.5 (C5), 118.2 (C3"), 112.5 (C1"), 55.5
(OMe), 21.0 (C8’), 20.6 (C9’), 20.6 (C7’); IR (neat) nmax 2924, 2845,
1710, 1630, 1511, 1481, 1357, 1276, 1219, 1066, 1021, 967, 810,
749 cmꢂ1; MS (ESI þ ve) m/z 344 ([MþH]þ); HRMS (ESI þ ve TOF)
calcd for C22H22N3O 344.1763, found 344.1758 ([MþH]þ).
C
20H18N3O2 332.1399, found 332.1388 ([MþH]þ).
4.10. 1-(2-Methoxynaphthalen-1-yl)-5-(o-tolyl)-1H-1,2,3-triazole
(2g)
This compound was prepared according to the general proced-
ure A using 1-azido-2-methoxynaphthalene (50 mg, 0.25 mmol), 1-
ethynyl-2-methylbenzene (32 mg, 0.27 mmol) and a 3 h reaction
time to give 2g (60 mg, 76%) as a cream waxy solid after purification
by column chromatography over SiO2 gel (EtOAc/n-hexane -
30:70 / 100:0). TLC (EtOAc/n-hexane 1:4): Rf ¼ 0.2; 1H NMR
4.13. 5-Isopentyl-1-(naphthalen-1-yl)-1H-1,2,3-triazole (2r)
This compound was prepared according to the general proced-
ure A using 1-azidonaphthalene (50 mg, 0.29 mmol), 5-methyl-1-
hexyne (31 mg, 0.32 mmol) and a 4 h reaction time to give 2r
(68 mg, 88%) as a brown waxy solid after purification by column
chromatography over SiO2 gel (EtOAc/n-hexane - 30:70 / 100:0).
TLC (EtOAc/n-hexane 1:4): Rf ¼ 0.2; 1H NMR (500 MHz, CDCl3)
(500 MHz, CDCl3)
d
7.92 (s, 1H, H4), 7.90 (d, J ¼ 9.1 Hz, 1H, H8"), 7.80
(d, J ¼ 8.2 Hz, 1H, H5"), 7.50e7.46 (m, 1H, H6"), 7.40e7.37 (m, 1H,
H7"), 7.33 (dd, J ¼ 8.6, 0.6 Hz, 1H, H4"), 7.18 (d, J ¼ 9.1 Hz, 1H, H3"),
7.15e7.11 (m, 2H, H3’ and H6’), 6.87e6.86 (m, 2H, H4’ and H5’), 3.67
d
8.04 (d, J ¼ 8.3 Hz,1H, H8"), 7.95 (d, J ¼ 8.2 Hz,1H, H5"), 7.70 (s,1H,
H4), 7.61e7.54 (m, 2H, H6" and H7"), 7.50e7.47 (m, 2H, H3" and
H4"), 7.16 (dd, J ¼ 8.5, 0.8 Hz, 1H, H2"), 2.45e2.42 (m, 2H, H1’),
1.46e1.36 (m, 3H, H2’ and H3’), 0.72 (d, J ¼ 6.2 Hz, 6H, H4’ and H5’);
(s, 3H, OMe), 2.27 (s, 3H, Me); 13C NMR (126 MHz, CDCl3)
d 152.1
(C2"), 139.5 (C8a"), 137.1 (C2’), 133.5 (C4), 131.8 (C4a"), 131.6 (C4"),
130.1 (C1’), 129.5 (C3’), 129.0 (C8"), 128.6 (C5"), 128.2 (C7"), 127.9
(C4’), 126.5 (C5’), 125.3 (C6"), 124.5 (C3"), 121.5 (C6’), 118.2 (C5),
112.7 (C1"), 56.1 (OMe), 20.1 (Me); IR (neat) nmax 3140, 2929, 2847,
1599, 1510, 1274, 1109, 1244, 1058, 1021, 815, 760 cmꢂ1; MS
(ESI þ ve) m/z 316 ([MþH]þ); HRMS (ESI þ ve TOF) calcd for
13C NMR (126 MHz, CDCl3)
d 140.1 (C5), 134.1 (C8a"), 132.5 (C4a"),
131.7 (C4), 130.6 (C8"), 129.9 (C5"), 128.4 (C4"), 128.0 (C6"), 127.2
(C7"), 125.0 (C3"), 125.0 (C1"), 122.2 (C2"), 37.1 (C2’), 27.2 (C3’), 22.0
(C4’ and C5’), 21.1 (C1’); IR (neat) nmax 2955, 2868, 1598, 1468, 1430,
1247, 1077, 960, 802, 773, 661 cmꢂ1; MS (ESI þ ve) m/z 266
([MþH]þ); HRMS (ESI þ ve TOF) calcd for C17H20N3 266.1657, found
266.1668 ([MþH]þ).
C
20H18N3O 316.1450, found 316.1448 ([MþH]þ).
4.11. 5-(3-Fluorophenyl)-1-(2-methoxynaphthalen-1-yl)-1H-1,2,3-
triazole (2h)
4.14. 5-Cyclohexyl-1-(naphthalen-1-yl)-1H-1,2,3-triazole (2s)
This compound was prepared according to the general proced-
ure A using 1-azido-2-methoxynaphthalene (50 mg, 0.25 mmol), 1-
ethynyl-3-fluorobenzene (33 mg, 0.27 mmol) and a 5 h reaction
time to give 2h (69 mg, 86%) as a light yellow solid after purification
This compound was prepared according to the general proced-
ure A using 1-azidonaphthalene (50 mg, 0.29 mmol), ethynylcy-
clohexane (35 mg, 0.32 mmol) and a 4 h reaction time to give 2s
(71 mg, 88%) as a brown gummy solid after purification by column
5

M.K. Mahadari, A.J. Tague, P.A. Keller et al.
Tetrahedron 81 (2021) 131916
chromatography over SiO2 gel (EtOAc/n-hexane - 40:60 / 100:0).
TLC (EtOAc/n-hexane 1:4): Rf ¼ 0.4; 1H NMR (500 MHz, CDCl3)
(500 MHz, CDCl3)
d
7.56 (s,1H, H4), 7.52e7.48 (m,1H, H6"), 7.32 (dd,
J ¼ 7.6, 1.3 Hz, 1H, H4"), 7.11e7.06 (m, 2H, H500 and H300), 3.77 (s, 3H,
OMe), 2.44e2.38 (m, 1H, H1’), 1.89e1.71 (m, 2H, H4’ and H5’),
1.67e1.64 (m, 3H, H2’, H3’ and H6’), 1.38e1.31 (m, 2H, H6’ and H4’),
1.27e1.23 (m, 1H, H5’), 1.22e1.16 (m, 2H, H2’ and H3’); 13C NMR
d
8.04 (d, J ¼ 8.3 Hz,1H, H8"), 7.95 (d, J ¼ 8.2 Hz,1H, H5"), 7.70 (s,1H,
H4), 7.61e7.54 (m, 2H, H6" and H7"), 7.50e7.46 (m, 2H, H3" and
H4"), 7.12 (dd, J ¼ 8.5, 0.8 Hz, 1H, H2"), 2.40e2.34 (m, 1H, H1’),
1.77e1.70 (m, 2H, H3’ and H2’), 1.66e1.55 (m, 3H, H4’, H6’ and H5’),
1.41e1.33 (m, 2H, H4’ and H5’),1.20e1.12 (m,1H, H6’),1.08e1.00 (m,
(126 MHz, CDCl3)
d 154.3 (C2"), 144.8 (C5), 131.4 (C4"), 130.0 (C4),
128.8 (C6"), 125.3 (C1"), 120.9 (C5"), 112.2 (C3"), 55.8 (OMe), 33.4
(C1’), 26.0 (C2’, C3’ and C4’), 25.6 (C6’ and C5’); IR (neat) nmax 2928,
2850, 1506, 1457, 1280, 1233, 1046, 1020, 994, 974, 838, 770,
671 cmꢂ1; MS (ESI þ ve) m/z 258 ([MþH])þ); HRMS (ESI þ ve TOF)
calcd for C15H20N3O 258.1606, found 258.1602 ([MþH]þ).
2H, H3’ and H2’); 13C NMR (126 MHz, CDCl3)
d 145.2 (C5), 134.1
(C8a"), 132.8 (C4a"), 130.8 (C4), 130.5 (C8"), 130.3 (C5"), 128.3 (C4"),
128.0 (C6"), 127.2 (C7"), 125.1 (C3"), 125.0 (C1"), 122.3 (C2"), 33.3
(C1’), 25.8 (C2’, C3’, and C6’), 25.5 (C4’ and C5’); IR (neat) nmax 2929,
2852, 1710, 1597, 1448, 1238, 1084, 1005, 960, 802, 772 cmꢂ1; MS
(ESI þ ve) m/z 278 ([MþH]þ-); HRMS (ESI þ ve TOF) calcd for
4.18. 1,5-Bis(2-methoxyphenyl)-1H-1,2,3-triazole (5c)
C
18H20N3 278.1657, found 278.1659 ([MþH]þ).
This compound was prepared according to the general proced-
ure B using 1-azido-2-methoxybenzene (50 mg, 0.33 mmol), 1-
ethynyl-2-methoxybenzene (49 mg, 0.37 mmol) and a 36 h reac-
tion time to give 5c (54 mg, 58%) as a pale yellow waxy solid after
purification by column chromatography over SiO2 gel (EtOAc/n-
hexane - 30:70 / 100:0). TLC (EtOAc/n-hexane 2:3): Rf ¼ 0.3; 1H
4.15. 5-(2-Methoxyphenyl)-1-(naphthalen-1-yl)-1H-1,2,3-triazole
(2t)
This compound was prepared according to the general proced-
ure A using 1-azidonaphthalene (50 mg, 0.29 mmol), 1-ethynyl-2-
methoxybenzene (43 mg, 0.32 mmol) and a 12 h reaction time to
give 2t (9 mg, 10%) as a brown waxy solid after purification by
NMR (500 MHz, CDCl3)
d
7.86 (s, 1H, H4), 7.41 (dd, J ¼ 7.8, 1.7 Hz, 1H,
H5’), 7.38e7.34 (m, 1H, H6"), 7.30e7.26 (m,1H, H4’), 7.10 (dd, J ¼ 7.6,
1.7 Hz, 1H, H4"), 7.02 (dt, J ¼ 7.6, 1.2 Hz, 1H, H3’), 6.88e6.85 (m, 2H,
H5" and H6’), 6.83 (dd, J ¼ 8.4, 0.7 Hz, 1H, H3"), 3.56 (s, 3H, OMe),
column chromatography over SiO2 gel (EtOAc/n-hexane
-
30:70 / 100:0). TLC (EtOAc/n-hexane 1:4): Rf ¼ 0.1; 1H NMR
3.46 (s, 3H, H7’); 13C NMR (126 MHz, CDCl3)
d 156.5 (C2’), 153.4
(500 MHz, CDCl3) d 7.99 (s, 1H, H4), 7.91e7.88 (m, 2H, H8" and H6’),
7.62e7.60 (m, 1H, H5"), 7.54e7.48 (m, 2H, H6" and H7"), 7.39 (dd,
J ¼ 10.3, 9.2 Hz, 1H, H3"), 7.26e7.21 (m, 2H, H4" and H5’), 7.14 (dd,
J ¼ 9.5, 2.1 Hz, 1H, H2"), 6.83 (dt, J ¼ 9.4, 1.2 Hz, 1H, H4’), 6.69 (dd,
J ¼ 8.4,1.0 Hz,1H, H3’), 3.16 (s, 3H, OMe); 13C NMR (126 MHz, CDCl3)
(C2"), 136.1 (C5), 133.6 (C4), 130.7 (C4"), 130.5 (C6’), 130.3 (C4’),
128.0 (C6"), 126.4 (C1"), 120.5 (C5"), 120.3 (C5’), 116.7 (C1’), 112.0
(C3"), 110.9 (C3’), 55.4 (C7’), 55.0 (OMe); IR (neat) nmax 2932, 2838,
1602, 1506, 1471, 1465, 1436, 1283, 1246, 1108, 1022, 989, 753 cmꢂ1
;
MS (ESI þ ve) m/z 282 ([MþH]þ); HRMS (ESI þ ve TOF) calcd for
d
156.4 (C2’), 136.6 (C8a"), 134.2 (C4a"), 134.1 (C1’), 133.8 (C4), 131.1
C
16H16N3O2 282.1243, found 282.1244 ([MþH]þ).
(C5"), 130.9 (C2"), 130.0 (C8"), 129.6 (C4"), 128.0 (C6’), 127.5 (C7"),
126.8 (C6"), 124.8 (C3"), 124.1 (C1"), 123.5 (C5), 120.5 (C4’), 115.7
(C5’), 110.8 (C3’), 54.5 (OMe); IR (neat) nmax 3051, 2928, 1597, 1481,
1464, 1270, 1103, 1050, 1023, 955, 802, 754 cmꢂ1; MS (ESI þ ve) m/z
302 ([MþH]þ); HRMS (ESI þ ve TOF) calcd for C19H16N3O 302.1293,
found 302.1305 ([MþH]þ).
4.19. 1-(2-Methoxyphenyl)-5-(naphthalen-1-yl)-1H-1,2,3-triazole
(5d)
This compound was prepared according to the general proced-
ure B using 1-azido-2-methoxybenzene (50 mg, 0.33 mmol), 1-
ethynylnaphthalene (56 mg, 0.37 mmol) and a 48 h reaction time
to give 5d (7 mg, 7%) as a pale brown waxy solid after purification
by column chromatography over SiO2 gel (EtOAc/n-hexane -
30:70 / 100:0). TLC (EtOAc/n-hexane 1:4): Rf ¼ 0.2; 1H NMR
4.16. 5-Isopentyl-1-(2-methoxyphenyl)-1H-1,2,3-triazole (5a)
This compound was prepared according to the general proced-
ure B using 1-azido-2-methoxybenzene (20 mg, 0.13 mmol), 5-
methyl-1-hexyne (14 mg, 0.15 mmol) and a 12 h reaction time to
give 5a (28 mg, 87%) as a brown oil after purification by column
chromatography over SiO2 gel (EtOAc/n-hexane - 30:70 / 100:0).
TLC (EtOAc/n-hexane 2:3): Rf ¼ 0.5; 1H NMR (500 MHz, CDCl3)
(500 MHz, CDCl3)
d 7.96 (s, 1H, H4), 7.88e7.81 (m, 3H, H4’, H7’ and
H10’), 7.50e7.44 (m, 3H, H5’, H6’ and H9’), 7.34e7.28 (m, 2H, H6"
and H8’), 7.16 (dd, J ¼ 7.1, 1.1 Hz, 1H, H4"), 6.96 (dt, J ¼ 7.7, 1.1 Hz, 1H,
H5"), 6.72 (dd, J ¼ 8.3, 0.9 Hz, 1H, H3"), 3.14 (s, 3H, OMe); 13C NMR
d
7.55 (s, 1H, H4), 7.50e7.47 (m, 1H, H6"), 7.32 (dd, J ¼ 7.9, 1.7 Hz, 1H,
(126 MHz, CDCl3)
d 153.2 (C2"), 137.4 (C5), 134.2 (C1’), 133.3 (C4),
H4"), 7.11e7.06 (m, 2H, H3"and H500), 3.78 (s, 3H, OMe), 2.47 (t,
J ¼ 7.9 Hz, 2H, H1’), 1.56e1.41 (m, 3H, H2’ and H3’), 0.82 (d,
131.6 (C3’), 131.0 (C4"), 129.4 (C6"), 128.2 (C2’), 128.1 (C7’), 127.6
(C10’), 126.7 (C8’), 126.2 (C9’), 125.2 (C1"), 125.1 (C4’), 124.9 (C5’),
124.7 (C6’), 120.6 (C5"), 111.8 (C3"), 54.9 (OMe); IR (neat) nmax 2925,
2849,1602, 1506, 1437, 1275, 1248, 1048, 1021, 977, 803, 778,
755 cmꢂ1; MS (ESI þ ve) m/z 302 ([MþH]þ); HRMS (ESI þ ve TOF)
calcd for C19H16N3O 302.1293, found 302.1297 ([MþH]þ).
J ¼ 8.0 Hz, 6H, H4’ and H5’); 13C NMR (126 MHz, CDCl3)
d 154.2
(C2"), 140.0 (C5), 131.5 (C4"), 131.3 (C4), 128.7 (C6"), 125.1 (C1"),
120.9 (C5"), 112.1 (C3"), 55.8 (OMe), 36.9 (C2’), 27.4 (C3’), 22.1 (C4’/
C5’), 21.0 (C1’); IR (neat) nmax 2954, 2868, 1602, 1506, 1473, 1285,
1251, 1233, 1122, 1043, 1021, 750 cmꢂ1; MS (ESI þ ve) m/z 246
([MþH]þ; HRMS (ESI þ ve TOF) calcd for C14H20N3O 246.1606,
found 246.1618 ([MþH]þ).
4.20. 4-Isopentyl-1-(2-methoxynaphthalen-1-yl)-1H-1,2,3-triazole
(6a)
4.17. 5-Cyclohexyl-1-(2-methoxyphenyl)-1H-1,2,3-triazole (5b)
This compound was prepared according to the general proced-
ure C using 1-azido-2-methoxynaphthalene (50 mg, 0.25 mmol), 5-
methyl-1-hexyne (46 mg, 0.5 mmol) and a 36 h reaction time to
give 6a (63 mg, 85%) as a brown waxy solid after purification by
This compound was prepared according to the general proced-
ure B using 1-azido-2-methoxybenzene (50 mg, 0.33 mmol),
ethynylcyclohexane (40 mg, 0.37 mmol) and a 12 h reaction time to
give 5b (66 mg, 78%) as a yellow waxy solid after purification by
column chromatography over SiO2 gel (EtOAc/n-hexane
-
40:60 / 100:0). TLC (EtOAc/n-hexane 1:4): Rf ¼ 0.4; 1H NMR
column chromatography over SiO2 gel (EtOAc/n-hexane
-
(500 MHz, CDCl3)
d
7.98 (d, J ¼ 11.4 Hz, 1H, H8"), 7.83 (d, J ¼ 9.5 Hz,
20:80 / 100:0). TLC (EtOAc/n-hexane 2:3): Rf ¼ 0.5; 1H NMR
1H, H5"), 7.52 (s, 1H, H5), 7.46e7.35 (m, 3H, H6", H7" and H4"), 7.16
6

M.K. Mahadari, A.J. Tague, P.A. Keller et al.
Tetrahedron 81 (2021) 131916
(dd, J ¼ 10.5, 0.9 Hz, 1H, H3"), 3.87 (s, 3H, OMe), 2.91e2.87 (m, 2H,
H1’), 1.73e1.69 (m, 3H, H2’ and H3’), 0.99 (d, J ¼ 7.9, 6H, H4’ and
time to give 6d (74 mg, 92%) as an off-white solid after purification
by column chromatography over SiO2 gel (EtOAc/n-hexane -
30:70 / 100:0). M.P: 109e111 ꢀC. TLC (EtOAc/n-hexane 1:4):
H5’); 13C NMR (126 MHz, CDCl3)
d 152.1 (C2"), 131.6 (C8a"), 131.2
(C4), 128.6 (C4"), 128.2 (C4a"), 127.8 (C5"), 124.5 (C7"), 124.3 (C8"),
122.1 (C6"), 121.4 (C5), 119.7 (C3"), 113.1 (C1"), 56.7 (OMe), 38.4
(C2’), 27.8 (C1’), 23.7 (C3’), 22.4 (C4’ and C5’); IR (neat) nmax 2952,
2869, 2352, 1630, 1600, 1507, 1457, 1365, 1275, 1255, 1149, 1110,
1064, 1041, 905, 809, 747 cmꢂ1; MS (ESI þ ve) m/z 296 ([MþH]þ);
HRMS (ESI þ ve TOF) calcd for C18H22N3O 296.1763, found 296.1771
([MþH]þ).
Rf ¼ 0.4; 1H NMR (500 MHz, CDCl3)
d
8.00 (d, J ¼ 9.1 Hz, 1H, H8"),
7.97 (s, 1H, H5), 7.94e7.91 (m, 2H, H2’/H6’), 7.84 (d, J ¼ 8.0 Hz, 1H,
H5"), 7.46e7.37 (m, 3H, H6", H7" and H4"), 7.25 (d, J ¼ 8.3 Hz, 1H,
H3"), 7.14 (t, J ¼ 8.6 Hz, 2H, H30-F/H50-F), 3.88 (s, 3H, OMe); 13C NMR
(126 MHz, CDCl3)
d
162.6 (d, 1JC-F ¼ 198.7 Hz, C4’), 152.1 (C2"), 146.4
2
(C4), 132.0 (C8a"), 131.0 (C4a’’), 128.5 (d, JC-F ¼ 18.1 Hz C2’/C6’),
127.9 (C4"),127.5 (C5"), 127.5 (C5),126.8 (d, 3JC-F ¼ 2.0 Hz, C1’), 124.7
(C7"), 123.3 (C8"), 121.3 (C6"), 119.2 (C3"), 115.9 (C3’), 115.7 (C5’),
113.0 (C1"), 56.7 (OMe); IR (neat) nmax 2919, 2849, 1714, 1598, 1507,
1482, 1457, 1276, 1258, 1223, 1218, 1146, 1079, 1032, 838, 811, 796,
755, 658 cmꢂ1. MS (ESI þ ve) m/z 320 ([MþH]þ); HRMS (ESI þ ve
TOF) calcd for C19H15FN3O 320.1199, found 320.1213 ([MþH]þ).
4.21. 4-Cyclohexyl-1-(2-methoxynaphthalen-1-yl)-1H-1,2,3-
triazole (6b)
This compound was prepared according to the general proced-
ure C using 1-azido-2-methoxynaphthalene (50 mg, 0.25 mmol),
ethynylcyclohexane (54 mg, 0.5 mmol) and a 48 h reaction time to
give 6b (62 mg, 81%) as a pale yellow waxy solid after purification
by column chromatography over SiO2 gel (EtOAc/n-hexane -
30:70 / 100:0). TLC (EtOAc/n-hexane 1:4): Rf ¼ 0.4; 1H NMR
4.24. 1-(2-Methoxynaphthalen-1-yl)-4-(4-nitrophenyl)-1H-1,2,3-
triazole (6e)
This compound was prepared according to the general proced-
ure C using 1-azido-2-methoxynaphthalene (50 mg, 0.25 mmol), 1-
ethynyl-4-nitrobenzene (74 mg, 0.5 mmol) and a 16 h reaction time
to give 6e (69 mg, 79%) as a yellow solid after purification by col-
(500 MHz, CDCl3)
d
7.97 (d, J ¼ 9.1 Hz, 1H, H8"), 7.83e7.81 (m, 1H,
H5"), 7.48 (s, 1H, H5), 7.44e7.36 (m, 2H, H6" and H7"), 7.35 (d,
J ¼ 9.1 Hz, 1H, H4"), 7.14 (dd, J ¼ 8.5, 0.7 Hz, 1H, H3"), 3.86 (s, 3H,
OMe), 2.93 (tt, J ¼ 11.3, 3.5 Hz, 1H, H1’), 2.24e2.20 (m, 2H, H2’ and
H3’),1.86 (dt, J ¼ 6.7, 3.4 Hz, 2H, H6’ and H5’),1.77e1.74 (m,1H, H4’),
umn chromatography over SiO2 gel (EtOAc/n-hexane
-
30:70 / 100:0). M.P: 118e120 ꢀC. TLC (EtOAc/n-hexane 1:4):
1.58e1.42 (m, 4H, H2’, H6’, H4’ and H5’), 1.35e1.25 (m, 1H, H3’); 13
C
Rf ¼ 0.3; 1H NMR (500 MHz, CDCl3)
d
8.33 (d, J ¼ 8.8 Hz, 2H, H30 and
H50), 8.18 (s, 1H, H5), 8.14 (d, J ¼ 8.8 Hz, 2H, H2’ and H6’), 8.07 (d,
J ¼ 9.1 Hz, 1H, H8"), 7.89 (d, J ¼ 8.0 Hz, 1H, H5"), 7.50e7.45 (m, 2H,
H6" and H7"), 7.43 (d, J ¼ 9.1 Hz, 1H, H4"), 7.26 (d, J ¼ 8.1 Hz, 1H,
NMR (126 MHz, CDCl3)
d 153.1 (C2"), 152.1 (C4), 131.6 (C8a"), 131.3
(C4"), 128.6 (C4a"), 128.2 (C5"), 127.7 (C7"), 124.5 (C8"), 123.1 (C5),
121.5 (C6"), 119.8 (C3"), 113.1 (C1"), 56.7 (OMe), 35.3 (C1’), 33.0 (C2’
and C3’), 26.2 (C4’), 26.1 (C6’ and C5’); IR (neat) nmax 2923, 2850,
1739, 1631, 1599, 1487, 1512, 1448,1364,1252, 1235,1069, 1028, 809,
796, 760, 652 cmꢂ1; MS (ESI þ ve) m/z 308 ([MþH]þ); HRMS
(ESI þ ve TOF) calcd for C19H22N3O 308.1763, found 308.1775
([MþH]þ).
H3"), 3.93 (s, 3H, OMe); 13C NMR (126 MHz, CDCl3)
d 152.1 (C2"),
147.3 (C4), 145.2 (C8a"), 136.9 (C1’), 132.3 (C4’), 130.9 (C400), 128.6
(C4a"), 128.5 (C5"), 128.0 (C2’), 126.2 (C6’), 126.1 (C7"), 125.1 (C5),
124.8 (C8"), 124.3 (C3’), 124.1 (C5’), 121.1 (C6"), 118.9 (C3"), 112.8
(C1"), 56.7 (OMe); IR (neat) nmax 3162, 2943, 2845, 1603, 1510, 1335,
1276, 1257, 1108, 1079, 1059, 1028, 852, 801, 757, 753 cmꢂ1. MS
(ESI þ ve) m/z 347 ([MþH]þ); HRMS (ESI þ ve TOF) calcd for
4.22. 1-(2-Methoxynaphthalen-1-yl)-4-(2-methoxyphenyl)-1H-
1,2,3-triazole (6c)
C
19H15N4O3 347.1144, found 347.1152 ([MþH]þ).
This compound was prepared according to the general proced-
ure C using 1-azido-2-methoxynaphthalene (50 mg, 0.25 mmol), 1-
ethynyl-2-methoxybenzene (66 mg, 0.5 mmol) and a 36 h reaction
time to give 6c (74 mg, 89%) as a light brown solid after purification
by column chromatography over SiO2 gel (EtOAc/n-hexane -
40:60 / 100:0). M.P: 112e114 ꢀC. TLC (EtOAc/n-hexane 1:4):
4.25. 1-(2-Methoxynaphthalen-1-yl)-4-(naphthalen-1-yl)-1H-
1,2,3-triazole (6f)
This compound was prepared according to the general proced-
ure C using 1-azido-2-methoxynaphthalene (50 mg, 0.25 mmol), 1-
ethynylnaphthalene (76 mg, 0.5 mmol) and a 12 h reaction time to
give 6f (80 mg, 91%) as a pale yellow waxy solid after purification by
Rf ¼ 0.4; 1H NMR (500 MHz, CDCl3)
d
8.54 (dd, J ¼ 7.7, 1.7 Hz, 1H,
H2’), 8.33 (s, 1H, H5), 8.02 (d, J ¼ 9.1 Hz, 1H, H8"), 7.87e7.85 (m, 1H,
H5"), 7.46e7.39 (m, 3H, H6", H7" and H4"), 7.36e7.33 (m, 1H, H4’),
7.25e7.23 (m, 1H, H3’), 7.15 (dt, J ¼ 7.6, 1.0 Hz, 1H, H5’), 7.00 (dd,
J ¼ 8.3, 0.6 Hz,1H, H3"), 3.90 (s, 3H, OMe), 3.89 (s, 3H, H7’); 13C NMR
column chromatography over SiO2 gel (EtOAc/n-hexane -
40:60 / 100:0). TLC (EtOAc/n-hexane 1:4): Rf ¼ 0.3; 1H NMR
(500 MHz, CDCl3)
d 8.58e8.55 (m, 1H, H10’), 8.09 (s, 1H, H5), 8.02
(d, J ¼ 10.7 Hz, 1H, H8"), 7.94e7.86 (m, 4H, H5", H2’, H4’ and H7’),
(126 MHz, CDCl3)
d 155.6 (C2"), 152.3 (C6’), 142.7 (C4), 131.8 (C8a"),
7.60e7.49 (m, 4H, H6", H7", H9’ and H3’), 7.45e7.38 (m, 3H, H4",
H3" and H8’), 3.93 (s, 3H, OMe); 13C NMR (126 MHz, CDCl3)
d 152.1
131.2 (C2’), 128.8 (C400), 128.8 (C4’), 128.2 (C4a’’), 127.8 (C5"), 127.6
(C7"), 126.9 (C5), 124.5 (C8"), 121.4 (C6"), 121.0 (C3’), 119.6 (C1’),
119.3 (C3"), 113.0 (C1"), 110.7 (C5’), 56.7 (C7’), 55.2 (OMe); IR (neat)
nmax 2922, 2851, 1601, 1506, 1486, 1465, 1275, 1246, 1076, 1058,
1032, 1020, 795, 751, 742, 669 cmꢂ1; MS (ESI þ ve) m/z 332
([MþH])þ; HRMS (ESI þ ve TOF) calcd for C20H18N3O2 332.1399,
found 332.1394 ([MþH]þ).
(C2"), 146.2 (C4), 134.0 (C1’), 131.9 (C8a"), 131.2 (C4b0), 131.1 (C8b0),
128.9 (C4a"), 128.7 (C400), 128.5 (C5’), 128.4 (C8’), 128.0 (C4’), 127.9
(C500), 127.4 (C7’), 126.6 (C7"), 126.5 (C5), 126.0 (C6’), 125.5 (C8"),
125.4 (C3’), 124.7 (C6"), 121.5 (C2’), 119.4 (C3"), 113.0 (C1"), 56.8
(OMe); IR (neat) nmax 3137, 2936, 2846,1629,1506,1462,1390,1278,
1264, 1064, 1044, 1021, 905, 803, 778, 749, 663 cmꢂ1. MS (ESI þ ve)
m/z 352 ([MþH]þþ); HRMS (ESI þ ve TOF) calcd for C23H18N3O
352.1450, found 352.1459 ([MþH]þ).
4.23. 4-(4-Fluorophenyl)-1-(2-methoxynaphthalen-1-yl)-1H-1,2,3-
triazole (6d)
4.26. 2-(1-(2-Methoxynaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)
This compound was prepared according to the general proced-
ure C using 1-azido-2-methoxynaphthalene (50 mg, 0.25 mmol), 1-
ethynyl-4-fluorobenzene (60 mg, 0.5 mmol) and a 12 h reaction
propan-2-ol (6g)
This compound was prepared according to the general
7

M.K. Mahadari, A.J. Tague, P.A. Keller et al.
Tetrahedron 81 (2021) 131916
procedure
C
using 1-azido-2-methoxynaphthalene (50 mg,
NMR (500 MHz, CDCl3)
d
8.50 (s, 1H, H5), 8.40 (dd, J ¼ 9.6, 2.2 Hz,
0.25 mmol), 2-methylbut-3-yn-2-ol (43 mg, 0.5 mmol) and a 12 h
reaction time to give 6g (61 mg, 86%) as a yellow solid after puri-
fication by column chromatography over SiO2 gel (EtOAc/n-hexane
- 40:60 / 100:0). M.P: 122e124 ꢀC; TLC (EtOAc/n-hexane 1:4):
1H, H2’), 7.74 (dd, J ¼ 9.8, 2.1 Hz, 1H, H6"), 7.41e7.37 (m, 1H, H4"),
7.32e7.28 (m, 1H, H5"), 7.10e7.04 (m, 3H, H3’, H4’ and H5’), 6.96
(dd, J ¼ 10.4, 1.0 Hz, 1H, H3"), 3.90 (s, 3H, OMe), 3.84 (s, 3H, H7’); 13
C
NMR (126 MHz, CDCl3)
d 155.7 (C6’), 151.6 (C2"), 142.6 (C4), 130.0
Rf ¼ 0.2; 1H NMR (500 MHz, CDCl3)
d
7.98 (d, J ¼ 9.1 Hz, 1H, H8"),
(C2’), 128.8 (C400), 127.7 (C4’), 126.5 (C600), 125.7 (C3’), 125.2 (C5),
121.0 (C5"), 121.0 (C1’), 119.5 (C3"), 112.3 (C1"), 110.9 (C5’), 55.9
(OMe), 55.4 (C7’); IR (neat) nmax 2936, 2838, 1601, 1506, 1489, 1465,
1287, 1247, 1161, 1130, 1078, 1022, 748, 689 cmꢂ1. MS (ESI þ ve) m/z
282 ([MþH]þ); HRMS (ESI þ ve TOF) calcd for C16H16N3O2 282.1243,
found 282.1234 ([MþH]þ).
7.84e7.82 (m, 1H, H5"), 7.69 (s, 1H, H5), 7.44e7.38 (m, 2H, H6" and
H7"), 7.36 (d, J ¼ 9.1 Hz, 1H, H4"), 7.14 (dd, J ¼ 8.4, 0.8 Hz, 1H, H3"),
3.87 (s, 3H, OMe), 2.94 (brs, 1H, eOH), 1.77 (s, 6H, H2’ and H3’); 13
C
NMR (126 MHz, CDCl3)
d 155.0 (C2"), 152.1 (C8a"), 131.8 (C4), 131.1
(C4"), 128.5 (C4a"), 128.3 (C5"), 127.8 (C7"), 124.6 (C8"), 123.0 (C5),
121.3 (C6"), 119.4 (C300), 113.0 (C1"), 68.6 (C1’), 56.6 (OMe), 30.5 (C2’
and C3’); IR (neat) nmax 3333, 2981, 2919, 2849, 1632, 1511, 1456,
1359, 1275, 1219, 1143, 1067, 1045, 805, 776, 757 cmꢂ1. MS (ESI þ ve)
m/z 284 ([MþH]þ); HRMS (ESI þ ve TOF) calcd for C16H18N3O2
284.1399, found 284.1396 ([MþH]þ).
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
4.27. 4-Isopentyl-1-(2-methoxyphenyl)-1H-1,2,3-triazole (7a)
Acknowledgments
This compound was prepared according to the general proced-
ure C using 1-azido-2-methoxybenzene (50 mg, 0.33 mmol), 5-
methyl-1-hexyne (65 mg, 0.66 mmol) and a 12 h reaction time to
give 7a (78 mg, 96%) as a pale-yellow oil after purification by col-
We thank the NHMRC (APP1124032) for supporting this
research. MKM thanks UOW for a University Postgraduate Award
and International Postgraduate Tuition Award scholarships.
umn chromatography over SiO2 gel (EtOAc/n-hexane
-
20:80 / 100:0). TLC (EtOAc/n-hexane 1:4): Rf ¼ 0.5; 1H NMR
Appendix A. Supplementary data
(500 MHz, CDCl3)
d
7.83 (s, 1H, H5), 7.73 (dd, J ¼ 10.3, 2.2 Hz, 1H,
H6"), 7.40e7.35 (m, 1H, H4"), 7.08e7.04 (m, 2H, H500 and H300), 3.86
(s, 3H, OMe), 2.82e2.78 (m, 2H, H1’), 1.70e1.60 (m, 3H, H2’ and
H3’), 0.96 (d, J ¼ 7.8 Hz, 6H, H4’ and H5’); 13C NMR (126 MHz, CDCl3)
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131916.
d
151.4 (C2"), 147.9 (C4), 129.8 (C4"), 126.5 (C6"), 125.4 (C5"), 122.7
References
(C5), 121.1 (C3"), 112.2 (C1"), 55.9 (OMe), 38.4 (C2’), 27.7 (C1’), 23.6
(C3’), 22.4 (C4’ and C5’); IR (neat) nmax 2953, 2868, 1601, 1506, 1473,
1285,1251,1233,1122, 1043,1021, 985, 795, 750 cmꢂ1. MS (ESI þ ve)
m/z 246 ([MþH]þ); HRMS (ESI þ ve TOF) calcd for C14H20N3O
246.1606, found 246.1617 ([MþH]þ).
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(500 MHz, CDCl3)
d
7.79 (d, J ¼ 0.7 Hz, 1H, H5), 7.75e7.73 (m, 1H,
H6"), 7.40e7.35 (m, 1H, H4"), 7.08e7.04 (m, 2H, H500 and H300), 3.86
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d 153.0
(C2"), 151.1 (C4), 129.7 (C4"), 126.6 (C6"), 125.5 (C5"), 121.5 (C5),
121.1 (C3"), 112.2 (C1"), 55.9 (OMe), 35.3 (C1’), 33.0 (C2’ and C3’),
26.2 (C4’), 26.1 (C5’ and C6’); IR (neat) nmax 2929, 2849, 1602, 1504,
1473, 1458, 1282, 1248, 1181, 1124, 1049, 1021, 748 cmꢂ1. MS
(ESI þ ve) m/z 258 ([MþH]þ); HRMS (ESI þ ve TOF) calcd for
C
15H20N3O 258.1606, found 258.1602 ([MþH]þ).
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