Chemoselective Organoclick-Click Sequence

Article abstract of DOI:10.1055/s-0037-1610192

A highly chemoselective bis-triazole synthesis based on a sequence organocatalyzed click reaction/copper-catalyzed click reaction is described in this paper. A range of bis-azides react with various ketones using proline catalysis through the aryl azide moiety while the alkyl azide one remains available for a metal-catalyzed triazole synthesis.

Full text of DOI:10.1055/s-0037-1610192

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–I
feature
A
en
M. Belkheira et al.
Feature
Synthesis
Chemoselective Organoclick–Click Sequence
Mokhtaria Belkheiraa,b,c
Douniazad El Abedb
Jean-Marc Ponsa
Chemoselective and
Regioselective Synthesis
of Bis-Triazoles
( )n
Organoclick
Reaction
N
N
CuAAC
N
N
N
N
Cyril Bressy*a
0
0
0
0
0-
0
0
3
2-
9
4
4
8-
2
7
4
R'
R
( )m
Bis-triazoles
1
2
O
a Aix-Marseille Université, CNRS, Centrale Marseille, iSm2,
Marseille, France
cyril.bressy@univ-amu.fr
b Université Oran 1 Ahmed Ben Bella, Laboratoire de Chimie
Fine, Département de Chimie, Faculté des Sciences Exactes
et Appliquées, B.P.1524, El M’naouer, Oran 31100, Algérie
c Université Tahri Mohamed-Bechar, B.P. 417, Bechar 08000,
Algérie
R'
( )n
N3
R
( )m
N3
Dissymmetrical
Diazides
Unactivated
Ketones
Alkynes
Published as part of the Special Section on the 26th French–
Japanese Symposium on Medicinal and Fine Chemistry
Received: 16.05.2018
Accepted: 17.05.2018
Published online: 19.07.2018
DOI: 10.1055/s-0037-1610192; Art ID: ss-2018-z0345-fa
Wittig.14 More recently organocatalyzed triazole synthe-
sis,15 based on the cycloaddition between enamine,16 eno-
late,17 or nitroolefin18 with azide, emerged. In 2016, De-
haen’s group developed an efficient three-component tri-
azole synthesis between a ketone, a primary amine, and p-
nitrophenyl azide (Scheme 1).19
Abstract A highly chemoselective bis-triazole synthesis based on a se-
quence organocatalyzed click reaction/copper-catalyzed click reaction
is described in this paper. A range of bis-azides react with various ke-
tones using proline catalysis through the aryl azide moiety while the al-
kyl azide one remains available for a metal-catalyzed triazole synthesis.
Thermal 1,3-Dipolar Cycloaddition (Huisgen)
N
N
R'
R'
N
N
Δ
N
N
+
R
+
N3 R'
Key words triazoles, organocatalysis, organoclick reaction, click reac-
R
R
tion, chemoselectivity
Copper-Catalyzed Alkyne–Azide Cycloaddition - CuAAC (Meldal, Sharpless)
N
R'
Cu cat.
N
N
The discovery of new chemoselective transformations is
a stimulating research area in organic chemistry.1 These re-
actions present the precious advantage to avoid the mask-
ing of functional group while another one is transformed.
The development of such transformations represents a cru-
cial challenge in multi-step synthesis to privilege short syn-
thetic sequence but could also be highly valuable for se-
quential cross-coupling,2 multicatalytic reactions,3 or in li-
gation in various reaction media.4
R
+
N3 R'
R
Ruthenium-Catalyzed Alkyne–Azide Cycloaddition - RuAAC (Fokin)
N
R'
Ru cat.
N
N
R
+
N3 R'
R
Strain-Promoted Alkyne–Azide Cycloaddition - SPAAC (Wittig, Bertozzi)
R'
N
In this last field, the preparation of triazoles played a pi-
oneer and pivotal role (Scheme 1). Since the independent
reports by the groups of Meldal5 and Sharpless6 about the
highly regioselective copper-catalyzed alkyne–azide Huis-
gen cycloaddition7 (CuAAC) under very mild conditions, the
synthesis of this aromatic nitrogenated heterocycle became
an intensive field of research. Indeed this reaction abusively
named ‘click reaction’ in reference to the Sharpless con-
cept,8 is used as a powerful tool in material sciences9 as well
as in chemical biology.10 The regioselectivity could be re-
versed towards the synthesis of the 1,5-disubstituted cyclo-
adduct using ruthenium-catalyzed11 (RuAAC) or base-cata-
lyzed12 reaction. Strain-promoted cycloadditions (SPAAC)
were elegantly used in a context of bioorthogonal ligation
by the Bertozzi’s group13 based on an initial report by
+
N3 R'
R
N
R
N
OrganoClick (Ramachary, Wang, Bressy)
R'
N
O
N
amine cat.
N
or
N3 R'
+
R
R
DBU cat.
Multi-components Triazole Synthesis (Dehaen)
O
R'
N
N
then H+
N
+
R
R'-NH2
+
N3
NO2
R
Scheme 1 Main triazole syntheses
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

B
M. Belkheira et al.
Feature
Synthesis
Few studies examined the chemoselectivity of bis-tri-
azole20 synthesis through alkyne–azide cycloaddition using
either diyne or diazide partners (Scheme 2). Several strate-
gies were adopted to use chemoselectively diynes by pro-
tection of one alkyne with bulky group21 or by activation
and/or deactivation of alkynes by neighboring effect.22 Re-
cently Wright and Couty developed a bis-triazole synthesis
using an azide bearing a latent alkyne functionality.23 Even
fewer studies were conducted on the use of diazides. An ef-
ficient double CuAAC was performed, by Zhu’s group, on
dissymmetrical diazides featuring a chelating group.24
In this paper, we describe the unprecedented chemo-
selective coupling between a ketone 1 and an alkyne 4 with
a dissymmetrical diazide 2 using an organoclick and a click
reaction (Scheme 3). In contrast to previous approaches,
this strategy does not require protection/deprotection
steps.
First, we determined the order of the sequence: organo-
click, then click reactions, or the reverse. We planned to use
diazide 2a bearing an aryl azide and a benzyl azide moieties
to evaluate the chemoselectivity of each step (Scheme 4).
The CuAAC approach, performed under Zhu’s conditions25
with 1 equivalent of propargyl alcohol (4a), exhibits a mod-
Biographical Sketches
Mokhtaria Belkheira studied
at the Université d’Oran, Es-
Sénia in Algeria where she ob-
tained her Magister’s degree in
2003 under the supervision of
Prof. Douniazad El Abed. In
2008, she joined as doctoral
student in the group of Prof.
Cyril Bressy and Prof. Jean-Marc
Pons in Marseille, France where
she developed a new organo-
catalyzed triazole synthesis. She
obtained her Ph.D. in 2012 and
was nominated Maître de Con-
férences at the Université Tahri-
Mohamed in Béchar-Algeria.
Douniazad El Abed studied at
the Université d’Oran Es-Sénia
where she obtained her DEA un-
der the supervision of Prof. Fer-
nand Texier. She then entered
as an Assistant at the Université
d’Oran Es-Sénia and defended a
Thèse de Doctorat de 3ème Cycle
in 1977. In 1982, she joined the
group of Prof. Maurice Santelli
in the Université d’Aix-Marseille
and defended a Thèse d’Etat in
1986. Back in Algeria, she
worked on the extraction of
natural products and synthesis
of heterocycles (triazoles and
triazolines). Since 1989 she
holds a position of Professor at
Université d’Oran Es-Sénia. Her
research focuses on synthesis of
nitrogenous bioactive mole-
cules obtained under environ-
mentally-friendly
conditions
that comply with the principles
of green chemistry by synthesis
or extraction.
Jean-Marc Pons studied at the
Université de Provence in Mar-
seille where he obtained his
Ph.D. in 1982 under the super-
vision of Prof. Maurice Santelli.
He then entered the CNRS as
Chargé de Recherches and de-
fended a Thèse d’Etat in 1987
on low valent transition metal
complexes in organic synthesis.
In 1988, he spent a year as a
post-doctoral fellow in the
group of Prof. Philip Kocienski at
Southampton, where he worked
on the total synthesis of natural
products. He was dean of the
faculty of sciences of Aix-Mar-
seille Université from 2008 to
2017. He is currently involved in
organocatalyzed
tions.
transforma-
Cyril Bressy studied at the
Université Claude Bernard in
Lyon where he obtained his
Ph.D. in 2004 under the super-
vision of Prof. Olivier Piva. He
then joined as a post-doctoral
researcher in the group of Prof.
Mark Lautens in Toronto, Cana-
da where he developed a novel
variant of the Catellani reaction.
Back in France, he worked on a
total synthesis project in Paris at
Ecole Supérieure de Physique et
Chimie Industrielle (ESPCI-Paris-
Tech) with Prof. Janine Cossy.
From 2006 he held a position of
Maître de Conférences at Aix-
Marseille Université (AMU). He
obtained in 2012 a Habilitation
à Diriger les Recherches (HDR)
and was promoted as full pro-
fessor in 2015 at AMU. His re-
search
focuses
on
total
synthesis using desymmetriza-
tion strategies and organocata-
lyzed transformations.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

C
M. Belkheira et al.
Feature
Synthesis
HO
HO
N
From diynes
Monoprotection of diynes (Aucagne-Leigh, Fiandanese)
Deprotection
N
N
N
N3
N
N3
N
OH
Cu(OAc)2
(5 mol%)
CuAAC
N
N
CuAAC
N
N
N
N
+
+
+
R3Si
N3 R'
N3
R
N
N
R
N
R
R3Si
t-BuOH, rt
4 d
R'
N
N
N3
N3
(De)Activation of alkynes (Grée, Girard, Beal, Watson-Burley)
N
N
O
O
N
N
OH
OH
O
N
N
N
N
N
N
N
N
4a
2a
6
7
8
CuAAC
N3 R'
Δ
N
H
N
N
H
N
H
N3
R
R
R'
R
1 equiv
5 equiv
1 equiv
1 equiv
24%
0%
73%
62%
3%
38%
From diazidoalkynes
Scheme 4 Evaluation of the click reaction chemoselectivity using
propargyl alcohol (4a) and diazide 2a
Masked alkyne (Wright-Couty)
Unmasking
alkyne then
CuAAC
N
N
N
N
FG
CuAAC
N3 R'
FG
N3
N
R
N
azide 2a and 1 equivalent of cyclohexanone (1a), led exclu-
sively to triazole 3aa in 56% yield. The presence of regioiso-
mer 9 or bistriazole 10 was not detected even with larger
amounts of ketone (5 equiv). An excess of ketone raised the
yield of aryltriazole 3aa up to 71%.
N
N
N
R
R
R'
latent alkyne
From diazides
R'
N
N
Chelating group assistance (Zhu)
N3
N
N3
CuAAC
CuAAC
R'
N
N
N
N
R
N
N3
N
N3
N
N
O
N
CO2H
cat.
N
N
N
N3
chelating group
H
N
N
R
R
N
N
+
+
+
CH2Cl2, 80 °C
MW, 1 h
Scheme 2 Chemoselective strategies to obtain bis-triazoles
N3
N
N
N3
N
N
N
N
Dissymmetrical
Diazides
1a
2a
3aa
9
10
1 equiv
5 equiv
1 equiv
1 equiv
56%
71%
0%
0%
0%
0%
( )n
( )n
( )n
N3
CuAAC
O
N3
N3
N
N
N
N
N
N
2y
N
Scheme 5 Evaluation of the organoclick reaction chemoselectivity using
cyclohexanone (1a) and diazide 2a
N
R
N
( )m
R'
R
R'
R
( )m
( )m
CO2H
cat.
N
4z
H
Unactivated
Ketones
Azidotriazoles
Bis-triazoles
These preliminary results exhibited the complete che-
moselectivity of the organoclick reaction in favor of aryl
azides. As a consequence, the coupling sequence should
have begun with the organoclick reaction and be followed
by the click reaction. The scope of this sequence was ex-
plored using the diazides, ketones, and alkynes depicted in
Figure 1.
The scope of the organoclick reaction between diazides
and ketones was first examined (Scheme 6). Cyclohexanone
(1a) was coupled with diazides 2a–e leading to the azido-
triazoles 3aa–ae. The formation of azidoanilines 11a–e was
observed during the course of the reaction resulting from a
selective reduction of the aromatic azide function. The
amount of this side-product (yields between parentheses)
seems to increase when the two azide functions become
closer (para < meta < ortho). Other cyclic and acyclic ke-
1x
3xy
5xyz
Scheme 3 Bis-triazole synthesis through organoclick–click sequence
erate chemoselectivity in favor of the benzyl azide moiety
(73%) leading to the formation of triazole 7. Nevertheless
significant amounts of triazole 6 were obtained through the
cycloaddition involving the aryl azide function (24%). Nota-
bly, only 3% of bistriazole 8 was formed under these condi-
tions. Using 5 equivalents of the same propargyl alcohol
(4a) led to the formation of monotriazole 7 in 62% yield, but
this was accompanied by a larger amount of bistriazole 8.
The organoclick reaction, previously developed by our
group,16c was tested with cyclohexanone (1a) and diazide
2a (Scheme 5). The proline-catalyzed reaction, run with di-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

D
M. Belkheira et al.
Feature
Synthesis
tones 1b–d were successfully used leading in some cases, 1c
and 1d, to dissymmetrical triazoles 3ca and 3da resulting
from a complete regioselectivity. Complete chemoselectivi-
ty was also observed for the formation, with yields from
37% to 82%, of azidotriazoles 3 reported in Scheme 6.
Having these azidotriazoles resulting from the organo-
click reaction in hand, we examined the click step of the se-
quence using copper acetate, as catalyst, in tert-butyl alco-
hol at room temperature. The bis-triazoles 5 obtained, in
excellent yields, through this last step are represented in
Scheme 7. The position of the alkyl azide moiety does not
seem to influence the efficiency of this step.
Finally, a one-pot procedure, combining sequentially
the two triazole syntheses without isolation of the azidotri-
azole intermediate 3ba was elaborated (Scheme 8). Follow-
ing the organoclick reaction, dichloromethane was re-
moved under vacuo and changed for t-BuOH before the ad-
O
O
O
O
Ketones
Me
1d
Me
Me
Me
Me
1a
1b
1c
N3
N3
N3
N3
Diazides
N3
N3
N3
N3
N3
N3
2a
2b
2c
Ts
2d
2e
OH
OH
N
Me
CO2Me
Alkynes
4a
4b
4c
4d
4e
Figure 1 Partners of the organoclick–click sequence
( )n
( )n
N3
N
N
( )n
N
CO2H
N
N
N
N
Cu(OAc)2 (5 mol%)
t-BuOH, rt, 15 min–10 h
N
N3
R'
H
N
N
N
O
N
+
(20 mol%)
R'
N
( )n
N3
R
R
( )n
N3
+
( )m
+
( )m
R
N3
R
CH2Cl2
(1.5 mL)
80 °C, MW
1 h
( )m
H2N
( )m
3aa–xx
4a–e
5aaa–xxx
(0.2 mmol)
(0.3 mmol)
R'
N
1a–d
(2 mmol)
2a–e
(1 mmol)
3aa–xx
11a–e
R'
N
N
N
N3
N
N
N3
N
N
5aaa 86%
5aab 98%
5aac 99%
5aad 95%
5aae 99%
N
N
N
R' = CH2OH
R' = Ph
R' = CH2NMeTs
R' = (CH2)2OH
R' = CO2Me
N
N
N
N
N
N
N
N
N
N3
R' = Ph
R' = (CH2)2OH
N3
N
N
N
N
5abb 98%
5abd 79%
Me
3aa
63% (7%)
3ab
56% (14%)
3ac
50% (40%)
3ad
62% (19%)
OH
Ph
N
N
N
N
N
N
N
N
Me
N
N
N
N
Ph
N
N3
N
N
N3
N
N
N
N
N
5aca 97%
5adb 99%
5aeb 81%
N
N
N
N
N3
N
N
N
Ph
N
N
N
OH
3ae
53% (7%)
3ba
82% (13%)
3bc
56% (23%)
N
N
N
N
N
N
N
N
N
N3
N3
5bab 99%
5bca 89%
OH
R'
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
Me
Me
Me
N
N
N
N
3ca
61% (13%)
3da
37% (10%)
Me
Me
Me
Me
5daa 94%
Scheme 6 Scope of organoclick reaction with diazides; yields in paren-
theses refer to the side-product 11 formed in the reaction
R' = CH2OH
R' = CH2NMeTs
5caa 89%
5cac 78%
Scheme 7 Scope of bis-triazoles
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

E
M. Belkheira et al.
Feature
Synthesis
Azidotriazoles 6 and 7, and Bistriazole 8
1-Azido-4-azidomethylbenzene (2a; 34.80 mg, 0.2 mmol), propargyl
alcohol (4a; 11.2 mg, 0.2 mmol), and t-BuOH (0.50 mL) were mixed
under argon. A 0.53 M aqueous solution (19 μL) of Cu(OAc)2 was then
added and the resulting mixture stirred for 4 days at r.t. The reaction
mixture was then diluted with CH2Cl2 (50 mL) before quenching with
H2O (10 mL). The organic phase was dried (MgSO4) and the solvent
removed under vacuo. Flash chromatography (EtOAc/MeOH 20:1) of
the crude product led to azidomethylphenyltriazole 6 (11.1 mg, 24%),
azidophenylmethyltriazole 7 (33.7 mg, 73%), and bistriazole 8 (1.7
mg, 3%).
N
N
N3
N
O
i) proline (20 mol%), CH2Cl2
80 °C, MW, 1 h
ii) removal of the volatiles
N
N
+
N
5bab
65%
iii) Cu(OAc)2 (5 mol%), t-BuOH
rt, 7 h
(81% in 2 pots)
N3
2a
1b
4b
Scheme 8 One-pot three-component reaction
Azidomethylphenyltriazole 6
White solid; mp 59 °C; Rf = 0.56 (EtOAc/PE 10:1).
1H NMR (400 MHz, DMSO-d6): δ = 8.69 (s, 1 H), 7.94 (d, J = 8.5 Hz, 2
H), 7.59 (d, J = 8.5 Hz, 2 H), 5.33 (t, J = 5.5 Hz, 1 H, OH), 4.61 (d, J = 5.5
Hz, 2 H), 4.55 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 149.1, 136.3, 136.0, 129.8 (2 C),
120.9, 120.1 (2 C), 54.9, 52.8.
dition of copper acetate. Bis-triazole 5bab was formed in
slightly lower yield (65%) than through the two-pot se-
quence (81% over 2 steps).
In conclusion, we have developed a new chemo- and re-
gioselective synthesis of bis-triazoles based on an organo-
click–click sequence. It allows the coupling of a ketone and
an alkyne through a diazide linker. The organoclick step,
combining the ketone and the diazide, furnishes a triazole
by reaction with the aryl azide with complete regio- and
chemoselectivities. The click step was revealed to be effi-
cient and robust on a large variety of alkynes. In addition,
we had shown the possibility to perform the one-pot syn-
thesis by sequential addition of catalytic system and re-
agent.
HRMS: m/z [M + H]+ calcd for C10H10N6O: 231.0989; found: 231.0997.
Azidophenylmethyltriazole 7
Yellow solid; mp 64 °C; Rf = 0.45 (EtOAc/MeOH 20:1).
1H NMR (400 MHz, DMSO-d6): δ = 7.98 (s, 1 H), 7.37 (d, J = 8.5 Hz, 2
H), 7.12 (d, J = 8.5 Hz, 2 H), 5.55 (s, 2 H), 5.17 (t, J = 5.5 Hz, 1 H, OH),
4.49 (d, J = 5.5 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 148.3, 139.2, 133.0, 129.7 (2 C),
122.6, 119.3 (2 C), 54.9, 51.9.
Bistriazole 8
White solid; mp 83 °C; Rf = 0.10 (EtOAc/MeOH 20:1).
Anhydrous CH2Cl2, Et2O, toluene, THF, and DMSO were obtained from
the Solvent Purification System BRAUN MB-SPS800. All experiments
using anhydrous solvents were performed under inert atmosphere of
argon, using dried apparatus and employing standard techniques for
handling air-sensitive materials. All reagents were obtained from
commercial suppliers, unless otherwise stated. Flash chromatography
was performed using Merck 40–63 μm particle-sized silica gel (230–
400 mesh) and eluted with EtOAc in petroleum ether (PE, bp 40–60
°C) or with MeOH in EtOAc, unless otherwise specified. Analytical TLC
was performed using 0.20 mm silica gel 60 plates. Visualization was
achieved under a UVP mineralight UVGL-58 lamp, and by developing
the plates with various stains (e.g., p-anisaldehyde, phosphomolybdic
acid). Melting points were determined with a Büchi Melting-point B-
450 apparatus and are not corrected. High-resolution mass spectra
(HRMS) were obtained from a QStar Elite spectrometer (Applied Bio-
systems SCIEX) by electrospray ionization. 1H NMR spectra were re-
corded at 300 MHz on a Bruker AC-300 and at 400 MHz on a Bruker
AC-400 spectrometer using as internal standard the residual CHCl3
signal for 1H NMR (δ = 7.26). 13C NMR spectra were similarly recorded
at 75.47 MHz on a Bruker AC-300 and at 100.61 MHz on a Brucker AC-
400 spectrometer, using a broadband decoupled mode with the mul-
tiplicities obtained using a JMOD or DEPT sequence and as internal
standard the CDCl3 solvent signal for 13C NMR (δ = 77.0). Chemical
shifts (δ) are reported in parts per million (ppm). Standard abbrevia-
tions are used for denoting the multiplicities. Coupling constants (J)
are reported in hertz (Hz).
1H NMR (400 MHz, DMSO-d6): δ = 8.67 (s, 1 H), 8.09 (s, 1 H), 7.91 (d,
J = 8.5 Hz, 2 H), 7.52 (d, J = 8.5 Hz, 2 H), 5.66 (s, 2 H), 5.32 (br s, 1 H,
OH), 5.19 (br s, 1 H, OH), 4.60 (s, 2 H), 4.51 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 149.1, 148.3, 136.4, 136.3, 129.3 (2
C), 122.9, 120.9, 120.1 (2 C), 54.9, 54.8, 51.9.
Azidotriazoles 3xy; General Procedure for the Organoclick Reac-
tion
Ketone 1 (2 mmol) and diazide 2 (1 mmol) were dissolved in CH2Cl2
(1.5 mL) in a sealed tube, followed by the addition of proline (20
mol%). The stirred mixture was then heated to 80 °C in a Micro-Wave
reactor (CEM Discover – 1-300 W oven). After 1 h, the solvent was re-
moved under vacuo and the crude product submitted to flash chro-
matography.
1-[4-(Azidomethyl)phenyl]-4,5,6,7-tetrahydro-1H-ben-
zo[d][1,2,3]triazole (3aa)
Prepared from cyclohexanone (1a) and 1-azido-4-azidomethylben-
zene (2a); yield: 160 mg (63%); brown solid; 63 °C; Rf = 0.42 (EtO-
Ac/PE 2:3).
1H NMR (300 MHz, CDCl3): δ = 7.60 (d, J = 8.6 Hz, 2 H), 7.47 (d, J = 8.6
Hz, 2 H), 4.44 (s, 2 H), 2.85 (t, J = 6.2 Hz, 2 H), 2.75 (t, J = 6.1 Hz, 2 H),
1.88 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 144.1, 136.7, 135.9, 132.0, 129.1 (2C),
123.3 (2 C), 54.0, 22.7, 22.3, 21.9, 21.8.
HRMS: m/z [M + H]+ calcd for C13H14N6: 255.1353; found: 255.1353.
Diazides 2a,16c, 2b,26 and 2c27 are known compounds. For the prepara-
tion of diazides 2d and 2e, see the Supporting Information.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

F
M. Belkheira et al.
Feature
Synthesis
1-[3-(Azidomethyl)phenyl]-4,5,6,7-tetrahydro-1H-ben-
zo[d][1,2,3]triazole (3ab)
1-[(2-Azidomethyl)phenyl]-1,4,5,6,7,8-hexahydrocyclohep-
ta[d][1,2,3]triazole (3bc)
Prepared from 1a and 1-azido-3-azidomethylbenzene (2b); yield: 137
mg (56%); brown solid; mp 75 °C; Rf = 0.30 (EtOAc/PE 2:3).
Prepared from 1b and 1-azido-2-azidomethylbenzene (2c); yield: 150
mg (56%); yellow solid; mp 77 °C; Rf = 0.29 (EtOAc/PE 1:3).
1H NMR (400 MHz, CDCl3): δ = 7.55 (d, J = 6.0 Hz, 1 H), 7.54 (t, J = 6.0
Hz, 1 H), 7.52 (t, J = 3.3 Hz, 1 H), 7.39 (d, J = 6.0 Hz, 1 H), 4.45 (s, 2 H),
2.85 (t, J = 5.7 Hz, 2 H), 2.76 (t, J = 5.9 Hz, 2 H), 1.89 (m, 4 H).
1H NMR (300 MHz, CDCl3): δ = 7.56 (m, 2 H), 7.49 (m, 1 H), 7.23 (d, J =
7.6 Hz, 1 H), 4.21 (s, 2 H), 2.98 (t, J = 5.6 Hz, 2 H), 2.54 (t, J = 5.6 Hz, 2
H), 1.78 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 144.1, 137.2, 137.3, 132.0, 130.0,
13C NMR (75 MHz, CDCl3): δ = 147.0, 137.0, 135.0, 133.3, 130.4, 130.2,
128.0, 122.6, 122.5, 54.1, 22.7, 22.4, 21.9, 21.8.
129.1, 127.7, 50.4, 30.9, 27.2 (2C), 26.9, 24.4.
HRMS: m/z [M + H]+ calcd for C13H14N6: 255.1353; found: 255.1356.
HRMS: m/z [M + H]+ calcd for C13H14N6: 269.1509; found: 269.1512.
1-[2-(Azidomethyl)phenyl]-4,5,6,7-tetrahydro-1H-benzo-
[d][1,2,3]triazole (3ac)
1-[4-(Azidomethyl)phenyl]-6,6-dimethyl-4,5,6,7-tetrahydro-1H-
benzo[d][1,2,3]triazole (3ca)
Prepared from 1a and 1-azido-2-azidomethylbenzene (2c); yield: 127
mg (50%); orange solid; mp 86 °C; Rf = 0.40 (EtOAc/PE 1:4).
1H NMR (300 MHz, CDCl3): δ = 7.56–7.48 (m, 2 H), 7.47 (td, J = 7.0, 1.7
Hz, 1 H), 7.25 (m, 1 H), 4.28 (s, 2 H), 2.84 (t, J = 5.1 Hz, 2 H), 2.50 (t, J =
5.1 Hz, 2 H), 1.86 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 143.4, 134.9, 133.8, 132.8, 130.3, 130.2,
129.1, 126.6, 50.5, 22.5, 22.4, 21.8, 20.5.
Prepared from 3,3-dimethylcyclohexanone (1c) and 1-azido-4-azi-
domethylbenzene (2a); yield: 172 mg (61%); yellow solid: mp 87 °C;
Rf = 0.32 (EtOAc/PE 2:3).
1H NMR (300 MHz, CDCl3): δ = 7.56 (d, J = 8.3 Hz, 2 H), 7 .47 (d, J = 8.3
Hz, 2 H), 4.43 (s, 2 H), 2.83 (t, J = 6.4 Hz, 2 H), 2.51 (s, 2 H), 1.66 (t, J =
6.4 Hz, 2 H), 1 .03 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 143.0, 136.7, 136.0, 132.0, 129.1 (2 C),
123.4 (2 C), 54.1, 35.5, 35.4, 19.1, 31.2, 27.7 (2 C).
HRMS: m/z [M + H]+ calcd for C15H18N6: 283.1666; found: 283.1666.
HRMS: m/z [M + H]+ calcd for C13H14N6: 255.1353; found: 255.1356.
1-[4-(2-Azidoethyl)phenyl]-4,5,6,7-tetrahydro-1H-ben-
zo[d][1,2,3]triazole (3ad)
1-[4-(Azidomethyl)phenyl]-5-ethyl-4-methyl-1H-[d][1,2,3]tri-
azole (3da)
Prepared from 1a and 1-azido-4-(2-azidoethyl)benzene (2d); yield:
166 mg (62%); viscous yellow oil; Rf = 0.36 (EtOAc/PE 2:3).
1H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 8.3 Hz, 2 H), 7.37 (d, J = 8.3
Hz, 2 H), 3.56 (t, J = 7.0 Hz, 2 H), 2.96 (t, J = 7.0 Hz, 2 H), 2.84 (t, J = 5.3
Hz, 2 H), 2.73 (t, J = 4.8 Hz, 2 H), 1.87 (m, 4 H).
Prepared from pentan-3-one (1d) and 1-azido-4-azidomethylben-
zene (2a); yield: 90 mg (37%); yellow oil; Rf = 0.26 (EtOAc/PE 1:2).
1H NMR (300 MHz, CDCl3): δ = 7.46 (m, 4 H), 4.45 (s, 2 H), 2.67 (q, J =
7.6 Hz, 2 H), 2.37 (s, 3 H), 1.07 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 144.0, 138.7, 135.7,132.0, 129.8 (2 C),
13C NMR (75 MHz, CDCl3): δ = 140.6, 136 .9, 136.7, 135.3, 129.0 (2 C),
123.3 (2 C), 52.2, 34.9, 22.7, 22.5, 21.9, 21.8.
125.6 (2 C), 54.0, 16.2, 13.1, 10.4.
HRMS: m/z [M + H]+ calcd for C14H16N6: 269.1509; found: 269.1508.
HRMS: m/z [M + H]+ calcd for C12H14N6: 243.1353; found: 243.1343.
1-[4-(1-Azidoethyl)phenyl]-4,5,6,7-tetrahydro-1H-ben-
zo[d][1,2,3]triazole (3ae)
Bistriazoles 5xyz; General Procedure
Azidotriazole 3 (0.2 mmol) and alkyne derivative 4 (0.3 mmol) were
dissolved under argon at r.t. in t-BuOH (0.5 mL) and then an aq 0.53 M
Cu(OAc)2 solution (19 μL, 5 mol%) was added. The reaction mixture
was then stirred at the same temperature (from 15 min to 10 h) until
complete disappearance of the starting triazole 3 (reaction followed
by TLC). The mixture was then diluted with CH2Cl2 (50 mL) and the
organic layer was washed with H2O (10 mL). The organic layer was
dried (MgSO4) and the volatiles were removed under vacuo. Bis-tri-
azole 5 was then purified by flash chromatography on silica gel.
Prepared from 1a and 1-azido-4-(1-azidoethyl)benzene (2e); yield:
142 mg (53%); yellow solid; mp 73 °C; Rf = 0.41 (EtOAc/PE 2:3).
1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 8.5 Hz, 2 H), 7.48 (d, J = 8.5
Hz, 2 H), 4.70 (q, J = 6.8 Hz, 1 H), 2.84 (t, J = 6.1 Hz, 2 H), 2.75 (t, J = 6.1
Hz, 2 H), 1.88 (m, 4 H), 1.58 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 144.1, 141.5, 136.6, 132.0, 127.5 (2 C),
123.3 (2 C), 60.4, 22.7, 22.4, 21.9, 21.8, 21.6.
HRMS: m/z [M + H]+ calcd for C14H16N6: 269.1509; found: 269.1509.
1-{[4-(4,5,6,7-Tetrahydro-1H-benzo[d][1,2,3]triazol-1-yl)benzyl]-
1H-1,2,3-triazol-4-yl}methanol (5aaa)
1-[4-Azidomethyl)phenyl]-1,4,5,6,7,8-hexahydrocyclohep-
ta[d][1,2,3]triazole (3ba)
Prepared from azidotriazole 3aa and propargyl alcohol (4a); yield: 53
mg (86%); yellow solid; mp 179 °C; Rf = 0.12 (EtOAc/MeOH 20:1).
1H NMR (300 MHz, DMSO-d6): δ = 8.09 (s, 1 H), 7.65 (d, J = 8.7 Hz, 2
H), 7.51 (d, J = 8.7 Hz, 2 H), 5.68 (s, 2 H), 4.52 (d, J = 5.4 Hz, 2 H), 4.05
(br s, 1 H, OH), 2.73 (t, J = 5.5 Hz, 2 H), 2.69 (t, J = 5.5 Hz, 2 H), 1.78 (m,
4 H).
Prepared from cycloheptanone (1b) and 1-azido-4-azidomethylben-
zene (2a); yield: 219 mg (82%); yellow solid; mp 48 °C; Rf = 0.40 (EtO-
Ac/PE 1:2).
1H NMR (300 MHz, CDCl3): δ = 7.48 (d, J = 8.5 Hz, 2 H), 7.43 (d, J = 8.5
Hz, 2 H), 4.44 (s, 2 H), 2.96 (t, J = 5.7 Hz, 2 H), 2.74 (t, J = 5.6 Hz, 2 H),
1.76 (m, 6 H).
13C NMR (75 MHz, DMSO-d6): δ = 148.4, 143.0, 136 .7, 136.0, 132.3,
129.1 (2 C), 123.2 (2 C), 123.0, 55.0, 52.0, 22.1, 21.9, 21.3, 20.7.
13C NMR (75 MHz, CDCl3): δ = 147.5, 136.7, 136 .4, 135.6, 129.0 (2 C),
125.7 (2 C), 54.0, 30.8, 27.2 (2 C), 27.0, 24.8.
HRMS: m/z [M + H]+ calcd for C14H16N6: 269.1509; found: 269.1505.
HRMS: m/z [M + H]+ calcd for C16H18N6O: 311.1615; found: 311.1610.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

G
M. Belkheira et al.
Feature
Synthesis
1-{4-[(4-Phenyl-1H-1,2,3-triazol-1-yl)methyl]phenyl}-4,5,6,7-tet-
rahydro-1H-benzo[d][1,2,3]triazole (5aab)
1H NMR (400 MHz, CDCl3): δ = 7.78 (dd, J = 7.2 Hz, 2.3 Hz, 2 H), 7.77
(s, 1 H), 7.51 (m, 3 H), 7.41–7.30 (m, 3 H), 7.31 (t, J = 7.2 Hz, 1 H), 5.64
(s, 2 H), 2.80 (t, J = 5.8 Hz, 2 H), 2.67 (t, J = 5.6 Hz, 2 H), 1.83 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 148.3, 144.2, 137.4, 136.6, 132.0,
130.2, 130.1, 128.7 (2 C), 128.1, 127.7, 125.6 (2 C), 122.8, 122.6, 119.8,
53.4, 22.6, 22.2, 21.8, 21.7.
Prepared from azidotriazole 3aa and ethynylbenzene (4b); yield: 70
mg (98%); white solid; mp 158 °C ; Rf = 0.39 (EtOAc/PE 3:2).
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 7.5 Hz, 2 H), 7 .73 (s, 1 H),
7.59 (d, J = 8.3 Hz, 2 H), 7.45 (d, J = 8.3 Hz, 2 H), 7.42 (t, J = 7.5 Hz, 2 H),
7.32 (t, J = 7.5 Hz, 1 H), 5.65 (s, 2 H), 2.82 (t, J = 6.0 Hz, 2 H), 2.72 (t, J =
6.1 Hz, 2 H), 1.86 (m, 4 H).
HRMS: m/z [M + H]+ calcd for C21H20N6: 357.1822; found: 357.1814.
13C NMR (100 MHz, CDCl3): δ = 148.4, 144.2, 137.1, 135.2, 132.0,
130.3, 129.0 (2 C), 128.8 (2 C), 128.3, 125.7 (2 C), 123.5 (2 C), 119.6,
53.4, 22.6, 22.3, 21.9, 21.8.
2-{1-[3-(4,5,6,7-Tetrahydro-1H-benzo[d][1,2,3]triazol-1-yl)ben-
zyl]-1H-1,2,3-triazol-4-yl}ethanol (5abd)
Prepared from azidotriazole 3ab and but-3-ynol (4d); yield: 51 mg
(79%); white solid; mp 138 °C; Rf = 0.14 (EtOAc/MeOH 20:1).
HRMS: m/z [M + H]+ calcd for C21H20N6: 357.1822; found: 357.1812.
1H NMR (400 MHz, DMSO-d6): δ = 7.99 (s, 1 H), 7.59 (m, 3 H), 7.42 (m,
1 H), 5.67 (s, 2 H), 4.68 (t, J = 5.3 Hz, 1 H, OH), 3.62 (td, J = 6.7, 5.3 Hz, 1
H), 2.76 (t, J = 6.7 Hz, 2 H), 2.70 (m, 4 H), 1.78 (m, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 144.8, 143.1, 138.0, 136.5, 132.2,
130.0, 127.9, 122.7, 122.2, 122.1, 60.2, 51.9, 29.0, 22.1, 21.8, 21.3,
20.8.
N,4-Dimethyl-N-({1-[4-(4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]tri-
azol-1-yl)benzyl]-1H-1,2,3-triazol-4-yl}methyl)benzenesulfon-
amide (5aac)
Prepared from azidotriazole 3aa and N-tosyl-N-methylpropargyl-
amine (4c); yield: 94 mg (99%); white solid; mp 153 °C; Rf = 0.30 (EtO-
Ac/PE 3:1).
1H NMR (300 MHz, CDCl3): δ = 7.68 (d, J = 8.0 Hz, 2 H), 7.60 (d, J = 8.5
Hz, 2 H), 7.59 (s, 1 H), 7.42 (d, J = 8.5 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H),
5.58 (s, 2 H), 4.31 (s, 2 H), 2.82 (t, J = 4.5 Hz, 2 H), 2.75 (t, J = 6.0 Hz, 2
H), 2.71 (s, 3 H), 2.44 (s, 3 H), 1.88 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 144.21, 144.20, 137.2, 134.8, 134.1,
132.0, 129.8 (2 C), 129.1 (2 C), 127.4 (2 C), 123.5 (2 C), 123.0, 53.5,
45.6, 34.9, 22.7, 22.3, 21.9 (2 C), 21.5.
HRMS: m/z [M + H]+ calcd for C17H20 N6O: 325.1771; found: 325.1772.
1-{[2-(4,5,6,7-Tetrahydro-1H-benzo[d][1,2,3]triazol-1-yl)benzyl]-
1H-1,2,3-triazol-4-yl}methanol (5aca)
Prepared from azidotriazole 3ac and propargyl alcohol (4a); yield: 60
mg (97%); white solid; mp 132 °C; Rf = 0.20 (EtOAc/MeOH 20:1).
1H NMR (300 MHz, CDCl3): δ = 7.50 (m, 3 H), 7.41 (s, 1 H), 7.24 (m, 1
H), 5.43 (s, 2 H), 4.71 (s, 2 H), 2.81 (t, J = 6.1 Hz, 2 H), 2.65 (br s, 1 H,
OH), 2.37 (t, J = 6.0 Hz, 2 H), 1 .79 (m, 4 H).
HRMS: m/z [M
+
H]+ calcd for C24H27N7O2S: 478.2020; found:
478.2010.
13C NMR (75 MHz, CDCl3): δ = 147.8, 143.6, 134.6, 133.9, 131.9, 130.9,
130.4, 129.6, 126.5, 122.4, 56.1, 49.9, 22.4, 22.2, 21.6, 20.3.
HRMS: m/z [M + H]+ calcd for C16H18N6O: 311.1615; found: 311.1621.
2-{1-[4-(4,5,6,7-Tetrahydro-1H-benzo[d][1,2,3]triazol-1-yl)ben-
zyl]-1H-1,2,3-triazol-4-yl}ethanol (5aad)
Prepared from azidotriazole 3aa and but-3-ynol (4d); yield: 62 mg
(95%); yellow solid; mp 114 °C; Rf = 0.16 (EtOAc/MeOH 20:1).
1H NMR (300 MHz, CDCl3): δ = 7.57 (d, J = 8.5 Hz, 2 H), 7.40 (d, J = 8.5
Hz, 2 H), 7.39 (s, 1 H), 5.58 (s, 2 H), 3.95 (t, J = 5.8 Hz, 2 H), 2.95 (t, J =
5.8 Hz, 2 H), 2.83 (t, J = 4.7 Hz, 2 H), 2.73 (t, J = 4.7 Hz, 2 H), 1.87 (m, 4
H), 1.85 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): δ = 144.3, 144.2, 137.1, 135.3, 132.0, 129.0
(2 C), 123.5 (2 C), 121.7, 61.4, 53.3, 28.7, 22.6, 22.3, 21.9, 21.8.
HRMS: m/z [M + H]+ calcd for C17H20N6O: 325.1771; found: 325.1773.
1-{4-[2-(4-Phenyl-1H-1,2,3-triazol-1-yl)ethyl]phenyl}-4,5,6,7-tet-
rahydro-1H-benzo[d][1,2,3]-triazole (5adb)
Prepared from azidotriazole 3ad and ethynylbenzene (4b); yield: 73
mg (99%); yellow solid; mp 204 °C; Rf = 0.25 (EtOAc/PE 5:2).
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 7.5 Hz, 2 H), 7 .53 (s, 1 H),
7.50 (d, J = 7.5 Hz, 2 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 1 H),
7.29 (d, J = 7.5 Hz, 2 H), 4.68 (t, J = 7.0 Hz, 2 H), 3.36 (t, J = 7.0 Hz, 2 H),
2.82 (m, 2 H), 2.71 (m, 2 H), 1.86 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 147.6, 137.6, 136.0, 132.4, 132.0,
130.4, 129.8 (2 C), 128.8 (2 C), 128.1, 125.6 (2 C), 123.3 (2 C), 119.9,
51.3, 36.2, 22.7, 22.3, 21.9, 21.8.
Methyl 1-[4-(4,5,6,7-Tetrahydro-1H-benzo[d][1,2,3]triazol-1-
yl)benzyl]-1H-1,2,3-triazolylcarboxylate (5aae)
HRMS: m/z [M + H]+ calcd for C22H22N6: 371.1979; found: 371.1977.
Prepared from azidotriazole 3aa and methyl propynoate (4e), yield:
67 mg (99%); white solid; mp 147 °C; Rf = 0.23 (EtOAc/PE 4:1).
1H NMR (300 MHz, CDCl3): δ = 8.08 (s, 1 H), 7.58 (d, J = 8.5 Hz, 2 H),
7.43 (d, J = 8.5 Hz, 2 H), 5.65 (s, 2 H), 3.92 (s, 3 H), 2.81 (t, J = 6.0 Hz, 2
H), 2.72 (t, J = 5.8 Hz, 2 H), 1.86 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 160.9, 144.3, 140.4, 137.4, 134.1, 132.0,
129.3 (2 C), 127.5,123.6 (2 C), 53.7, 52.2, 22.6, 22.3, 21.8 (2 C).
1-{4-[1-(4-Phenyl-1H-1,2,3-triazol-1-yl)ethyl]phenyl}-4,5,6,7-tet-
rahydro-1H-benzo[d][1,2,3]-triazole (5aeb)
Prepared from azidotriazole 3ae and ethynylbenzene (4b); yield: 60
mg (81%); white solid; mp 133 °C; Rf = 0.30 (EtOAc/PE 3:2).
1H NMR (400 MHz, CDCl3): δ = 7.82 (dd, J = 7.5, 1.4 Hz, 2 H), 7.72 (s, 1
H), 7.57 (d, J = 8.5 Hz, 2 H), 7.46 (d, J = 8.5 Hz, 2 H), 7.41 (t, J = 7.5 Hz, 2
H), 7.32 (tt, J = 7.5, 1.4 Hz, 1 H), 5.94 (q, J = 7.1 Hz, 1 H), 2.83 (t, J = 5.3
Hz, 2 H), 2.72 (t, J = 4.3 Hz, 2 H), 2.08 (d, J = 7.1 Hz, 3 H), 1.87 (m, 4 H).
HRMS: m/z [M + H]+ calcd for C17H18N6O2: 339.1564; found: 339.1557.
1-{3-[(4-Phenyl-1H-1,2,3-triazol-1-yl)methyl]phenyl}-4,5,6,7-tet-
rahydro-1H-benzo[d][1,2,3]triazole (5abb)
13C NMR (100 MHz, CDCl3): δ = 148.0, 144.2, 140.5, 137.0, 132.0,
130.4, 128.8 (2 C), 128.2, 127.6 (2 C), 125.7 (2 C), 123.5 (2 C), 118.3,
59.7, 22.7, 22.4, 21.9, 21.8, 21.3.
Prepared from azidotriazole 3ab and ethynylbenzene (4b); yield: 70
mg (98%); white solid; mp 125 °C; Rf = 0.34 (EtOAc/PE 2:1).
HRMS: m/z [M + H]+ calcd for C22H22N6: 371.1979; found: 371.1969.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

H
M. Belkheira et al.
Feature
Synthesis
1-{4-[(4-Phenyl-1H-1,2,3-triazol-1-yl)methyl]phenyl}-1,4,5,6,7,8-
hexahydrocyclohepta[d][1,2,3]triazole (5bab)
13C NMR (75 MHz, CDCl3): δ = 148.5, 140.8, 137.1, 136.0, 135.3, 129.0
(2 C), 125.8 (2 C), 121.8, 56.4, 53.4, 16.2, 13.0, 10.4.
HRMS: m/z [M + H]+ calcd for C15H18N6O: 299.1615; found: 299.1617.
Prepared from azidotriazole 3ba and ethynylbenzene (4b); yield: 73
mg (99%); white solid; mp 179 °C; Rf = 0.29 (EtOAc/PE 3:2).
1H NMR (300 MHz, CDCl3): δ = 7.82 (dd, J = 8.2, 1.5 Hz, 2 H), 7.75 (s, 1
H), 7.51–7.43 (m, 4 H), 7.40 (m, 2 H), 7.33 (tt, J = 7.5, 1.2 Hz, 1 H), 5.66
(s, 2 H), 2.95 (t, J = 5.7 Hz, 2 H), 2.71 (t, J = 5.8 Hz, 2 H), 1.87–1.68 (m, 6
H).
13C NMR (75 MHz, CDCl3): δ = 148.5, 147.6, 136.8, 135.9, 135.6, 130.3,
128.9 (2 C), 128.8 (2 C), 128.3, 125.9 (2 C), 125.7 (2 C), 119.6, 53.5,
30.8, 27.1, 26.9 (2 C), 24.7.
One-Pot Preparation of Bistriazole 5bab
Cycloheptanone (1b; 224 mg, 2 mmol) and 1-azido-4-azidomethyl-
benzene (2a; 174 mg, 1 mmol) were dissolved in CH2Cl2 (1.5 mL) in a
sealed tube, followed by the addition of proline (23 mg, 20 mol%). The
stirred mixture was then heated to 80 °C in a Micro-Wave reactor
(CEM Discover – 1-300 W oven). After 1 h, the solvent was removed
under vacuo. The crude azidotriazole 3ba formed was mixed with
ethynylbenzene (4b; 153 mg, 1.5 mmol) in t-BuOH (2.5 mL) under ar-
gon at r.t., followed by the addition of an aq 0.53 M Cu(OAc)2 solution
(95 μL, 5 mol%). The reaction mixture was then stirred at the same
temperature for 7 h until complete disappearance of the starting tri-
azole 3ba (reaction followed by TLC). The mixture was then diluted
with CH2Cl2 (150 mL) and the organic layer was washed with H2O (20
mL). The organic layer was dried (MgSO4) and the volatiles were re-
moved under vacuo. Bis-triazole 5bab (239 mg, 65%) was obtained
pure by flash chromatography on silica gel.
HRMS: m/z [M + H]+ calcd for C22H22N6: 371.1979; found: 371.1968.
1-[4-(6,6-Dimethyl-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-
1-yl)benzyl]-1H-1,2,3-triazol-4-yl)methanol (5caa)
Prepared from azidotriazole 3ca and propargyl alcohol (4a); yield: 60
mg (89%); brown solid; mp 197 °C; Rf = 0.24 (EtOAc/MeOH 20:1).
1H NMR (300 MHz, DMSO-d6): δ = 8.09 (s, 1 H), 7.63 (d, J = 8.5 Hz, 2
H), 7 .52 (d, J = 8.5 Hz, 2 H), 5.68 (s, 2 H), 5.19 (t, J = 5.6 Hz, 1 H, OH),
4.52 (d, J = 5.6 Hz, 2 H), 2.69 (t, J = 6.4 Hz , 2 H), 2.54 (s, 2 H), 1.59 (t, J =
6.4 Hz, 2 H), 0.95 (s, 6 H).
13C NMR (75 MHz, DMSO-d6): δ = 148.4, 141.2, 136.7, 135.9, 132.2,
Acknowledgment
129.2 (2 C), 123.2 (2 C), 122.9, 55.0, 52.0, 34.8, 34.1, 18.5, 30.6, 27.2 (2
C).
HRMS: m/z [M + H]+ calcd for C18H22N6O: 339.1928; found: 339.1919.
The authors thank Aix-Marseille Université and the Centre National
de la Recherche Scientifique (CNRS) for funding.
N-({1-[4-(6,6-Dimethyl-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]tri-
azol-1-yl)benzyl]-1H-1,2,3-triazol-4-yl}methyl)-N,4-dimethylben-
zenesulfonamide (5cac)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610192.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Prepared from azidotriazole 3ca and N-tosyl-N-methylpropargyl-
amine (4c); yield: 79 mg (78%); yellow solid; mp 154 °C; Rf = 0.20
(EtOAc/PE 3:2).
1H NMR (300 MHz, CDCl3): δ = 7.68 (d, J = 8.3 Hz, 2 H), 7.61 (s, 1 H),
7.58 (d, J = 8.0 Hz, 2 H), 7.42 (d, J = 8.3 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H),
5.58 (s, 2 H), 4.31 (s, 2 H), 2.84 (t, J = 6.0 Hz, 2 H), 2.72 (s, 3 H), 2.53 (s,
2 H), 2.44 (s, 3 H), 1.67 (t, J = 6.0 Hz, 2 H), 1.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 144.4, 144.3, 143.7, 137.3, 137.2, 134.8,
134.2, 129.8 (2 C), 129.1 (2 C), 127.4 (2 C), 123.6 (2 C), 123.0, 53.6,
45.6, 35.5 (2 C), 35.0, 31.2, 27.7 (2 C), 21.5, 19.1.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I