Design of α7 nicotinic acetylcholine receptor ligands using the (het)Aryl-1,2,3-triazole core: Synthesis, in vitro evaluation and SAR studies

Article abstract of DOI:10.1016/j.ejmech.2015.11.001

We report here the synthesis of a large library of 1,2,3-triazole derivatives which were in vitro tested as α7 nAchR ligands. The SAR study revealed that several crucial factors are involved in the affinity of these compounds for α7 nAchR such as a (R) quinuclidine configuration and a mono C-3 quinuclidine substitution. The triazole ring was substituted by a phenyl ring bearing small OMe/CH₂F groups or fluorine atom and by several heterocycles such as thiophenes, furanes, benzothiophenes or benzofuranes. Among the 30 derivatives tested, the two derivatives 10 and 39 with Ki in the nanomolar range were identified (2.3 and 3 nM respectively). They exhibited a strict selectivity toward the α4β2 nicotinic receptor (up to 1 μM) but interacted with the 5HT₃ receptors with Ki around 3 nM. Synthesis, SAR studies and a full description of the derivatives are reported.

Full text of DOI:10.1016/j.ejmech.2015.11.001

European Journal of Medicinal Chemistry 107 (2016) 153e164
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Research paper
Design of
a
7 nicotinic acetylcholine receptor ligands using the (het)
Aryl-1,2,3-triazole core: Synthesis, in vitro evaluation and SAR studies
Aziz Ouach a, Frederic Pin a, Emilie Bertrand a, Johnny Vercouillie b, Zuhal Gulhan b,
c
c
b
a
ꢀ
Celine Mothes , Jean-Bernard Deloye , Denis Guilloteau , Franck Suzenet ,
Sylvie Chalon b, Sylvain Routier a
,
*
a Universite Orleans, CNRS, ICOA, UMR 7311, F-45067 Orleans, France
b UMR Inserm U930, Universite François Rabelais de Tours, CHRU de Tours, Tours, France
c
^
Laboratoires Cyclopharma, Biopole Clermont-Limagne, 63360 Saint-Beauzire, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report here the synthesis of a large library of 1,2,3-triazole derivatives which were in vitro tested as
Received 14 August 2015
Received in revised form
30 October 2015
Accepted 1 November 2015
Available online xxx
a
7 nAchR ligands. The SAR study revealed that several crucial factors are involved in the affinity of these
compounds for 7 nAchR such as a (R) quinuclidine configuration and a mono C-3 quinuclidine sub-
a
stitution. The triazole ring was substituted by a phenyl ring bearing small OMe/CH2F groups or fluorine
atom and by several heterocycles such as thiophenes, furanes, benzothiophenes or benzofuranes. Among
the 30 derivatives tested, the two derivatives 10 and 39 with Ki in the nanomolar range were identified
(2.3 and 3 nM respectively). They exhibited a strict selectivity toward the
M) but interacted with the 5HT3 receptors with Ki around 3 nM. Synthesis, SAR studies and a full
description of the derivatives are reported.
a4b2 nicotinic receptor (up to
Keywords:
1
m
Alpha 7 nicotinic acetylcholine receptors
Quinuclidine
Tropane
© 2015 Elsevier Masson SAS. All rights reserved.
Triazole synthesis
SAR
In vitro evaluation
1. Introduction
schizophrenia [9e12] and Alzheimer's disease [13,14].
Ligand families bind to the receptor directly on the active site or
following an allosteric mode and researches are always in progress
[15e17]. Several a7 nAChR agonists (such as EVP-6124 or GTS-21)
The neurotransmitter acetylcholine (ACh) exerts its effects on
the central nervous system (CNS) through two distinct muscarinic
and nicotinic receptor types. The nicotinic receptors belong to the
superfamily of ligand-gated transmembrane ion channels pos-
sessing homo or hetero pentameric structures and are structurally
have entered clinical trials [18]. While the promising drugs show
some structural diversity, a general similarity between them can be
discerned, making it possible to propose a general pharmacophoric
model I (Fig. 1). We speculate that receptor binding could occur
when a nitrogen-containing heterocycle (NCHC) is linked to a (het)
Ar skeleton via an electron rich fraction which can reinforce the
binding and form additional strong bonds [19,20]. Between the
previous two components, a donor/acceptor of hydrogen bond
(DAHB) is positioned. This moiety is subjected to numerous mod-
ulations (amide, urea, carbamate, oxazole, oxadiazole and furane)
and achieves the required tridimensional conformations as well as
the completion of the binding mode. A combination of sigma and
spiranic bonds or fusion with the tertiary amine or the (het)Ar
fractions are often observed to link the three key parts together.
composed of 5 subunits belonging to the subfamily of
2 to 10) and/or 2 to 4), the heteropentameric
homopentameric 7 subtypes being predominant [1e4]. Alpha-7
nicotinic receptors ( 7 nAChR) are highly permeable to calcium
and are distinguished by their tight binding to -bungarotoxin.
Previous studies indicated that 7 nAChR play important roles in
a
(9 subunits,
a
a
b
(b
b
a4b
2 and
a
a
a
a
modulating neurotransmission, cognition, sensory gating and
anxiety [5e8]. Thus, there has been renewed interest in the use of
nicotinic agonists to treat CNS diseases, and several studies show
their beneficial effects on cognitive symptoms particularly in
Numerous representative drugs which bind to the a7 nAchR re-
ceptor have been with a high affinity answer this general descrip-
tion [21e30].
* Corresponding author.
E-mail address: sylvain.routier@univ-orleans.fr (S. Routier).
http://dx.doi.org/10.1016/j.ejmech.2015.11.001
0223-5234/© 2015 Elsevier Masson SAS. All rights reserved.

154
A. Ouach et al. / European Journal of Medicinal Chemistry 107 (2016) 153e164
N
MeO
OMe
O
N
PSAB-OFP
N
N
O
O
Me
GTAS-21
N
N
H
N
(Het)Ar
I
S
S
Cl
DAHB
O
NCHC
NH
O
N
N
EVP-6124
O
N
O
N
Pharmacophoric model I
H
N
PHA-709829
O
O
N
N
PHA-543613
N
N
N
II
Fig. 1. Pharmacophoric model and representative
a7 nAchR agonists. NCHC ¼ nitrogen containing heterocycle. DAHB ¼ donor and/or acceptor of hydrogen bond. Link ¼ linker.
It seems that quinuclidine represents a chosen structure in the
obtaining of drugs having potential beneficial effects in CNS dis-
orders such as AD [31,32]. We previously reported the design of
Their rapid consumption in the presence of the alkyne IV, sodium
ascorbate and copper catalyst led after 12 h at room temperature to
the attempted final derivatives of type IIIa.
several series of
a
7 nAChR ligands possessing quinuclidine, tropane
Several click cross couplings were first performed with
commercially available alkynes (Table 1, entries 1e15). Due to the
instability of 1 [40] and 3, which required great precaution when
generated, stored or used, yields did not exceed 38% whatever the
nature of the aryl substituents and the quinuclidinic isomer
involved in the reaction. Derivatives 4e29 are obtained as a single
isomer. Other are racemic compounds.
and quinazoline skeletons as NCHC group, as well as amide or
spiranic oxazoles as links to the (het)Ar moieties. While molecules
having a quinuclidine/amide enchainment remain good ligands,
other NCHC series containing a tropane or a spiranic function are
less efficient. Moreover, in the quinuclidine series, we speculated
that the amide linker could be replaced by a small nitrogen-
containing heterocycle. To investigate this possibility, we
explored the use of 1,2,3-triazoles. Based on our expertise in het-
erocyclic bio-mimetic development [33e36], we synthesized a
large library of 1,2,3-triazole derivatives of type IIIa and IIIb which
Pyridine, benzofurane or benzothiophene containing terminal
alkynes were commercially unavailable and thus required special
preparation (Scheme 2). 2-Fluoro-3-iodopyridine was first sub-
jected to a palladium catalyzed Sonogashira procedure in the
presence of trimethylsilylacetylene to afford the alkyne 19, which
was treated with tetrabutylammonium fluoride (TBAF). After a
few minutes, derivative 20 was isolated in 82% yield. Interestingly,
the treatment of the crude derivative 19 with methanol in
basic medium led to the simultaneous release of the trimethylsilyl
group and the nucleophilic fluorine atom substitution. Compound
21 was isolated in a 75% yield. This Sonogashira/desilylation
tandem procedure was next applied to several bromo aryl
derivatives. Para substituted phenyl acetylenes 22e26 were readily
obtained in moderate to good yields. Next, the 1-diazo-2-
oxopropylphosphonate 27 (Bestmann Ohira reagent) easily trans-
formed the 5-formylbenzothiophene or 5-formylbenzofurane, un-
der a basic medium, into alkynes 28 and 29 which were obtained in
very satisfactory yields.
were in vitro tested as a7 nAchR ligands (Fig. 2). From in vitro assays,
structureeactivity relationships (SAR) were depicted and the
selectivity of the best ligands was assessed.
2. Chemistry
Click chemistry (Huisgen type reactions) is able to commonly
build 1,2,3-triazoles from an azide and terminal alkyne in the
presence of a copper catalyst. This useful chemical step is seldom
described in the 3-quinuclidine triazole series, however [37,38].
The extreme instability of alkyl azides prompted us to prepare the
targeted 4-(het)Ar-1,2,3-triazole quinuclidines in a single step
(Scheme 1). In the presence of a catalytic amount of copper sulfate,
1H-imidazole-1-sulfonyl azide 1 and enantiopure commercially
available (R)- or (S)-3-aminoquinuclidines of type 2, which were
both released from their respective hydrochloric acid salts using a
stoichiometric amount of K2CO3, led after 6 h at room temperature
to the enantiopure (R)- or (S)-3-azidoquinuclidine 3a or 3b [39].
The alkyne precursors of derivatives IIIb were obtained
following another route. Isomerization of the triazole involves
condensation of the alkyne on the commercially available quinu-
clidinone. This step was carried out at low temperature with a near
H
N
(Het)Ar
(Het)Ar
N
N
N
N
N
N
(Het)Ar
(Het)Ar
R
O
N
O
IIIa
IIIb
N
N
NH
N
(Het)Ar : phenyl, thiophene, pyridine, benzofurane,
benzothiophene, indole...
Fig. 2. Main synthetic objectives.

A. Ouach et al. / European Journal of Medicinal Chemistry 107 (2016) 153e164
155
N
O
S
O
N
N
N
(Het)Ar
(Het)Ar
IV (1.0 equiv.)
N3
N
HCl 1 (1.1 equiv.)
NH2
N3
2HCl
Na ascorbate (0.2 equiv.)
CuSO4.5H2O 10 %,
MeOH, time, r.t.
CuSO4.5H2O 10 %,
K2CO3 (3.0 equiv.)
MeOH, 6h, r.t.
N
N
IIIa
N
2a
R isomer
2b S isomer
3a
R isomer
3b S somer
Scheme 1. General synthesis of derivatives of type IIIa.
stoichiometric amount of the in situ formed ((trimethylsilyl)ethy-
nyl)lithium salt. The direct trimethylsilyl (TMS) removal of 30 was
achieved as described before and pure alkyne 31 was isolated in a
43% global yield [37].
As for the derivatives of type IIIa, the previously described
condensation with novel alkynes furnished the final derivatives
32e42 in very high yields. The triazole building method appears to
be more efficient than an inverse strategy with aliphatic alkynes
Table 1
Series of
a
7 nAchR ligands obtained from commercially available alkynes.
(Het)Ar alkyne IV
Product of type III, yield %a
Entry
1
Entry
14
(Het)Ar alkyne IV
Product of type III, yield %a
4, 33
17, 38
2
3
4
5, 29
6, 29
7, 22
15
16
17
18, 32
32, 18
33, 28
20
21
5
6
7
8
8, 33
18
19
20
21
22
23
24
25
34, 38
35, 44
36, 30
37, 17
9, 21
10, 32
11, 28
9
12, 28
13, 17
14, 24
22
23
24
26
28
29
38, 11
39, 34
40, 32
10
11
12
13
15, 21
16, 30
25
26
31
31
41, 91[b]
42, 87[b]
a
Yields are indicated in isolated product and calculated from quinuclidine.
Yields calcd. from 30.
b

156
A. Ouach et al. / European Journal of Medicinal Chemistry 107 (2016) 153e164
TBAF (1.0 equiv.)
THF, r.t., 15 min
20, 82%
21, 75%
Si
F
N
I
Pd(PPh3)2Cl2 (10%)
Si
+
CuI (10%),
Et3N, r.t., 12 h
K2CO3 (1.0 equiv.)
MeOH, r.t., 3 h
F
N
19
(1.1 equiv.)
F
N
O
N
1) Pd(PPh3)2Cl2 (10%)
CuI (10%),
Et3N, r.t., 12 h
22, R = CH2CH2OH, 62 %
23, R = OCH2CH2OH, 73 %
24, R = OCH2CH2OMOM, 81%
25, R = CH2CH2F, 45 %
Br
2 ) K2CO3 (1.0 equiv.)
MeOH, r.t., 3 h
R
26, R = OCH2CH2F, 51 %
R
O
P
O
OHC
MeO
MeO
K2CO3 (2.0 equiv.)
MeOH, r.t., 12 h
28, X = O, 90 %
29, X = S, 84 %
+
X
X
N2
27 (1.2 equiv.)
X = O or X = S
OH
OH
O
K2CO3 (1.0 equiv.)
MeOH, r.t., 3 h
n-BuLi (1.0 equiv.)
THF, -10°C à -78°C, 2 h
TMS
+
TMS
N
N
31, 43 %
N
30
Scheme 2. Synthesis of unavailable terminal alkynes.
and aromatic azides.
Finally benzyl alcohols 18 and quinuclidinol 40 or 41 were
subjected to direct electrophilic fluorination with dieth-
also well tolerated (entry 12). The change of the symmetric center
(R) for the (S) configuration led to a 7-fold increase in binding
strength (entry 3 vs 6).
a
ylaminosulfur trifluoride (DAST). This step was efficiently carried
out on the three derivatives and led without any difficulties to
43e45 in satisfactory yields (Scheme 3).
A similar behavior was observed using the electron rich
methoxy group when this function was positioned either on the
meta or the para phenyl positions (entries 7, 8), with a slight
preference for the meta substitution as the Ki of 10 reached 2.3 nM.
When the methoxy group was attached in ortho, steric hindrance
appeared to disrupt the flatness due to the conjugation of the tri-
azole and the phenyl moieties which resulted in a great loss of af-
finity (11, Ki ¼ 112 nM, entry 9).
3. Biological evaluation
3.1. Binding to a7 nAchR and SAR
Comparing 4 vs 16, 5 vs 32 and 9 vs 33, the introduction of a
pyridine instead of a phenyl group led to a strong decrease in af-
finity by at least tenfold. Fortunately, thiophene, benzothiophene
and benzofurane heterocycles were very well tolerated as the af-
finity returned to the nanomolar range (entries 15, 24, 25). More
precisely, an oxygen atom gave a better affinity than a sulfur atom
(39, Ki ¼ 3 nM f and 40 Ki ¼ 19 nM). Finally, we replaced the (het)Ar
part with a naphthyl group but steric hindrance appeared to be too
high and resulted in a loss of affinity as the Ki of 15 (entry 13) then
reached 200 nM.
All the synthesized compounds of type IIIa and IIIb were eval-
uated for their inhibitory effect on the binding of [125I]
-bungar-
otoxin as reference ligand. In our screening experiments, we
obtained a Ki of 1.27 0.25 nM for the 7 nAchR ligand PHA543613,
in agreement with the literature data [41]. The measured affinities
are reported in Table 2. In our first report we measured the inhib-
itory constant of the reference derivative 46 (Ki ¼ 17 nM, entry 1)
[21]. The replacement of the amide by an 1,2,3-triazole moiety
appears immediately relevant as the Ki of 12 was reduced to 8 nM
(entry 10). Without any halogen atom (entry 2), the Ki value
remained unchanged, as was also the case when a fluorine atom
was added in the three available aryl positions (entries 3e5). Un-
surprisingly, two fluorine atoms in meta and para position were
a
a
To pursue the SAR study, we introduced small flexible side
chains containing alkyl, hydroxy, ether and fluorine (entries 16,
19e23, 28). Except for compounds 18 and 43, with Ki values of 10
N
N
N
DAST (1.4 equiv.)
N
N
N
F
CH2Cl2, 0°C, 1 h
Idem
OH
N
43
, 51 %
18
N
N
N
N
N
N
F
N
HO
Br
Br
44, R = Br, 64 %
45, R = OMe, 64 %
41, R = Br
42, R = OMe
N
N
Scheme 3. Electrophilic fluorination of hydroxylated derivatives 18, 41 and 42.

A. Ouach et al. / European Journal of Medicinal Chemistry 107 (2016) 153e164
157
Table 2
Ki values of derivatives IIIa and IIIb.
Entry
1
Compound of type III
Ki (nM)a
Entry
16
Compound of type III
Ki (nM)a
46 [7]
17
5
18
10
3
2
3
4
4
5
6
8
15
10
13
4
4
1
3
17
18
19
32
33
34
469
6
105 29
130 20
5
6
7
7
8
9
20
21
22
35
36
37
215 10
225 15
230 10
114 38
11
1
1
8
9
10
11
2.3
23
24
38
39
190 10
112 26
3
1
10
12
8
3
25
40
19
1
11
12
13
14
19
10
6
4
26
27
41
42
>103
>103
13
14
15
15
16
17
196 21
141 41
28
29
30
43
44
45
21
7
150
>103
4
9.5
3
a
Values are expressed as an average of 3 values from 3 independent experiments SEM.
and 21 nM respectively, all the other derivatives displayed an af-
which present a triazole isomerization, can be considered as quite
finity over 100 nM. The incorporation of a long and flexible (hetero)
inactive compounds. Compound 44 was the only one that could be
alkyl side chain was detrimental to the biological target interaction
and the occupancy of the corresponding pocket site. Finally, the
preparation of type IIIb derivatives led to disappointing results. The
3-hydroxy or 3-fluoro quinuclidine derivatives 41, 42, 44 and 45,
considered as a weak a7 nAchR ligand. This SAR analysis confirmed
the strong effect of the 3D triazole environment as well as of the
nitrogen triazole positions on the interaction with the biological
target.

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A. Ouach et al. / European Journal of Medicinal Chemistry 107 (2016) 153e164
Overall, the SAR study indicated that several crucial factors are
involved in the affinity for 7 nAchR. Derivatives of type IIIa with a
visualized by UV light at 254 nm and 356 nm. Column chroma-
a
tographies were performed using silica gel 60 (0.063e0.200 mm,
Merck). Microwave irradiation was carried out in sealed 2e5 mL
vessels placed in a Biotage Initiator system using a standard
absorbance level (300 W maximum power). The temperatures
were measured externally by an IR probe that determined the
temperature on the surface of the vial and could be read directly
from the instrument screen. The reaction time was measured from
when the reaction mixture reached the stated temperature for
temperature-controlled experiments. Pressure was measured by a
non-invasive sensor integrated into the cavity.
(R) configuration were preferred. Phenyl, thiophene, benzothio-
phene and benzofurane could be attached to the triazole and led to
compounds with 3e19 nM affinity. In the phenyl series, OMe and
CH2OH groups proved suitable to modulate the ligand efficiency. To
date, derivatives 10 and 39 were the best two ligands we found in
the IIIa series.
3.2. Selectivity
It appeared from the above results that two compounds had a
much higher affinity for
a
7 nAchR than the others, i.e. compounds
5.1.1. General procedure A for the synthesis of derivatives IIIa
Under argon, to a solution containing 3-aminoquinuclidine bis-
hydrochloride salt 2 (212 mg, 1.00 mmol) and 1H-imidazole-1-
sulfonyle azide 1 (232 mg, 1.10 mmol) in MeOH (6 mL) was
portion wise added K2CO3 (415 mg, 3.00 mmol) and next a catalytic
amount of CuSO4, 5H2O (25 mg, 0.10 mmol). The reaction mixture
was stirred at room temperature for 6 h and then concentrated
under reduced pressure. The crude solid was solubilized in Et2O
(10 mL), filtered and the precipitate washed with an additional
amount of Et2O (10 mL). The combined organic layers were reduced
under reduced pressure and the (R) intermediate 3a used in the
next step. After addition of MeOH (6 mL), the desired terminal
alkyne 4 (1.00 mmol) and next CuSO4, 5H2O (25 mg, 0.10 mmol),
sodium ascorbate (40 mg, 0.20 mmol) were successively added. The
reaction mixture was stirred for 12 h at room temperature. Volatiles
were evaporated under reduced pressure and the residue purified
by flash chromatography. When some traces of imidazole were
observed, EtOAc (20 mL) was added. After washing with water
(2 ꢁ 10 mL), the organic layer was dried over MgSO4, filtered and
evaporated under reduced pressure to afford the pure derivative of
type IIIa.
10 and 39, with a Ki of 2.3 and 3 nM, respectively. The affinity of
these two compounds was therefore evaluated in the CEREP
profiling, using cells transfected with human recombinants on the
a
4b
2 sub-type of nicotinic receptors and on the 5-HT3 receptors
which are structural homologs of 7 nAchR. Compounds 10 and 39
showed a very high selectivity toward 2 nicotinic receptors as
no interaction was detected down to 1 M. However, both bound to
the 5-HT3 receptors with a Ki around 3 nM. Our best derivatives can
therefore be considered as full dual 5-HT3/ 7 receptor ligands and
a
a4b
m
a
could be of real interest for the development of innovative treat-
ments for CNS disorders as these two targets have been fully vali-
dated to treat such pathologies [42]. Indeed, a non-selective indole
derivative of our quinuclidine series [43] named IND8 which
exhibited a Kd of 0.12
mM against
a
7 nAChR, 0.052
mM against 5-and
a
4
b
2 nicotinic receptor subtype (Ki ¼ 0.75
mM) [43], respectively,
showed promising improvements in cognitive tests in a mouse
model of amnesia.
4. Conclusions
We have reported herein the synthesis and SAR study in the
quinuclidin-1,2,3-triazole series. Compounds were synthetized in
only a few steps and scale up is possible to ensure further in vivo
developments. The synthesis mainly involved the preparation of
quinuclidin 3-azide, several terminal alkynes and a key Huisgen
reaction. However, other reactions were performed on pre-built
ligands. A series of 30 new compounds were designed and tested
5.1.2. (R)-3-(4-phenyl-1H-1,2,3-triazol-1-yl)quinuclidine 4
Compound 4 was obtained from ethynylbenzene following the
general procedure A and isolated as a white solid in 33% yield. Rf:
0.29 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p. 132e134 ꢂC; IR
(ATR, Diamond):
n
(cmꢀ1) 973, 1023, 1043, 1060, 1072, 1211, 1227,
1411, 1453, 1482, 2870, 2937; 1H NMR (250 MHz, CDCl3):
d (ppm)
for their potent
a
7 nAChR affinity. The SAR study clearly showed
1.45e1.61 (m, 1H), 1.68e1.79 (m, 1H), 1.82e1.92 (m, 1H), 2.32 (q,
J ¼ 3.1 Hz, 1H), 2.90e3.10 (m, 3H), 3.15e3.35 (m, 1H), 3.56 (dd,
J ¼ 2.2 Hz, J ¼ 9.9 Hz, 1H), 3.62 (dd, J ¼ 2.2 Hz, J ¼ 9.9 Hz, 1H), 3.81
(dd, J ¼ 5.2 Hz, J ¼ 14.4 Hz, 1H), 4.69e4.79 (m, 1H), 7.29e7.37 (m,
1H), 7.39e7.47 (m, 2H), 7.81e7.86 (m, 2H), 7.85 (s, 1H); 13C NMR
that the quinuclidine/triazole/(het)Ar association is highly valuable
for the design of very active derivatives. Four derivatives 4, 18, 19
and 39 bind the receptor with inhibition constants less than 10 nM.
Additionally, the leaders 10 and 38 exhibit full selectivity towards
the
a
4
b2 receptor subtype (up to 1
mM) but bind to 5-HT3 receptors
(100 MHz, CDCl3): d (ppm) 19.9 (CH2), 25.6 (CH2), 28.3 (CH), 47.0
in an interesting nanomolar range. In vivo behavioral experiments
using these compounds in animal models are in progress.
(CH2), 47.4 (CH2), 52.4 (CH2), 58.0 (CH), 119.4 (CH), 125.9 (2 ꢁ CH),
128.4 (CH), 129.1 (2 ꢁ CH), 130.7 (Cq), 147.9 (Cq); HRMS (ESI): m/z
calcd. for C15H19N4 [M þ H]þ: 255.1610, found: 255.1613.
5. Experimental section
5.1.3. (R)-3-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine
5
5.1. Chemistry
Compound 5 was obtained from 1-ethynyl-4-fluorobenzene
following the general procedure A and isolated as a white solid in
29% yield. Rf: 0.37 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p.
1H NMR and 13C NMR spectra were recorded on a Bruker DPX
250 MHz or 400 MHz instrument using CDCl3 or DMSO-d6. The
chemical shifts are reported in parts per million (
d
scale) and all
180e182 ꢂC; IR (ATR, Diamond): (cmꢀ1) 973, 1014, 1044, 1060,
n
coupling constant (J) values are in Hertz (Hz). The following ab-
breviations were used to explain the multiplicities: s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet) and dd (doublet
doublet). Melting points are uncorrected. IR absorption spectra
were obtained on a PerkineElmer PARAGON 1000 PC and values
are reported in cmꢀ1. HRMS were recorded on a Bruker maXis mass
spectrometer by the “Federation de Recherche” ICOA/CBM
(FR2708) platform. Monitoring of the reactions was performed
using silica gel TLC plates (silica Merck 60 F254). Spots were
1160, 1225, 1453, 1495, 1560, 2375, 2869, 2936; 1H NMR (250 MHz,
DMSO-d6): (ppm) 1.49e1.62 (m, 2H),1.81e1.94 (m, 2H), 2.31e2.36
d
(m, 1H), 2.94e3.08 (m, 3H), 3.12e3.26 (m, 1H), 3.57e3.71 (m, 2H),
3.91e4.02 (m, 1H), 7.34 (t, J ¼ 8.6 Hz, 2H), 7.94 (dd, J ¼ 5.3 Hz,
J ¼ 8.6 Hz, 2H), 8.83 (s, 1H); 13C NMR (100 MHz, DMSO-d6):
d (ppm)
19.7 (CH2), 23.8 (CH2), 27.1 (CH), 45.9 (CH2), 46.1 (CH2), 50.8 (CH2),
56.3 (CH), 115.8 (d, J ¼ 22.0 Hz, 2 ꢁ CH), 121.0 (CH), 127.1 (d,
J ¼ 8.0 Hz, 2 ꢁ CH), 127.3 (d, J ¼ 3.0 Hz, Cq), 145.4 (Cq), 161.7 (d,
J ¼ 244.0 Hz, Cq); HRMS (ESI): m/z calcd. for C15H18FN4 [M þ H]þ:

A. Ouach et al. / European Journal of Medicinal Chemistry 107 (2016) 153e164
159
273.1516, found: 273.1508.
(250 MHz, DMSO-d6):
d
(ppm) 1.38e1.50 (m, 2H), 1.72e1.82 (m,
2H), 2.19e2.26 (m, 1H), 2.74e2.92 (m, 3H), 2.96e3.17 (m, 1H),
3.33e3.62 (m, 2H), 3.83 (s, 3H), 4.74e4.83 (m, 1H), 7.05 (d,
J ¼ 8.5 Hz, 2H), 7.83 (d, J ¼ 8.6 Hz, 2H), 8.66 (s, 1H); 13C NMR
5.1.4. (R)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine
6
Compound 6 was obtained from 1-ethynyl-3-fluorobenzene
following the general procedure A and isolated as a white solid in
29% yield. Rf: 0.31 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p.
(100 MHz, DMSO-d6): d (ppm) 19.6 (CH2), 25.2 (CH2), 27.6 (CH), 46.3
(CH2), 46.6 (CH2), 51.8 (CH2), 55.1 (CH3), 57.2 (CH), 114.2 (2 ꢁ CH),
119.9 (CH), 123.5 (Cq), 126.5 (2 ꢁ CH), 146.1 (Cq), 158.9 (Cq); HRMS
120e122 ꢂC; IR (ATR, Diamond):
n
(cmꢀ1) 1041, 1061, 1148, 1214,
(ESI): m/z calcd. for
285.1726.
C
16H21N4O [M þ H]þ: 285.1715, found:
1266, 1315, 1345, 1449, 1487, 1589, 1620, 2869, 2936; 1H NMR
(250 MHz, CDCl3): (ppm) 1.40e1.55 (m, 1H), 1.60e1.72 (m, 1H),
d
1.73e1.86 (m, 2H), 2.28 (q, J ¼ 3.1 Hz, 1H), 2.84e3.00 (m, 3H),
3.08e3.22 (m, 1H), 3.50 (ddd, J ¼ 2.0 Hz, J ¼ 9.8 Hz, J ¼ 14.5 Hz, 1H),
3.70 (dd, J ¼ 5.0 Hz, J ¼ 14.5 Hz, 1H), 4.60e4.70 (m, 1H), 7.03 (td,
J ¼ 2.3 Hz, J ¼ 8.3 Hz, 1H), 7.33e7.44 (m, 1H), 7.52e7.63 (m, 1H), 7.59
5.1.8. (R)-3-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)
quinuclidine 10
Compound 10 was obtained from 1-ethynyl-3-methoxybenzene
following the general procedure A and isolated as pale yellow
viscous oil in 32% yield. Rf: 0.45 (CH2Cl2/MeOH þ NH4OH: 80/
(s, 1H), 7.82 (s, 1H); 13C NMR (100 MHz, CDCl3):
d (ppm) 20.2 (CH2),
20 þ 1%); IR (ATR, Diamond):
n
(cmꢀ1) 1040, 1158, 1243, 1282, 1321,
26.2 (CH2), 28.4 (CH), 47.1 (CH2), 47.5 (CH2), 52.9 (CH2), 58.8 (CH),
112.8 (d, J ¼ 22.0 Hz, CH), 115.1 (d, J ¼ 22.0 Hz, CH), 119.6 (CH), 121.5
(d, J ¼ 3.0 Hz, CH), 130.6 (d, J ¼ 8.0 Hz, CH), 133.0 (d, J ¼ 8.0 Hz, Cq),
146.8 (d, J ¼ 3.0 Hz, Cq), 163.4 (d, J ¼ 246.0 Hz, Cq); HRMS (ESI): m/z
calcd. for C15H18FN4 [M þ H]þ: 273.1516, found: 273.1516.
1455, 1483, 1584, 1610, 2872, 2942; 1H NMR (250 MHz, CDCl3):
(ppm) 1.39e1.54 (m, 1H), 1.61e1.72 (m, 1H), 1.73e1.85 (m, 2H),
d
2.27e2.37 (m,1H), 2.84e2.98 (m, 3H), 3.08e3.22 (m,1H), 3.48 (ddd,
J ¼ 2.2 Hz, J ¼ 9.8 Hz, J ¼ 14.5 Hz, 1H), 3.71 (dd, J ¼ 4.8 Hz,
J ¼ 14.5 Hz, 1H), 3.85 (s, 3H), 4.59e4.68 (m, 1H), 6.85e6.90 (m, 1H),
7.28e7.38 (m, 2H), 7.44e7.47 (m, 1H), 7.80 (s, 1H); 13C NMR
5.1.5. (R)-3-(4-(2-fluorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine
7
(100 MHz, CDCl3):
d (ppm) 20.2 (CH2), 26.2 (CH2), 28.3 (CH), 47.1
Compound 7 was obtained from 1-ethynyl-2-fluorobenzene
following the general procedure A and isolated as a white solid in
22% yield. Rf: 0.42 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p.
(CH2), 47.5 (CH2), 52.8 (CH2), 55.6 (CH3), 58.6 (CH), 110.9 (CH), 114.4
(CH), 118.2 (CH), 119.4 (CH), 130.1 (CH), 132.1 (Cq), 147.6 (Cq), 160.2
(Cq); HRMS (ESI): m/z calcd. for C16H21N4O [M þ H]þ: 285.1715,
found: 285.1719.
94e98 ꢂC; IR (ATR, Diamond): (cmꢀ1) 970, 1045, 1068, 1227, 1328,
n
1452, 1487, 1644, 2932, 3142, 3352; 1H NMR (250 MHz, CDCl3):
(ppm) 1.41e1.55 (m, 1H), 1.63e1.74 (m, 1H), 1.76e1.88 (m, 2H),
d
5.1.9. (R)-3-(4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)
quinuclidine 11
2.30 (q, J ¼ 3.1 Hz, 1H), 2.87e3.00 (m, 3H), 3.10e3.24 (m, 1H), 3.50
(ddd, J ¼ 2.2 Hz, J ¼ 9.8 Hz, J ¼ 14.4 Hz, 1H), 3.75 (dd, J ¼ 4.7 Hz,
J ¼ 14.4 Hz,1H), 4.63e4.72 (m,1H), 7.09e7.18 (m,1H), 7.22e7.34 (m,
Compound 11 was obtained from 1-ethynyl-2-methoxybenzene
following the general procedure A and isolated as a white solid in
28% yield. Rf: 0.50 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p.
2H), 7.98 (d, J ¼ 3.7 Hz, 1H), 8.32 (dd, J ¼ 2.2 Hz, J ¼ 7.5 Hz, 1H); 13
C
NMR (100 MHz, CDCl3):
d (ppm) 20.2 (CH2), 26.2 (CH2), 28.4 (CH),
120e122 ꢂC; IR (ATR, Diamond):
n
(cmꢀ1) 969, 1017, 1043, 1067,
47.1 (CH2), 47.5 (CH2), 52.8 (CH2), 58.6 (CH), 115.8 (d, J ¼ 22.0 Hz,
CH), 118.8 (d, J ¼ 13.0 Hz, Cq), 122.4 (d, J ¼ 13.0 Hz, CH), 124.8 (d,
J ¼ 3.0 Hz, CH), 128.0 (d, J ¼ 3.0 Hz, CH), 129.5 (d, J ¼ 8.0 Hz, CH),
141.2 (Cq), 159.4 (d, J ¼ 248.0 Hz, Cq); HRMS (ESI): m/z calcd. for
1120, 1240, 1322, 1434, 1488, 1583, 2864, 2927; 1H NMR (250 MHz,
CDCl3): (ppm) 1.37e1.52 (m, 1H), 1.63e1.74 (m, 1H), 1.75e1.85 (m,
d
2H), 2.28e2.39 (m, 1H), 2.85e2.99 (m, 3H), 3.10e3.24 (m, 1H), 3.46
(ddd, J ¼ 2.2 Hz, J ¼ 9.8 Hz, J ¼ 14.3 Hz, 1H), 3.75 (dd, J ¼ 5.2 Hz,
J ¼ 14.3 Hz, 1H), 3.94 (s, 3H), 4.59e4.68 (m, 1H), 6.97 (d, J ¼ 8.3 Hz,
1H), 7.08 (td, J ¼ 1.1 Hz, J ¼ 7.6 Hz, 1H), 7.31 (ddd, J ¼ 1.8 Hz,
J ¼ 7.6 Hz, J ¼ 8.3 Hz, 1H), 8.08 (s, 1H), 8.35 (dd, J ¼ 1.8 Hz, J ¼ 7.6 Hz,
C
15H18FN4 [M þ H]þ: 273.1516, found: 273.1529.
5.1.6. (S)-3-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine
8
1H); 13C NMR (100 MHz, CDCl3):
d (ppm) 20.3 (CH2), 26.2 (CH2),
Compound 8 was obtained from 1-ethynyl-4-fluorobenzene and
(S) intermediate 3b following the general procedure A and isolated
as a white solid in 33% yield. Rf: 0.37 (CH2Cl2/MeOH þ NH4OH: 80/
28.4 (CH), 47.2 (CH2), 47.5 (CH2), 52.8 (CH2), 55.6 (CH3), 58.4 (CH),
111.0 (CH), 120.0 (Cq), 121.3 (CH), 122.7 (CH), 127.8 (CH), 129.0 (CH),
143.1 (Cq), 155.8 (Cq); HRMS (ESI): m/z calcd. for C16H21N4O
[M þ H]þ: 285.1723, found: 285.1715.
20 þ 1%); M.p. 139e141 ꢂC; IR (ATR, Diamond):
n
(cmꢀ1) 974, 1022,
1042, 1060, 1160, 1225, 1330, 1400, 1494, 1560, 1612, 2869, 2936; 1H
NMR (250 MHz, CDCl3):
d (ppm) 1.39e1.54 (m, 1H), 1.60e1.74 (m,
1H), 1.75e1.88 (m, 2H), 2.26e2.36 (m, 1H), 2.84e2.98 (m, 3H),
3.07e3.21 (m, 1H), 3.48 (ddd, J ¼ 2.3 Hz, J ¼ 9.8 Hz, J ¼ 14.4 Hz, 1H),
3.70 (dd, J ¼ 5.1 Hz, J ¼ 14.4 Hz, 1H), 4.59e4.68 (m, 1H), 7.11 (t,
J ¼ 8.6 Hz, 2H), 7.77 (s, 1H), 7.79e7.84 (m, 2H); 13C NMR (100 MHz,
5.1.10. (R)-3-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)
quinuclidine 12
Compound 12 was obtained from 1-ethynyl-4-chlorobenzene
following the general procedure A and isolated as a white solid in
28% yield. Rf: 0.41 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p.
CDCl3):
d (ppm) 20.3 (CH2), 26.2 (CH2), 28.4 (CH), 47.2 (CH2), 47.5
(CH2), 52.9 (CH2), 58.7 (CH), 116.0 (d, J ¼ 22.0 Hz, 2 ꢁ CH), 118.9
(CH), 127.1 (d, J ¼ 3.0 Hz, Cq), 127.6 (d, J ¼ 8.0 Hz, 2 ꢁ CH), 146.9 (Cq),
162.8 (d, J ¼ 247.0 Hz, Cq); HRMS (ESI): m/z calcd. for C15H18N4F
[M þ H]þ: 273.1516, found: 273.1509.
144e146 ꢂC; IR (ATR, Diamond): (cmꢀ1) 971, 1014, 1060, 1092,
n
1190, 1202, 1324, 1401, 1433, 1452, 1468, 1484, 2868, 2939, 3110;
1H NMR (400 MHz, CDCl3):
d
(ppm) 1.40e1.50 (m, 1H), 1.60e1.73
(m, 1H), 1.74e1.87 (m, 2H), 2.28e2.39 (m, 1H), 2.84e3.00 (m, 3H),
3.08e3.22 (m, 1H), 3.49 (ddd, J ¼ 2.2 Hz, J ¼ 9.9 Hz, J ¼ 14.3 Hz,
1H), 3.70 (dd, J ¼ 5.0 Hz, J ¼ 14.3 Hz, 1H), 4.55e4.71 (m, 1H), 7.40
(d, J ¼ 8.7 Hz, 2H), 7.77 (d, J ¼ 8.7 Hz, 2H), 7.80 (s, 1H); 13C
5.1.7. (R)-3-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)
quinuclidine 9
Compound 9 was obtained from 1-ethynyl-4-methoxybenzene
following the general procedure A and isolated as a white solid in
21% yield. Rf: 0.33 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p.
NMR (100 MHz, CDCl3): d (ppm) 20.2 (CH2), 26.2 (CH2), 28.4 (CH),
47.1 (CH2), 47.5 (CH2), 52.9 (CH2), 58.7 (CH), 119.2 (CH), 127.1
(2 ꢁ CH), 129.3 (2 ꢁ CH), 129.4 (Cq), 134.1 (Cq), 146.7 (Cq); HRMS
122e124 ꢂC; IR (ATR, Diamond):
n
(cmꢀ1) 1029, 1060, 1106, 1177,
(ESI): m/z calcd. for
289.1211.
C
15H18N4Cl [M þ H]þ: 289.1220, found:
1249, 1307, 1454, 1497, 1561, 1618, 2870, 2937, 3399; 1H NMR

160
A. Ouach et al. / European Journal of Medicinal Chemistry 107 (2016) 153e164
5.1.11. (R)-3-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)
quinuclidine 13
J ¼ 14.4 Hz, 1H), 4.63e4.72 (m, 1H), 7.73 (d, J ¼ 6.0 Hz, 2H), 7.95 (s,
1H), 8.66 (d, J ¼ 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d (ppm)
Compound 13 was obtained from 1-ethynyl-3,4-dichlorob-
enzene following the general procedure A and isolated as a white
solid in 17% yield. Rf: 0.33 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%);
20.2 (CH2), 26.2 (CH2), 28.4 (CH), 47.1 (CH2), 47.5 (CH2), 52.9 (CH2),
59.0 (CH), 120.1 (2 ꢁ CH), 120.7 (CH), 138.2 (Cq), 145.3 (Cq), 150.7
(2 ꢁ CH); HRMS (ESI): m/z calcd. for C14H18N5 [M þ H]þ: 256.1562,
found: 256.1550.
M.p.108e110 ꢂC; IR (ATR, Diamond): (cmꢀ1) 986, 1029, 1044,1133,
n
1231, 1324, 1457, 1561, 1606, 2871, 2942, 3385; 1H NMR (400 MHz,
CDCl3): (ppm) 1.41e1.57 (m, 1H), 1.59e1.74 (m, 1H), 1.76e1.87 (m,
d
5.1.15. (R)-3-(4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)quinuclidine
17
2H), 2.28 (q, J ¼ 3.0 Hz, 1H), 2.86e3.00 (m, 3H), 3.08e3.22 (m, 1H),
3.44e3.57 (m, 1H), 3.70 (dd, J ¼ 5.0 Hz, J ¼ 14.4 Hz, 1H), 4.61e4.71
(m, 1H), 7.48 (d, J ¼ 8.4 Hz, 1H), 7.65 (dd, J ¼ 1.9 Hz, J ¼ 8.4 Hz, 1H),
7.84 (s, 1H), 7.91 (d, J ¼ 1.9 Hz, 1H); 13C NMR (100 MHz, CDCl3):
Compound 17 was obtained from 2-ethynylthiophene following
the general procedure A and isolated as a white solid in 38% yield.
Rf: 0.42 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p. 137e139 ꢂC; IR
(ATR, Diamond):
n
(cmꢀ1) 931, 973, 1027, 1042, 1062, 1159, 1212,
d
(ppm) 20.1 (CH2), 26.0 (CH2), 28.3 (CH), 47.1 (CH2), 47.4 (CH2), 52.7
1295,1316,1432, 1451, 2867, 2937, 3074; 1H NMR (400 MHz, CDCl3):
(ppm) 1.38e1.53 (m, 1H), 1.59e1.72 (m, 1H), 1.73e1.85 (m, 2H),
(CH2), 58.7 (CH), 119.7 (CH), 125.0 (CH), 127.6 (CH), 130.9 (Cq), 131.0
(CH), 132.1 (Cq), 133.2 (Cq), 145.6 (Cq); HRMS (ESI): m/z calcd. for
d
C
15H17N4Cl2 [M þ H]þ: 323.0830, found: 323.0827.
2.26 (q, J ¼ 3.1 Hz, 1H), 2.83e2.98 (m, 3H), 3.06e3.20 (m, 1H), 3.47
(ddd, J ¼ 2.0 Hz, J ¼ 9.7 Hz, J ¼ 14.5 Hz, 1H), 3.68 (dd, J ¼ 5.0 Hz,
J ¼ 14.5 Hz, 1H), 4.57e4.66 (m, 1H), 7.07 (dd, J ¼ 3.6 Hz, J ¼ 5.0 Hz,
1H), 7.25e7.30 (m, 1H), 7.38 (dd, J ¼ 1.1 Hz, J ¼ 3.6 Hz, 1H), 7.73 (s,
5.1.12. (R)-3-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)
quinuclidine 14
Compound 14 was obtained from 1-ethynyl-3,4-difluorobenz-
ene following the general procedure A and isolated as a white
solid in 24% yield. Rf: 0.33 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%);
1H); 13C NMR (100 MHz, CDCl3):
d (ppm) 20.2 (CH2), 26.2 (CH2),
28.3 (CH), 47.1 (CH2), 47.4 (CH2), 52.8 (CH2), 58.7 (CH), 118.7 (CH),
124.3 (CH), 125.2 (CH), 127.8 (CH), 133.2 (Cq), 142.9 (Cq); HRMS
(ESI): m/z calcd. for C13H17N4S [M þ H]þ: 261.1174, found: 261.1185.
M.p. 122e124 ꢂC; IR (ATR, Diamond): (cmꢀ1) 969, 989, 1025, 1045,
n
1059, 1207, 1281, 1449, 1508, 1606, 2869, 2942; 1H NMR (400 MHz,
CDCl3): (ppm) 1.40e1.55 (m, 1H), 1.59e1.74 (m, 1H), 1.75e1.88 (m,
d
5.1.16. (R)-(4-(1-(quinuclidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)
methanol 18
2H), 2.26e2.30 (m, 1H), 2.85e2.99 (m, 3H), 3.07e3.20 (m, 1H), 3.48
(ddd, J ¼ 2.1 Hz, J ¼ 9.7 Hz, J ¼ 14.4 Hz, 1H), 3.69 (dd, J ¼ 4.8 Hz,
J ¼ 14.4 Hz,1H), 4.59e4.68 (m,1H), 7.14e7.26 (m,1H), 7.50e7.57 (m,
Compound 18 was obtained from (4-ethynylphenyl)methanol
following the general procedure A and isolated as a white solid in
32% yield. Rf: 0.11 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p.
1H), 7.66 (ddd, J ¼ 2.1 Hz, J ¼ 7.6 Hz, J ¼ 11.2 Hz, 1H), 7.78 (s, 1H); 13
C
NMR (100 MHz, CDCl3):
d (ppm) 20.2 (CH2), 26.2 (CH2), 28.4 (CH),
200e202 ꢂC; IR (ATR, Diamond):
n
(cmꢀ1) 978, 1017, 1041, 1059,
47.1 (CH2), 47.5 (CH2), 52.8 (CH2), 58.8 (CH), 114.9 (d, J ¼ 18.0 Hz,
CH), 117.9 (d, J ¼ 18.0 Hz, CH), 119.4 (CH), 121.9 (q, J ¼ 5.0 Hz, CH),
128.0 (q, J ¼ 5.0 Hz, Cq), 146.0 (Cq), 150.3 (q, J ¼ 248.0 Hz, Cq), 150.8
(q, J ¼ 248.0 Hz, Cq); HRMS (ESI): m/z calcd. for C15H17F2N4
[M þ H]þ: 291.1421, found: 291.1423.
1221, 1337, 1428, 1450, 1610, 2878, 2939, 3127, 3353; 1H NMR
(400 MHz, DMSO-d6): (ppm) 1.39e1.56 (m, 2H),1.71e1.82 (m, 2H),
d
2.22 (q, J ¼ 3.0 Hz, 1H), 2.77e2.87 (m, 3H), 2.95e3.08 (m, 1H),
3.34e3.55 (m, 3H), 4.62 (d, J ¼ 4.4 Hz, 1H), 4.74e4.83 (m, 1H), 5.25
(t, J ¼ 4.4 Hz,1H), 7.42 (d, J ¼ 8.3 Hz, 2H), 7.87 (d, J ¼ 8.3 Hz, 2H), 8.74
(s, 1H); 13C NMR (100 MHz, DMSO-d6):
d (ppm) 19.6 (CH2), 25.3
5.1.13. (R)-3-(4-(6-methoxynaphthalen-2-yl)-1H-1,2,3-triazol-1-
yl)quinuclidine 15
(CH2), 27.6 (CH), 46.3 (CH2), 46.6 (CH2), 51.9 (CH2), 57.4 (CH), 62.6
(CH2), 120.6 (CH), 124.9 (2 ꢁ CH), 126.8 (2 ꢁ CH), 129.3 (Cq), 142.1
(Cq), 146.1 (Cq); HRMS (ESI): m/z calcd. for C16H21N4O [M þ H]þ:
285.1715, found: 285.1702.
Compound 15 was obtained from 2-ethynyl-6-methoxynaphth-
alene following the general procedure A and isolated as a white
solid in 21% yield. Rf: 0.29 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%);
M.p.186e188 ꢂC; IR (ATR, Diamond): (cmꢀ1) 906, 1025, 1123, 1162,
n
1210, 1262, 1344, 1394, 1454, 1479, 1612, 1630, 2869, 2932; 1H NMR
(400 MHz, CDCl3): (ppm) 1.42e1.56 (m, 1H), 1.65e1.76 (m, 1H),
5.1.17. 5-Ethynyl-2-fluoropyridine 20
d
To a degassed solution of 2-fluoro-5-iodopyridine (4.00 g,
17.9 mmol) in triethylamine (30 mL) were successively added
ethynyl(trimethyl)silane (2.78 mL, 19.7 mmol), copper iodide
(340 mg, 1.79 mmol) and Pd(PPh3)2Cl2 (1.25 g, 1.79 mmol). The
reaction mixture was stirred at room temperature for 12 h. After
cooling to room temperature, water (100 mL) was added and the
organic material was extracted with Et2O (5 ꢁ 20 mL). The com-
bined organic layers were dried with MgSO4, filtered and concen-
trated under reduced pressure to obtain 19 as a crude solid
material. The crude derivative 19 was dissolved in THF (50 mL) and
a TBAF solution (17.9 mL, 1 M in THF) was added dropwise. After
15 min, solvents were removed under reduced pressure and the
residue was purified under flash chromatography to afford the
alkyne 20 (petroleum ether/EtOAc 95/5) as a red oil in 82% yield. Rf:
1.77e1.88 (m, 2H), 2.31 (q, J ¼ 3.1 Hz, 1H), 2.86e3.02 (m, 3H),
3.10e3.24 (m, 1H), 3.52 (ddd, J ¼ 2.1 Hz, J ¼ 9.7 Hz, J ¼ 14.4 Hz, 1H),
3.73 (dd, J ¼ 5.2 Hz, J ¼ 14.4 Hz, 1H), 3.93 (s, 3H), 4.58e4.75 (m, 1H),
7.14 (s, 1H), 7.16e7.20 (m, 1H), 7.79 (d, J ¼ 9.0 Hz, 2H), 7.89 (s, 1H),
7.91 (dd, J ¼ 1.7 Hz, J ¼ 9.0 Hz, 1H), 8.26 (s, 1H); 13C NMR (100 MHz,
CDCl3):
d (ppm) 20.3 (CH2), 26.2 (CH2), 28.4 (CH), 47.2 (CH2), 47.5
(CH2), 52.9 (CH2), 55.6 (CH3), 58.7 (CH), 106.0 (CH), 119.0 (CH), 119.5
(CH), 124.5 (CH), 124.6 (CH), 126.1 (Cq), 127.6 (CH), 129.2 (Cq), 129.9
(CH), 134.6 (Cq), 148.0 (Cq), 158.1 (Cq); HRMS (ESI): m/z calcd. for
C
20H23N4O [M þ H]þ: 335.1872, found: 335.1866.
5.1.14. (R)-3-(4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)quinuclidine
16
Compound 16 was obtained from 4-ethynylpyridine following
the general procedure A and isolated as a white solid in 30% yield.
Rf: 0.21 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p. 150e152 ꢂC; IR
0.49 (petroleum ether/EtOAc: 95/5); IR (ATR, Diamond):
927, 1020, 1130, 1240, 1365, 1477, 1575, 3074; 1H NMR (250 MHz,
CDCl3):
(ppm) 3.19 (s, 1H), 6.90 (dd, J ¼ 3.0 Hz, J ¼ 8.5 Hz, 1H), 7.85
(ddd, J ¼ 2.3 Hz, J ¼ 7.6 Hz, J ¼ 8.5 Hz, 1H), 8.34 (d, J ¼ 2.3 Hz, 1H);
13C NMR (63 MHz, CDCl3):
n )
(cmꢀ1
d
(ATR, Diamond):
n
(cmꢀ1) 991, 1041, 1058, 1073, 1208, 1227, 1325,
1413, 1430, 1562, 1613, 2869, 2935; 1H NMR (400 MHz, CDCl3):
(ppm) 1.42e1.56 (m, 1H), 1.60e1.76 (m, 1H), 1.77e1.88 (m, 2H),
d
(ppm) 79.2 (CH), 80.7 (d, J ¼ 1.0 Hz, Cq),
d
109.6 (d, J ¼ 38.0 Hz, CH),117.3 (d, J ¼ 5.0 Hz, Cq),144.4 (d, J ¼ 8.0 Hz,
CH),151.4 (d, J ¼ 15.0 Hz, CH),163.1 (d, J ¼ 243.0 Hz, Cq); MS (IS): m/z
for C7H5NF [M þ H]þ: 122.0.
2.29 (q, J ¼ 3.1 Hz, 1H), 2.86e3.00 (m, 3H), 3.07e3.25 (m, 1H), 3.50
(ddd, J ¼ 2.1 Hz, J ¼ 9.7 Hz, J ¼ 14.5 Hz, 1H), 3.71 (dd, J ¼ 5.0 Hz,

A. Ouach et al. / European Journal of Medicinal Chemistry 107 (2016) 153e164
161
5.1.18. 5-Ethynyl-2-methoxypyridine 21
(250 MHz, CDCl3):
d
(ppm) 3.03 (s, 1H), 6.75 (d, J ¼ 2.2 Hz, 1H),
The crude alkyne 19 (vide supra) was dissolved in MeOH (60 mL)
in the presence of K2CO3 (2.47 g, 17.9 mmol) for 3 h at room tem-
perature. Solvents were removed under reduced pressure and the
crude material was purified by flash chromatography (petroleum
ether/EtOAc 95/5) to afford 21 as a pale yellow oil in 75% yield. Rf:
7.43e7.46 (m, 2H), 7.64 (d, J ¼ 2.2 Hz, 1H), 7.77 (s, 1H); 13C NMR
(100 MHz, CDCl3):
d (ppm) 76.0 (CH), 84.2 (Cq), 106.7 (CH), 111.7
(CH), 116.8 (Cq), 125.6 (CH), 127.7 (Cq), 128.6 (CH), 146.1 (CH), 155.0
(Cq); MS (IS): m/z for C10H7O [M þ H]þ: 143.1.
0.72 (petroleum ether/EtOAc: 96/4); IR (ATR, Diamond):
1021, 1126, 1251, 1284, 1305, 1367, 1488, 1559, 1600, 3290; 1H NMR
(250 MHz, CDCl3): (ppm) 3.10 (s, 1H), 3.94 (s, 3H), 6.69 (d,
J ¼ 8.6 Hz,1H), 7.63 (dd, J ¼ 2.3 Hz, J ¼ 8.6 Hz,1H), 8.30 (d, J ¼ 2.3 Hz,
1H); 13C NMR (100 MHz, CDCl3):
(ppm) 53.9 (CH3), 78.8 (CH), 80.9
n
(cmꢀ1
)
5.1.25. 5-Ethynylbenzo[b]thiophene 29
Compound 29 was obtained from 5-formylbenzothiophene as
described for 28 as a white solid in 84% yield. Rf: 0.40 (petroleum
d
ether/EtOAc: 99/1); M.p. 55e57 ꢂC; IR (ATR, Diamond):
n )
(cmꢀ1
d
1050, 1088, 1222, 1258, 1324, 1411, 1431, 3082, 3101, 3277; 1H NMR
(Cq), 110.9 (CH), 112.1 (Cq), 141.8 (CH), 151.0 (CH), 163.9 (Cq); MS (IS):
(250 MHz, CDCl3):
d
(ppm) 3.11 (s, 1H), 7.31 (d, J ¼ 5.5 Hz, 1H),
m/z for C8H8NO [M þ H]þ: 134.0.
7.43e7.51 (m, 2H), 7.83 (d, J ¼ 8.4 Hz, 1H), 7.99 (s, 1H); 13C NMR
(100 MHz, CDCl3):
d (ppm) 76.9 (CH), 84.1 (Cq), 118.1 (Cq), 122.6
5.1.19. 2-(4-Ethynylphenyl)ethanol 22 [43]
(CH), 123.8 (CH), 127.6 (CH), 127.7 (2 ꢁ CH), 139.6 (Cq), 140.3 (Cq);
Compound 22 [39] was obtained from 2-(4-bromophenyl)
ethanol as described for 21 and was isolated as a white solid in 62%
yield. Rf: 0.40 (petroleum ether/EtOAc: 80/20); 1H NMR (400 MHz,
MS (IS): m/z for C10H7S [M þ H]þ: 159.1.
5.1.26. 3-Ethynylquinuclidin-3-ol 31 [35]
CDCl3):
d
(ppm) 1.51e1.65 (m, 1H), 2.84e2.90 (m, 2H), 3.07 (s, 1H),
A solution of ethynyl(trimethyl)silane (4.44 mL, 31.4 mmol) in
dry THF (30 mL) was cooled at ꢀ10 ꢂC and solution of n-BuLi
(12.6 mL, 2.5 M in hexane) was dropwise added. After 10 min at this
temperature, the reaction mixture was cooled at ꢀ78 ꢂC and a so-
lution of 3-quinuclidone (3.74 g, 29.9 mmol) in THF (70 mL) was
slowly added. The cold bath was removed just after the introduc-
tion of the ketone and after one hour of reaction at room temper-
ature, brine (70 mL) was added. After extraction with EtOAc
(2 ꢁ 35 mL), the combined organic layers were dried over MgSO4,
filtered and evaporated under reduced pressure. The crude silylated
derivative 30 was dissolved again in MeOH (60 mL) in the presence
of K2CO3 (3.89 g, 28.1 mmol). The novel reaction mixture was
reduced under vacuum and the residue purified by flash chroma-
tography (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%). The pure alkyne
derivative 31 [45] was isolated as a white solid with a global yield of
43% (calcd from 3-quinuclidinone). Rf: 0.35 (CH2Cl2/
MeOH þ NH4OH: 80/20 þ 1%); M.p. 201e203 ꢂC; IR (ATR, Dia-
3.83e3.89 (m, 2H), 7.19 (d, J ¼ 8.3 Hz, 2H), 7.44 (d, J ¼ 8.3 Hz, 2H);
MS (IS): m/z for C10H11O [M þ H]þ: 147.0.
5.1.20. 2-(4-Ethynylphenoxy)ethanol 23 [44]
Compound 23 [40] was obtained from 2-(4-bromophenoxy)
ethanol as described for 21 and was isolated as a white solid in 73%
yield. Rf: 0.20 (petroleum ether/EtOAc: 80/20); 1H NMR (400 MHz,
CDCl3):
d (ppm) 2.15e2.18 (m, 1H), 3.00 (s, 1H), 3.94e3.97 (t,
J ¼ 4.5 Hz, 2H), 4.05e4.09 (m, 2H), 6.85 (d, J ¼ 8.3 Hz, 2H), 7.42 (d,
J ¼ 8.3 Hz, 2H); MS (IS): m/z for C10H11O2 [M þ H]þ: 163.0.
5.1.21. 1-Ethynyl-4-(2-(methoxymethoxy)ethoxy)benzene 24
Compound 24 was obtained from 1-bromo-4-(2-(methox-
ymethoxy)ethoxy)benzene as described for 20 and was isolated as
a white solid in 81% yield. Rf: 0.70 (petroleum ether/EtOAc: 80/20);
1H NMR (400 MHz, CDCl3):
d (ppm) 3.05 (s, 1H), 3.39 (s, 3H),
3.87e3.90 (m, 2H), 4.10e4.16 (m, 2H), 4.70 (s, 2H), 6.83 (d,
J ¼ 8.7 Hz, 2H), 7.39 (d, J ¼ 8.7 Hz, 2H); MS (IS): m/z for C12H15O3
[M þ H]þ: 207.0.
mond):
2754, 2873, 2934, 2950, 2965, 3216; 1H NMR (250 MHz, MeOD):
(ppm) 1.38e1.53 (m, 1H), 1.61e1.75 (m, 1H), 1.93e2.10 (m, 3H),
n
(cmꢀ1) 989, 1024, 1048, 1071, 1138, 1154, 1317, 1455, 2596,
d
2.73e2.84 (m, 4H), 2.88 (d, J ¼ 13.8 Hz, 1H), 2.89 (s, 1H), 3.13 (d,
5.1.22. 1-Ethynyl-4-(2-fluoroethyl)benzene 25
J ¼ 13.8 Hz, 1H); MS (IS): m/z for C9H14NO [M þ H]þ: 152.8.
Compound 25 was obtained from 1-bromo-4-(2-fluoroethyl)
benzene as described for 20 and was isolated as a white solid in 45%
yield. Rf: 0.20 (petroleum ether/EtOAc: 80/20); 1H NMR (400 MHz,
5.1.27. (R)-3-(4-(6-fluoropyridin-3-yl)-1H-1,2,3-triazol-1-yl)
quinuclidine 32
CDCl3):
d
(ppm) 2.99 (dt, J ¼ 6.4 Hz, J ¼ 23.7 Hz, 2H), 3.12 (s, 1H),
Compound 32 was obtained from 5-ethynyl-2-fluoropyridine 20
following the general procedure A and isolated as a white solid in
18% yield. Rf: 0.32 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p.
4.61 (dt, J ¼ 6.4 Hz, J ¼ 46.8 Hz, 2H), 7.17 (d, J ¼ 8.3 Hz, 2H), 7.41 (d,
J ¼ 8.3 Hz, 2H); MS (IS): m/z for C10H10F [M þ H]þ: 149.0.
147e149 ꢂC; IR (ATR, Diamond):
n
(cmꢀ1) 976, 1024, 1044, 1060,
5.1.23. 1-Ethynyl-4-(2-fluoroethoxy)benzene 26
1237, 1316, 1429, 1471, 1552, 1593, 2870, 2935; 1H NMR (400 MHz,
CDCl3): (ppm) 1.45e1.54 (m, 1H), 1.63e1.72 (m, 1H), 1.74e1.90 (m,
Compound 26 was obtained from 1-bromo-4-(2-fluoroethoxy)
benzene as described for 20 and was isolated as a white solid in 51%
yield. Rf: 0.20 (EP/AcOEt: 80/20); 1H NMR (400 MHz, CDCl3):
d
2H), 2.29 (q, J ¼ 3.1 Hz, 1H), 2.87e3.02 (m, 3H), 3.11e3.20 (m, 1H),
3.51 (ddd, J ¼ 2.0 Hz, J ¼ 9.8 Hz, J ¼ 14.4 Hz, 1H), 3.71 (dd, J ¼ 5.1 Hz,
J ¼ 14.4 Hz, 1H), 4.63e4.69 (m, 1H), 7.02 (dd, J ¼ 2.9 Hz, J ¼ 8.5 Hz,
1H), 7.87 (s,1H), 8.28e8.37 (m,1H), 8.60 (d, J ¼ 2.5 Hz,1H); 13C NMR
d
(ppm) 2.99 (dt, J ¼ 6.6 Hz, J ¼ 23.7 Hz, 2H), 3.08 (s, 1H), 4.60 (dt,
J ¼ 6.6 Hz, J ¼ 47.0 Hz, 2H), 7.16 (d, J ¼ 7.8 Hz, 2H), 7.41 (d, J ¼ 7.8 Hz,
2H); MS (IS): m/z for C10H10FO [M þ H]þ: 165.0.
(100 MHz, CDCl3):
d (ppm) 20.2 (CH2), 26.2 (CH2), 28.4 (CH), 47.1
(CH2), 47.5 (CH2), 52.9 (CH2), 58.9 (CH), 110.1 (d, J ¼ 38.0 Hz, CH),
119.4 (CH), 125.3 (d, J ¼ 5.0 Hz, Cq), 138.7 (d, J ¼ 8.0 Hz, CH), 143.8
(Cq), 144.9 (d, J ¼ 15.0 Hz, CH), 163.5 (d, J ¼ 240.0 Hz, Cq); HRMS
(ESI): m/z calcd. for C14H17N5F [M þ H]þ: 274.1468, found: 274.1465.
5.1.24. 5-Ethynylbenzo[b]furane 28
To a solution of dimethyl 1-diazo-2-oxopropylphosphonate 27
(1.15 g, 6.0 mmol) in anhydrous MeOH (60 mL) were successively
added 5-formylbenzofuran (730 mg, 5.0 mmol) and K2CO3 (1.38 g,
10.0 mmol). The reaction mixture was stirred at room temperature
for 12 h. After a careful removal of solvent under reduced pressure,
the crude material was purified by flash chromatography to furnish
compound 28 as a white solid in 90% yield. Rf: 0.52 (petroleum
5.1.28. (R)-3-(4-(6-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)
quinuclidine 33
Compound 33 was obtained from 5-ethynyl-2-methoxypyridine
21 following the general procedure A and isolated as a white solid
in 28% yield. Rf: 0.28 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p.
ether/EtOAc: 95/5); M.p. 66e68 ꢂC; IR (ATR, Diamond):
n )
(cmꢀ1
882, 1029, 1107, 1118, 1195, 1265, 1329, 1436, 1460, 3290; 1H NMR
155e157 ꢂC; IR (ATR, Diamond):
n
(cmꢀ1) 973, 1027, 1215, 1254,

162
A. Ouach et al. / European Journal of Medicinal Chemistry 107 (2016) 153e164
1282, 1325, 1420, 1481, 1555, 1614, 1729, 2869, 2938; 1H NMR
(250 MHz, CDCl3): (ppm) 1.40e1.55 (m, 1H), 1.62e1.74 (m, 1H),
5.1.32. (R)-3-(4-(4-(2-fluoroethyl)phenyl)-1H-1,2,3-triazol-1-yl)
quinuclidine 37
d
1.75e1.88 (m, 2H), 2.27 (q, J ¼ 3.0 Hz, 1H), 2.84e3.00 (m, 3H),
3.08e3.22 (m, 1H), 3.42e3.56 (m, 1H), 3.72 (dd, J ¼ 4.3 Hz,
J ¼ 14.3 Hz, 1H), 3.97 (s, 3H), 4.58e4.69 (m, 1H), 6.81 (d, J ¼ 8.6 Hz,
1H), 7.77 (s, 1H), 8.07 (dd, J ¼ 2.2 Hz, J ¼ 8.6 Hz, 1H), 8.56 (d,
Compound 37 was obtained from alkyne 25 following the gen-
eral procedure A and isolated as a white solid in 17% yield. Rf: 0.35
(CH2Cl2/MeOH þ NH4OH: 95/5 þ 1%); M.p. 108e110 ꢂC; IR (ATR,
Diamond):
n
(cmꢀ1) 612, 662, 781, 802, 834, 969, 1014, 1161, 1180,
J ¼ 2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d
(ppm) 20.3 (CH2), 26.2
1261, 1655, 2118, 2940, 2958; 1H NMR (400 MHz, CDCl3):
d (ppm)
(CH2), 28.4 (CH), 47.2 (CH2), 47.5 (CH2), 52.9 (CH2), 53.8 (CH3), 58.8
(CH), 111.3 (CH), 118.7 (CH), 120.5 (Cq), 136.5 (CH), 144.3 (CH), 145.0
(Cq), 164.2 (Cq); HRMS (ESI): m/z calcd. for C15H20N5O [M þ H]þ:
286.1668, found: 286.1681.
1.45e1.51 (m, 1H), 1.67e1.88 (m, 3H), 2.28 (q, J ¼ 3.2 Hz, 1H),
2.94e3.09 (m, 5H), 3.11e3.23 (m, 1H), 3.48e3.54 (m, 1H), 3.73 (d,
J ¼ 12.2 Hz, 1H), 4.57e4.73 (m, 3H), 7.30 (d, J ¼ 8.0 Hz, 2H),
7.78e7.80 (m, 3H); 13C NMR (100 MHz, CDCl3):
d (ppm) 19.8 (CH2),
25.8 (CH2), 28.0 (CH), 36.4 (CH2), 36.6 (CH2), 46.9 (d, J ¼ 36.0 Hz,
CH2), 52.4 (CH2), 58.1 (CH), 83.8 (d, J ¼ 168.0 Hz, CH2), 118.7 (CH),
125.7 (2 ꢁ CH), 129.0 (Cq), 129.3 (2 ꢁ CH), 137.0 (d, J ¼ 6.0 Hz, Cq),
147.2 (Cq); HRMS (ESI): m/z calcd. for C17H22FN4 [M þ H]þ: 301.1822,
found: 301.1824.
5.1.29. (R)-2-(4-(1-(quinuclidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)
ethanol 34
Compound 34 was obtained from alkyne 22 following the
general procedure A and isolated as a white solid in 38% yield. Rf:
0.35 (CH2Cl2/MeOH þ NH4OH: 95/5 þ 1%); M.p. 148e150 ꢂC; IR
(ATR, Diamond):
n
(cmꢀ1) 788, 815, 917, 1038, 1153, 1265, 1452,
5.1.33. (R)-3-(4-(4-(2-fluoroethoxy)phenyl)-1H-1,2,3-triazol-1-yl)
quinuclidine 38
1502, 1613, 2853, 2930; 1H NMR (400 MHz, CDCl3):
d (ppm)
Compound 38 was obtained from alkyne 26 following the
general procedure A and isolated as a white solid in 11% yield. Rf:
0.35 (CH2Cl2/MeOH þ NH4OH: 95/5 þ 1%); M.p. 126e128 ꢂC; IR
1.44e1.51 (m, 1H), 1.64e1.71 (m, 1H), 1.75e1.84 (m, 2H), 2.17 (br s,
1H), 2.27 (q, J ¼ 3.0 Hz, 1H), 2.88e2.98 (m, 5H), 3.09e3.16 (m, 1H),
3.42e3.48 (m, 1H), 3.67 (dd, J ¼ 4.8 Hz, J ¼ 14.4 Hz, 1H), 3.88 (t,
J ¼ 6.5 Hz, 2H), 4.61e4.66 (m, 1H), 7.30 (d, J ¼ 8.0 Hz, 2H), 7.77e7.79
(ATR, Diamond):
n
(cmꢀ1) 618, 787, 802, 837, 888, 926, 1047, 1072,
1107, 1249, 1316, 1428, 1489, 1617, 1688, 2867, 2938, 3120; 1H NMR
(400 MHz, CDCl3): (ppm) 1.42e1.51 (m, 1H), 1.65e1.83 (m, 3H),
(m, 3H); 13C NMR (100 MHz, CDCl3):
d (ppm) 19.9 (CH2), 25.9 (CH2),
d
28.1 (CH), 39.0 (CH2), 46.8 (CH2), 47.2 (CH2), 52.5 (CH2), 58.2 (CH),
63.4 (CH2), 118.8 (CH), 125.9 (2 ꢁ CH), 128.8 (Cq), 129.5 (2 ꢁ CH),
138.8 (Cq), 147.4 (Cq); HRMS (ESI): m/z calcd. for C17H23N4O
[M þ H]þ: 299.1872, found: 299.1870.
2.26 (q, J ¼ 3.2 Hz, 1H), 2.85e3.00 (m, 3H), 3.10e3.17 (m, 1H),
3.44e3.51 (m, 1H), 3.69 (dd, J ¼ 4.6 Hz, J ¼ 14.6 Hz, 1H), 4.25 (dt,
J ¼ 4.4 Hz, J ¼ 27.6 Hz, 2H), 4.61e4.64 (m, 1H), 4.77 (dt, J ¼ 4.4 Hz,
J ¼ 47.2 Hz, 2H), 6.98 (d, J ¼ 8.7 Hz, 2H), 7.73 (s, 1H), 7.76 (d,
J ¼ 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d (ppm) 19.8 (CH2), 25.8
5.1.30. (R)-2-(4-(1-(quinuclidin-3-yl)-1H-1,2,3-triazol-4-yl)
phenoxy)ethanol 35
(CH2), 27.9 (CH), 46.7 (CH2), 47.1 (CH2), 52.5 (CH2), 58.2 (CH), 67.0
(d, J ¼ 21.0 Hz, CH2), 81.7 (d, J ¼ 170.0 Hz, CH2), 114.8 (2 ꢁ CH), 118.1
(CH), 123.8 (Cq), 126.8 (2 ꢁ CH), 147.1 (Cq), 158.2 (Cq); HRMS (ESI):
m/z calcd. for C17H22FN4O [M þ H]þ: 317.1772, found: 317.1774.
Compound 35 was obtained from alkyne 23 following the
general procedure A and isolated as a white solid in 44% yield. Rf:
0.35 (CH2Cl2/MeOH þ NH4OH: 95/5 þ 1%), M.p. 168e170 ꢂC; IR
(ATR, Diamond):
n
(cmꢀ1) 694, 822, 925, 1040, 1155, 1267, 1458,
5.1.34. (R)-3-(4-(benzofuran-5-yl)-1H-1,2,3-triazol-1-yl)
quinuclidine 39
1530, 1602, 2836, 2950; 1H NMR (400 MHz, DMSO-d6):
d (ppm)
1.34e1.47 (m, 2H), 1.67e1.78 (m, 2H), 2.17 (q, J ¼ 3.0 Hz, 1H),
2.71e2.79 (m, 3H), 2.93e3.00 (m, 1H), 3.32e3.47 (m, 2H), 3.73 (d,
J ¼ 3.0 Hz, 2H), 4.02 (t, J ¼ 5.0 Hz, 2H), 4.70e4.74 (m, 1H), 4.87 (br s,
Compound 39 was obtained from alkyne 28 following the
general procedure A and isolated as a white solid in 34% yield. Rf:
0.34 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p. 180e182 ꢂC; IR
1H), 7.01 (d, J ¼ 8.8 Hz, 2H), 7.78 (d, J ¼ 8.8 Hz, 2H), 8.60 (s, 1H); 13
C
(ATR, Diamond):
n
(cmꢀ1) 989, 1029, 1062, 1109, 1194, 1221, 1321,
1455, 1497, 2870, 2935; 1H NMR (400 MHz, CDCl3):
d (ppm)
NMR (100 MHz, CDCl3):
d (ppm) 20.1 (CH2), 25.8 (CH2), 28.1 (CH),
46.8 (CH2), 47.1 (CH2), 52.4 (CH2), 57.8 (CH2), 60.0 (CH2), 70.0 (CH),
115.2 (2 ꢁ CH), 120.3 (CH), 123.9 (Cq), 126.9 (2 ꢁ CH), 146.5 (Cq),
158.8 (Cq); HRMS (ESI): m/z calcd. for C17H23N4O2 [M þ H]þ:
315.1815, found: 315.1817.
1.44e1.53 (m, 1H), 1.67e1.77 (m, 1H), 1.78e1.89 (m, 2H), 2.30 (q,
J ¼ 3.0 Hz,1H), 2.88e3.00 (m, 3H), 3.12e3.22 (m,1H), 3.46e3.55 (m,
1H), 3.73 (dd, J ¼ 4.3 Hz, J ¼ 14.3 Hz, 1H), 4.63e4.69 (m, 1H), 6.81 (d,
J ¼ 2.1 Hz, 1H), 7.54 (d, J ¼ 8.6 Hz, 1H), 7.64 (d, J ¼ 2.1 Hz, 1H), 7.76
(dd, J ¼ 1.6 Hz, J ¼ 8.6 Hz,1H), 7.82 (s,1H), 8.10 (d, J ¼ 1.6 Hz,1H); 13
C
5.1.31. (R)-3-(4-(4-(2-(methoxymethoxy)ethoxy)phenyl)-1H-1,2,3-
triazol-1-yl) quinuclidine 36
NMR (100 MHz, CDCl3): d (ppm) 20.3 (CH2), 26.2 (CH2), 28.4 (CH),
47.2 (CH2), 47.5 (CH2), 52.9 (CH2), 58.6 (CH), 107.0 (CH), 111.9 (CH),
118.6 (CH), 118.8 (CH), 122.6 (CH), 125.9 (Cq), 128.2 (Cq), 145.9 (CH),
148.2 (Cq), 155.1 (Cq); HRMS (ESI): m/z calcd. for C17H19N4O
[M þ H]þ: 295.1559, found: 295.1557.
Compound 36 was obtained from alkyne 24 following the
general procedure A and isolated as a white solid in 30% yield. Rf:
0.35 (CH2Cl2/MeOH þ NH4OH: 95/5 þ 1%); M.p. 125e127 ꢂC; IR
(ATR, Diamond):
n
(cmꢀ1) 610, 789, 802, 917, 989, 1041, 1109, 1153,
1249, 1452, 1497, 1613, 2865, 2940; 1H NMR (400 MHz, CDCl3):
5.1.35. (R)-3-(4-(benzo[b]thiophen-5-yl)-1H-1,2,3-triazol-1-yl)
quinuclidine 40
d
(ppm) 1.45e1.56 (m, 1H), 1.67e1.88 (m, 3H), 2.26 (q, J ¼ 3.0 Hz,
1H), 2.89e2.98 (m, 3H), 3.10e3.17 (m,1H), 3.40 (s, 3H), 3.43e3.51 (t,
J ¼ 12.6 Hz, 1H), 3.67e3.72 (dd, J ¼ 4.3 Hz, J ¼ 14.1 Hz, 1H),
3.90e3.92 (t, J ¼ 3.1 Hz, 2H), 4.17e4.20 (t, J ¼ 5.1 Hz, 2H), 4.61e4.63
(m, 1H), 4.72 (s, 2H), 6.97e6.99 (d, J ¼ 9.1 Hz, 2H), 7.72 (s, 1H),
Compound 40 was obtained from alkyne 29 following the
general procedure A and isolated as a white solid in 32% yield. Rf:
0.32 (CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p. 178e180 ꢂC; IR
(ATR, Diamond): n
(cmꢀ1) 1023, 1047, 1202, 1223, 1323, 1440, 2866,
7.74e7.76 (d, J ¼ 9.1 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d
(ppm)
2933; 1H NMR (400 MHz, CDCl3):
d (ppm) 1.44e1.53 (m, 1H),
19.9 (CH2), 25.9 (CH2), 27.9 (CH), 46.8 (CH2), 47.1 (CH2), 52.5 (CH2),
55.1 (CH3), 58.1 (CH), 65.7 (CH2), 67.2 (CH2), 96.4 (CH2), 114.7
(2 ꢁ CH), 117.9 (CH), 123.4 (Cq), 126.7 (2 ꢁ CH), 147.2 (Cq), 158.5 (Cq),
HRMS (ESI): m/z calcd. for C19H27N4O3 [M þ H]þ: 359. 2078, found:
359.2081.
1.66e1.76 (m, 1H), 1.77e1.88 (m, 2H), 2.30 (q, J ¼ 3.0 Hz, 1H),
2.86e3.00 (m, 3H), 3.11e3.21 (m, 1H), 3.50 (ddd, J ¼ 2.1 Hz,
J ¼ 9.8 Hz, J ¼ 14.5 Hz, 1H), 3.70 (dd, J ¼ 5.0 Hz, J ¼ 14.5 Hz, 1H),
4.62e4.69 (m, 1H), 7.37 (d, J ¼ 5.4 Hz, 1H), 7.47 (d, J ¼ 5.4 Hz, 1H),
7.80 (dd, J ¼ 1.1 Hz, J ¼ 8.4 Hz, 1H), 7.86 (s, 1H), 7.92 (d, J ¼ 8.4 Hz,

A. Ouach et al. / European Journal of Medicinal Chemistry 107 (2016) 153e164
163
1H), 8.33 (d, J ¼ 1.1 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d
(ppm)
1038, 1075, 1222, 1246, 1321, 1453, 1497, 2869, 2933; 1H NMR
(250 MHz, CDCl3): (ppm) 1.46e1.68 (m, 2H), 1.69e1.84 (m, 1H),
20.3 (CH2), 26.2 (CH2), 28.4 (CH), 47.2 (CH2), 47.5 (CH2), 52.9 (CH2),
58.6 (CH), 119.1 (CH), 120.8 (CH), 122.4 (CH), 123.1 (CH), 124.2 (CH),
127.2 (Cq), 127.4 (CH), 139.6 (Cq), 140.2 (Cq), 147.9 (Cq); HRMS (ESI):
m/z calcd. for C17H19N4S [M þ H]þ: 311.1330, found: 311.1322.
d
2.05e1.19 (m, 1H), 2.28e2.35 (m, 1H), 2.76e2.92 (m, 1H), 2.93e3.06
(m, 3H), 3.29 (dd, J ¼ 15.2 Hz, J ¼ 30.5 Hz, 1H), 3.82 (dd, J ¼ 15.2 Hz,
J ¼ 24.8 Hz, 1H), 7.59e7.69 (m, 4H), 8.01 (s, 1H); 13C NMR (100 MHz,
CDCl3):
d
(ppm) 20.6 (d, J ¼ 8.0 Hz, CH2), 22.3 (d, J ¼ 6.0 Hz, CH2),
5.1.36. 3-(1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl)quinuclidin-3-
ol 41
32.9 (d, J ¼ 24.0 Hz, CH), 46.5 (CH2), 47.0 (CH2), 59.7 (d, J ¼ 24.0 Hz,
CH2), 93.4 (d, J ¼ 177.0 Hz, Cq), 119.6 (d, J ¼ 5.0 Hz, CH), 122.1
(2 ꢁ CH), 122.8 (Cq), 133.1 (2 ꢁ CH), 136.0 (Cq), 151.0 (d, J ¼ 32.0 Hz,
Cq); HRMS (ESI): m/z calcd. for C15H17BrFN4 [M þ H]þ: 351.0621,
found: 351.0637.
Compound 41 was obtained from alkyne 31 following the gen-
eral procedure A and isolated as a white solid in 91% yield. Rf: 0.22
(CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p. 214e216 ꢂC; IR (ATR,
Diamond):
n
(cmꢀ1) 994, 1040, 1214, 1320, 1445, 1496, 2871, 2927,
3112; 1H NMR (250 MHz, CDCl3):
d (ppm) 1.42e1.58 (m, 3H),
5.1.40. 3-Fluoro-3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)
quinuclidine 45
2.15e2.31 (m, 2H), 2.72e3.04 (m, 4H), 3.08 (d, J ¼ 14.3 Hz, 1H), 3.32
(br s, 1H), 3.62 (dd, J ¼ 1.3 Hz, J ¼ 14.3 Hz, 1H), 7.59e7.68 (m, 4H),
Compound 45 was obtained as described for 43 starting from 42
as a pale viscous oil in 64% yield. Rf: 0.54 (CH2Cl2/MeOH þ NH4OH:
7.99 (s, 1H); 13C NMR (100 MHz, CDCl3):
d (ppm) 21.8 (CH2), 23.1
80/20 þ 1%); IR (ATR, Diamond):
n
(cmꢀ1) 992, 1043, 1110, 1175,
(CH2), 33.7 (CH), 46.4 (CH2), 47.1 (CH2), 62.3 (CH2), 69.7 (Cq), 119.0
(CH), 122.1 (2 ꢁ CH), 122.7 (Cq), 133.1 (2 ꢁ CH), 136.1 (Cq), 155.1 (Cq);
HRMS (ESI): m/z calcd. for C15H18BrN4O [M þ H]þ: 349.0664, found:
349.0657.
1254, 1306, 1462, 1518, 1611, 2961, 3392; 1H NMR (250 MHz, CDCl3):
(ppm) 1.45e1.62 (m, 2H), 1.64e1.82 (m, 1H), 2.02e2.19 (m, 1H),
d
2.28e2.36 (m, 1H), 2.74e2.90 (m, 1H), 2.91e3.04 (m, 3H), 3.28 (dd,
J ¼ 15.2 Hz, J ¼ 30.5 Hz, 1H), 3.75e3.83 (m, 1H), 3.85 (s, 3H), 7.01 (d,
J ¼ 8.9 Hz, 2H), 7.62 (d, J ¼ 8.9 Hz, 2H), 7.93 (s, 1H); 13C NMR
5.1.37. 3-(1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)quinuclidin-
3-ol 42
(100 MHz, CDCl3):
d
(ppm) 20.7 (d, J ¼ 8.0 Hz, CH2), 22.4 (d,
Compound 42 was obtained from alkyne 31 following the gen-
eral procedure A and isolated as a white solid in 87% yield. Rf: 0.22
(CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p. 174e176 ꢂC; IR (ATR,
J ¼ 8.0 Hz, CH2), 32.9 (d, J ¼ 24.0 Hz, CH), 46.5 (CH2), 47.0 (CH2), 55.8
(CH3), 59.7 (d, J ¼ 24.0 Hz, CH2), 93.4 (d, J ¼ 175.0 Hz, Cq), 115.0
(2 ꢁ CH),119.9 (d, J ¼ 4.0 Hz, CH),122.4 (2 ꢁ CH),130.6 (Cq),150.4 (d,
J ¼ 32.0 Hz, Cq), 160.1 (Cq); HRMS (ESI): m/z calcd for C16H20FN4O
[M þ H]þ: 303.1621, found: 303.1623.
Diamond):
n
(cmꢀ1) 992, 1049, 1133, 1231, 1305, 1439, 1517, 2873,
2928, 2998, 3112, 3348; 1H NMR (250 MHz, CDCl3):
d (ppm)
1.42e1.58 (m, 3H), 2.17e2.31 (m, 2H), 2.76e2.95 (m, 3H), 2.96e3.14
(m, 2H), 3.20e3.43 (m, 1H), 3.61 (dd, J ¼ 1.6 Hz, J ¼ 14.4 Hz, 1H),
3.86 (s, 3H), 7.00 (d, J ¼ 8.9 Hz, 2H), 7.62 (d, J ¼ 8.9 Hz, 2H), 7.89 (s,
5.2. In vitro biological evaluations
1H); 13C NMR (100 MHz, CDCl3):
d (ppm) 21.2 (CH2), 23.3 (CH2), 33.7
The measurement of Ki towards
membrane preparation from rat frontal cortices according to a
previously described method [19e21]. Stable -bungarotoxin was
obtained from Tocris Bioscience (R&D Systems, Lille, France) and
125I]
-bungarotoxin (specific activity 81.4 TBq/mmol) from Per-
a7 nAChR was performed on a
(CH), 46.5 (CH2), 47.1 (CH2), 55.8 (CH3), 62.4 (CH2), 69.7 (Cq), 115.0
(2 ꢁ CH),119.2 (CH),122.4 (2 ꢁ CH),130.7 (Cq), 154.5 (Cq),160.0 (Cq);
HRMS (ESI): m/z calcd. for C16H21N4O2 [M þ H]þ: 301.1665, found
m/z ¼ 301.1669.
a
[
a
kineElmer (Courtaboeuf, France). The IC50 values were determined
5.1.38. (R)-3-(4-(4-(fluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)
quinuclidine 43
graphically for each compound and the Ki calculated [46]. Selec-
tivity experiments towards the
a4b2 and 5-HT3 receptors were
To a solution of alcohol 18 (140 mg, 0.500 mmol) in CH2Cl2
performed by CEREP (Poitiers, France) on cells transfected with
human recombinants using as reference ligands [3H]cytisine and
[3H]BRL 43694, respectively.
(10 mL) at 0 ꢂC, was added dropwise the DAST (92
mL, 0.70 mmol).
After 1 h, a saturated aqueous NaHCO3 solution (20 mL) was added.
After extraction, the organic layer was dried over MgSO4, filtered
and concentrated under reduced pressure. The crude residue was
purified by flash chromatography (CH2Cl2/MeOH þ NH4OH: 90/
10 þ 1%) to afford 43 as a white solid with a 51% yield. Rf: 0.41
(CH2Cl2/MeOH þ NH4OH: 80/20 þ 1%); M.p. 148e150 ꢂC; IR (ATR,
Acknowledgments
This research was supported by grants from the Region Centre
Val de Loire/FEDER (IMAD program), the ANR Malz program (ANR-
10-MALZ-0004) and France Alzheimer. The two teams (ICOA, U930)
involved in the project are members of Labex IRON (ANR-11-LABX-
0018-01) which is associated with this work.
Diamond):
1500, 2870, 2940; 1H NMR (250 MHz, CDCl3):
n
(cmꢀ1) 974, 1010, 1060, 1212, 1317, 1382, 1407, 1453,
d
(ppm) 1.41e1.56 (m,
1H), 1.62e1.74 (m, 1H), 1.76e1.94 (m, 2H), 2.30 (q, J ¼ 3.0 Hz, 1H),
2.86e3.00 (m, 3H), 3.09e3.24 (m, 1H), 3.50 (ddd, J ¼ 2.0 Hz,
J ¼ 9.6 Hz, J ¼ 14.6 Hz, 1H), 3.72 (dd, J ¼ 5.1 Hz, J ¼ 14.5 Hz, 1H),
4.61e4.70 (m, 1H), 5.41 (d, J ¼ 47.8 Hz, 2H), 7.44 (dd, J ¼ 1.6 Hz,
Appendix A. Supplementary data
J ¼ 8.6 Hz, 2H), 7.84 (s, 1H), 7.88 (dd, J ¼ 1.0 Hz, J ¼ 8.6 Hz, 2H); 13
C
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2015.11.001.
NMR (100 MHz, CDCl3):
d (ppm) 20.3 (CH2), 26.2 (CH2), 28.4 (CH),
47.1 (CH2), 47.5 (CH2), 52.9 (CH2), 58.7 (CH), 84.5 (d, J ¼ 166.0 Hz,
CH2), 119.4 (CH), 126.1 (2 ꢁ CH), 128.2 (d, J ¼ 6.0 Hz, 2 ꢁ CH), 131.4
(d, J ¼ 3.0 Hz, Cq), 136.2 (d, J ¼ 17.0 Hz, Cq), 147.3 (Cq); HRMS (ESI):
m/z calcd. for C16H20N4F [M þ H]þ: 287.1672, found: 287.1660.
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