Synthesis and biological evaluation of novel N-substituted nipecotic acid derivatives with an alkyne spacer as GABA uptake inhibitors

Article abstract of DOI:10.1016/j.bmc.2018.05.049

In this study, we present the synthesis and structure–activity relationships (SAR) of novel N-substituted nipecotic acid derivatives closely related to (S)-SNAP-5114 (2) in the pursuit of finding new and potent mGAT4 selective inhibitors. By the use of iminium ion chemistry, a series of new N-substituted nipecotic acid derivatives containing a variety of heterocycles, and an alkyne spacer were synthesized. Biological evaluation of the prepared compounds showed, how the inhibitory potency and subtype selectivity for the murine GABA transporters (mGATs) were influenced by the performed modifications.

Full text of DOI:10.1016/j.bmc.2018.05.049

Accepted Manuscript
Synthesis and biological evaluation of novel N-substituted nipecotic acid de-
rivatives with an alkyne spacer as GABA uptake inhibitors
Krisztián Tóth, Georg Höfner, Klaus T. Wanner
PII:
S0968-0896(18)30715-6
https://doi.org/10.1016/j.bmc.2018.05.049
BMC 14391
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 April 2018
25 May 2018
30 May 2018
Please cite this article as: Tóth, K., Höfner, G., Wanner, K.T., Synthesis and biological evaluation of novel N-
substituted nipecotic acid derivatives with an alkyne spacer as GABA uptake inhibitors, Bioorganic & Medicinal
Chemistry (2018), doi: https://doi.org/10.1016/j.bmc.2018.05.049
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Synthesis and biological evaluation of novel N-substituted
nipecotic acid derivatives with an alkyne spacer as GABA
uptake inhibitors
Krisztián Tóth, Georg Höfner, Klaus T. Wanner*
Department of Pharmacy–Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 5–13, 81377
Munich, Germany, klaus.wanner@cup.uni-muenchen.de
Highlights:



New alkyne analogs of SNAP-5114 based on DDPM-1457 with increased rigidity
Variation in spacer length had limited effect on potency at mGAT4
Benzothiophene as part of the triaryl residue showed promising result.
Abstract:
In this study, we present the synthesis and structure-activity relationships (SAR) of novel
N-substituted nipecotic acid derivatives closely related to SNAP-5114 (2) in the pursuit of finding new
and potent mGAT4 selective inhibitors. By the use of iminium ion chemistry, a series of new N-
substituted nipecotic acid derivatives containing a variety of heterocycles, and an alkyne spacer were
synthesized. Biological evaluation of the prepared compounds showed, how the inhibitory potency and
subtype selectivity for the murine GABA transporters (mGATs) were influenced by the performed
modifications.
Keywords: GABA uptake inhibitor, mGAT4, nipecotic acid, iminium ion chemistry
1. Introduction
The major inhibitory neurotransmitter in the central nervous system (CNS) is gamma-aminobutyric
acid (GABA).1 The decrease in the GABAergic neurotransmission can cause severe neurological
disorders like epilepsy,2,3 Alzheimer’s disease,4 and depression5. The concentration of GABA in the
synaptic cleft is amongst other factors controlled by the GABA transporters (GATs).6 These
membrane-bound proteins,7,8 that exist in four different subtypes, belong to the solute carrier 6 (SLC6)
family.9,10 The nomenclature for these proteins that vary with regard to their distribution and function

depends on the species from which they are cloned. GABA transporters cloned from mice are named
as mGAT1, mGAT2, mGAT3, and mGAT4, whereas according to the Human Genome Organization
(HUGO), they are denoted as GAT1 (≡ mGAT1), BGT-1 (≡ mGAT2), GAT2 (≡ mGAT3), and GAT3 (≡
mGAT4).11 mGAT1 and mGAT4 have been found to be clearly predominating in the CNS.7,12 Of these,
mGAT1 is mainly responsible for the neuronal uptake of GABA in presynaptic cells. Whereas mGAT4
mediates, in particular, GABA transport from the synaptic cleft into glial cells.13,14 mGAT2 and mGAT3
are playing a rather insignificant role in the termination of the GABAergic neurotransmission,15 but are
present at high levels in the kidneys and liver.16
Through the inhibition of mGAT1 and mGAT4, elevated levels of GABA can be achieved in the
CNS which offers a treatment for diverse neurological disorders mentioned before. Tiagabine (1) is a
selective mGAT1 reuptake inhibitor used in the treatment of epilepsy, anxiety disorders, and
neuropathic pain, but its main drawbacks are side effects such as dizziness, asthenia, nervousness,
tremor, diarrhea, and depression.17,18 The selective inhibition of mGAT4 could open up a new
therapeutic approach with less side effects, but selective and potent mGAT4 inhibitors are not
available so far.
In addition to highly potent mGAT1 selective reuptake inhibitors such as tiagabine (1)19,20 also
several ligands of the three non-mGAT1 proteins, i.e. mGAT2–mGAT4 have been identified, though
for the most part of these compounds the potency and selectivity are far behind that of mGAT1
21,22,23,24,25
inhibitors.
(S)-SNAP-5114 (2) represents the first prototypic mGAT4 inhibitor with
reasonable potency at and selectivity for this target.26 Later on, carba-analogs of 2 such as DDPM-
1457 (3) were identified to display similar potencies and subtype selectivities, but to be devoid of the
chemical instability encountered for trityl derivative 2.27 More recently, isatin derivatives have been
reported as a new class of hGAT3 (≡ mGAT4) inhibitors with compound 4 representing the most
potent member.28
Tiagabine (1)
(S)-SNAP-5114 (2)
2

DDPM-1457 (3)
Figure 1. Selected GABA uptake inhibitors.
4
3

In this study, we report on our efforts to broaden the structure-activity relationship of the
carba-analogs of (S)-SNAP-5114 (2) i.e. of compounds such as DDPM-1457 (3), at the same time
aiming at the identification of more potent and selective inhibitors for mGAT4. To this end, the
structure of DDPM-1457 (3) has been varied in different respects, as shown in Figure 2. The first two
modifications involved the linker between the nipecotic acid and the aromatic lipophilic residue. Herein
as a major modification, instead of a trans-moiety as in 3, an alkyne subunit was implemented
resulting as a first representative in rac-5a. In a second step, one of the aromatic moieties of the
lipophilic residue was replaced with a series of new residues (rac-5b–j), like aromatic and
heteroaromatic cycles, benzylic residues or sterically less demanding groups (Table 1). Furthermore,
we also increased the length of the alkyne spacer by insertion of one methylene group. This was
performed at two different positions, both directly adjacent to the triple bond, either oriented towards
the nipecotic acid residue (rac-6a, rac-6k) or the lipophilic residue (rac-7a, rac-7k). That way the effect
of the linker length on the potency of the test compounds should be elucidated.
rac-5a–j
a: R = -C6H4-4-OCH3
DDPM-1457 (3)
rac-6a; m = 1, n = 0 (a: OCH3)
rac-6k; m = 1, n = 0 (k: H)
rac-7a; m = 0, n = 1
rac-7k; m = 0, n = 1
Figure 2. General structures of targeted N-substituted nipecotic acid derivatives rac-5a–j, rac-6a, rac-6k and rac-7a, rac-7k; for
structures of residues R see Table 4.
4

2. Results and Discussion
2.1.Chemistry
A retrosynthetic analysis for the carboxylic acid ethyl esters of the targeted scaffolds (rac-8a–j for
rac-5a–j; rac-11a for rac-6a, rac-11k for rac-6k, rac-13a for rac-7a, rac-13k for rac-7k, Figure 3) led us
by disconnecting the linker to following building blocks for the synthesis of the targeted compounds: A
common iminium compound rac-9 to be trapped with various Grignard reagents (10a–j, 12a, 12k, 14a,
14k). Iminium compound rac-9 could be expected to be easily accessible from an N,O-acetal
derivative rac-23 of ethyl nipecotate rac-22 (Table 2). The use of iminium ion chemistry for the outlined
purpose seemed highly rewarding as only organomagnesium species would have to be varied and
only non-toxic and inexpensive chemicals would be involved (Table 2).
rac-8a–j
rac-9
10a–j
rac-11a (a: OCH3)
rac-11k (k: H)
rac-9
12a
12k
rac-13a (a: OCH3)
rac-13k (k: H)
rac-9
14a
14k
Figure 3. Retrosynthetic analysis of targeted N-substituted nipecotic acid ester analogs rac-8a–j, rac-11a, rac-11k, rac-13a,
rac-13k.
5

2.1.1. Preparation of the alkynes
The synthesis of alkynes 18a–j required as precursors of the organomagnesium species, that were
to be reacted with iminium salt rac-9, is summarized in Table 1. In the first step, the alcohols 16a–f
were formed by the reaction of 4,4′-dimethoxybenzophenone (15) with the respective organometallic
reagent. For the synthesis of 16a–b and 16f Grignard reagents, 4-methoxyphenylmagnesium
bromide,29 benzo[d][1,3]dioxol-5-ylmagnesium bromide,30 and benzo[b]thiophen-5-ylmagnesium
bromide31 were employed and for the preparation of alcohols 16c–e organolithium reagents, i. e.
thiazol-2-yllithium,32 (1-methyl-1H-imidazol-2-yl)lithium,33 and thiophen-3-yllithium32 were used,
respectively (yields 60% - 98%). To obtain chlorides 17a–f, in the following step alcohols 16a, 16f
were reacted34 with acetyl chloride (AcCl), alcohols 16b, 16c, 16e with thionyl chloride (SOCl2),35 and
alcohol 16d with a mixture36 of AcCl and SOCl2, respectively. As such chlorides are usually unstable
due to the ease of carbenium ion formation,37 compounds 17a–f were used without any further
purification. Alkynes 18a-d were synthesized from chlorides 17a–d by reaction with ethynylmagnesium
bromide in analogy to a literature method,38 in reasonable to excellent yields (42-97%).
Attempts to synthesize 18e–f by the same protocol, i.e. by reaction of chlorides 17e–f comprising
heterocyclic residues (thiophene or benzothiophene) with ethynylmagnesium bromide failed. Hence a
modified
method
was
used.
Here,
instead
of
ethynylmagnesium
bromide,
(trimethylsilyl)ethynyllithium39 was employed which gave the TMS protected alkynes 21e–f in
reasonable yields (52% and 63%). Finally, after removal of the TMS protective group by means of
K2CO3 in MeOH,40 the desired alkynes 18e-f were obtained in yields of 84% and 95%, respectively.
Alkyne 18g exhibiting a hydroxy function instead of an aromatic moiety was synthesized by addition of
ethynylmagnesium bromide to 15 according to a literature procedure.41
The known TMS diaryl alkyne 21h42 as precursor of the desired alkyne 18h was synthesized
according to a literature method43 from diaryl alcohol 19 via diaryl bromide 20.44 Removal of the TMS
group by the treatment with K2CO3 in MeOH yielded the diaryl alkyne 18h. TMS protected alkyne 21h
was further employed for the construction of 18i–j by the introduction of a benzyl residue in the first
step. Treatment45 of the alkyne 21h with nBuLi and subsequently with either benzyl bromide or
4-methoxybenzyl chloride46 gave TMS protected alkynes 21i–j (96% and 90%) which after removal of
the TMS group delivered alkynes 18i–j in 77% and 88% yield, respectively.
6

Table 1.
Synthesis of the alkynes 18a–j.
15
16a–f
17a–f
18a–d
18g41
18e–f
18i–j
19
2044
21h42
18h
21e–f
21i–j
TMS
Alkynes
21
Entry
R
Alcohols
Yield
%
Halides
17, 20
Yield
%
Conditions
Yield
%
Alkynes
18
Conditions
Yield
%
i
j
i
i
16
1
2
3
16a29
16b
86
98
60
17a34
89
95
99
-
-
-
-
-
-
-
-
-
18a38
c
c
c
97
97
52
17b
17c
17d
17e
17f
-
18b
18c
18d
18e
18f
16c
4
5
16d
16e
16f
-
97
95
76
-
95
99
99
-
-
-
d
d
-
-
c
h
h
c
h
h
h
42
84
95
91
83
70
88
21e
21f
-
52
63
-
6
7
OH
H
18g41
18h
18i
8
19
-
-
2044
99
-
21h42
21i
21j
f
93
96
90
9
-
-
g
g
10
-
-
-
-
18j
Reagents and conditions: (a) RMgBr or RLi; (b) AcCl or SOCl2; (c) HC≡CMgBr; (d) TMSC≡CLi; (e) AcBr, toluene;
(f) TMSC≡CMgCl, CuBr, THF; (g) nBuLi, 4-methoxybenzyl chloride or benzyl bromide, THF, –78 °C; (h) K2CO3, MeOH.
iYield after chromatography; jYield after removal of the solvents
7

2.1.2. Synthesis of the N-substituted nipecotic acid esters by the coupling of the nipecotic acid derived
iminium salt with alkynyl Grignard reagents, and the subsequent hydrolysis to the corresponding
acids.
Reactions between iminium salts and organometallic nucleophiles are well precedented in the
literature.47,48,49 As a source for the iminium ion rac-9, we intended to use the N,O-acetal derivative
rac-23. This compound could be efficiently synthesized by reaction of rac-22 with paraformaldehyde
(PFA) in EtOH, the yield amounting to 88% (Table 2).50 For the in situ generation of iminium salt rac-9
analogously to a literature method,51 the N,O-acetal rac-23 was treated with trimethylsilyl chloride
(TMSCl) prior to every coupling reaction. The formation of the expected iminium salt rac-9 has
exemplarily been verified in an 1H NMR experiment. For the coupling reactions, the iminium salt rac-9
was reacted with the respective ethynylmagnesium nucleophiles 10a–j prepared from alkynes 18a–j
and nBuMgCl. This delivered the desired esters rac-8a–j in moderate to good yields (39% – 85%,
Table 2). In case of the synthesis of rac-8g from alkyne 18g (Table 2, entry 7), the amount of nBuMgCl
needed for the deprotonation of 18g was doubled to account for the acidic property of the hydroxy
group also present in the molecule. The chemoselectivity of this reaction deserves extra mentioning.
Though highly nucleophilic Grignard reagents were employed in the presence of an ester function at
elevated temperatures (40 °C), no significant formation of side products could be observed.
Finally, all of the thus obtained ethyl esters rac-8a–j were hydrolyzed by treatment with 12 M NaOH
in MeOH22 to give after wash up the free acids rac-5a–j in good to very good yields (79% – 98%, Table
2). In case of the diaryl derivative rac-18h (Table 2, entry 8), an acidic hydrolysis52 with 3 M HCl at
elevated temperature was performed to obtain rac-5h as under basic conditions side reactions leading
to an inseparable compound mixture occurred.53
8

Table 2.
Formation of the N-substituted nipecotic acid esters rac-8a–j, and their hydrolysis to the corresponding acid derivatives rac-5a–j.
rac-22
rac-23
rac-9
rac-8a–j
rac-5a–j
18a–j
10a–j
Entry
Alkynes
18
R
Esters
rac-8
Yield %f
80
Acids
rac-5
Yield %g
18a38
81
93
rac-8a
rac-8b
rac-5a
rac-5b
1
2
18b
18c
18d
18e
18f
71
rac-8c
rac-8d
rac-8e
rac-8f
rac-8g
rac-8h
rac-8i
rac-8j
rac-5c
rac-5d
rac-5e
rac-5f
rac-5g
rac-5h
rac-5i
rac-5j
3
4
85
39
57
62
72h
56
57
75
95
98
95
85
83
99i
90
90
5
6
7
18g41
18h
18i
OH
H
8
9
10
18j
Reagents and conditions: (a) PFA, K2CO3, EtOH; (b) TMSCl, THF; (c) nBuMgCl, THF; (d) THF, 45 °C; (e) 12 M NaOH, MeOH;
fIsolated yield after chromatography; gIsolated yield after extraction; h2 equiv. nBuMgCl was used; iAcidic hydrolysis: 3 M HCl,
50°C, isolated as HCl salt.
9

2.1.3. Synthesis of the N-substituted nipecotic acid esters with a longer spacer, and subsequent
hydrolysis to the corresponding acids.
For the synthesis of the desired alkynes exhibiting a longer spacer between the nipecotic acid
moiety and the lipophilic residue (Scheme 1), chlorides 17a, 17k were reacted with
propargylmagnesium bromide54 or with lithium chloropropargylide55 to get to the targeted alkynes 25a,
25k, and 26a, 26k, respectively. The subsequent coupling reactions in which the iminium salt rac-9
was treated either with the Grignard reagents 14a and 14k derived from alkynes 25a and 25k or with a
propargylic Grignard reagent 12a and 12k prepared56 from the propargyl chlorides 26a and 26k
yielded the carboxylic esters rac-13a, rac-13k, rac-11a, and rac-11k, respectively, with a spacer
elongated from three to four carbon atoms. According to literature,57 propargylic Grignard reagents like
12a, 12k (Scheme 1) can undergo a rearrangement to give allenic isomers. This was also observed in
the case of the reaction of the iminium salt rac-9 with 12a, and 12k, as a side reaction and led to the
formation of allenic side products rac-27a, rac-27k which diminished the yields for the desired
compounds rac-11a (22%), and rac-11k (21%) substantially.
The same standard procedure as employed for the preparation of free acids rac-5a–g and rac-5i–j
(12 M NaOH, MeOH) was used for the hydrolysis of esters rac-13a, rac-13k, rac-11a, and rac-11k to
obtain the acids rac-6a, rac-6k, rac-7a, and rac-7k (Table 5), respectively in good to very good yields
(79% – 98%). The N-substituted nipecotic acid ester side products with an allene functionality rac-27a
and rac-27k (Scheme 1) were hydrolyzed under the same conditions giving the N-substituted nipecotic
acids rac-24a and rac-24k (Table 5) in 97% and 92% yields, respectively.
10

25a
25k
86%
86%
14a
14k
rac-13a
rac-13k
46%
76%
17a
17k
rac-11a
rac-11k
22%
21%
26a
26k
83%
73%
12a
12k
rac-27a
rac-27k
34%
34%
Scheme 1. Synthesis of alkynes 25a, 25k, and 26a, 26k, and the subsequent coupling to the corresponding N-substituted
nipecotic acid esters with a longer spacer rac-13a, rac-13k, rac-11a, rac-11k, and the N-substituted nipecotic acid esters with an
allenic spacer rac-27a, rac-27k. Reagents and conditions: (a) HC CCH2MgBr; (b) nBuMgCl, THF, 45 °C; (c) rac-9, THF, 45 °C;
(d) ClCH2C CLi, THF, –78 °C; (e) Mg, THF.
11

2.2.Biological evaluation
The newly synthesized N-substituted nipecotic acid derivatives with an alkyne spacer rac-5a–j,
rac-6a, rac-6k, rac-7a, rac-7k and also the N-substituted nipecotic acid derivatives with an allenic
moiety rac-24a, rac-24k were evaluated for their inhibitory potencies at mGAT4 and additionally for the
non-mGAT4 transporter subtypes mGAT1–mGAT3, using a standardized [3H]GABA uptake assay
based on HEK cells developed by our group.58 In addition, also binding affinities of these compounds
towards mGAT1 (expressed in HEK cells) were determined using a standardized MS Binding Assay.59
The measurements were done in triplicates and wherever possible, the potencies of the tested
compounds in the uptake assays are given as pIC50 values and the binding affinities as pKi values. In
cases where test compounds at a concentration of 100 µM were not able to reduce [3H]GABA uptake
to a value below 50%, which equals pIC50 values ≤ 4.00, only the percent values of the remaining
[3H]GABA uptake is given. Analogously, where test compounds applied at 100 µM did not reduce
specific MS Marker binding to a value below 50%, only the percentage of remaining MS Marker bound
to the target is given (≡ pKi ≤ 4.00).
Both (S)-SNAP-5114 (2) and DDPM-1457 (3) are enantiopure compounds derived from (S)-
nipecotic acid which exhibit the same nonpolar residue, but differ with regard to their linker connecting
their two subunits. In one case, this is an ethyloxy moiety (SNAP-5114, 2), in the other a trans-
configured propenyl chain (DDPM-1457, 3) and as thus triatomic as the former. These differences in
the nature of the linker, an ether function versus a C-C double bond, caused only minor differences in
the binding affinities and inhibitory potencies, but led to a distinctly improved stability for DDPM-1457
(3, Table 3). Besides, for comparison purposes also DDPM-859 (29) and compound 30 have been
included in Table 3.27 Both are closely related to (S)-SNAP-5114 (2) from which they only differ by an
additional ortho-methyl substituent at either one (29) or two (30) of the three phenyl residues present
in these compounds. Analogue 30, still being racemic, had a somewhat reduced mGAT4 inhibitory
potency as compared to (S)-SNAP-5114 (2) whereas its chemical stability was distinctly higher. In
contrast, enantiopure DDPM-859 (29) was characterized by not only a nominally slightly higher
mGAT4 inhibitory potency as compared to 2, but also a clearly improved subtype selectivity in regard
to mGAT3, the chemical stability remained, however, largely unchanged.
For economic reasons, for the synthesis of all compounds listed in Table 4, racemic ethyl
nipecotate (rac-22) has been employed. This also warrants that the biological activity of both
12

enantiomers is reflected in the test data. In general, for mGAT4 inhibitors derived from nipecotic acid,
the higher potency resides in the (S)-enantiomer. Still, by testing the (S)-enantiomers, potent (R)-
enantiomers might be missed. As for the comparison of the test results obtained for the new
compounds, in Table 4, all being racemic, enantiopure mGAT4-selective DDPM-1457 (3) seemed less
appropriate in these cases, the racemic form, DDPM-1007 (28), was used as reference point. 27, 60
Compound rac-5a (Table 4) differs from DDPM-1007 (28) only by the exchange of the trans-
configured C-C double bond in the spacer by an alkyne group. This relatively small change resulted in
a drop of the potency of rac-5a at mGAT4 by about one log unit, whereas the potency at mGAT1 was
increased by about 0.5 log units (compare Table 4, entry 1 with Table 3, entry 3). Compounds rac-5b
to rac-5g show the effects the modification of the lipophilic moiety exerts (Table 4), namely the
replacement of one aromatic moiety of the triaryl methyl residue with a heterocyclic or heteroaromatic
(rac-5b–f) or benzylic group (rac-5i–j) or by a hydrogen atom or hydroxyl group (rac-5g–h).
Compound rac-5b with an additional oxygen-containing ring shows nominally slightly lower potencies
on all mGATs except for mGAT2 for which they remain the same. Compounds rac-5c–d with a
thiazole or imidazole residue similarly to rac-5g possessing only a hydroxy group instead of one of the
three 4-methoxyphenyl moieties, in rac-5a, were devoid of any reasonable activity at the mGATs
(pIC50 = 4.00; Table 4, entries 3, 4, and 7). The potency displayed at mGAT4 of the thiophene ring
containing rac-5e was similar to that of rac-5a, whereas the mGAT1–3 values were nominally slightly
lower (Table 4, entry 5). Interestingly, rac-5f bearing a benzothiophene ring has higher potencies at all
mGATs than rac-5a, but possesses no reasonable selectivity for either of the four subtypes. In case of
rac-5h, where one of the three aromatic residues of 5a had been omitted, the potency at mGAT4
remained unchanged, but the potency at and selectivity for mGAT1 was somewhat higher, whereas at
mGAT3, it was lower and at mGAT2 practically inactive (Table 4, entry 8). Compounds rac-5i–j with a
benzylic moiety showed slightly reduced potencies at mGAT2–4 whereas at mGAT1, it was nominally
similar to rac-5i or slightly improved (rac-5j), (Table 4, entry 9-10).
Finally, we turned our attention toward compounds with an, as compared to rac-5a, by one carbon
extended spacer. The results for the respective compounds rac-6a, rac-6k, rac-7a, and rac-7k as well
as for rac-24a, and rac-24k containing an allene subunit are shown in Table 5. For compounds rac-6a,
and rac-7a differing from rac-5a by formal insertion of one methylene group adjacent to the nipecotic
acid or the trityl residue the potencies at all transporters remains very similar (Table 5, entry 1 and 3).
13

The corresponding compounds without methoxy groups in the para-position of the phenyl rings,
(rac-6k, and rac-7k, Table 5, entry 2 and 4) had, as compared to rac-6a and rac-7a, distinctly lower
potencies at mGAT3–4, and significantly increased at mGAT1. This was especially true for rac-6k
having a pIC50 of 6.37 ± 0.09 at mGAT1 (Table 5, entry 2). Compounds 24a, and rac-24k exhibiting an
allene functionality were found to neither possess any reasonable potency at or selectivity for mGAT1–
4 (Table 5, entry 5–6).
The binding affinities at mGAT1 determined for the compounds listed in Table 4, and Table 5 in
MS Binding Assays and given as pKi values were all in the same range as the corresponding
potencies, pIC50 values, for the same transporters. Thereby, all of the pKi values tend to be higher than
the corresponding pIC50 data up to about a half log unit. This is a general phenomenon which has
been reported already earlier.21,59
14

Table 3.
Binding affinities and inhibitory potencies of reference compounds 2, 3, 28, 29, 30, and 1 from the literature.
(S)-SNAP-5114 (2)
DDPM-1457 (3)
DDPM-1007 (28)
DDPM-859 (29)
30
Tiagabine(1)
b
pIC50
Entry
Compound
pKia
mGAT1
mGAT2
mGAT3
mGAT4
4.56e
±0.02
4.07
±0.09
5.29
±0.04
5.71
±0.07
(S)-SNAP-5114 (2)c
1
56%
4.33e
±0.06
4.40
±0.05
4.42
±0.11
5.47
±0.02
5.87
±0.08
2
3
4
5
6
DDPM-1457 (3)c
DDPM-1007 (28)c
DDPM-859 (29)c
30c
4.83e
±0.04
4.32
±0.05
4.68
±0.09
5.19
±0.06
5.67
±0.06
59%e
4.19
0.07
4.12
±0.08
4.85
±0.04
5.78
±0.03
4.42e
±0.02
4.17
±0.02
4.49
±0.09
4.54
±0.10
5.07
±0.09
7.43
±0.11
6.88
±0.12
Tiagabine(1)d
50%
64%
73%
aResults of MS Binding Assay results are given as pKi ± SEM. Percentages represent remaining specific NO711 binding in
presence of 100 µM test compound; bResults of [3H]GABA uptake assays results are given as pIC50 ± SEM. Percentages
represent remaining [3H]GABA uptake in presence of 100 µM test compound; cReference literature;27 dReference literature;60
epKi results were determined in our group from compounds synthesized according to literature26,27
15

Table 4.
Binding affinities and inhibitory potencies of the N-substituted nipecotic acids rac-5a–j.
rac-5a–j
b
pIC50
Entry
Compound
R
pKia
mGAT1
mGAT2
mGAT3
mGAT4
5.36
±0.02
rac-5a
1
4.84
4.36
4.61
4.53
5.31
±0.04
rac-5b
rac-5c
rac-5d
rac-5e
rac-5f
rac-5g
rac-5h
rac-5i
rac-5j
2
3
4.64
68%
80%
4.60
4.96
66%
4.38
84%
106%
70%
4.93
72%
80%
53%
67%
4.22
82%
103%
4.37
4.29
79%
91%
4.46
4.92
69%
4.63
4.44
4.38
4.11
83%
4
5.28
±0.12
5
5.72
±0.11
5.06
±0.04
6
7
OH
H
59%
74%
4.02
4.38
4.41
5.96
±0.05
5.43
±0.09
8
5.72
±0.09
9
4.88
5.67
±0.06
5.08
±0.08
10
aResults of MS Binding Assay results are given as pKi ± SEM. For low pKi values only one measurement was performed in
triplicate, therefore no SEM could be calculated. Percentages represent remaining specific NO711 binding in presence of 100
µM test compound; bResults of [3H]GABA uptake assays results are given as pIC50 ± SEM. For low pIC50 values only one
measurement was performed in triplicate, therefore no SEM could be calculated. Percentages represent remaining [3H]GABA
uptake in presence of 100 µM test compound
16

Table 5.
Binding affinities and inhibitory potencies of the N-substituted nipecotic acids with a longer spacer rac-6a, rac-6k, rac-7a, rac-7k,
and the N-substituted nipecotic acids with an allenic spacer rac-24a, rac-24k.
rac-6a (a: OCH3)
rac-6k (k: H)
rac-7a
rac-7k
rac-24a
rac-24k
b
pIC50
Entry
Compound
Residue
pKia
mGAT1
mGAT2
mGAT3
mGAT4
5.56
±0.03
rac-6a
1
OCH3
4.80
4.45
4.38
4.59
7.04
±0.11
6.37
±0.09
rac-6k
rac-7a
2
3
4
5
6
H
OCH3
H
66%
4.47
66%
77%
87%
61%
4.55
50%
4.37
80%
64%
4.76
4.15
4.31
54%
4.43
4.84
57%
70%
4.28
4.45
±0.03
rac-7k
rac-24a
rac-24k
OCH3
H
69%
62%
aResults of MS Binding Assay results are given as pKi ± SEM For low pKi values only one measurement was performed in
triplicate, therefore no SEM could be calculated. Percentages represent remaining specific NO711 binding in presence of 100
µM test compound; bResults of [3H]GABA uptake assays results are given as pIC50 ± SEM. For low pIC50 values only one
measurement was performed in triplicate, therefore no SEM could be calculated. Percentages represent remaining [3H]GABA
uptake in presence of 100 µM test compound
17

3. Conclusion
For the development of new mGAT4 inhibitors, the structure of DDPM-1457 (3), a carba-analogue
of prototypic mGAT4 inhibitor (S)-SNAP-5114 (2) has been extensively varied. For the construction of
the new compounds, iminium ion chemistry involving addition reaction of organomagnesium reagents
to a nipecotic acid derived iminium ion, rac-9, was found to be well suited. As a major modification, to
further increase the rigidity of the linker, the linker double bond was replaced by a triple bond.
Furthermore, this new linker was elongated by one carbon atom by introduction of a CH2 moiety on
either side of the triple bond. In any case, a significant decrease in mGAT4 potency, of about one log
unit, as compared to DDPM-1457 (3), resulted.
Additionally, the structure of the triarylmethyl moiety of rac-5a, the direct alkyne analogue of
DDPM-1457 (3), was modified by replacing one of the three aryl residues by different aryl, heteroaryl,
and benzyl groups. As compared to the parent compound rac-5a, the mGAT4 potency remained
mostly unaltered. Only for the benzothiophene derivative rac-5f, a reasonable increase in mGAT4
potency occurred. With the benzothiophene residue being similar in size and shape to the 4-
methoxyphenyl moiety present in the parent compound rac-5a, but more rigid, this may indicate that
especially electron rich and planar aryl moieties are particularly suitable for interaction with mGAT4
proteins.
18

4. Experimental section
4.1.Chemistry
Reactions were carried out in vacuum dried glassware under argon atmosphere. Tetrahydrofuran
(THF) and diethyl ether (Et2O) were distilled from sodium benzophenone ketyl. Dichloromethane
(DCM) was distilled from CaH2. All commercially available starting materials were used without further
purification and solvents were distilled before use. As petroleum ether (PE) the fraction 40–60°C was
used. Flash chromatography was performed on silica gel (Merck 60 F-254, 0.040–0.063 mm). HRMS
data were obtained with JMS-GCmate II (EI, Jeol) or Thermo Finnigan LTQ FT Ultra (ESI, Thermo
Finnigan). NMR spectra were recorded with a JNMR-GX (JEOL 400 or 500 MHz) or Bruker BioSpin
Avance III HD (400 or 500 MHz). As an internal standard, the known chemical shift of solvent traces
were used to reference the spectra. Spectra were processed using the software MestReNova. All
melting points are uncorrected and were determined using an Electrothermal IA9100 apparatus. For
IR spectroscopy, a Perkin Elmer FT-IR Spectrometer 1600 was used.
4.2.General procedures
4.2.1. Synthesis of the Grignard reagents from aryl, or alkyl halides (GP 1)
Magnesium turnings (1.3 equiv) were suspended in THF (2 mL) and 1,2-dibromoethane (0.1 equiv)
was added. The suspension was heated to 60 °C for 15 min. After cooling to 25 °C the solution of the
appropriate aryl, or alkyl halide (1.1 equiv) in THF (2 mL/ mmol) was added dropwise, and after the
exothermic reaction was finished the mixture was heated to 60 °C for 1 h. The slightly colored mixture
was cooled to 25 °C to obtain the corresponding Grignard reagent.
4.2.2. Synthesis of the triaryl alcohols from a Grignard reagent and ketone 15 (GP 2)
The appropriate Grignard reagent (1.3 equiv) generated according to GP 1 was added to ketone 15
(1.0 equiv) suspended in THF (2 mL/ mmol) and heated to 60 °C for 2 h. At 25 °C the mixture was
quenched with saturated aqueous NH4Cl solution and extracted with Et2O. The organic phases were
dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by
recrystallization or by column chromatography over silica gel.
4.2.3. Synthesis of the triaryl chlorides with acetyl chloride (GP 3)
AcCl (3 equiv) was added to the appropriate alcohol (1 equiv) dissolved in toluene (2 mL/ mmol)
and the mixture was heated to 100 °C. After 2 h, the volatiles were removed under reduced pressure
and the solid was dissolved in dry toluene (4 mL/ mmol) and evaporated to dryness three times. The
crude product was used without any further purification.
4.2.4. Synthesis of the triaryl chlorides with thionyl chloride (GP 4)
The appropriate alcohol (1 equiv) and DMF (0.02 equiv) was dissolved in SOCl2 (5 equiv) at 0 °C
and stirred for 4 h at 25 °C. The volatiles were removed under reduced pressure and the residue was
taken up in DCM (4 mL/ mmol) and evaporated to dryness three times. The crude product was used
without any further purification.
4.2.5. Synthesis of the alkynes from triaryl chlorides and ethynylmagnesium bromide (GP 5)
Ethynylmagnesium bromide (2 equiv, 0.5 M in THF) was added to a stirred solution of the
appropriate triaryl chloride (1 equiv) in toluene (2 mL/ mmol) at 0 °C.38 After 15 min, the mixture was
heated to 60 °C for 2 h, then allowed to cool to 25 °C, quenched with saturated aqueous NH4Cl, and
extracted with Et2O three times. The combined organic phases were dried over Na2SO4 and
concentrated under reduced pressure to get the crude product. This crude product was then purified
by column chromatography over silica gel.
19

4.2.6. Synthesis of the alkynes from triaryl chlorides and (trimethylsilyl)ethynyllithium (GP 6)
nBuLi (1.1 equiv, 2.5 M in hexanes) was added to ethynyltrimethylsilane (1.1 equiv) in THF
(2 mL/ mmol) at 0 °C. After stirring for 1 h at 0 °C, this solution was added to the appropriate triaryl
chloride (1 equiv) in THF (2 mL/ mmol) cooled to –78 °C and stirred for 1 h. Finally, the mixture was
warmed to 0 °C, stirred for 1 h and then quenched with saturated aqueous NH4Cl solution. The
aqueous layer was separated and extracted three times with Et2O. The combined organic fractions
were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude
product was purified by flash chromatography over silica gel.
4.2.7. Deprotection of the TMS protected alkynes (GP 7)
K2CO3 (3 equiv) was added to a stirred solution of the appropriate TMS alkyne (1 equiv) in MeOH
(4 mL/ mmol) at 0 °C. The mixture was stirred for 1 h at 0 °C and for further 3–5 h at 25 °C until TLC
showed complete conversion. The mixture was quenched with H2O at 0 °C and extracted with Et2O
three times. The combined organic phases were dried over Na2SO4 and concentrated under reduced
pressure to get the crude product. This crude product was purified by column chromatography over
silica gel.
4.2.8. Coupling of the N,O-acetal rac-23 with alkynes to form the N-substituted nipecotic acid esters
(GP 8)
TMSCl (1.15 equiv) was added to a stirred solution of N,O-acetal rac-23 (1.15 equiv) in THF
(3 mL/ mmol) at 0 °C. After 15 min, the solution was warmed to 25 °C and stirred for further 3 h at 25
°C to form a white suspension. nBuMgCl (1.05 equiv, 2 M in THF) was added in a separate Schlenk
tube to a stirred solution of the appropriate alkyne (1 mmol) in THF (1 mL/ mmol) at 0 °C and stirred
for 1 h at 25 °C. To complete the deprotonation, the solution was stirred for another 1 h at 45 °C to
form a slightly colored solution. To perform the coupling reaction, the solution of the deprotonated
alkyne was added dropwise to the suspension of the iminium salt at 0 °C. After 1 h at 0 °C, a clear
solution was formed and it was then heated at 45 °C for 1 h. The mixture was quenched with H2O and
extracted with Et2O three times. The combined organic phases were dried over Na2SO4 and
concentrated under reduced pressure to get the crude product. This crude product was purified by
flash chromatography on silica gel with DCM/MeOH (99:1).
4.2.9. Hydrolysis of the N-substituted nipecotic acid esters (GP 9)
NaOH (5 equiv., 12 M in H2O) was added dropwise to the appropriate ester (1 equiv) dissolved in
MeOH (1 mL/ mmol) at 0 °C. The mixture was stirred at 25 °C for 3–6 h until the hydrolysis was
complete (TLC). The mixture was diluted with H2O, stirred for 1 h at 25 °C and extracted with Et2O.
The water phase was collected and pH= 6.0 was set by adding HCl (5 equiv., 6 M in H2O), and
phosphate buffer (pH= 6.0). This mixture was extracted with DCM. The combined organic layers were
dried over Na2SO4 and concentrated under reduced pressure to get the pure product as an oil. To get
the N-substituted nipecotic acid as a solid, the oil was dissolved in DCM (0.1 mL), H2O (2 mL) was
added and an emulsion was prepared by sonication. This emulsion was freeze-dried to obtain a white,
amorphous solid.
20

4.3.Synthesized compounds
4.3.1. Ethyl 1-(ethoxymethyl)piperidine-3-carboxylate, (rac-23)
K2CO3 (4.2 g, 30 mmol) was added to a solution of ethyl nipecotate (rac-22) (4.9 g, 30 mmol,
4.9 mL) in EtOH (5.52 g, 120 mmol, 7.01 mL) at 0 °C. Paraformaldehyde (PFA) (0.98 g, 30 mmol) was
added after 15 min and the mixture was stirred at 25 °C for 6 h. The mixture was diluted with Et2O and
filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by
distillation (Kugelrohr distillation) at 130 °C (0.4 Torr) to obtain the product N,O-acetal (rac-23) as a
colorless oil (5.6 g, 88%).
~
IR (Film):  = 2975, 2940, 2862, 1733, 1465, 1447, 1375, 1355, 1312, 1273, 1231, 1174, 1159,
1
1091, 1069, 1035, 981, 863, 796, 669 cm-1. H NMR (500 MHz, CD2Cl2) δ = 1.15 (t, J = 7.0 Hz, 3H),
1.23 (t, J = 7.2 Hz, 3H), 1.40 – 1.55 (m, 2H), 1.67 – 1.73 (m, 1H), 1.84 – 1.91 (m, 1H), 2.40 – 2.52 (m,
2H), 2.55 – 2.61 (m, 1H), 2.72 – 2.80 (m, 1H), 2.96 – 3.01 (m, 1H), 3.45 (q, J = 7.0 Hz, 2H), 4.03 (s,
2H), 4.09 (q, J = 7.1 Hz, 2H) ppm. 13C NMR (126 MHz, CD2Cl2) δ = 14.58, 15.67, 25.24, 27.38, 42.59,
50.59, 52.74, 60.69, 64.41, 89.24, 174.54 ppm. HRMS (EI): [M]+ calcd. for C11H21NO3, 215.1521;
found: 215.1518.
4.3.2. 3-(Ethoxycarbonyl)-1-methylenepiperidin-1-ium chloride, (rac-9)
TMSCl (60 mg, 0.50 mmol, 68 µL) was added to a stirred solution of N,O-acetal rac-23 (113 mg,
0.50 mmol) in THF (1.5 mL) at 0 °C. After 15 min the solution was warmed to 25 °C and stirred for
further 3 h at 25 °C to form a white suspension. The volatiles were removed under vacuum to obtain a
white residue (95 mg, 92%).
~
IR (KBr):  = 3084, 2962, 2868, 2637, 2532, 1731, 1678, 1454, 1390, 1368, 1331, 1301, 1208,
1
1151, 1135, 1113, 1046, 923, 867, 850, 769, 726, 673, 584, 563, 511, 470 cm-1. H NMR (500 MHz,
CD2Cl2) δ 1.71 (dtd, J = 14.1, 10.1, 4.1 Hz, 1H), 1.83 – 1.97 (m, 2H), 2.05 – 2.12 (m, 2H), 2.96 (tt, J =
9.7, 4.2 Hz, 1H), 3.37 – 3.44 (m, 1H), 3.50 – 3.56 (m, 1H), 3.75 (d, J = 12.4 Hz, 1H), 3.88 (d, J = 12.2
Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 7.42 (s, 2H) ppm. 13C NMR (126 MHz, CD2Cl2) δ 14.43, 24.07,
25.96, 41.02, 54.97, 56.10, 61.58, 132.36, 172.36 ppm. HRMS (ESI): [M-Cl]+ calcd. for C9H16O2N,
170.1175; found: 170.1176.
4.3.3. Tris(4-methoxyphenyl)methanol, (16a)
According to GP2: Magnesium turnings (370 mg, 15.0 mmol), 4-bromoanisole (2.5 g, 13 mmol,
1.7 mL), and ketone 15 (2.5 g, 10 mmol). The crude product was recrystallized from EtOAc/PE. White
solid (2.6 g, 74%).
~
Mp: 80 °C. IR (KBr):  = 3541, 3074, 3014, 2956, 2894, 2835, 2545, 2361, 2038, 1908, 1773,
1608, 1581, 1508, 1459, 1442, 1412, 1329, 1295, 1247, 1171, 1154, 1112, 1026, 948, 903, 826, 725,
638, 584 cm-1. 1H NMR (500 MHz, CD2Cl2) δ = 2.75 (s, 1H), 3.78 (s, 9H), 6.79 – 6.86 (m, 6H), 7.10 –
7.18 (m, 6H) ppm. 13C NMR (126 MHz, CD2Cl2) δ = 55.77, 81.49, 113.57, 129.50, 140.32, 159.21
ppm. HRMS (EI): [M]+ calcd. for C22H22O4, 350.1518; found: 350.1500.
Analytical data corresponds with the known literature.29 Additional data is shown above.
4.3.4. 4,4',4''-(chloromethanetriyl)tris(methoxybenzene), (17a)
According to GP3: AcCl (1.4 g, 18 mmol, 1.3 mL) and alcohol 16a (2.1 g, 6.0 mmol). Red solid
(1.9 g, 90%).
~
Mp: 142-144 °C. IR (KBr):  = 3015, 2962, 2931, 2840, 2554, 2035, 1909, 1780, 1607, 1579, 1508,
1459, 1442, 1414, 1364, 1305, 1290, 1252, 1178, 1149, 1117, 1091, 1024, 943, 905, 829, 809, 774,
708, 629, 604, 577 cm-1. 1H NMR (500 MHz, CD2Cl2) δ = 3.85 (s, 9H), 6.86 – 6.92 (m, 6H), 7.17 – 7.23
(m, 6H) ppm. 13C NMR (126 MHz, CD2Cl2) δ = 55.77, 56.11, 113.89, 133.12, 137.59 , 161.26 ppm.
HRMS (EI): [M-Cl]+ calcd. for C22H21O3, 333.1491; found: 333.1522.
21

Analytical data corresponds with the known literature.61
4.3.5. 4,4',4''-(Prop-2-yne-1,1,1-triyl)tris(methoxybenzene), (18a)
According to GP5: Alcohol 17a (1.2 g, 3.0 mmol) and ethynylmagnesium bromide (12 mL, 6.0
mmol, 0.5 M in THF). The crude product was purified by flash chromatography over silica gel with
PE/EtOAc (95:5). White solid (1.0 g, 97%).
~
Mp: 128-130 °C. IR (KBr):  = 3277, 2954, 2935, 2839, 1606, 1582, 1507, 1459, 1447, 1415, 1293,
1
1251, 1176, 1117, 1030, 828, 679 cm-1.) H NMR (500 MHz, CD2Cl2) δ = 2.74 (s, 1H), 3.78 (s, 9H),
6.79 – 6.84 (m, 6H), 7.13 – 7.18 (m, 6H) ppm. 13C NMR (126 MHz, CD2Cl2) δ = 54.03, 55.79, 73.55,
90.71, 113.74, 130.47, 137.95, 159.02 ppm. (HRMS (EI): [M]+ calcd. for C24H22O3, 358.1569; found:
358.1564.
Analytical data corresponds with the known literature.38 Additional data is shown above.
4.3.6. Benzo[d][1,3]dioxol-5-ylbis(4-methoxyphenyl)methanol, (16b)
According
to
GP2:
Magnesium
turnings
(305
mg,
12.5
mmol),1-bromo-3,4-
(methylenedioxy)benzene (2.4 g, 11.5 mmol, 1.4 mL), ketone 15 (2.5 g, 10 mmol) The crude product
was purified by flash chromatography over silica gel with DCM. Violet oil (3.6 g, 98%).
~
IR (Film):  = 3490, 3000, 2955, 2933, 2900, 2836, 1608, 1582, 1507, 1484, 1463, 1435, 1298,
1
1246, 1116, 1089, 1036, 932, 860, 828, 810, 731, 668 cm-1. H NMR (500 MHz, CDCl3) δ = 2.68 (s,
1H), 3.80 (s, 6H), 5.94 (s, 2H), 6.68 (dd, J = 8.1, 1.8 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 1.8
Hz, 1H), 6.81 – 6.85 (m, 4H), 7.15 – 7.19 (m, 4H) ppm. 13C NMR (126 MHz, CDCl3) δ = 55.40, 81.47,
101.21, 107.47, 108.91, 113.31, 121.45, 129.18, 139.58, 141.78, 146.68, 147.48, 158.78 ppm. HRMS
(EI): [M]+ calcd. for C22H20O5, 364.1311; found: 364.1305.
4.3.7. 5-[Chlorobis(4-methoxyphenyl)methyl]benzo[d][1,3]dioxole, (17b)
According to GP4: Alcohol 16b (0.2 g, 0.5 mmol), DMF (10 µL, 0.05 mmol) and SOCl2 (375 mg,
6.0 mmol, 230 µL). The mixture was stirred at 45 °C for 2 h. Brown oil (190 mg, 99%).
~
IR (Film):  = 3088, 2844, 1579, 1505, 1484, 1451, 1374, 1358, 1314, 1274, 1165, 1144, 1125,
1
1107, 1031, 1009, 917, 853, 812, 763, 734, 686 cm-1. H NMR (500 MHz, CDCl3) δ = 3.88 (s, 6H),
6.05 (s, 2H), 6.70 (dd, J = 8.1, 1.8 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 1.7 Hz, 1H), 6.93 (d, J
= 8.4 Hz, 4H), 7.23 – 7.29 (m, 4H) ppm. 13C NMR (126 MHz, CDCl3) δ = 55.91, 102.10, 107.68,
113.88, 127.00, 133.66, 136.75, 138.82), 148.04, 149.74, 161.63 ppm. HRMS (EI): [M-Cl]+ calcd. for
C22H19O4, 347.1283; found: 347.1277.
4.3.8. 5-[1,1-Bis(4-methoxyphenyl)prop-2-yn-1-yl]benzo[d][1,3]dioxole, (18b)
According to GP5: Chloride 17b (0.2 g, 0.5 mmol), and ethynylmagnesium bromide (1.0 mmol,
0.5 M in THF). The crude product was purified by flash chromatography over silica gel with PE/EtOAc
(98:2). Slightly red solid (180 mg, 97%).
~
Mp: 114-116 °C. IR (KBr):  = 2930, 2835, 1606, 1506, 1481, 1437, 1298, 1248, 1177, 1115, 1094,
1036, 932, 855, 811, 760, 739, 719, 657, 635, 600, 574, 547 cm-1. 1H NMR (500 MHz, CDCl3) δ = 2.68
(s, 1H), 3.80 (s, 6H), 5.94 (s, 2H), 6.66 (dd, J = 8.2, 1.9 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 6.80 – 6.84
(m, 5H), 7.15 – 7.20 (m, 4H) ppm. 13C NMR (126 MHz, CDCl3) δ = 54.01, 55.41, 73.11, 90.31, 101.27,
107.52, 110.03, 113.44, 122.40, 130.15, 137.38, 139.59, 146.51, 147.60, 158.53 ppm. HRMS (EI):
[M]+ calcd. for C24H20O4, 372.1362; found: 372.1361.
4.3.9. Bis(4-methoxyphenyl)(thiazol-2-yl)methanol, (16c)
nBuLi (3.45 mmol, 2.5 M in hexane) was added to 2-bromothiazole (602 mg, 3.60 mmol, 331 µL)
dissolved in Et2O (6 mL) at –78 °C. After 1 h this solution was cannulated to keton 15 (0.74 g,
22

3.05 mmol) suspended in Et2O (5 mL) at –78 °C and stirred for 1 h. After 1 h at 25 °C, the mixture was
quenched with saturated aqueous NH4Cl solution and extracted with DCM. The organic phases were
dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified
by flash chromatography over silica gel with DCM/MeOH (99:1). Brown solid (580 mg, 60%).
~
Mp: 146-148 °C. IR (KBr):  = 3271, 3128, 3060, 3013, 2961, 2929, 2898, 2832, 2035, 1605, 1583,
1508, 1459, 1436, 1415, 1381, 1303, 1250, 1210, 1194, 1169, 1135, 1108, 1056, 1044, 1029, 934,
1
913, 897, 871, 828, 812, 804, 768, 757, 726, 684, 637, 611, 577, 562, 537 cm-1. H NMR (500 MHz,
CD2Cl2) δ = 3.79 (s, 6H), 4.18 (s, 1H), 6.82 – 6.87 (m, 4H), 7.25 – 7.30 (m, 4H), 7.34 (d, J = 3.3 Hz,
1H), 7.76 (d, J = 3.2 Hz, 1H) ppm. 13C NMR (126 MHz, CD2Cl2) δ = 55.79, 80.59, 113.76, 120.47,
129.21, 138.41, 143.13, 159.79, 178.49 ppm. HRMS (EI): [M]+ calcd. for C18H17O3NS, 327.0929;
found: 327.0932.
4.3.10.
2-[Chlorobis(4-methoxyphenyl)methyl]thiazole, (17c)
According to GP4: Alcohol 16c (2.0 g, 6.0 mmol, 1.2 equiv), DMF (10 µL, 0.12 mmol), and SOCl2
(3.8 g, 30 mmol, 2.3 mL). Brown oil (2.07 g, 99%).
~
IR (Film):  = 3120, 3042, 3005, 2960, 2936, 2837, 1907, 1607, 1583, 1558, 1510, 1462, 1418,
1
1387, 1372, 1303, 1255, 1178, 1118, 1031, 865, 828, 734, 698 cm-1. H NMR (500 MHz, CDCl3) δ =
3.82 (s, 6H), 6.86 – 6.91 (m, 4H), 7.27 – 7.32 (m, 4H), 7.62 (d, J = 3.5 Hz, 1H), 8.11 (d, J = 3.3 Hz,
1H) ppm. 13C NMR (126 MHz, CDCl3) δ = 55.55, 75.58, 114.10, 122.32, 130.22, 133.49, 139.51,
160.38, 177.94 ppm. HRMS (EI): [M-Cl]+ calcd. for C18H16NO2S, 310.0902; found: 310.0901.
4.3.11. 2-[1,1-Bis(4-methoxyphenyl)prop-2-yn-1-yl]thiazole, (18c)
According to GP5: Chloride 17c (2.0 g, 5.5 mmol), and ethynylmagnesium bromide (8.25 mmol,
0.5 M in THF). The crude product was purified by flash chromatography over silica gel with DCM.
Brown solid (950 mg, 52%).
~
Mp: 103-105 °C. IR (KBr):  = 3285, 3108, 3078, 3001, 2956, 2930, 2900, 2835, 1606, 1582, 1508,
1461, 1441, 1014, 1300, 1251, 1178, 1112, 1032, 885, 861, 822, 791, 757, 731, 648, 601, 581,
547 cm- 1. 1H NMR (400 MHz, CD2Cl2) δ = 2.92 (s, 1H), 3.79 (s, 6H), 6.81 – 6.86 (m, 4H), 7.27 – 7.32
(m, 4H), 7.33 (d, J = 3.3 Hz, 1H), 7.77 (d, J = 3.3 Hz, 1H) ppm. 13C NMR (101 MHz, CD2Cl2) δ = 53.86,
55.82, 75.76, 87.81, 113.90, 120.46, 130.04, 136.20, 143.63, 159.53, 175.13 ppm. HRMS (EI): [M]+
calcd. for C20H17O2NS, 335.0980; found: 335.0966.
4.3.12. Bis(4-methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methanol, (16d)
nBuLi (17.3 mmol, 2.5 M in hexanes) was added to a solution of 1-methylimidazole (1.4 g,
16.5 mmol, 1.3 ml) in THF (16 ml) at –78 °C and stirred for 1 h, then cannulated slowly to a solution of
ketone 15 (3.7 g, 15.3 mmol) in THF (15 ml) at –78 °C. The mixture was then stirred for 2 h at this
temperature, then further 2 h at 25 °C. The mixture was quenched with saturated aqueous NH4Cl,
extracted with DCM, dried over Na2SO4, and concentrated under reduced pressure. The crude product
was recrystallized from DCM/PE. White solid (4.7 g, 97%).
~
Mp: 158-160 °C. IR (KBr):  = 3196, 2954, 2913, 2835, 1703, 1609, 1586, 1511, 1468, 1445, 1415,
1359, 1297, 1283, 1249, 1175, 1132, 1030, 1009, 943, 925, 898, 838, 821, 795, 755, 738, 693, 613,
583, 562, 540, 506 cm-1. 1H NMR (500 MHz, CD2Cl2) δ = 3.20 (s, 3H), 3.79 (s, 6H), 4.66 (s, 1H), 6.82
– 6.86 (m, 4H), 6.86 (d, J = 1.1 Hz, 1H), 6.89 (d, J = 1.2 Hz, 1H), 7.08 – 7.14 (m, 4H) ppm. 13C NMR
(126 MHz, CD2Cl2) δ = 35.23, 55.79, 78.27, 113.78, 123.74, 126.22, 129.41, 137.31, 151.53,
159.63 ppm. HRMS (EI): [M]+ calcd. for C19H20N2O3, 324.1474; found: 324.1473.
4.3.13. 2-[Chlorobis(4-methoxyphenyl)methyl]-1-methyl-1H-imidazole, (17d)
Alcohol 16d (2 g, 6 mmol) was treated with SOCl2 (4.2 g, 36 mmol, 2.6 mL) and AcCl (1.9 g,
24 mmol, 1.7 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h and then heated at 50 °C for 1 h.
23

The volatiles were evaporated under vacuum; toluene (5 mL) was added and removed under reduced
pressure three times. The crude product was used without further purification. Grey gum (2.3 g, 99%).
~
IR (KBr):  = 2954, 2835, 1608, 1582, 1511, 1461, 1417, 1372, 1301, 1254, 1177, 1106, 1027,
911, 828, 793, 761, 731, 612, 581 cm-1. 1H NMR (400 MHz, CDCl3) δ = 3.65 (s, 3H), 3.82 (s, 6H), 6.89
– 6.96 (m, 4H), 7.06 – 7.13 (m, 4H), 7.47 (s, 1H), 7.62 (s, 1H), 14.68 (s, 1H) ppm. 13C NMR (101 MHz,
CDCl3) δ = 37.54, 55.68, 71.06, 114.84, 120.15, 125.95, 129.95, 145.80, 160.89 ppm. HRMS (ESI):
[M-Cl]+ calcd. for C19H19O2N2, 307.1446; found: 307.1443.
4.3.14. 2-[1,1-Bis(4-methoxyphenyl)prop-2-yn-1-yl]-1-methyl-1H-imidazole, (18d)
According to GP5: Chloride 17d (2.3 g, 5.6 mmol) and ethynylmagnesium bromide (17 mmol, 0.5 M
in THF, 34 mL). The crude product was purified by flash chromatography over silica gel with Et2O/PE
(80:20). Yellow oil (560 mg, 30%).
~
IR (KBr):  = 3282, 3002, 2954, 2835, 1606, 1583, 1508, 1460, 1298, 1279, 1250, 1177, 1134,
1
1116, 1084, 1031, 824, 745, 685, 603, 585, 541 cm-1. H NMR (500 MHz, CDCl3) δ = 2.77 (s, 1H),
3.45 (s, 3H,), 3.79 (s, 6H), 6.83 – 6.87 (m, 4H), 6.88 (d, J = 1.3 Hz, 1H), 6.97 (d, J = 1.3 Hz, 1H), 7.16
– 7.21 (m, 4H) ppm. 13C NMR (126 MHz, CDCl3) δ = 35.00, 49.86, 55.34, 74.64, 85.82, 113.68,
123.03, 127.01, 129.52, 134.41, 148.49, 158.79 ppm. HRMS (EI): [M]+ calcd. for C21H20O2N2,
332.1525; found: 332.1522.
4.3.15. Bis(4-methoxyphenyl)(thiophen-3-yl)methanol, (16e)
nBuLi (12 mmol, 1.6 M in hexanes) was added to 3-bromothiophene (1.9 g, 11.5 mmol, 1.1 mL) in
Et2O (12 mL) at –78 °C. After 1 h, this mixture was added to a suspension of ketone 15 (2.5 g,
10.3 mmol) in Et2O (12 mL) at –78 °C. After 1 h, the mixture was allowed to warm to room temperature
and was stirred for further 3 h. Finally, the mixture was heated for 1 h at 50 °C, then quenched with
saturated aqueous NH4Cl solution. The aqueous layer was separated and extracted three times with
Et2O. The combined organic fractions were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The crude product was purified by flash chromatography over silica gel with
PE/Et2O (60:40). Yellow oil (3.1 g, 95%).
-1
1
~
IR (Film):  = 3448, 2835, 1608, 1508, 1458, 1299, 1248, 1175, 1033, 829, 795, 771, 651 cm . H
NMR (400 MHz, CD2Cl2) δ = 2.80 (s, 1H), 3.79 (s, 6H), 6.81 – 6.86 (m, 4H), 6.93 (dd, J = 3.0, 1.4 Hz,
1H), 6.95 (dd, J = 5.1, 1.4 Hz, 1H), 7.18 – 7.23 (m, 4H), 7.31 (dd, J = 5.1, 3.1 Hz, 1H) ppm. 13C NMR
(101 MHz, CD2Cl2) δ = 55.78, 79.75, 113.66, 123.46, 126.21, 128.34, 129.02, 139.86, 149.89,
159.35 ppm. HRMS (EI): [M]+ calcd. for C19H18O3S, 326.0977; found: 326.0971.
4.3.16. 3-[Chlorobis(4-methoxyphenyl)methyl]thiophene, (17e)
According to GP4: Alcohol 16e (0.7 g, 2.1 mmol), DMF (10 µL), and SOCl2 (750 mg, 6.30 mmol,
460 µL). The mixture was stirred at 45 °C for 4 h. Brown gum (720 mg, 95%).
~
IR (KBr):  = 3097, 3004, 2966, 2933, 2840, 2044, 1900, 1607, 1580, 1459, 1508, 1459, 1415,
1384, 1306, 1292, 1250, 1177, 1136, 1078, 1026, 831, 798, 783, 770, 753, 703, 646, 631, 614, 589,
564, 533 cm-1. 1H NMR (500 MHz, CD2Cl2) δ = 3.83 (s, 6H), 6.81 (dd, J = 2.9, 1.3 Hz, 1H), 6.85 – 6.90
(m, 4H), 7.12 (dd, J = 5.1, 1.4 Hz, 1H), 7.20 – 7.24 (m, 4H), 7.38 (dd, J = 5.1, 3.0 Hz, 1H) ppm.
13C NMR (126 MHz, CD2Cl2) δ = 56.02, 85.95, 113.77, 126.60, 127.37, 130.38, 131.84, 137.49,
147.68, 160.70 ppm. HRMS (EI): [M-Cl]+ calcd. for C19H17O2S, 309.0949; found: 309,0924.
4.3.17. [3,3-Bis(4-methoxyphenyl)-3-(thiophen-3-yl)prop-1-yn-1-yl]trimethylsilane, (21e)
According to GP6: Ethynyltrimethylsilane (261 mg, 2.40 mmol, 375 µL), nBuLi (2.4 mmol, 2.5 M in
hexanes) chloride 17e (0.7 g, 2.0 mmol). The crude product was purified by flash chromatography
over silica gel with PE/DCM (80:20). Colorless oil (420 mg, 53%).
24

~
IR (Film):  = 3000, 2956, 2901, 2834, 2167, 1606, 1581, 1507, 1462, 1441, 1414, 1298, 1250,
1
1114, 1066, 1035, 842, 828, 793, 771, 759, 697, 646 cm-1. H NMR (400 MHz, CD2Cl2) δ = 0.23 (s,
9H), 3.78 (s, 6H), 6.78 (dd, J = 3.7, 1.1 Hz, 1H), 6.80 – 6.84 (m, 4H), 7.00 (d, J = 3.7 Hz, 1H), 7.16 –
7.21 (m, 4H), 7.29 (dd, J = 5.1, 3.0 Hz, 1H) ppm. 13C NMR (101 MHz, CD2Cl2) δ = 0.23, 52.33, 55.80,
89.50, 111.54, 113.80, 123.68, 126.04, 129.41, 129.98, 137.81, 147.29, 159.09 ppm. HRMS (EI):
[M]+ calcd. for C24H26O2SSi, 406.1423; found: 406.1418.
4.3.18. 3-[1,1-Bis(4-methoxyphenyl)prop-2-yn-1-yl]thiophene, (18e)
According to GP7: TMS alkyne 21e (0.5 g, 1.2 mmol) was dissolved in MeOH/ THF (2 mL/ 1 mL),
and K2CO3 (0.8 g, 6.0 mmol). The crude product was purified by flash chromatography over silica gel
with PE/EtOAc (98:2). White solid (320 mg, 80%).
~
Mp: 122-124 °C. IR (KBr):  = 3265, 3108, 3016, 2951, 2835, 1605, 1582, 1507, 1463, 1438, 1415,
1365, 1307, 1294, 1175, 1080, 1035, 1021, 910, 829, 810, 793, 780, 773, 694, 676, 653, 603, 579,
541 cm-1. 1H NMR (400 MHz, CD2Cl2) δ = 2.76 (s, 1H), 3.78 (s, 6H), 6.79 – 6.85 (m, 5H), 7.00 (dd, J =
5.1, 1.4 Hz, 1H), 7.17 – 7.23 (m, 4H), 7.30 (dd, J = 5.0, 3.0 Hz, 1H) ppm. 13C NMR (101 MHz, CD2Cl2)
δ = 51.42, 55.81, 73.60, 89.49, 113.84, 123.81, 126.19, 129.27, 129.95, 137.49, 147.00, 159.17 ppm.
HRMS (EI): [M]+ calcd. for C21H18O2S, 334.1028; found: 334.1023.
4.3.19. Benzo[b]thiophen-5-ylbis(4-methoxyphenyl)methanol, (16f)
According to GP 2: Magnesium turnings (440 mg, 18.0 mmol), 1,2-dibromethane (25 µL),
5-bromobenso(b)thiophene (3.7 g, 17.3 mmol) ketone 15 (3.7 g, 15.3 mmol) The crude product was
purified by recrystallization (Et2O/PE). White solid (4300 mg, 76%).
~
Mp: 168-170 °C. IR (KBr):  = 3560, 3092, 3058, 3005, 2963, 2929, 2899, 2836, 2029, 1903, 1772,
1653, 1604, 1581, 1456, 1438, 1409, 1331, 1295, 1251, 1176, 1160, 1138, 1117, 1089, 1049, 1023,
960, 943, 913, 899, 886, 868, 835, 808, 791, 767, 721, 712, 683, 643, 634, 612, 583, 561, 550, 507,
491 cm-1. 1H NMR (500 MHz, CD2Cl2) δ = 2.87 (s, 1H), 3.79 (s, 6H), 6.82 – 6.86 (m, 4H), 7.17 – 7.22
(m, 4H), 7.27 (dd, J = 5.4, 0.7 Hz, 1H), 7.30 (dd, J = 8.5, 1.9 Hz, 1H), 7.46 (d, J = 5.5 Hz, 1H), 7.69 (d,
J = 1.7 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H) ppm. 13C NMR (126 MHz, CD2Cl2) δ = 55.79, 81.94, 113.65,
122.31, 123.15, 124.73, 125.16, 127.40, 129.64, 139.00, 139.83, 140.11, 144.59, 159.32 ppm. HRMS
(EI): [M]+ calcd. for C23H20O3S, 376.1133; found: 376.1124.
4.3.20. 5-[Chlorobis(4-methoxyphenyl)methyl]benzo[b]thiophene, (17f)
According to GP3: Alcohol 16f (2 g, 5 mmol), and AcCl (3.3 g, 41 mmol, 3.0 mL). Red solid (2 g,
99%).
~
Mp: 165-167 °C. IR (KBr):  = 3099, 3060, 3012, 2957, 2933, 2902, 2836, 1604, 1576, 1508, 1457,
1439, 1409, 1330, 1307, 1296, 1255, 1223, 1177, 1130, 1117, 1089, 1049, 1029, 964, 913, 897, 866,
1
847, 825, 810, 790, 778, 762, 711, 678, 634, 624, 593, 565, 550, 516, 490 cm- 1. H NMR (500 MHz,
CD2Cl2) δ = 3.82 (s, 6H), 6.82 – 6.86 (m, 4H), 7.15 – 7.19 (m, 4H), 7.26 (dd, J = 5.5, 0.7 Hz, 1H), 7.40
(dd, J = 8.6, 2.0 Hz, 1H), 7.49 (d, J = 5.4 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H)
ppm. 13C NMR (126 MHz, CD2Cl2) δ = 55.90, 84,81, 113.51, 122.30, 124.81, 125.07, 127.16, 127.82,
131.73, 138.12, 139.50, 139.80, 142.72, 159.91 ppm. HRMS (ESI): [M-Cl]+ calcd. for C23H19O2S,
359.1105; found: 359.1101.
4.3.21. (3-(Benzo[b]thiophen-5-yl)-3,3-bis(4-methoxyphenyl)prop-1-yn-1-yl)trimethylsilane, (21f)
According to GP7: Ethynyltrimethylsilane (45 mg, 0.44 mmol, 64 µL), nBuLi (0.46 mmol, 2 M in
hexanes), chloride 17f (0.17 g, 0.40 mmol). The crude product was purified by flash chromatography
over silica gel with PE/EtOAc (95:5). White solid (115 mg, 63%).
~
Mp: 159-161 °C. IR (KBr):  = 3102, 3006, 2955, 2932, 2898, 2836, 2172, 2039, 1892, 1769, 1646,
1606, 1580, 1508, 1463, 1440, 1413, 1296, 1252, 1176, 1117, 1089, 1074, 1049, 1031, 956, 914, 893,
25

1
841, 830, 808, 791, 756, 706, 693, 630, 613, 591, 574, 557, 534, 479 cm-1. H NMR (400 MHz,
CD2Cl2) δ = 0.24 (s, 9H), 3.79 (s, 6H), 6.79 – 6.85 (m, 4H), 7.15 – 7.20 (m, 4H), 7.24 (dd, J = 5.5, 0.7
Hz, 1H), 7.35 (ddd, J = 8.6, 1.9, 0.5 Hz, 1H), 7.43 – 7.47 (m, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.80 (dt, J =
8.6, 0.7 Hz, 1H) ppm. 13C NMR (101 MHz, CD2Cl2) δ = 0.22), 55.57, 55.80, 89.79, 112.86, 113.77,
122.39, 124.17, 124.67, 126.48, 127.39, 130.65, 137.98, 138.71, 139.94, 142.85, 159.03 ppm. HRMS
(EI): [M]+ calcd. for C28H28O2SSi, 456.1579; found: 456.1574.
4.3.22. 5-[1,1-Bis(4-methoxyphenyl)prop-2-yn-1-yl]benzo[b]thiophene, (18f)
According to GP7: TMS alkyne 21f (0.7 g, 1.5 mmol) was dissolved in MeOH/THF (6 mL/ 6 mL),
and K2CO3 (0.6 g, 4.4 mmol). The crude product was recrystallized from DCM. White solid (560 mg,
99%)
~
Mp: 192-194 °C. IR (KBr):  = 3255, 2933, 2839, 1603, 1579, 1507, 1458, 1437, 1410, 1295, 1250,
1
1178, 1117, 1088, 1052, 1030, 895, 866, 831, 807, 790, 760, 696, 635, 602, 581, 552, 490 cm-1. H
NMR (400 MHz, CD2Cl2) δ = 0.24 (s, 9H), 3.79 (s, 6H), 6.79 – 6.85 (m, 4H), 7.15 – 7.20 (m, 4H), 7.24
(dd, J = 5.5, 0.7 Hz, 1H), 7.35 (ddd, J = 8.6, 1.9, 0.5 Hz, 1H), 7.43 – 7.47 (m, 1H), 7.57 (d, J = 1.6 Hz,
1H), 7.80 (dt, J = 8.6, 0.7 Hz, 1H) ppm. 13C NMR (101 MHz, CD2Cl2) δ = 0.22, 55.57, 55.80, 89.79,
112.86, 113.77, 122.39, 124.17, 124.67, 126.48, 127.39, 130.65, 137.98, 138.71, 139.94, 142.85,
159.03 ppm. HRMS (EI): [M]+ calcd. for C25H20O2S, 384.1184; found: 384.1179.
4.3.23. 1,1-Bis(4-methoxyphenyl)prop-2-yn-1-ol, (18g)
Ethynylmagnesium bromide (4 mmol, 0.5 M in THF) was added to the suspension of ketone 15
(0.5 g, 2.0 mmol) in THF (2 mL) at 25 °C. The mixture was then stirred at 60 °C for 2 h and then
quenched with saturated aqueous NH4Cl solution. The aqueous layer was separated and extracted
three times with Et2O. The combined organic fractions were washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The crude product was recrystallized from Et2O/PE. White solid
(490 mg, 91%).
~
Mp: 90-91 °C. IR (KBr):  = 3472, 3245, 3004, 2959, 2932, 2836, 2545, 2102, 2039, 1933, 1902,
1886, 1870, 1683, 1635, 1607, 1584, 1506, 1464, 1455, 1440, 1415, 1350, 1305, 1295, 1251, 1241,
1199, 1180, 1164, 1199, 1180, 1164, 1119, 1062, 1025, 991, 967, 930, 897, 842, 882, 815, 782, 764,
1
732, 715, 685, 633, 627, 587, 526, 510, 488 cm-1. H NMR (500 MHz, CDCl3) δ 2.79 (s, 1H), 2.86 (s,
1H), 3.79 (s, 6H), 6.83 – 6.89 (m, 4H), 7.47 – 7.53 (m, 4H) ppm. 13C NMR (126 MHz, CDCl3) δ 55.42,
73.76, 75.22, 86.92, 113.68, 127.46, 137.06, 159.26 ppm. HRMS (EI): [M]+ calcd. for C17H16O3,
268.1099; found: 268.1096.
Analytical data corresponds with the known literature.62 Additional data is shown above.
4.3.24. 4,4'-(Bromomethylene)bis(methoxybenzene), (20)
Acetyl bromide (AcBr) (3.9 g, 30.0 mmol, 2.4 mL) was added to a stirred solution of alcohol 19
(2.5 g, 10 mmol) in toluene (15 mL) at 0 °C and stirred for 2 h at 25 °C. The volatiles were removed
under reduced pressure. The remaining mixture was diluted with toluene (10 mL) and evaporated
under reduced pressure three times. The obtained red solid was used without any further purification.
Red solid (3 g, 99%).
~
Mp: 71-72 °C. IR (KBr):  = 3011, 2960, 2928, 1603, 1582, 1458, 1440, 1417, 1313, 1300, 1253,
1238, 1198, 1172, 1112, 1024, 852, 822, 808, 757, 721, 698, 615, 580, 545 cm-1. 1H NMR (400 MHz,
CDCl3) δ = 3.80 (s, 6H), 6.31 (s, 1H), 6.84 – 6.89 (m, 4H), 7.35 – 7.41 (m, 4H) ppm. 13C NMR (101
MHz, CDCl3) δ = 55.48, 56.07, 113.97, 129.83, 133.70, 159.37 ppm. HRMS (EI): [M]+ calcd. for
C15H15O2Br, 306.0255; found: 306.0248.
Analytical data corresponds with the known literature.44
26

4.3.25. 3,3-Bis(4-methoxyphenyl)prop-1-yn-1-yl)trimethylsilane, (21h)
nBuMgCl (10 mmol, 2 M in THF, 5 mL) was added to a stirred solution of ethynyltrimethylsilane
(982 mg, 10.0 mmol) in THF (15 mL) at 0 °C and stirred for 1 h at 45 °C. CuBr (180 mg, 1.25 mmol)
was added at 25 °C and stirred for 30 min. Finally, the solution of bromide 20 (1.5 g, 5.0 mmol) in THF
(20 mL) was added at 0 °C and stirred for 2 h at 60 °C. The mixture was quenched with saturated
aqueous NH4Cl solution and extracted with Et2O three times. The combined organic phases were
dried over Na2SO4 and concentrated under reduced pressure to get the crude product. This was then
purified by flash chromatography over silica gel with PE/EtOAc (98:2). Yellow oil (1.5 g, 93%)
Note: CuBr (black, discolored) was purified63 by rinsing it with AcOH, EtOH and Et2O under argon
to get an off white powder.
~
IR (Film):  = 3001, 2958, 2902, 2836, 2170, 1609, 1585, 1463, 1442, 1419, 1327, 1302, 1247,
1
1174, 1034, 1011, 846, 809, 761, 699, 668, 633 cm-1. H NMR (400 MHz, CD2Cl2) δ = 0.21 (s, 9H),
3.77 (s, 6H), 4.93 (s, 1H), 6.81 – 6.86 (m, 4H), 7.24 – 7.29 (m, 4H) ppm. 13C NMR (101 MHz, CD2Cl2)
δ = 0.31, 42.97, 55.79, 89.09, 107.82, 114.42, 129.17, 134.64, 159.12 ppm. HRMS (EI): [M]+ calcd. for
C20H24O2Si, 324.1546; found: 324.1541.
Analytical data corresponds with the known literature.42 Additional data is shown above.
4.3.26. 4,4'-(Prop-2-yne-1,1-diyl)bis(methoxybenzene), (18h)
According to GP7: TMS alkyne 21h (0.32 g, 1.0 mmol), and K2CO3 (0.2 g, 1.5 mmol). The crude
product was purified by flash chromatography over silica gel with PE/EtOAc (97:3). White solid (210
mg, 83%).
~
Mp: 69-70 °C. IR (KBr):  = 3257, 3035, 3011, 2958, 2907, 2835, 2053, 2012, 1884, 1607, 1584,
1506, 1464, 1441, 1417, 1327, 1300, 1254, 1239, 1175, 1108, 1033, 986, 930, 865, 843, 830, 804,
766, 721, 700, 670, 631, 590, 570, 538, 510 cm-1. 1H NMR (500 MHz, CD2Cl2) δ = 2.52 (d, J = 2.7 Hz,
1H), 3.77 (s, 6H), 4.92 (d, J = 2.6 Hz, 1H), 6.82 – 6.86 (m, 4H), 7.25 – 7.30 (m, 4H) ppm. 13C NMR
(126 MHz, CD2Cl2) δ = 41.76, 55,79, 72.90, 85.65, 114.45, 129.15, 134.27, 159.19 ppm. HRMS (EI):
[M]+ calcd. for C17H16O2, 252.1150; found: 252.1142.
4.3.27. Trimethyl[3,3,4-tris(4-methoxyphenyl)but-1-yn-1-yl]silane, (21i)
nBuLi (2.3 mmol, 2.5 M in hexanes) was added to the solution of TMS alkyne 21h (0.66 mg,
2.0 mmol) in THF (7 mL) at –78 °C. The resulting mixture was stirred at –78 °C for 1 h. 4-
Methoxybenzyl chloride (0.4 g, 2.4 mmol) was added and the mixture was stirred at 0 °C for 1 h.
Finally, the mixture was heated to 40 °C for 1 h and quenched with saturated aqueous NH4Cl solution.
The aqueous layer was separated and extracted three times with DCM. The combined organic
fractions were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The
crude product was purified by flash chromatography over silica gel with PE/EtOAc (98:2). White solid
(855 mg, 96%).
~
Mp: 79-82 °C. IR (KBr):  = 2995, 2955, 2835, 2171, 1699, 1653, 1610, 1577, 1558, 1540, 1508,
1457, 1437, 1417, 1301, 1249, 1178, 1112, 1074, 1035, 887, 832, 759, 669, 606, 585, 516, 485 cm- 1.
1H NMR (500 MHz, CD2Cl2) δ = 0.19 (s, 9H), 3.44 (s, 2H), 3.73 (s, 3H), 3.78 (s, 6H), 6.61 – 6.66 (m,
2H), 6.78 – 6.84 (m, 6H), 7.26 – 7.31 (m, 4H) ppm. 13C NMR (126 MHz, CD2Cl2) δ = 0.24, 46.88,
50.82, 55.55, 55.74, 91.73, 110.73, 112.91, 113.74, 129.22, 129.84, 132.54, 137.72, 158.77 ppm.
HRMS (EI): [M]+ calcd. for C28H32O3Si, 444.2121; found: 444.2113.
4.3.28. 4,4',4''-(But-3-yne-1,2,2-triyl)tris(methoxybenzene), (18i)
According to GP7: TMS alkyne 21i (0.81 g, 1.7 mmol) dissolved in MeOH/ THF (3 mL/ 3 mL),
K2CO3 (1.2 g, 8.7 mmol). The crude product was purified by flash chromatography over silica gel with
PE/Et2O (85:15). White solid (450 mg, 70%).
27

~
Mp: 142-145 °C. IR (KBr):  = 3284, 2932, 2834, 1609, 1582, 1509, 1463, 1300, 1249, 1178, 1110,
1
1034, 828, 784, 737, 650, 601, 581, 548 cm-1. H NMR (500 MHz, CD2Cl2) δ = 2.63 (s, 1H), 3.49 (s,
2H), 3.73 (s, 3H), 3.78 (s, 6H), 6.63 – 6.67 (m, 2H), 6.79 – 6.84 (m, 6H), 7.28 – 7.32 (m, 4H) ppm. 13
C
NMR (126 MHz, CD2Cl2) δ = 46.69, 49.83, 55.53, 55.75, 75.64, 88.49, 113.08, 113.81, 129.20,
129.69, 132.39, 137.61, 158.79, 158.85 ppm. HRMS (EI): [M]+ calcd. for C25H24O3, 372.1725; found:
372.1719.
4.3.29. 3,3-Bis[4-methoxyphenyl)-4-phenylbut-1-yn-1-yl]trimethylsilane, (21j)
nBuLi (2.7 mmol, 2.5 M in hexanes) was added to the solution of TMS alkyne 21h (803 mg,
2.45 mmol) in THF (6 mL) at –78 °C. The resulting mixture was stirred at –78 °C for 1 h. Benzyl
bromide (0.5 g, 2.9 mmol) was added and the mixture was stirred at 0 °C for 1 h. Finally, the mixture
was heated to 40 °C for 1 h and quenched with saturated aqueous NH4Cl solution. The aqueous layer
was separated and extracted three times with DCM. The combined organic fractions were washed
with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was
purified by flash chromatography over silica gel with PE/EtOAc (98:2). White solid (915 mg, 90%).
~
Mp: 103-104 °C. IR (KBr):  = 3031, 3005, 2958, 2899, 2835, 2166, 1607, 1580, 1508, 1461, 1438,
1414, 1315, 1294, 1260, 1245, 1182, 1116, 1090, 1030, 995, 913, 881, 835, 800, 758, 737, 700 cm- 1.
1H NMR (400 MHz, CD2Cl2) δ = 0.18 (s, 9H), 3.50 (s, 2H), 3.77 (s, 6H), 6.77 – 6.82 (m, 4H), 6.88 –
6.92 (m, 2H), 7.06 – 7.15 (m, 3H), 7.26 – 7.31 (m, 4H) ppm. 13C NMR (101 MHz, CD2Cl2) δ = 0.20,
47.71, 50.66, 55.75, 91.91, 110.52, 113.76, 126.73, 127.53, 129.20, 131.65, 137.68, 137.86, 158.80
ppm. HRMS (EI): [M]+ calcd. for C27H30O2Si, 414.2015; found: 414.2008.
4.3.30. 4,4'-(1-Phenylbut-3-yne-2,2-diyl)bis(methoxybenzene), (18j)
According to GP7: TMS alkyne 21j (891 mg, 2.15 mmol) dissolved in MeOH/ THF (3 mL/ 3 mL),
K2CO3 (0.9 g, 6.5 mmol). The crude product was purified by flash chromatography over silica gel with
PE/Et2O (90:10). White solid (650 mg, 88%).
~
Mp: 107-109 °C. IR (KBr):  = 3287, 3031, 3001, 2932, 2835, 1607, 1582, 1508, 1455, 1441, 1417,
1
1290, 1250, 1179, 1119, 1084, 1034, 827, 758, 730, 700, 650, 607, 584, 565, 546 cm-1. H NMR
(500 MHz, CD2Cl2) δ = 2.45 (s, 1H), 3.36 (s, 2H), 3.60 (s, 6H), 6.61 – 6.65 (m, 4H), 6.70 – 6.73 (m,
2H), 6.90 – 6.98 (m, 3H), 7.08 – 7.14 (m, 4H) ppm. 13C NMR (126 MHz, CD2Cl2) δ = 47.50, 49.67,
55.76, 75.75, 88.31, 113.82, 126.80, 127.70, 129.17, 131.49, 137.55, 137.76, 158.88 ppm. HRMS
(EI): [M]+ calcd. for C24H22O2, 342.1620; found: 342.1615.
4.3.31. 4,4',4''-(But-3-yne-1,1,1-triyl)tris(methoxybenzene), (25a)
Propargyl bromide (4.6 mmol, 80% in toluene) was added dropwise to a suspension of magnesium
turnings (0.12 g, 4.8 mmol) and HgCl2 (11 mg, 0.04 mmol) in Et2O (5 mL) at 25 °C. This mixture was
stirred at 25 °C for 1 h, cooled to 0 °C and a solution of chloride 17a (1.5 g, 4.0 mmol) in toluene
(10 mL) was added. After 1 h at 25 °C, it was heated at 40 °C for 1 h. The mixture was quenched with
saturated aqueous NH4Cl solution, extracted with Et2O and dried over Na2SO4 to get the crude
product. The crude product was purified by flash chromatography over silica gel with PE/EtOAc (96:4).
White solid (1.3 g, 86%).
~
Mp: 91-92 °C. IR (KBr):  = 3293, 2997, 2956, 2931, 2910, 2837, 1605, 1577, 1508, 1440, 1297,
1248, 1180, 1121, 1033, 827, 729, 668, 641, 599, 575 cm-1. 1H NMR (500 MHz, CD2Cl2) δ = 1.96 (t, J
= 2.7 Hz, 1 H), 3.42 (d, J = 2.7 Hz, 2 H), 3.78 (s, 9 H), 6.76 – 6.84 (m, 6 H), 7.04 – 7.15 (m, 6 H) ppm.
13C NMR (126 MHz, CD2Cl2): δ = 33.07, 54.57, 55.70, 72.13, 83.48, 113.49, 130.58, 139.76, 158.49
ppm. HRMS (EI): [M]+ calcd. for C25H24O3, 372.1726; found: 372.1725.
4.3.32. But-3-yne-1,1,1-triyltribenzene, (25k)
Propargyl bromide (4.6 mmol, 80% in toluene) was added dropwise to magnesium turnings (0.13 g,
5.0 mmol) suspended in Et2O (5 mL) with HgCl2 (12 mg, 0.05 mmol) while maintaining a temperature
28

below 25 °C. After 1 h, a solution of chloride 17k (1.16 g, 4.12 mmol) in toluene (5 mL) was added.
The mixture was heated to 50 °C and stirred for 1 h. After cooling to 25 °C, it was quenched with
saturated aqueous NH4Cl solution, extracted with Et2O, the organic layer was dried over Na2SO4, and
concentrated under reduced pressure. The crude product was purified by flash chromatography over
silica gel with PE/EtOAc (99:1). White solid (1.0 g, 86%).
~
Mp: 82-83 °C. IR (KBr):  = 3285, 3048, 3019, 2930, 2900, 1955, 1890, 1816, 1772, 1718, 1683,
1656, 1591, 1488, 1443, 1420, 1310, 1269, 1310, 1269, 1186, 1154, 1080, 1029, 997, 970, 908, 878,
843, 802, 760, 745, 698, 668, 654, 636, 589 cm-1. 1H NMR (500 MHz, CD2Cl2) δ = 1.95 (t, J = 2.6 Hz,
1H), 3.52 (d, J = 2.6 Hz, 2H), 7.20 – 7.26 (m, 9H), 7.26 – 7.32 (m, 6H) ppm. 13C NMR (126 MHz,
CD2Cl2) δ = 32.69, 56.51, 72.30, 83.08, 126.92, 128.35, 129.70, 147.10 ppm. HRMS (EI): [M]+ calcd.
for C22H18, 282.1409; found: 282.1396.
4.3.33. 4,4',4''-(4-Chlorobut-2-yne-1,1,1-triyl)tris(methoxybenzene), (26a)
nBuLi (6.9 mmol, 2.5 M in hexanes) was added to propargyl chloride (0.55 g, 7.20 mmol) dissolved
in Et2O (6 mL) cooled to –78 °C. After 20 min at –78 °C a solution of chloride 17a (2.3 g, 6.0 mmol) in
toluene (20 mL) was added and the mixture was stirred at –60 °C for 2 h, then brought to 25 °C. After
2 h the mixture was quenched with H2O and extracted with Et2O and dried. The crude product was
purified by flash chromatography over silica gel with PE/EtOAc (90:10). Yellow solid (2.0 g, 82%).
~
Mp: 93-94 °C. IR (KBr):  = 3016, 2999, 2963, 2926, 2902, 2831, 2219, 2035, 1893, 1605, 1583,
1
1506, 1461, 1440, 1412, 1298, 1248, 1177, 1111, 1028, 902, 826, 784, 683, 636 cm-1. H NMR
(400 MHz, CD2Cl2) δ 3.78 (s, 9H), 4.35 (s, 2H), 6.74 – 6.88 (m, 6H), 7.04 – 7.19 (m, 6H) ppm. 13C
NMR (101 MHz, CD2Cl2) δ 31.97, 54.15, 55.80, 80.08, 93.60, 113.79, 130.46, 137.88, 159.07 ppm.
HRMS (EI): [M]+ calcd. for C25H23O3Cl, 406.1336; found: 406.1337.
4.3.34. (4-Chlorobut-2-yne-1,1,1-triyl)tribenzene, (26k)
nBuLi (5.75 mmol, 2.5 M in hexanes) was added to propargyl chloride (0.5 g, 6.0 mmol) dissolved
in Et2O (8 mL) cooled to –78°C. After 20 min at –78 °C, a solution of chloride 17k (1.5 g, 5.0 mmol) in
toluene (10 mL) was added and the mixture was stirred at –60 °C for 2 h, then brought to 25 °C. After
2 h, the mixture was quenched with H2O and extracted with Et2O and dried. The crude product was
purified by flash chromatography over silica gel with PE/EtOAc (99:1). Yellow solid (1.2 g, 76%).
~
Mp: 141-142 °C. IR (KBr):  = 2057, 3019, 2234, 1954, 1899, 1812, 1775, 1689, 1592, 1488, 1445,
1321, 1261, 1198, 1179, 1156, 1129, 1076, 1031, 1001, 928, 890, 845, 760, 748, 698, 637, 530,
1
516 cm- 1. H NMR (500 MHz, CD2Cl2) δ = 4.37 (s, 2H), 7.22 – 7.33 (m, 15H) ppm. 13C NMR
(126 MHz, CD2Cl2) δ = 31.85, 56.18, 80.74, 92.95, 127.56, 128.62, 129.56, 145.26 ppm. HRMS (EI):
[M]+ calcd. for C22H17Cl, 316.1019; found: 316.1016.
4.3.35. Ethyl 1-[4,4,4-tris(4-methoxyphenyl)but-2-yn-1-yl]piperidine-3-carboxylate, (rac-8a)
According to GP8: N,O-acetal rac-23 (230 mg, 1.05 mmol), TMSCl (112 mg, 1.00 mmol, 130 µL),
alkyne 18a (330 mg, 0.90 mmol) and nBuMgCl (0.9 mmol, 2 M in THF). The crude product was
purified by flash chromatography over silica gel with DCM/MeOH (99:1). Yellow oil (380 mg, 80%).
~
IR (Film):  = 2938, 2836, 2803, 1729, 1606, 1583, 1506, 1464, 1442, 1297, 1250, 1176, 1152,
1
1092, 1034, 825 cm-1. H NMR (500 MHz, CD2Cl2) δ = 1.21 (t, J = 7.1 Hz, 3H), 1.33 – 1.47 (m, 1H),
1.50 – 1.64 (m, 1H), 1.68 – 1.78 (m, 1H), 1.84 – 1.92 (m, 1H), 2.24 (td, J = 10.9, 3.1 Hz, 1H), 2.40 (t, J
= 10.5 Hz, 1H), 2.55 (tt, J = 10.4, 3.9 Hz, 1H), 2.76 (d, J = 11.2 Hz, 1H), 3.00 (d, J = 11.0 Hz, 1H), 3.45
(s, 2H), 3.78 (s, 9H), 4.04 – 4.15 (m, 2H), 6.78 – 6.83 (m, 6H), 7.12 – 7.17 (m, 6H) ppm. 13C NMR (126
MHz, CD2Cl2) δ = 14.58, 25.12, 27.08, 42.49, 48.35, 53.10, 54.26, 55.08), 55.77, 60.74, 80.86, 91.87,
113.65, 130.53, 138.69, 158.89, 174.35 ppm. HRMS (ESI): [M+H]+ calcd. for C33H38O5N, 528.2744;
found: 528.2752.
29