Activation of Quinolines by Cationic Chalcogen Bond Donors

Article abstract of DOI:10.1055/s-0039-1690110

The application of already established as well as novel selenium- and sulfur-based cationic chalcogen bond donors in the catalytic activation of quinoline derivatives is presented. In the presence of selected catalysts, rate accelerations of up to 2300 compared to virtually inactive reference compounds are observed. The catalyst loading can be reduced to 1 molpercent while still achieving nearly full conversion for electron-poor and electron-rich quinolines. Contrary to expectations, preorganized catalysts were less active than the more flexible variants.

Full text of DOI:10.1055/s-0039-1690110

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Georg Thieme Verlag Stuttgart · New York
2019, 30, 1673–1678
cluster
1673
en
P. Wonner et al.
Cluster
Synlett
Activation of Quinolines by Cationic Chalcogen Bond Donors
P. Wonner§
T. Steinke§
N
N
S. M. Huber*
0
0
0
0-
0
0
0
2-4
1
2
5-1
5
9
X
+N
Oct
N+
Oct
Ch
2 OTf–
Ch
Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum,
Universitätsstraße 150, 44801 Bochum, Germany
stefan.m.huber@rub.de
H
EtOOC
COOEt
H
§ Both authors contributed equally
N
Ph
H
N
Ph
N
H
Published as part of the Cluster Organosulfur and Organoselenium
Compounds in Catalysis
H
H
2 Equivalents
Without any activating agent
and selected Lewis acids
Received: 25.04.2019
Accepted after revision: 17.06.2019
Published online: 07.08.2019
ity may be fine-tuned by variation of both substituents R
and R′ (Figure 1). In solid-state chemistry and crystal engi-
neering, chalcogen bonding has increasingly been utilized
in the last 20 years or so.11,15,16 As an intramolecular inter-
action, it has also been used in organic synthesis since the
pioneering works of Tomoda17 and Wirth.18 Pioneering
studies on intermolecular interactions in solution were re-
cently published by Taylor19,20 and Beer21–23 in anion-recog-
nition processes, and in 2017 the group of Matile24,25 and
our group26,27 reported the first applications of intermolec-
ular chalcogen bonding in organocatalysis: quinoline deriv-
atives were activated by neutral ChB donors, while cationic
ChB donors were used in halide abstraction reactions. Two
further reactions of the latter type were reported subse-
quently.28,29
DOI: 10.1055/s-0039-1690110; Art ID: st-2019-w0236-c
License terms:
Abstract The application of already established as well as novel seleni-
um- and sulfur-based cationic chalcogen bond donors in the catalytic
activation of quinoline derivatives is presented. In the presence of se-
lected catalysts, rate accelerations of up to 2300 compared to virtually
inactive reference compounds are observed. The catalyst loading can
be reduced to 1 mol% while still achieving nearly full conversion for elec-
tron-poor and electron-rich quinolines. Contrary to expectations, pre-
organized catalysts were less active than the more flexible variants.
Key words chalcogen bonding, Lewis acids, organocatalysis, nonco-
valent interactions, intermolecular interactions, chalcogens, reduction
However, the application of cationic ChB catalysts in the
activation of neutral compounds is still unexplored, even
though a significantly stronger activation should be expect-
ed compared with neutral catalysts. This is particularly true
since in these reactions – in contrast to halide abstractions
– no interfering anion (leaving from the substrate) is present.
In the field of organocatalysis, noncovalent interactions
play an important role, which was so far dominated by hy-
drogen bonding.1,2 In the last years, however, less typical
noncovalent interactions such as anion- 3,4 halogen,5–8 and
chalcogen9–12 bonding has become a focus of current re-
search and have predominantly been applied in supramo-
lecular assembly and anion recognition processes. To date,
both anion- and halogen bonding (XB) have been intro-
duced in organocatalysis, whereas the application of chal-
cogen bonding (ChB) in this area is far less studied.
Chalcogen bonding is based on electrophilic chalcogen
substituents in organic or inorganic compounds, which act
as Lewis acidic centers. The origin of the interaction with
Lewis bases can be explained by an n → * type orbital in-
teraction (Figure 1) and by electrostatic attraction, since the
chalcogen substituents feature a region of positive electro-
static potential (-hole) in the elongation of the R–Ch
bond.13–15 In comparison to halogen bonding, chalcogen-
bond donors possess two of these electron-deficient axes in
a perpendicular arrangement. Furthermore, the Lewis acid-
R'
s*
n
R
Ch
LB
chalcogen bond
donor
Figure 1 Chalcogen bonding as n → * type interaction between a
Lewis base (LB) and a chalcogen bond donor (Ch = S, Se, Te)
As a simple benchmark reaction, the reduction of quino-
line derivatives (Scheme 1) was chosen for several reasons:
(a) most importantly, a series of reports is available with
data on the performance of halogen or (neutral) chalcogen
bonding organocatalysts;24,25,30 (b) the reaction can be easi-
ly monitored via 1H NMR spectroscopy; (c) a large number
of quinoline derivatives can be employed; and (d) no back-
Synlett 2019, 30, 1673–1678
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1674
P. Wonner et al.
Cluster
Synlett
ground reactivity is observed at room temperature in the
absence of activating agent (Table 1, entry 1). It should be
noted that, at the same time, the reaction is not without its
issues, particularly with regard to halogen bonding, as the
action of hidden acid traces such as HI cannot easily be
ruled out.31,32 This is less relevant for chalcogen bonding,
though, as the generation of acid seems much less likely.
As cationic ChB donors, sulfur- and selenium-based im-
idazolium and benzimidazolium derivatives were chosen,
with the selenium compounds already having been applied
in halide abstraction reactions.26,27
Table 1 Performance of Reference Compounds (Figure 2) in the Re-
duction of 2-Phenylquinoline (1a)
Entry
Catalyst
mol%a
Yield of 3a (%)b
1
2
–
–
1
1
1
1
1
1
1
1
1
1
1
1
<5
64
53
18
<5
88
<5
<5
<5
<5
<5
<5
<5
8H
3
9H
4
syn/anti-10H c
anti-10Cl
syn-10I
11S
5
6
7
H
N
R1
ChB Donor (1 mol%)
CDCl3, rt, 12 h
N
R1
8
11Se
R2
9
12S
R2
EtOOC
COOEt
10
11
12
13
12Se
1a–d
3a–d
N
H
syn-13S
anti-13S
anti-13Se
2
a: R1 = Ph and R2 = H
c: R1 = H and R2 = NO2
b: R1 = Me and R2 = F
d: R1 = H and R2 = OMe
a Catalyst loading with respect to the amount of 1a.
Scheme 1 Reduction of different quinoline derivatives 1a–d with
Hantzsch ester 2 (2.4 equiv) in the presence of sulfur- and selenium-
based cationic chalcogen bond donors
b After 12 h reaction time. Determined via 1H NMR spectroscopy and rela-
tive to TES as internal standard. Averaged values of three measurements. A
measurement / analysis error of ±10% is assumed.
c Inseparable 40:60 mixture of syn-10H and anti-10H.
The preparation of all ChB donors investigated herein
followed the same synthetic route, which is given in
Scheme 2 (yields for each step and more details are provid-
ed in the Supporting Information). The first step involves
the alkylation of the bis-heterocyclic compound, followed
by introduction of the chalcogen under basic conditions
and a second alkylation of the resulting chalcogenourea to
yield the final catalysts as triflate salts.26
This serves two purposes: it allows easy tracking of poten-
tial catalyst decomposition via 19F NMR spectroscopy and it
allows the separation of syn- and anti-isomers. Based on
the well-known supramolecular concept of preorganiza-
tion, the former is expected to be more active than analo-
gous compounds with freely rotating chalcogen bonding
moieties (such as 8 or 9).
The tested ChB donors and reference compounds are
shown in Figure 2. Each contains a characteristic cationic
bis(benz)imidazolium scaffold as well as octylated side
chains for improved solubility. Some of the compounds fea-
ture a trifluoromethyl group on the central benzene core.
First orientating experiments were performed with our
previously most active ChB catalyst26,27 syn-10SeMe and 2-
phenylquinoline (1a) as substrate to find an optimal reac-
tion profile regarding reaction time, catalyst loading, and
overall concentration (in view of solubility issues of com-
i)
N
N
N
N
CF3
+N
N+
C8H17
CF3
N
N
2 OTf–
C8H17
4
5
ii)
N
N
N
N
iii)
CF3
Ch
CF3
Ch
+N
N+
N
N
Ch
Ch
C8H17
C8H17
C8H17
C8H17
2 OTf–
7
6
Scheme 2 Schematic syntheses of different sulfur- and selenium-based chalcogen bond donors. (i) C8H17OTf (2.5 equiv), anhyd. CH2Cl2 (0.1 M), r.t.,
24 h; (ii) Ch(2.5 equiv), Cs2CO3 (2.5 equiv), anhyd. MeOH (0.1 M), reflux, 24 h; (iii) MeOTf (2.5 equiv), anhyd. CH2Cl2 (0.1 M), r.t., 24 h; Ch = S, Se.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, 1673–1678

1675
P. Wonner et al.
Cluster
Synlett
ingly, however, the non-selenated compounds syn/anti-10H,
8H and 9H were also active (Table 1, entries 2–4). For in-
stance, the most active reference compound 8H gave 64%
yield of compound 3a after 12 h reaction time. To exclude
the possibility that the observed activation is solely driven
by cation- interactions or hydrogen bonds via the back-
bone protons, the chlorinated reference compound anti-
10Cl was tested.34 As previous work had shown that its chlo-
rine substituents do not form halogen bonds,35,36 its poten-
tial modes of action (cation- and hydrogen bonding)
would be shared by the core structure of syn-10SeMe. The
chlorinated compound showed no activity (Figure 3; Table
1, entry 5), which strongly indicates that the activity of syn-
10SeMe can indeed be ascribed to chalcogen bonding. As a
further consequence, the performance of compounds
syn/anti-10H, 8H and 9H is likely based on hydrogen bond-
ing. To verify these results, reference compound syn-10I and
urea derivatives 11–13 (Figure 2 and Scheme 2) were also
employed as catalyst candidates. The iodinated compound
syn-10I provided 88% yield of 3a after 12 h reaction time, in
line with expectations for this strong XB donor (Table 1, en-
try, 6). Compounds 11–13 showed no activity (Table 1, en-
tries 7–13), likely due to the lack of chalcogen bonding op-
tions and strong - interactions, respectively.
N
N
N
N
+N
N+
C8H17
+N
N+
C8H17
Ch
Ch
Ch
Ch
C8H17
C8H17
2 OTf–
8ChMe
2 OTf–
9ChMe
Ch
N
N
N
N
N+ C8H17
+N
N+
C8H17
+N
CF3
Ch
CF3
Ch
Ch
C8H17
C8H17
2 OTf–
syn-10ChMe
2 OTf–
anti-10ChMe
X
N
N
N
N
N+ C8H17
+N
N+
C8H17
+N
CF3
CF3
X
X
X
C8H17
C8H17
2 OTf–
syn-10X
2 OTf–
anti-10X
N
N
N
N
+N
N+
C8H17
+N
N+
H
H
H
H
Based upon these findings, all remaining catalyst candi-
dates shown in Figure 2 were tested in the benchmark reac-
tion (Table 2, entries 1–8). Both sulfur- and selenium-based
bisbenzimidazolium catalysts 9–10 were similarly active
and induced nearly quantitative conversion of compound
1a after 12 h. This is somewhat unexpected given the high-
er polarizability of the heavier chalcogen, which should
form stronger ChB donors. It is also interesting to note that
the more flexible core structure in catalysts 9SMe and 9SeMe
is slightly superior to more preorganized framework struc-
tures such as in catalysts 10. For the latter, the difference in
activity between the syn- and anti-atropisomer is negligi-
ble in the observed timeframe. More precisely, catalyst
C8H17
C8H17
C8H17
2 OTf–
2 OTf–
9H
8H
N
N
N
N
N
N
N
N
Ch
Ch
Ch
Ch
C8H17
C8H17
C8H17
C8H17
11Ch
12Ch
Ch
N
N
N
N
N
N
C8H17
CF3
Ch
CF3
N
N
Ch
Ch
C8H17
9
SeMe yielded 95% of compound 3a, whereas syn-10SeMe and
C8H17
C8H17
anti-10SeMe provided 91% and 90% of the product, respec-
tively (Table 2, entries 4, 6 and 8). These findings could po-
tentially be explained by the fact that syn-10SeMe may not
bind in a clean bidentate fashion to the substrate. Its core
structure, it should be stressed, was developed for halogen
bond donors interacting with halides. Thus, it seems that
the more flexible backbone of 9SeMe is better able to adapt to
the coordination of the target. The corresponding sulfur-based
catalysts show the same trend (Table 2, entries 3, 5 and 7).
In contrast, a significant decrease in the conversion of
1a was observed when catalysts 8SMe and 8SeMe, with the
less polarizing imidazolium moieties, were used (Table 2,
entries 1 and 2). After 12 h reaction time, only 21% of com-
pound 3a were obtained with catalyst 8SeMe and only 15%
with catalyst 8SMe. Even after 24 h reaction time, both cata-
lysts yielded only approximately 50% of compound 3a. This
syn-13Ch
anti-13Ch
Figure 2 Overview of the tested chalcogen bond donors and reference
compounds; Ch = S, Se (except syn-13); X = H, I, Cl (only anti-10).
pound 2). In the presence of 1 mol% of catalyst syn-10SeMe
,
full conversion of the reaction in CDCl3 (0.042 mM) was ob-
served after 12 h.33 Accompanying 19F NMR measurements
(see the Supporting Information) confirmed the stability of
the catalyst under these reaction conditions. This was also
corroborated by a second run, in which further starting ma-
terial 1a was added to a fully converted reaction mixture,
giving a virtually identical yield of product 3a and thus rul-
ing out the action of accumulated decomposition products.
With this promising lead result in hand, various refer-
ence compounds (Figure 2) were investigated to dismiss an
activation that is not based on chalcogen bonding. Surpris-
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, 1673–1678

1676
P. Wonner et al.
Cluster
Synlett
Table 2 Overview of the Cationic Sulfur- and Selenium-Based Cata-
lysts (Figure 1) in the Reduction of 2-Phenylquinoline (1a)
Entry
Catalyst
Mol%a
Yield of 3a (%)b
8SMe
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
15
21
94
95
92
91
90
90
8SeMe
9SMe
9SeMe
syn-10SMe
syn-10SeMe
anti-10SMe
anti-10SeMe
a Catalyst loading with respect to the amount of 1a.
b After 12 h reaction time. Determined via 1H NMR spectroscopy and rela-
tive to TES as internal standard. Averaged values of three measurements. A
measurement error of ±10% is assumed.
Figure 3 Kinetic profile of the reduction of 2-phenylquinoline (1a) in
the presence of selected ChB, HB and XB donors. Kinetic profile for 12 h
reaction time is given in the Supporting Information.
observation is in accordance with previous results concern-
ing the weak performance of imidazolium-based ChB do-
nors in carbon–chlorine bond activation.27
based chalcogen bonds play a major role in the stabilization
of transition states of organocatalyzed reactions.37–43
In comparison to neutral ChB donors, which were re-
ported earlier as catalysts for this reaction, the selenium-
based cationic catalysts were approximately twice as active
(based on the time needed for full conversion),25 whereas
the sulfur-based compounds were about 24 times more ac-
tive, even though 1 mol% of catalyst was used compared
with the 30 mol% of the earlier reports.24 This impressively
demonstrates the power of charge-assisted chalcogen
bonding, particularly for the comparably weakly polariz-
able sulfur center.
Finally, the most active bisbenzimidazolium based cata-
lysts 9SMe and 9SeMe were applied in a small substrate
screening involving selected quinolines 1b–d, which had
proven to be very challenging for neutral chalcogen bond
donors.24,25 First, the background reactivity of the quinolo-
nes in the absence of any activating reagent was deter-
mined (Table 4, entries 1–3) and was found to be very low.
In contrast to neutral ChB donors, which provided no or
very low yields of products 3b–d, the cationic ChB catalysts
induced up to 82% product formation (Table 4, entries 4–9).
For both catalysts, the very electron-poor quinoline 3c
was reduced most efficiently (Table 4, entries 5 and 8). Sele-
nium-based catalyst 9SeMe seems less suitable for the reduc-
tion of electron-rich quinolines (such as 3d) than its sulfur-
based analogue 9SMe (cf. entries 6 and 9). This could be ex-
plained by either a stronger catalyst-substrate coordination
(which may result in a less favorable product liberation
from the catalyst) or by a competing coordination of the
catalyst to the electron-rich methoxy substituent of the
substrate.25
Finally, relative rate constants were determined for se-
lected catalysts (Table 3 and Figure 3; shown for the first 5 h
of reaction time, full kinetic profile is given in the Support-
ing Information). To this end, the least active reference
compound anti-10Cl served as standard for comparison (krel
= 1). For the most potent catalysts 9SMe and 9SeMe, relative
rate accelerations of about 2000 and 2300 were determined
(Table 3, entries 6 and 7). In both cases, the related syn-at-
ropisomers were markedly less active, with rate accelera-
tions being 1.7 (9SeMe vs. syn-10SeMe) or 1.8 times (9SMe vs.
syn-10SMe) higher for the more flexible catalysts (entries 4
and 5). The analogous hydrogen-bond donors syn/anti-10H
and 9H showed 5–15 fold less rate acceleration than the best
ChB donors (entries 2 and 3).
Table 3 Relative Rate Constants for Selected ChB Donors, with Refer-
ence Compound anti-10Cl as Standard.
a
krel
Entry
Catalyst
1
2
3
4
5
6
7
anti-10Cl
syn/anti-10H b
9H
1
150
450
syn-10SeMe
syn-10SMe
9SeMe
1200
1300
2000
2300
9SMe
a Normalized rate constant (relative to anti-10Cl as standard).
b Inseparable 40:60 mixture of syn/anti-10H.
The strong performance of the sulfur-based catalysts
may in fact not be entirely unexpected, as there are several
examples in the literature in which intramolecular sulfur-
In conclusion, the first application of cationic sulfur-
and selenium-based chalcogen bond donors in the activa-
tion of neutral compounds was presented. Based on a series
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, 1673–1678

1677
P. Wonner et al.
Cluster
Synlett
Table 4 Yields for the Reduction of Quinolines 1b–d in the Presence of
Chalcogen Bond Donors 9
(4) Schottel, B. L.; Chifotides, H. T.; Dunbar, K. R. Chem. Soc. Rev.
2008, 37, 68.
(5) Bulfield, D.; Huber, S. M. Chem. Eur. J. 2016, 41, 14434.
(6) Cavallo, G.; Metrangolo, P.; Milani, R.; Pilati, T.; Priimagi, A.;
Resnati, G.; Terraneo, G. Chem. Rev. 2016, 116, 2478.
(7) Nagorny, P.; Sun, Z. Beilstein J. Org. Chem. 2016, 12, 2834.
(8) Tepper, R.; Schubert, S. U. Angew. Chem. Int. Ed. 2018, 57, 6004.
(9) Vogel, L.; Wonner, P.; Huber, S. M. Angew. Chem. Int. Ed. 2019,
58, 1880.
(10) Lim, J. Y. C.; Beer, P. D. Chemistry 2018, 4, 731.
(11) Gleiter, R.; Haberhauer, G.; Werz, D. B.; Rominger, F.; Bleiholder,
C. Chem. Rev. 2018, 118, 2010.
Entry
Catalysta
Product
Yield of 3b–d (%)b
1
2
3
4
5
6
7
8
9
–
3b
3c
3d
3b
3c
3d
3b
3c
3d
0
–
6 (13)
0
–
9SMe
9SMe
9SMe
9SeMe
9SeMe
9SeMe
57 (62)
88 (>95)
56 (73)
50 (63)
92 (>95)
38 (61)
(12) Mahmudov, K. T.; Kopylovich, M. N.; Guedes da Silva, M. F. C.;
Pombeiro, A. J. L. Dalton Trans. 2017, 10121.
(13) (a) Murray, J. S.; Lane, P.; Clark, T.; Politzer, P. J. Mol. Model.
2007, 13, 291. (b) Rosenfield, R. E.; Parthasarathy, R.; Dunitz, J.
D. J. Am. Chem. Soc. 1977, 99, 4860. (c) Murray, J. S.; Lane, P.;
Clark, T.; Politzer, P. J. Mol. Model. 2009, 15, 723. (d) Pearson, R.
G. J. Am. Chem. Soc. 1963, 85, 3533. (e) Ramasubbu, N.;
Parthasarathy, R.; Murray-Rust, P. J. Am. Chem. Soc. 1986, 108,
4308. (f) Murray-Rust, P.; Motherwell, W. D. S. J. Am. Chem. Soc.
1979, 101, 4374. (g) Politzer, P.; Murray, J. S.; Clark, T. Phys.
Chem. Chem. Phys. 2010, 12, 7748. (h) Politzer, P.; Riley, K. E.;
Bular, F. A.; Murray, J. S. Comput. Theor. Chem. 2012, 998, 2.
(14) Wang, W.; Ji, B.; Zhang, Y. J. Phys. Chem. A 2009, 113, 8132.
(15) Bleiholder, C.; Gleiter, R.; Werz, D. B.; Köppel, H. Inorg. Chem.
2007, 46, 2249.
(16) (a) Mukherjee, A. J.; Zade, S. S.; Singh, H. B.; Sunoj, R. B. Chem.
Rev. 2010, 110, 4357. (b) Werz, D. B.; Gleiter, R.; Rominger, F.
J. Am. Chem. Soc. 2002, 124, 10638. (c) Werz, D. B.; Gleiter, R.;
Romiger, F. J. Org. Chem. 2002, 67, 4290. (d) Schulte, J. H.; Werz,
D. B.; Romiger, F.; Gleiter, R. Org. Biomol. Chem. 2003, 1, 2788.
(e) Werz, D. B.; Gleiter, R.; Romiger, F. Organometallics 2003, 22,
843. (f) Gleiter, R.; Werz, D. B.; Rausch, B. J. Chem. Eur. J. 2003, 9,
2676. (g) Bleiholder, C.; Werz, D. B.; Köppel, H.; Gleiter, R. J. Am.
Chem. Soc. 2006, 128, 2666.
a 1 mol% catalyst was applied with respect to the amount of 1b–d.
b After 12 h reaction time. Yield in brackets after 24 h. Determined via 1
H
NMR spectroscopy. Averaged values of two measurements. A measure-
ment error of ±10% is assumed.
of comparison experiments, alternative modes of activation
could be ruled out. Overall, rate accelerations of up to 2300
were observed compared with inactive reference com-
pounds. The strong performance of the cationic ChB donors
allowed the activation of very electron-poor or electron-
rich substrates, which were hitherto difficult to activate.
Two findings in particular were somewhat unexpected:
the better performance of catalysts with flexible core struc-
tures in comparison to their conformationally locked syn-
atropisomers, and the potency of sulfur-based ChB donors.
Given that the latter are easier to synthesize and handle
than their selenium-based analogues, it seems that sulfur-
containing Lewis acids could have great potential in chalco-
gen-bonding-based catalysis. Additional studies to further
implement such compounds in noncovalent organocatalysis
are under way.
(17) Iwaoka, M.; Tomoda, S. J. Am. Chem. Soc. 1996, 118, 8077.
(18) Wirth, T. Angew. Chem. Int. Ed. Engl. 1995, 34, 1726.
(19) Garrett, G. E.; Carrera, E. I.; Seferos, D. S.; Taylor, M. S. Chem.
Commun. 2016, 52, 9881.
(20) Garrett, G. E.; Gibson, G. L.; Straus, R. N.; Seferos, D. S.; Taylor, M.
S. J. Am. Chem. Soc. 2015, 137, 4126.
(21) Lim, J. Y. C.; Marques, I.; Félix, V.; Beer, P. D. Chem. Commun.
2018, 54, 10851.
Funding Information
(22) Lim, J. Y. C.; Marques, I.; Thompson, A. L.; Christensen, K. E.;
Félix, V.; Beer, P. D. J. Am. Chem. Soc. 2017, 139, 3122.
(23) Lim, J. Y. C.; Liew, J. Y.; Beer, P. D. Chem. Eur. J. 2018, 24, 14560.
(24) Benz, S.; López-Andarias, J.; Mareda, J.; Sakai, N.; Matile, S.
Angew. Chem. Int. Ed. 2017, 56, 812.
This project has received funding from the European Research Coun-
cil (ERC) under the European Union’s Horizon 2020 research and in-
novation programme (638337).
H
ori
z
o
n
2
0
2
0
Fra
m
e
w
orkProgra
m
m
e
(6
3
8
3
3
7)
(25) Benz, S.; Mareda, J.; Besnard, C.; Sakai, N.; Matile, S. Chem. Sci.
2017, 8, 8164.
(26) (a) Wonner, P.; Vogel, L.; Düser, M.; Gomes, L.; Kniep, F.;
Mallick, B.; Werz, D. B.; Huber, S. M. Angew. Chem. Int. Ed. 2017,
56, 12009.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690110.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
(b) General procedure for the synthesis of chalcogeno ureas
11–13: Under an argon atmosphere, the respective
bis(benz)imidazolium compound (1 equiv) was added to a
Schlenk flask and dissolved in anhydrous methanol (0.17 M;
dried for 24 h over molecular sieve). To the solution, elemental
selenium powder or sulfur (2.5 equiv) and cesium carbonate
(2.5 equiv) were added. The mixture was heated at reflux for
24 h and finally filtered (hot solution) over a short plug of silica
and rinsed with CH2Cl2. After the solvent was removed, the
References and Notes
(1) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
(2) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem. Eur. J.
2011, 17, 6890.
(3) Zhao, Y.; Beuchat, C.; Domoto, Y.; Gajewy, J.; Wilson, A.;
Mareda, J.; Sakai, N.; Matile, S. J. Am. Chem. Soc. 2014, 136, 2101.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, 1673–1678

1678
P. Wonner et al.
Cluster
Synlett
crude solid was purified by column chromatography (solvents
noted for specific compounds). All spectroscopic data are given
in the Supporting Information.
8.04 (dd, J = 7.3, 2.0 Hz, 2 H), 7.81 (dtd, J = 13.0, 7.3, 1.4 Hz, 4 H),
7.67 (d, J = 7.7 Hz, 2 H), 4.71 (td, J = 7.4, 1.9 Hz, 4 H), 2.51 (s,
6 H), 2.03 (m, 4 H), 1.28 (m, 20 H), 0.87 (m, 6 H).13C NMR (101
MHz, CD3CN):  = 151.83, 138.65, 136.31, 135.17, 133.42 (d, J =
1.60 Hz), 132.81, 129.84, 129.26, 127.14 (q, J = 31.0 Hz), 122.12
(d, J = 321.5 Hz), 114.93, 114.37, 49.30, 32.36, 29.88, 29.68 (d,
J = 8.80 Hz), 27.09, 23.30, 18.89, 14.34. 19F NMR (235 MHz,
CD3CN):  = −56.73 (s, 3 F), −79.32 (s, 6 F). ATR-IR: 2927 (w),
2857 (w), 1547 (w), 1501 (w), 1477 (w), 1433 (w), 1364 (w),
1256 (vs), 1223 (m), 1175 (m), 1140 (m), 1028 (s), 984 (w),
858 (w), 752 (m), 687 (w), 635 (s), 573 (m), 517 (w), 434
(w) cm–1. ESI-MS (+): m/z [M+OTf ]+ calcd. 845.31; found:
845.27; ESI-MS (–): m/z [OTf]– calcd. 148.95; found: 148.66.
Anal. calcd. CHNS: C, 49.49; H, 5.17; N, 5.63; S, 12.89; found: C,
48.55; H, 4.94; N, 5.53; S, 12.37.
(c) General methylation procedure for the synthesis of com-
pounds 8–10: Under an argon atmosphere, the respective chal-
cogenourea compound (1 equiv) was dissolved in anhydrous
CH2Cl2. Then methyl trifluoromethanesulfonate (2.5 equiv) was
slowly added at 0 °C and the reaction mixture was stirred for
24 h at room temperature. After the solvent was removed under
reduced pressure, the crude residual was diluted in a little ace-
tonitrile and was precipitated by addition of diethyl ether. The
solid was filtered off, washed with diethyl ether and pentane
and dried under high vacuum. Alternatively, the solvent was
removed, and the residue was washed under sonification
several times with ether and pentane. Finally, the respective
methylated chalcogenated compound was obtained as colorless
solid. All spectroscopic data are given in the Supporting Infor-
mation.
(27) Wonner, P.; Vogel, L.; Kniep, F.; Huber, S. M. Chem. Eur. J. 2017,
23, 16972.
(28) Benz, S.; Besnard, C.; Matile, S. Helv. Chim. Acta 2018, 101,
e1800075.
(29) Sebastian, B.; Poblador-Bahamonde, A. I.; Nicolas, L. D.; Stefan,
M. Angew. Chem. Int. Ed. 2018, 57, 5408.
(d) Spectroscopic data for selected compounds 9SeMe, 9SMe
and syn-10SMe
:
Compound 9SeMe: Yield: 294 mg (74%); solid; 1H NMR (300 MHz,
CDCl3):  = 8.50 (s, 1 H), 8.17 (dd, J = 7.10, 1.80 Hz, 2 H), 8.08
(dd, J = 9.00, 6.80 Hz, 1 H), 7.69 (m, 6 H), 7.43 (dd, J = 7.50,
0.80 Hz, 2 H), 4.67 (d, J = 8.00 Hz, 4 H), 2.41 (s, 6 H), 2.01 (q, J =
7.70 Hz, 4 H), 1.31 (m, 20 H), 0.87 (m, 6 H). 13C NMR (101 MHz,
CD3CN):  = 147.29, 136.10, 135.34, 133.76, 133.48, 131.77,
128.22, 128.59, 128.39, 122.09 (d, J = 321.0 Hz), 114.49, 114.07,
49.88, 32.48, 30.24, 28.79 (d, J = 4.50 Hz), 27.34, 23.34, 14.38,
11.51. 19F NMR (235 MHz, CD3CN):  = −78.53 (s, 6 F). ATR-IR:
3073 (w), 2928 (w), 2857 (w), 1738 (w), 1603 (w), 1501 (m),
1477 (m), 1429 (m), 1358 (w), 1250 (vs), 1223 (s), 1148 (s),
1086 (w), 1028 (vs), 926 (w), 831 (w), 800 (w), 752 (s), 698
(w), 635 (vs), 571 (m), 515 (s), 432 (w) cm–1. ESI-MS (+): m/z
[M-OTf]+ calcd. 873.21; found: 872.87; ESI-MS (–): m/z [OTf]–
calcd. 148.95; found 148.80. Anal. calcd. for CHNS: C, 51.82; H,
5.65; N, 6.04; S, 13.83; found: C, 51.79; H, 5.42; N, 5.77; S, 13.72.
Compound 9SMe: Yield: 620 mg (79%); solid; 1H NMR (300 MHz,
CDCl3):  = 8.50 (s, 1 H), 8.15 (m, 3 H), 7.68 (sd, J = 8.4, 1.3 Hz,
6 H), 7.43 (d, J = 7.7 Hz, 2 H), 4.64 (d, J = 7.7 Hz, 4 H), 2.51 (s,
6 H), 2.02 (p, J = 7.7 Hz, 4 H), 1.38 (m, 20 H), 0.87 (m, 6 H). 13C
NMR (101 MHz, CD3CN):  = 151.20, 135.35, 134.66, 134.08,
132.97, 131.67, 129.18, 128.83, 127.88, 114.53, 113.93, 48.76,
32.48, 30.11, 29.79 (d, J = 5.40 Hz), 27.35, 23.40, 18.51, 14.37.
19F NMR (235 MHz, CD3CN):  = −79.28 (s, 6 F). ATR-IR: 3073
(w), 2928 (w), 2857 (w), 1738 (w), 1603 (w), 1501 (w), 1477
(w), 1462 (w), 1431 (w), 1364 (w), 1254 (s), 1223 (m), 1150
(m), 1088 (w), 1028 (vs), 847 (w), 802 (w), 752 (m), 698 (w),
634 (vs), 571 (w), 515 (m) cm–1. ESI-MS (+): m/z [M + OTf ]+
calcd. 777.32; found: 777.51; ESI-MS (–): m/z [OTf]– calcd.
148.95; found: 149.00. Anal. calcd. CHNS: C, 51.82; H, 5.65; N,
6.04; S, 13.83; found: C, 51.79; H, 5.42; N, 5.77; S, 13.72.
(30) Bolm, C.; Bruckmann, A.; Pena, M. Synlett 2008, 900.
(31) Jungbauer, S. H.; Schindler, S.; Kniep, F.; Walter, S. M.; Rout, L.;
Huber, S. M. Synlett 2013, 24, 2624.
(32) Togo, H.; Iida, S. Synlett 2006, 2159.
(33) General Procedure for the Reduction of 1a:
In a dry NMR tube, freshly prepared stock solutions of the
respective catalyst (100 L, 2.5 mM), the quinoline derivative
(100 L, 250 mM) and the Hantzsch ester (400 L, 150 mM)
were added, sealed and shaken for 1 min. Afterwards, a series of
1H NMR measurements were performed with a total duration of
12 h (for selected derivatives 24 h). As internal standard TES
(0.125 equiv) was added to the quinoline stock solution.
(34) The syn-12BIm-Cl atropisomer decomposed during its synthe-
sis.
(35) Jungbauer, S. H.; Huber, S. M. J. Am. Chem. Soc. 2015, 137, 12210.
(36) Gliese, J. P.; Jungbauer, S. H.; Huber, S. M. Chem. Commun. 2017,
53, 12052.
(37) Srivastava, K.; Chakraborty, T.; Singh, H. B.; Butcher, R. J. Dalton
Trans. 2011, 4489.
(38) Srivastava, K.; Shah, P.; Singh, H. B.; Butcher, R. J. Organometal-
lics 2011, 30, 534.
(39) Nagao, T.; Hirata, S.; Goto, S.; Sano, S.; Kakehi, A.; Iizuka, K.;
Shiro, M. J. Am. Chem. Soc. 1998, 12, 3104.
(40) Franchetti, P.; Cappellacci, L.; Grifantini, M.; Barzi, A.; Nocentini,
G.; Yang, H.; O’Connor, A.; Jayaram, H. N.; Carrell, C.; Goldstein,
B. M. J. Med. Chem. 1995, 38, 3829.
(41) Birman, V. B.; Li, X. Org. Lett. 2008, 10, 1115.
(42) Leverett, C. A.; Vikram, V. C.; Purohit, C.; Romo, D. Angew. Chem.
Int. Ed. 2010, 49, 9479.
(43) Robinson, E. R. T.; Fallan, C.; Simal, C.; Slawin, A. M. Z.; Smith, A.
D. J. Am. Chem. Soc. 2013, 4, 2193.
Compound syn-10SMe: Yield: 323 mg (87%); solid; 1H NMR (300
MHz, CD3CN):  = 8.40 (t, J = 8.1 Hz, 1 H), 8.24 (d, J = 8.1 Hz, 2 H),
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, 1673–1678