Pyridinyl Amide Ion Pairs as Lewis Base Organocatalysts

Article abstract of DOI:10.1021/acs.joc.0c00114

Pyridinyl amide ion pairs carrying various electron-withdrawing substituents were synthesized with selected ammonium or phosphonium counterions. Compared to neutral pyridine-based organocatalysts, these new ion pair Lewis bases display superior catalytic

Full text of DOI:10.1021/acs.joc.0c00114

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Article
Pyridinyl Amide Ion Pairs as Lewis Base Organocatalysts
Julian Helberg, Torsten Ampßler, and Hendrik Zipse
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00114 • Publication Date (Web): 30 Mar 2020
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The Journal of Organic Chemistry
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Pyridinyl Amide Ion Pairs as Lewis Base Organocatalysts
Julian Helberg, Torsten Ampßler and Hendrik Zipse*
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Department of Chemistry, Ludwig-Maximilians-Universität, Butenandtstrasse 5-13, 81377 München, Germany
Supporting Information Placeholder
P
Ar
O2S
R4
N
N
N
N
N
N
SICITIES
LEWIS BA
ABSTRACT: Pyridinyl amide ion pairs carrying various electron withdrawing substituents were synthesized with selected
ammonium or phosphonium counter ions. Compared to neutral pyridine-based organocatalysts these new ion pair Lewis bases display
superior catalytic reactivity in the reaction of isocyanates with alcohols and the aza-Morita-Baylis-Hillman reaction of hindered
electrophiles. The high catalytic activity of ion pair catalysts appears to be due to their high Lewis basicities towards neutral
electrophiles as quantified through quantum chemically calculated affinity data.
INTRODUCTION
Lewis Base Catalyst
Reagents
The vast increase in catalytic potential caused by electron-
donating substituents attached to pyridine derivates has been
known and exploited for decades, 4-dimethylaminopyridine
(DMAP, 1a) being the most widely known example (Figure 1).1
Efforts to improve the catalytic performance of 1a have
eventually led to 9-azajulolidine (TCAP, 1b), which still
represents the standard for a commercially available, high-
performance Lewis basic organocatalyst, and has not been
significantly surpassed by other pyridine-derivatives since.2
Further increases in catalytic activity may be expected from
pyridines carrying anionic substituents. Anders et al. found that
sufficiently stabilized anions of 4-methylpyridine 2 underwent
N-substitution instead of the expected reaction on the alkyl
carbon, and also isolated a stable adduct of pyridinyl anions and
activated sulfonic acids that yielded sulfonic esters when
reacted with alcohols.3 This adduct matches what is believed to
be the first intermediate in the corresponding catalytic cycle of
Lewis base-catalyzed reactions. Also, Sheldrake reported that -
depending on reaction conditions - in situ generated 4-pyridinyl
carbonyl anions 3 were acylated exclusively at the N-position,
while a mixture of constitutionally isomeric products was
obtained in alkylation reactions.4 When developing a synthetic
route to alkyl-substituted 3,4-diaminopyridines, we had earlier
observed that 4-pyridinylamide anions 4 react with alkylation
reagents preferentially at the pyridine nitrogen atom.5 Very
recently, Böttcher et. al. described the synthesis and
characterization of 4-borate pyridine anion 5 intended for use as
strong ligand.6
Ph
S
O
N
N
N
S
N
N
N
O
O
1a
1b
2
3
Ligands
Mes
Ph
N
N
N
N
N
R
R
N
BR3
Ph
S
O
O
O
N
N
O
Mes
6
7
4
5
Figure 1. Neutral and anionic pyridine compounds used as
Lewis base organocatalysts, reagents, or ligands.
The catalytic activity of anionic sulfonamide pyridines 6 and
7 has only been described for the oligomerization of isocyanates
in the patent literature.7 Unfortunately, no comparison has been
made to commonly used (neutral) organocatalysts and
characterization was omitted. In contrast to most other reactions
in organocatalysis, the oligomerization of isocyanates
commonly proceeds under neat conditions and includes no
proton transfer steps. We therefore analyze here whether the
catalytic potential of ion pair catalysts based on the 4-
pyridinylamide motif also present in anion 6 survives in
reactions of unreactive electrophiles involving proton transfer
steps. For the sake of comparison, we select here (a) the
formation of urethane from alcohols and isocyanates as a
common reaction type for this class of electrophile, and (b) the
aza-Morita-Baylis-Hillman reaction of terminally substituted
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Michael acceptors.8 In addition, we also quantify the Lewis
Page 2 of 13
1
basicity of all catalysts through quantum chemical calculations.
2
3
4
RESULTS
Neutral sulfonamides 8 as the direct precursors for the
anionic pyridine catalysts were synthesized by condensation of
4-aminopyridine 9 with the corresponding sulfonyl chlorides.
X-Ray crystallographic analysis indicates that 8 is mainly
present as the sulfonimide tautomer as indicated in Scheme 1
(see SI). The phosphonic amide salt 10 was synthesized in a
similar manner using diphenylphosphinic chloride as the
reagent. In the case of the "extended" sulfonamide 14,
saccharine 12 was first transformed into the corresponding
imidoyl chloride 13, which was then reacted with 9.
Deprotonation of neutral amides was carried out using aqueous
sodium hydroxide or sodium methoxide solutions, followed by
salt metathesis with the appropriate cation and extraction with
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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60
CH2Cl2.
Subsequent
crystallization
from
CH2Cl2/toluene/heptane mixtures gave the ion pair catalysts 6,
10, and 15.
Scheme 1. Synthesis of ion pair catalysts.
O
O
S
O
O
R
R
R
R
S
NH2
S
S
X
N
Cl
NH
N
1) (a) or (b)
2) XBr/XCl
O
O
O
O
Base
8
N
9
N
H
N
N
6
O
P
Ph
N
Ph
Ph
Ph
Ph
Ph
NH2
P
P
PBu4
X
Cl
NH
phosphonium,
ammonium,
benzimidazolium
PBu4OH
=
O
O
Figure 2. Pyridine ion pair catalysts synthesized and
characterized in this study.
Base
N
9
(a) = NaOH/H2O
(b) = NaOMe/MeOH
N
10
N
Table 1. Selected anion-cation distances observed in the
solid state.
11
PPh4
O
O
D4
O
O
R'
9
SOCl2
+
S
1) (a)
S
R
X
O
N
N
D1
N
N
NH
N
S
R
O
O
O
O
S
2) PPh4Br
N
N
S
O
R
Cl
O
N
N
13
D3
R
H
15
14
12
D2
X = N, P
X-Ray crystallographic data for all synthesized ion pair
Ent
ry
Catal
yst
D1
D2
D3
D4
catalysts shown in Figure 2 could be obtained except for 6ab,
which is a room temperature ionic liquid (IL) (see SI). Table 1
collects the closest contacts between selected atoms of the
cation and the pyridine anion that were derived from X-ray
crystallographic data. Based on the values for those selected
examples, some general observations can be made. In all cases,
the shortest distance between the cation center atom (P or N) to
the anion heteroatoms originates from an oxygen atom (distance
D1). This is also true for the shortest interaction between an
anion heteroatom and any cation atom (distance D4), except for
the special case of 7e featuring a very strong intermolecular
hydrogen bond (entry 4). Both observations indicate that the
cation is located closer to the formally charge-bearing amide
groups than to the pyridine ring. This is actually not obvious
when comparing the amide-N to cation distances (D3) with the
pyridine-N to cation distances (D2), both of which are typically
longer as compared to the shortest oxygen(anion) to cation
distance D4 (see full Table for the eleven crystallized ion pair
catalysts in the SI).
heteroatom(a
nion)P/N(
cation)a
pyridine-
N
amide-N
heteroatom
(anion)
cationa
cationa
cationa
1
2
3
6aa
6bc
6cg
395.0
(ON)
399.5
257.3
(α-H)
254.2
(α-H)
285.7
(α-H)
246.3
(α-H)
254.2
(α-H)
267.6
(β-H)
244.9
(Oβ-H)
234.1
(OP)
467.9
(Oα-H)
241.4
(Me-OP)
(Me-Oα-
H)
4
7e
388.4
243.6
217.6
217.6
(ON)
(α-H)
(α-H)
(amide-
Nα-H)
5
6
10d
15g
368.9
(OP)
506.6
247.9
(α-H)
251.8
(γ-H)
286.2
(δ-H)
280.1
(β-H)
219.5
(Oα-H)
238.3
(OP)
(Oγ-H)
a in pm.
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Due to the significance of catalytic activation of isocyanates
loading (keff(3)) are shown graphically in Fig. 3b. The reaction
benefits notably from the addition of catalysts since 3 mol% of
1a accelerates it by more than a factor of six compared to the
uncatalyzed background reaction (Table 2; entries 1, 5).
1
2
3
4
5
6
7
8
for nucleophilic attack, we chose the synthesis of urethane 16
from p-tolyl isocyanate (17) and butan-1-ol (18) as the primary
benchmark reaction (Scheme 2).9 The more reactive catalysts
were then tested in the aza-MBH reaction of tosyl imine 19 and
cyclohexenone 20 as intrinsically unreactive substrate
system.8a,10 Also, an exploratory study of esterification
reactions was conducted. After initial screening this was not
investigated further, because reactions employing ion pair
catalysts such as 6cg (Figure 2) did not follow the same rate
laws observed for the neutral organocatalysts 1a and 1b (see
SI). Scheme 2 also shows the proposed Lewis base adducts
occurring as intermediates after the first step of the catalytic
cycle for the chosen benchmark reactions.
keff
(1)
17 18
16
+
keff = kcat  [catalyst]
(2)
Table 2. Effective rate constants keff(X) (catalyzed by X
mol% catalyst relative to 17) obtained for the synthesis of
urethane 16 (ordered by keff(3)).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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53
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56
57
58
59
60
Catalyst
X mol%
HO
+
Scheme 2. Reference reactions used in this study and the
proposed Lewis base adducts. (a) Urethane synthesis, and
(b) aza-MBH reaction. Protons printed in bold are used to
determine turnover by 1H NMR spectroscopy.
CDCl3
23°C
HN
O
N
C
O
C
O
0.1 M
17
0.3 M
18
16
E
nt
ry
풌풆풇풇(ퟑ)(퐜퐚퐭퐚퐥퐲퐬퐭)
풌풆풇풇(ퟑ)(ퟏ퐚)
CH3
(a)
CH3
Catal
yst
a,b
keff(3)a,c
kcat
keff(X)a,c
Lewis base
catalyst
1 - 30 mol%
HO
+
1
2
3
none
22
---
0.16
0.13
0.13
---
4.54E-05(X=0)
3.50E-05(X=30)
C
CDCl3
H2
HN
O
N
0.00
6
C
O
C
C
3.55E-05
3.63E-05
0.3 M
18
O
H2
0.1 M
17
24
---
---
16
1.14E-04(X=15)
1.72E-04(X=30)
6.26E-
05d
0.00
6
4
23
0.22d
- LB
+ 18
or
+ LB
0.08
6
1.27E-03(X=15)
2.35E-03(X=30)
5
6
1a
2.80E-04
3.65E-04
1.00
1.30
O
N
O
N
C
C
0.11
5
6.07E-04 (X=5)
2.02E-03(X=20)
6aa
LB
LB
anionic
neutral
5.02E-05(X=0.1)
1.44E-04(X=1)
2.50E-04(X=2)
6.54E-04(X=5)
1.25E-03(X=10)
2.64E-03(X=20)
Lewis base
Lewis base
(b)
0.18
0
O
O
7
1c
3.83E-04
1.37
or
+ LB
+ 19
- LB
LB
LB
0.13
0
8
9
6ab
6ac
3.89E-04
4.71E-04
1.39
1.68
---
---
Ts
Ts
O
N
HN
O
Lewis base
catalyst
5 - 25 mol%
H
0.37
9
+
H
1.72E-04(X=1)
8.25E-04(X=5)
2.43E-04(X=1)
1.16E-03(X=5)
2.41E-04(X=1)
1.09E-03(X=5)
6.32E-05(X=0.1)
2.78E-04(X=1)
1.37E-03(X=5)
6.63E-03(X=30)
0.16
7
CDCl3
Cl
Cl
10
11
12
1d
1e
1f
5.05E-04
6.57E-04
6.61E-04
1.96
2.35
2.36
21
1.0 M
20
0.25 M
19
0.23
4
1
Reaction progress was quantified by H NMR spectroscopy
via integration of the well-separated signals of the hydrogen
atoms highlighted in Scheme 2. For the synthesis of urethane
16, the obtained turnover curves were validated by GC-FID
measurements of reactions catalyzed by several of the neutral
organocatalyts (see SI). Turnover values were fed into a
numerical simulation based on the effective second order
mechanism represented by Eq. 1 to obtain the effective rate
constant of the reaction keff, which can be used to obtain the
concentration-independent rate constant of each catalyst
according to Eq. 2. The kinetic data obtained for the urethane
synthesis reaction shown in Scheme 2a in the presence of
various catalysts has been collected in Table 2. Figure 3a shows
examples of the respective turnover curves in CDCl3 catalyzed
by 3 mol% each of 1a, 1b, and 6cg together with the fitted
curves. Effective rate constants obtained at 3 mol% catalyst
0.22
6
0.36
4
13
14
1b
7.50E-04
8.34E-04
2.68
0.27
3
1.61E-03(X=6)
3.22E-03(X=12)
15g
2.98
5.13
15
16
6bf
6bc
1.43E-03
1.44E-03
---
0.47
6
6.94E-03(X=15)
8.04E-04(X=1.2)
3.96E-03(X=6)
7.78E-03(X=12)
0.66
1
17
6cg
1.99E-03
7.10
a
b
c
d
Averaged values (see SI). in L2 mol-2 s−1. in L mol−1 s−1.
extrapolated value.
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relative catalytic performance reflected in the concentration-
1
2
3
4
5
6
7
8
independent rate constant kcat (the slopes of the correlation lines
in Fig. 4) is almost identical to that seen already in the catalytic
rate constant keff(3) at 3 mol% catalyst loading. It should be
noted, that for the combinations of more (Brønsted) acidic
cations and strongly basic anions, the final conversion is
noticeably lower than expected. We find this having some effect
when
methyltriphenylphosphonium
and
benzyltriphenylphosphonium ions were used as cations (as in
catalysts 6bc and 6bf), although this effect is negligible in
experiments using 3 mol% catalyst loadings. When using
diethyl benzimidazolium as cation (as in ion pairs 6be, 6ce, and
7e), we observe formation of the formal adduct of this cation to
isocyanate 17, most likely through transient C2-deprotonation
of diethyl benzimidazolium cation and formation of the
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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40
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
respective
N-heterocyclic
carbene
(see
SI).
For
tetraphenylphosphonium as the counter ion (present in 15g and
in the most active catalyst 6cg) we found no such issues under
the reaction conditions employed here. Finally, phosphonamide
ion pair 10d was not included in the catalysis studies due to its
instability in CDCl3 as well as CH2Cl2. Already when
attempting to characterize this compound in these solvents by
NMR spectroscopy, the compound degrades rapidly.
Figure 3. (a) Turnover curves obtained for the synthesis of
urethane 16, and (b) keff(3) values obtained for this reaction.
TCAP (1b) performs best of all investigated neutral catalyst
systems, while the diaminosubstituted pyridines 1e and 1f show
slightly lower activity (Table 2, entries 11
-
13).
Triphenylphosphine (22) does not act as a catalyst under the
chosen reaction conditions, which is also true for
tetrabutylammonium bis-sulfonamide salt 24 included here to
test the general catalytic activity of sulfonamide anions (Table
2, entries 2,3). The only catalyst systems more active than 1b
were four anionic pyridine catalysts. The novel, imine-bridged
sulfonamide 15g catalyzes the reaction three times faster than
DMAP (Table 2, entry 14), while tosyl amides 6bc and 6bf,
which only differ in the nature of the cation, are both approx.
five times faster than DMAP (Table 2, entries 15, 16). The
highest catalytic activity was found for donor-substituted
sulfonamide 6cg, which exceeds the performance of 1a by a
factor of 7 (Table 2, entry 17). On the lower end of activities for
ion pair catalysts we find the highly stabilized triflic amides 6aa
(IL), 6ab (a room temperature IL), and 6ac, whose structures
differ in the choice of the counter ion, but whose catalytic
activities are all rather similar and close to that of 4-
pyrrolidinopyridine (PPY, 1c). This implies that the influence
of the counter ion on the addition reaction studied here is rather
moderate.
Figure 4. Catalytic activity at different catalyst loadings for the
urethane synthesis.
From the mode of activation shown in Scheme 2 it is expected
that the catalyst concentration enters in first order in the
respective rate equation. In order to test this hypothesis
concentration-dependent reaction rates were measured for all
catalysts except for 6ab, 6ac (because of similar activity to
6aa), and 24. As an example for an unreactive pyridine
compound this also includes isoquinoline 23 (Table 2, entry 4).
Figure 4 shows clear linear correlations between the catalyst
concentrations and reaction rates for all of the investigated
systems. For reasons of readability, we excluded labels for the
less active or less established catalyst systems in Figure 4. The
Having found that the catalytic performance of the
investigated catalyst systems surpasses those of the most
reactive commercially available pyridine organocatalysts, we
turned to the aza-MBH reaction of 19 with 20 as the second
benchmark reaction. This is an intrinsically slow addition
reaction due to the steric hindrance present in the Michael
acceptor 20, and results for selected Lewis base catalysts are
collected in Table 3 and graphically shown in Figure 5. The
progress of the reaction was monitored by 1H NMR signals of
the protons highlighted in Scheme 2b. Since no conversion is
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observed without addition of catalyst, all plots are fitted through
0.0 and the slope of the fit is used to compare catalyst
performance (kcat).
1
2
3
4
5
6
7
8
Similar trends as for the urethane synthesis are found here.
Again, the anionic pyridine catalysts are much more efficient as
compared to their neutral counterparts. While DMAP (1a)
shows quite low catalytic activity, TCAP (1b) is roughly 25
times more active. Reaction rates are significantly higher for the
ion pair catalysts: 6bc is more reactive than DMAP by a factor
of 285 and 6cg by a factor of 385. These results again show the
superiority of the anionic systems investigated in this study. As
before, 22 is not active as a catalyst in this reaction.
Table 3. Aza-MBH reaction of 19 with 20 catalyzed by
selected Lewis base catalysts. Entries are ordered by kcat.
Ts
Ts
Catalyst
X mol%
O
N
HN
O
+
CDCl3
23°C
9
In order to test whether the observed catalytic activities
correlate with calculated Lewis basicity parameters, methyl
cation affinities (MCA) and phenyl isocyanate affinities (PIA)
have been calculated. Such relative affinity values have been
shown to correlate well with experimentally determined rate
constants in previous investigations.11 In line with those studies
we calculated these affinities relative to pyridine as the
reference base. Relative Lewis basicities towards Me+ (ΔMCA)
and phenyl isocyanate (ΔPIA) have been calculated as the
reaction enthalpies at 298.15 K for the isodesmic group transfer
reactions shown in Eq. 3 and 4.
Cl
Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
0.25 M
1.0 M
19
20
21
풌풄풂풕(퐜퐚퐭퐚퐥퐲퐬퐭)
풌풄풂풕(ퟏ퐚)
----
a,b,c
Entry
Catalyst
kcat
keff(X)a,d
1
2
3
none
22
---e
---e
---e
---
1
---e(X=25)
1a
2.00E-05
1.46E-06(X=25)
1.73E-05(X=12.5)
3.24E-05(X=25)
4
1b
5.00E-04
5.70E-03
25
6.73E-05(X=5.7)
1.60E-04
MCA
R
(3)
+
R
+
(X=11.5)
1.82E-04
N
N
5
6bc
285
N
N
(X=12.5)
3.55E-04(X=25)
O
O
PIA
R
8.53E-05(X=5)
2.49E-04(X=12.5)
4.81E-04(X=25)
+
(4)
R
+
N
N
N
N
6
6cg
7.70E-03
385
N
N
b
a Averaged values (see SI). kcat is obtained as the slope of the
correlations shown in Figure 5. c in L2 mol-2 s−1. d in L mol−1 s−1. e
no turnover after >18500 min.
Recent studies showed that reliable results taking dispersive
interactions into account are obtained at the DLPNO-
CCSD(T)/def2-TZVPP//SMD(CHCl3)/B3LYP-D3/6-31+G(d)
level of theory (in the following referred to as "CC"). The
SMD(CHCl3)/B3LYP-D3/6-31+G(d) level used for geometry
optimizations is referred to as "DFT".12 ΔMCA and ΔPIA
values calculated with these two approaches have been
summarized in Table 4. For ion pair catalysts based on the 4-
pyridinylamide core structure, addition to the pyridine-N and
amide-N positions may both be competitive. We have therefore
listed reaction energies for both positions in Table 4. In order to
cope with the enormous conformational space accessible to ion
pair structures in a systematic manner, initial starting
geometries for ion pair catalysts were generated using a
randomization approach as detailed in the SI.13 The results in
Table 4 are based on the energetically most favorable
conformations identified in these extensive search procedures.
Figure 5. Benchmarking of catalyst activity at different catalyst
loadings for selected catalysts in the aza-MBH reaction.
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Page 6 of 13
here. Already at the DFT level of theory, the correlation
1
between experimental rate data and ΔPIA values is much better
as compared to the ΔMCA values. On closer analysis of the two
correlations shown in Fig. 6 this is, at least in part, due to the
affinity values calculated for triphenylphosphine (22).
According to the ΔMCA values, 22 is expected to be a
moderately active Lewis base, that is much more active than the
pyridine reference (Table 4, entry 17). However, the
experimental observations as well as the ΔPIA values show that
22 is much less active than isoquinoline (23), whose basicity is
close to that of pyridine. From all the systems studied here, the
ion pair catalysts such as 6cg carrying electron donating groups
have the highest affinities towards phenyl isocyanate. This
effect is less pronounced in the ΔMCA than the ΔPIA values.
These findings are in complete agreement with the results from
our two benchmark reactions, where catalyst 6cg performs best.
We believe the large difference in the catalytic activity between
ion pair and neutral Lewis base catalysts to originate from the
already existing charge separation in the ion pair systems. This
difference is most easily appreciated from the initial addition
step of Lewis base catalysts to isocyanate 17 shown in Scheme
2a. For DMAP (1a) this addition step transforms the two neutral
reactants into a zwitterionic adduct and thus requires the formal
separation of unit charges. No such charge separation is
required in the reaction of ion pair catalysts such as 6cg, where
the addition step simply transforms the reactant ion pair into a
new (intermediate) ion pair structure.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 6. Correlation of reaction rates keff(3) measured for
urethane formation with Lewis basicity parameters ΔMCA and
ΔPIA calculated for pyridine-N (DFT).
Table 4. Calculated ΔMCA and ΔPIA values ordered by
ΔPIA (DFT).
ΔH298K
ΔH298K
DLPNO-CCSD(T)/def2-
SMD(CHCl3)/
Lewis
basic
atoma
TZVPP//
En
try
Cata
lyst
B3LYP-D3/
6-31+G(d)
SMD(CHCl3)/B3LYP-
D3/6-31+G(d)
ΔMCAb
ΔPIAb
-61.2
-56.7
-53.1
-45.7
-39.3
-38.1
-34.2
-32.5
-30.9
-30.6
-28.5
-27.2
-25.7
-24.4
-11.9
-1.7
ΔMCAb
-62.7
-63.0
-68.0
-43.0
-47.8
-38.4
-46.3
-43.9
-37.9
-39.0
-64.0
-38.4
-35.2
-67.8
-42.8
-2.3
ΔPIAb
-61.7
-58.1
-53.3
-42.1
-37.2
-38.3
-32.2
-29.9
-31.8
-27.7
-34.7
-26.3
-24.8
-31.4
-27.9
-0.5
1
2
6cg
6bc
10hc
15g
1f
N1
N1
N1
N1
N1
N1
N1
N1
N1
N1
N2
N1
N1
N2
N2
N1
P
-65.6
-64.8
-72.2
-47.0
-54.7
-43.2
-52.2
-48.8
-40.5
-45.7
-57.9
-40.9
-37.0
-61.2
-32.0
-7.1
Scheme 3. ΔPIA values for the pyridinyl adduct 6c-PhNCO
and for ion pair adduct 6cg-PhNCO.
3
O
O
4
O
N
O
N
N
O
S
5
PIA
N
S
O
N
O
6
6ac
1e
O
6c
6c-PhNCO
C
N
7
PhNCO
Ph
Ph
Ph
8
1b
Ph
PIA
O
P
P
O
Ph
O
Ph
Ph
Ph
9
6ahc
1d
N
N
N
O
O
S
S
O
6cg
10
11
12
13
14
15
16
17
18
N
N
O
6cg-PhNCO
6bc
1c
6c
-46.9
-47.7
6cg
-61.2
-61.7
PIA (DFT) / kJ mol-1
PIA (CC) / kJ mol-1
:
:
1a
On a methodological note, it should be added that the affinity
data calculated at DFT or CC level are quite similar. However,
whether the calculation of affinities is based on full ion pairs or
only on the anionic fragment acting as the Lewis base leads to
substantially different results. This is illustrated in Scheme 3 for
the addition of phenylisocyanate (PhNCO) to ion pair catalyst
6cg, which is exothermic by 61.2 kJ mol-1 at DFT level.
Addition of the same electrophile to the corresponding 4-
pyridinylamide anion 6c is exothermic by only 46.9 kJ mol-1,
which represents a difference of 14.3 kJ mol-1. Calculations on
the anionic components of ion pair catalysts will thus not
display the full Lewis base capacities of these systems! A final
result from the calculated affinity data in Table 4 concerns the
relative Lewis basicity of the pyridine-N vs. the amide-N center.
For neutral catalysts such as DMAP (1a) it is well established
that the pyridine nitrogen atom is the more Lewis basic center.
Therefore, the good correlation of calculated pyridine-N
affinity values with experimental findings for both neutral and
ionic catalysts supports the assumption that in both cases the
6cg
15g
23
22
-45.2
-0.8
+8.2
-53.7
-12.2
+8.8
6ahc
N2
+10.7
+3.9
a N1 = pyridine-N; N2 = amide-N. b in kJ mol−1; c h = PEt4
+
Figure 6 shows a correlation of the calculated ΔMCA and
ΔPIA values for the pyridine-N position with the logarithmic
effective rate constant measured for 3 mol% catalyst loading
(ln(keff(3)) for the urethane formation reaction. Although
calculated ΔMCA values correlated well with experimentally
determined catalytic activities in earlier studies,8 we find here
that computational modeling closer to the experiment
ultimately pays off for the broader selection of catalysts studied
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The Journal of Organic Chemistry
pyridine nitrogen atom is the Lewis basic center involved in Urethane Benchmark Reaction Experiments. Three
1
2
3
4
5
6
7
8
catalysis. The same insight is gained when comparing the ΔPIA
values of the competing nitrogen atoms. In all cases listed in
Table 4 (entries 1&14, 2&11, 4&15, 9&18), the pyridine-N-
isocyanate adduct is approx. 30-40 kJ mol−1 more stable as
compared to the amide-N adduct. This leads us to believe that,
in the investigated reactions, the pyridine-nitrogen atom is more
Lewis basic and therefore the catalytically active center (see SI
for more details).
different stock solutions were prepared under N2 atmosphere:
SSA: 0.30 mol L−1 isocyanate 17 in CDCl3; SSB: 0.90 mol L−1
butanol 18 and ca. 0.15 mol L−1 Si2Me6 in CDCl3. SSC: 0.0003
– 0.09 mol L−1 catalyst in CDCl3. NMR kinetics: Samples were
prepared by transferring 0.2 mL of SSB, the appropriate amount
of SSC and CDCl3 and 0.2 mL of SSA (total of 0.6 mL sample
volume) into a dried, N2-purged NMR tube. The sample was
caped and sealed by Parafilm unless stated otherwise. It was
then stored in the bath of a thermostat set at 23 °C or in an NMR
machine temperature controlled to remain at 23 °C. Once a
sample was not kept in the NMR machine for continuous
measuring anymore, it was stored in the bath of a thermostat
until the reaction was complete. The samples were only taken
9
CONCLUSION
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We find that stabilized 4-amide pyridinyl anions, which so
far have only been used for oligomerization reactions of
isocyanides, show high catalytic activity in urethane synthesis
and in aza-MBH reactions. Furthermore, characterization of
several such previously undescribed ion pairs could be
achieved, including crystal structures. We also report and
characterize ion pairs based on the imine-bridged pyridinyl
anion 15 and the 4-pyridinyl phosphonamide 10. Our results
indicate that catalyst performance is primarily dictated by the
anion substitution pattern, while only moderate effects appear
to be due to the choice of cation (both in the experiments and
the calculated affinity values). Extensive ion pair modeling
involving randomized starting geometries allowed us to
calculate phenyl isocyanate affinities (ΔPIA) that correlate very
well with the experimental results. This finding documents the
added benefit of computational modeling close to the
experimental conditions, since the more established methyl
cation affinities (ΔMCA) gave much poorer correlations. These
quantum chemical results also confirm, that the pyridine
nitrogen atom is the Lewis basic center responsible for catalytic
activity. In more general terms we find the investigated
pyridinyl salts to be a class of easily accessible, inexpensive and
modular catalyst systems that show very good performance for
the investigated reactions. After beginning to understand the
reactivity of such ion pair catalysts, we look forward to future
modifications imparting selectivity. We expect this to be quite
promising due to the exchangeability of the cations and high
Lewis basicity of the pyridinyl “warheads”.
1
out of the thermostat for measuring H NMR spectra. The
protons highlighted in Scheme 2 were used to calculate
conversion. GC kinetics: Samples were prepared by
transferring 0.2 mL of SSB, the appropriate amount of SSC and
CDCl3 and 0.2 mL of SSA (total of 0.6 mL sample volume) into
a dried, N2-purged GC-vial. The sample was caped under N2
atmosphere and stored in the temperature-controlled
autosampler of the GC machine at 23°C. Multiple identical
samples were prepared and then measured repeatedly (up to 4
times each). This enabled us to measure at several points of the
reaction progress as well as keeping the sample protected from
moisture. In between the individual measurements, cleaning
runs were done. 55(0)-5-150(0)-20-280(5) was used as a
heating regime of the column, meaning: start at 55 °C, remain
at this temperature for 0 min, heating to 150 °C with a rate of 5
°C/min, hold at 150 °C for 0 min, heating with a rate of 20
°C/min up to 280 °C which remains constant for 5 min. The
injector was heated to at 200 °C. Conversion was calculated
from the ratio of integrals with the internal standard Si2Me6. See
SI for details on data processing.
Aza-MBH Benchmark Reaction Experiments. Two
different stock solutions were prepared under N2 atmosphere:
SSD: 0.30 mol L−1 tosyl imine 19, 1.2 mol L−1 cyclohex-2-en-
1-one 20 and ca. 0.08 mol L−1 1,3,5-trimethoxybenzene in
CDCl3. SSE: 0.075 – 0.375 mol L−1 Catalyst in CDCl3. Samples
were prepared by transferring 0.5 mL of SSD, the appropriate
amount of SSE and CDCl3 (total of 0.6 mL sample volume) into
a dried, N2-purged NMR tube. The sample was flame-sealed
unless stated otherwise. It was then stored in the bath of a
thermostat set at 23 °C or in an NMR machine temperature
controlled to remain at 23 °C. Once a sample was not kept in
the NMR machine for continuous measuring anymore, it was
stored in the bath of a thermostat until the reaction was
completed. The samples were only taken out of the thermostat
EXPERIMENTAL SECTION
General Information. All air and water sensitive processes
were performed under N2-atmosphere using standard Schlenk
techniques. Commercial catalysts (purchased from Sigma
Aldrich, except for TCAP 1b, which was bought from TCI) and
Si2Me6 were of reagent grade and used as received unless stated
otherwise. p-Tolyl isocyanate (17) was of reagent grade and
distilled prior to use. Butan-1-ol (18) was of reagent grade and
distilled and stored over molecular sieves under N2. Catalysts
1d, 1e, 1f were prepared as described in our previous
studies.2,5,14 NMR spectra were recorded on a Bruker Avance III
HD 400, a Bruker Ascend 400, or a Varian Mercury 200 MHz
1
for measuring H NMR spectra. The protons highlighted in
Scheme 2 were used to calculate conversion. See SI for details
on data processing.
Synthesis of Pyridinyl Amide Ion Pair Catalysts. All
synthesized catalysts were bench stable and stored under
ambient laboratory conditions unless stated otherwise. Despite
the different syntheses given for the catalyst systems in the
following section, the approach described for 6cg may be the
most practical in general terms.
1
spectrometer. All H chemical shifts are reported in ppm (δ)
relative to TMS (0.00, internal standard). 13C chemical shifts are
reported in ppm (δ) relative to CDCl3 (77.16, internal standard),
31P chemical shifts are reported in ppm (δ) relative to 85%
H3PO4 in water (0.00). CDCl3 was refluxed for at least one hour
over CaH2 and subsequently distilled. GC-measurements were
done on a Shimadzu GC-2010 Plus Gas Chromatograph with
AOC-20i autosampler (with temperature-controlled sample
holder) and an Optima 1701-0.26 μm (25 m * 0.25 mm) column.
Tetrabutylammonium pyridin-4-yl((trifluoromethyl)sulfonyl)
amide (6aa). 0.489 g Sulfonamide 8a (2.26 mmol, 1.0 eq) were
suspended in 20 mL of dry methanol under N2 and a solution of
0.052 g sodium (2.26 mmol, 1.0 eq) in 10 mL dry methanol was
added. After stirring the resulting, clear solution for 1 h at room
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Page 8 of 13
temperature, 0.729 g (2.26 mmol, 1.0 eq) tetrabutylammonium
bromide were added and the mixture was stirred for another
hour. The solvent was removed in vacuo giving the crude
39%) as colorless crystals with mp: 101 – 104 °C. 1H NMR (400
1
2
3
4
5
6
7
8
MHz, CDCl3) δ [ppm] = 8.05 (dd, J = 4.8, 1.5 Hz, 2H), 7.77 (tq,
J = 7.0, 1.3 Hz, 3H), 7.63 (td, J = 7.9, 3.6 Hz, 6H), 7.60 – 7.52
(m, 6H), 6.94 (dd, J = 4.8, 1.5 Hz, 2H), 2.83 (d, J = 13.3 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ [ppm] = 155.8, 149.5,
135.5 (d, J = 3.0 Hz), 133.0 (d, J = 10.7 Hz), 130.7 (d, J = 12.9
Hz), 122.1 (q, J = 328.2 Hz), 118.8 (d, J = 88.8 Hz), 118.0 , 9.7
product. Repeated recrystallization from
a mixture of
hexane/toluene (6/1) and CH2Cl2 (by evaporation of CH2Cl2 by
means of a N2 flux) gave 0.707 g of catalyst 6aa (1.51 mmol,
1
67%) as colorless crystals with mp: 83 – 85 °C. H NMR (400
MHz, CDCl3) δ [ppm] = 8.14 (d, J = 6.3 Hz, 2H), 7.03 (d, J =
6.3 Hz, 2H), 3.20 – 3.04 (m, 8H), 1.54 (p, J = 8.1, 7.7 Hz, 8H),
1.35 (h, J = 7.3 Hz, 8H), 0.93 (t, J = 7.3 Hz, 12H). 13C{1H}
NMR (101 MHz, CDCl3) δ [ppm] = 156.0, 149.4, 121.3 (q, J =
(d, J = 58.4 Hz,). 19F NMR (377 MHz, CDCl3) δ [ppm] = −76.8.
31
휈
P NMR (162 MHz, CDCl3) δ [ppm] = +21.2. IR (ATR):
(cm−1) = 3056 (vw), 2973 (vw), 2901 (vw), 1586 (w), 1535
(vw), 1495 (w), 1482 (w), 1438 (m), 1323 (s), 1300 (m), 1288
(vw), 1195 (vs), 1156 (vs), 1146 (vs), 1116 (vs), 1004 (s), 998
(s), 986 (m), 911 (m), 904 (s), 856 (vw), 833 (m), 781 (w), 755
(m), 743 (s), 717 (s), 691 (s), 682 (s), 666 (m), 630 (m), 601
(vs), 566 (vs). Elemental analysis: C25H22F3N2O2PS (502.49 g
mol−1): Calc. (%): C, 59.76; H, 4.41; N, 5.58; S, 6.38. Found
(%): C, 59.57; H, 4.48; N, 5.57; S, 6.58. HRMS (ESI) m/z: [M]+
calcd for C19H18P+, 277.1146; found, 277.1136. [M]− calcd for
C6H4F3N2O2S−, 224.9951; found, 224.9949.
9
328.2 Hz), 118.1, 58.8, 23.9, 19.7, 13.6. 19F NMR (377 MHz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
−1
휈
CDCl3) δ [ppm] = −76.8. IR (ATR): (cm ) = 3392 (vw), 2960
(m), 2935 (w), 2874 (w), 1633 (vw), 1585 (w), 1534 (vw), 1494
(w), 1476 (w), 1465 (w), 1418 (vw), 1379 (vw), 1346 (vw),
1321 (s), 1285 (s), 1194 (vs), 1164 (vs), 1130 (s), 1066 (vw),
1031 (vw), 999 (s), 984 (m), 965 (w), 927 (vw), 899 (vw), 885
(w), 832 (m), 782 (w), 764 (vw), 736 (w), 666 (w), 626 (m), 601
(vs), 567 (vs). Elemental analysis: C22H40F3N3O2S (467.64 g
mol−1): Calc. (%): C, 56.51; H, 8.62; N, 8.99; S, 6.86; Found
(%): C, 56.01; H, 8.54; N, 8.88; S, 6.73. HRMS (ESI) m/z: [M]+
calcd for C16H36N+, 242.2842; found, 242.2846. [M]− calcd for
C6H4F3N2O2S−, 224.9951; found, 224.9949.
Tetrabutylphosphonium pyridin-4-yl((trifluoromethyl)sul-
fonyl) amide (6ad). 0.40 g Sulfonamide 8a (1.77 mmol, 1.0 eq)
were suspended in 1.24 mL tetrabutylphosphonium hydroxide
(40% in H2O, 1.77 mmol, 1.0 eq) and 2 mL of H2O. The mixture
was stirred at room temperature for 0.5 h and the clear,
separated phases extracted with CH2Cl2. The organic phases
were dried over Na2SO4 and the solvents removed to give the
colorless crude product which was recrystallized from
toluene/CH2Cl2 to yield 0.682 g catalyst 6ad (1.41 mmol, 79%)
in the form of colorless crystals with mp: 56 – 60 °C. 1H NMR
(400 MHz, CDCl3) δ [ppm] = 8.16 (dd, J = 6.4, 3.2 Hz, 2H),
7.03 (dd, J = 6.3, 3.2 Hz, 2H), 2.27 – 2.02 (m, 8H), 1.57 – 1.34
(m, 16H), 0.92 (t, J = 6.9 Hz, 12H). 13C{1H} NMR (101 MHz,
CDCl3) δ [ppm] = 155.7, 149.7, 122.1 (q, J = 328.3 Hz), 118.1,
23.9 (d, J = 15.2 Hz), 23.7 (d, J = 4.8 Hz), 18.7 (d, J = 47.5 Hz),
Tetraoctylammonium pyridin-4-yl((trifluoromethyl)sulfonyl)
amide (6ab). 0.517 g Sulfonamide 8a (2.39 mmol, 1.0 eq) were
suspended in 20 mL dry methanol under N2, and a solution of
0.055 g sodium (2.39 mmol, 1.0 eq) in 10 mL dry methanol was
added. After stirring the resulting, clear solution for 1 h at room
temperature,
1.307 g
tetraoctylammonium
bromide
(2.39 mmol, 1.0 eq) was added and the mixture was stirred for
14 h. The solvent was removed in vacuo and 16 mL CH2Cl2
were added. Remaining solids were filtered off and the solvent
removed. The process was repeated with decreasing amounts of
CH2Cl2 several times yielding 1.57 g of catalyst 6ab
1
(2.27 mmol, 95%) as a colorless oil. H NMR (400 MHz,
13.4. 19F NMR (377 MHz, CDCl3) δ [ppm] = −76.8. 31P NMR
−1
CDCl3) δ [ppm] = 8.15 (d, J = 6.2 Hz, 2H), 7.05 (d, J = 6.3 Hz,
2H), 3.33 – 2.97 (m, 8H), 1.72 – 1.50 (m, 8H), 1.50 – 1.10 (m,
40H), 0.85 (t, J = 6.8 Hz, 12H). 13C{1H} NMR (101 MHz,
CDCl3) δ [ppm] = 155.8, 149.6, 122.3 (q, J = 328.2 Hz), 118.1,
휈
(162 MHz, CDCl3) δ [ppm] = +33.2. IR (ATR): (cm ) = 2959
(m), 2933 (w), 2873 (w), 2106 (vw), 1585 (m), 1534 (vw), 1493
(m), 1479 (w), 1465 (w), 1406 (vw), 1380 (vw), 1320 (s), 1279
(s), 1232 (w), 1192 (s), 1163 (vs), 1130 (s), 1101 (m), 1054
(vw), 998 (s), 984 (s), 907 (m), 830 (s), 782 (m), 747 (w), 730
(w), 702 (w), 666 (w), 626 (m), 599 (vs), 567 (vs). Elemental
analysis: C22H40F3N2O2PS (484.60 g mol−1): Calc. (%): C,
54.53; H, 8.32; N, 5.78; S, 6.62. Found (%): C, 54.40; H, 8.41;
N, 5.74; S, 6.23. HRMS (ESI) m/z: [M]+ calcd for C16H36P+,
259.2549; found, 259.2545. [M]− calcd for C6H4F3N2O2S−,
224.9951; found, 224.9949.
59.0, 31.7, 29.1, 29.1, 26.3, 22.7, 22.1, 14.2. 19F NMR
−1
휈
(377 MHz, CDCl3) δ [ppm] = −76.8. IR (ATR): (cm ) = 2954
(w), 2925 (m), 2856 (w), 1589 (m), 1534 (vw), 1495 (w), 1468
(w), 1378 (vw), 1314 (s), 1282 (s), 1195 (vs), 1156 (vs), 1132
(s), 1085 (vw), 1000 (s), 984 (w), 830 (w), 782 (w), 723 (w),
666 (vw), 628 (w), 602 (vs), 568 (s). Elemental analysis:
C38H72F3N3O2S (692.07 g mol−1): Calc. (%): C, 65.95; H,
10.49; N, 6.07; S, 4.63. Found (%): C, 65.76; H, 10.49; N, 5.94;
S, 4.76. HRMS (ESI) m/z: [M]+ calcd for C32H68N+, 466.5346;
found, 466.5341.[M]− calcd for C6H4F3N2O2S−, 224.9951;
found, 224.9949.
Methyltriphenylphosphonium
pyridin-4-yl(tosyl)amide
(6bc). 0.124 g Sodium hydroxide (3.1 mmol, 1.1 eq) were
dissolved in 5 mL H2O and this solution was added to 0.70 g of
sulfonamide 8b (3 mmol, 1.0 eq). After 10 min stirring at room
temperature, 1.00 g methyltriphenylphosphonium bromide (3
mmol, 1.0 eq) were added with additional 3 mL of H2O and the
resulting viscous suspension was stirred for 45 min. Extraction
with CH2Cl2 (3 × 30 mL), drying of the organic phase over
Na2SO4 and removal of the solvent gave the crude product. It
was recrystallized from 18 mL of CH2Cl2 by layering of 8 mL
of toluene on top to yield 0.873 g catalyst 6bc (1.66 mmol, 54%)
in the form of colorless needles with mp: 195 - 199 °C. 1H NMR
(400 MHz, CDCl3) δ [ppm] = 7.87 (d, J = 6.1 Hz, 2H), 7.83 –
7.66 (m, 5H), 7.66 – 7.49 (m, 12H), 7.05 (d, J = 7.9 Hz), 6.71
(d, J = 6.2 Hz, 2H), 2.93 (d, J = 13.2 Hz, 3H), 2.26 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ [ppm] = 157.5, 149.2,
143.1, 139.7, 135.2 (d, J = 3.0 Hz), 133.1 (d, J = 10.7 Hz), 130.5
Methyltriphenylphosphonium pyridin-4-yl((trifluoromethyl)
sulfonyl) amide (6ac). 0.532 g Sulfonamide 8a (2.46 mmol,
1.0 eq) were suspended in 20 mL dry methanol under N2, and a
solution of 0.057 g sodium (2.46 mmol, 1.0 eq) in 10 mL dry
methanol was added. After stirring the resulting, clear solution
for
1
h
at
room
temperature,
0.879 g
methyltriphenylphosphonium bromide (2.46 mmol, 1.0 eq) was
added and the mixture was stirred for 14 h. The solvent was
removed in vacuo and 5 mL CH2Cl2 were added. Remaining
solids were filtered off and the solvent removed in vacuo giving
the crude product, which was recrystallized from a mixture of
hexane/toluene (6/1) and CH2Cl2 (by evaporation of CH2Cl2 by
means of a N2 flux) to give 0.484 g of catalyst 6ac (0.96 mmol,
ACS Paragon Plus Environment

Page 9 of 13
The Journal of Organic Chemistry
(d, J = 12.9 Hz), 128.8, 126.8, 119.1 (d, J = 88.6 Hz), 116.2,
N, 4.66; S, 5.34; found (%):C, 71.82; H, 5.34; N, 4.48; S, 5.29.
21.4, 9.7 (d, J = 57.7 Hz). 31P NMR (162 MHz, CDCl3) δ [ppm]
HRMS (ESI) m/z: [M]+ calcd for: C25H22P+, 353.1454; found,
653.1451. [M]− calcd for C12H11N2O2S−, 247.0547; found,
247.0546.
1
2
3
4
5
6
7
8
−1
휈
= +21.4. IR (ATR): (cm ) = 2965 (w), 2895 (w), 1640 (w),
1587 (m), 1515 (w), 1482 (m), 1438 (m), 1314 (s), 1240 (s),
1215 (m), 1165 (w), 1118 (vs), 1082 (vs), 1055 (m), 1022 (w),
990 (m-s), 968 (m), 931 (m), 914 (m), 860 (w), 830 (w), 815
(w), 798 (w), 778 (w), 763 (w), 745 (w), 719 (m), 696 (w), 690
(w), 665 (w). Elemental analysis: C31H29N2O2PS (524.62 g
mol−1): Calc. (%): C, 70.97; H, 5.57; N, 5.34; S, 6.11; found
(%): C, 71.04; H, 5.61; N, 5.31; S, 6.23. HRMS (ESI) m/z: [M]+
calcd for C19H18P+, 277.1146; found, 277.1138. [M]− calcd for
C12H11N2O2S−, 247.0547; found, 247.0547.
1,3-Diethyl-benzimidazolium ((4-methoxyphenyl)sulfonyl)
(pyridin-4-yl) amide (6ce). Sodium hydroxide (0.088 g, 2.2
mmol, 1.1 eq) was dissolved in 5 mL H2O and this solution was
added to 0.529 g of sulfonamide 8c (2.0 mmol, 1.0 eq) with
additional 5 mL of H2O. After 15 min stirring at room
temperature, a solution of 0.510 g 1,3-diethyl-benzimidazolium
bromide 26 (2.0 mmol, 1.0 eq) in 5 mL of CH2Cl2 were added
with further 5 mL of CH2Cl2 and the resulting mixture was
stirred for 15 min. Extraction with 40 mL CH2Cl2, drying of the
organic phase over Na2SO4 (with addition of 4 pellets of
activated charcoal) and reduction of the solvent gave a
concentrated, yellow solution. The product was crystallized by
layering of toluene/hexane (10/1) on top to yield 0.363 g
catalyst 6ce (0.83 mmol, 41%) in the form of light-yellow
crystals with mp: 144 – 146 °C. 1H NMR (400 MHz, CDCl3) δ
[ppm] = 10.53 (s, 1H), 7.97 (dd, J = 5.0, 1.4 Hz, 2H), 7.83 (dd,
J = 8.8, 4.8 Hz, 2H), 7.70 – 7.55 (m, 4H, H-13), 6.81 (dd, J =
8.8, 4.9 Hz, 2H), 6.75 (dd, J = 4.9, 1.5 Hz, 2H), 4.51 (q, J = 7.3
Hz, 4H), 3.75 (s, 3H), 1.58 (t, J = 7.3 Hz, 6H). 13C{1H} NMR
(101 MHz, CDCl3) δ [ppm] = 161.0, 157.0, 149.5, 142.4, 137.4,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1,3-Diethyl-benzimidazolium pyridin-4-yl(tosyl)amide (6be).
0.110 g Sodium hydroxide (2.75 mmol, 1.1 eq) were dissolved
in 5 mL H2O and this solution was added to 0.621 g of
sulfonamide 8b (2.50 mmol, 1.0 eq) with additional 5 mL of
H2O. After 15 min stirring at room temperature, a solution of
0.638 g 1,3-diethyl-benzimidazolium bromide 26 (2.5 mmol,
1.0 eq) in 5 mL of CH2Cl2 were added with further 5 mL of
CH2Cl2 and the resulting mixture was stirred for 15 min.
Extraction with CH2Cl2 (3 × 30 mL), drying of the organic
phase over Na2SO4 (with addition of 4 pellets of activated
charcoal) and removal of the solvent gave the crude product. It
was recrystallized from toluene/CH2Cl2 by layering of hexane
on top to yield 0.607 g catalyst 6be (1.44 mmol, 58%) in the
form of colorless crystals with mp: 148 – 150 °C. 1H NMR (400
MHz, CDCl3) δ [ppm] = 10.49 (s, 1H), 7.95 (d, J = 6.3 Hz, 2H),
7.77 (d, J = 8.1 Hz, 2H), 7.69 – 7.51 (m, 4H, H-13), 7.10 (d, J
= 8.0 Hz, 2H), 6.73 (d, J = 6.4 Hz, 2H), 4.49 (q, J = 7.3 Hz, 4H),
2.27 (s, 3H), 1.56 (t, J = 7.3 Hz, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ [ppm] = 156.9, 149.4, 142.3, 140.3, 131.2, 129.0,
127.1, 126.6, 115.9, 113.0, 42.9, 21.4, 14.8. Elemental analysis:
C23H26N4O2S (422.55 g mol−1): Calc. (%): C, 65.38; H, 6.20; N,
13.26; S, 7.59; found (%): C, 65.29; H, 6.18; N, 13.18; S, 7.71.
131.2, 128.5, 127.2, 115.9, 113.6, 113.1, 55.4, 43.0, 14.9. IR
−1
휈
(ATR): (cm ) = 3057 (vw), 1556 (s), 1568 (m), 1520 (w),
1484 (s), 1432 (m), 1350 (vw), 1300 (s), 1252 (s), 1225 (s),
1120 (vs), 1081 (vs), 1030 (m), 1011 (w) 990 (s), 971 (s), 851
(vw), 822 (s), 805 (s), 780 (m), 756 (s), 667 (w). Elemental
analysis: C23H26N4O3S (438.55 g mol−1): Calc. (%): C, 62.99;
H, 5.98; N, 12.78; S, 7.31; found (%): C, 62.70; H, 5.81; N,
+
12.71; S, 7.35. HRMS (ESI) m/z: [M]+ calcd for C11H15N2 ,
175.1230; found, 175.1231. [M]− calcd for C12H11N2O3S−,
263.0496; found, 263.0500.
+
HRMS (ESI) m/z: [M]+ calcd for C11H15N2 , 175.1230; found,
Tetraphenylphosphonium ((4-methoxyphenyl)sulfonyl)(pyri-
din-4-yl) amide (6cg). 0.132 g NaOH (2.0 mmol 1.1 eq) were
dissolved in 10 mL H2O and the solution was added to 0.793 g
sulfonamide 8c (3.0 mmol, 1.0 eq). The mixture was stirred at
room temperature for 15 min forming a milky suspension.
Tetraphenylphosphonium bromide (1.26 g, 3 mmol 1.0 eq) was
added with 10 mL of H2O and stirring was continued for 10 min.
Addition of 2 mL of toluene and 7 mL of CH2Cl2 caused
separation of two clear phases which were extracted with 40 mL
of CH2Cl2. The organic phases were dried over MgSO4 (under
addition of 10 pellets of activated charcoal) and removal of the
solvents gave the crude product as a sticky, colorless foam.
Crystallization from a mixture of 10 mL toluene and 8 mL
CH2Cl2 by layering of 10 mL of toluene on top yielded 1.037 g
(1.72 mmol, 57%) of catalyst 6cg in the form of colorless
175.1230. [M]− calcd for C12H11N2O2S−, 247.0547; found,
247.0545.
Benzyltriphenylphosphonium pyridin-4-yl(tosyl) amide
(6bf). 0.80 g Sulfonamide 8b (3.2 mmol, 1.0 eq) were added to
a solution of 0.141 g sodium hydroxide (3.52 mmol, 1.2 eq) in
5 mL H2O. 1.39 g Benzyltriphenylphosphonium bromide were
added with 12 mL of CH2Cl2 and the mixture was stirred at
room temperature for 30 min. Extraction with CH2Cl2, drying
of the organic phase over Na2SO4 and removal of the solvent
gave the crude product. It was dissolved in 10 mL of CH2Cl2,
upon which were layered 10 mL of toluene and 3 mL of hexane
to grow crystals overnight. This yielded 1.228 g catalyst 6bf
(2.04 mmol, 64%) in the form of colorless crystals with mp: 197
– 200 °C. 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.84 (d, J =
6.4 Hz, 2H), 7.77 – 7.65 (m, 5H), 7.58 – 7.43 (m, 12H), 7.22 –
7.13 (m, 1H), 7.05 (t, J = 7.6 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H),
6.84 (d, J = 7.6 Hz, 2H), 6.73 (d, J = 6.4 Hz, 2H), 4.78 (d, J =
14.2 Hz, 2H), 2.23 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
[ppm] = 157.7, 148.7, 143.1, 139.6, 135.2 (d, J = 3.0 Hz), 134.1
(d, J = 9.7 Hz), 131.3 (d, J = 5.5 Hz), 130.3 (d, J = 12.6 Hz),
129.0 (d, J = 3.3 Hz), 128.7, 128.6 (d, J = 3.8 Hz), 126.8 (d, J =
8.7 Hz), 126.8, 117.4 (d, J = 85.8 Hz), 116.2, 30.5 (d, J = 47.7
1
crystals with mp: 153-156 °C. H NMR (400 MHz, CDCl3) δ
[ppm] = 7.88 – 7.75 (m, 8H), 7.70 (td, J = 7.8, 3.6 Hz, 8H), 7.53
(dd, J = 13.0, 7.5 Hz, 8H), 6.75 (d, J = 6.4 Hz, 2H), 6.72 (d, J =
8.8 Hz, 2H), 3.70 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
[ppm] = 160.4, 157.8, 148.9, 138.8, 135.9 (d, J = 3.0 Hz), 134.4
(d, J = 10.3 Hz), 130.8 (d, J = 12.9 Hz), 128.6, 117.4 (d, J =
89.5 Hz), 116.2, 113.1, 55.3. 31P NMR (162 MHz, CDCl3) δ
−1
휈
[ppm] = +23.06. IR (ATR): (cm ) = 3056 (vw), 1590 (m),
Hz), 21.4. 31P{1H} NMR (162 MHz, CDCl3) δ [ppm] = +22.7.
1484 (m), 1434 (m), 1317 (s), 1241 (s), 1238 (s), 1168 (w), 1123
(s) 1105 (s), 1084 (s), 1026 (w), 986 (s), 957 (s), 829 (m), 808
(m), 748 (w), 721 (vs), 692 (m), 661 (w). Elemental analysis:
C36H31N2O3PS (602.69 g mol−1): Calc. (%): C, 71.74; H, 5.18;
N, 4.65; S, 5.32; Found (%):C, 71.00; H, 5.01; N, 4.55; S, 5.57.
HRMS (ESI) m/z: [M]+ calcd for: C24H20P+, 339.1297; found,
−1
휈
IR (ATR): (cm ) = 2938 (vw), 1980 (vw), 1586 (s), 1493 (m),
1478 (m), 1436 (m), 1308 (vs), 1219 (s) 1208 (m), 1121 (vs),
1090 (vs), 991 (s), 947 (m), 836 (m), 815 (w), 782 (w), 750 (vs),
719 (m), 691 (s), 666 (m), 656 (m). Elemental analysis:
C37H33N2O2PS (600.72 g mol−1): Calc. (%): C, 73.98; H, 5.54;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 13
339.1293. [M]− calcd for C12H11N2O3S−, 263.0496; found,
263.0496.
Tetraphenylphosphonium (1,1-dioxidobenzo[d]isothiazol-3-
1
yl)(pyridin-4-yl)amide (15g). 0.088 g Sodium hydroxide (2.2
mmol, 1.1 eq) were dissolved in 5 mL H2O and this solution
was added to 0.519 g of sulfonamide 14 (2.0 mmol, 1.0 eq) with
additional 5 mL of H2O. After 15 min stirring at room
temperature, a solution of Tetraphenylphosphonium bromide
(0.839 g, 2.0 mmol, 1.0 eq) in 5 mL of CH2Cl2 were added with
further 5 mL of CH2Cl2 and the resulting mixture was stirred for
15 min. Extraction with 40 mL CH2Cl2, drying of the organic
phase over Na2SO4 (with addition of 4 pellets of activated
charcoal) and removal of the solvent gave the crude product.
The product was crystallized from a mixture of 10 ml of toluene
and 12 mL of CH2Cl2 by layering of toluene/hexane (10/1) on
top, yielding 0.872 g catalyst 15g (0.971 mmol, 49%) in the
form of yellow needles with mp: 189-192 °C. 1H NMR
(400.22 MHz, CDCl3): δ [ppm] = 8.17 (d, J = 5.9 Hz, 2H), 7.93
(dd, J = 6.0, 1.5 Hz, 1H), 7.85 – 7.76 (m, 4H), 7.74 – 7.61 (m,
9H), 7.51 (ddd, J = 13.0, 8.3, 1.1 Hz, 8H), 7.42 (ddd, J = 7.2,
5.3, 1.4 Hz, 2H), 7.38 (dd, J = 4.7, 1.5 Hz, 2H). 13C{1H} NMR
(101 MHz, CDCl3): δ [ppm] = 158.9, 158.1, 149.4, 142.6,
137.6, 135.9 (d, J = 3.0 Hz), 134.4 (d, J = 10.3 Hz), 131.0, 130.8
(d, J = 12.9 Hz), 130.0, 123.1, 120.4, 119.8, 117.4 (d, J = 89.5
2
3
4
5
6
7
8
9
1,3-Diethyl-benzimidazolium pyridin-2-yl(tosyl)amide (7e).
0.110 g Sodium hydroxide (2.75 mmol, 1.1 eq) were dissolved
in 5 mL H2O and this solution was added to 0.621 g of
sulfonamide 25 (2.5 mmol, 1.0 eq) with additional 5 mL of H2O.
After 15 min stirring at room temperature, a solution of 0.638 g
1,3-diethyl-benzimidazolium bromide 26 (2.5 mmol, 1.0 eq) in
5 mL of CH2Cl2 were added with further 5 mL of CH2Cl2 and
the resulting mixture was stirred for 15 min. Extraction with 40
mL CH2Cl2, drying of the organic phase over Na2SO4 (with
addition of 4 pellets of activated charcoal) and reduction of the
solvent gave a concentrated, yellow solution. The product was
crystallized by layering of toluene/hexane (10/1) on top to yield
0.596 g catalyst 7e (1.41 mmol, 56%) in the form of colorless,
fine needles with mp: 118 - 120 °C. 1H NMR (400 MHz, CDCl3)
δ [ppm] = 11.85 (s, 1H), 8.02 (dd, J = 6.2, 1.3 Hz, 1H), 7.87 (d,
J = 8.1 Hz, 2H), 7.74 – 7.50 (m, 4H), 7.22 (td, J = 8.7, 2.0 Hz,
1H), 7.10 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.44 (t,
J = 6.0 Hz, 1H), 4.71 (q, J = 7.3 Hz, 4H), 2.28 (s, 3H), 1.59 (t,
J = 7.3 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ [ppm] =
161.8, 148.0, 144.7, 143.3, 139.8, 136.7, 131.3, 128.8, 126.8,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hz). 31P{1H} NMR (162 MHz, CDCl3) δ [ppm] = +22.06. IR
휈
126.7, 114.3, 112.97, 112.9, 42.8, 21.4, 15.0. IR (ATR):
−1
휈
(ATR): (cm ) = 2356 (vw), 1587 (w), 1552 (s), 1481 (w),
(cm−1) = 2894 (w), 1585 (m), 1552 (m), 1462 (s), 1422 (s), 1351
(w), 1306 (s), 1294 (s), 1232 (s), 1142 (m), 1124 (s) 1097 (s),
1084 (vs), 1034 (m), 996 (s), 972 (m), 804 (m), 776 (vs), 756
(vs), 710 (m), 658 (s). Elemental analysis: C23H26N4O2S (422.55
g mol−1): Calc. (%): C, 65.38; H, 6.20; N, 13.26; S, 7.59; found
(%): C, 64.63; H, 6.37; N, 13.21; S, 7.97. HRMS (ESI) m/z:
1436 (m), 1293 (m), 1248 (s), 1213 (w), 1165 (m), 1138 (s),
1107 (vs), 1055 (m), 994 (m), 777 (m), 754 (s), 722 (vs), 691
(s), 673 (s). Elemental analysis: C36H28N3O2PS (597,67 g
mol−1): Calc. (%): C, 72.35; H, 4.72; N, 7.03; S, 5.36; Found:
C, 72.36; H, 4.48; N, 6.93; S, 5.39. HRMS (ESI) m/z: [M]+
calcd for: C24H20P+, 339.1297; found, 339.1293. [M]− calcd for:
C12H8N3O2S−, 258.0343; found, 258.0341.
+
[M]+ calcd for C11H15N2 , 175.1230; found, 175.1230. [M]−
calcd for C12H11N2O2S−, 247.0547; found, 247.0547.
Tetrabutylammonium
bis((trifluoromethyl)sulfonyl)amide
Tetrabutylphosphonium (diphenylphosphoryl)(pyridin-4-yl)
amide (10d). 0.147 g Phosphinic amide 11 (0.5 mmol, 1.0 eq)
were dissolved in 0.5 mL MeOH and 0.35 mL
tetrabutylphosphonium hydroxide (40% in H2O, 0.5 mmol, 1.0
eq) were added. The solution was stirred for 10 min before all
solvents were removed. The remaining solids were extracted
with 4 mL of toluene and the product was crystallized by
layering of hexane on top. 0.134 g catalyst 10d (0.24 mmol,
48%) were obtained in the form of colorless crystals with mp:
110-112 °C that were stored under N2. Ion pair catalyst 10d
decomposes quickly when in contact with CHCl3 or CH2Cl2 and
appears to be highly hygroscopic. 1H NMR (400 MHz, toluene-
d8) δ [ppm] = 8.42 – 8.22 (m, 4H), 8.12 (d, J = 5.3 Hz, 2H),
7.20 (td, J = 7.5, 2.2 Hz, 4H), 7.15 – 7.09 (m, 2H), 7.07 (d, J =
5.8 Hz, 2H), 2.22 – 1.92 (m, 8H), 1.30 (h, J = 7.2 Hz, 8H), 1.11
(dq, J = 15.6, 7.6 Hz, 8H), 0.88 (t, J = 7.3 Hz, 12H). 13C{1H}
NMR (101 MHz, toluene-d8) δ [ppm] = 163.2, 149.7 (d, J = 1.9
Hz), 142.7 (d, J = 122.0 Hz), 133.1 (d, J = 8.2 Hz), 129.4 (d, J
= 2.4 Hz), 128.1 (d, J = 11.0 Hz), 119.4 (d, J = 21.1 Hz), 24.6
(d, J = 15.6 Hz), 24.4 (d, J = 4.7 Hz), 18.9 (d, J = 47.3 Hz), 14.2.
(24). 0.500 g Lithium bis((trifluoromethyl)sulfonyl)amide (1.74
mmol, 1.0 eq) were dissolved in 5 mL of iPrOH and added to a
solution of 0.561 g tetrabutylammonium bromide (1.74 mmol,
1.0 eq) in 3 mL of iPrOH. The mixture was left stirring at room
temperature overnight after which the solvents were removed in
vacuo. The solid residue was extracted with toluene and
repeatedly recrystallized from toluene/hexane/CH2Cl2 to give
0.301 g amide salt 24 (0.58 mmol, 33%) in the form of colorless
1
needles with mp: 88 – 90 °C. H NMR (400 MHz, CDCl3) δ
[ppm] = 3.27 – 3.04 (m, 8H), 1.58 (p, J = 8.1, 7.7 Hz, 8H), 1.39
(h, J = 7.3 Hz, 8H), 0.97 (t, J = 7.3 Hz, 12H). 13C{1H} NMR
(101 MHz, CDCl3) δ [ppm] = 120.0 (q, J = 321.6 Hz), 58.7,
23.9, 19.6, 13.5. 19F NMR (377 MHz, CDCl3) δ [ppm] =
−1
휈
−78.82. IR (ATR): (cm ) = 2968 (m), 2881 (w), 1463 (vw),
1381 (vw), 1348 (s), 1332 (m), 1224 (m), 1178 (vs), 1136 (s),
1110 (w), 1050 (vs), 884 (m), 791 (w), 762 (vw), 740 (m).
Elemental analysis: C18H36N2O4F6S2 (522.61 g mol−1): Calc.
(%): C, 41.37; H, 6.94; N, 5.36; S, 12.27; found (%): C, 42.21;
H, 7.07; N, 5.39; S, 11.90. HRMS (ESI) m/z: [M]+ calcd for
C16H36N+, 242.2842; found, 242.2847. [M]− calcd for
31P{1H} NMR (162 MHz, toluene-d8) δ [ppm] = +32.16 (P+),
−
−1
C2F6NOS2 , 279.9178; found, 279.9177.
휈
+10.86 (P=O). IR (ATR): (cm ) = 3053 (vw), 2957 (m), 2928
(m), 2870 (m), 1583 (vs), 1493 (vs), 1464 (m), 1434 (w), 1355
(vs), 1320 (m), 1226 (vw), 1206 (m), 1150 (vs), 1117 (s), 1103
(s), 1063 (w), 1000 (w), 986 (vs), 969 (s), 908 (w), 826 (s), 772
(w), 758 (w), 748 (m), 718 (s), 698 (vs), 658 (w). Elemental
analysis: C33H50N2OP2 (552.72 g mol−1): Calc. (%):C, 71.71; H,
9.12; N, 5.07; found (%):C, 69.63; H, 9.16; N, 4.77. HRMS
(ESI) m/z: [M]+ calcd for: C16H36P+, 259.2549; found,
259.2547. [M]− calcd for: C17H14N2OP−, 293.0849; found,
293.0850.
Synthesis of Neutral Amides. Despite the different
syntheses given for the neutral amides in the following section,
the approach described for 8c may represent the most practical
procedure for all amides.
1,1,1-Trifluoro-N-(pyridin-4(1H)-ylidene)methanesulfon-
amide (8a). 0.023 g 4-Dimethylaminopyridine 1a (0.191 mmol,
0.01 eq) and 1.40 g 4-aminopyridine 9a (14.8 mmol, 1.0 eq)
were dissolved in 26 mL CH2Cl2, 2.07 mL NEt3 (14.8 mmol,
1.0 eq) and 1 mL acetonitrile under N2 atmosphere. 1.58 mL
ACS Paragon Plus Environment

Page 11 of 13
The Journal of Organic Chemistry
Trifluormethanesulfonyl chloride (14.8 mmol, 1.0 eq) were
(264.30 g mol−1): Calc. (%): C, 54.53; H, 4.58; N, 10.60; S,
12.13; found (%): C, 53.86; H, 4.53; N, 10.98; S, 13.74. HRMS
(EI) m/z: [M]+ calcd for: C12H12N2O3S+, 264.0563, found:
264.0567.
1
2
3
4
5
6
7
8
added dropwise and the reaction mixture was stirred at rt for
five days before the solvents were removed in vacuo. The
remaining solid was taken up in 30 mL of chloroform, heated
to reflux, filtered off hot and washed with chloroform yielding
2.29 g (10.1 mmol, 68%) of compound 8a as an off-white
powder with mp: 300 – 304 °C. 1H NMR (400.22 MHz, DMSO-
d6): δ [ppm] = 13.63 (s, 1H), 8.28 (d, J = 7.4 Hz, 2H), 7.28 (d,
J = 7.4 Hz, 2H). 13C{1H} NMR (100.65 MHz, DMSO-d6): δ
P,P-Diphenyl-N-(11yridine-4-yl)phosphinic amide (11). 1.98
g 4-Aminopyridine 9a (21 mmol) were dissolved in acetonitrile
(20.0 mL), CH2Cl2 (10.0 mL), and 2.9 mL NEt3 (21 mmol, 1.0
eq) under N2. This solution was added dropwise to a flask
containing 5.0 g diphenylphosphonic chloride (21 mmol, 1.0
eq) under N2 and the mixture was stirred for 24 h. The solvents
were removed in vacuo and the remaining solids were taken up
in saturated Na2CO3 solution (20.0 mL) and filtered. The filtrate
was brought to ca. pH 7 and the precipitate filtered off. After
drying, 11 was obtained as a white powder (1.76 g, 5.96 mmol,
28%) whose spectroscopic data is in agreement with the
literature data.15 1H NMR (400 MHz, CDCl3) δ [ppm] = 8.15 (d,
J = 6.0 Hz, 2H), 7.81 (dd, J = 12.6, 7.1 Hz, 4H), 7.54 (td, J =
7.5, 1.3 Hz, 2H), 7.44 (td, J = 7.5, 3.4 Hz, 4H), 6.85 (d, J = 6.2
Hz, 2H), 6.62 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
[ppm] = 150.3, 148.4, 132.8 (d, J = 2.8 Hz), 131.9 (d, J = 10.3
Hz), 131.0 (d, J = 128.9 Hz), 129.1 (d, J = 13.2 Hz), 113.1 (d, J
= 6.8 Hz).
[ppm] = 163.8, 140.2, 120.8 (q, J = 325.5 Hz), 117.0. 19F NMR
9
−1
휈
(376.55 MHz, DMSO-d6): δ [ppm] = −77.8. IR (ATR): (cm )
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
= 3237 (vw), 3052 (vw), 2934 (vw), 2891 (vw), 2848 (vw),
2794 (vw), 2663 (vw), 1911 (vw), 1820 (vw), 1635 (m), 1615
(w), 1514 (vw), 1483 (s), 1330 (s), 1312 (s), 1256 (w), 1209
(m), 1184 (vs), 1165 (vs), 1123 (vs), 1098 (s), 1009 (w), 970
(vs), 916 (vw), 825 (s), 782 (s), 749 (w), 654 (w). Elemental
analysis: C6H5F3N2O2S (226.17 g mol−1) Calc. (%): C, 31.86;
H, 2.23; N, 12.39; S, 14.17; found (%): C, 31.93; H, 2.43; N,
12.36; S, 14.17. HRMS (EI) m/z: [M]+ calcd for C6H5F3N2O2S+,
226.0018; found, 226.0019.
4-Methyl-N-(pyridin-4(1H)-ylidene)benzenesulfonamide
(8b). 4.71 g 4-Aminopyridine 9a (21.2 mmol, 1.0 eq) were
dissolved in 50 mL pyridine under N2 atmosphere. 11.13 g 4-
Methylbenzenesulfonyl chloride (58.4 mmol, 1.17 eq) and 15
mL NEt3 were added and the mixture was refluxed for 2 h
before being allowed to cool to room temperature. The solvent
phase was decanted off the precipitated solids and the remaining
solids washed with 200 mL of hot H2O. The solids were
collected and the filtrate was brought to pH = 5 which caused
further precipitation. All precipitates were combined and
washed with boiling H2O, boiling MeCN, boiling acetone and
boiling chloroform repeatedly to give 11.22 g (45.1 mmol, 90
%) of sulfonamide 8b in the form of a colorless powder with
mp: 304 – 308 °C. Due to the very low solubility of sulfonamide
8b, not all expected 13C signals were found. 1H NMR
(400.22 MHz, DMSO-d6): δ [ppm] = 12.25 (s, 1H), 8.01 (d, J =
5.9 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H),
6.90 (d, J = 6.7 Hz, 2H), 2.33 (s, 3H). 13C{1H} NMR
3-Chlorobenzo[d]isothiazole 1,1-dioxide (13). 5.49
g
Saccharine (30 mmol) and 0.4 mL DMF were dissolved in 25
mL of 1,4-dioxane and 9 mL (45 mmol, 1.5 eq) thionyl chloride
were added. The mixture was refluxed for 46 h and all liquids
were removed under reduced pressure to give a yellow, gum-
like substance. It was extracted with a boiling mixture of
toluene and n-heptane (1/1) from which imidoyl chloride 13
crystalized in the form of light-yellow needles (5.32 g, 26.4
mmol, 88%) whose 1H NMR spectrum is in agreement with the
literature data.16 1H NMR (400.22 MHz, CDCl3): δ [ppm] =
7.96 – 7.90 (m, 1H), 7.90 – 7.80 (m, 3H). 13C{1H} NMR
(100.65 MHz, CDCl3): δ [ppm] = 166.3, 140.5, 135.2, 134.7,
129.9, 125.3, 122.6.
3-(Pyridin-4-ylamino)benzo[d]isothiazole 1,1-dioxide (14).
1.05 g 4-Aminopyridine 9a (11.2 mmol, 2.0 eq) were dissolved
in 10 mL dry dioxane under N2. 1.13 g (5.6 mmol) Imidoyl
chloride 13 were added and the mixture was stirred overnight at
room temperature. The solvents were removed in vacuo and the
solids taken up in 80 mL of H2O and 4 mL aqueous NaOH
(40%). The remaining solids were filtered off and the filtrate
brought to ca. pH = 7. The precipitate was filtered off, washed
with H2O and dried to give 1.20 g (4.6 mmol, 83%) of
compound 14 in the form of a colorless solid with mp: >300 °C.
1H NMR (400.22 MHz, DMSO-d6): δ [ppm] = 11.14 (s, 1H),
8.62 (d, J = 5.7 Hz, 2H), 8.51 (d, J = 7.2 Hz, 1H), 8.12 (d, J =
6.7 Hz, 1H), 8.03 – 7.80 (m, 4H). 13C{1H} NMR (101 MHz,
(100.65 MHz, DMSO-d6): δ [ppm] = 141.6, 140.2, 129.3,
−1
휈
126.2, 114.3, 20.9. IR (ATR): (cm ) = 3054 (w), 2647 (w),
1928 (w), 1636 (m), 1620 (m), 1477 (s), 1382, (w), 1334 (s),
1296 (m), 1280 (m), 1250 (m), 1195 (m), 1135 (vs), 1102 (w),
1081, (vs), 1018 (w), 983 (w), 942 (vs), 838 (s), 812 (m), 801
(m), 773 (s), 707 (m), 660 (m). Elemental analysis:
C12H12N2O3S (248.30 g mol−1): Calc. (%): C, 58.05; H, 4.87; N,
11.28; S, 12.91; Found (%): C, 57.87; H, 4.87; N, 11.21; S,
13.18. HRMS (EI) m/z: [M]+ calcd for C12H12N2O3S+,
248.0614; found, 248.0612.
N-(1,4-dihydropyridin-4-yl)-4-methoxybenzenesulfonamide
(8c). To a solution of 0.941 g 4-aminopyridine 9a (10 mmol,
1.0 eq) in 10 mL of pyridine under N2 atmosphere, 2.07 g 4-
methoxybenzenesulfonyl chloride (10 mmol, 1.0 eq) were
added. The mixture was stirred for 10 min at RT, 3 mL of NEt3
were added and refluxed for 2 h. The solvents were then
removed in vacuo and the resulting dark brown solid was
washed with boiling H2O, boiling acetone and boiling MTBE.
After drying, 2.05 g (7.76 mmol, 78%) sulfonamide 8c were
obtained in the form of a colorless solid with mp: 279 – 280 °C.
1H NMR (400 MHz, DMSO-d6) δ [ppm] = 12.12 (s, 1H), 8.04
(d, J = 6.2 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8
Hz, 2H), 6.93 (d, J = 6.8 Hz, 2H), 3.78 (s, 3H). 13C{1H} NMR
(101 MHz, DMSO-d6) δ [ppm] = 161.7, 157.3, 141.9, 134.4,
128.4, 114.1, 113.9, 55.5. Elemental analysis: C12H12N2O3S
DMSO-d6): δ [ppm] = 157.6, 150.5, 145.0, 140.4, 134.1, 133.6,
−1
휈
128.2, 124.1, 121.8, 115.7. IR (ATR): (cm ) = 3601 (vw),
2891 (b, w), 1634 (m), 1593 (m), 1546 (s), 1496 (m), 1465 (w),
1423 (m), 1366 (m), 1312 (vs), 1281 (w), 1214 (vw), 1158 (vs),
1127 (s), 1067 (vw), 1051 (vw), 1005 (w), 954 (s), 866 (w), 832
(m), 778 (vs), 749 (s), 707 (m), 664 (m), 650 (s). Elemental
analysis: C12H9N3O2S (259.28 g mol−1): Calc. (%): C, 55.59; H,
3.50; N, 16.21; O, 12.34; S, 12.36; found (%): C, 52.65; H, 3.93;
N, 15.23; S, 11.84. HRMS (EI) m/z: [M]+ calcd for
C12H9N3O2S+, 259.0410; found, 259.0414.
4-Methyl-N-(pyridin-2-yl)benzenesulfonamide (25). 0.941 g
2-Aminopyridine 9b (10.0 mmol, 1.0 eq) were dissolved in 10
mL pyridine under N2 atmosphere. 2.287 g 4-Methyl-
benzenesulfonyl chloride (12 mmol, 1.2 eq) and 4 mL NEt3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 13
were added and the mixture was refluxed for 2 h before being
allowed to cool to room temperature. Cold H2O was added and
the precipitate was filtered off. It was washed with toluene and
a boiling mixture of 3/1 EtOAc/acetone before drying yielded
0.855 g (3.36 mmol, 33%) of sulfonamide 25 in the form of a
colorless solid. NMR spectroscopy is in agreement with the
literature data.17 1H NMR (400.22 MHz, DMSO-d6): δ [ppm] =
δ 11.90 (s, 1H), 8.01 (d, J = 4.6 Hz, 1H), 7.76 (d, J = 8.2 Hz,
2H), 7.73 – 7.64 (m, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.13 (d, J =
8.6 Hz, 1H), 6.92 – 6.77 (m, 1H), 2.33 (s, 3H). 13C{1H} NMR
(101 MHz, DMSO-d6): δ [ppm] = 153.1, 143.7, 142.5, 140.2,
129.0, 129.4, 126.7, 115.8, 113.6, 21.0.
MHz, CDCl3) δ [ppm] = 154.0, 135.5, 133.0, 129.7, 118.9, 65.2,
−1
1
2
3
4
5
6
7
8
휈
31.1, 20.9, 19.2, 13.9. IR (ATR): (cm ) = 3318 (w), 3290
(vw), 3196 (vw), 3132 (vw), 3030 (vw), 2963 (w), 2930 (vw),
2870 (vw), 2301 (vw), 1892 (vw), 1786 (vw), 1719 (w), 1696
(m), 1599 (m), 1537 (s), 1515 (s), 1477 (w), 1463 (w), 1409
(m), 1390 (w), 1377 (vw), 1355 (vw), 1344 (vw), 1315 (s), 1297
(m), 1269 (w), 1233 (vs), 1211 (vs), 1131 (w), 1122 (w), 1064
(vs), 1017 (m), 979 (w), 937 (vw), 902 (vw), 854 (w), 814 (vs),
769 (m), 739 (m), 708 (m), 692 (m). Elemental analysis:
C12H17N O2 (207.27 g mol−1): Calc. (%): C, 69.54; H, 8.27; N,
6.76; found (%): C, 69.75; H, 8.35; N, 6.74. HRMS (EI) m/z:
[M]+ calcd for C12H17NO2, 207.1254; found, 207.1254.
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16
17
18
19
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21
22
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25
26
27
28
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Synthesis of Benchmark Reaction Precursors and Products.
ASSOCIATED CONTENT
Supporting Information
The provided supporting information contains details regarding
kinetic measurements, crystallographic data, NMR spectroscopic
data. Furthermore, computational details, thermochemical data and
structural data for the quantum chemical study are included.
N-(4-Chlorobenzylidene)-4-methylbenzenesulfonamide (19).
5.0 g (35.55 mmol) 4-Chlorobenzaldehyde and 6.09 g (35.55
mmol) 4-methylbenzenesulfonamide were dissolved in 100 mL
of toluene. The mixture was refluxed under N2 atmosphere for
24 h using a Dean-Stark trap. The solvents were removed under
reduced pressure and the resulting crude product was
recrystallized twice from toluene and finally from CHCl3 to
give 6.74 g (22.9 mmol, 64%) tosyl imine 19 in the form of
colorless needles that were stored under N2. The spectral data is
in accordance with the one published in the literature.18 1H
NMR (400 MHz, CDCl3) δ [ppm] = 8.98 (s, 1H), 7.97 – 7.78
(m, 4H, H-3), 7.45 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H),
2.43 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ [ppm] =
168.8, 144.9, 141.5, 134.9, 132.5, 130.9, 130.0, 129.7, 128.2,
21.8.
AUTHOR INFORMATION
Corresponding Author
*zipse@cup.lmu.de.
ORCID:
Hendrik Zipse: 0000-0002-0534-3585
Julian Helberg: 0000-0001-9520-2913
N-((4-Chlorophenyl)(6-oxocyclohex-1-en-1-yl)methyl)-4-
methylbenzenesulfonamide (21). After completion of the
reaction, four MBH kinetic experiments catalyzed by TCAP
(2×12.5 mol%, 2×25.0 mol%), initially containing a total of
0.176 g (0.60 mmol) tosyl imine 19, 0.232 g (2.4 mmol, 4.0 eq)
cyclohexenone 20 and 19.6 mg (0.113 mmol) TCAP (1b) in 2.4
mL CDCl3 were combined and the solvents were removed in
vacuo. The crude mixture was purified by column
chromatography (SiO2, IH/EtOAc = 9/1  EtOAc) and then
recrystallization from IH/acetone to yield 0.196 g (0.50 mmol,
83%) tosyl amine 21 in the form of colorless crystals. The
analytical data is in accordance with the already published
one.10 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.61 (d, J = 8.3
Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 7.12
(d, J = 8.6 Hz, 2H), 6.79 (t, J = 4.1 Hz, 1H), 6.00 (d, J = 9.6 Hz,
1H), 5.05 (d, J = 9.6 Hz, 1H), 2.41 (s, 3H), 2.38 – 2.01 (m, 4H),
1.94 – 1.58 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ [ppm]
= 199.1, 149.5, 143.5, 138.0, 137.9, 136.6, 133.4, 129.6, 128.6,
127.8, 127.4, 59.2, 38.5, 25.9, 22.1, 21.6.
Conflicts of interest
There are no conflicts to declare.
ACKNOWLEDGMENT
The authors wish to thank Dr. Peter Mayer for providing X-ray
measurements and analysis and the Leibniz Supercomputer Center
(www.lrz.de) for computational resources.
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