Cooperative Al(salen)-pyridinium catalysts for the asymmetric synthesis of trans-configured β-lactones by [2+2]-cyclocondensation of acylbromides and aldehydes: Investigation of pyridinium substituent effects

Article abstract of DOI:10.3390/molecules17067121

The trans-selective catalytic asymmetric formation of β-lactones constitutes an attractive surrogate for anti-aldol additions. Recently, we have reported the first catalyst which is capable of forming trans-β-lactones with high enantioselectivity from aliphatic (and aromatic) aldehyde substrates by cyclocondensation with acyl bromides. In that previous study the concepts of Lewis acid and organic aprotic ion pair catalysis were combined in a salen-type catalyst molecule. Since a pyridinium residue on the salen periphery is essential for high trans- and enantioselectivity, we were interested in the question of whether substituents on the pyridinium rings could be used to further improve the catalyst efficiency, as they might have a significant impact on the effective charges within the heterocycles. In the present study we have thus compared a small library of aluminum salen/bispyridinium catalysts mainly differing in the substituents on the pyridinium residues. As one result of these studies a new catalyst was identified which offers slightly superior stereoselectivity as compared to the previously reported best catalyst. NBO calculations have revealed that the higher stereoselectivity can arguably not be explained by the variation of the effective charge.

Full text of DOI:10.3390/molecules17067121

Molecules 2012, 17, 7121-7150; doi:10.3390/molecules17067121
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Cooperative Al(Salen)-Pyridinium Catalysts for the Asymmetric
Synthesis of trans-Configured β-Lactones by
[2+2]-Cyclocondensation of Acylbromides and Aldehydes:
Investigation of Pyridinium Substituent Effects
Patrick Meier 1,2, Florian Broghammer 1, Katja Latendorf 1, Guntram Rauhut 2 and René Peters 1,*
1
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart,
Germany; E-Mails: meier@theochem.uni-stuttgart.de (P.M.);
florian.broghammer@oc.uni-stuttgart.de (F.B.); katja.latendorf@oc.uni-stuttgart.de (K.L.)
2
Institut für Theoretische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart,
Germany; E-Mail: rauhut@theochem.uni-stuttgart.de
* Author to whom correspondence should be addressed; E-Mail: rene.peters@oc.uni-stuttgart.de;
Tel.: +49-711-685-64330; Fax: +49-711-685-54330.
Received: 26 April 2012; in revised form: 23 May 2012 / Accepted: 4 June 2012 /
Published: 12 June 2012
Abstract: The trans-selective catalytic asymmetric formation of β-lactones constitutes an
attractive surrogate for anti-aldol additions. Recently, we have reported the first catalyst
which is capable of forming trans-β-lactones with high enantioselectivity from aliphatic
(and aromatic) aldehyde substrates by cyclocondensation with acyl bromides. In that
previous study the concepts of Lewis acid and organic aprotic ion pair catalysis were
combined in a salen-type catalyst molecule. Since a pyridinium residue on the salen
periphery is essential for high trans- and enantioselectivity, we were interested in the
question of whether substituents on the pyridinium rings could be used to further improve
the catalyst efficiency, as they might have a significant impact on the effective charges
within the heterocycles. In the present study we have thus compared a small library of
aluminum salen/bispyridinium catalysts mainly differing in the substituents on the
pyridinium residues. As one result of these studies a new catalyst was identified which
offers slightly superior stereoselectivity as compared to the previously reported best
catalyst. NBO calculations have revealed that the higher stereoselectivity can arguably not
be explained by the variation of the effective charge.

Molecules 2012, 17
Keywords: aluminum; cooperative catalysis; ion pair catalysis; ketene; 2-oxetanone;
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pyridinium
1. Introduction
β-Lactones (systematic name 2-oxetanones), are attracting the interest of scientists for mainly two
reasons: (1) a number of natural and synthetic β-lactones are known to act as specific enzyme
inhibitors [1–4]. Tetrahydrolipstatin (Xenical®, orlistat), for instance, is used for the treatment of
obesity and has recently received renewed attention due to the finding that it is capable of specifically
inhibiting fatty acid synthase (FAS-TE), an approved drug target for cancer treatment [5–7]; (2) as a
result of their inherent ring strain [8] β-lactones are useful synthetic building blocks. Ring opening
with hard nucleophiles offers the possibility to a divergent access to aldol products [9–13], whereas
treatment with soft nucleophiles can be utilized to synthesize β-functionalized carboxylic acid
derivatives [9,10,12]. In both cases the stereoinformation of the β-lactone ring can be completely
transferred into the ring opening product and the acyl-oxygen bond cleavage with hard nucleophiles
typically proceeds with retention of configuration. Cis- and trans-configured β-lactones thus behave as
masked and activated syn- and anti-aldol equivalents, respectively.
The catalytic asymmetric formation of ester or amide aldol derivatives via β-lactones is not only
attractive for the high divergency of accessible aldol structures, but also for the high atom-economy of
the overall process, since no preformation of silylketene acetals or related nucleophiles is necessary [14].
Instead an acyl halide is usually used to generate a ketene in situ as a reactive intermediate by
dehydrohalogenation induced by a base [15–19]. The ketene then undergoes a cycloaddition with an
aldehyde, either catalyzed by a Lewis acid [20–29] or by a Lewis base [30–37] or by a combination of
both [38–42]. Particularly appealing appears the development of trans-selective catalytic asymmetric
β-lactone formations as a surrogate for anti-aldol additions, since for the latter reaction type only few
efficient catalytic asymmetric protocols exist to date [43–46].
Unfortunately, the catalytic asymmetric [2+2] cycloaddition approach of ketenes and aldehydes
provides in general only cis-diastereomers as the major products [47–49]. In 2008, Calter et al.
described the first catalytic enantioselective access to trans-configured β-lactones by a formal [2+2]
cycloaddition [39]. However, this method is so far limited to the use of aromatic aldehydes, whereas
the large majority of bioactive compounds such as tetrahydrolipstatin carry an aliphatic chain at the
4-position of the 3,4-disubstituted 2-oxetanone core [50–52].
Recently, we have reported a conceptually new approach which is applicable to both aliphatic and
aromatic aldehydes [53,54]. Aluminum salen complexes carrying aprotic organic ion pairs in the
periphery of the salen core were investigated. The most useful described catalyst 4aA in terms of
enantioselectivity and reactivity was equipped with two pyridinium bromide functionalities connected
via benzylic methylene linkers to the ortho-position of the phenolate O atoms (3/3'-position, Scheme 1).

Molecules 2012, 17
Scheme 1. Application of bispyridinium Al-salen complex 4aA for the trans-selective
7123
catalytic asymmetric synthesis of 3,4-disubstituted 2-oxetanones 3 [53,54].
10 mol% 4aA,
iPr2NEt, CH2Cl2,
70 °C, 24 h
N
O
N
O
O
O
O
O
Al
R1
tBu
tBu
+
Br
H
R2
Me
R1
R2
Br
N
Br
N
1
2
3
4aA
By the choice of a Lewis acid with only one available coordination site a cyclic Zimmerman-
Traxler-type transition state leading to the cis-configured product would be avoided. Our catalyst
combines the cooperative action of a Lewis acid and of an aprotic onium halide ion pair Q+X− (in the
case of 4aA pyridinium bromide), the latter being arguably used to generate the acyl halide enolate 6
in the catalyst sphere (Scheme 2). Q+ might stabilize the otherwise unstable enolate [55–58] by ion pair
formation to increase the lifetime of the enolate species and to direct the enolate to the
aldehydeLewis acid complex 7 via an open transition state 8 adopting a staggered conformation
around the generated C–C bond [54]. In the reactive conformation the disubstituted enolate C-1 atom
should be oriented gauche to the aldehyde function’s H atom and the C-2-enolate-H atom would be
expected to direct toward the sterically demanding Lewis acid-ligand complex, so as to minimize
repulsive interactions. The initial aldol adduct could then cyclize to form the heterocyclic product 3.
Scheme 2. Rationale of the catalyst design for the trans-selective catalytic asymmetric
synthesis of 3,4-disubstituted 2-oxetanones 3 [54].
The general catalyst principle, utilizing the cooperative action of a Lewis acid and an aprotic
organic ion pair, is illustrated in Figure 1.

Molecules 2012, 17
Figure 1. Cooperative action of a Lewis acid and an aprotic organic ion pair within a
7124
single catalyst entity: the Lewis-acid serves to activate an electrophile, whereas the in situ
generated anionic nucleophile forms an ion pair with an aprotic organic cation (Q+), which
stabilizes and directs the nucleophile towards the electrophile [53,54].
Salen ligands were chosen due to their modular nature and their ready and rapid accessibility [59–61].
As a result of the proposed stabilizing electrostatic interaction of Q+ and the acyl halide enolate 6, the
charge density of Q+ was expected to play a decisive role on the reaction outcome, in particular in
terms of trans/cis-diastereoselectivity and enantioselectivity, because neutral substituents at the
3/3'-position lead predominantly to the undesired almost racemic cis-diastereomer [53,54].
In our continuing efforts to utilize ketenes [62–65] and related reactive intermediates [66–71] for a
rapid and practical access to chiral building blocks we have therefore investigated a series of Al-salen
catalysts 4 (Figure 2) carrying different substituents Z on the pyridinium moiety (acting as Q+) to study
electronic effects on the catalyst performance. The results are compared to NBO calculations which
have revealed the charge distribution within the pyridinium rings.
Figure 2. Structure of the investigated aluminum-bispyridinium catalysts 4 carrying
different residues R1 and pyridinium substituents Z.
R1
Z
N
N
N
O
Al Me
O
Br
Br
N
Z
R1
4
2. Results and Discussion
2.1. Ligand Preparation
In our previous studies we found that a major limitation of catalyst 4aA results from its relatively
low solubility at low reaction temperatures. For that reason we were also interested in derivatives in
which the phenolic t-Bu-substituents have been formally replaced by n-pentyl groups in order to

Molecules 2012, 17
7125
increase the rotational freedom of the alkyl substituents R1 and hence the catalyst solubility. To
investigate the steric influence of the R1 substituent on the stereoselectivity, R1 = Me was also studied.
Based on our previously established protocol [53,54] the ligands 14 could be prepared via a general
4-step procedure (Scheme 3). Phenols 9 were formylated with paraformaldehyde in the presence of
NEt3 and MgCl2 [72,73]. A subsequent bromomethylation of 10 with paraformaldehyde, HBr and
catalytic amounts of sulfuric acid gave benzyl bromides 11 in high yields [74]. The latter were then
treated with different commercially available pyridine derivatives in a nucleophilic substitution reaction
in acetonitrile (Table 1). The pyridinium salts 12 could be isolated and purified by precipitation and
washing with diethyl ether. Nucleophilic substitution proceeded smoothly in most cases. Only the 4-Cl
derivative 12bH was prone to releasing the starting pyridine in the back reaction (entry 11). This is
ascribed to the electron-withdrawing character of the Cl-substituent, which reduces the nucleophilicity
of the pyridine N and leads to a more potent leaving group. The chloro- and iodo-substituents at the
4-position of the pyridine were also found to be sensitive to a partial halogen exchange with bromide
(entries 10 and 11).
Scheme 3. Synthesis of a salen ligand library 14 with different residues R1 and R2.
OH O
OH
Br OH O
(CH2O)n, MgCl2,
NEt3, MeCN, RT
(CH2O)n, HBr,
cat. H2SO4, 70 °C
R1
R1
R1
10a (R1 = tBu): 90%
10b (R1 = nPent): 84%
10c (R1 = Me): 76%
11a (R1 = tBu): 98%
11b (R1 = nPent): 93%
11c (R1 = Me): 76%
9
pyridine derivative,
CH3CN, RT
R1
NH2
(R,R)-13
NH2
R2
Br
Br
R2 OH O
Br
N
N
OH
OH
EtOH, 4 MS Å, RT
R2
R1
R1
14
12
Treatment of two equivalents of the corresponding aldehyde 12 with enantiopure (R,R)-1,2-
diaminocyclohexane (13) in EtOH at room temperature for 15 h in the presence of 4 Å molecular
sieves provided the salen ligands 14 (Scheme 3 and Table 1). The diimine formation from aldehydes
12 usually furnished 14 in high yields, with the exception of the 4-chloro- and the 4-cyanopyridine
derivatives 14bH and 14bI (entries 11 and 12). In both cases none of the desired ligands was obtained,
again arguably due to the pronounced leaving group properties of the more electron poor pyridines.

Molecules 2012, 17
Table 1. Preparation of pyridinium aldehydes 12 and the ionic salen ligands 14.
7126
Entry
R1
R2
12
Yield 12 [%] a
14
Yield 14 [%] a
1
tBu
12aA
92
14aA
100
91
N
2
3
n-Pent
12bA
12cA
62
79
14bA
14cA
N
Me
84
N
Me
4
5
6
t-Bu
12aB
12bB
12bC
67
91
14aB
14bB
14bC
89
93
82
N
Me
n-Pent
n-Pent
N
96
Me
Me
7
8
n-Pent
nPent
12bD
12bE
54
47
14bD
14bE
91
86
N
9
n-Pent
12bF
81
14bF
92
I
10
11
12
n-Pent
n-Pent
n-Pent
12bG
12bH
12bI
65
29
80
14bG
14bH
14bI
77
0
N
Cl
N
CN
0
N
a Yield of isolated product.

Molecules 2012, 17
7127
2.2. Catalysis
To examine the impact of the different pyridinium residues R2, all accessible ligands were
investigated in the cyclocondensation of propionylbromide (1A) and dihydrocinnamaldehyde (2a,
Table 2). Due to the air and moisture sensitivity of the investigated aluminum complexes 4, the
catalysts were generated in situ from 10 mol% of the corresponding ligand 14 and 10 mol% AlMe3 in
CH2Cl2 at room temperature. We have previously already reported that the yields of β-lactone
formation are generally higher with isolated catalysts, but isolation has only a small impact on enantio-
and diastereoselectivity [53,54]. The catalyst solution was cooled to −70 °C and treated with both
reagents and finally with iPr2NEt. After stirring for 24 h at −70 °C, the reaction was terminated by
addition of hydrochloric acid.
Table 2. Investigation of salen ligands 14 carrying different pyridinium moieties R2 in the
cyclocondensation reaction of propionylbromide (1A) and dihydrocinnamaldehyde (2a) a.
Conversion
[%] b
Yield 3Aa
[%] b
dr 3Aa
ee 3Aa
Entry 14
R1
R2
N
[trans/cis] c
[%] d
1
2
3
14aA t-Bu
14bA n-Pent
>95
>98
n.d.
91
98
71
93:7
93:7
91:9
89
88
88
N
14cA
Me
N
Me
4
14aB t-Bu
71
29
97:3
89
N

Molecules 2012, 17
7128
Table 2. Cont.
Conversion
[%] b
Yield 3Aa
[%] b
dr 3Aa
ee 3Aa
Entry 14
R1
R2
[trans/cis] c
[%] d
Me
5
6
14bB n-Pent
88
75
60
56
97:3
90
N
14bC n-Pent
92:8
80
Me
Me
7
8
14bD n-Pent
14bE n-Pent
82
62
39
38
88:12
88:12
80
77
N
9
14bF n-Pent
14bG n-Pent
73
78
37
45
94:6
92:8
82
81
10
a The catalyst was prepared in situ from 14 and AlMe3; b Determined by 1H-NMR using mesitylene
as standard; c Determined by 1H-NMR; d Determined by HPLC on a chiral stationary phase.
In most cases, conversion of the aldehyde was good and yields of β-lactone 3Aa were moderate to
good. Catalysts generated from 14bA and 14bB with R1 = n-Pent (entries 2 and 5) resulted in higher
conversions and yields than their direct counterparts derived from 14aA and 14aB, respectively,
carrying a t-Bu residue R1 (entries 1 and 4). This is attributed to a higher solubility in CH2Cl2 at −70 °C
with a more flexible alkyl chain [75]. 14cA with R1 = Me resulted in poor solubility, explaining the
lower yield (entry 3) compared to the results with 14aA and 14bA, respectively (entries 1 and 2). For
that reason additional Me derivatives were not studied.
Interestingly, the nature of R1 was found to have only a minor effect on both enantio- and
diastereoselectivity (compare entries 1, 3, 4 and 5), whereas most salen catalyzed reactions require
enhanced steric demand at that position for an efficient transfer of chirality [76]. In the present case,
the stereoselectivity is much more dependent on the pyridine substituents. The best combination of
enantioselectivity (ee = 90%) and diastereoselectivity (trans/cis = 97:3) was attained with ligand 14bB
carrying a 4-Me substituent as a weak -donor on the pyridine ring (entry 5). This ligand also allowed
for a useful product yield.
Increasing the steric demand of the pyridine by a 4-t-Bu substituent had only a minor impact on
the reactivity, but both the dr (92:8) and the ee (80%) were negatively affected (entry 6). Reduced

Molecules 2012, 17
7129
diastereoselectivity data were also noticed with a 3,5-dimethyl substitution pattern on the pyridine
(entry 7) or with a quinoline residue (entry 8).
The DMAP derivative 14bF (entry 9) carrying the potent -donor group NMe2 at the pyridine
4-position and the derivative 14bG (entry 10) carrying an iodo atom as a weak -acceptor at the
4-position resulted in similar reactivity and stereoselectivity. For 14bF, a lower diastereoselectivity
was expected as a consequence of the +M-effect which should result in a wider charge distribution
thereby weakening the postulated contact ion pair with the acyl halide enolate 6. Consequently,
-acceptors like in 14bG should result in a more efficient ion pair formation and improved
stereoselectivity, but steric effects as well as the poor solubility of 14bG even at room temperature
might have overwritten this effect. Unfortunately, it appears to be difficult to study the effect of
-acceptors in ligands 14, as they result in a lower stability of the catalysts.
In contrast, the 4-Me group does not only lead to an improved catalyst stability (the ligand 14bB
can be stored for at least two months at room temperature with no decomposition detected) and
solubility, but might also have a positive effect on a uniform reactive conformation of the generated
acyl halide enolate, whereas larger residues might hamper an efficient ion pair formation of the enolate
and the pyridinium residue.
The most stereoselective catalyst 4bB was applied to different substrates (Table 3). For the
investigated aldehydes and acyl bromides 4bB gave always slightly higher enantioselectivities
compared to our previously reported system 4aA.
Table 3. Asymmetric synthesis of trans-configured β-lactones 3 catalyzed by the
aluminum bis-picolinium catalyst 4bB.
Entry
1d
1
R1
2
R2
(CH2)2Ph
(CH2)2Ph
Et
Ph
(CH2)2Ph
3
Yield [%] a
dr [trans/cis] b
97:3 (97:3)
97:3 (97:3)
98:2 (95:5)
98:2 (94:6)
99:1 (98:2)
ee [%] c
90 (88)
90 (88)
90 (87)
96 (91)
95 (94)
1A Me 2a
1A Me 2a
1A Me 2b
1A Me 2c
1B n-Pr 2a
3Aa
3Aa
3Ab
3Ac
3Ba
60
69
59
37
59
2e
3d
4d
5d
a Yield of isolated product; b Diastereomeric ratio determined by 1H-NMR (data in brackets refer to
c
the reported data obtained with 10 mol% catalyst 4aA); Determined by HPLC on a chiral
stationary phase (data in brackets refer to the reported data obtained with 10 mol% catalyst 4aA);
d The catalyst was formed in situ; e The catalyst was isolated prior to use.

Molecules 2012, 17
7130
Moreover, the trans-selectivity was equal (entries 1 and 2) or better (entries 3 and 5) than with
catalyst 4aA. Entry 2 shows that improved yields can be obtained with the isolated catalyst 4bB.
However, the more convenient protocol with in-situ catalyst formation allows for similar diastereo-
and enantioselectivity (compare entries 1 and 2). The highest enantioselectivity was attained with the
aromatic benzaldehyde (entry 4, ee = 96%), but the yield is significantly lower than for aliphatic
aldehydes. This is mainly a consequence of the marked sensitivity towards elimination of 4-aryl
substituted 2-oxetanones explaining a partial decomposition during the workup [77].
2.3. Mechanistic and Theoretical Investigations
Reactions catalyzed by salen complexes are known to proceed in several cases via bimetallic
reaction pathways [78]. As part of our programme on bimetallic cooperative catalysis [79–82], we
were therefore interested if two salen units might also cooperate to form the β-lactone products 3.
In that case the presence of a non-linear effect (NLE) would be expected [78,83]. The absence of a
NLE in the present case (Figure 3) indicates that a major product formation pathway involving two
salen molecules is most likely no realistic scenario. Our mechanistic considerations thus focus on
reaction pathways involving a single catalyst molecule.
Figure 3. Investigation of a potential nonlinear effect for the formation of 3Ad catalyzed by 4bA.
As mentioned above, we have previously shown that a cationic residue on the salen periphery is
essential for high trans-selectivity, but also for high enantioselectivity and reactivity [53,54]. In the
case of standard Al-salen complexes carrying a H atom or an isobutyl residue at the 3/3'-position,
reactivity was poor and almost racemic product was formed favoring the cis-isomer. With a t-Bu
residue no product was formed at all. In the initial study a pyridinium residue was found to be superior

Molecules 2012, 17
7131
compared to ammonium residues [53,54]. We have tentatively explained this preference by a more
efficient contact ion pair formation of the planar enolate moiety with the planar pyridinium system as
compared to tetrahedral ammonium moieties.
As the positive charge of the substituent at the 3/3'-position is essential for a successful reaction
outcome, we were interested in the effective charges for the derivatives described above. For that
reason we accomplished a series of NBO analyses using the MOLPRO package of ab initio
programmes [84]. For the electronic structure calculations we chose density functional theory in
combination with a double-ζ basis set, i.e., B3LYP/cc-pVDZ. Our original idea was that an acceptor
substituent in the 4-position of the pyridinium ring might amplify the effect of the positive charge and
could further stabilize the contact ion pair. In agreement with the literature [85], our calculations
revealed a negative partial charge for the nitrogen atoms, for both tetramethylammonium and
pyridinium cation systems (see Table 4). The positive partial charges in the tetramethylammonium
reference are distributed over the nine hydrogen atoms. In contrast the pyridinium cation has positive
partial charges on the α-carbon atoms, which might stabilize the enolate in the proposed contact ion
pair more efficiently than in the case of quaternary ammonium cations, since the positive charge is
wider distributed in the latter case. Pyridinium derivatives with substituents in the 4-position give
nearly identical partial charges for the nitrogen and the α-carbon atoms as the parent system with a H
atom in 4-position. Only the partial charge of the carbon in the 4-position shows a noticeable change
on substitution.
Table 4. Results of the NBO analysis.
10
H
10
Cl
5
16-18H
11 H
10
5
H 9
H 8
11 H
H 9
H 8
11 H
H 9
H 8
5
6
4
3
6
6
4
3
4
3
1
Me
N
1
1
12 H
N2
12 H
N2
12 H
N2
Me
7
Me
H13-15
7
7
Me
H13-15
H13-15
atom
charge
atom
C (1)
N (2)
C (3)
C (4)
C (5)
C (6)
C (7)
H (8)
H (9)
H (10)
H (11)
H (12)
charge
+0.11
−0.35
+0.11
−0.22
−0.12
−0.22
−0.41
+0.26
+0.28
+0.27
+0.28
+0.26
+0.25
atom
C (1)
N (2)
C (3)
C (4)
C (5)
C (6)
C (7)
H (8)
H (9)
Cl (10)
H (11)
H (12)
charge
+0.12
−0.36
+0.11
−0.24
+0.02
−0.24
−0.40
+0.26
+0.29
+0.14
+0.29
+0.26
+0.25
atom
C (1)
N (2)
C (3)
C (4)
C (5)
C (6)
C (7)
H (8)
H (9)
C (10)
H (11)
H (12)
charge
+0.11
−0.36
+0.10
−0.22
+0.07
−0.23
−0.41
+0.26
+0.27
−0.67
+0.27
+0.26
+0.25
+0.26
N
C
H
−0.36
−0.41
+0.25
H (13–15)
H (13–15)
H (13–15)
H (16–18)

Molecules 2012, 17
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Exemplarily, the 4-chloropyridinium cation is shown in Table 4 as an example of a -acceptor
substituent and the 4-methylpyridinium cation bearing a -donor substituent. Hence the most
important effects of the substituents are presumably: (1) the (de)stabilization of the bond between the
pyridinium and the salen framework, since electron acceptors result in a higher leaving group tendency
of the corresponding pyridine, whereas donor substituents have the opposite effect, and (2) the steric
influence on the enolate.
For the cooperative contact ion pair/Lewis acid activation two reaction pathways appear to be
feasible (Scheme 4), both leading to the observed absolute and relative β-lactone configurations. The
two reaction mechanisms differ in the reactive conformations of the coordinated aldehyde and in the
pyridinium unit involved. In path A presented in Scheme 4, the aldehyde group’s H atom is expected to
point toward the C=N imine bond in 15 connected to phenolate ring A. Pyridinium ring A forms the
reactive contact ion pair with the acylbromoenolate. The depicted aldehyde conformation appears to be
required to get the aldehyde in close distance to the reactive enolate in a transition state adopting
the above proposed staggerd conformation (see Scheme 2) to form the trans-β-lactone with a
(3S,4S)-configuration.
Scheme 4. Two plausible reaction pathways via cooperative contact ion pair directed
Lewis acid activation leading to the observed absolute and relative configurationof
β-lactones 3.
Me
Path A:
O
Me
R2
R2
R1
R1
R1
R1
Br
A
O C
N
N
O
H
A
O
Br
N
N
O
O
Al
Al
N
N
R2
H
O
R1
O
Me
Me
O
O
Br
H
B
R1
R1
N
N
Br
15
Br
B
Me
Me
O
O
Path B:
R1
R2
3
R2
R2
R1
R1
R2
Br
R2
Br
O
O
N
N
Me
O
R1
O
Al
Me
R1
O
Al
N
N
R2
H
O
H
R1
O
Me
Me
O
O
B
N
C O
Br
Br
N
B
R1
R1
Br
16

Molecules 2012, 17
7133
In path B the same aldehyde H atom would point away from the chiral salen backbone. To form the
product with the observed absolute configuration again the Re-face of the aldehyde has to react and
this would require the action of the other pyridinium moiety B.
We favor this scenario because the repulsive interactions of the aldehyde and the salen core would
be minimized. An aldehyde conformation like in path B is often hampered in salen-complex catalyzed
reactions by the presence of tBu groups at the 3/3'-position [76,86]. However, the aldehyde conformation
in path A appears more unfavorable in the present case given the folding of chiral salen metal
complexes derived from trans-1,2-diaminocyclohexane which describes the ligand deviation from a
planar arrangement [87–89]. In the present case phenolate ring B is expected, based on literature
precedent for related Al salen complexes [90], to fold downward toward the Me-Al bond in a stepped
conformation. That means, the B-half offers more available space for substrate accomodation.
3. Experimental
3.1. General
1H-NMR and 13C-NMR spectra were measured on a Bruker Avance spectrometer (300 or 500 MHz,
Rheinstetten, Germany) in CDCl3 or DMSO as solvent using TMS as internal standard and chemical
shifts are expressed as δ in ppm. Molecular masses were determined with the electron spray ionization
(ESI) method on a MicroTOFQ (Bruker, Bremen, Germany) spectrometer. IR spectra were recorded
on a Bruker Vector 22 FT-IR spectrometer (Bremen, Germany) with an ATR module (Golden Gate).
Melting points are uncorrected and were measured on a Büchi Melting Point B-535 analysis device.
The enantiomeric excesses were determined by HPLC on an Elite LaChrom system equipped with
Hitachi modules. A chiral stationary phase Daicel column of the Chiracel OD-H type was used.
3.2. General Procedure for the Synthesis of 10 (GP1)
This procedure was according to a published protocol [72,73]. To a solution of the phenol
derivative 9 (1 eq., 15.0 mmol) in acetonitrile, paraformaldehyde (6.7 eq.), magnesium chloride
(1.5 eq.) and triethylamine (3.8 eq.) were added and the mixture was heated under reflux for 24 h.
After cooling to ambient temperature, 1 M hydrochloric acid was added till the yellow residue
dissolved, followed by extraction with diethyl ether (3 × 20 mL). The organic layers were dried over
MgSO4, filtered and the solvent was removed in vacuo. Purification by column chromatography
(petroleum ether/ethyl acetate 10:1) gave the aldehyde 10.
2-Hydroxy-5-tert-butylbenzaldehyde (10a) was prepared according to GP1 using 4-tert-butylphenol
(1 eq., 15.0 mmol, 2.25 g) and paraformaldehyde (6.7 eq., 101 mmol, 3.02 g). The product was formed
as a yellow oil (13.5 mmol, 2.40 g, 90%). C11H14O2, MW: 178.23 g/mol. 1H-NMR (300 MHz, CDCl3,
20 °C): δ = 10.87 (s, 1H, Ar-OH), 9.89 (s, 1H, Ar-CHO), 7.58 (dd, J = 8.8, 2.5, 1H, p-Ar-H), 7.51 (d,
J = 2.5, 1H, o-Ar-H), 6.94 (d, J = 8.7, 1H, m-Ar-H), 1.33 (s, 9H, Ar-C(CH3)3). The analytical data
were in agreement with the literature values [72].
2-Hydroxy-5-pentylbenzaldehyde (10b) was prepared according to GP1 using 4-n-pentylphenol (1 eq.,
8.0 mmol, 1.31 g, 1.4 mL) and paraformaldehyde (6.7 eq., 53.6 mmol, 1.61 g). The product was

Molecules 2012, 17
7134
1
formed as a yellow oil (6.7 mmol, 1.29 g, 84%). C12H16O2, MW: 192.25 g/mol. H-NMR (300 MHz,
CDCl3, 20 °C): δ = 10.85 (s, 1H, Ar-OH), 9.87 (s, 1H, Ar-CHO), 7.33–7.37 (m, 2H, o-, p-Ar-H),
6.91 (d, J = 8.5, 1H, m-Ar-H), 2.59 (t, J = 7.7, 2H, Ar-CH2(CH2)3CH3), 1.65–1.55 (m, 2H,
Ar-CH2CH2(CH2)2CH3), 1.36–1.28 (m, 4H, Ar-(CH2)2(CH2)2CH3), 0.90 (t, J = 6.9, 3H, Ar-(CH2)4CH3).
The analytical data are in agreement with the literature [91].
2-Hydroxy-5-methylbenzaldehyde (10c) was prepared according to GP1 using 4-methylphenol (1 eq.,
14.0 mmol, 1.50 g) and paraformaldehyde (6.7 eq., 93.0 mmol, 2.80 g). The product was formed as a
slightly yellow oil (10.5 mmol, 1.43 g, 76%) after Kugelrohr distillation (no column chromatography
1
in this case). C8H8O2, MW: 136.15 g/mol. H-NMR (300 MHz, CDCl3, 20 °C): δ = 10.84 (s, 1H,
Ar-OH), 9.86 (s, 1H, Ar-CHO), 7.35–7.33 (m, 2H, o-, p-Ar-H), 6.90 (d, J = 9.2, 1H, m-Ar-H), 2.34 (s,
3H, CH3). The analytical data are in agreement with the literature [72].
3.3. General Procedure for the Synthesis of 11 (GP2)
This procedure was according to a published protocol [74]. To the corresponding aldehyde 10 (1 eq.,
10.5 mmol) were added aq. hydrobromic acid (48%, 7.5 eq., 78.9 mmol, 8.6 mL), paraformaldehyde
(1.5 eq., 15.8 mmol, 0.47 g) and a catalytic amount of sulfuric acid (3 drops). Depending on the alkyl
chain R1, the mixture was stirred at 70 °C for 1 to 5 days. After cooling to ambient temperature, water
(10 mL) was added followed by extraction with methylene chloride (3 × 10 mL). The collected organic
layers were dried over Na2SO4, filtered and the solvent was removed in vacuo.
3-(Bromomethyl)-2-hydroxy-5-tert-butylbenzaldehyde (11a) was prepared according to GP2 using 10a
(1 eq., 13.5 mmol, 2.40 g), paraformaldehyde (1.5 eq., 20.2 mmol, 0.61 g) and aq. hydrobromic acid
(48%, 7.5 eq., 101.1 mmol, 11.5 mL). After 1 day reaction time a brown oil (13.3 mmol, 3.61 g, 98%)
was isolated. C12H15BrO2, MW: 271.15 g/mol. 1H-NMR (300 MHz, CDCl3, 20 °C): δ = 11.32 (s, 1H,
Ar-OH), 9.90 (s, 1H, Ar-CHO), 7.64 (d, J = 2.5, 1H, Ar-H), 7.51 (d, J = 2.5, 1H, Ar-H), 4.59(s, 2H,
CH2Br), 1.34 (s, 9H, C(CH3)3). The analytical data are in agreement with the literature [74].
3-(Bromomethyl)-2-hydroxy-5-pentylbenzaldehyde (11b) was prepared according to GP2 using 10b (1 eq.,
10.5 mmol, 2.02 g), paraformaldehyde (1.5 eq., 15.8 mmol, 0.47 g) and aq. hydrobromic acid (48%,
7.5 eq., 78.9 mmol, 8.6 mL). After 5 days reaction time a brown oil (9.77 mmol, 2.79 g, 93%) was
1
isolated. C13H17BrO2, MW: 285.18 g/mol. M.p.: 32–34 °C. H-NMR (300 MHz, CDCl3, 20 °C):
δ = 11.31 (s, 1H, Ar-OH), 9.87 (s, 1H, Ar-CHO), 7.43 (d, J = 2.1, 1H, Ar-H), 7.33 (d, J = 2.1, 1H,
Ar-H), 4.57 (s, 2H, CH2Br), 2.59 (t, J = 7.8, 2H, Ar-CH2-C4H9), 1.61 (m, 2H, (CH2)pentyl), 1.33 (m, 4H,
(CH2)pentyl), 0.90 (t, J = 6.9, 3H, CH3). 13C-NMR (75 MHz, CDCl3, 21 °C): δ = 196.5 (1C, CHO),
157.6 (1C, CAr-OH), 138.3 (1C, CAr-H), 134.5 (1C, CAr-C5H11), 133.6 (1C, CAr-H), 126.0 (1C,
CAr-CH2Br), 120.5 (1C, CAr-CHO), 34.6 (1C, CAr-CH2-C4H9), 31.3 (1C, (CH2)pentyl), 31.0 (1C,
~
(CH2)pentyl), 26.8 (1C, CAr-CH2Br), 22.5 (1C, (CH2)pentyl), 14.0 (1C, CH3). IR (solid):  = 3046, 2954,
2930, 2854, 2753, 2185 (b), 1967 (b), 1811, 1646, 1438, 1209, 760. HRMS (EI) m/z: Anal. Calcd. for
+
[C13H17BrO2 ]: 284.0412, found 284.0412.

Molecules 2012, 17
7135
3-(Bromomethyl)-2-hydroxy-5-methylbenzaldehyde (11c) was prepared according to GP2 using 10c
(1 eq., 9.0 mmol, 1.23 g), paraformaldehyde (1.5 eq., 13.5 mmol, 0.407 g) and aq. hydrobromic acid
(48%, 7.5 eq., 67.5 mmol, 7.8 mL). After 70 h reaction time a beige-colored solid (5.8 mmol, 1.58 g,
1
76%) was isolated. C9H9BrO2, MW: 229.07 g/mol. H-NMR (300 MHz, CDCl3, 20 °C): δ = 11.28 (s,
1H, Ar-OH), 9.84 (s, 1H, Ar-CHO), 7.42 (d, J = 1.9, 1H, o-Ar-H), 7.31 (d, J = 1.9, 1H, p-Ar-H), 4.54
(s, 2H, Ar-CH2-Br), 2.33 (s, 3H, CH3). The analytical data are in agreement with the literature [74].
3.4. General Procedure for the Synthesis of 12 (GP3)
This procedure was according to a published protocol [92]. To a solution of 11 (1 eq., 3.0 mmol) in
acetonitrile (8 mL) was added the corresponding pyridine derivative (1.1 eq., 3.3 mmol). The mixture
was stirred for 15 h at ambient temperature. For the workup the solvent was removed in vacuo till a
volume of ca. 5 mL was reached and the product was precipitated with diethyl ether (10 mL). After
drying in vacuo the salt 12 was obtained.
1-(5-tert-Butyl-3-formyl-2-hydroxybenzyl)pyridinium bromide (12aA) was prepared according to GP3
using 11a (1 eq., 1.50 mmol, 406.7 mg) and pyridine (1.1 eq., 1.65 mmol, 130.5 mg, 133 µL). The
product was formed as a white solid (1.39 mmol, 483.2 mg, 92%). C17H20BrNO2, MW: 350.25 g/mol.
1H-NMR (300 MHz, CDCl3, 20 °C): δ =11.37 (s, 1H, Ar-OH), 9.83 (s, 1H, Ar-CHO), 9.62 (d,
J = 6.6, 2H, o-Py-H), 8.70 (d, J = 2.5, 1H, Ar-H), 8.38 (tt, J = 7.9, 1.3, 1H, p-Py-H), 7.97 (t, J = 7.0,
2H, m-Py-H), 7.57 (d, J = 2.5, 1H, Ar-H), 6.30 (s, 2H, Ar-CH2-Py), 1.32 (s, 9H, C(CH3)3). The
analytical data are in agreement with the literature [54].
1-(3-Formyl-2-hydroxy-5-pentylbenzyl)pyridinium bromide (12bA) was prepared according to GP3
using 11b (1 eq., 9.8 mmol, 2.79 g) and pyridine (1.1 eq., 10.7 mmol, 0.85 g, 866 µL). The product
was formed as a beige-colored solid (6.1 mmol, 3.56 g, 62%). C18H22BrNO2, MW: 364.28 g/mol.
1
M.p.: 146–147 °C. H-NMR (300 MHz, CDCl3, 20 °C): δ =14.45 (s, 1H, Ar-OH), 9.87 (s, 1H,
Ar-CHO), 9.63 (d, J = 6.1, 2H, o-Py-H), 8.43 (d, J = 2.5, 1H, Ar-H), 8.39 (tt, J = 7.9, 1.3, 1H, p-Py-H),
7.99 (t, J = 7.2, 2H, m-Py-H), 7.47 (d, J = 2.1, 1H, Ar-H), 6.35 (s, 2H, Ar-CH2-Py), 2.67 (t, J = 8.0,
2H, Ar-CH2-C4H9), 1.64 (m, 2H, (CH2)pentyl), 1.33 (m, 4H, (CH2)pentyl), 0.89 (t, J = 6.9, 3H, CH3).
13C-NMR (75 MHz, CDCl3, 21 °C): δ = 196.6 (1C, CHO), 157.9 (1C, CAr-OH), 145.6 (1C, α-CPy),
145.6 (1C, α-CPy), 145.1 (1C, γ-CPy), 140.2 (1C, CAr-H), 136.2 (1C, CAr-C5H11), 135.0 (1C, CAr-CHO),
127.8 (2C, β-CPy), 121.1 (1C, CAr-H), 120.6 (1C, CAr-CH2-NPy), 59.2 (1C, CAr-CH2-NPy), 34.5 (1C,
CAr-CH2-C4H9), 31.4 (1C, (CH2)Pentyl). 31.0 (1C, (CH2)Pentyl), 22.5 (1C, (CH2)Pentyl), 14.1 (1C, CH3). IR
~
(solid):  = 3046, 2949, 2860, 2196, 1966, 1641,1627, 1154, 690. HRMS (ESI) m/z: Anal. Calcd. for
[[C18H22NO2]+]: 284.1645, found 284.1641.
1-(3-Formyl-2-hydroxy-5-methylbenzyl)pyridinium bromide (12cA) was prepared according to GP3
using 11c (1 eq., 7.0 mmol, 1.62 g) and pyridine (1.1 eq., 7.7 mmol, 597 μL). The product was formed
as a colorless solid (6.5 mmol, 1.99 g, 92%). C14H14BrNO2, MW: 308.17 g/mol. M.p.: 189–192 °C.
1H-NMR (300 MHz, CDCl3, 20 °C): δ = 11.39 (s, 1H, Ar-OH), 9.84 (s, 1H, Ar-CHO), 9.63 (d, J = 5.7,
2H, o-Py-H), 8.44 (m, 2H, p-CPy-H und CAr-H), 8.02 (t, J = 7.2, 2H, m-Py-H), 7.44 (d, J = 1.9, 1H,
o-Ar-H), 6.33 (s, 2H, Ar-CH2-Py), 2.39 (s, 9H, CH3). 13C-NMR (75 MHz, CDCl3, 20 °C): δ = 196.6

Molecules 2012, 17
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(CO), 157.7 (CAr-OH), 145.6 (α-Py-C), 145.1 (α-Py-C), 140.8 (γ-Py-C), 135.7 (CArH), 135.7 (CAr-CH3),
131.0 (CAr-CO), 127.8 (2 x β-Py-C), 121.1 (CAr-CH2-Py), 120.5 (CArH), 58.9 (CAr-CH2-Py), 20.2
~
(CH3). IR (solid):  = 3446, 3378, 3117, 3046, 2927, 2051, 1882, 1626, 1463. MS (ESI) m/z: 228.1
(20%, M+), 149.1 (100%, M+–pyridine), 133.1 (10%, M+–pyridine–OH).
1-(5-tert-Butyl-3-formyl-2-hydroxybenzyl)-4-methylpyridinium bromide (12aB) was prepared
according to GP3 using 11a (1 eq., 3.00 mmol, 813.5 mg) and picoline (1.1 eq., 3.30 mmol, 307.3 mg,
321 µL). The product was formed as a white solid (2.02 mmol, 734.9 mg, 67%). C18H22BrNO2, MW:
364.28 g/mol. M.p.: 247.2–248.0 °C. 1H-NMR (300 MHz, DMSO, 20 °C): δ = 11.16 (b, 1H, Ar-OH),
10.06 (s, 1H, Ar-CHO), 8.99 (d, J = 6.7, 2H, o-Py-H), 8.09 (d, J = 2.4, 1H, Ar-H), 7.98 (d, J = 6.5, 2H,
m-Py-H), 7.89 (d, J = 2.6, 1H, Ar-H), 5.82 (s, 2H, Ar-CH2-Py), 2.59 (s, 3H, Py-CH3), 1.32 (s, 9H,
13
C(CH3)3). C-NMR (125 MHz, DMSO, 20 °C): δ = 196.5, 159.3, 156.7, 143.9, 142.8, 136.1, 130.8,
~
128.3, 122.0, 121.2, 58.2, 34.1, 31.0, 21.4. IR (solid):  = 3419, 3018, 2951, 2864, 1639, 1473, 1379,
1280, 1226, 1151, 1018, 826, 761, 700, 617. MS (ESI) m/z: 284.2 (57%, [M]+), 191.1 (100%,
[M]+−[Py]), 94.1 (15%, [PyH]+). HRMS (ESI) m/z: Anal. Calcd. for [[C18H22NO2]+]: 284.1645, found:
284.1634.
1-(3-Formyl-2-hydroxy-5-pentylbenzyl)-4-methylpyridinium bromide (12bB) was prepared according
to GP3 using 11b (1 eq., 14.0 mmol, 4.0 g) and picoline (1.1 eq., 15.4 mmol, 1.4 g, 1.5 mL). The
product was formed as a yellow solid (12.8 mmol, 4.8 g, 91%). C19H24BrNO2, MW: 378.30 g/mol.
1
M.p.: 118.2–120.6 °C. H-NMR (300 MHz, CDCl3, 20 °C): δ = 11.41 (s, 1H, Ar-OH), 9.86 (s, 1H,
Ar-CHO), 9.40 (d, J = 6.7, 2H, o-Py-H), 8.39 (d, J = 2.0, 1H, Ar-H), 7.72 (d, J = 6.4, 2H, m-Py-H),
7.45 (d, J = 2.1, 1H, Ar-H), 6.24 (s, 2H, Ar-CH2-Py), 2.68–2.63 (m, 5H, Ar-CH2-C4H9 and Py-CH3),
1.68–1.58 (m, 2H, (CH2)pentyl), 1.38–1.25 (m, 4H, (CH2)pentyl), 0.89 (t, J = 6.8, 3H, CH3). 13C-NMR
(75 MHz, CDCl3, 20 °C): δ = 196.6, 158.9, 157.9, 144.6, 140.3, 136.2, 134.9, 128.2, 121.3, 120.5,
~
58.3, 34.5, 31.4, 31.0, 22.5, 22.3, 14.1. IR (solid):  = 3013, 2927, 2855, 1637, 1466, 1278, 1151,
1016, 830, 748, 699. MS (ESI) m/z: 298.2 (100%, [M]+), 205.1 (13%, [M]+−[Py]). HRMS (ESI) m/z:
Anal. Calcd. for [[C19H24NO2]+]: 298.1802, found: 298.1793.
4-tert-Butyl-1-(3-formyl-2-hydroxy-5-pentylbenzyl)-pyridinium bromide (12bC) was prepared
according to GP3 using 11b (1 eq., 1.0 mmol, 285.2 mg) and 4-tert-butylpyridine (1.1 eq., 1.1 mmol,
148.7 mg, 107 µL). The product was formed as a yellow solid (0.96 mmol, 403.4 mg, 96%).
1
C22H30BrNO2, MW: 420.38 g/mol. M.p.: 188.6–189.8 °C. H-NMR (300 MHz, CDCl3, 20 °C):
δ = 11.45 (s, 1H, Ar-OH), 9.87 (s, 1H, Ar-CHO), 9.50 (d, J = 6.8, 2H, o-Py-H), 8.46 (d, J = 2.0, 1H,
Ar-H), 7.86 (d, J = 6.8, 2H, m-Py-H), 7.45 (d, J = 2.0, 1H, Ar-H), 6.24 (s, 2H, Ar-CH2-Py), 2.67 (t,
J = 7.7, 2H, Ar-CH2-C4H9), 1.69–1.59 (m, 2H, (CH2)pentyl), 1.39 (s, 9H, Py-C(CH3)3). 1.37–1.25 (m,
4H, (CH2)pentyl), 0.89 (t, J = 6.8, 3H, CH3). 13C-NMR (75 MHz, CDCl3, 20 °C): δ = 196.7, 157.9,
144.8, 140.5, 136.3, 134.8, 124.7, 121.3, 120.5, 58.0, 36.6, 34.5, 31.4, 31.0, 30.0, 22.5, 14.1. IR
~
(solid):  = 3035, 2956, 2928, 2857, 1643, 1462, 1384, 1270, 1219, 1169, 1109, 1015, 849, 749, 712,
647, 561. MS (ESI) m/z: 340.2 (15%, [M]+), 205.1 (100%, [M]+−[Py]). HRMS (ESI) m/z: Anal. Calcd.
for [[C22H30NO2]+]: 340.2271, found: 340.2255.

Molecules 2012, 17
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3,5-Dimethyl-1-(3-formyl-2-hydroxy-5-pentylbenzyl)-pyridinium bromide (12bD) was prepared
according to GP3 using 11b (1 eq., 1.0 mmol, 285.2 mg) and 3,5-dimethylpyridine (1.1 eq., 1.1 mmol,
117.9 mg, 126 µL). The product was formed as a yellow solid (0.54 mmol, 211.4 mg, 54%).
1
C20H26BrNO2, MW: 392.33 g/mol. M.p.: 150.3–151.3 °C. H-NMR (300 MHz, CDCl3, 20 °C):
δ = 11.37 (s, 1H, Ar-OH), 9.86 (s, 1H, Ar-CHO), 9.24 (b, 2H, o-Py-H), 8.39 (b, 1H, Ar-H), 7.94 (s,
1H, p-Py-H), 7.44 (m, 1H, Ar-H), 6.15 (s, 2H, Ar-CH2-Py), 2.64 (t, J = 7.8, 2H, Ar-CH2-C4H9), 2.54
(s, 6H, Py-CH3). 1.61 (m, 2H, (CH2)pentyl), 1.30 (m, 4H, (CH2)pentyl), 0.86 (t, J = 6.6, 3H, CH3).
13C-NMR (125 MHz, CDCl3, 20 °C): δ = 196.7, 157.9, 146.2, 142.3, 140.5, 138.5, 136.1, 134.8, 121.3,
~
120.6, 58.5, 34.5, 31.4, 30.9, 22.5, 18.6, 15.3, 14.1. IR (solid):  = 2994, 2927, 2869, 1650, 1467,
1279, 1224, 1020, 1005, 922, 871, 781, 738, 699. MS (ESI) m/z: 312.2 (34%, [M]+), 205.1 (100%,
[M]+−[Py]), 108.1 (52%, [PyH]+). HRMS (ESI) m/z: Anal. Calcd. for [[C20H26NO2]+]: 312.1958,
found: 312.1962.
1-(3-Formyl-2-hydroxy-5-pentylbenzyl)-quinolinium bromide (12bE) was prepared according to GP3
using 11b (1 eq., 1.0 mmol, 285.2 mg) and quinoline (1.1 eq., 1.1 mmol, 142.1 mg, 129 µL). The
product was formed as a white solid (0.47 mmol, 194.0 mg, 47%). C22H24BrNO2, MW: 414.34 g/mol.
1
M.p.: 215.1–216.4 °C. H-NMR (300 MHz, DMSO, 20 °C): δ = 11.20 (s, 1H, Ar-OH), 10.04 (s, 1H,
Ar-CHO), 9.68 (d, J = 5.8, 1H, quinoline-H), 9.37 (d, J = 8.3, 1H, quinoline-H), 8.58–8.50 (m, 2H,
quinoline-H), 8.29–8.19 (m, 2H, quinoline-H), 8.03 (t, J = 7.6, 1H, quinoline-H), 7.65 (d, J = 1.8, 1H,
Ar-H), 7.57 (d, J = 1.8, 1H, Ar-H), 6.32 (s, 2H, Ar-CH2-quinoline), 2.52 (m, 2H, Ar-CH2-C4H9), 1.50
(m, 2H, (CH2)pentyl), 1.20 (m, 4H, (CH2)pentyl), 0.80 (t, J = 6.9, 3H, CH3). 13C-NMR (125 MHz, DMSO,
20 °C): δ = 196.2, 156.3, 150.7, 148.1, 137.6, 137.0, 135.7, 134.3, 133.1, 130.9, 129.9, 129.7, 122.1,
~
121.7, 121.3, 118.9, 55.7, 33.6, 30.5, 30.3, 21.8, 13.9. IR (solid):  = 3024, 2924, 2852, 1644, 1620,
1527, 1449, 1370, 1278, 1224, 1158, 1012, 821, 785, 709. MS (EI) m/z: 334.2 (32%, [M]+), 205.1
(100%, [M]+−[quinoline]). HRMS (ESI) m/z: Anal. Calcd. for [[C22H24NO2]+]: 334.1802, found:
334.1796.
4-Dimethylamino-1-(3-formyl-2-hydroxy-5-pentylbenzyl)-pyridinium bromide (12bF) was prepared
according to GP3 using 11b (1 eq., 1.0 mmol, 285.2 mg) and 4-dimethylaminopyridine (1.1 eq., 1.1 mmol,
134.4 mg). The product was formed as a beige-colored solid (0.81 mmol, 330.2 mg, 81%).
1
C20H27BrN2O2, MW: 407.34 g/mol. M.p.: 187.6–188.9 °C. H-NMR (300 MHz, CDCl3, 20 °C):
δ = 11.29 (b, 1H, Ar-OH), 9.85 (s, 1H, Ar-CHO), 8.68 (d, J = 7.8, 2H, o-Py-H), 8.08 (d, J = 2.2, 1H,
Ar-H), 7.38 (d, J = 2.2, 1H, Ar-H), 6.88 (d, J = 7.8, 2H, m-Py-H), 5.65 (s, 2H, Ar-CH2-Py), 3.22 (s,
6H, Py-CH3), 2.61 (t, J = 7.8, 2H, Ar-CH2-C4H9), 1.60 (m, 2H, (CH2)pentyl), 1.29 (m, 4H, (CH2)pentyl),
13
0.86 (t, J = 6.8, 3H, CH3). C-NMR (75 MHz, CDCl3, 20 °C): δ = 196.6, 157.8, 156.2, 143.0, 139.7,
~
135.7, 134.2, 122.4, 120.5, 107.8, 55.3, 40.4, 34.5, 31.4, 31.0, 22.5, 14.1. IR (solid):  = 3065, 2955,
2927, 2855, 1640, 1562, 1443, 1402, 1384, 1261, 1164, 1013, 943, 838, 820, 770, 715, 702. MS (EI)
m/z: 327.2 (68%, [M]+), 205.1 (70%, [M]+−[Py]), 123.1 (100%, [PyH]+). HRMS (ESI) m/z: Anal.
Calcd. for [[C20H27N2O2]+]: 327.2067, found: 327.2069.
1-(3-Formyl-2-hydroxy-5-pentylbenzyl)-4-iodopyridinium bromide (12bG) was prepared according to
GP3 using 11b (1 eq., 1.0 mmol, 285.2 mg) and 4-iodopyridine (1.1 eq., 1.1 mmol, 225.5 mg). The

Molecules 2012, 17
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product was formed as a green solid (0.68 mmol, 332.7 mg, 65%). C18H21BrINO2, MW: 490.17 g/mol.
M.p.: 182.5–183.3 °C (decomposition). 1H-NMR (300 MHz, CDCl3, 20 °C): δ = 11.34 (s, 1H, Ar-OH),
9.86 (s, 1H, Ar-CHO), 9.21 (d, J = 6.7, 2H, o-Py-H), 8.35 (d, J = 2.0, 1H, Ar-H), 8.30 (d, J = 6.8, 2H,
m-Py-H), 7.47 (d, J = 2.1, 1H, Ar-H), 6.22 (s, 2H, Ar-CH2-Py), 2.66 (t, J = 7.7, 2H, Ar-CH2-C4H9),
1.69–1.58 (m, 2H, (CH2)pentyl), 1.38–1.28 (m, 4H, (CH2)pentyl), 0.89 (t, J = 6.8, 3H, CH3). 13C-NMR
(125 MHz, CDCl3, 20 °C): δ = 196.0, 156.7, 144.1, 138.3, 137.1, 134.2, 133.4, 121.8, 121.5, 120.9,
~
58.5, 33.6, 30.7, 30.2, 21.8, 13.8. IR (solid):  = 3012, 2959, 2928, 2856, 1645, 1615, 1448, 1275,
1261, 1223, 1153, 1017, 837, 807, 703. MS (ESI) m/z: 410.1 (9%, [M]+), 205.1 (100%, [M]+−[Py]).
HRMS (ESI) m/z: Anal. Calcd. for [[C18H21INO2]+]: 410.0611, found: 410.0609.
4-Chloro-1-(3-formyl-2-hydroxy-5-pentylbenzyl)-pyridinium bromide (12bH) was prepared according
to GP3 using 11b (1 eq., 1.0 mmol, 285.2 mg) and 4-chloropyridine (1.1 eq., 1.1 mmol, 187.3 mg, 156 µL).
The product was formed as a beige-colored solid (0.67 mmol, 267.2 mg, 29%). C18H21BrClNO2, MW:
1
398.72 g/mol. M.p.: 131.6–133.2 °C. H-NMR (500 MHz, CDCl3, 20 °C): δ = 11.35 (s, 1H, Ar-OH),
9.84 (s, 1H, Ar-CHO), 9.59 (d, J = 6.8, 2H, o-Py-H), 8.29 (m, 1H, Ar-H), 7.94 (d, J = 6.8, 2H, m-Py-H),
7.44 (m, 1H, Ar-H), 6.31 (s, 2H, Ar-CH2-Py), 2.63 (t, J = 7.8, 2H, Ar-CH2-C4H9), 1.60 (m, 2H,
(CH2)pentyl), 1.30 (m, 4H, (CH2)pentyl), 0.86 (t, J = 6.6, 3H, CH3). 13C-NMR (125 MHz, CDCl3, 20 °C):
δ = 196.5, 157.9, 154.0, 146.6, 139.9, 136.1, 135.0, 128.1, 121.0, 120.6, 59.0, 34.5, 31.4, 31.0, 22.5,
~
14.1. IR (solid):  = 3021, 2952, 2925, 2857, 1650, 1622, 1493, 1456, 1275, 1224, 1212, 1108, 1020,
845, 821, 713, 697. MS (EI) m/z: 318.1 (100%, [M]+), 205.1 (54%, [M]+−[Py]). HRMS (ESI) m/z:
Anal. Calcd. for [[C18H21ClNO2]+]: 318.1255, found: 318.1255.
4-Cyano-1-(3-formyl-2-hydroxy-5-pentylbenzyl)-pyridinium bromide (12bI) was prepared according to
GP3 using 11b (1 eq., 1.0 mmol, 285.2 mg) and 4-cyanopyridine (1.1 eq., 1.1 mmol, 114.5 mg). The
product was formed as a yellow solid (0.80 mmol, 312.5 mg, 80%). C19H21BrN2O2, MW: 389.29 g/mol.
1
M.p.: 131.6–133.2 °C. H-NMR (300 MHz, CDCl3, 20 °C): δ = 11.43 (s, 1H, Ar-OH), 9.88–9.85 (m,
3H, Ar-CHO and o-Py-H), 8.30 (m, 1H, Ar-H), 8.23 (d, J = 6.5, 2H, m-Py-H), 7.49 (m, 1H, Ar-H),
6.46 (s, 2H, Ar-CH2-Py), 2.66 (t, J = 7.8, 2H, Ar-CH2-C4H9), 1.63 (m, 2H, (CH2)pentyl), 1.33 (m, 4H,
13
(CH2)pentyl), 0.89 (t, J = 6.8, 3H, CH3). C-NMR (125 MHz, CDCl3, 20 °C): δ = 196.5, 157.9, 147.3,
139.9, 136.2, 135.3, 130.1, 128.1, 120.7, 120.4, 113.7, 60.8, 34.5, 31.4, 31.0, 22.5, 14.1. IR (solid):
~
 = 3112, 2960, 2928, 2849, 1654, 1635, 1603, 1456, 1274, 1189, 1142, 1010, 830, 716, 557. MS (EI)
m/z: 309.2 (11%, [M]+), 205.1 (100%, [M]+−[Py]). HRMS (ESI) m/z: Anal. Calcd. for
[[C19H21N2O2]+]: 309.1598, found: 309.1606.
3.5. General Procedure for the Synthesis of 14 (GP4)
This procedure is according to a published protocol [54]. To a solution of (1R,2R)-(−)-1,2-
diaminocyclohexane (1 eq., 0.15 mmol, 17.1 mg) in ethanol (0.7 mL) at ambient temperature
molecular sieves (4 Å) and the corresponding salt 12 (2 eq., 0.30 mmol) were added. The mixture was
stirred for 15 h at ambient temperature. For workup the mixture was filtered and washed with ethanol.
The solvent was removed in vacuo till a volume of 5 mL was reached and the ligand was precipitated
with diethyl ether (30 mL). The solid product was then dried in vacuo.

Molecules 2012, 17
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(R,R)-(−)-N,N'-Bis(3-tert-butyl-5-(pyridinium-1-ylmethyl)salicylidene)-1,2-cyclohexanediamine dibromide
(14aA) was prepared according to GP4 using 12aA (2 eq., 1.06 mmol, 371.3 mg) and (1R,2R)-(−)-1,2-
diaminocyclohexane (1 eq., 0.53 mmol, 60.5 mg). The product was formed as an orange solid (0.53 mmol,
438.0 mg, 100%). C40H50Br2N4O2, MW: 778.66 g/mol. 1H-NMR (300 MHz, CD2Cl2, 20 °C): δ = 14.16
(b, 2H, Ar-OH), 9.55 (d, J = 5.5, 4H, o-Py-H), 8.46 (t, J = 7.8, 2H, p-Py-H), 8.38 (s, 2H, Ar-CH=N-Cy),
8.22 (d, J = 2.5, 2H, Ar-H), 7.99 (m, 4H, m-Py-H), 7.32 (d, J = 2.5, 2H, Ar-H), 6.13 (m, 4H, Ar-CH2-Py),
3.43 (d, J = 9.5, 2H, Cy-HN=CHR)), 1.90 (m, 4H, Cy-H2), 1.67 (m, 2H, Cy-H2), 1.47 (m, 2H, Cy-H2),
1.27 (s, 18H, C(CH3)3). The analytical data are in agreement with the literature [54].
(R,R)-(−)-N,N'-Bis(3-pentyl-5-(pyridinium-1-ylmethyl)salicylidene)-1,2-cyclohexanediamine dibromide
(14bA) was prepared according to GP4 using 12bA (2 eq., 0.90 mmol, 328.0 mg) and (1R,2R)-(−)-1,2-
diaminocyclohexane (1 eq., 0.45 mmol, 51.4 mg). The product was formed as an orange solid (0.41 mmol,
329.3 mg, 91%). C42H54Br2N4O2, MW: 806.71 g/mol. M.p.: 128.4–129.6 °C. []20 C (c = 10 mg/mL,
D
1
CH2Cl2) = −273.0. H-NMR (300 MHz, CD2Cl2, 20 °C): δ = 14.13 (b, 2H, Ar-OH), 9.44 (d, J = 9.7,
4H, o-Py-H), 8.41 (tt, J = 7.9, 1.4, 2H, p-Py-H), 8.32 (s, 2H, Ar-CH=N-Cy), 7.94 (t, J = 7.2, 4H, m-Py-H),
7.81 (d, J = 2.2, 2H, Ar-H), 7.13 (d, J = 1.9, 2H, Ar-H), 6.09 (m, 4H, Ar-CH2-Py), 3.41 (m, 2H,
Cy-HN=CHR)), 2.51 (m, 4H, Ar-CH2-C4H9), 1.98–1.85 (m, 4H, Cy-H2), 1.72–1.43 (m, 10H, Cy-H2
13
und (CH2)pentyl), 1.33–1.25 (m, 8H, (CH2)pentyl), 0.86 (t, J = 6.7, 6H, (CH3)pentyl). C-NMR (125 MHz,
CD2Cl2, 21 °C): δ = 164.8 (2C, CAr-CH=N), 159.4 (2C, CAr-OH), 145.6 (2C, α -CPy), 145.6 (2C,
α-CPy), 145.4 (2C, γ -CPy), 135.5 (2C, CAr-C5H11), 134.0 (2C, CAr), 133.5 (2C, CAr), 128.2 (4C, β-CPy),
120.8 (2C, CAr-CH2-NPy), 118.9 (2C, CAr-CHN), 71.7 (2C, CCyHN), 60.4 (2C, Ar-CH2-Py), 35.0 (2C,
CAr-CH2-C4H9), 33.2 (2C, CCyH2), 31.8 (2C, (CH2)Pentyl), 31.6 (2C, (CH2)Pentyl), 24.5 (2C, CCyH2), 22.9
~
(2C, (CH2)Pentyl), 14.2 (2C, CH3). IR (solid):  = 3396, 2925, 2854, 2561, 2374, 2186, 1967, 1627,
1472, 683. HRMS (ESI) m/z: Anal. Calcd. for [[C42H54BrN4O2]+]: 725.3413, found 725.3422.
(R,R)-(−)-N,N'-Bis(3-methyl-5-(pyridinium-1-ylmethyl)salicylidene)-1,2-cyclohexanediamine dibromide
(14cA) was prepared according to GP4 using 12cA (2 eq., 6.5 mmol, 2.0 g) and (1R,2R)-(−)-1,2-
diaminocyclohexane (1 eq., 3.2 mmol, 370 mg). The product was formed as a slightly yellow solid
(2.7 mmol, 1.89 g, 84%). C34H38Br2N4O2, MW: 694.50 g/mol. M.p.: Decomp. at T > 200 °C. []20 C
D
1
(c = 10 mg/mL, CH2Cl2) = −296.0. H-NMR (300 MHz, CD2Cl2, 20 °C): δ = 14.09 (b, 1H, Ar-OH),
9.48 (d, J = 9.7, 4H, o-Py-H), 8.42 (tt, J = 7.9, J = 1.4, 2H, p-Py-H), 8.31 (s, 2H, Ar-CH=N-Cy), 7.96 (t,
J = 7.2, 4H, m-Py-H), 7.84 (d, J = 2.2, 2H, Ar-H), 7.12 (d, J = 1.9, 2H, Ar-H), 6.08 (q, J = 13.7,
13
Ar-CH2-Py), 3.42 (m, 2H, CCyHN=CHR), 2.26 (s, 6H, CH3), 1.98–1.48 (m, 8H, (CH2)Cy). C-NMR
(75 MHz, CDCL3, 21 °C): 164.8 (2C, CHN), 159.2 (2C, CAr-OH), 145.6 (2C, γ-CPy), 145.6 (2C, α-Py-C),
145.5 (2C, α-Py-C), 136.1 (2C, CAr), 134.1 (2C, CAr-Me), 128.6 (2C, CAr), 128.3 (4C, β-Py-C), 120.9
(2C, CAr-CH2-Py), 118.9 (2C, CAr-CHN), 71.8 (2C, CCyHN), 60.1 (2C, Ar-CH2-Py), 33.1 (2C, CCyH2),
~
24.5(2C, CCyH2), 20.4 (2C, CH3). IR (solid):  = 3381, 3123, 3044, 2928, 2857, 2054, 1627, 1476.
MS (ESI) m/z: 613.2 (20%, M+), 597.1 (60%, M+–OH), 518.0 (100%, M+–Br), 454.2 (90%,
M+–pyridine). HRMS (ESI) m/z: Anal. Calcd. for [[C34H38BrN4O2]+]: 613.2173, found: 613.2182.
(R,R)-(−)-N,N'-Bis(3-tert-butyl-5-(4-methylpyridinium-1-ylmethyl)salicylidene)-1,2-cyclohexane-diamine
dibromide (14aB) was prepared according to GP4 using 12aB (2 eq., 0.30 mmol, 109.3 mg) and

Molecules 2012, 17
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(1R,2R)-(−)-1,2-diaminocyclohexane (1 eq., 0.15 mmol, 17.1 mg). The product was formed as a
yellow solid (0.13 mmol, 107.3 mg, 89%). C42H54Br2N4O2, MW: 806.71 g/mol. M.p.: 198.2–200.3 °C
1
(decomposition). []2D0 C (c = 6.4 mg/mL, CH2Cl2) = −286.1. H-NMR (500 MHz, CDCl3, 20 °C):
δ =14.00 (b, 2H, Ar-OH), 9.31 (d, J = 6.4, 4H, o-Py-H), 8.37 (s, 2H, Ar-CH=N-Cy), 8.08 (d, J = 3.3,
2H, Ar-H), 7.78 (d, J = 6.3, 4H, m-Py-H), 7.28 (d, J = 2.3, 2H, Ar-H), 6.07–5.94 (m, 4H, Ar-CH2-Py),
3.42 (m, 2H, Cy-HN=CHR)), 2.59 (s, 6H, Py-CH3), 1.94–1.84 (m, 4H, Cy-H2), 1.67 (m, 2H, Cy-H2),
13
1.46 (m, 2H, Cy-H2), 1.25 (s, 18H, C(CH3)3). C-NMR (125 MHz, CDCl3, 20 °C): δ = 164.7, 158.9,
158.7, 144.4, 142.1, 132.7, 130.2, 128.4, 120.5, 118.0, 71.4, 59.4, 34.3, 33.1, 31.5, 24.1, 22.3. IR
~
(solid):  = 3387, 2946, 2862, 1628, 1469, 1280, 1224, 1149, 1019, 824, 787. MS (ESI) m/z: 725.3
(1%, [M]+−[Br]), 552.4 (7%, [M]+−[Py]), 459.3 (100%, [M]+−2×[Py]), 323.2 (1%, [M]2+), 276.7 (93%,
[M]2+−[Py]). HRMS (ESI) m/z: Anal. Calcd. for [[C42H54N4O2]2+]: 323.2118, found: 323.2097.
(R,R)-(−)-N,N'-Bis(3-pentyl-5-(4-methylpyridinium-1-ylmethyl)salicylidene)-1,2-cyclohexanediamine
dibromide (14bB) was prepared according to GP4 using 12bB (2 eq., 0.30 mmol, 113.5 mg) and
(1R,2R)-(−)-1,2-diaminocyclohexane (1 eq., 0.15 mmol, 17.1 mg). The product was formed as a beige-
colored solid (0.14 mmol, 116.9 mg, 93%). C44H58Br2N4O2, MW: 834.76 g/mol. M.p.: 143.7–146.8 °C.
1
[]2D0 C (c = 9.5 mg/mL, CH2Cl2) = −289.1. H-NMR (300 MHz, CDCl3, 20 °C): δ = 13.97 (b, 2H,
Ar-OH), 9.26 (d, J = 6.7, 4H, o-Py-H), 8.33 (s, 2H, Ar-CH=N-Cy), 7.78 (m, 2H, Ar-H), 7.76 (m, 4H,
m-Py-H), 7.11 (m, 2H, Ar-H), 6.08–5.91 (m, 4H, Ar-CH2-Py), 3.41 (m, 2H, Cy-HN=CHR)), 2.59 (s,
6H, Py-CH3), 2.48 (t, J = 7.8, 4H, Ar-CH2C4H9), 1.93–1.84 (m, 4H, Cy-H2), 1.71–1.62 (m, 2H, Cy-H2),
1.55–1.43 (m, 6H, (CH2)pentyl und Cy-H2), 1.29–1.19 (m, 8H, (CH2)pentyl), 0.81 (t, J = 6.8, 6H,
13
C4H9CH3). C-NMR (125 MHz, CDCl3, 20 °C): δ =164.4, 159.0, 158.7, 144.3, 135.0, 133.6, 133.1,
~
128.4, 120.6, 118.4, 71.4, 59.2, 34.6, 33.0, 31.5, 31.3, 24.1, 22.5, 22.3, 14.1. IR (solid):  = 3380,
2926, 2855, 1629, 1468, 1276, 1152, 1028, 829, 787. MS (ESI) m/z: 487.3 (5%, [M]+−2×[Py]), 337.2
(1%, [M]2+), 290.7 (100%, [M]2+−[Py]), 244.2 (8%, [M]2+−2×[Py]). HRMS (ESI) m/z: Anal. Calcd. for
[[C44H58N4O2]2+]: 337.2274, found: 337.2298.
(R,R)-(−)-N,N'-Bis(3-pentyl-5-(4-tert-butylpyridinium-1-ylmethyl)salicylidene)-1,2-cyclohexane-diamine
dibromide (14bC) was prepared according to GP4 using 12bC (2 eq., 0.30 mmol, 126.1 mg) and
(1R,2R)-(−)-1,2-diaminocyclohexane (1 eq., 0.15 mmol, 17.1 mg). The product was formed as a beige-
colored solid (0.12 mmol, 113.1 mg, 82%). C50H70Br2N4O2, MW: 918.92 g/mol. M.p.: 154.7–157.3 °C.
1
[]2D0 C (c = 10.2 mg/mL, CH2Cl2) = −289.1. H-NMR (300 MHz, CDCl3, 20 °C): δ = 13.97 (b, 2H,
Ar-OH), 9.44 (d, J = 6.7, 4H, o-Py-H), 8.34 (s, 2H, Ar-CH=N-Cy), 7.89 (d, J = 6.8, 4H, m-Py-H), 7.84
(m, 2H, Ar-H), 7.11 (m, 2H, Ar-H), 6.13–5.95 (m, 4H, Ar-CH2-Py), 3.42 (m, 2H, Cy-HN=CHR)), 2.48
(t, J = 7.8, 4H, Ar-CH2C4H9), 1.92–1.85 (m, 4H, Cy-H2), 1.72–1.61 (m, 2H, Cy-H2), 1.55–1.44 (m, 6H,
(CH2)pentyl and Cy-H2), 1.34 (s, 18H, Py-C(CH3)3), 1.29–1.19 (m, 8H, (CH2)pentyl), 0.81 (t, J = 6.8, 6H,
13
C4H9CH3). C-NMR (125 MHz, CDCl3, 20 °C): δ = 170.6, 164.5, 158.9, 144.7, 135.2, 133.7, 133.1,
~
124.9, 120.7, 118.4, 71.5, 58.8, 36.5, 34.6, 33.1, 31.5, 31.3, 30.5, 30.0, 24.0, 22.5, 14.1. IR (solid):  =
3380, 2927, 2857, 1630, 1459, 1275, 1167, 1109, 1025, 850, 815. MS (ESI) m/z: 379.3 (27%, [M]2+),
311.7 (100%, [M]2+−[Py]). HRMS (ESI) m/z: Anal. Calcd. for [[C50H70N4O2]2+]: 379.2744, found:
379.2770.

Molecules 2012, 17
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(R,R)-(−)-N,N'-Bis(3-pentyl-5-(3,5-dimethylpyridinium-1-ylmethyl)salicylidene)-1,2-cyclohexane-diamine
dibromide (14bD) was prepared according to GP4 using 12bD (2 eq., 0.30 mmol, 117.8 mg) and
(1R,2R)-(−)-1,2-diaminocyclohexane (1 eq., 0.15 mmol, 17.1 mg). The product was formed as a
yellow solid (0.14 mmol, 117.9 mg, 91%). C46H62Br2N4O2, MW: 862.82 g/mol. M.p.: 139.3–141.2 °C.
1
[]2D0 C (c = 10.7 mg/mL, CH2Cl2) = −271.0. H-NMR (300 MHz, CDCl3, 20 °C): δ = 13.91 (b, 2H,
Ar-OH), 9.13 (m, 4H, o-Py-H), 8.33 (s, 2H, Ar-CH=N-Cy), 7.92 (m, 2H, p-Py-H), 7.80 (d, J = 2.0, 2H,
Ar-H), 7.08 (d, J = 2.0, 2H, Ar-H), 6.06–5.91 (m, 4H, Ar-CH2-Py), 3.43 (m, 2H, Cy-HN=CHR)),
2.54–2.47 (m, 16H, Ar-CH2C4H9 and Py-CH3), 1.93–1.85 (m, 4H, Cy-H2), 1.73–1.60 (m, 2H, Cy-H2),
1.55–1.43 (m, 6H, (CH2)pentyl und Cy-H2), 1.29–1.20 (m, 8H, (CH2)pentyl), 0.82 (t, J = 6.8, 6H,
13
C4H9CH3). C-NMR (125 MHz, CDCl3, 20 °C): δ = 164.5, 158.8, 146.0, 142.0, 138.3, 135.4, 133.7,
~
133.0, 120.6, 118.4, 71.6, 59.4, 34.6, 33.2, 31.5, 31.2, 24.1, 22.5, 18.7, 14.1. IR (solid):  = 3386,
2924, 2855, 1627, 1468, 1277, 1171, 1030, 863, 783, 700. MS (ESI) m/z: 487.3 (52%, [M]+−2 × [Py]),
351.2 (34%, [M]2+), 595.4 (100%, [M]2+−[Py]). HRMS (ESI) m/z: Anal. Calcd. for [[C46H62N4O2]2+]:
351.2431, found: 351.2424.
(R,R)-(−)-N,N'-Bis(3-pentyl-5-(quinolinium-1-ylmethyl)salicylidene)-1,2-cyclohexanediamine dibromide
(14bE) was prepared according to GP4 using 12bE (2 eq., 0.30 mmol, 124.3 mg) and (1R,2R)-(−)-1,2-
diaminocyclohexane (1 eq., 0.15 mmol, 17.1 mg). The product was formed as an orange solid (0.14 mmol,
127.9 mg, 94%). C50H58Br2N4O2, MW: 906.83 g/mol. M.p.: 146.2–147.8 °C. []20 C (c = 10.4 mg/mL,
D
1
CH2Cl2) = −193.3. H-NMR (300 MHz, CDCl3, 20 °C): δ = 14.15 (b, 2H, Ar-OH), 10.32 (d, J = 5.5,
2H, quinoline-H), 9.17 (d, J = 8.3, 2H, quinoline-H), 8.59 (d, J = 8.9, 2H, quinoline-H), 8.39 (s, 2H,
Ar-CH=N-Cy), 8.23 (d, J = 7.8, 2H, quinoline-H), 8.08 (m, 2H, quinoline-H), 7.83 (m, 2H, quinoline-
H), 7.73 (m, 2H, quinoline-H), 7.43 (m, 2H, Ar-H), 7.11 (m, 2H, Ar-H), 6.48–6.36 (m, 4H, Ar-CH2-
quinolinium), 3.47 (m, 2H, Cy-HN=CHR)), 2.59 (s, 6H, Py-CH3), 2.44 (t, J = 7.8, 4H, Ar-CH2C4H9),
1.96–1.84 (m, 4H, Cy-H2), 1.73–1.61 (m, 2H, Cy-H2), 1.54–1.38 (m, 6H, (CH2)pentyl and Cy-H2),
13
1.28–1.12 (m, 8H, (CH2)pentyl), 0.77 (t, J = 6.8, 6H, C4H9CH3). C-NMR (125 MHz, CDCl3, 20 °C):
δ = 164.5, 158.6, 150.8, 147.6, 137.9, 135.7, 133.7, 133.3, 132.9, 130.9, 129.9, 122.0, 119.5, 119.0,
~
118.5, 71.1, 56.6, 34.6, 32.9, 31.3, 31.2, 24.1, 22.4, 14.1. IR (solid):  = 3385, 2924, 2854, 1626, 1593,
1526, 1465, 1373, 1230, 1020, 769. MS (ESI) m/z: 616.4 (10%, [M]+−[quinoline]), 487.3 (80%,
[M]+−2×[quinoline]), 373.2 (14%, [M]2+), 308.7 (100%, [M]2+−[quinoline]). HRMS (ESI) m/z: Anal.
Calcd. for [[C50H58N4O2]2+]: 373.2274, found: 373.2284.
(R,R)-(−)-N,N'-Bis(3-pentyl-5-(4-(dimethylamino)pyridinium-1-ylmethyl)salicylidene)-1,2-cyclo-
hexanediamine dibromide (14bF) was prepared according to GP4 using 12bF (2 eq., 0.30 mmol,
122.2 mg) and (1R,2R)-(−)-1,2-diaminocyclohexane (1 eq., 0.15 mmol, 17.1 mg). The product was
formed as a yellow solid (0.14 mmol, 123.1 mg, 92%). C46H64Br2N6O2, MW: 892.85 g/mol. M.p.:
1
145.9–147.1 °C. []2D0 C (c = 10.2 mg/mL, CH2Cl2) = −269.1. H-NMR (300 MHz, CDCl3, 20 °C):
δ = 13.91 (b, 2H, Ar-OH), 8.51 (d, J = 7.7, 4H, o-Py-H), 8.35 (s, 2H, Ar-CH=N-Cy), 7.73 (d, J = 1.9,
2H, Ar-H), 7.09 (d, J = 2.0, 2H, Ar-H), 6.89 (d, J = 7.8, 4H, m-Py-H), 5.50–5.37 (m, 4H, Ar-CH2-Py),
3.42 (m, 2H, Cy-HN=CHR)), 3.21 (s, 12H, Py-N(CH3)2), 2.47 (t, J = 7.8, 4H, Ar-CH2C4H9), 1.96–1.86
(m, 4H, Cy-H2), 1.74–1.59 (m, 2H, Cy-H2), 1.54–1.45 (m, 6H, (CH2)pentyl and Cy-H2), 1.33–1.20 (m,
8H, (CH2)pentyl), 0.82 (t, J = 6.7, 6H, C4H9CH3). 13C-NMR (125 MHz, CDCl3, 20 °C): δ = 164.5, 158.4,

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156.2, 142.6, 134.4, 133.4, 132.5, 121.5, 118.5, 108.0, 71.5, 56.0, 40.6, 34.7, 33.0, 31.5, 31.3, 24.1,
~
22.5, 14.1. IR (solid):  = 3378, 2924, 2855, 1643, 1563, 1443, 1400, 1226, 1160, 1027, 823, 775. MS
(ESI) m/z: 487.3 (38%, [M]+−2×[Py]), 366.3 (26%, [M]2+), 305.2 (100%, [M]2+−[Py]). HRMS (ESI)
m/z: Anal. Calcd. for [[C46H64N6O2]2+]: 366.2540, found: 366.2536.
(R,R)-(−)-N,N'-Bis(3-pentyl-5-(4-iodopyridinium-1-ylmethyl)salicylidene)-1,2-cyclohexanediamine
dibromide (14bG) was prepared according to GP4 using 12bG (2 eq., 0.30 mmol, 147.1 mg) and
(1R,2R)-(−)-1,2-diaminocyclohexane (1 eq., 0.15 mmol, 17.1 mg). The product was formed as a brown
solid (0.14 mmol, 142.4 mg, 77%). C42H52Br2I2N4O2, MW: 1058.50 g/mol. M.p.: 221.2–223.7 °C
1
(decomposition). []2D0 C (c = 9.6 mg/mL, DMSO) = −242.8. H-NMR (300 MHz, DMSO, 20 °C):
δ = 14.19 (b, 2H, Ar-OH), 8.73 (d, J = 6.4, 4H, o-Py-H), 8.54 (d, J = 6.5, 4H, m-Py-H), 8.48 (s, 2H,
Ar-CH=NCy), 7.47 (b, 2H, Ar-H), 7.20 (b, 2H, Ar-H), 5.69–5.60 (m, 4H, Ar-CH2-Py), 3.49 (m, 2H,
Cy-HN=CHR)), 2.46 (m, 4H, Py-CH2C4H9), 1.93–1.86 (m, 4H, Cy-H2), 1.81–1.74 (m, 4H, (CH2)pentyl),
1.63–1.40 (m, 4H, Cy-H2), 1.33–1.19 (m, 8H, (CH2)pentyl), 0.84 (t, 6H, C4H8CH3). 13C-NMR (125
MHz, DMSO, 20 °C): δ = 165.4, 159.7, 144.0, 137.0, 134.7, 132.8, 132.7, 131.5, 121.1, 118.4, 117.4,
~
69.4, 58.9, 33.8, 32.2, 30.7, 30.4, 23.5, 21.8, 13.8. IR (solid):  = 3396, 2923, 2852, 1615, 1441, 1160,
1026, 806. MS (ESI) m/z: 977.1 (1%, [M]+−[Br]), 4.87.3 (31%, [M]+−2×[Py]), 346.6 (100%,
[M]2+−[Py]). HRMS (ESI) m/z: Anal. Calcd. for [[C42H52I2N4O2]2+]: 449.1084, found: 449.1105.
3.6. General Procedure for the Catalytic Asymmetric Synthesis of 3 (GP5)
To a solution of the salen ligand 14 (0.1 eq., 75 µmol) in CH2Cl2 (3 mL) a solution of Me3Al in
toluene (2 M, 0.1 eq., 75 µmol, 38 µL) was added and the mixture was stirred for 3 h at ambient
temperature. Afterwards aldehyde 1 (1 eq., 0.75 mmol), acylbromide 2 (6 eq., 4.5 mmol) and
diisopropylethylamine (2.5 eq., 1.88 mmol) were added at −70 °C and the reaction mixture was stirred
for 24 h at this temperature. The reaction was quenched by pouring into aqueous 1 M HCl (30 mL) and
the product was extracted with CH2Cl2 (2 × 20 mL). The combined organic layers were dried over
MgSO4 and filtered through a pad of silica gel. After removing the solvent in vacuo the desired trans-
β-lactone 3 was obtained.
(3S,4S)-trans-3-Methyl-4-(2-phenylethyl)-oxetan-2-one (3Aa, 0.45 mmol, yield: 60%, ee = 90%, dr = 97:3)
was prepared from propionyl bromide (1A) and 3-phenylpropionaldehyde (2a) according to GP5. The
1
dr value was determined by H-NMR and the ee value by HPLC (Chiralcel OD-H, 97:3 n-hexane/
iPrOH, 1.0 mL/min, 210 nm). An analytically pure sample was obtained as a colorless oil by flash
1
chromatography (pentane/diethyl ether 20:1). C12H14O2, MW: 190.24 g/mol. H-NMR (300 MHz,
CDCl3, 20 °C): δ = 7.34–7.17 (m, 5H, Ar-H), 4.16 (ddd, J = 7.5, 5.9, 4.0, 1H, CH-O), 3.20 (qd, J = 7.5,
4.0, 1H, CH-C(O)), 2.77 (m, 2H, CH2-CH2-Ph), 2.13 (m, 2H, CH2-CH2-Ph), 1.32 (d, J = 7.5, 3H, CH3).
The analytical data are in agreement with the literature [54].
(3S,4S)-trans-3-Methyl-4-ethyloxetan-2-one (3Ab, 0.44 mmol, yield: 59%, ee = 90%, dr = 98:2) was
prepared from propionyl bromide (1A) and propanal (2b) according to GP5. The dr value was
1
determined by H-NMR and the ee value by GC (Fisons Instruments HRGC Mega 2, Bondex-UN-β-
column 20 m × 0.30 mm, 0.5 bar H2, method: 40 °C hold 5 min, ramp @ 2.5 °C/min till 100 °C, ramp

Molecules 2012, 17
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@ 10.0 °C/min till 200 °C). An analytically pure sample was obtained as a colorless oil by flash
1
chromatography (pentane/diethyl ether 20:1). C6H10O2, MW: 114.14 g/mol. H-NMR (300 MHz,
CDCl3, 20 °C): δ = 4.13 (td, J = 6.6, 4.0, 1H, CH-O), 3.23 (qd, J = 7.5, 4.0, 1H, CH-C(O)), 1.97–1.72
(m, 2H, CH3-CH2-CH-O), 1.39 (d, J = 7.5, 3H, CH-CH3), 1.02 (t, J = 7.5, 3H, CH2-CH3). The
analytical data are in agreement with the literature [54].
(3S,4S)-trans-3-Propyl-4-(2-phenylethyl)-oxetan-2-one (3Ba, 0.44 mmol, yield: 59%, ee = 95%,
dr = 99:1) was prepared from valeroyl bromide (1B) and 3-phenylpropionaldehyde (2a) according to
1
GP5. The dr value was determined by H-NMR and the ee value by HPLC (Chiralcel OD-H, 97:3
n-hexane/iPrOH, 1.0 mL/min, 210 nm). An analytically pure sample was obtained as a colorless oil
by flash chromatography (CH2Cl2/pentane 3:1, then pentane/diethyl ether 40:1). C14H18O2, MW:
1
218.29 g/mol. H-NMR (300 MHz, CDCl3, 20 °C): δ =7.34–7.16 (m, 5H, Ar-H), 4.22 (ddd, J = 7.9,
5.0, 4.0, 1H, CH-O), 3.19 (ddd, J = 8.4, 6.9, 4.0, 1H, CH-C(O)), 2.75 (m, 2H, CH2-CH2-Ph), 2.11 (m,
2H, CH2-CH2-Ph), 1.70 (m, 2H, CH2-CH-C(O)), 1.41 (m, 2H, CH3-CH2-CH2), 0.92 (t, J = 7.3, 3H,
CH3). The analytical data are in agreement with the literature [54].
(3S,4R)-trans-3-Methyl-4-phenyloxetan-2-one (3Ac, 0,18 mmol, yield 37%, ee = 96%, dr = 98:2) was
prepared from propionyl bromide (1A) and benzaldehyde (2c) according to GP5, but using 0.49 mmol
of aldehyde in 2 mL of CH2Cl2 and basic workup conditions. The reaction mixture was quenched with
diisopropylethylamine (2 mL) and filtered through a short plug of Et3N-deactivated silica gel. CH2Cl2
was subsequently removed in vacuo. The crude mixture was purified by flash chromatography
(Et3N-deactivated silica gel, ethyl acetate/petroleum ether 1:10). The dr value was determined by
1H-NMR and the ee value by HPLC (Chiralcel OD-H, 99:1 n-hexane/iPrOH, 0.5 mL/min, 210 nm).
C10H10O2, MW: 162.18 g/mol. 1H-NMR (300 MHz, CDCl3, 20 °C): δ = 7.45–7.36 (m, 5H, Ar-H), 5.15
(d, J = 4.2, 1H, CH-O), 3.58 (qd, J = 7.5, 4.2, 1H, CH-C(O)), 1.53 (d, J = 7.5, 3H, CH3). The
analytical data are in agreement with the literature [54].
Preformation of the catalyst {[1,1'-[(1R,2R)-1,2-cyclohexandiylbis[imino-2N[5-pentyl-2-(hydroxy-
2O)-3,1-phenylen]methylen]bis[4-methyl-pyridinium]](2-)]-methylaluminum(III)}dibromide (4bB):
To a solution of ligand 14bB (0.13 g, 0.16 mmol, 1.0 equiv.) in CH2Cl2 (3.0 mL) a solution of Me3Al
in toluene (2 M, 0.10 mL, 0.16 mmol, 1.0 equiv.) was added. The mixture was stirred for 3 h at
ambient temperature. The reaction mixture was poured into 20 mL of pentane to precipitate complex
4bB. Subsequently the mixture was centrifuged and the supernatant removed. Washing the catalyst
with additional pentane (10 mL) and drying in vacuo afforded the active catalyst as orange powder in
1
quantitative yield. C45H59AlBr2N4O2, MW: 874.77 g/mol. H-NMR (500 MHz, CD2Cl2, 20 °C):
δ = 9.48 (m, 2H, o-Py-H), 9.42 (m, 2H, o-Py-H), 8.49 (m, 1H, Ar-CH=N-Cy), 8.15 (m, 1H,
Ar-CH=NCy), 7.78 (m, 1H, m-Py-H), 7.74–7.71 (m, 3H, m-Py-H), 7.53 (d, J = 5.5, 2H, Ar-H), 7.28
(m, 1H, Ar-H), 7.24 (m, 1H, Ar-H), 6.52 (d, J = 13.7, 1H, Ar-CH2-Py), 6.38 (d, J = 13.5, 1H,
Ar-CH2-Py), 5.98 (d, J = 13.7, 1H, Ar-CH2-Py), 5.86 (d, J = 13.5, 1H, Ar-CH2-Py), 3.63 (m, 1H,
Cy-HN=CHR), 3.15 (m, 1H, Cy-HN=CHR), 2.61–2.45 (m, 11H, Cy-H2 and (CH2)pentyl and Py-CH3),
2.34 (m, 1H, Cy-H2), 2.05 (m, 2H, Cy-H2), 1.66–1.58 (m, 4H), 1.52–1.45 (m, 4H), 1.39–1.26 (m, 8H,
(CH2)pentyl), 0.93–0.87 (m, 6H, (CH2)pentyl), −1.31 (s, 3H, Al-CH3). 13C-NMR (125 MHz, CD2Cl2, 20 °C):

Molecules 2012, 17
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δ = 168.8, 162.1, 161.3, 160.7, 158.7, 158.4, 144.6, 144.5, 138.5, 136.9, 135.5, 134.5, 131.9, 131.3,
127.9, 127.7, 124.9, 124.3, 119.2, 119.1, 66.2, 62.5, 60.6, 60.1, 34.4, 31.5, 31.4, 31.2, 31.2, 29.7, 26.9,
24.1, 23.7, 22.5, 22.3, 21.9, 13.9, 13.8. MS (ESI) m/z: 793.4 (100%, [M]+–Br) 700.3 (86%, [M]+–Py–Br).
HRMS (ESI) m/z: Anal. Calcd. for [[C45H59AlBrN4O2]+]: 793.3631, found: 793.3620.
4. Conclusions
In summary, we have reported a catalyst which offers the highest enantio- and trans-selectivity
known so far for the catalytic asymmetric synthesis of β-lactones by [2+2] cyclocondensation of acyl
halides and aldehydes. Catalysts for the asymmetric formation of trans-β-lactones are of major
interest, since trans-β-lactones offer a divergent and atom-economic access to the important class of
anti-aldol products. In our catalyst, an Al-center (offering a single coordination site) cooperates with a
picolinium bromide moiety based on our recently published strategy to combine the concepts of Lewis
acid and organic aprotic ion pair catalysis in a single catalyst system. Since cationic residues like
pyridinium units have been found to be essential for both high trans- and enantioselectivity
(suggesting that the positive charge enables an ion pair catalysis pathway), we have investigated the
question, if substituents on the pyridinium rings can be utilized to further improve the catalyst
efficiency, as they might display a significant impact on the effective charges. In the present study we
have thus compared a small library of aluminum-salen/bispyridinium catalysts, mainly differing in the
substituents on the pyridinium rings. NBO calculations have revealed though that the different catalyst
efficiencies can arguably not be explained by the variation of the effective charges, since there are only
very small differences for -donor or -acceptor substituted pyridinium systems. However, we have
noticed that the substituents have a major impact on the catalyst stability and presumably they have
also an impact on the reactive conformation of the proposed acyl halide enolate intermediates.
Acknowledgements
This work was financially supported by the Deutsche Forschungsgemeinschaft (DFG, PE 818/3-1).
We thank Thomas Kull (Peters group) for initial investigations on substituent effects.
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