Synthesis of cinchonidinium salts containing sulfonamide functionalities and their catalytic activity in asymmetric alkylation reactions

Article abstract of DOI:10.1016/j.tetlet.2014.09.052

Various kinds of 4-(bromomethyl)benzenesulfonamides were prepared as quaternization reagent of cinchonidine. Cinchonidinium salts obtained from the quaternization of cinchonidine with 4-(bromomethyl)benzenesulfonamide showed highly enantioselective cataly

Full text of DOI:10.1016/j.tetlet.2014.09.052

Tetrahedron Letters 55 (2014) 6117–6120
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of cinchonidinium salts containing sulfonamide
functionalities and their catalytic activity in asymmetric
alkylation reactions
⇑
Shinichi Itsuno , Shunya Yamamoto, Shohei Takata
Department of Environmental & Life Sciences, Toyohashi University of Technology, Toyohashi 441-8580, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2014
Revised 3 September 2014
Accepted 10 September 2014
Available online 17 September 2014
Various kinds of 4-(bromomethyl)benzenesulfonamides were prepared as quaternization reagent of
cinchonidine. Cinchonidinium salts obtained from the quaternization of cinchonidine with 4-(bromo-
methyl)benzenesulfonamide showed highly enantioselective catalytic activity in the asymmetric benzy-
lation of N-(diphenylmethylene)glycine tert-butyl ester. The corresponding phenylalanine derivative was
obtained in high yield with a high level of enantioselectivity, up to 98% ee.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Cinchonidinium salt
Organocatalyst
Sulfonamide
Asymmetric alkylation
Cinchona alkaloids have been utilized for the preparation of
various types of chiral organocatalysts.1 Particularly, the quater-
nary ammonium salts of cinchona alkaloids2 are an important class
of organocatalysts that have been developed for asymmetric
reactions, including Michael reactions,3 Darzen reactions,4 cyclo-
propanations,5 aldol reactions,6 fluorinations,7 epoxidations,8 and
alkylations.9 Among these transformations, the asymmetric alkyl-
ation of N-(diphenylmethylene)glycine tert-butyl ester has
attracted much attention because it affords a simple synthesis of
are available to chemically modify the N-benzyl substituents and
thereby tune the catalytic activity of the corresponding cinchonid-
inium salts, sulfonamides, to our knowledge, have not been
explored for use in this chemistry. Accordingly, we examined the
effects of incorporating sulfonamide functionalities into the para
position of the N-benzyl substituents in cinchonidinium catalysts
and observed higher enantioselectivity in the alkylation of N-
(diphenylmethylene)glycine tert-butyl ester. Since para substitu-
tion of these functionalities makes them unable to participate in
internal hydrogen bonding, steric factors may instead influence
the observed enantioselectivity. Herein we discuss the preparation
of the cinchonidinium salts possessing sulfonamide-substituted N-
benzyl derivatives and their catalytic activity in asymmetric
benzylation reactions.
optically active
a
-amino acids.10 Additionally, quinuclidine nitro-
gen can be easily quaternized using various reagents.11 N-benzyl
quaternary ammonium salts of cinchona alkaloids are most
commonly used as chiral organocatalysts12 and some of them are
commercially available.13 Chemical modification of the N-benzyl
substituents on these cinchona alkaloids can strongly affect their
catalytic activity. Incorporation of methoxy, methyl, nitro, and flu-
oro groups on the N-benzyl substituents has been examined in the
literature.11 For example, a previous study reported that a 20-F
group presumably participates in an internal hydrogen bonding
interaction with C(9)OH via an H2O solvent molecule, which results
in a more rigid conformation.14 However, substituent effects from
other groups besides the fluoro group have not been clearly eluci-
dated. Sulfonamide is another possible and promising functionality
of the N-benzyl substituent. While various sulfonamide structures
Synthesis of cinchonidinium salts having sulfonamide
functionality
We have synthesized a series of 4-(bromomethyl)benzenesulf-
onamides 3a–3j as novel quaternization reagents of cinchona
alkaloids from 4-(bromomethyl)benzenesulfonyl chloride 1 and
amines 2a–2j (Scheme 1). Since nucleophilic attack by the amine
may occur both at the sulfonyl and benzyl positions of 1, we were
prompted to find suitable reaction conditions to prepare the sulfon-
amides 3a–3j selectively. Typical reaction conditions used for sul-
fonamide formation were unsuccessful in our attempts to prepare
the latter.15,16 For example, the reaction of 1 with amines 2a–2j in
⇑
Corresponding author. Tel./fax: +81 532 44 6813.
E-mail address: itsuno@ens.tut.ac.jp (S. Itsuno).
http://dx.doi.org/10.1016/j.tetlet.2014.09.052
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

6118
S. Itsuno et al. / Tetrahedron Letters 55 (2014) 6117–6120
Table 2
R1
Br
R1
Asymmetric benzylation reaction of N-(diphenylmethylene)glycine tert-butyl ester by
Br
Cl
using cinchonidinium saltsa
+
2
NH
N
R2
S
R2
2
S
O
O
1
O
O
Catalyst (10 mol%)
3
O
O
Benzyl bromide (1.2 equiv)
Ph
N
2a: R1 = butyl, R2 = H
OBut
Ph
N
OBut
: R1 = t-butyl, R2 = H
2b
2c
2d
2e
2f
2g
50 wt% KOH, 0 oC
Toluene/CHCl3
Ph
: R1 = phenyl, R2 = H
Ph
9
10
: R1 = 1-naphthyl, R2 = H
: R1 = 4(trifluromethyl) phenyl, R2 = H
: R1 = 3,4,5-trifluorophenyl, R2 = H
Entry
Cinchonidinium salts
Time (h)
% Yieldb
% eeb,c
: R1 = 4-methylphenyl, R2 = H
1d
2
3
4
5
6
7
8
9
10
11
12
13
6
5
91
80
72
87
60
73
75
80
84
53
86
79
75
71 (S)
87 (S)
90 (S)
93 (S)
87 (S)
91 (S)
90 (S)
91 (S)
94 (S)
91 (S)
91 (S)
91 (S)
78 (S)
2h: R1 = 4-methoxyphenyl, R2 = H
: R1 = phenyl, R2 =Me
5a
5b
5c
5d
5e
5f
5g
5h
5i
17
14
20
15
17
14
17
24
5
2i
2j
: R1 = 4-iodophenyl, R2 = H
Scheme 1. Synthesis of sulfonamide 3.
Br
5i
5j
7
20
20
17
-
Br
+
N
N
R1
N
R2
+
R1
a
OH
OR3
Reaction was carried out with 1.2 equiv of benzyl bromide and 50 wt % aqueous
O
S
N
S
N
KOH in the presence of 10 mol % of the catalyst in toluene–chloroform (7:3) at 0 °C.
N
O
R2
O
b
O
Isolated yield.
4
5
3
c
ee values were determined by HPLC using a Chiralcel OD-H column.
See Ref. 23
d
Scheme 2. Synthesis of cinchonidinium salt 5 having the sulfonamide group.
the presence of pyridine or Na2CO3 gave only complex mixtures,17,18
and we found that the use of two equivalents of amine was neces-
sary to prepare 3a–3j. Accordingly, the treatment of 1 with 2 equiv
of aniline in CH2Cl2 at 25 °C afforded the sulfonamide 3c in high
yield. Under these conditions, the N-benzyl aniline side product
was not obtained.
The resulting quaternization reagents 3a–3j were then
employed on cinchonidine 4 to afford the corresponding cinchonid-
inium salts 5a–5j, which contain sulfonamide moieties on the N-
benzyl substituents (Scheme 2). However, typical quaternization
conditions for cinchonidine failed to synthesize 5. Quaternization
of cinchonidine usually required vigorous conditions such as reflux
in toluene.19 Many cinchonidinium salts such as N-benzylcinchon-
idinium bromide 6 were easily obtained under these reaction condi-
tions. While Park and Jew reported that the use of a mixed solvent
system consisting of ethanol/DMF/CHCl3 (5:6:2 ratio) resulted in
higher yields of the quaternized cinchona alkaloid derivatives,20
these reaction conditions did not afford 5a–5j as isolable products.
We eventually discovered that the quaternization of cinchonidine 4
with 3a–3j required only mild reaction conditions to give 5a–5j, and
these syntheses are summarized in Table 2. From the reaction
between 3a and cinchonidine in DMF at 25 °C for 20 h, 5a was
obtained in high yield (94%, Table 1, entry 1). All other cinchonidini-
um salts 5b–5j were also obtained in high yields. When the
reactions were conducted above 50 °C, unknown side reactions
occurred, which inhibited the isolation of the desired quaternized
products. The quaternization reactions also proceeded successfully
in MeOH at 40 °C for several derivatives (Table 1, entries 2, 4–7).
Under these mild reaction (see Fig. 1) conditions, the chiral
quaternary ammonium salts 5 were selectively synthesized in high
yield, as shown in Table 1. For comparison, the ortho-sulfonamide-
substituted N-benzyl derivative 7 was also prepared by the same
method (Table 1, entry 12). It is worth mentioning that substitution
on the C(3)-position of the cinchonidinium salt can also influence
the degree of enantioselectivity. The 3-ethyl derivatives 8 of the
cinchonidinium salts were analogously prepared (Table 1, entries
13 and 14). Introduction of an allyl ether on the C(9)-OH position
often afforded higher enantioselectivity in asymmetric alkylation
Table 1
Synthesis of sulfonamide containing cinchonidinium salts
Entry
Cinchonidinium salts
R1
R2
R3
Solvent
Temp °C
Time (h)
% Yield
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
Butyl
t-Butyl
Phenyl
H
H
H
H
H
H
H
H
Me
H
H
—
H
H
H
H
H
H
H
H
H
H
H
H
Allyl
—
H
DMF
MeOH
DMF
MeOH
MeOH
MeOH
MeOH
DMF
DMF
DMF
DMF
DMF
25
40
25
40
40
40
40
25
25
25
25
25
25
25
20
15
20
18
12
15
15
20
20
20
20
20
20
20
94
97
92
94
83
90
97
97
94
94
80
70
83
75
1-Naphthyl
4-(Trifluoromethyl)phenyl
3,4,5-Trifluorophenyl
4-Methylphenyl
4-Methoxyphenyl
Phenyl
4-Iodophenyl
Phenyl
—
9
5i
5j
10
11
12
13
14
5c(allyl)
7
8c
8h(allyl)
Phenyl
4-Methoxyphenyl
DMF
DMF
Allyl

S. Itsuno et al. / Tetrahedron Letters 55 (2014) 6117–6120
6119
Br
-
-
Br
+
N
Br
+
N
+
+
N
N
-
OH
N
O
OH
O
N
NH
O
S
N
NH
tBuO
O
O
N
N
O
S
HN Ph
S
6
Br
O
7
O
O
-
Br
A
B
+
N
R1
N
Figure 2. Plausible reaction mechanism of asymmetric benzylation with cinchon-
idinium salt catalyst.
OR3
R2
S
N
O
O
8
We subsequently investigated the effect of chemically modify-
ing the cinchonidine double bond (C10–C11) and the OH group in
Figure 1. Cinchonidinium salts used as organocatalysts.
5
on the observed enantioselectivity. Park and co-workers
reported that the use of cinchonidinium salts hydrogenated at
the C10–C11 double bond resulted in higher enantioselectivity
in asymmetric alkylation reactions compared with the N-benzyl
cinchonidinium salt 6 (Table 2, entry 1).20 Further, Corey et al.
reported that O-allylation of the 9-OH group in cinchonidinium
salts provided catalysts that exhibited greater activity in asym-
metric alkylation reactions.21 Based on these findings, we synthe-
sized both the hydrogenated and O-allylated analogues of 5c to
give 8c and 5c(allyl), respectively. As shown in Table 3 (entry
1), a slight increase in enantioselectivity was attained in the pres-
ence of 5c(allyl) versus 5c. Similarly, 8c displayed increased
enantioselectivity over 5c (Table 3, entry 2). Since 5h showed
the highest enantioselectivity (94% ee) in the asymmetric benzy-
lation of 9 (Table 2, entry 9), we were interested in exploring the
catalytic activity of its C10–C11 hydrogenated and O-allylated
analogue, 8h(allyl). Indeed, greater enantioselectivity was
obtained with 8h(allyl) both at 0 °C (97% ee, Table 3, entry 3),
and at ꢀ20 °C (98% ee, Table 3, entry 4). Some other alkylating
agents also showed high enantioselectivities using 8h(allyl)
(entries 5 and 6).
In conclusion, we have prepared various novel cinchonidinium
salt derivatives containing sulfonamide-substituted benzyl
ammonium groups (5, 7, and 8). We reasoned that the presence
of 40-sulfonamide substituents provided steric protection at the
right hand side of the catalyst molecule A, as illustrated in Fig-
ure 2. This steric protection presumably controls the approach
of the enolate intermediate in the transition state B, thereby
resulting in higher enantioselectivity in asymmetric benzylation
reactions. To provide further evidence of the usefulness and effec-
tiveness of the catalyst design explored in this study, we are
investigating the catalytic activities of these ammonium salts in
other asymmetric transformations.
reactions.21 C(9)O-allyl derivatives (5c(allyl), 8h(allyl)) were also
synthesized (Table 1, entries 11 and 14).22 To determine the effect
of an NH group in the 40-sulfonamide moiety, 5i was prepared from
N-methyl aniline using the same method (Table 1, entry 9).
Asymmetric benzylation with cinchonidinium catalysts
In order to examine the catalytic activity of novel cinchonidi-
nium salts containing sulfonamide substituents, we employed
the chiral quaternary ammonium salts 5, 7, and 8 as catalysts in
asymmetric benzylation reactions of N-(diphenylmethylene)gly-
cine tert-butyl ester 9. Results are summarized in Table 2. By
using 5a, which contains an aliphatic sulfonamide group on the
N-benzyl substituent, the asymmetric reaction proceeded
smoothly to afford the corresponding phenylalanine derivative
10 with 87% ee (Table 2, entry 2), which was higher than that
obtained from the N-benzyl cinchonidinium salt 6 (74% ee,
Table 2, entry 1). Compared to the N-benzyl cinchonidinium salt
6, the 40-sulfonamide-substituted N-benzyl derivatives exhibited
greater levels of enantioselectivity. We additionally observed that
the bulky tert-butyl sulfonamide derivative 5b gave somewhat
higher selectivity (Table 2, entry 3). Both electron-withdrawing
groups (Table 2, entries 6, 7, and 12) and electron-donating
groups (Table 2, entries 8 and 9) gave ee values that were greater
than 90%. On the other hand, the effect of the sulfonamide NH
group on the enantioselectivity was less pronounced (Table 2,
entries 4 and 10), while the use of the ortho-substituted cinchon-
idinium salt 7 resulted in a decrease in the enantioselectivity
(Table 2, entry 13). Although the relatively long reaction times
were required with catalysts 5, no racemization occurred after
20 h reaction with 5i (entries 10 and 11).
Table 3
Asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester by using O-allylated cinchonidinium saltsa
Entry
Cinchonidinium salts
Alkylating agent
Time (h)
% Yieldb
% eeb,c
1
2
5c(allyl)
8c
8h(allyl)
8h(allyl)
8h(allyl)
8h(allyl)
Benzyl bromide
Benzyl bromide
Benzyl bromide
Benzyl bromide
4-Methylbenzyl bromide
Allyl bromide
18
16
14
24
15
15
80
72
91
90
92
89
95 (S)
94 (S)
97 (S)
98 (S)
96 (S)
93 (S)
3
4d
5
6
a
b
c
Reaction was carried out with 1.2 equiv of alkylating agent and 50 wt% aqueous KOH in the presence of 10 mol % of the catalyst in toluene–chloroform (7:3) at 0 °C.
Isolated yield.
ee values were determined by HPLC using Chiralcel OD-H column.
Reaction was carried out at ꢀ20 °C.
d

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S. Itsuno et al. / Tetrahedron Letters 55 (2014) 6117–6120
5. Herchl, R.; Waster, M. Tetrahedron Lett. 2013, 54, 2472–2475.
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This work was partially supported by a Grant-in-Aid for Scien-
tific Research on Innovative Areas ‘New Polymeric Materials Based
on Element-Blocks’ (No. 25102515) from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
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14. Jew, S.-S.; Yoo, M.-S.; Jeong, B.-S.; Park, I. Y.; Park, H.-G. Org. Lett. 2002, 4, 4245–
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