Asymmetric Mannich reaction catalyzed by N-arylsulfonyl-l-proline amides

Article abstract of DOI:10.1016/j.tetasy.2009.12.013

Proline-derived N-sulfonylcarboxamides efficiently catalyze the asymmetric Mannich reaction of cyclic ketones with N-(p-methoxyphenyl)-protected iminoglyoxylate. Both classical organic solvents and ionic liquids were used as the reaction media. With cyclo

Full text of DOI:10.1016/j.tetasy.2009.12.013

Tetrahedron: Asymmetry 21 (2010) 58–61
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric Mannich reaction catalyzed by N-arylsulfonyl-L-proline amides
*
*
Eva Veverková, Jana Štrasserová, Radovan Šebesta , Štefan Toma
Department of Organic Chemistry, Faculty of Organic Chemistry, Comenius University, Mlynska dolina, 84215 Bratislava, Slovakia
a r t i c l e i n f o
a b s t r a c t
Article history:
Proline-derived N-sulfonylcarboxamides efficiently catalyze the asymmetric Mannich reaction of cyclic
ketones with N-(p-methoxyphenyl)-protected iminoglyoxylate. Both classical organic solvents and ionic
liquids were used as the reaction media. With cyclohexanone, the reaction proceeded with high enanti-
oselectivity (99% ee). Enamine intermediates were investigated by DFT calculations.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 5 November 2009
Accepted 21 December 2009
Available online 18 January 2010
1. Introduction
dodecylphenylsulfonyl pyrrolidinecarboxamide as a catalyst for
the aldol18 and Mannich reaction in apolar solvents.19
The asymmetric Mannich reaction is one of the most useful car-
bon–carbon bond forming reactions for the synthesis of chiral nitro-
gen-containing molecules.1 The resulting b-amino carbonyl
compounds are valuable synthons in the preparation of many natu-
ralproducts. Theproducts of theMannichreactioncanoftenbe read-
ily converted into compounds with useful biological properties.
Traditionally, asymmetric Mannich reactions are catalyzed by chiral
Herein we demonstrate usefulness of three, differently substi-
tuted, N-arylsulfonyl pyrrolidinecarboxamides in the Mannich
reaction in organic solvents as well as in ionic liquids.
2. Results and discussion
Addition of cyclohexanone 1 to N-p-methoxyphenyl(PMP)-pro-
tected a-imino ethylglyoxylate 2 was selected as a test reaction for
the evaluation of the suitability of N-arylsulfonyl pyrrolidinecarb-
oxamides in Mannich-type reactions (Scheme 1).
transition-metal complexes.2–4 In 2000 List described the
L-proline-
mediated Mannich reaction.5,6 This landmark discovery stimulated
the rapid development of many asymmetric organocatalytic Man-
nich reactions.7–11 The typical organocatalytic approach to asym-
metric Mannich reaction is based on enamine activation of
carbonyl compounds using secondary amine organocatalysts.10
Other types of organocatalysts have also been successfully used for
Mannich-type reactions. These catalysts include chiral Brønsted
acids,12 cinchona alkaloids,13 or phase-transfer catalysts.14
Proline-based N-arylsulfonylcarboxamide derivatives are an
interesting class of organocatalysts, originally developed by
Berkessel for aldol reactions.15,16 These catalysts have often signif-
icantly higher reactivities and enantioselectivities (up to 98% ee)
O
O
NHPMP
CO2Et
PMP
H
N
catalyst
+
solvent
24h, r.t.
H
CO2Et
3
2
1
Scheme 1.
We selected catalysts with three different substituents on phen-
ylsulfonyl group. Figure 1 shows the structures of the catalysts 4–6
used in this study.
Our research started with an investigation of the influence of
various reaction parameters. Catalyst loading is often an important
compared with
in many respects similar to
proton is of similar acidity to the
L
-proline (80% ee). Arylsulfonylcarboxamides are
-proline itself. For instance, the amidic
-proline carboxylic function. On
L
L
the other hand, the N-arylsulfonyl group enables further optimiza-
tion of the catalyst properties by variation of substituents on the
aryl residue. Ley further expanded upon the catalytic possibilities
of N-sulfonyl proline amides to other aldol, nitro-aldol as well as
Mannich reactions.17 The addition of cyclohexanone to imino
glyoxalate proceeded well with methyl and phenylsulfonyl pyrroli-
dinecarboxamides. In all cases, these catalysts gave superior or at
factor, especially in organocatalytic reactions. For instance, L-pro-
line is typically used at levels of around 20 mol %. We also found,
as can be seen from Table 1, that less than 20 mol % of catalyst 4
is not satisfactory for good results (entries 1 and 2). On the other
hand, an increased amount of the catalyst is not necessary either,
because similar results were obtained using 20 as well as
30 mol % of catalyst 4 (entries 3 and 4). Therefore we continued
our investigation with 20 mol % of sulfonamide organocatalysts
4–6. Product 3 was usually obtained with high diastereoselectivity
(syn/anti up to 97:3) and high enantiomeric purity of the syn-dia-
stereoisomer (up to 99% ee).
least equivalent results compared with L-proline. Carter developed
* Corresponding author. Tel.: +421 2 60296603; fax: +421 2 60296337.
E-mail address: sebesta@fns.uniba.sk (Štefan Toma).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.013

E. Veverková et al. / Tetrahedron: Asymmetry 21 (2010) 58–61
59
mides.22 Barbas et al. reported the
nich reaction of the N-PMP-iminoglyoxylate with cyclohexanone
in [bmim]BF4 and they obtained the product in quantitative yield
with excellent enantioselectivity (99% ee).23 For the sake of compar-
L
-proline-catalyzed direct Man-
O
4, R = Me
5, R = NO2
6, R = Bu
O
S
N
H
HN
R
O
ison, we againperformedthisreactionwithL-proline, butinionicliq-
uids used in our experiments; yields were slightly lower than those
obtained by Barbas. From experiments with sulfonamides 4–6 in io-
nic liquids, several interesting observation can be made. The diaste-
reoselectivity of the reaction decreased considerably. In
[emim]EtSO4 and [hmim]NTf2, the syn-isomer of 3 prevailed while
in [bmim]C8H17SO4 anti-3 was dominant, although only slightly.
Compared to ionic liquids [emim]EtSO4 and [hmim]NTf2, in
[bmim]C8H17SO4, a dramatic decrease of enantioselectivity was ob-
served. Catalyst 5 gave in all the evaluated ionic liquids, the lowest
ees as well as chemical yields. These differences in reactivity further
support the notion that the solvating properties of the ionic liquids
are very different from those of common organic solvents
(Table 2).24
With other cyclic ketones apart from cyclohexanone, the Man-
nich reaction succeeded only with cyclobutanone and cyclohepta-
none (Scheme 2). Nevertheless, only small amounts of products
were detected after one day. After four days, product 9 was isolated
in good yields in THF (87%) as well as in DMSO (77%) and with very
good enantioselectivity (94% and 93% ee, respectively) (Table 3, en-
tries 6 and 7). Cyclopentanone and cyclooctanone were unreactive
under these conditions and only traces of products were detected
by 1H NMR analysis of the crude reaction mixture after four days
in both THF and DMSO (Table 3, entries 3, 4, 8, and 9).
Figure 1. Structures of proline-derived arylsulfonyl carboxamides.
Table 1
The effect of catalyst and solvent on the Mannich reaction between cyclohexanone
and imine 2
Entry Catalyst Catalyst
loading
Solvent Yielda
(%)
syn:antib ee sync
(%)
1
2
3
4
5
6
7
4
4
4
4
5
6
5
10
20
30
20
20
20
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
7
—
—
91:9
93:7
92:8
96:4
94:6
97:3
60
58
57
97
77
77
60
62
73
77
44
L-Pro
8
9
10
11
4
5
6
20
20
20
20
THF
THF
THF
THF
33
41
98
65
92:8
95:5
96:4
97:3
58
99
99
86
L-Pro
12
13
14
15
4
5
6
20
20
20
20
DMSO
DMSO
DMSO
DMSO
71
83
67
74
94:6
97:3
96:4
97:3
88
99
99
99
L-Pro
a
b
c
Isolated yield of pure product 3.
Determined by 1H NMR spectroscopy.
Determined by chiral HPLC on Chiralpak AD-H column.
O
O
PMP
NHPMP
CO2Et
6 (20 mol%)
N
+
To explore the solvent scope, three commonly used solvents of
different polarities (DMSO, CH2Cl2, THF) were screened. Compari-
son experiments with -proline were also performed. All catalysts
were soluble in DMSO and comparable catalytic properties of cat-
alysts 4 and 6 with -proline were observed in this solvent (Table 1,
solvent
24h, r.t.
n
n
H
CO2Et
H
n = 1-5
L
7, n = 1
8, n = 2
9, n = 4
L
10, n = 5
entries 12, 14, 15). Better result in terms of chemical yield (83%)
with catalyst 5, carrying an electron-withdrawing nitro group,
are probably caused by the higher acidity of the N–H amide proton
(Table 1, entry 13). High enantioselectivity (99% ee) was obtained
with catalyst 5 also in THF, although the yield was lower, probably
due to its low solubility in this solvent. The low solubility resulted
in a small effective catalyst concentration, which is critical for the
success of this reaction (Table 1, entry 9). In THF, catalyst 6, with a
larger alkyl group, was the most active and selective (98% yield,
99% ee) (Table 1, entry 10). These results show that even common
low boiling solvent can be used, without compromising the yield or
enantioselectivity. This is in accord with the Carter study, in which
a dodecyl-substituted phenylsulfonyl catalyst also proved to be
useful in apolar solvents, such as dichloroethane and 2-meth-
yltetrahydrofuran.19 It is interesting to note that under the same
Scheme 2.
Ley described the reaction of cyclobutanone with the N-PMP-
iminoglyoxylate in CH2Cl2 catalyzed by 5-pyrrolidin-2-yltetrazole,
giving ketone 7 in 74% yield and 94% ee.25 With catalyst 6 only
small amounts of product 7 were obtained (18% in THF, 26% in
DMSO), but the enantioselectivity, although lower, was still satis-
factory (69% and 72% ee, respectively) (Table 3, entries 1 and 2).
In an attempt to gain an insight with regards to the reactivity of
cyclic ketones, we investigated also the structures of likely
Table 2
Mannich reaction of cyclohexanone and
a
-imino ethyl glyoxylate in ionic liquids
Entry Catalyst Solvent
Yielda (%) syn:antib ee (%)c syn/anti
reaction conditions, L-proline gave a considerably lower yield and
1
2
3
4
4
5
6
[emim]EtSO4
[emim]EtSO4
[emim]EtSO4
[emim]EtSO4
32
69
75
39
77:23
70:30
70:30
75:25
80/47
68/8
81/82
91/65
enantioselectivity (Table 1, entry 11). The activities of catalysts 5
and 6 are comparable to Ley’s catalysts.17 Interestingly, tolylsulf-
onamide 4 gave slightly inferior results to phenyl substituted ones,
as reported by Ley.
In recent years, ionic liquids have attracted great attention as no-
vel and potentially green reaction media.20 There is also a growing
number of asymmetric organocatalytic reactions successfully per-
formed in ionic liquids.21 Considering the optimization of a Mannich
reaction, we decided to study the influence of three different ionic
liquids ([emim]EtSO4, [bmim]C8H17SO4 and [hmim]NTf2) over the
course of this reaction. The choice of catalytic system catalyst/ionic
liquid stemmed from our previous experiences with these solvents
in aldol reactions catalyzed by N-arylsulfonyl pyrrolidinecarboxa-
L
-Pro
5
6
7
8
4
5
6
[bmim]C8H17SO4 47
[bmim]C8H17SO4 54
[bmim]C8H17SO4 98
[bmim]C8H17SO4 73
37:63
47:53
47:53
44:56
31/34
20/18
27/29
28/24
L
-Pro
9
10
11
12
4
5
6
[hmim]NTf2
[hmim]NTf2
[hmim]NTf2
[hmim]NTf2
34
97
62
60
60:40
58:42
71:29
57:43
72/35
48/9
72/77
90/78
L
-Pro
a
b
c
Isolated yield of pure product 3.
Determined by 1H NMR spectroscopy.
Determined by chiral HPLC on Chiralpak AD-H column.

60
E. Veverková et al. / Tetrahedron: Asymmetry 21 (2010) 58–61
Table 3
OMe
N
Investigation of the size of cyclic ketones on the Mannich reaction
Entry
Product
Time (d)
Solvent
Yielda
syn:antib
ee sync (%)
1
2
3
4
5
6
7
8
9
7
7
8
8
9
9
9
10
10
4
4
4
4
1
4
4
4
4
THF
DMSO
THF
DMSO
THF
THF
DMSO
THF
DMSO
18
26
Traces
Traces
0
87
77
Traces
Traces
91:9
94:6
—
—
—
92:8
93:7
—
69
72
n.d.
n.d.
—
94
93
n.d.
n.d.
N
H
H
O
N
CO2Et
O
S
O
—
a
b
c
Isolated yield of pure product.
Determined by 1H NMR spectroscopy.
Determined by chiral HPLC on Chiralpak AD-H column.
R
Figure 3. Proposed transition state model for Mannich reaction catalyzed by
proline-derived arylsulfonyl carboxamides.
enamine intermediates formed from these ketones (cyclohexanone
and cyclopentanone) and model phenylsulfonamide catalyst by
N-PMP-protected
ges in comparison with
a
-imino ethylglyoxylate with practical advanta-
computational methods. DFT (B3LYP functional,26,27 6-31G basis
*
L-proline in different solvents and ionic liq-
set as implemented in NWChem program28 from ECCE package29
)
uids. Ionic liquids can be used as solvents as well, although in this
case, proline sulfonamides are less diastereo- and enantioselective
than common organic solvents. Owing to larger differences in ionic
liquids than in molecular solvents, a broader range of ionic liquids
seems to be necessary to gain deeper insight into the reactivity of
these catalysts in the Mannich reaction. Screening of various cyclic
ketones showed that under similar conditions, only cyclohexa-
none, cyclobutanone and cycloheptanone afforded the desired
products, although for the latter two ketones reaction time must
be prolonged to four days. Other cyclic ketones were unreactive
under these conditions.
calculations of enamines 11 and 12 revealed that conformers (11b
and 12b) with hydrogen bond between amide NH and pyrrolidine
nitrogen have approximately 40 kJ/mol lower relative energy than
conformers 11a and 12a, respectively (Fig. 2). However there are
no significant differences between enamines 11 and 12. Thus the
reason for such different reactivities of cyclohexanone and cyclo-
pentanone remains unclear.
4. Experimental
The solvents were purified by standard methods. NMR spectra
were recorded on Varian Mercury plus instrument (300 MHz for
1H, 75 MHz for 13C). Chemical shifts (d) are given in ppm relative
to tetramethylsilane for 1H NMR, relative to residual solvent peak
for 13C NMR. Specific rotations were measured on a Perkin–Elmer
instrument and are given in deg cmꢀ3 gꢀ1 dmꢀ1. Column chroma-
tography was performed on Merck Silica Gel 60. Thin-layer
chromatography was performed on Merck TLC-plates silica gel
60, F-254. Enantiomeric excesses were determined by HPLC using
Chiralpak AD-H (Daicel Chemical Industries) column using n-hex-
ane/propan-2-ol as
254 nm. N-PMP-protected
according to published method.30 N-Toluenesulfonyl-
a
mobile phase and detected by UV at
-imino ethyl glyoxalate was prepared
-proline
-proline amide 5 were
a
L
amide 4 and N-4-nitrobenzenesulfonyl-
L
synthesized according to literature procedures.16 The absolute con-
figurations of products 3, 7, and 9 were assigned by comparison of
the sign of optical rotation with literature data.17,31
4.1. N-4-Butylbenzenesulfonyl-L-proline amide 6
Figure 2. DFT-optimized structures of cyclopentanone 11a and 11b and cyclohex-
anone 12a and 12b enamines with phenylsulfonyl pyrrolidinecarboxamide.
To a solution of 4-butylbenzenesulfonamide (1.23 g, 5.8 mol) in
anhydrous DMF (20 mL), NaH (268 mg, 60% dispersion in mineral
oil, 6.69 mmol) was added. After stirring for 0.5 h at room temper-
With the help of these calculations, and in analogy to a model
suggested by Ley24 for 5-pyrrolidin-2-yltetrazole as a catalyst, we
propose a similar transition state model which explains the ob-
served absolute configuration of products of Mannich reaction
(Fig. 3).
ature, Boc-L-proline (4-nitrophenyl) ester (1.50 g, 4.46 mol), dis-
solved in DMF (5 mL) was added. The reaction mixture was
stirred overnight at room temperature and then poured onto
crushed ice. The pH of the solution was adjusted to 3 by addition
of citric acid and the aqueous layer was extracted with EtOAc
(3 ꢁ 20 mL).The combined organic extracts were dried (MgSO4),
filtered and solvent evaporated in vacuo. The residue was tritu-
rated with Et2O (10 mL). The resulting solid Boc-protected N-4-
3. Conclusions
In conclusion,
L-proline-derived sulfonamides 4–6 proved to be
butylbenzenesulfonyl-L-proline amide was collected by filtration.
effective catalysts in the Mannich reaction of cyclohexanone with
Deprotection was performed with 50% TFA in CH2Cl2 (10 mL) for

E. Veverková et al. / Tetrahedron: Asymmetry 21 (2010) 58–61
61
1 h at room temperature. After concentration, TFA salts were re-
moved by trituration of the residue with MeOH saturated with
ammonia (10 mL,). Sulfonamide 6 was obtained as a colourless so-
(Daicel Chiralpak AD-H, hexane/iPrOH 94:6, 0.75 mL/min): tR (ma-
jor) = 25.43 min; tR (minor) = 27.14 min. NMR and specific rotation
data in agreement with the literature.17
lid; yield 608 mg (32%). Mp 223–225 °C (MeOH). [
a
]
D = ꢀ29.1 (c
1.0, CHCl3). 1H NMR (300 MHz, DMSO-d6) d = 0.90 (t, J = 7.5 Hz,
3H), 1.26–1.33 (m, 2H), 1.52–1.57 (m, 2H), 1.64–1.82 (m, 2H),
2.08–2.17 (m, 2H), 2.59 (t, J = 7.8 Hz, 2H), 3.13–3.22 (m, 1H),
3.04–3.11 (m, 1H), 3.78–3.83 (m, 1H), 7.20 (d, J = 8.4 Hz, 2H),
7.67 (d, J = 8.4 Hz, 2H). 13C NMR (75 MHz, CDCl3) d = 13.9, 22.3,
24.6, 30.1, 33.3, 35.5, 46.6, 62.7, 126.4, 128.5, 140.3, 147.0, 173.8.
Anal. Calcd for C15H22N2O3S: C, 58.04; H, 7.14; N, 9.02; S, 10.33.
Found: C, 58.21; H, 7.18; N, 8.92; S, 9.94.
Acknowledgement
ˇ
We thank Mr. Filip Bilcík for performing HPLC measurements.
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4.2.2. (2S, 10S)-Ethyl-2-(4-methoxyphenylamino)-2-(20-oxocyclobut
-10-yl)-acetate 7
[
a
]
D = ꢀ28.3 (c 0.1, CHCl3, ee = 69%).1H NMR (300 MHz, CDCl3)
d = 1.21 (t, J = 7.1, 3H), 1.83–2.04 (m, 2H), 2.76–3.08 (m, 2H), 3.73
(s, 3H), 4.12 (m, 1H), 4.16 (m, 1H), 6.59 (d, J = 9.2, 2H), 6.62 (d,
J = 9.2, 2H). HPLC (Daicel Chiralpak AD-H, hexane/iPrOH 90:10,
0.75 mL/min): tR (major) = 16.06 min; tR (minor) = 43.83 min.
NMR and specific rotation data in agreement with the literature.17
4.2.3. (2S,10S)-Ethyl-2-(4-methoxyphenylamino)-2-(20-
oxocyclohept-10-yl)-acetate 9
[
a
]
D = ꢀ18.3 (c 0.1, CHCl3, ee = 75%). 1H NMR (300 MHz, CDCl3)
d = 1.21 (t, J = 6.9 Hz, 3H), 1.36–1.96 (m, 8H), 2.49–2.54 (m, 2H),
2.85–2.96 (m, 1H), 3.75 (s, 3H), 4.14 (q, J = 6.9 Hz, 2H), 4.25 (d,
J = 4.8 Hz, 1H), 6.58 (d, J = 9.3 Hz, 2H), 6.69 (d, J = 9.3 Hz, 2H). HPLC