Use of prolyl sulfonimidamides in solvent-free organocatalytic asymmetric aldol reactions

Article abstract of DOI:10.1055/s-0029-1217727

Prolyl-substituted sulfonimidamides have been synthesized and applied as organocatalysts in solvent-free asymmetric aldol reactions.

Full text of DOI:10.1055/s-0029-1217727

LETTER
A
Use of Prolyl Sulfonimidamides in Solvent-Free Organocatalytic Asymmetric
Aldol Reactions
P
rolyl Sulfonimid
h
amides in
A
r
symmet
i
r
ic
A
ld
s
R
eactio
t
ns in Worch, Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany
Fax +49(241)8092391; E-mail: carsten.bolm@oc.rwth-aachen.de
Received 12 May 2009
been applied as organocatalysts, and thus we expected
Abstract: Prolyl-substituted sulfonimidamides have been synthe-
sized and applied as organocatalysts in solvent-free asymmetric al-
dol reactions.
promising findings to open new research opportunities.
Here, we report our first results illustrating the concept by
describing the synthesis and use of prolyl sulfonimid-
amides 10.
Keywords: aldehyde, aldol reaction, amino acids, ketone, organo-
catalysis, sulfonimidamide
The synthesis of 10 started from N-carbobenzyloxy (Cbz)
protected L-proline (7), which was coupled with enan-
tiopure N-tosyl-protected sulfonimidamide 88 to give
acylsulfonimidamide 9 (Scheme 1).9 Removal of the Cbz-
group by catalyzed hydrogenolysis led to prolyl sulfon-
imidamides 10 in good yields (>80%). In this manner both
diastereomers (S,R)-10 and (S,S)-10 were accessible start-
ing from (R)-8 and (S)-8, respectively.
Much effort has been devoted to the development of cata-
lytic asymmetric aldol reactions.1 Various proline deriva-
tives proved applicable as organocatalysts, and their
reaction behavior has been thoroughly investigated.2 In
2004, Berkessel described the synthesis of N-sulfonylated
proline amides 1–3 and their use as catalysts for the enan-
tioselective addition of acetone to 4-nitrobenzaldehyde
(Figure 1).3 Subsequently, Ley applied compounds 4 and
5 in catalytic asymmetric Mannich-type reactions and al-
dol additions of ketones to 4-nitrobenzaldehyde.4 Kokotos
tested a series of related 4-substituted prolyl sulfonamides
and a dipeptide derived from proline, phenylalanine and
sulfonamide on their effectiveness in organocatalytic al-
dol reactions.5
NTs
O
EDC (1.0 equiv),
O
S
DMAP (0.25 equiv)
NH2
+
N
CH2Cl2, r.t., 24 h
OH
Cbz
Me
O
(S)-7
(R)-8 or (S)-8
O
NTs
Pd/C, H2 (1 atm)
CH2Cl2, r.t., 24 h
S
N
H
N
1 R = 4-MeC6H4
Me
Cbz
O
2 R = 2,4,6-i-Pr3C6H2
3 R = 4-NO2C6H4
4 R = Me
O
O
(S,R)-9 or (S,S)-9,
respectively
S
N
R
5 R = Ph
6 R = C12H25C6H4
H
NH
O
O
O
NTs
O
TsN
Figure 1 Selected prolyl-substituted sulfonamides
S
S
N
H
N
or
H
NH
NH
Almost all of these procedures required a large excess of
ketone (27 equiv or 20 vol%),6 which represents a signif-
icant limitation for potential applications. Recently, this
problem was addressed by the introduction of prolyl sul-
fonamide 6 (Figure 1).7 In this case, only five equivalents
of ketone were required and, in asymmetric aldol reac-
tions, products with excellent enantioselectivities were
obtained in very high yields.
Me
respectively
Me
(S,R)-10
(S,S)-10
Scheme 1 Synthesis of sulfonimidamides (S,R)-10 and (S,S)-10
As a test reaction for the catalytic potential of sulfon-
imidamides 10, the aldol addition of cyclohexanone (11)
to 4-nitrobenzaldehyde (12a) was chosen (Table 1). In or-
der to investigate whether there was any catalytic activity,
the first experiments were carried out at room temperature
with 20 mol% of a diastereomeric mixture (ca. 1:1) of
(S,R)-10 and (S,S)-10 derived from L-proline and rac-8.
To our delight, addition product 13a was obtained in 86%
yield with a very good anti/syn ratio (95:5) and an ee of
95% (Table 1, entry 1). The major isomer of 13a had
(2S,1¢R)-configuration. No solvent was required10 but, un-
fortunately, even with a large excess of ketone (30 equiv)
the reaction time was long (8 d). Increasing the reaction
temperature to 30 °C improved the catalyst performance
As sulfonimidamides are the aza-analogues of sulfona-
mides, we hypothesized that these compounds could also
have a potential in organocatalysis. The additional stereo-
genic center at the sulfur could then be beneficial for con-
trolling the stereoselectivity in asymmetric processes. To
the best of our knowledge, sulfonimidamides have never
SYNLETT 2009, No. x, pp 000A–000D
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Advanced online publication: xx.xx.2009
DOI: 10.1055/s-0029-1217727; Art ID: G17009ST
© Georg Thieme Verlag Stuttgart · New York

B
C. Worch, C. Bolm
LETTER
to give 13a in 84% yield after only two days (Table 1, en- With respect to the substrate tolerance, the following con-
try 2). It is worth noting that the stereoselectivity re- clusions can be drawn: The electron-withdrawing nitro
mained almost unaffected (anti/syn = 95:5, 92% ee). group in the substituted benzaldehydes 12a–c has a posi-
When diastereomerically pure (S,R)-10 was applied as tive effect on the catalysis and, in general, very good dia-
catalyst under the same reaction conditions, both the de stereo- and enantioselectivities are achieved for the
and the ee slightly increased to 94 and 95%, respectively formation of the corresponding products 13a–c (Table 2,
(Table 1, entry 3). Diastereomeric sulfonimidamide (S,S)- entries 1–6). The strongest substrate activation is ob-
10 proved to be less effective (see Table 2). Varying the served when the nitro group is in the para position of the
catalyst loading from 20 to 10, 7, and 5 mol% (Table 1, aromatic system (as in 12a).12 Use of benzaldehydes 12b
entries 4–6) indicated an optimum at 10 mol% of (S,R)- and 12c having meta and ortho nitro groups, respectively,
10, which gave 13a with 96% de and 98% ee in 92% yield. require longer reaction times for achieving good yields.
However, the aldehyde-to-ketone ratio had an effect on The same is true for conversions of 4-chlorobenzaldehyde
the catalyst performance (Table 1, entries 4, 7–9). Taking (12d) and benzaldehyde (12e), with the latter being the
all factors (substrate amount, stereoselectivity and least reactive substrate. Although in both cases the stereo-
product yield) into account, the best result was obtained selectivities are acceptable, the yields are only moderate
with 10 mol% of (S,R)-10 and five equivalents of ketone (Table 2, entries 7–10). In all cases the major isomers had
11 (entry 8).
(2S,1¢R)-configuration.
Next, the application of other aldehydes was tested Finally, the carbonyl component was varied. Starting
(Table 2),11 and the catalytic activities of diastereomeric from cyclopentanone (14) and 4-nitrobenzaldehyde (12a),
sulfonimidamides (S,R)-10 and (S,S)-10 were compared. hydroxy ketone 15 was obtained in 73% yield under the
In all cases, the former diastereomer gave higher yields standard conditions (Scheme 2). Although the diastereo-
and better stereoselectivities than the latter. Although the selectivity was only very moderate (36% de), the enantio-
differences were usually only minor, in conversions of 4- selectivity was high (95% ee). Again, the major isomer
chlorobenzaldehyde (12d), for example, the Dde and Dee had (2S,1¢R)-configuration.13
reached values of 18 and 11%, respectively (Table 2, en-
In summary, we have prepared prolyl-substituted sulfon-
tries 7 and 8). Apparently, the stereogenic center at sulfur
imidamides and demonstrated their applicability as orga-
influenced the stereochemical result of the catalysis, and
nocatalysts in solvent-free asymmetric aldol reactions. In
a fine-tuning of the sulfonimidamide structure was impor-
additions of cyclic ketones to aromatic aldehydes, the ste-
tant.
reoselectivities are good to excellent, and the products are
formed in moderate to very good yields. The excess of ke-
Table 1 Optimization of the Aldol Addition of Cyclohexanone (11) to 4-Nitrobenzaldehyde (12a)a
O
O
OH
O
sulfonimid-
amide 10
+
solvent-free
NO2
NO2
11
12a
13a
Entry
Sulfonimidamide Catalyst loading Ketone
Time
(d)
Temp
(°C)
Yield
(%)b
anti/syn
ee (anti)
10
(mol%)
(equiv)
30
30
30
30
30
30
10
5
ratoc
(%)d
1
2
3
4
5
6
7
8
9
(S,S) + (S,R)
(S,S) + (S,R)
(S,R)
20
8
2
2
2
2
2
2
2
2
~20
30
30
30
30
30
30
30
30
86
84
74
92
82
75
85
88
55
95:5
95:5
97:3
98:2
95:5
89:11
96:4
97:3
95:5
95
92
95
98
96
95
96
96
94
20
20
(S,R)
10
(S,R)
7
(S,R)
5
(S,R)
10
(S,R)
10
(S,R)
10
2
a All reactions were performed solvent-free on a 0.30 mmol scale.
b Determined after column chromatography.
c Ascertained from 1H NMR of the crude reaction mixture.
d The enantiomeric ratios were determined by HPLC using a Chiralpak AD-H column (heptane–i-PrOH, 90:10, 1.0 mL/min). The major product
had (2S,1¢R)-configuration.
Synlett 2009, No. x, A–D © Thieme Stuttgart · New York

LETTER
Prolyl Sulfonimidamides in Asymmetric Aldol Reactions
C
Table 2 Reaction of Cyclohexanone (11) and Various Aromatic Aldehydes 12a–ea
sulfonimid-
amide 10
(10 mol%)
O
O
OH
O
+
R
R
solvent-free
11
12a–e
13a–e
Entry
Sulfonimidamide
10
R
Aldehyde
12
Time
(d)
Productb
Yield
(%)c
anti/syn
ee (anti)
ratiod
(%)e
95
93
97
96
98
93
89
78
96
90
1
2
(S,R)
(S,S)
(S,R)
(S,S)
(S,R)
(S,S)
(S,R)
(S,S)
(S,R)
(S,S)
4-NO2
4-NO2
3-NO2
3-NO2
2-NO2
2-NO2
4-Cl
12a
12a
12b
12b
12c
12c
12d
12d
12e
12e
2
2
3
3
4
4
4
4
4
4
13a
13a
13b
13b
13c
13c
13d
13d
13e
13e
84
80
81
72
74
55
40
31
22
35
96:4
94:6
96:4
96:4
94:6
92:8
91:9
87:13
92:8
87:13
3
4
5
6
7
8
4-Cl
9
H
10
H
a All reactions were performed solvent-free at 30 °C, on a 0.60 mmol scale utilizing 10 mol% of sulfonimidamide 10 and 5 equiv of cyclohex-
anone (11).
b The major isomers had (2S,1¢R)-configuration.
c Determined after column chromatography.
d Ascertained from 1H NMR of the crude reaction mixture.
e Determined by HPLC using columns with chiral stationary phases.
2249. (c) Mlynarski, J.; Paradowska, J. Chem. Soc. Rev.
2008, 37, 1502.
(2) For recent reviews, see: (a) Kotsuki, H.; Ikishima, H.;
Okuyama, A. Heterocycles 2008, 75, 493. (b) Kotsuki, H.;
Ikishima, H.; Okuyama, A. Heterocycles 2008, 75, 575.
(3) Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004,
346, 1141.
tone could be limited to five equivalents. By studying the
diastereomeric catalysts it was shown that the stereogenic
center at the sulfur atom of the sulfonimidamide unit had
only a minor impact on the formation of the products.
O
O
OH
O
(S,R)-10
(10 mol%)
(4) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.;
Ley, S. V. Org. Biomol. Chem. 2005, 3, 84.
+
30 °C, 2 d
(5) (a) Bellis, E.; Vasilatou, K.; Kokotos, G. Synthesis 2005,
2407. (b) Tsandi, E.; Kokotos, C. G.; Kousidou, S.;
Ragoussis, V.; Kokotos, G. Tetrahedron 2009, 65, 1444.
(6) For the use of a ketone/aldehyde ratio of 3:1, see: Wu, Y.;
Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8,
4417.
solvent-free
NO2
12a
NO2
14
15 (73% yield)
(anti/syn = 68:32, 95% ee)
Scheme 2 Catalytic use of sulfonimidamide (S,R)-10 in the reaction
of cyclopentanone (14) and 4-nitrobenzaldehyde (12a)
(7) Yang, H.; Carter, R. G. Org. Lett. 2008, 10, 4649.
(8) (a) Di Chenna, P. H.; Robert-Peillard, F.; Dauban, P.; Dodd,
R. H. Org. Lett. 2004, 6, 4503. (b) Fruit, C.; Robert-
Peillard, F.; Bernardinelli, G.; Müller, P.; Dodd, R. H.;
Dauban, P. Tetrahedron: Asymmetry 2005, 16, 3484.
(9) Syntheses of (2S)-benzyl 2-(N-tosyl-4-tolylsulfonimid-
oylcarbamoyl)pyrrolidine-1-carboxylates 9; General
Procedure: To a solution of Cbz-L-proline (L-7, 374 mg,
1.50 mmol), sulfonimidamide 8 (487 mg, 1.50 mmol) and
DMAP (46 mg, 0.375 mmol) in CH2Cl2 (9 mL), was added
EDC (233 mg, 263 mL, 1.50 mmol). After stirring of the
reaction mixture at room temperature for 24 h, EtOAc (30
mL) was added. The resulting mixture was then sequentially
washed with 1 M HCl (10 mL) and half-saturated brine (10
mL). Drying the organic phase over MgSO4 and concentra-
tion under reduced pressure gave white solids that were used
without further purification.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by the Fonds der Chemischen Industrie
and the Deutsche Forschungsgemeinschaft (SPP 1179).
References and Notes
(1) Selected reviews: (a) Palomo, C.; Oiarbide, M.; García,
J. M. Chem. Soc. Rev. 2004, 33, 65. (b) Guillena, G.;
Nájera, C.; Ramón, D. J. Tetrahedron: Asymmetry 2007, 18,
Synlett 2009, No. x, A–D © Thieme Stuttgart · New York

D
C. Worch, C. Bolm
LETTER
For analytical data of (S,R)-9 and (S,R)-9 see Supporting
Information.
(11) Aldol Reaction; General Procedure: A vial was charged
with sulfonimidamide 10 (10 mol%), ketone (5.0 equiv, 3.0
mmol) and aldehyde (1.0 equiv, 0.6 mmol) and sealed. The
mixture was stirred at 30 °C for the indicated period of time.
After the addition of ethyl acetate (5 mL) the reaction
mixture was filtered thought a pad of silica gel, then the
solvent was removed in vaccuo, and purified by column
chromatography on silica gel to afford the corresponding
aldol products.
(12) In an unoptimized ball milling experiment (at 400 rpm) the
aldol reaction between ketone 11 (5 equiv) and aldehyde 12a
catalyzed by 10 mol% of (S,R)-10 led to 35% conversion of
12a after 5.3 h, giving 13a with 66% ee (anti/syn, 88:12) in
31% yield. For recent guiding reviews in this area, see:
(a) Rodriguez, B.; Rantanen, T.; Bruckmann, A.; Bolm, C.
Adv. Synth. Catal. 2007, 349, 2213. (b) Bruckmann, A.;
Krebs, A.; Bolm, C. Green Chem. 2008, 10, 1131.
(13) The catalyst performance in the reaction of acetone and 4-
nitrobenzaldehyde was poor. The product was isolated after
6 d at 30 °C with 49% ee in 23% yield.
Syntheses of (2S)-N-(N-tosyl-4-tolylsulfonimidoyl)pyr-
rolidine-2-carboxamides 10; General Procedure: To a
solution of (2S)-benzyl 2-(N-tosyl-4-tolylsulfonimidoyl-
carbamoyl)pyrrolidine-1-carboxylate (9; 800 mg, 1.44
mmol) in CH2Cl2 (32 mL), was added 10% Pd/C (86 mg).
The mixture was stirred for 24 h at room temperature under
a hydrogen atmosphere. The reaction mixture was filtered
through a pad of Celite® and silica and rinsed with CH2Cl2–
MeOH (9:1, 30 mL). The solvent was removed under
reduced pressure and the residue was purified by column
chromatography (CH2Cl2–MeOH, 9:1). Products 10 were
isolated as white solids.
For analytical data of (S,R)-10 and (S,R)-10 see Supporting
Information.
(10) The use of solvents such as dimethylsulfoxide, methanol,
tetrahydrofuran, and dichloromethane led to low catalyst
activity and stereoselectivity.
Synlett 2009, No. x, A–D © Thieme Stuttgart · New York

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