Ionic liquids incorporating camphorsulfonamide units for the Ti-promoted asymmetric diethylzinc addition to benzaldehyde

Article abstract of DOI:10.1016/j.tetlet.2004.09.038

New hydrophobic ionic liquids containing camphorsulfonamide units were used as chiral auxiliaries in the titanium catalyzed asymmetric addition of diethylzinc to benzaldehyde. New hydrophobic ionic liquids containing chiral camphorsulfonamide units were used as chiral auxiliaries in the titanium catalyzed asymmetric diethylzinc addition to benzaldehyde. The ionic catalyst system shows catalytic properties similar to those of related nonionic counterparts in terms of activity and enantioselectivity. Interestingly, the ionic ligands can easily be recycled and re-used without loss of activity or selectivity.

Full text of DOI:10.1016/j.tetlet.2004.09.038

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8157–8160
Ionic liquids incorporating camphorsulfonamide units for the
Ti-promoted asymmetric diethylzinc addition to benzaldehyde
*
ˆ
Benoıt Gadenne, Peter Hesemann and Joe¨l J. E. Moreau
´ ´ ´ ´
UMR5076 CNRS/ENSCM, Heterochimie Moleculaire et Macromoleculaire, 8, rue de l’Ecole Normale, 34296 Montpellier, France
Received 15 July 2004; revised 3 September 2004; accepted 6 September 2004
Available online 21 September 2004
Abstract—New hydrophobic ionic liquids containing chiral camphorsulfonamide units were used as chiral auxiliaries in the titanium
catalyzed asymmetric diethylzinc addition to benzaldehyde. The ionic catalyst system shows catalytic properties similar to those of
related nonionic counterparts in terms of activity and enantioselectivity. Interestingly, the ionic ligands can easily be recycled and re-
used without loss of activity or selectivity.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Transition metal catalysis in ionic liquids (ILs) is a field
of intense research activity and led to numerous applica-
tions in organic synthesis1,2 and asymmetric catalysis.3
A variety of catalytic reactions was successfully per-
formed in biphasic mixtures consisting in ionic liquids
and nonpolar organic solvents. This ÔheterogenizationÕ
of reaction media offers a promising way for catalyst
separation and recovery. The utilization of task specific
ionic liquids (TSILs) as metal ligands4 is also attractive
in view of the recycling of the ionic auxiliary. This strat-
egy, particularly interesting for precious chiral auxilia-
ries for asymmetric catalysis, leads also to enhanced
catalyst stability and avoids catalyst leaching.5
sion problems can be excluded, as the reactions are
performed in monophasic media. (3) Since ionic com-
pounds are insoluble in nonpolar solvents, the pure
functional ionic liquid can easily be separated from the
reaction products by a simple diethyl ether treatment.
The recovered chiral ionic auxiliary can subsequently
be re-used for a new reaction cycle.
We decided to focus on the synthesis of ionic com-
pounds bearing chiral camphorsulfonamide units. Yus
et al. described that camphorsulfonamides are efficient
chiral ligands in the titanium promoted addition of
organozinc reagents to aldehydes and ketones.8 A large
variety of chiral ligands bearing camphorsulfonamide
units has been studied during the last few years.9
Our current interest in heterogenized enantioselective
catalyst systems6 led us to explore functionalized ionic
compounds bearing chiral entities. Here, we report the
use of TSILs as reusable chiral auxiliaries in homogene-
ous asymmetric catalysis using organic solvents as reac-
tion media. We wanted to take advantage of the
solubility of numerous hydrophobic ionic liquids in
polar organic solvents (dichloromethane, alcohols) in
order to perform asymmetric reactions in a monophasic
reaction medium. This approach presents several advan-
tages compared with catalytic reactions performed in
biphasic reaction media. (1) It avoids the utilization of
conventional ionic liquids based on imidazolium species,
which may appear of low chemical stability.7 (2) Diffu-
The synthesis of an imidazole functionalized
camphorsulfonamide was firstly achieved by reacting
D-camphor-10-sulfonyl chloride and N-(3-aminopro-
pyl)-imidazole 1 (Scheme 1).
N
N
NH2
CH2Cl2, NEt3
r. t.
SO2
O
+
N
N
N
H
ClO2S
O
(1)
Keywords: Ionic liquids; Asymmetric catalysis; Chiral auxiliaries.
*
Scheme 1. Synthesis of the imidazole functionalized D-camphorsul-
fonamide (1).
Corresponding author. Tel.: +33 4 67 14 72 11; fax: +33 4 67 14 72
12; e-mail: jmoreau@cit.enscm.fr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.038

8158
B. Gadenne et al. / Tetrahedron Letters 45 (2004) 8157–8160
-
-
-
NTf
NTf
2
2
NTf
2
OH
SO2
SO2
C4H9
C4H9
OH
N
N
N
H
N
N
N
H
SO2
a)
O
Bu
N
N
N
H
(6a)
(6b)
1. alkylation (BuBr)
2. anion exchange (LiNTf )
2
(2)
Scheme 4. TSILs bearing borneol (6a) and isoborneol (6b) entities.
(1)
1. alkylation (BuBr)
2. reduction (NaBH )
4
3. anion exchange (LiNTf )
2
-
OH
CH3
NTf
H
O
2
H
i
b)
Ti(OPr ) , L*(10 mol-%)
4
OH
SO2
Bu
+
Et Zn
2
N
N
N
H
CH Cl
2
2
(3)
Scheme 2. Synthesis of TSILs bearing camphorsulfonamide entities.
Scheme 5. Addition of diethylzinc to benzaldehyde.
Alkylation of 1 with n-butylbromide and subsequent an-
ion exchange using lithio-bis-trifluorosulfonylimide led
to the formation of the hydrophobic ionic compound
2 functionalized with D-camphorsulfonamide entities
(Scheme 2, a).
with borneol (6a) or isoborneol groups (6b) (Scheme
4).10
The catalytic properties of the ligands 1, 2, 3, 6a and 6b
were evaluated in the addition of diethylzinc to benzal-
dehyde (Scheme 5).11
In a similar way, we synthesized ionic compounds bear-
ing borneol units. The ionic compound 3 was prepared
in a three step synthesis involving an alkylation–reduc-
tion–anion exchange sequence from the imidazole func-
tionalized camphorsulfonamide 1 (Scheme 2, b). The
reduction of the keto group of the camphor unit in 1
was performed using sodium borohydride, yielding a
mixture of ionic borneol (endo-) and isoborneol (exo-)
diastereoisomers. The exo:endo ratio of the hydroxyl
groups in the reduced product, determined by 1H
NMR spectroscopy, was found to be 60:40.8a
The test reaction was carried out in homogeneous solu-
tion using dichloromethane as solvent.12 The treatment
of the reaction mixture by a simple evaporation–hydro-
lysis–diethyl ether work-up permitted the separation of
the chiral ionic liquids from the reaction products. The
recovered ionic camphorsulfonamide ligands were re-
used in other reaction cycles.
The results are summarized in Table 1.
The evaluation of the catalytic properties of the chiral
ligands showed high activities for all synthesized chiral
auxiliaries. In all cases, the observed conversions in the
TiIV-catalyzed alkylation of benzaldehyde in the pres-
ence of the camphorsulfonamide ligands were >99%.
The exo/endo stereochemistry of the hydroxyl group
is of particular importance for the selectivity of the
borneol derived ligands. Isoborneol (exo-borneol) deri-
vatives showed higher selectivities than the corres-
ponding borneol diastereoisomers.8a We therefore
synthesized enantiopure samples of these chiral ionic
auxiliaries. As the separation of the diastereoisomeric
Concerning the enantioselectivity, the nonionic cam-
phorsulfonamide ligand 1 showed low enantioselectivity
(3% ee, entry 1), which may be due to a coordinating
effect of the terminal imidazole substructures. Increased
functionalized borneol derivatives
4
by column
chromatography was unsuccessful, we synthesized the
brominated sulfonamide 5 (Scheme 3) by coupling 3-
bromopropylammonium bromide with D-camphor-10-
sulfonyl chloride and subsequent reduction using
sodium borohydride. Column chromatography allowed
the separation of the two diastereoisomers.
Table 1. Enantioselective addition of diethylzinc to benzaldehydea
Entry
Ligand
ee (configuration)b
First
cycle
Second
cycle
Third
cycle
Fourth
cycle
Reaction of exo-5 and endo-5 with n-butylimidazole, fol-
lowed by bromide–bis-trifluorosulfonylimide exchange
led to the enantiopure ionic liquids functionalized either
1
2
3
4
5
6
7
1
3 (S)
—
—
—
2
40 (S)
50 (S)
24 (S)
65 (S)
27 (S)
64 (S)
39 (S)
49 (S)
—
39 (S)
49 (S)
—
38 (S)
—
—
3
6a
6b
7ac
7bc
64 (S)
—
—
65 (S)
—
—
64 (S)
—
—
SO2
SO2
OH
OH
a General reaction conditions: benzaldehyde:ligand:Ti(OiPr)4:Et2Zn =
1.0:0.1:1.1:1.2 (molar ratio), reaction time 18h, reaction temperature
N
N
N
Br
N
H
H
(4)
(5)
25ꢁC.
b Determined by HPLC using a Daicel Chiralcel OD column.
c Ref. 8a.
Scheme 3. Borneol/isoborneol sulfonamides functionalized with imi-
dazole (4) and bromide (5) groups.

B. Gadenne et al. / Tetrahedron Letters 45 (2004) 8157–8160
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Y.; Yang, J. Y. Tetrahedron Lett. 2002, 43, 8741; (f) Fraile,
enantioselectivity is observed with the corresponding
alkylated imidazolium compound 2 (40% ee, entry 2).
We also tested three different ionic borneol derived lig-
ands 3, 6a and 6b. The diastereoisomeric mixture 3 con-
taining the exo- and endo-isomer (ratio: 60:40) gave a
slightly higher enantioselectivity than the ionic cam-
phorsulfonamide ligand 2 (50% ee, entry 3). The enan-
tiopure samples 6a and 6b led to the formation of
(S)-1-phenylpropanol with ee values of 24% and 65%,
respectively (entries 4 and 5). The ionic ligand appeared
efficient since the obtained enantioselectivities are simi-
lar to those reported for related nonionic species as for
the tert-butyl derivatives 7a and 7b (entries 6 and 7).8a
´
J. M.; Garcıa, J. I.; Herrerıas, C. I.; Mayoral, J. A.; Carrie,
D.; Vaultier, M. Tetrahedron: Asymmetry 2001, 12, 1891;
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´
4. (a) Audric, N.; Clavier, H.; Mauduit, M.; Guillemin, J.-C.
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J.; Silva, S. M.; Kamer, P. C. J.; van Leeuwen, P. W. N.
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Waffenschmidt, H.; Machnitzki, P.; Kottsieper, K. W.;
Stelzer, O. Chem. Commun. 2001, 451; (e) Favre, F.;
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Chem. Commun. 2001, 1360; (f) Brasse, C. C.; Englert,
U.; Salzer, A. Organometallics 2000, 19, 3818.
OH
SO2
SO2
OH
N
H
N
H
(7a)
(7b)
We also studied the recycling of the ionic chiral auxilia-
ries. After the separation from the reaction products, by
an ether treatment, the ionic ligands 2, 3 and 6b were re-
used up to three times in the asymmetric addition of
diethylzinc to benzaldehyde. We observed no variation
of the catalytic activity or selectivity of the ionic com-
pounds (entries 2, 3 and 5). The identical spectroscopic
properties of the TSILs after the repeated reaction cycles
indicated high chemical stability of the ionic ligands un-
der the reaction conditions.
5. Chiral ionic liquids in asymmetric catalysis: (a) Baleiza˜o,
C.; Gigante, B.; Garcia, H.; Corma, A. Tetrahedron Lett.
2003, 44, 6813; (b) Lee, S. G.; Zhang, Y. J.; Piao, J. Y.;
Yoon, H.; Song, C. E.; Choi, J. H.; Hong, J. Chem.
Commun. 2003, 2624.
6. (a) Hesemann, P.; Moreau, J. J. E. Tetrahedron: Asym-
metry 2000, 11, 2183; (b) Herres, S.; Hesemann, P.;
Moreau, J. J. E. Eur. J. Org. Chem. 2003, 99; (c) Brethon,
A.; Moreau, J. J. E.; Wong Chi Man, M. Tetrahedron:
Asymmetry 2004, 15, 495.
7. Aggarwal, V. K.; Emme, I.; Mereu, A. Chem. Commun.
2002, 1612.
´
8. (a) Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 1997,
8, 2479; (b) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed.
2004, 43, 284, and references cited therein.
9. (a) Bauer, T.; Gajewiak, J. Tetrahedron 2003, 59, 10009;
In conclusion, we report the utilization of new chiral
TSILs as enantioselective ligands in homogeneous asym-
metric catalysis. Here, we focused on the synthesis of
new TSILs functionalized with camphor- and borneol-
sulfonamides. These ionic ligands show catalytic proper-
ties similar to nonionic counterparts.8a This approach
offers advantages in combining homogeneous catalysis
and easy separation of the chiral ionic ligand. The ionic
ligand can be re-used several times without loss in activ-
ity or selectivity.
´
´
(b) Garcıa, C.; Walsh, P. J. Org. Lett. 2003, 5, 3641; (c)
Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125,
9544, and references cited therein.
10. Selected data for 1-butyl-3-3-[(1S,2S,4S)-(2-hydroxy-7,7-
dimethyl-bicyclo[2.2.1]hept-1-ylmethyl)sulfamoyl]-propyl-
3H-imidazol-1-ium
bis-(trifluoromethanesulfonyl)imide
1
6a: H NMR (CDCl3): d 0.8–1.1 (m, 9H, 3 · CH3), 1.20–
1.40 (m, 3H, CH + CH2), 1.68–1.95 (m, 4H, 2 · CH2),
2.10–2.20 (m, 2H), 2.25–2.4 (m, 2H), 2.98 (d, 1H,
J = 14.4Hz), 3.10 (d, 1H, J = 14.4Hz), 3.10–3.20 (m,
2H), 3.94 (br s, 1H), 4.00 (t, 2H, J = 7.2Hz), 4.14 (t, 2H,
J = 7.4Hz), 4.22–4.40 (m, 3H, CH + CH2), 6.08 (br s, 1H),
7.26 (s, 1H), 7.47 (s, 1H), 8.80 (s, 1H); 13C NMR (CDCl3)
d 13.6, 19.1, 19.8, 20.7, 24.1, 28.6, 30.5, 32.1, 39.0, 40.3,
44.4, 47.6, 50.4, 51.3, 51.9, 55.2, 75.6, 120.3 (q, –CF3,
J = 323Hz), 122.6, 123.2, 136.1; HRMS [FAB+] calcd. for
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2004.
09.038.
25
C20H36N3O3S1 (M)+ 398.2477, found 398.2501; ½aꢀD +5.5
References and notes
(c 0.55, CH2Cl2).Selected data for 1-butyl-3-3-
[(1S,2R,4S)- (2-hydroxy-7,7-dimethyl-bicyclo[2.2.1]hept-1-
1. Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis;
Wiley-VCH: Weinheim, 2002.
ylmethyl)sulfamoyl]-propyl-3H-imidazol-1-ium
bis-(tri-
fluoromethanesulfonyl)imide 6b: 1H NMR (CDCl3): d
0.78 (s, 3H), 0.92 (t, 3H, J = 7.4Hz), 1.01 (s, 3H), 1.22–
1.46 (m, 3H, CH + CH2), 1.56–1.89 (m, 8H, 4 · CH2), 2.12
(m, 2H), 2.87 (d, 1H, J = 13.9Hz), 3.15 (m, 3H,
CH + CH2), 3.39 (d, 1H, J = 13.9Hz), 3.99 (m, 1H), 4.12
(t, 2H, J = 7.4Hz), 4.31 (t, 2H, J = 6.4Hz), 5.61 (bt, 1H),
7.27 (s, 1H), 7.44 (s, 1H), 8.69 (s, 1H); 13C NMR (CDCl3)
d 13.6, 19.8, 20.1, 20.7, 27.7, 30.4, 30.9, 32.1, 39.5, 40.1,
2. Recent review articles: (a) Welton, T. Chem. Rev. 1999, 99,
2071–2083; (b) Wasserscheid, P.; Keim, W. Angew. Chem.,
Int. Ed. 2000, 39, 3772–3789; (c) Sheldon, R. Chem.
Commun. 2001, 2399–2407; (d) Gordon, C. M. Appl.
Catal. A: General 2001, 222, 101–117.
3. For a review article see: (a) Baudequin, C.; Baudoux, J.;
Levillain, J.; Cahard, D.; Gaumont, A.-C.; Plaquevent, J.-C.

8160
B. Gadenne et al. / Tetrahedron Letters 45 (2004) 8157–8160
44.8, 47.4, 49.2, 50.4, 50.7, 51.8, 76.7, 120.1 (q, –CF3,
J = 321Hz), 122.7, 123.2, 136.0; HRMS [FAB+] calcd. for
stirred for another 15min and benzaldehyde (228lL,
2.5mmol) was added. After stirring at room temperature
during 18h, the solvent was pumped off. The reaction
mixture was dissolved in 1mL of EtOH and quenched by
the addition of 15mL of 1N hydrochloric acid. The
diethyl ether extract of this mixture was dried and the
conversion and ee value were determined by 1H NMR and
chiral HPLC (stationary phase: Chiralcel OD, mobile
phase: hexane/isopropanol 9/1), respectively. A second
extraction of the hydrolysed reaction medium using
dichloromethane afforded the TSIL. The purity of the
25
C20H36N3O3S1 (M)+ 398.2477, found 398.2477; ½aꢀD ꢁ16.4
(c 0.97, CH2Cl2).
11. (a) Walsh, P. J. Acc. Chem. Res. 2003, 36, 739; (b) Pu, L.
Chem. Rev. 2001, 101, 757–824.
12. General procedure for the asymmetric addition of dieth-
ylzinc to benzaldehyde. A Schlenk tube equipped with a
stirring bar was charged with the ionic liquid (0.25mmol).
After drying in vacuo, the solvent dichloromethane
(10mL) and Ti(O-iPr)4 (810lL, 2.75mmol) were added.
The resulting mixture was stirred at room temperature for
1h. Then, diethylzinc (1M in hexane) (3.0mL, 3.0mmol)
was added. The resulting homogeneous solution was
1
recovered TSIL was checked by H NMR after washing
the CH2Cl2 extract with 1N hydrochloric acid and water,
drying and solvent evaporation.