Nonenzymatic kinetic resolution of amines in ionic liquids

Article abstract of DOI:10.1055/s-2007-1000879

Ionic liquids are remarkably suitable and clean media for performing nonenzymatic kinetic resolution (KR) of amines through enantioselective N-acetylation: high levels of selectivity were obtained with a large variety of amines at room temperature (up to s = 30). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000879

2
68
LETTER
1
Nonenzymatic Kinetic Resolution of Amines in Ionic Liquids
ds Sabot, Pithani V. Subhash, Alain Valleix, Stellios Arseniyadis,* Charles Mioskowski*a,b
a
a
b
a,2
N
C
onenzymatic
K
i
y
netic Resolu
r
tion of
A
i
mines
l
in Ioni
l
c
Liqui
e
a
Laboratoire de Synthèse Bio-Organique associé au CNRS, Faculté de Pharmacie, Université Louis Pasteur de Strasbourg,
4 route du Rhin, 67401 Illkirch-Graffenstaden, France
7
Fax +33(1)40794660; E-mail: stellios.arseniyadis@espci.fr
CEA-Saclay, Service des Molécules Marquées, Bât. 547, Département de Biologie Cellulaire et Moléculaire,
b
91191 Gif-sur-Yvette, France
Received 5 October 2007
been reported to offer practically useful levels of stereose-
lectivity (selectivity factor s ≥10). Recently, we reported
the design, the synthesis, and the use of a highly enan-
tioselective acetylating agent for the KR of primary
amines (Figure 2). Derived from chiral 1,2-disulfonamide
Abstract: Ionic liquids are remarkably suitable and clean media for
performing nonenzymatic kinetic resolution (KR) of amines
through enantioselective N-acetylation: high levels of selectivity
were obtained with a large variety of amines at room temperature
(
up to s = 30).
(
1S,2S)-1, this new reagent led to unprecedented levels of
Key words: kinetic resolution, amines, ionic liquids, nonenzymatic
selectivity (s = 115) at –20 °C along with a unique sol-
vent-induced reversal of stereoselectivity.1 Following
this work, we also reported the first example of a fully re-
cyclable polymer-supported acetylating agent which of-
fered good enantioselection on a wide range of
substrates.20 The power of this methodology was further
demonstrated by Anstiss and Nelson in their recent total
synthesis of dragmacidin A in which the various existing
methods were compared.21
8,19
Ionic liquids, also known as molten salts, have gained in-
creasing attention as environmentally benign reaction me-
dia as they possess many attractive properties such as
negligible vapor pressure, high thermal and chemical sta-
bility, and good solvating ability for a large range of sub-
3
strates. Made of poorly coordinating ions, they have the
potential of being highly polar and yet noncoordinating
solvents. Finally, another attractive feature concerns the
ability to readily tune their physical and chemical proper-
ties by modifying their structure with respect to the choice
of the anion and/or the organic cation (Figure 1). As a
consequence, ionic liquids have been widely used as alter-
native solvents in a plethora of useful synthetic transfor-
O
Tf
N
Tf
N
H
H
R
N
N
Tf
Tf
4
5
9
mations such as oxidations,
hydrogenations,
R = H
(1S,2S)-2
(1S,2S)-1
6
7
8
esterifications, alkylations, Friedel–Crafts, Mannich
and Baeyer–Villiger reactions, silyl enol ether formation
from aldehydes and ketones, Diels–Alder cycloaddi-
tions, cross-coupling reactions, and various enzymatic
1
0
Figure 2 Enantioselective acetylating agent for the KR of primary
amines
1
1
1
2
13
1
4
transformations.
Herein, we wish to report the first example of a nonenzy-
matic amine KR process to be performed in an ionic liquid
medium which offers high levels of selectivity at room
temperature.
X–
X–
X–
X–
R
R
N
R
R'
P
N
N
R
R'
R
R'
N
R
R
Following our initial observation that dipolar aprotic sol-
vents such as DMPU and DMF lead to high levels of enan-
tioselection with preferential acetylation of the (S)-
enantiomer, we decided to investigate further the influ-
ence of the solvent with the scope to improve the selectiv-
ity and perhaps propose a mechanistic rationale. The use
of ionic liquids appeared to us as the most appealing vari-
ation as they are both highly polar and readily tunable sol-
vents. In order to increase our chances of observing good
enantioselection, we initially focused on screening room
R'
I
II
III
X = Cl, Br, BF4, NTf2, PF6 ...
IV
Figure 1 Ionic Liquids
In recent years, important research efforts were dedicated
to the development of an efficient nonenzymatic process
which would enable separation of two enantiopure amines
from a racemic mixture. As a result, several families of
3d
temperature ionic liquids (RTILs) such as 1-butyl-3-
1
5,16
17
chiral reagents
as well as one catalytic system have
methylimidazolium tetrafluoroborate [bmim][BF ], 1-
4
ethyl-3-methylimidazolium
bistrifluoromethylsulfo-
SYNLETT 2008, No. 2, pp 0268–0272
Advanced online publication: 04.01.2008
DOI: 10.1055/s-2007-1000879; Art ID: D31607ST
x
x.
x
x.
2
0
0
7
nylimide [emim][NTf ], 1-butyl-3-methylimidazolium
2
bistrifluoromethylsulfonylimide [bmim][NTf ], 1-butyl-
2
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Nonenzymatic Kinetic Resolution of Amines in Ionic Liquids
269
Table 1 Influence of the IL on the Selectivity Using (1S,2S)-2
3-methylimidazolium hexafluorophosphate [bmim][PF6],
and N-butylpyridinium bistrifluoromethylsulfonylimide
NH2
NHAc
NH2
(
1S,2S)-2 (0.5 equiv)
[
bupy][NTf ]. Reactions were typically carried out by
2
+
R
R'
solvent, temp.
R
*
R'
R
R'
adding two equivalents of (±)-1-phenylethylamine to a
0.12 M solution of (1S,2S)-2 in the selected ionic liquid at
room temperature. The results are reported in Table 1.
*
racemic
a
Entry
Time (h) Temp (°C) Molten salt
ee (%)
Unfortunately, while complete conversion of the starting
material was observed in all five RTILs tested, the enan-
tiomeric excess of the acetylated product was low, rang-
ing from 0% to 20% (Table 1, entries 1–5). For
comparison purposes, the same acetamide was isolated in
quantitative yield and up to 84% ee when the reaction was
performed in DMPU under otherwise identical conditions
(s = 30).18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
25
25
[bmim][BF4]
0
[emim][NTf2]
0
25
[bmim][NTf2]
10 (S)b
20 (S)
20 (S)
60 (S)
40 (S)
64 (S)
70 (S)
84 (S)
25
[bmim][PF6]
25
[bupy][NTf2]
Interestingly, however, when the reactions were run in tet-
90
[n-Bu N][Cl]
4
rabutylammonium chloride [n-Bu N][Cl], tetrabutylphos-
4
90
[n-Bu P][Cl]
4
phonium chloride [n-Bu P][Cl], tetrabutylpyridinium
4
chloride [bupy][Cl], and tetrabutylphosphonium bromide
120
120
30
[bupy][Cl]
[
n-Bu P][Br], which all possess high melting points rang-
4
[n-Bu P][Br]
4
ing from 90 °C to 120 °C, we were able to isolate the de-
sired acetamide in excellent yields and moderate to good
selectivities (Table 1, entries 6–9). For example, up to
10
[n-Oct MeN][Cl]
3
a
Enantiomeric excess was determined by HPLC analysis using a
chiral phase column.
Absolute configuration of the acetylated enantiomer was assigned
by comparison with an authentic standard.
7
0% ee (s = 12) could be reached at temperatures as high
as 120 °C when [n-Bu P][Br] was used (Table 1, entry 9).
b
4
These interesting yet unexpected results, for temperatures
of this magnitude, set the grounds for our study. As a di-
rect consequence, imidazolium-based ionic liquids were
Table 2 Kinetic Resolution of Various Amines Using (1S,2S)-2
NH2
NHAc
NH2
(
1S,2S)-2 (x equiv)
+
R
R'
solvent, temp.
R
*
R'
R
R'
*
racemic
a
Entry
Amine
Product
ee (%)
DMPUb
Aliquat 336c
®
NH2
NHAc
*
1
2
3
90 (s = 29)
84 (s = 30)
NH2
NH2
NHAc
*
86 (s = 20)
69 (s = 7)
80 (s = 22)
NHAc
*
40 (s = 3)
NH2
NHAc
*
4
73 (s = 9)
78 (s = 19)
82 (s = 25)
CO2Me
NH2
CO2Me
*
5
80 (s = 13)
NHAc
a
Enantiomeric excess was determined by HPLC analysis using a chiral phase column.
b
c
The reaction was performed in DMPU at –20 °C using 3 equiv of (±)-1-phenylethylamine with respect to (1S,2S)-2.
®
The reaction was performed in Aliquat 336 (n-Oct MeN][Cl]) at 30 ºC using 2 equiv of (±)-1-phenylethylamine with respect to (1S,2S)-2.
3
Synlett 2008, No. 2, 268–272 © Thieme Stuttgart · New York

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70
C. Sabot et al.
LETTER
discarded in favor of an ammonium-based ionic liquid. Hence, we could achieve the stereoselective acetylation of
Hence, a new experiment was performed using methyltri- a family of racemic amines with moderate to good enan-
octyl ammonium chloride [n-Oct MeN][Cl]. Also known tioselection.22 For example, KR of (±)-a-ethylbenzyl-
3
®
as Aliquat 336, this ionic liquid has the advantage of be- amine (Table 2, entry 2) was obtained with 80% ee (s =
ing liquid at room temperature. Thus, the reaction was 22),
performed under the standard acetylating conditions, i.e. (Table 2, entry 3), (±)-1-naphthylethylamine (Table 2, en-
.5 equivalent of (1S,2S)-2 with respect to the racemic try 4) and (±)-phenylalanine methyl ester (Table 2, entry
while
(±)-1,2,3,4-tetrahydro-1-naphthylamine
0
amine used. Surprisingly, under these reaction conditions, 5) were resolved with 40% (s = 3), 78% (s = 19) and 82%
the KR of (±)-1-phenylethylamine was obtained in quan- ee (s = 25) values, respectively. In addition, it is notewor-
titative yield and up to 84% ee, which represented a selec- thy that the selectivities observed when using [n-
tivity factor s of 30 that compared favorably with most of Oct MeN][Cl] as the solvent at room temperature with
3
the nonenzymatic methods reported so far in the two equivalents of racemic amine (50% maximum con-
1
5–20
literature
(Table 1, entry 10). Moreover, as anticipat- version) were higher than those observed in DMPU using
ed, the selectivity observed in this solvent system was three equivalents of racemic amine at –20 °C.18
similar to that observed in conventional polar nonprotic
Another aspect of the project was to propose a mechanism
solvents such as DMF and DMPU as preferential acetyla-
which could explain the selectivities observed during the
tion of the S-enantiomer occurred.
KR process. In a previous paper, we had suggested that in
®
Aliquat 336 therefore became the ionic liquid of choice polar solvents the attack of the amine could be guided by
for performing nonenzymatic KR of primary amines. the strong hydrogen bonding with the acid-free sulfon-
Scheme 1
Synlett 2008, No. 2, 268–272 © Thieme Stuttgart · New York

LETTER
Nonenzymatic Kinetic Resolution of Amines in Ionic Liquids
271
amide NH while sterics would mainly govern the selectiv-
ity in nonpolar solvents, thus making polarity a key factor.
We now believe that it is more the Lewis acid/base char-
acter of the solvent, rather than its polarity, that governs
the selectivity. Since (1S,2S)-2 is S-selective in basic sol-
(3) For recent reviews on ionic liquids, see: (a) Zhao, H.;
Malhotra, S. V. Aldrichimica Acta 2002, 35, 75.
(
(
1
(
b) Sheldon, R. Chem. Commun. 2001, 2399.
c) Wasserscheid, P.; Kein, W. Angew. Chem. Int. Ed. 2001,
12, 3926. (d) Welton, T. Chem. Rev. 1999, 99, 2071.
e) Tzschucke, C. C.; Markert, C.; Bannwarth, W.; Roller,
2
3
vents such as DMF, DMPU and now ionic liquids, and
S.; Hebel, A.; Haag, R. Angew. Chem. Int. Ed. 2002, 41,
3964.
1
8
is R-selective in more acidic solvents such as CH Cl ,
2
2
we suggest that the reaction proceeds via one of two dis-
tinct pathways depending on the nature of the solvent used
(4) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V.
Tetrahedron 2004, 60, 2131.
(
5) (a) Anderson, K.; Fernández, S. C.; Hardacre, C.; Marr, P. C.
Inorg. Chem. Commun. 2004, 7, 73. (b) Berthod, M.;
Joerger, J.-M.; Mignani, G.; Vaultier, M.; Lemaire, M.
Tetrahedron: Asymmetry 2004, 15, 2219. (c) Lee, S.-G.;
Zhang, Y. J.; Piao, J. Y.; Yoon, H.; Song, C. E.; Choi, J. H.;
Hong, J. Chem. Commun. 2003, 2624. (d) Wolfson, A.;
Vankelecom, I. F. J.; Jacobs, P. A. Tetrahedron Lett. 2003,
(
Scheme 1). The first one (Path A), involves a reversible,
nonselective attack of the amine onto the activated acetyl
group, thus leading to a mixture of four hemiaminal dia-
2
4
stereoisomeric intermediates, followed by a selective
cleavage which leads to the enantioenriched acetylated
amine product. The selectivity in this case would there-
fore be under thermodynamic control. The second path-
way (Path B), on the other hand, involves an
enantioselective attack of the amine onto the activated
acetyl group (probably governed by steric effects), and
leads to a mixture of just two hemiaminal diastereoiso-
meric intermediates which would both cleave to give the
same enantioenriched acetylated amine product. As the
formation/cleavage of hemiaminals is known to be acid-
catalyzed, we speculate that the acid-free sulfonamide NH
could be responsible for the equilibrium displacement in
Path A, thus making this pathway favored in more acidic
media. On the other hand, more basic solvents should pre-
vent the equilibrium from taking place, resulting in the se-
lectivity being mainly induced during the attack of the
amine onto the activated acetyl group as illustrated in Path B.
4
4, 1195.
6) (a) Itoh, T.; Han, S.; Matsushita, Y.; Hayase, S. Green Chem.
004, 6, 437. (b) Imrie, C.; Elago, E. R. T.; McCleland, C.
(
(
(
(
2
W.; Williams, N. Chem. Commun. 2002, 159.
7) (a) Law, M. C.; Wong, K.-Y.; Chan, T. H. Green Chem.
2004, 6, 241. (b) Yoo, K.; Namboodiri, V. V.; Varma, R. S.;
Smirniotis, P. G. J. Catal. 2004, 222, 511.
8) (a) Baleizão, C.; Pires, N.; Gigante, B.; Curto, M. J. M.
Tetrahedron Lett. 2004, 45, 4375. (b) Gmouh, S.; Yang, H.;
Vaultier, M. Org. Lett. 2003, 5, 2219.
9) (a) Zhao, G.; Jiang, T.; Gao, H.; Han, B.; Huang, J.; Sun, D.
Green Chem. 2004, 6, 75. (b) Kabalka, G. W.; Venkataiah,
B.; Dong, G. Tetrahedron Lett. 2004, 45, 729. (c) Yang, X.-
F.; Wang, M.; Varma, R. S.; Li, C.-J. Org. Lett. 2003, 5, 657.
(10) Bernini, R.; Coratti, A.; Fabrizi, G.; Goggiamani, A.
Tetrahedron Lett. 2003, 44, 8991.
(
(
11) Smietana, M.; Mioskowski, C. Org. Lett. 2001, 3, 1037.
12) (a) Kumar, A.; Pawar, S. S. J. Org. Chem. 2004, 69, 1419.
(b) Yadav, J. S.; Reddy, B. V. S.; Reddy, J. S. S.; Rao, R. S.
Tetrahedron 2003, 59, 1599. (c) Meracz, I.; Oh, T.
Tetrahedron Lett. 2003, 44, 6465.
13) (a) Wang, A.-E.; Zhong, J.; Xie, J.-H.; Li, K.; Zhou, Q.-L.
Adv. Synth. Catal. 2004, 346, 595. (b) Arentsen, K.;
Caddick, S.; Cloke, F. G. N.; Herring, A. P.; Hitchcock, P.
B. Tetrahedron Lett. 2004, 45, 3511. (c) Jensen, J. F.;
Johannsen, M. Org. Lett. 2003, 5, 3025. (d) Miao, W.;
Chan, T. H. Org. Lett. 2003, 5, 5003. (e) Rajagopal, R.;
Jarikote, D. V.; Srinivasan, K. V. Chem. Commun. 2002,
In summary, we have developed the first example of a
nonenzymatic amine KR process to be performed in an
ionic liquid medium, with relatively high selectivities as
compared to all the other methods described in the litera-
ture. The main features of this reaction are as follows: (1)
the procedure is operationally simple; (2) the KR of a va-
riety of amines resulted in quantitative yields and high
enantioselectivities without the need to recourse to low
temperatures; (3) the method provides a green alternative
as it avoids the use of hazardous organic solvents. Finally,
we have proposed a plausible mechanistic rationale which
could explain the selectivities observed.
(
616. (f) Park, S. B.; Alper, H. Org. Lett. 2003, 5, 3209.
(
(
14) (a) Erbeldinger, M.; Mesiano, A. J.; Russel, A. Biotechnol.
Prog. 2000, 16, 1131. (b) Lau, R. M.; Van Rantwijk, F.;
Seddon, K. R.; Sheldon, R. A. Org. Lett. 2000, 2, 4189.
(
c) Lundell, K.; Kurki, T.; Lindroos, M.; Kanerva, L. T. Adv.
Synth. Catal. 2005, 347, 1110.
Acknowledgment
15) Kondo, K.; Kurosaki, T.; Murakami, Y. Synlett 1998, 725.
The authors would like to thank Professor T. Welton (Imperial Col-
lege London) for fruitful discussions and Rhodia for financial sup-
port.
(16) Ie, Y.; Fu, G. C. Chem. Commun. 2000, 119.
(17) (a) Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem.
Int. Ed. 2001, 40, 234. (b) Arp, F. O.; Fu, G. C. J. Am.
Chem. Soc. 2006, 128, 14264.
(
18) Arseniyadis, S.; Valleix, A.; Wagner, A.; Mioskowski, C.
Angew. Chem. Int. Ed. 2004, 43, 3314.
References and Notes
(
19) Arseniyadis, S.; Subhash, P. V.; Valleix, A.; Mathew, S. P.;
Blackmond, D. G.; Wagner, A.; Mioskowski, C. J. Am.
Chem. Soc. 2005, 127, 6138.
20) Arseniyadis, S.; Subhash, P. V.; Valleix, A.; Wagner, A.;
Mioskowski, C. Chem. Commun. 2005, 3310.
(
(
1) Charles Mioskowski (1946–2007).
2) Present address: Laboratoire de Chimie Organique, CNRS,
ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France.
(
(
(
21) Anstiss, M.; Nelson, A. Org. Biomol. Chem. 2006, 4, 4135.
22) General Procedure: The racemic amine (0.24 mmol) was
added to a stirred solution of (1S,2S)-2 (50 mg, 0.12 mmol)
in the chosen ionic liquid at the selected temperature. The
Synlett 2008, No. 2, 268–272 © Thieme Stuttgart · New York

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C. Sabot et al.
LETTER
reaction mixture was stirred at the same temperature until
complete conversion of the acetylating agent [reaction
followed by TLC analysis (EtOAc–n-hexane, 2:8)]. Once
chromatography on silica gel (EtOAc–hexane, 1:1), and the
enantiomeric excess was determined by HPLC on a chiral
stationary phase.
–
–
complete conversion of the reagent was observed, H O and
(23) The counterion (Cl , NTf , etc.) confers the basic character
2
2
EtOAc were added and the two phases were separated. The
to the ionic liquids.
organic phase was dried over MgSO and evaporated under
reduced pressure. The resulting residue was purified by flash
(24) The equilibrium could be displaced in an enantioselective
fashion by the acid-free sulfonamide.
4
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