(S)-Pyrrolidin-2-ylmethyl-1,2,3-triazolium salts - Ionic liquid supported organocatalysts for enantioselective Michael additions to β-nitrostyrenes

Article abstract of DOI:10.1055/s-2008-1078593

(S)-Pyrrolidin-2-ylmethyl-1,2,3-triazolium salts were synthesized as new task-specific ionic liquids via click reaction and alkylation. They serve as excellent recyclable catalysts in enantioselective Michael additions to nitrostyrenes in excess of carbon

Full text of DOI:10.1055/s-2008-1078593

2342
LETTER
(S)-Pyrrolidin-2-ylmethyl-1,2,3-triazolium Salts – Ionic Liquid Supported
Organocatalysts for Enantioselective Michael Additions to b-Nitrostyrenes
(S
)-Pyrrolidin-2
e
-ylmethyl-
k
aum Salt rias Yacob, Jabbar Shah, Joachim Leistner, Jürgen Liebscher*
Institut für Chemie, Humboldt-Universität Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
Fax +49(30)20937552; E-mail: liebscher@chemie.hu-berlin.de
Received 12 May 2008
Abstract: (S)-Pyrrolidin-2-ylmethyl-1,2,3-triazolium salts were
X–
R
synthesized as new task-specific ionic liquids via click reaction and
alkylation. They serve as excellent recyclable catalysts in enantiose-
lective Michael additions to nitrostyrenes in excess of carbonyl
compounds as reactant and as solvent providing high yields and ste-
reoselectivities.
N
H
N
N
N
H
N
N
R
N
N
+
N
N
1
2
Figure 1
Key words: asymmetric organocatalysis, ionic liquids, Michael ad-
dition, task-specific ionic liquids
1. MeI, MeCN
reflux, 15 h
90–98%
I–
N
N
N
N
H
+
The Michael addition of CH-acidic carbonyl compounds
to nitroalkenes is the major pathway to g-nitrocarbonyl
compounds.1 The resulting motif can serve as reactant in
the synthesis of heterocycles, e.g. chiral lactones,2 pyr-
rolidine carboxylic acids,3 nitrocycloalkanes4 or b-carbo-
lines.5 For direct Michael additions to nitroalkenes a
number of organocatalytic systems,6 mainly (S)-pyrroli-
din-2-ylmethyl or proline derivatives,3,7–21 were applied
providing excellent yields and stereoselectivities. The
proline-derived 1,2,3-triazoles 1 (Figure 1) were obtained
by Cu(I)-mediated click reaction of (S)-N-Boc-pyrrolidin-
2-ylmethyl azide and alkynes and they allowed to perform
the addition of cyclohexanone to 1-nitro-2-arylethenes in
water.22,23 In order to facilitate easy catalyst recycling,
Michael additions to nitroalkenes were performed in ionic
liquids.24,25 Further interesting alternative task specific
ionic liquids (TSIL) were developed, where (S)-pyrroli-
din-2-ylmethyl moieties were covalently linked to
imidazolium26,27 or pyridinium rings.28 Amongst them the
triazolylphenyl-linked imidazolium salt 2 was found.4
Again, high yields and stereoselectivities were achieved
and catalyst recycling was straightforward. Their perfor-
mance was better than normal organocatalysts when dis-
solved in ionic liquids.
N
N
Boc
2. HCl/EtOH,
50 °C, 2 h
3. NaHCO3
84–90%
R
R
N
N
Me
3
4a R = Ph
4b R = n-Bu
Scheme 1
ing azide and then submitted to a Cu(I)-catalyzed click
reaction with alkynes according to a reported procedure.22
The resulting triazoles 3 were alkylated with iodomethane
and finally deprotected affording the envisaged TSIL 4,
appearing as yellowish oil 4b and as low melting solid 4a,
with melting point of 34 °C (Scheme 1).
In comparison with the known TSIL 2 the 1,2,3-triazole
ring of our compounds 4 does not only serve as a linker,
but also acts as the phase tag for convenient recycling.
Due to the closer proximity of the charged phase tag to the
organocatalytic pyrrolidine unit, better performance can
be expected in our case as is observed in analogues imida-
zolium compounds 2.27
We checked the performance of the triazolium salts 4 as
ionic liquid supported organocatalysts in Michael addi-
tion of cyclohexanone to b-nitrostyrenes (Table 1) and
studied the addition to b-nitrostyrene in more detail (en-
tries 1–7). The carbonyl component was used in excess as
solvent. Excellent yields, diastereoselectivities, and enan-
tioselectivities were obtained in the addition to b-nitrosty-
rene in the presence of the phenylsubstituted TSIL 4a
(entry 1).30 The catalyst could be easily recycled by ex-
traction of the reaction mixture with diethyl ether leaving
4a, which was then combined with a fresh batch of reac-
tants. In the second and third run (entries 2 and 3) slightly
reduced, yet still high yields and stereoselectivities were
achieved. However, after the catalyst had been recycled
for the third time, the enantioselectivity dropped to 58%.
Reduction of the amount of catalyst 4a to 5 mol% contin-
ued to give excellent yield and diastereoselectivity, but a
We recently disclosed a versatile novel concept for TSIL,
in which 1,2,3-triazolium salts serve as the IL unit and
other functions are covalently tethered in the side chains.29
We sought to verify whether this concept could be applied
in order to develop TSIL applicable in the direct asym-
metric Michael addition to nitroalkenes. The (S)-pyrroli-
din-2-ylmethyl group was chosen as chiral moiety. The
synthetic route started with (S)-N-Boc-pyrrolidin-2-yl-
methyltosylate, which was transferred to the correspond-
SYNLETT 2008, No. 15, pp 2342–2344
1
5
.0
9
.2
0
0
8
Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1078593; Art ID: G15308ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
(S)-Pyrrolidin-2-ylmethyl-1,2,3-triazolium Salts
2343
Table 1 Michael Addition of Cyclohexanone to b-Nitrostyrenes
Table 2 Michael Addition of Aldehydes or Acetone to b-Nitro-
styrene
O
O
R
O
Ar
O
4 (10 mol%)
4 (10 mol%)
R1
R1
TFA (2 mol%)
NO2
R2
NO2
R2
TFA (2.5 mol%)
6
+
5
+
7
NO2
NO2
R
Ph
Entry Catalyst
Product 5
R
Time Yield drb
ee
Entry Catalyst Product 7
Time Yield dr
(h) (%)
ee (%)
(h)
24
24
(%)a
(%)c
1
2
4a
Ph
Ph
98
99:1 99
Ph
O
1
2
4a
4a
24
24
95
98
–
–
71
72
4a
90
94:6 90
93:7 88
93:7 58
97:3 82
93:7 82
H
H
(1st recycled)
NO2
NO2
Ph
Ph
Ph
3
4
5
6
4a
Ph
Ph
Ph
Ph
Ph
24
24
40
48
24
83
74
95
83
O
3
4
4a
4b
30
27
84
87
95:5
95:5 36
9
(2nd recycled)
4a
(3rd recycled)
O
4a
5
6
4b
4b
17
45
85
84
–
52
(only 5 mol%)
NO2
NO2
4a
(without TFA)
O
7
8
4b
4a
4a
4a
98
93
97
95
99:1 99
99:1 83
95:5 90
95:5 84
67:33 82
2-O2NC6H4 20
4-MeOC6H4 22
4-MeC6H4 23
9
10
a Yield of isolated product, cyclohexanone, and nitrostyrene were
used in a molar ratio of 20:1, the absolute configuration of the major
isomer was determined by comparison with literature data.18,19
,b Determined by 1H NMR of the crude product.
c Determined by chiral HPLC (Chiralpak AD and AS, hexane–i-PrOH
as eluent). Absolute configuration of major isomer was determined by
comparison with literature data.19,23
We further varied the Michael donor in Michael additions
to b-nitrostyrene, catalyzed by the TSIL 4 (Table 2).
Isobutyraldehyde provided high yields, but the enantiose-
lectivities were lower (71–72%) as compared with cyclo-
hexanone. High yields and diastereoselectivities were
observed with isopentanal, however, enantioselectivities
were unsatisfactory (entries 3, 4). Acetone reacted com-
paratively fast affording high yield and an ee of 52%.
Similar results were obtained by Yan et al. when the 1,2,3-
triazoles 1 were used.22 Cyclopentanone was repeatedly
reported to gives more unfavorable results than cyclohex-
anone in organocatalyzed additions to b-nitrostyrenes.
This is in line with our observation in which a low diaste-
reoselectivity (67:33) was achieved (entry 6).
decrease of both the ee to 82% and the rate of reaction (en-
try 5). The same effect was notified when the reaction was
conducted without trifluoroacetic acid. This confirms
manifold observations in the literature underlining the im-
portance of the presence of an acid as a co-catalyst in the
reaction mixture. It seems that the substituent R in the tri-
azolium ring of the TSIL 4 does not have an effect on the
outcome of the reaction, as the butyl-substituted tri-
azolium salt 4b gave virtually the same result as 4a (com-
pare entries 1 and 7). Thus the situation is different, as
compared with reported Michael additions to b-nitrosty-
renes which are catalyzed by the corresponding non-
charged 1,2,3-triazoles 1, where the aryl-substituted
catalysts gave higher diastereoselectivities than the alkyl-
substituted. The triazolium salt 4a was also applied as ion-
ic liquid supported organocatalyst in reactions of b-ni-
trostyrenes with additional substituents in the aryl ring. In
all these cases (entries 8–10) excellent yields and diaste-
reoselectivities were achieved but with somewhat lower
enantioselectivities (>83%).
We expect that the Michael addition to b-nitrostyrenes,
catalyzed by the TSIL 4 runs via a similar transition state
8 (Figure 2) as proposed for other (S)-pyrrolidin-2-yl-
methyl-derived organocatalysts.22 It can be assumed that
the nitro group electrostatically interacts with the posi-
tively charged 1,2,3-triazolium ring and thus effectively
shields the si face of the attacking enamine.
Synlett 2008, No. 15, 2342–2344 © Thieme Stuttgart · New York

2344
Z. Yacob et al.
LETTER
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N
I–
N
–N
O
N
+
N+
R
O
8
Figure 2
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In summary, we have developed novel TSIL assembled
from a chiral (S)-pyrrolidin-2-ylmethyl moiety and a
1,2,3-triazolium salt as phase tag. The synthesis of such
TSIL is straightforward and they prove as efficient and
easily recyclable organocatalysts in the asymmetric
Michael addition to b-nitrostyrenes. We are presently in-
vestigating further effects, such as solvents, acids, and
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Acknowledgment
We gratefully acknowledge the donation of chemicals by Bayer
Services GmbH & Co. OHG, BASF AG, and Sasol GmbH. Zekari-
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Tetrahedron: Asymmetry 2007, 18, 2086.
Nitrostyrene (37 mg, 0.25 mmol) and 4 (10 mol%) were
mixed with cyclohexanone (0.5 mL, 5 mmol) in the presence
of TFA (0.00625 mmol, 0.2 mL) at r.t. (bulk solution of TFA
in cyclohexanone was freshly prepared from 5 mL TFA in
12.5 mL of cyclohexanone). After stirring for 24 h, the
homogeneous reaction mixture was diluted with Et2O to
precipitate the catalyst. The organic layer was separated and
loaded onto a silica gel column to afford the Michael adduct
(60 mg, 98%) as white solid; syn/anti = 99:1, 99% ee [by
HPLC on a Chiralpak AD column, l = 215 nm, eluent
i-PrOH–hexane (10:90), flow rate = 0.8 mL min–1;
tR = 10.90 (minor), 15.53 min (major)]. All the Michael
addition products are known compounds.
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Synlett 2008, No. 15, 2342–2344 © Thieme Stuttgart · New York

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