Enantiopure imidazolinium-dithiocarboxylates as highly selective novel organocatalysts

Article abstract of DOI:10.1039/b817991c

Asymmetric imidazolinium-dithiocarboxylates have been found for the first time to be highly selective catalysts; in the present case, the novel organocatalysts were able to catalyze the Staudinger reaction in up to 96% ee and 99% yield. The Royal Society

Full text of DOI:10.1039/b817991c

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Enantiopure imidazolinium-dithiocarboxylates as highly selective
novel organocatalystsw
´ ´
Oksana Sereda, Amelie Blanrue and Rene Wilhelm*
Received (in Cambridge, UK) 14th October 2008, Accepted 4th December 2008
First published as an Advance Article on the web 24th December 2008
DOI: 10.1039/b817991c
Asymmetric imidazolinium-dithiocarboxylates have been found
for the first time to be highly selective catalysts; in the present
case, the novel organocatalysts were able to catalyze the
Staudinger reaction in up to 96% ee and 99% yield.
Scheme 1 Imidazolinium-dithiocarboxylates.
Imidazolinium-dithiocarboxylate1,2 inner salts belong to the
The [2+2] cycloaddition of ethylphenylketene7c and
N-tosylbenzaldimine10 was tested with zwitterion 1 in CH2Cl2
at rt for 16 h. However, it was not possible to isolate the
desired product.
extraordinary class of carbene complexes of nonmetals.1a They
can be formally prepared by the addition of an imidazolinium
carbene to CS2. These zwitterions are known to be stable1,2
contrary to their CO2 analogues.1a,3 The CS2 group is tilted
almost perpendicularly relative to the imidazolinium ring and
may be regarded as a Lewis base center (Scheme 1).
Recently, we reported the application of symmetric imidazo-
linium-dithiocarboxylates as catalysts for the TMSCN addition
on aldehydes.4 Due to our interest in the Staudinger reaction5
we were wondering if the CS2 unit of an imidazolinium-
dithiocarboxylate would be a sufficient Lewis base catalyst and
the positive center of the imidazolinium ring could stabilize a
transition state of the intermediate. Hence, we would like to
present the application of enantiopure imidazolinium-dithio-
carboxylates for the first time as highly selective novel asymmetric
organocatalysts6 in the Staudinger reaction7 for the preparation
of b-lactams. Highly selective catalytic systems for the
Staudinger reaction were developed by Lectka et al.7a,d,f,g using
cinchona alkaloid derivatives and Fu et al.7b,c using a planar
chiral ferrocene-DMAP analogue as catalyst. Recently, the
groups of Ye and Smith could apply chiral carbenes in an
asymmetric Staudinger reaction with either Boc protected imines
with up to 99% ee and yields between 53 and 78% or tosyl
protected imines in yields of up to 96% with up to 75% ee.7g,h
First, enantiopure imidazolinium-dithiocarboxylates depicted
above were prepared. The new zwitterion 3 was prepared from
its corresponding diamine8 according to a literature procedure2h
in 68% yield. The zwitterions 1, 2 and 4 were synthesised
from their corresponding imidazolinium salts9 via two routes.
Zwitterions 1 and 2 were prepared by the addition of 1 equiv.
KOtBu to the imidazolinium salts in order to generate the
carbene in 30 min, followed by the addition of 5 equiv. of CS2
in 43 and 74% yield, respectively. Zwitterion 4 was obtained by
mixing the corresponding imidazolinium salt with 5 equiv. of
CS2 followed by the addition of 1.5 equiv. KHMDS in 54%
yield after 15 min.
Assuming that the tosyl group is not activating the imine
enough for our system, next the para-nosyl group11 (4-nitro-
benzenesulfonyl-), an excellent base and acid stable protecting
group, which can be easily removed, was chosen. Under the
given conditions with N-para-nosylbenzaldimine12 the desired
product was obtained in 98% yield with a trans–cis ratio of
62 : 38 related to the position of the two phenyl groups but
with low ee (Scheme 2, Table 1, entry 1).
With the much hindered catalyst 2 no conversion was
observed. Next, toluene was used as a solvent. The imine
and zwitterion were not completely but sufficiently dissolved
Institute of Organic Chemistry, Clausthal University of Technology,
Leibnizstr. 6, 38678 Clausthal-Zellerfeld, Germany.
E-mail: rene.wilhelm@tu-clausthal.de; Fax: +49 (0)5323 722834;
Tel: +49 (0)5323 723886
w Electronic supplementary information (ESI) available: Full
experimental procedures and data. see DOI: 10.1039/b817991c
Scheme 2 Staudinger reaction.
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Table 1 Staudinger reaction with 1.5 equiv. ketene (Ar1 = Ph, R = Et)
and imine (Ar2 = Ph) with 10 mol% zwitterion under various conditions
in a 0.1 M solution for 16 h
Entry
Catalyst
Solvent
Yield (trans : cis)a
ee (trans : cis)b
1
2
3
4
5
1
2
3
3
4
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Toluene
98% (62 : 38)
—
99% (81 : 19)
99% (22 : 78)
98% (15 : 85)
6% : 4%
—
11% : 22%
80% : 74%
65% : 87%c
a
Assignment of diastereomers via H-NMR CH2 signal (m for trans and
b
q for cis) in analogy to ref. 13. Absolute configurations trans/cis: 1
c
(3S,4S)/(3R,4S); 3 (3S,4S)/(3R,4S); 4 (3R,4R)/(3S,4R). ee could be
increased to 99% through simply washing three times with 10%
iPrOH–hexane.
Scheme 3 Deprotection of b-lactams.
to have an effective catalyst loading of 4 mol% in order to
have no influence on the reaction time. However, the diastereo-
meric ratio shifted in favour of the cis diastereomer and
more importantly, the obtained ee increased and gave with
zwitterion 3 up to 74% ee for the major diastereomer (Table 1,
entry 4). The reverse of the diastereoselectivity switching from
a polar to an unpolar solvent may be explained by possible
equilibriums involving ionic intermediates before the ring
closing step leading in a polar solvent to the trans product.
Zwitterion 4, with its slightly bulkier groups in the backbone
of the imidazolinium ring and its complete solubility in
toluene, was prepared, which increased the ee of the cis-
diastereomer to 87% (Table 1, entry 5). In addition, it was
possible to increase the ee of this 87% ee sample to 99% ee by
simply washing it three times with 10% iPrOH–hexane with a
yield of 90%. Obviously, the racemate has a better solubility in
the solvent mixture than the pure enantiomer.
10% iPrOH–hexane mixture to give the compounds in 91 and
85% ee, respectively. However, when the standard conditions
for the deprotection of a pNs group were used with either
HSCH2CO2H or PhSH as nucleophiles under basic condi-
tions, the only product obtained was due to the substitution of
the nitro group with the nucleophiles. That this reaction can
occur, although just as a minor side reaction, is known.11b
After extensive studies it was possible to find a new proce-
dure. As shown in Scheme 3 the protection group could be
removed under mild conditions with butanethiol as solvent
and piperidine to give the unprotected lactams cis-6 and 8 in
nearly quantitative yield. The use of butanethiol as solvent
instead of DMF was essential.11c A possible ring opening of
the lactams was not observed.11d The deprotected lactams
were protected either with a Boc or tosyl group in order to
give the literature known Boc protected lactam from cis-67g
and the tosyl protected lactam from 8.7h By comparing the
optical rotation it was possible to assign the absolute configu-
ration. The determined ee revealed that no racemisation
took place.
With the optimized conditions, several imines and ketenes
were investigated with catalyst 4 as shown in Table 2.z In
all cases very good enantioselectivities were obtained for the
cis isomers with up to 96%, while the trans isomers gave
constantly lower ee with up to 83%.
In order to compare the zwitterions with carbenes in the
presented reaction system, a reaction was carried out with
10 mol% of the precursor salt of 3 and 9 mol% DBU in
toluene with ethylphenylketene7c and N-para-nosylbenz-
aldimine.12 After 16 h, the two diastereomers were obtained
in 44% yield with a trans–cis ratio of 40 : 60. Both diastereo-
mers were racemic. Taking into account that the base used to
generate the carbene could have an influence on the outcome
of the reaction, several other bases like n-BuLi, KOtBu and
KHMDS were tested. The highest ee was obtained with
10 mol% of the precursor salt of ent-4 and 8 mol% KHMDS.
The product was obtained in a trans–cis ratio of 40 : 60 with
the trans product as racemate and the cis isomer 5 with
20% ee. These experiments should exclude the unprecedented
although for many applications desirable possibility that small
amounts of carbenes are generated from the zwitterions
under the reaction conditions and are therefore coherent with
literature.1a
Due to the difficulty of acquiring an X-ray structure in order
to determine the absolute configuration of the products, the
opportunity arose to show the excellent behaviour of the pNs
protecting group for deprotection.11a Therefore, samples of
cis-5 and 7 were prepared with ent-4 and washed once with a
Table 2 Staudinger reaction with 1.5 equiv. ketene and imine with
10 mol% 4 in a 0.1 M solution of toluene for 16 h
Ketene
(Ar1, R)
Yield
(trans : cis)
ee
(trans : cis)
Entry
Imine (Ar2)
1
2
3
4
5
6
7
8
Ph, Et
Ph, Et
Ph, Et
Ph, Et
Ph, Et
Ph, Et
Ph, Et
Ph, Me
Ph, Ph
Ph, Ph
2-Naphthyl
4-Cl-C6H4
4-CF3-C6H4
4-NC-C6H4
4-F-C6H4
2-Thiophenyl
1-Naphthyl
4-F-C6H4
4-F-C6H4
Ph
99% (14 : 86)
98% (25 : 75)
96% (13 : 87)
99% (24 : 76)
99% (18 : 82)
99% (25 : 75)
96% (11 : 89)
99% (25 : 75)
96%
62% : 92%
48% : 90%
83% : 95%
74% : 93%
64% : 96%
65% : 84%
70% : 83%
56% : 86%
76%
In order to determine the possible reaction mechanism, a
reaction was carried out in an NMR tube and followed over
time by NMR. It was not possible to observe any shift changes
of the zwitterion 3, ketene and imine and it was only possible
to observe the appearance of the product.
9
10a
96%
67%
a
Reaction performed with ent-4.
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Scheme 4 Possible mechanism.
Therefore, the following two Lewis base catalysed sequen-
ces7b,g,h could be possible in the present case. Either the
zwitterion is activating the ketene, which is reacting further
with the imine, or it is activating the very electron deficient
imine, which is reacting further with the ketene. In Scheme 4,
the latter possibility is depicted.
4 A. Blanrue and R. Wilhelm, Synlett, 2004, 2621.
5 O. Sereda and R. Wilhelm, Synlett, 2007, 3032.
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Wiley-VCH, Weinheim, 2007.
In conclusion we have shown that the utilization of enantio-
pure imidazolinium-dithiocarboxylates as novel organo-
catalysts in the Staudinger reaction with pNs protected imines
can give the product in high yield and high enantiomeric
excess. In addition, a procedure has been found to deprotect
pNs protected b-lactams in short times and high yields.
Currently, the mechanism of the reaction is being further
investigated.
7 For enantioselective examples see: (a) A. E. Taggi, A. M. Hafez,
H. Wack, B. Young, D. Ferraris and T. Lectka, J. Am. Chem. Soc.,
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and G. C. Fu, J. Am. Chem. Soc., 2005, 127, 11586;
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(e) S. France, D. J. Guerin, S. J. Miller and T. Lectka, Chem. Rev.,
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This work was supported by the DFG in the framework of
the priority research program ‘‘Organocatalysis’’ SPP 1179.
Financial support by Fonds der Chemischen Industrie is
gratefully acknowledged. In addition, Dr Drager from the
¨
University of Hannover is acknowledged for HRMS
measurements.
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Notes and references
z General experimental procedure for the Staudinger reaction. An
imine12 (0.1 mmol),
a a zwitterion
ketene7c (0.25 mmol) and
(10 mol%) were dissolved in dry toluene (1 ml) and left to stir for
16 h. After total conversion, the reaction mixture was applied to
column chromatography on silica gel, and products were eluted with
1 : 8 diethyl ether–petrol ether mixture to give the desired compounds
as white solids (yields: 96–99%). General experimental procedure for
the preparation of zwitterions. A salt and 5 equiv. CS2 were dissolved in
THF. 1.5 equiv. KHMDS were added, and the reaction was quenched
with NH4Cl solution after 15 to 30 min. The aqueous solution was
extracted with CH2Cl2, the solvent was removed, and the crude
product was purified on silica gel.
13 J. Decazes, J. L. Luche and H. B. Kagan, Tetrahedron Lett., 1970,
11, 3661.
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