Chiral ionic liquid/ESI-MS methodology as an efficient tool for the study of transformations of supported organocatalysts: Deactivation pathways of jorgensen-hayashi-type catalysts in asymmetric Michael reactions

Article abstract of DOI:10.1002/chem.201100388

The deactivation pathways of Jorgensen-Hayashi-type organocatalysts modified with an ionic liquid fragment in asymmetric Michael reactions of α,β-enals with C- (nitromethane, dimethylmalonate) or N-nucleophiles (N-carbobenzyloxyhydroxylamine) that involve

Full text of DOI:10.1002/chem.201100388

FULL PAPER
DOI: 10.1002/chem.201100388
Chiral Ionic Liquid/ESI-MS Methodology as an Efficient Tool for the Study
of Transformations of Supported Organocatalysts: Deactivation Pathways of
Jørgensen–Hayashi-Type Catalysts in Asymmetric Michael Reactions
Oleg V. Maltsev,[a, b] Alexander O. Chizhov,[a] and Sergei G. Zlotin*[a]
Abstract: The deactivation pathways of
Jørgensen–Hayashi-type organocata-
tions and undesirable cation intermedi-
ates that poisoned the catalysts were
identified in accordance with their m/z
values as well as their relation to the
reported mechanisms of Michael reac-
tions in the presence of O-TMS-a,a-di-
arylprolinol (TMS=trimethylsilyl) de-
rivatives. The proposed approach may
be useful for the study of transforma-
tions of other types of organocatalysts
modified with ionic groups in various
organocatalytic reactions and for the
development of novel robust catalysts
and processes that would be suitable
for large-scale industrial applications.
lysts modified with an ionic liquid frag-
ment in asymmetric Michael reactions
of a,b-enals with C- (nitromethane, di-
methylmalonate) or N-nucleophiles (N-
carbobenzyloxyhydroxylamine) that in-
volved an iminium-ion formation step
were studied for the first time by the
electrospray ionization mass spectrom-
etry (ESI-MS). “Parasitic” side reac-
Keywords: ionic liquids
·
mass
spectrometry · Michael addition ·
organocatalysis
mechanisms
·
reaction
Introduction
Asymmetric organocatalysis is a rapidly developing area of
modern organic chemistry.[1] In the presence of small metal-
free chiral organic molecules (organocatalysts) simple pro-
chiral compounds afford the chiral products with extremely
high ee values. The organocatalysts have a wider substrate
scope in comparison with biocatalysts; on the other hand,
they eliminate the risk of the contamination of final prod-
ucts by toxic heavy metals, which is inherent to transition-
metal catalysts.[2]
Scheme 1. Jørgensen–Hayashi-type supported organocatalysts (PG: poly-
mer group, DG: dendritic group, RF: perfluoroalkyl group, IG: ionic
group, SG: superparamagnetic group).
Among known organocatalysts, the O-TMS-a,a-diarylpro-
linol derivatives 1 (Scheme 1), which have been developed
recently by the groups of Jørgensen[3] and Hayashi,[4] occupy
a special place. Due to their ability to activate the carbonyl
compounds by means of enamine[5] or iminium-ion[5c,6] for-
mation, they efficiently catalyze a wide range of asymmetric
reactions that involve these intermediates,[7] in particular,
conjugate additions,[8] cycloadditions,[9] Mannich,[10] a-func-
tionalization,[11] and some other reactions[12] or their cas-
cade/tandem combinations,[13] which allow for the prepara-
tion of complex chiral molecules that have several asymmet-
ric centers in a single operation step. The catalysts 1 are ap-
plied to the synthesis of chiral natural products and medica-
tions.[14] However, being taken in amounts of 10–20 mol%,
they are usually lost during workup. Clearly, their recovera-
ble immobilized forms are needed for the industrial applica-
tion of this as well as of a majority of other types of organo-
catalysts.[15]
Supported Jørgensen–Hayashi-type catalysts 2–5 that con-
tain polymeric,[16] dendritic,[17] perfluoroalkyl,[18] ionic,[19] or
paramagnetic groups[20] have been prepared so far
(Scheme 1). However, in most cases they became much less
active after 1–3 regenerations no matter which modifying
group or reagents were used,[16a,b,d,e,18,19f,g,20] whereas enantio-
selectivity remained almost at the same level.[16a,b,e,18,19f,g,20]
The significant deactivation cannot be explained by the cata-
lyst “leaching” during the extraction of products, because its
mass loss after the recovery was usually no more than
10 wt% per cycle.[17,18,19d,g] It may be attributed to the hy-
[a] O. V. Maltsev, Dr. A. O. Chizhov, Prof. Dr. S. G. Zlotin
N.D. Zelinsky Institute of Organic Chemistry
119991 Moscow, Leninsky prosp., 47 (Russian Federation)
Fax : (+7)499-135-53-28
E-mail: zlotin@ioc.ac.ru
[b] O. V. Maltsev
Department of Technology of Organic Compounds
D.I. Mendeleev University of
Chemical Technology of Russia
125047 Moscow, Miusskaya pl., 9 (Russian Federation)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100388.
[16b,c,e,19a]
ꢀ
drolysis of the O Si bond
that the lifetime of the re-
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covered catalyst upon the treatment by a silylating agent
(Me3SiOTf[16b] or Me2NCOOSiMe3[16c]) increased. However,
such a reactivation method is not always convenient.[16b]
Moreover, the supported OMe-prolinols also lose their acti-
vity.[16a,e]
On the other hand, the a,a-diarylprolinol derivatives 6
(the Corey–Bakshi–Shibata catalysts)[21] and their analogues
7[22] and 8[23] that bear boron, zinc, or carbon atoms at the
pyrrolidine nitrogen atom (Scheme 2) efficiently catalyze
the reduction of ketones by diethylzinc[23] or boranes;[24]
they have been reused at least eight times.
the main catalytic cycle and the products of undesirable side
reactions that poisoning the catalyst—whereas the molecules
that do not contain ionic groups (reagents, intermediates,
products, and so on) would give much lower peaks. Further-
more, we believed that the intensities of the peaks of stable
imidazolium-containing cations in the ESI-MS spectra
would correspond approximately to their concentrations in
the studied catalyst sample. We expected that this approach
would allow us to track directly the composition of recov-
ered catalysts cycle-by-cycle without their purification or
other treatment (protonation), which might change the com-
position. Starting with this information, we attempted to for-
mulate plausible origins of the catalyst deactivation and to
find out the ways to suppress the deactivation processes and
to extend the operation period of the catalysts.
Results and Discussion
To examine this hypothesis, we studied the transformations
of organocatalysts 9[19a] and 10[19a] (10 mol%), which contain
a,a-diphenylprolinol and 1-methyl-1H-imidazolium frag-
ments within a single molecule, in the asymmetric reaction
of trans-cinnamaldehyde (11) with nitromethane (12) by the
ESI-MS technique. The product 13 of this reaction is of spe-
cial interest because it is the direct precursor of the S enan-
tiomer of antidepressant Phenibut[19d] (Scheme 3). The
Scheme 2. Corey–Bakshi–Shibata catalyst 6 and analogues 7 and 8.
The relative stability of catalysts 6–8 indicates the occur-
rence of side reactions that involve the unprotected pyrroli-
dine nitrogen atom, which results in deactivation of catalysts
2–5. Attempts to reveal these reactions have so far failed:
the 1H NMR spectra of the recovered catalysts 3 and 4
are complex and uninforma-
tive.[16b,e,19d]
We assumed that the detailed
information about the “parasit-
ic” transformations of support-
ed organocatalysts including the
Jørgensen–Hayashi-type cata-
lysts could be obtained by elec-
trospray ionization mass spec-
trometry (ESI-MS). The ESI-
MS method is a powerful tool
Scheme 3. Michael addition of 12 to 11 in the presence of ionic catalysts 9 or 10.
for the analysis of ionic spe-
cies[25] and it is widely used for
the study of the mechanisms of homogeneous reactions,[26]
in particular, for studies of ionic intermediates that are
formed in the presence of chiral organocatalysts and/or
Brønsted acid additives in the main catalytic cycle of asym-
metric aldol,[27] Michael,[28] Mannich,[29] Diels–Alder,[30]
Baylis–Hillman,[31] a-halogenation,[32] and tandem (domino)
reactions.[25,33] However, to the best of our knowledge, ESI-
MS has not yet been applied to the investigation of the side
reactions responsible for the deactivation of supported orga-
nocatalysts.
Organocatalysts 4 that bear an ionic group (the imidazoli-
um cation) and the chiral inductor 1 attached to each other
by a covalent bond seemed to be suitable for these type of
investigations. We supposed that the ESI-MS spectra of
their recovered samples would contain mainly the peaks of
catalyst 4 and of ionic compounds that are formed from the
catalyst and reagents—including intermediates involved in
model reaction was carried out in 96% aqueous MeOH at
ambient temperature in air; the ratio 11/12 was 1:3.[19d]
Upon reaction completion (TLC monitoring), the catalysts
were recovered by the evaporation of the solvent followed
by the extraction of reagents and products from the remain-
ing catalyst with diethyl ether, in which compounds 9 and 10
are practically insoluble. The ether solution (after evapora-
tion) was analyzed by NMR spectroscopy, and the recovered
catalysts 9 or 10 were dissolved in MeCN and injected into
an ESI source. The conditions of the ESI-MS experiment
(e.g., low cone voltage) did not favor in-source fragmenta-
tion processes, and peaks of small fragments were not ac-
tually observed.
We recorded the ESI-MS(+) spectra of the freshly pre-
pared catalyst 9 and two other samples, one of which was
taken from the reaction stopped after 10 min from the be-
ginning and another one after completion of four catalytic
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Jørgensen–Hayashi-Type Catalysts
FULL PAPER
Figure 1. ESI-MS(+) monitoring of the composition of catalyst 9 in the Michael reaction between 11 and 12 in air.
cycles (24 h each; (Figure 1). To compare O-TMS-protected
and hydrolyzed forms 9 and 10, we also registered spectra of
the starting catalyst 10 and of the catalyst 10 that operated
in the reaction over four cycles (120 h each; see the Sup-
porting Information).
tively[5c,6f] added to nitromethane (12) to afford enamine 26.
The catalytic cycle completed by the hydrolysis of enamine
26 through nitroalcohol i3 followed by the elimination of
the Michael adduct 13 and releasing catalyst 16 (Scheme 4).
However, ESI-MS data revealed previously unknown de-
tails of this scheme. First of all, the enamine cation 26 ap-
peared to be a rather stable compound that accumulated in
the reaction mixture after just 10 min from the beginning of
the reaction. It was one of the major components of recov-
ered samples of catalyst 9 (for convenience, we further used
the peak of cation 26, m/z 681.35, as the reference one, i.e.,
100%) and served as the main source of active cation 16 for
each successive cycle. To the best of our knowledge, relative
rates of the formation and the consumption of enamine in-
termediates in chiral amine-catalyzed asymmetric reactions
have not been discussed so far, though rather stable N-vinyl-
pyrrolidine derivatives are known.[5c,28c] The relative stability
of the enamine cation 26 explains why this reaction usually
proceeds faster and more selectively in the presence of
water and/or acidic or basic additives[19d,f,35] that are needed
for the efficient hydrolysis of the key enamine intermedi-
ates.
The ESI-MS(+) spectra of the starting catalysts 9 and 10
contained mainly peaks of corresponding cations 16 (m/z
506.2830) and 14 (m/z 434.2438), respectively. However, the
relative abundance of other peaks presented in the spectra
of the recovered samples along with the peaks of 16 and/or
14 depends on the operation period of the catalyst. These
peaks were assigned to corresponding cations 15, 17–28, and
30 in accordance with their m/z values and their relation to
the reported mechanisms of the organocatalytic Michael re-
action in the presence of Jørgensen–Hayashi-type cata-
lysts[5,6] (see Figure 1, Scheme 4, and Table 1, columns 1–3).
Along with reported literature data, these results allowed us
to monitor transformations of catalyst 9 in the model reac-
tion. The main catalytic cycle can be described by the con-
ventional scheme,[6] which includes the reaction of the cata-
lyst cation 16 with trans-cinnamaldehyde (11) to afford the
hemiaminal i1, followed by its transformation to the imini-
um cation i2 by the elimination of OHꢀ. The iminium inter-
mediate i2 was identified by the detection of the compound
22, which apparently formed through the reversible intramo-
lecular reaction of the imidazolium cation with the activated
double bond in compound i2.[34] Intermediate i2 stereoselec-
It became clear that cationic intermediates i1–i3 and en-
amine 26 react with nucleophiles (nitroaldehyde 13, metha-
nol, water) and oxidizing agents (presumably air oxygen) to
afford addition, desilylation, and oxidation side products 17,
19–24, 27, and 30, which were determined by ESI-MS(+)
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S. G. Zlotin et al.
Scheme 4. Transformations of catalyst 9 in the asymmetric Michael reaction between 11 and 12 according to ESI-MS(+). [a] See the Supporting Informa-
tion.
Table 1. Compositions of the samples of catalyst 9 depending on their operation period in the reaction of 11 with 12 in air or under argon according to
ESI-MS(+).[a]
Formula
Relative abundance[b,c] [%]
(calcd mass)
in air
after 4 cycles,
24 h each
3
under argon
after 7 cycles,
after
10 min
2
after 4 cycles,
120 h each[d]
4
after
24 h
5
after 4 cycles,
24 h each
6
after 10 cycles,
24 h each
8
24 h each
7
1
14 (434.2438)
15 (462.2387)
16 (506.2833)
17 (534.2783)
18 (548.2908)
19 (564.2857)
20 (580.3170)
21 (609.3071)
22 (620.3303)
23 (636.3252)
24 (668.3514)
25 (670.3235)
26 (681.3467)
27 (697.3416)
28 (741,3647)
29 (742.3631)
30 (795.3936)
<1
5
103
12
50
220
10
2
5
19
10
4
14
5
<1
1
180
14
140
50
17
120
2
2
2
14
6
100
13
15
38
16
56
17
13
1
7
100
1
100
14
100
87
10
100
1
100
1
65
92
16
90
20
92
19
4
19
[a] Structural formulas of compounds 14–30 and corresponding experimental m/z values are given in detail in the Supporting information. [b] Peak inten-
sities are referred to the intensity of the peak of cation 26 (100%). [c] The peaks with relative intensities ꢁ100% are boldface. [d] The composition of
recovered sample of the catalyst 10 (10 mol%) is given; peak intensities are referenced to the peak of cation 21 (100%).
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Jørgensen–Hayashi-Type Catalysts
FULL PAPER
Table 3. Recycling of catalyst 9 in the reaction of 11 with 12 under
spectra. The intermediate i1 oxidized to amide 23, which in
turn afforded prolinol 19 by means of the hydrolysis of the
argon.[a]
Cycle Conversion[b] (lit.[c]
[%]
)
ee[d]
[%]
Recovered/starting catalyst
ratio[e]
ꢀ
O Si bond. The inverted sequence (hydrolysis!oxidation)
seems unlikely, since compound 19 was not formed in the
reaction between compounds 11 and 12 in the presence of
prolinol 10 under similar conditions (Table 1, column 4).
The iminium cation i2 reacted with the Michael adduct 13
to yield intermediate 30, a precursor of the cyclohexene de-
rivative 31 recently isolated in a similar reaction.[36] More-
over, the reversible reaction of i2 with methanol[37] followed
by the hydrolysis of adduct i4 afforded compounds 20 and
i5. This scheme is in accordance with the absence of com-
pound 20 in the corresponding reaction catalyzed by proli-
nol 10 (Table 1, column 4). Unstable intermediate i5 oxi-
dized then to amide 24; the relative intensity of the peak of
24 (m/z 668.3514) was 120% in the recovered sample of cat-
alyst 9, which operated the reaction for 96 h (4 cycles). Evi-
dently, enamine cation 26 also underwent oxidation and hy-
drolysis reactions to afford catalytically inactive N-formyl-
pyrrolidine 17 (the oxidation of N-alkenyl- to N-formylpyr-
rolidines by O2 see ref. [38]) in which the amino group was
irreversibly blocked by the carbonyl group, and OH-prolinol
21, respectively. Cation 21 (relative intensity 140% after 4
cycles, 24 h each) may serve as a source of OH–catalyst 10
(see Scheme 4, side catalytic cycle 2), which is also able to
catalyze the Michael reaction (see corresponding intermedi-
ates 18, 20, 21, 25, and 28; Table 3, column 4; and catalytic
cycle in the Supporting information), though less efficiently
than O-TMS-catalyst 9.[19d] Remarkably, catalyst 10 ap-
peared to be much more stable than catalyst 9; its ESI-MS
spectrum after four operation cycles (120 h each) remained
actually the same (see the Supporting Information). Finally,
the presence of intermediate i3 was indirectly proven by the
recording of its oxidation product 27.
1
2
3
4
5
6
7
8
>99 (>99)
>99 (>99)
>99 (>99)
>99 (89)
>99 (70)
>99
95
95
94
95
95
94
95
94
95
95
1.53ꢂ0.06
1.76ꢂ0.06
1.88ꢂ0.06
1.71ꢂ0.06
1.76ꢂ0.06
1.76ꢂ0.06
1.71ꢂ0.06
1.65ꢂ0.06
1.71ꢂ0.06
1.65ꢂ0.06
>99
>99
>99
>99
9
10
[a] All reactions were carried out with 11 (0.25 mmol), 12 (0.75 mmol),
and 96 vol% aqueous MeOH (0.5 mL) in the presence of catalyst 9
(10 mol%) at room temperature under argon. [b] The conversion of 11
was estimated by 1H NMR spectroscopy. [c] Data for reactions that were
carried out in air; see Ref. [19d]. [d] Determined by chiral HPLC analysis
of the isolated product 13. [e] The ratio is given for each cycle.
chael reactions of trans-cinnamaldehyde (11) with other C-
(dimethylmalonate (32)[19a]) and N-nucleophiles (N-carbo-
benzyloxyhydroxylamine (33)[19e]; Scheme 5).
Scheme 5. Michael additions of 32 and 33 to 11 in the presence of catalyst
9.
The ESI-MS(+) method was found to be applicable to re-
tracing the transformations of catalyst 9 in asymmetric Mi-
Indeed, we detected similar enamine cations 22 and 37 as
well as hydrolysis 36 and oxidation products 17 and 19 in re-
covered samples of ionic catalyst 9 (10 mol%), which had
operated the reaction of aldehyde 11 with dimethylmalonate
(32) (2:1 molar ratio) for 24 or 168 h (7 cycles, 24 h each)
(see Figure 2, Table 2). Remarkably, the side ions 17 and 36
became the major components of the recovered catalyst
after seven cycles, which led to a decrease in the conversion
of compounds 11 and 32 (100% in the first cycle and 32%
in the seventh cycle).[19a] The “parasitic” products of oxida-
tion 17 and hydrolysis 38 also accumulated (though in small-
er amounts) in catalyst 9, which operated the reaction be-
tween aldehyde 11 and N-carbobenzyloxyhydroxylamine
(33) (1:1.3 molar ratio) (see Figure 3, Table 2), thereby in-
ducing the conversion decrease from >99% (first cycle) to
60% (seventh cycle).[19d] We supposed that atmospheric
oxygen was responsible for the formation of the “parasitic”
catalytic species 17, 19, and 24, which irreversibly removed
catalyst 9 from the catalytic cycle. It might be expected that
performing catalytic reactions under oxygen-free conditions
would allow us to suppress unfavorable oxidation processes
and to increase the lifetime of catalyst 9. To examine this as-
sumption, we removed oxygen from the reagents and sol-
Table 2. The composition of recovered samples of catalyst 9 depending
on their operation period in reactions of 11 with 32 or 33 according to
high-resolution ESI-MS(+).[a]
Formula
(calcd mass)
Relative abundance[b] [%]
Michael reaction with 32[c] domino reaction with 33[d]
after 1 cycle after 7 cycles, after 1 cycle after 7 cycles,
of 24 h
2
24 h each
3
of 24 h
4
24 h each
5
1
16 (506.2833)
17 (534.2783) 23
19 (564.2857)
3
14
5800
200
3
6
2
52
22 (620.3303) 28
400
25
48
36 (680.3330)
7
920
37 (752.3726) 100
38 (715.3490)
100
3
36
39 (787.3885)
100
100
[a] Structural formulas of compounds 16, 17, 19, 22, and 36–39 as well as
corresponding m/z values are given in detail in the Supporting informa-
tion. [b] The peaks with relative intensities ꢁ100% are in boldface.
[c] Peak intensities are referred to the intensity of the peak of cation 37
(100%). [d] Peak intensities are referenced to the intensity of the peak
of cation 39 (100%).
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S. G. Zlotin et al.
Figure 2. ESI-MS(+) monitoring of the composition of catalyst 9 in the Michael reaction of 11 with 32.
Figure 3. ESI-MS(+) monitoring of the composition of catalyst 9 in the Michael reaction of 11 with 33.
vents and carried out the O-TMS-prolinol-catalyzed reaction
of aldehyde 11 with nitromethane (12) as well as the catalyst
recovery under argon atmosphere (see the Supporting Infor-
mation). It was found that the ESI-MS(+) spectrum of the
recovered catalyst 9 that had operated under oxygen-free
conditions for 96 h (4 cycles, 24 h each) (see Figure 4, and
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Jørgensen–Hayashi-Type Catalysts
FULL PAPER
Figure 4. ESI-MS(+) monitoring of the composition of catalyst 9 in the Michael reaction of 11 with 12 under argon atmosphere.
Table 1, column 5) differed considerably from that of the
catalyst that was recovered after the same period working
under air (see Figure 1 and Table 1, column 3). In the
former case, the peaks of hydrolysis- and oxidation-derived
ions 17, 19–21, 23, 24, and 27 of poisoning side products
were almost absent, whereas the peaks of catalytically active
ions 26 and 29 became the major ones. Surprisingly, dinitro
compound 29, which is apparently the product of reversible
Michael/Henry tandem reactions of iminium intermediate i2
with nitromethane (12), formed only under oxygen-free con-
ditions. Whereas the inhibition of the oxidative side reac-
tions of catalyst 9 under oxygen-free conditions was predict-
able, the remarkable decrease of its hydrolysis rate was
rather unexpected. Apparently, cinnamic acid formed from
spectrum of the sample that had been recovered after work-
ing for 96 h (4 cycles, 24 h each) (see Figure 2 and Table 1,
column 5) under the same conditions. According to ESI-
MS(+) spectra, the amount of dinitro compound 29 in the
recovered catalyst remained practically the same independ-
ently of its operation period, thus giving evidence that com-
pound 29 reversibly eliminated nitromethane to yield enam-
ine cation 26 under the studied conditions. The only noticea-
ble difference was a slight increase in the amount of desily-
lated amide 21; however, the intensity of corresponding
“parasitic” peak (m/z 609.31, 56%), even after a 240 h
period of the catalyst working under argon, remained con-
siderably lower than that of the peaks of catalytically active
intermediates 26 (m/z 681.35, 100%) and 29 (m/z 742.36,
92%), and considerably lower than the intensity of this
peak (140%) in the ESI-MS spectrum of the recovered cata-
lyst 9, which conducted the reaction for 96 h (4 cycles, 24 h
each) in air. The ESI-MS(+) data are in good agreement
with the results of catalysis under oxygen-free conditions.
The conversion and ee values of product 13 in the reaction
of nitromethane (12) with aldehyde 11 in the presence of
nine-times-recovered catalyst 9, which had been operating
cinnamaldehyde due to oxidation with atmospheric oxygen
[39]
ꢀ
may accelerate the O Si bond cleavage in catalyst 9.
It was found that increasing the operation period of cata-
lyst 9 under argon up to 168 h (7 cycles, 24 h each) (see
Figure 2 and Table 1, column 6) and even up to 240 h (10
cycles, 24 h each) (see Figure 2 and Table 1, column 7) did
not result in a considerable change in the number or intensi-
ties of peaks in its ESI-MS(+) spectra compared to the
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S. G. Zlotin et al.
for 240 h (10 cycles, 24 h each), were similar to the corre-
sponding data for the reaction in the presence of freshly
prepared catalyst 9, and the amount of the catalyst did not
noticeably decrease after multiple regeneration procedures
(Table 3). Remarkably low intensities of peaks of poisoning
byproducts in the mass spectra of regenerated catalysts indi-
cate that the operation period of catalyst 9 during which it
retains its catalytic properties may be much more than 240 h
(10 cycles).
Acknowledgements
High-resolution mass spectra were recorded in the Department of Struc-
tural Studies of Zelinsky Institute of Organic Chemistry, Moscow. Finan-
cial support from the Ministry of Education and Science of the Russian
Federation (contract no. 02.740.11.0630), the Russian Foundation of
Basic Research (grant no. 09-03-00384), and of the Russian Academy of
Sciences (Department of Chemistry and Material Sciences, Basic Re-
search Program DC-01) is gratefully acknowledged.
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Conclusion
In summary, we have proposed an efficient approach to the
study of transformations of supported organocatalysts in
asymmetric organocatalytic reactions by modifying them
with ionic-liquid fragments followed by the ESI-MS analysis
of recovered catalyst samples. This approach was successful-
ly applied to the study of deactivation pathways of Jørgen-
sen–Hayashi-type catalysts in asymmetric Michael reactions
that involved an iminium-ion formation step. Using this
methodology, we revealed undesirable side reactions that
poisoned the catalyst and found a solution (inert atmos-
phere) to increase its operation period significantly. The
proposed approach may be useful for the study of transfor-
mations of other types of organocatalysts and for the devel-
opment of new robust catalysts and processes that would be
suitable for large-scale industrial applications.
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Experimental Section
High-resolution mass spectra (HRMS) were measured using a Bruker mi-
crOTOF II instrument with electrospray ionization (ESI).[26a] The meas-
urements were done in a positive-ion mode (interface capillary voltage
ꢀ4500 V, end-plate offset ꢀ500 V); mass range from m/z 50 to 3000 Da;
external or internal calibration was done using electrospray calibrant so-
lution (Fluka). A syringe injection was used for solutions in acetonitrile
or MeOH (flow rate 3 mLminꢀ1). Nitrogen was applied as a dry gas; in-
terface temperature was set at 1808C.
ˇ
2010, 16, 95–99; f) D. Seebach, R. Gilmour, U. Groselj, G. Deniau,
ˇ
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Michael reaction of 11 with 12 under oxygen-free conditions: O-TMS-
catalyst 9 (17 mg, 0.025 mmol, 10 mol%) was placed into a round-bot-
tomed flask (5 mL), and the flask was filled with argon. Oxygen-free (see
the Supporting Information) 11 (33 mg, 0.25 mmol, 1 equiv), 12 (46 mg,
0.75 mmol, 3 equiv), and 96 vol% aqueous MeOH (0.5 mL) were added
under argon to catalyst 9. The flask with the reaction mixture was placed
in the vacuum desiccator, which then was filled with argon. The reaction
mixture was stirred at ambient temperature (208C) for 24 h. The solvent
was evaporated under reduced pressure (10 bar, T<458C), then freshly
distilled under argon. Et2O (2 mL) was added to the residue, and the re-
sulting mass was stirred for 10 min. The ether extract of product 13 was
decanted, and the extraction step with Et2O (2 mL) was repeated to
afford the recovered catalyst 9, which after drying under vacuum pump
(2 bar, 10 min, T<358C) was analyzed by ESI-MS and then reused. The
combined ether extracts were evaporated under reduced pressure to
1
afford product 13; its purity was monitored by H NMR spectroscopy.
Catalyst recycling: The flask that contained recovered catalyst was filled
with argon, and the reaction was performed again with fresh portions of
oxygen-free 11 (33 mg, 0.25 mmol, 1 equiv), 12 (46 mg, 0.75 mmol,
3 equiv), and 96 vol% aqueous MeOH (0.5 mL) as described above.
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 6109 – 6117

Jørgensen–Hayashi-Type Catalysts
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Received: February 3, 2011
Published online: May 6, 2011
Chem. Eur. J. 2011, 17, 6109 – 6117
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6117