Hydrogen-bond-mediated supramolecular iminium ion catalysis

Article abstract of DOI:10.1002/anie.201206881

Mod squad: Multiple small molecules appear to spontaneously self-assemble to form supramolecular amine catalysts that have high reactivity, good efficiency, and enhanced turnover numbers. These modular organocatalysts should be applicable to many iminium as well as hydrogen-bond catalytic reactions and provide new insights into asymmetric catalysis. Copyright

Full text of DOI:10.1002/anie.201206881

Angewandte
Chemie
DOI: 10.1002/anie.201206881
Asymmetric Catalysis
Hydrogen-Bond-Mediated Supramolecular Iminium Ion Catalysis**
Yao Wang, Tian-Yang Yu, Hong-Bo Zhang, Yong-Chun Luo, and Peng-Fei Xu*
The manufacture of enantiomerically pure pharmaceutical
and agrochemical products is an ongoing requirement for the
chemical industry. As a result, the challenge of significantly
improving the efficiency of expensive chiral catalysts and
exploring their new reactivities has captured the attention of
synthetic chemists. Over the past decade, iminium ion
activation has been demonstrated to be a powerful strategy
for asymmetric catalysis and many reactions catalyzed by
iminium ions have been successfully applied in the synthesis
of medicinal agents and natural products.[1] To date, this so-
called iminium catalysis generally involves an amine catalyst
and an acid cocatalyst, and iminium ions form as ion pairs.[1]
We envisioned that an appropriate cocatalyst (denoted as Y)
could disperse the negative charge and consequently separate
the ion pair by interaction with the counteranion (Figure 1).
inefficient reactions. Another advantage of this strategy is
that the stereocontrol of the modularly designed supramolec-
ular iminium catalysts can be easily fine-tuned by simple
modification or replacement of any of the components. As
a consequence, a library of diverse catalysts could be used to
make a wide range of enantioselective supramolecular
iminium catalysts.
We envisaged that cocatalyst Y might interact with the
iminium ion pair by a weak interaction such as anion binding
or Coulomb interactions or by a combination of these types of
forces. A related approach, thiourea anion-binding catalysis,
has emerged as a new method for asymmetric catalysis.[2] By
judicious choice of catalysts, we reasoned that the merging of
these fields in a SIC approach could result in desirable levels
of stereocontrol and efficiency for a wide range of catalytic
asymmetric transformations associated with new reactivity.
Notably, despite important advances in the development and
application of supramolecular catalysis,[3] the use of discrete
and rationally designed chiral supramolecular catalysts for
asymmetric transformations still remains a significant chal-
lenge.[4] Herein, we report our findings on this new strategy.
The generation of iminium ions is crucial to iminium
catalysis. Thus, to determine the influence of the hydrogen-
bond-mediated supramolecular ammonium catalysts on the
1
generation of iminium ions, several control H NMR experi-
ments were carried out in C6D6. To test the feasibility of our
hypothesis, diphenylprolinol trimethylsilyl ether and imida-
zolinone were selected as amine catalysts since they are the
most widely used and reliable iminium catalysts and have
been successfully applied in numerous transformations.[1] To
Figure 1. The concept of supramolecular iminium catalysis.
1
clearly identify and interpret the H NMR signals of crucial
Such strategies based on supramolecular iminium catalysis
(SIC) could significantly improve the catalytic activity of
iminium catalysts and provide new opportunities for asym-
metric catalysis. In view of the limitations on the use of
organocatalysis in industry, the design and discovery of
catalysts with higher reactivity, better efficiency, and greater
turnover numbers is a major goal. This concept is very
important because, in principle, it will aid in accelerating the
reaction rate, reducing the loading of the expensive chiral
catalysts, and improving the efficiency of some of the more
protons, it was necessary to employ easily identifiable acids as
cocatalysts and a symmetrical thiourea as an anion-binding
catalyst.
In initial studies when diphenylprolinol trimethylsilyl
ether served as the amine catalyst and traditional organic
salts B (B1–B4) were condensed with cinnamyl aldehyde (1)
(1:1 ratio), to our surprise neither iminium ions nor any other
new species were detected by 1H NMR spectroscopy
(Figure 2). The signal ratios of both cinnamyl aldehyde and
carboxylic acid remained unchanged. As shown in Figure 2,
only a single set of signals appeared which correspond to
organic salts B. In sharp contrast, the supramolecular
ammonium complex A reacted with cinnamyl aldehyde (1:1
ratio) to afford a considerable amount of the supramolecular
iminium complex A-Im (A-Im/A > 1:1 equilibrium ratio). As
shown in Figure 2, two sets of signals for the pyrrolidine ring
and the cinnamyl group appeared. Meanwhile, when the
reaction mixture of A1 and cinnamyl aldehyde was analyzed
by ESI-MS (see the Supporting Information), strong signals at
m/z 440.2407 and m/z 613.0067 were observed which corre-
spond to the iminium cation (m/z(calcd) 440.2404) and
[*] Dr. Y. Wang, T.-Y. Yu, H.-B. Zhang, Dr. Y.-C. Luo, Prof. Dr. P.-F. Xu
State Key Laboratory of Applied Organic Chemistry
College of Chemistry and Chemical Engineering
Lanzhou University, Lanzhou 730000 (P.R. China)
E-mail: xupf@lzu.edu.cn
[**] We thank the NSFC (21032005, 20972058, 21172097), the National
Basic Research Program of China (no. 2010CB833203), and the
“111” program from MOE of P.R. China.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206881.
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Table 1: Generation of iminium ions by supramolecular ammonium ion
pairs and traditional organic salts; compounds shown in Figures 2 and
3.
Entry
R
A
A-Im
A-Im/A[a]
B
B-Im
B-Im/B
1
2
3
4
5
6
7
CF3
Ph
A1 A1-Im 1.66:1
A2 A2-Im 1.31:1
B1
B2
B3
B4
B2
–
–
–
–
–
–
–
–
–
–
4-MeO-C6H4 A3 A3-Im 1.14:1
4-F-C6H4
Ph
CF3
A4 A4-Im 1.52:1
A5 A5-Im 2.63:1
A6 A6-Im 0.34:1
B6 B6-Im 0.04:1
B7
Ph
A7 trace
n.d.[b]
–
–
[a] Determined by 1H NMR analysis. [b] n.d.=not determined.
anion complex, were found by analysis of A1 and A6 using
ESI-MS.[6] Given the fact that H-bond interactions to stabilize
the charged intermediate or transition state will be favored
and can significantly promote the proton-transfer equilibrium
process, we suggest H-bond-stabilized ammonium salts A1–A7
to be favorable equilibrium products. In sharp contrast,
traditional organic salts do not form high concentrations of
iminium ions, regardless of the acids employed (Table 1,
entries 1–4). Similar results were observed when imidazoli-
none was employed as an iminium catalyst. A trace amount of
the iminium ion was generated by condensation of B6 with
cinnamyl aldehyde. However, in sharp contrast, newly
designed catalyst A6 can successfully generate a significant
amount of iminium A6-Im (Table 1, entry 6).
Imidazolinone has been proven to be an efficient organo-
catalyst, generally with a strong Brønsted acid as a cocatalyst.
Indeed, we find here in the presence of benzoic acid that only
a trace amount of iminium formed in the presence of
supramolecular iminium catalyst A7 in C6D6 and no iminium
generation was detected with the organic salt B7 (Figure 3;
Table 1, entry 7). Furthermore, when these reactions in the
presence of supramolecular ammonium catalysts were moni-
tored in toluene by in situ infrared spectroscopy, we found the
generation of iminium ions achieved equilibrium almost
immediately (generally within several seconds). These novel
results are very important because they not only provide
a powerful and general strategy for the expeditious formation
of high concentrations of iminium ions, but shed new light on
the selection of an acid cocatalyst.
Figure 2. Top: The generation of iminium ions through supramolecular
ammonium complexes and traditional organic salts with the diphenyl-
1
prolinol trimethylsilyl ether catalyst. Bottom: H NMR spectra (C6D6,
400 MHz).
thiourea anion-binding unit (m/z(calcd) 613.0072), respec-
tively, of the supramolecular iminium complex A1-Im.
Interestingly, when the benzoic acid module of both A2
and B2 was replaced by 4-nitrobenzoic acid, both of the ion
pairs formed white suspensions in Et2O. However, in sharp
contrast, when cinnamyl aldehyde was added to 10 mol%
supramolecular ammonium catalyst in Et2O, a clear yellow
solution formed immediately; in the presence of 10 mol%
traditional organic salt the white suspension remained even
after several hours (see the Supporting Information). The
above observation can be explained by the fact that the
supramolecular ammonium catalyst could immediately gen-
erate the iminium ion.
With this useful information in hand, we next questioned
whether a supramolecular iminium catalyst could significantly
enhance the catalytic activity in an iminium-catalyzed reac-
tion. In order to clearly illustrate the new concept, it is
necessary to choose model reactions that are not only widely
With this useful information in hand, we tested different
acids as components in the supramolecular ammonium
complex. We found that iminium generation improved with
increased acidity (Table 1, entries 1–4). Note that the acidity
of N,N’-bis[3,5-bis(trifluoromethyl)]phenyl thiourea is quite
high in the polar solvent DMSO.[5] However, its relative
acidity in the nonpolar solvent C6D6 is not known. The use of
the strong Brønsted acid CF3COOH also resulted in a high
concentration of the iminium ion. This finding indicates that
the generation of the supramolecular iminium ion complex is
not necessarily a result of the higher pKa of thiourea.
Furthermore, also when a less acidic thiourea (corresponding
to A5) was used, a high concentration of the iminium ion
complex was generated (Table 1, entry 5). Strong signals at
m/z 613.0077 and 613.0066, which correspond to the thiourea–
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lent selectivity, regardless of thiourea, it is evident that the
expeditious formation of higher concentrations of iminium
ion and the generation of a more reactive charge-separated
iminium ion account for the increased reaction rate.
The new concept was next applied to the asymmetric
organocatalytic Friedel–Crafts alkylation reaction of N-meth-
ylindole with an a,b-unsaturated aldehyde.[8] The control
experiments of the reaction between N-methylindole and
cinnamyl aldehyde were carried out in various solvents, such
as CH2Cl2, toluene, and CHCl3 at À508C in the presence of
catalysts A11 and B6, respectively. In all of these solvents the
catalytic activities of the supramolecular ammonium catalysts
A11 and traditional organic salt B6 contrasted sharply. As
shown in Figure 5, the reaction catalyzed by 5 mol% A11 in
CH2Cl2 at À508C proceeded efficiently to afford product 5 in
81% yield at 92% conversion after 45 h. Similarly, enhanced
reactivity was also displayed by catalyst A12 at a loading of
5 mol%. In sharp contrast, only 27% conversion was
obtained in the presence of B6 after 45 h. As expected,
conversions of 81% and 63% were obtained in the presence
of A11 in toluene and CHCl3, respectively. In contrast,
conversions of 43% and 24% were observed under the
catalysis of B6. However, thioureas 6 or 7 alone could not
catalyze this reaction. These results clearly indicate that
Figure 3. Top: The generation of iminium ions through supramolecular
ammonium complexes and traditional organic salts with the imidazo-
linone catalyst. Bottom: 1H NMR spectra (C6D6, 400 MHz).
used in organic synthesis but also do not include interferential
proton-transfer processes. Therefore, we selected the Diels–
Alder reaction and the Friedel–Crafts reaction as model
reactions for investigation.
To identify and explain crucial information clearly and
exclude thiourea itself from interfering in the Diels–Alder
reaction, an intramolecular Diels–Alder reaction[7] can be an
ideal model. As shown in Figure 4, for the intramolecular
reaction of triene aldehyde 2 in a range of solvents such as
toluene, CH2Cl2, and CH3CN, the reactivities of the supra-
molecular ammonium catalyst A8 and the traditional organic
salt B6 strongly diverged. The reaction proceeded efficiently
to afford product 3 with 75% and 67% conversion catalyzed
by A6 and A8 after 1 h in toluene, respectively. In contrast,
only 28% conversion was obtained in the presence of B6 after
1 h. When the loading of A6 was reduced to 5 mol%, the
reaction proceeded smoothly to give more than 90%
conversion after 5 h with the same excellent selectivity. The
enhanced reactivity was also observed with the bulky, steri-
cally hindered chiral thioureas in A9 and A10 and these two
catalysts maintain the high stereoselectivity. All these reac-
tions catalyzed by supramolecular iminium catalysts can
achieve more than 90% conversion after 4 h. With respect to
the greatly improved conversion and nearly constant excel-
Figure 4. An intramolecular Diels–Alder reaction used to test the new
strategy and traditional iminium catalysis.
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Figure 5. A Friedel–Crafts alkylation reaction to test the new strategy
and traditional iminium catalysis.
supramolecular ammonium catalysts could significantly
improve the reactivities of traditional organic salts.
In conclusion, we have developed a new strategy for
asymmetric catalysis. The supramolecular ammonium cata-
lysts described here have higher reactivity, better efficiency,
and greater turnover numbers. This concept should be
applicable to a vast number of iminium- as well as hydro-
gen-bond-catalyzed processes and provide new insights into
asymmetric catalysis beyond the scope developed in our
group. We are currently focusing our research on the wide
application of this strategy.
Received: August 24, 2012
Published online: November 4, 2012
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Keywords: asymmetric catalysis · iminium catalysis ·
organocatalysis · supramolecular chemistry
.
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