Probing the mechanism of the asymmetric aminolysis of meso-epoxides catalyzed by a proline-based N,N'-dioxide-indium tris(triflate) complex

Article abstract of DOI:10.1002/adsc.201200142

An exploration of the mechanism of the aminolysis of meso-epoxides catalyzed by the proline-based N,N'-dioxide-indium tris(triflate) complex was performed using control experiments, UV-Vis spectroscopy, ¹H NMR, electrospray ionization mass spectrometry (ESI-MS) and scanning electron microscopy (SEM). Control experiments disclosed that the ligand-to-indium tris(triflate) ratio, the catalyst loading, the concentration, and the presence of 4 A MS have dramatic effects on this reaction with regard to both the yield and the enantioselectivity. Combined with control experiments, UV-Vis spectroscopy, ¹H NMR, ESI-MS and SEM analyses revealed that molecular sieves perform multiple functions in the catalysis. A plausible molecular sieves-assisted reaction pathway was proposed. In this pathway, molecular sieves perform (i) as desiccant to in situ dry the reaction system, (ii) as proton transfer agent to accelerate the catalysis, and (iii) as counter ion source to preserve the electroneutrality of the transition states. Besides, the generality of the substrate scope was further explored; excellent yields (up to 99%) and enantioselectivities (up to 99% ee) were obtained. Copyright

Full text of DOI:10.1002/adsc.201200142

FULL PAPERS
DOI: 10.1002/adsc.201200142
Probing the Mechanism of the Asymmetric Aminolysis of meso-
Epoxides Catalyzed by a Proline-Based N,N’-Dioxide-Indium
Tris(triflate) Complex
G
Bo Gao,a Mingsheng Xie,b Aimin Sun,a Xiaolei Hu,b Xueqing Ding,a Xiaohua Liu,b
Lili Lin,b and Xiaoming Fengb,*
a
Analytical & Testing Center, Sichuan University, Chengdu 610064, Peopleꢀs Republic of China
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
b
Chengdu 610064, Peopleꢀs Republic of China
Fax : (+86)-28-8541-8249; e-mail: xmfeng@scu.edu.cn
Received: February 19, 2012; Revised: April 2, 2012; Published online: May 9, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200142.
Abstract: An exploration of the mechanism of the tions in the catalysis. A plausible molecular sieves-as-
aminolysis of meso-epoxides catalyzed by the pro- sisted reaction pathway was proposed. In this path-
line-based N,N’-dioxide-indium trisACTHNUTRGNEUG(N triflate) complex way, molecular sieves perform (i) as desiccant to in
was performed using control experiments, UV-Vis situ dry the reaction system, (ii) as proton transfer
1
spectroscopy, H NMR, electrospray ionization mass agent to accelerate the catalysis, and (iii) as counter
spectrometry (ESI-MS) and scanning electron mi- ion source to preserve the electroneutrality of the
croscopy (SEM). Control experiments disclosed that transition states. Besides, the generality of the sub-
the ligand-to-indium trisACTHUNTGRNEUNG(triflate) ratio, the catalyst strate scope was further explored; excellent yields
loading, the concentration, and the presence of 4ꢁ (up to 99%) and enantioselectivities (up to 99% ee)
MS have dramatic effects on this reaction with were obtained.
regard to both the yield and the enantioselectivity.
Combined with control experiments, UV-Vis spec-
1
troscopy, H NMR, ESI-MS and SEM analyses re- Keywords: amino alcohols; aminolysis; N,N’-dioxide-
vealed that molecular sieves perform multiple func- indium trisACTHNUTRGNE(NUG triflate) complex; mechanism analysis
Introduction
asymmetric reactions.[1,2] These chiral ligands are gen-
erally prepared via the coupling of two functional
With the development of asymmetric catalysis, two amino acid units at the N-termini (type A) or at the
types of proline-based N,N’-dioxide and analogues C-termini (type B) followed by a hydrogen bond-di-
(Figure 1) have been developed to serve as excellent rected, highly diastereoselective amine oxidation.[3]
chiral ligands in a wide variety of metal-catalyzed 1H NMR and X-ray analyses disclosed that the two
N-oxides and the two amide oxygens of these two
types of C2-symmetric N,N’-dioxide coordinated to
the metal in a tetradentate manner dominantly.[1a,d]
Despite this fact, however, the N,N’-dioxide-metal
complexes have a number of unaccountable features
to affect the reactivity and selectivity of the whole
catalysis, such as ligand-to-metal ratio,[1c] molecular
sieves (MS),[1b] solvent,[1a–c] temperature,[1a] and so on.
Meanwhile, according to the principles of green
chemistry,[4] the utilization of air- and moisture-toler-
ant and low toxic metal complexes in organic synthe-
sis is emerging as one of the environmentally benign
strategies. Indium complexes, which bear high toler-
Figure 1. The two types of N,N’-dioxide developed.
ance, have received widespread interest in this field
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Table 1. Effects of the N,N’-dioxide B1-to-InACTHNUGTRENUNG(OTf)3 ratio
and catalyst loading.[a]
Entry
B1:In
(OTf)3 (mol%)
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
5.0:5.0
5.5:5.0
10.0:5.0
5.0:5.5
3.3:3.0
1.1:1.0
3.3:0
99
99
trace
99
99
48
trace
82
89
91[1a]
–
87
91[1a]
91[1a]
–
8
0:3.0
0:3.0
0
0
9[d]
10
[a]
All reactions were performed with meso-epoxide 1a
(0.2 mmol), aniline (0.3 mmol), 4 ꢁ MS (20 mg) in THF
(0.1 mL) at 08C for 69 h.
Isolated yield.
Determined by HPLC on a Chiralcel OD-H column.
No 4ꢁ MS.
Scheme 1.
recently.[5] Thereby, the chiral organoindium Lewis
acids have successfully catalyzed the enantioselective
allylation of aldehydes,[6] Mannich-type reactions,[7] al-
kynylation of aldehydes,[8] Diels–Alder reactions,[1b,9]
thiolysis[10] and aminolysis[1a] of meso-epoxides, addi-
[b]
[c]
[d]
tion of pyrroles to isatins,[5e] etc. Among the rest, the plex in the asymmetric aminolysis of meso-epoxide-
N,N’-dioxide B1-InACTHNUTRGNEUNG
(OTf)3 complex catalyzing the s,[1a] control experiments were executed using differ-
asymmetric aminolysis of meso-epoxides (Scheme 1) ent catalyst species from different ligand-to-metal
is especially interesting, since it is a potential alterna- ratio and Lewis acid loadings in THF at 08C with 4ꢁ
tive to the functional group manipulation of naturally MS, firstly. When 5.0 mol% N,N’-dioxide B1 and
occurring molecules,[11] the aminohydroxylation of 5.0 mol% In
ACTHNUTRGNEN(UG OTf)3 were used, the aminolysis of
olefins,[12] the addition of a-hydroxy ketones to meso-epoxide 1a proceeded smoothly with high yield
imines,[13] the aminolytic kinetic resolution of trans-ar- and enantioselectivity (Table 1, entry 1). When
omatic epoxides[14a] and racemic terminal epoxi- 5.5 mol% N,N’-dioxide B1 and 5.0 mol% In
ACHTUNGTRENNUNG(OTf)3
des[14b,c] for the preparation of biologically and syn- were used, the enantiomeric excess of 2a increased
thetically chiral b-amino alcohols. The reaction was slightly without any yield change (Table 1, entry 2).
performed in THF at 08C in the presence of However, when the amount of N,N’-dioxide B1 was
3.0 mol% catalyst loading and 4ꢁ MS to give chiral further raised to 10.0 mol%, the reaction was almost
b-amino alcohols in high yields (up to 99%) and ex- completely inhibited, and no product 2a was isolated
cellent enantioselectivities (up to 99% ee). Although (Table 1, entry 3). When 5.0 mol% N,N’-dioxide B1
a transition state model was proposed on the basis of and 5.5 mol% InACTHNURGTNEUNG(OTf)3 were used, the observed enan-
X-ray crystal structure of N,N’-dioxide B1 and NMR tioselectivity was sacrificed slightly (Table 1, entry 4).
analysis of the catalyst in our recent report,[1a] the re- The reduction of catalyst loading from 5.0 mol% to
markable practical importance of the reaction with 3.0 mol% had no effect on the aminolysis (Table 1,
the intriguing role of 4ꢁ MS in the reaction prompt- entry 5). Futher reduction of catalyst loading to
ed us to undertake a further study on the reaction 1.0 mol% also had no effect on the enantioselectivity,
mechanism as a part of our ongoing interest in devel- but resulted in an obvious yield decrease (Table 1,
oping of chiral N,N’-dioxide-metal complex catalysis. entry 6). Besides, when 3.0 mol% N,N’-dioxide B1
Herein, we report our further findings on the mecha- alone was used in the asymmetric aminolysis of meso-
nism aspects of the aminolysis reaction of meso-epox- epoxides, no product was obtained (Table 1, entry 7).
ides utilizing control experiments, UV-Vis spectrosco- Also a background reaction was observed in the ab-
1
py, H NMR, ESI-MS and SEM.
sence of N,N’-dioxide B1 (Table 1, entries 8 and
9).These findings disclosed that (i) there exists some
dynamic equilibria involving N,N’-dioxide B1 and In-
Results and Discussion
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Control Experiments: Effects of the Ligand-to-Metal
Ratio, the Catalyst Loading, the Concentration, and
the Presence of Molecular Sieves
excess of N,N’-dioxide ligand for the in situ formation
of this catalytic species dynamically; (iv) excessive
N,N’-dioxide ligand may coordinate with the Lewis
acid center of the catalytic species and block the
Building on the initiative understanding of the cata- active site to prevent the whole catalysis; and (v) the
lytic capability of the N,N’-dioxide B1-In(OTf)3 com- excess of In(OTf)3 with 4ꢁ MS will trigger a back-
A
ACHTUNGTRENNUNG
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Probing the Mechanism of the Asymmetric Aminolysis of meso-Epoxides
Figure 2. Effects of the concentration on reactivity and selectivity. All reactions were performed with meso-epoxide 1a
(0.2 mmol), aniline (0.3 mmol), B1:InACTHNUTRGNEUNG(OTf)3 (3.3:3.0 mol%), 4ꢁ MS (20 mg) in THF at 08C for 69 h.
ground reaction of the asymmetric aminolysis to some thetic laboratory, namely 3ꢁ MS and 5ꢁ MS, were
extent. also employed in control experiments. Both of them
On the other hand, the competitive coordination of afforded good reactivities and enantioselectivities
the nucleophile amine and the aminolysis product to (Table 2, entries 6 and 7).
the N,N’-dioxide-In
G
The main functions of molecular sieves in asymmet-
tial challenge to substrate-catalyst interaction and ric reactions are protection of the chiral organometal
active site release for the aminolysis of meso-epox- complex catalyst from adventitious water,[17a] accelera-
ides. To solve this problem, the use of a moderately
polar solvent under low concentration conditions was
recommended by Yamashita.[15] During our initial
Table 2. Effect of molecular sieves on the asymmetric meso-
epoxides aminolysis.[a,b]
studies, the aminolysis performed in THF and CH2Cl2
exhibited higher reactivity and enantioselectivity than
that performed in Et2O, PhOCH3 and toluene.[1a] Pres-
ently, the effect of the concentration on the aminoly-
sis of meso-epoxide 1a was studied. As shown in
Figure 2, with the decrease of reaction concentration,
the conversion was cut down sharply, but the selectivi-
ty was maintained at a high level. This result does not
well agree with the Yamashitaꢀs comment. It is plausi-
ble that the coordinative capability of aniline and
aminolysis product 2a is not so strong as that of ali-
phatic amines. In our initial screening[1a] and further
optimization, the efforts to achieve aminolysis by ali-
phatic amines were unsuccessful; and the efforts by
others[16] have also failed.
Entry MS
Type
Amount of MS
(mg)
Yield
[%][c]
ee
[%][d]
1
2
3
4
5
6
4ꢁ
0
5
16
18
99
99
99
99
99
99
76
14
0
2
4ꢁ
4ꢁ
4ꢁ
4ꢁ
3ꢁ
5ꢁ
4ꢁ
4ꢁ
10
20
40
20
20
20
20
20
89
91[1a]
90
89
88
91
77
4
7
8[e]
9[f]
10[g] 4ꢁ
[a]
All reactions were performed with meso-epoxide 1a
(0.2 mmol), aniline (0.3 mmol), B1:In(OTf)3
ACHTUNGTRENNUNG
Notably, the use of molecular sieves for the aminol-
ysis of meso-epoxides furnishes more striking and
puzzling effects in contrast to previous N,N’-dioxide-
metal complex catalysis.[1b] As shown in Table 2, to
keep the high catalytic activity of the in situ generated
(3.3:3.0 mol%), in THF (0.1 mL) at 08C for 69 h.
Molecular sieves were used directly as received.
Isolated yield.
Determined by HPLC on Chiralcel OD-H column.
4ꢁ MS were dried in muffle oven at 3208C for 3.5 h
prior to use.
10.0 mol% water were added.
4ꢁ MS were filtered off after the chiral catalyst solution
had been prepared.
[b]
[c]
[d]
[e]
B1-InACHTUNGTRENNUNG(OTf)3 complex, the amount of 4ꢁ MS has to
[f]
be more than 0.25 wt equivalent relative to the epox-
ide 1a (Table 2, entries 1–5). Meanwhile, another two
kinds of molecular sieves generally used in the syn-
[g]
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tion of the coordination between metal and chiral li- Analysis of the Catalytic System
gand,[17b,c] preservation of a certain moisture content
for the catalysis[17d] and so forth.[17e–i] To ascertain the Firstly, a UV-Vis absorption spectroscopy experiment
role of 4ꢁ MS in the present N,N’-dioxide-InACHTNUGTRNEUNG(OTf)3 was used to analyze the catalytic species. As shown in
complex-catalyzed aminolysis, the molecular sieves Figure 4, a solution of N,N’-dioxide B1 in CH3CN has
were dried using a muffle oven at 3208C for 3.5 h a maximum UV absorbance band at 209.20 nm
prior to use. It turned out that the use of dry 4ꢁ MS (Figure 4, a); however, the maximum UV absorbance
afforded the same yield and enantioselectivity of the band observed for a solution of B1-InACHTUNRGTNEUNG(OTf)3 in
isolated aminolysis product (Table 2, entries 4 and 8). CH3CN prepared with 4ꢁ MS and without 4ꢁ MS is
It seems that the presence of a certain moisture con- at 219.80 nm, 220.60 nm, respectively (Figure 4, b and
tent is actually disadvantageous for the formation of c). Compared with the result obtained for B1, there
an active catalytic species, which is further confirmed exists an obvious red shift phenomenon for
by the addition of water (Table 2, entry 9). If this is
the sole function of molecular sieves in the present
catalysis, a molecular sieves-free procedure may be
developed for the B1-In
of meso-epoxides. However, under the optimal condi-
tions, the activity of B1-In(OTf)3 was depressed dra-
ACHTUNGRTEN(NUNG OTf)3 catalyzed aminolysis
AHCTUNGTRENNUNG
matically (Table 2, entry 10), when 4ꢁ MS were fil-
tered off after the chiral catalyst solution had been
prepared, which shows that molecular sieves maybe
help the coordination between B1 and InACTHNURGTNEUNG(OTf)3 and
participate in the catalytic cycle.
Investigation of Non-Linear Effect
To gain insight into the origin of the enantioselectivi-
ty, the non-linear effect was investigated under
3.0 mol% catalyst loading conditions (Figure 3). Con-
trol experiments demonstrated that the active catalyt-
Figure 4. UV-Vis absorption curves of B1 (a), B1/InACHTUNGTRENNUNG
(1:1) (b, with 4ꢁ MS), B1/InACHTGNUTRENNUNG
MS) in CH3CN.
ic species is a 1:1 B1-In
ACHTUNGRTEN(NUNG OTf)3 complex, and the 2:1
B1-In(OTf)3 complex is an inactive complex (Table 1,
ACHTUNGTRENNUNG
entries 1–4). Therefore, the formation of a homodimer
or heterodimer complex would deactivate the catalyst,
and a reservoir effect[18] should be observed. Howev-
er, our results revealed a linear effect. This phenom-
enon can be attributed to the fact that the quadriden-
tate behavior of N,N’-dioxide B1 makes the formation
of the 1:1 B1-In
ACHTUNGTRENNUNG
formation of the 2:1 B1-InAHCTNUGTRENNNUG
lower catalyst concentration (0.06M in THF) condi-
tions.
Figure 5. 1H NMR spectra of the NH group of N,N’-dioxide
B1 in diverse conditions: (a) B1 in DMSO-d6; (b)
Figure 3. Non-linear effect of the ring opening of meso-ep-
B1/In
ACHTUNGTRENNUNG
oxide 1a with aniline catalyzed by B1-In
G
B1/InACHTNUGTRENNUNG
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Probing the Mechanism of the Asymmetric Aminolysis of meso-Epoxides
Figure 6. ESI-mass spectra in positive and negative ion modes for B1/InACTHNUGTRENNUG(OTf)3 (1:1)/4ꢁ MS (a, c); B1/InACHTUNGTREN(NUGN OTf)3 (1:1) (b, d).
B1-In
G
ESI-mass spectroscopy, which has been successfully
these observations, it was assumed that there should used in the identification of reactive intermediates in
be an interaction between B1 and InACTHUNGTRENNNUG
without 4ꢁ MS.
In(OTf)3 complex catalysis. The ESI-mass spectra
ACHTUNGTRENNUNG
1
Then, a H NMR analysis was carried out to pro- were collected in positive and negative ion modes by
vide a further insight on the catalytic species. As diluting the THF solution of 1:1 B1-In
shown by the 1H NMR spectra (Figure 5), upon and without 4ꢁ MS in CH3OH, respectively. As
mixing 1:1 B1-In(OTf)3 with 4ꢁ MS and without 4ꢁ shown in Figure 6, the results with and without 4ꢁ
ACHTUNGRTENN(UNG OTf)3 with
ACHTUNGTRENNUNG
MS in DMSO-d6, both amide proton signals of B1 are MS obtained were quite different. For the positive ion
obviously shifted up-field from 11.88 ppm to 8.37 ppm spectrum with 4ꢁ MS, the mononuclear complex
and 8.39 ppm, respectively. This indicated that, in the [B1+In
(OTf)2 +TfOH]+
(m/z=1067.50,
calcd.:
B1-In(III) complex, in the presence and absence of 1067.14) is detected (Figure 6, a), however, without
ACHTUNGTRENNUNG
4ꢁ MS, the intramolecular hydrogen bonds of B1 4ꢁ MS, the active species was not found (Figure 6,
should be dissociated and the two N-oxides might be b). As well, for the negative ion spectrum with 4ꢁ
stabilized via coordination with In3+.
MS, the mononuclear complexes [B1+In
(m/z=1215.47, calcd.: 1215.08) and [B1+In(OTf)4 +
(OTf)4]À
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
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Figure 7. SEM imaging of 4ꢁ MS (a: 1 mmꢃ20000, 10.0 kV SEI; b: 1 mmꢃ10000, 10.0 kV SEI); B1/InACHTNUTGRNEUNG(OTf)3 (1:1)/4ꢁ MS
(c: 1 mmꢃ10000, 10.0 kV SEI); InACTHNUTRGENUG(N OTf)3/4ꢁ MS (d: 1 mmꢃ10000, 10.0 kV SEI); B1/4ꢁ MS (e: 1 mmꢃ10000, 10.0 kV SEI).
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Probing the Mechanism of the Asymmetric Aminolysis of meso-Epoxides
TfOH]À (m/z=1365.43, calcd.: 1365.04) were detected (2M in THF) conditions (Figure 2) further indirectly
(Figure 6, c); without 4ꢁ MS, the active species was demonstrates that the interaction between reactant
not found (Figure 6, d). Therefore, it is notable that and MS surface is favorable to the catalysis. So it can
4ꢁ MS plays a crucial role in helping the formation be considered that the catalytic behavior of 4ꢁ MS is
of the active species.
attributed to both its particular microstructure that
Finally, an SEM experiment was used to survey the makes it easier to absorb the reactant, and the extra-
catalytic behavior of molecular sieves. A-type molecu- framework cations resulting in a synergy effect.
lar sieves are composed of crystalline silica frame-
works and extra-framework cations. The framework
has a three-dimensional structure that forms uniform- Insight on the Reaction Pathway
ly sized pores of molecular dimensions (Figure 7, a).
Under SEM (1 mmꢃ10000, 10.0 kV SEI), 4ꢁ MS ac- Control experiments, UV-Vis absorption spectrosco-
1
cumulate together exhibiting a larger surface area py, H NMR, ESI-MS and SEM analyses have dis-
(Figure 7, b). On the other hand, at some places in closed that, in the meso-epoxide aminolysis reactions,
the SiO2 framework Al3+ has replaced Si4+ and the molecular sieves not only assist the formation of the
framework carries a negative charge. As a result, an actual catalytic species but also accelerate the activity
extra-framework cation is needed to balance its of the catalyst. It has been widely discovered that mo-
charge. For 4ꢁ MS, the extra-framework cation is lecular sieves can function as a proton transfer agent-
Na+. The extra-framework cation is relatively mobile to promote chemical transformations.[17b,c,21] Analo-
and can be exchanged.[20] As shown in Figure 7, c–e, gously, in the meso-epoxide aminolysis, 4ꢁ MS can
(OTf)3/4ꢁ MS are transfer a proton from aniline to the amino alcohol.[22]
B1/InACHTUNGTRENNUNG(OTf)3 (1:1)/4ꢁ MS and InCAHTUNGTRENNUGN
dispersed loosely (Figure 7, c and d), while B1/4ꢁ So, it is reasonable to assume that the extra-frame-
MS is disposed tightly (Figure 7, e). This minor differ- work cation function as a counter ion is not only to
ences between the microstructures of the B1/In
(1:1)/4ꢁ MS, In
(OTf)3/4ꢁ MS and B1/4 ꢁ MS may sieves[20] but also to preserve the electroneutrality of
result in major variations of the distribution of the the transition states.
ACHTUNGRTEN(NGNU OTf)3 preserve the electroneutrality of the molecular
ACHTUNGTRENNUNG
sodium cations of 4ꢁ MS, which further leads to ob-
viously different catalytic behaviors (Table 1, en-
As a result, a plausible catalytic cycle for the B1-In-
AHCTUNGRTEGNUN(N OTf)3 complex-catalyzed aminolysis of meso-epox-
tries 5, 7–9). In addition, the fact that the reaction ides is proposed (Scheme 2). B1 coordinates with
takes place well under higher substrate concentration InACTHNUTRGNEUNG(OTf)3 to form complex A containing two trifyl
Scheme 2. A proposed catalytic cycle.
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groups, in which InACTHNUTRGNE(NUG III) coordinates with both oxy- excellent yields (up to 99%) and enantioselectivities
gens of the N-oxide as well as both carbonyl oxygens. (up to 99% ee).
Noteworthily, the structure of N,N’-dioxide is tightly
changed in the presence of the hard acid In
which oxygens of the N-oxide form a covalent coordi- Conclusions
nation bond with In(III) rather than the nitrogens of
the N-oxide. Also In(III) acts as Lewis acid to acti- The mechanism of the meso-epoxide aminolysis reac-
vate the incoming meso-stilbene oxide to form com- tion by aromatic amines catalyzed by a proline-based
plex B. With the aid of molecular sieves, aniline is in- N,N’-dioxide-In(OTf)3 complex generated in situ was
ACHTUNGTRENN(UNG III), in
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
troduced to chiral B by hydrogen bonding with one progressively investigated using a combination of con-
amide proton of B1 to form transition state C. After trol experiments, UV-Vis spectroscopy, 1H NMR,
SN2 reaction of aniline to epoxide and H-snatch from ESI-MS, and SEM analysis. Notably, 4ꢁ MS are dem-
aniline by molecular sieves, transition state D is onstrated to have multiple functions for the aminoly-
formed. Then, the proton absorbed on the molecular sis. Molecular sieves perform as (i) a desiccant to in
sieves is tansferred to assist the regeneration of chiral situ dry the reaction system, (ii) a proton transfer
complex catalyst A and the production of the amino agent to accelerate the catalysis, and (iii) a counter
alcohol. The electroneutrality of the transition states ion source to preserve the electroneutrality of the
C and D is preserved by the extra-framework sodium transition states. In addition, a possible catalytic cycle
cations.
and transition states have been proposed. The results
from the study are expected to provide new insights
into the asymmetric catalysis, where water or molecu-
lar sieves are found to play an important role. Finally,
the substrate generality was further explored and re-
Substrate Generality Enlargement
Finally, we attempted to extend the scope of the cur- vealed excellent asymmetric induction, which pro-
rent catalysis[1a] by examining the ring opening reac- vides a highly practical and useful tool for the prepa-
tions of amines. The results are summarized in ration of optically pure b-amino alcohols.
Table 3. The aminolysis of aromatic meso-epoxides
with the sterically hindered aniline (o-MeOC6H4NH2)
experienced a further increase in enantioselectivity
than with aniline. (Table 3, entries 2, 4, and 6). In gen-
Experimental Section
eral, both electron-donating and electron-withdrawing
groups at meta or para position of aromatic meso-ep-
oxides[23] furnished the desired b-amino alcohols in
Typical Aminolysis Procedure
To a stirred mixture of N,N’-dioxide B1 (0.0066 mmol), In-
AHCTUNGRTEN(NGUN OTf)3 (0.006 mmol) and 4ꢁ MS (20 mg) in THF (0.1 mL)
Table 3. Enantioselective ring opening of meso-epoxides with aromatic amines promoted by N,N’-dioxide B1-In
ACHTUNGRTENN(UNG OTf)3 com-
plex.[a]
Entry
meso-Epoxide
Ar
Product
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
1a
1a
1b
1b
1c
1c
C6H5
o-MeO-C6H4
C6H5
o-MeO-C6H4
C6H5
o-MeO-C6H4
2a[b]
2b[b]
2c[b]
2d
99
99
90
89
99
99
91[1a]
98[1a]
91
99
94
2e[b]
2f
99
[a]
All reactions were performed under the conditions of entry 5 (Table 1), unless otherwise noted.
Absolute configuration of the major product was assigned as (1S, 2S) by comparison with the optical rotation values in
[b]
the literature.
Isolated yield.
Determined by HPLC (see Supporting Information).
[c]
[d]
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Probing the Mechanism of the Asymmetric Aminolysis of meso-Epoxides
were added the epoxide (0.2 mmol) and aromatic amine
(0.3 mmol) at 08C. Then the reaction was performed at 08C
for 69 h. After completion, the reaction mixture was purified
by silica gel chromatography with mixtures of petroleum
ether-ethyl acetate as eluent to give the pure amino alcohol.
All known compounds were characterized by comparison of
their date with those reported in the literature; all new com-
pounds were fully characterized.
[9] a) Y.-C. Teo, T.-P. Loh, Org. Lett. 2005, 7, 2539–2541;
b) F. Fu, Y.-C. Teo, T.-P. Loh, Org. Lett. 2006, 8, 5999–
6001.
[10] M. V. Nandakumar, A. Tschop, H. Krautscheid, C.
Schneider, Chem. Commun. 2007, 2756–2758.
[11] S. C. Bergmeier, Tetrahedron 2000, 56, 2561–2576, and
references cited therein.
[12] P. O’Brien, Angew. Chem. 1999, 111, 339–342; Angew.
Chem. Int. Ed. 1999, 38, 326–329, and references cited
therein.
[13] For some leading references, see: a) B. List, J. Am.
Chem. Soc. 2000, 122, 9336–9337; b) A. Cꢄrdova, W.
Notz, G. Zhong, J. M. Betancort, C. F. Barbas III, J.
Am. Chem. Soc. 2002, 124, 1842–1843; c) B. M. Trost,
L. R. Terrell, J. Am. Chem. Soc. 2003, 125, 338–339;
d) B. M. Trost, J. Jaratjaroonphong, V. Reutrakul, J.
Am. Chem. Soc. 2006, 128, 2778–2779.
[14] a) G. Bartoli, M. Bosco, A. Carlone, M. Locatelli, M.
Massaccesi, P. Melchiorre, L. Sambri, Org. Lett. 2004,
6, 2173–2176; b) S. K. Kim, E. N. Jacobsen, Angew.
Chem. 2004, 116, 4042–4044; Angew. Chem. Int. Ed.
2004, 43, 3952–3954; c) G. Bartoli, M. Bosco, A. Car-
lone, M. Locatelli, P. Melchiorre, L. Sambri, Org. Lett.
2004, 6, 3973–3975.
[15] H. Yamashita, Chem. Lett. 1987, 525–528.
[16] a) C. Schneider, A. R. Sreekanth, E. Mai, Angew.
Chem. 2004, 116, 5809–5812; Angew. Chem. Int. Ed.
2004, 43, 5691–5694; b) S. Azoulay, K. Manabe, S. Ko-
bayashi, Org. Lett. 2005, 7, 4593–4595; c) H. L. Bao, J.
Wu, H. J. Li, Z. Wang, T. P. You, K. L. Ding, Eur. J.
Org. Chem. 2010, 6722–6726.
[17] a) Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H.
Masamune, K. B. Sharpless, J. Am. Chem. Soc. 1987,
109, 5765–5780; b) K. Mikami, M. Terada, T. Nakai, J.
Am. Chem. Soc. 1990, 112, 3949–3954; c) K. Mikami, Y.
Motoyama, M. Terada, J. Am. Chem. Soc. 1994, 116,
2812–2820; d) G. H. Posner, H. Y. Dai, D. S. Bull, J. K.
Lee, F. Eydoux, Y. Ishihara, W. Welsh, N. Pryor Jr, S.
Petr, J. Org. Chem. 1996, 61, 671–676; e) L. Tottie, P.
Baeckstrçm, C. Moberg, J. Tegenfeldt, A. Heumann, J.
Org. Chem. 1992, 57, 6579–6587; f) T. Iida, N. Yamamo-
to, H. Sasai, M. Shibasaki, J. Am. Chem. Soc. 1997, 119,
4783–4784; g) J. M. Ready, E. N. Jacobsen, J. Am.
Chem. Soc. 1999, 121, 6086–6087; h) S. Matsunaga, J.
Das, J. Roels, E. M. Vogl, N. Yamamoto, T. Iida, K. Ya-
maguchi, M. Shibasaki, J. Am. Chem. Soc. 2000, 122,
2252–2260; i) K. Arai, S. Lucarini, M. M. Salter, K.
Ohta, Y. Yamashita, S. Kobayashi, J. Am. Chem. Soc.
2007, 129, 8103–8111.
Acknowledgements
We thank the National Natural Science Foundation of China
(No. 20902064) and Youth Foundation of Sichuan University
(No. 2008009) for financial support. We also thank the Si-
chuan University Analytical & Testing Center for UV-Vis
spectroscopy, NMR, SEM analysis and the State Key Labora-
tory of Biotherapy for HR-MS analysis.
References
[1] a) B. Gao, Y. H. Wen, Z. G. Yang, X. Huang, X. H. Liu,
X. M. Feng, Adv. Synth. Catal. 2008, 350, 385–390;
b) Z. P. Yu, X. H. Liu, Z. H. Dong, M. S. Xie, X. M.
Feng, Angew. Chem. 2008, 120, 1328–1331; Angew.
Chem. Int. Ed. 2008, 47, 1308–1311; c) X. Yang, X.
Zhou, L. L. Lin, L. Chang, X. H. Liu, X. M. Feng,
Angew. Chem. 2008, 120, 7187–7189; Angew. Chem.
Int. Ed. 2008, 47, 7079–7081; d) Y. L. Liu. D. J. Shang,
X. Zhou, X. H. Liu, X. M. Feng, Chem. Eur. J. 2009,
15, 2055–2058; e) X. H. Liu, L. L. Lin, X. M. Feng, Acc.
Chem. Res. 2011, 44, 574–587; f) K. Shen, X. H. Liu,
L. L. Lin, X. M. Feng, Chem. Sci. 2012, 3, 327–334.
[2] For work by other groups, see: a) M. Kokubo, C.
Ogawa, S. Kobayashi, Angew. Chem. 2008, 120, 7015–
7017; Angew. Chem. Int. Ed. 2008, 47, 6909–6911; b) S.
Kobayashi, M. Kokubo, K. Kawasumi, T. Nagano,
Chem. Asian J. 2010, 5, 490–492.
[3] I. A. O’Neil, N. D. Miller, J. Peake, J. V. Barkley,
C. M. R. Low, S. B. Kalindjian, Synlett 1993, 515–518.
[4] P. T. Anastas, J. C. Warner, Green Chemistry: Theory
and Practice, Oxford University Press, New York, 1998.
[5] a) C. G. Frost, J. P. Hartley, Mini-Rev. Org. Chem. 2004,
1, 1–7; b) T.-P. Loh, G.-L. Chua, Chem. Commun. 2006,
2739–2749; c) J. S. Yadav, A. Antony, J. George, B. V. S.
Reddy, Eur. J. Org. Chem. 2010, 591–605; d) M. G. Hu,
M. Wang, P. L. Zhang, L. Wang, F. J. Zhu, L. C. Sun,
Inorg. Chem. Commun. 2010, 13, 968–971; e) E. G. Gu-
tierrez, C. J. Wong, A. H. Sahin, A. K. Franz, Org. Lett.
2011, 13, 5754–5757, and references cited therein.
[6] a) Y.-C. Teo, K.-T. Tan, T.-P. Loh, Chem. Commun.
2005, 1318–1320; b) J. Lu, S.-J. Ji, Y.-C. Teo, T.-P. Loh,
Org. Lett. 2005, 7, 159–161.
[18] C. Girard, H. B. Kagan, Angew. Chem.1998, 110, 3088–
3127; Angew. Chem. Int. Ed. 1998, 37, 2922–2959, and
references cited therein.
[19] L. S. Santos, Reactive Intermediates MS Investigations
in Solution, John Wiley, New York, 2010.
[20] L. B. McCusker, C. Baerlocher, in: Introduction to Zeo-
[7] S. Harada, S. Handa, S. Matsunaga, M. Shibasaki,
Angew. Chem. 2005, 117, 4439–4442; Angew. Chem.
Int. Ed. 2005, 44, 4365–4368.
[8] a) R. Takita, K. Yakura, T. Ohshima, M. Shibasaki, J.
Am. Chem. Soc. 2005, 127, 13760–13761; b) S. Harada,
R. Takita, T. Ohshima, S. Matsunaga, M. Shibasaki,
Chem. Commun. 2007, 948–950.
ˇ
lite Science and Practice, 3rd edn., Eds.: J. Cejka, H.
van Bekkum, A. Corma, F. Schꢅth, Elsevier B.V., Am-
sterdam, 2007, pp 13–37.
[21] 3ꢁ MS and 4ꢁ MS can snatch protons from alcohol to
promote etherification, for example, see: M. V. Fernan-
dez Cid, M. van der Kraan, W. J. T. Veugelers, G. F.
Adv. Synth. Catal. 2012, 354, 1509 – 1518
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1517

Bo Gao et al.
FULL PAPERS
Woerlee, H. van Bekkum, G. J. Witkamp, Microporous
Mesoporous Mater. 2005, 81, 269–276.
[22] Water has a similar function in the asymmetric ring-
Guo, T. P. You, K. L. Ding, J. Am. Chem. Soc. 2008,
130, 10116–10127.
[23] For the preparation of substituted meso-epoxides, see:
E. Mai, C. Schneider, Chem. Eur. J. 2007, 13, 2729–
2741, and references cited therein.
opening aminolysis of 4,4-dimethyl-3,5,8-trioxabicyclo-
ACHTUNGTRENNUNG[5.1.0]octane, see: H. L. Bao, J. Zhou, Z. Wang, Y. L.
1518
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