Asymmetric ring opening of meso-epoxides with aromatic amines using (R)-(+)-BINOL-Sc(OTf)3-NMM complex as an efficient catalyst

Article abstract of DOI:10.1002/ejoc.201300818

This work reports the asymmetric ring-opening reaction of meso-epoxides with aromatic amines by using the highly efficient in situ generated (R)-(+)-BINOL-Sc(OTf)₃-N-methylmorpholine complex. The asymmetric ring opening of cis-stilbene oxide wi

Full text of DOI:10.1002/ejoc.201300818

Job/Unit: O30818
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Date: 03-09-13 17:42:04
Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201300818
Asymmetric Ring Opening of meso-Epoxides with Aromatic Amines Using
(R)-(+)-BINOL-Sc(OTf)3-NMM Complex as an Efficient Catalyst
Ganesh V. More[a] and Bhalchandra M. Bhanage*[a]
Keywords: Synthetic methods / Asymmetric catalysis / Enantioselectivity / Epoxides / Amines / Amino alcohols
This work reports the asymmetric ring-opening reaction of
meso-epoxides with aromatic amines by using the highly ef-
ficient in situ generated (R)-(+)-BINOL-Sc(OTf)3-N-methyl-
morpholine complex. The asymmetric ring opening of cis-
stilbene oxide with various substituted aromatic amines gave
enantioenriched β-amino alcohols in good yields and with
excellent enantioselectivities when the reaction was con-
ducted at 0 °C for 12 h. The reaction proceeded under mild
conditions using simple and inexpensive starting materials
such as (R)-(+)-1,1Ј-bi-2-naphthol [(R)-(+)-BINOL], meso-
stilbene oxide, aniline derivatives, and 4 Å molecular sieves.
This new and versatile catalytic system has competitive ad-
vantages such as short reaction times, no additives, and no
expensive chiral ligands that require a multistep synthesis
under harsh reaction conditions.
Introduction
Enantiomerically pure β-amino alcohols have been found
in many biologically active natural products, new thera-
peutic agents, unnatural amino acids, β-blockers, insectici-
dal agents, antimalarial agents, and oxazolines.[1] After
derivatization, β-amino alcohols have shown strong chelat-
ing abilities and steric directing effects. Hence, they are
widely used as chiral ligands and auxiliaries for numerous
enantioselective organic transformations[2] (see Figure 1).
Moreover, β-amino alcohols also play a crucial role in living
organisms, and, therefore, the synthesis of enantiomerically
pure β-amino alcohols has gained considerable interest.[3]
Several strategies for their preparation have been developed
such as: (a) a Sharpless osmium-catalyzed aminohydroxyla-
tion of olefins,[4] (b) an addition of α-hydroxy ketones to
imines,[5] and (c) an aminolytic kinetic resolution of racemic
terminal epoxides[6a] and trans-aromatic epoxides with anil-
ines.[6b,6c] Among these approaches, the enantioselective
ring-opening reaction of epoxides with amines is an impor-
tant and atom-economical route to synthesize optically en-
riched β-amino alcohols.
Figure 1. Examples of chiral ligands and auxiliaries that contain β-
amino alcohols.
opening (ARO) of meso-epoxides with anilines.[15] However,
despite their potential utility, the above protocols suffer
from one or more drawbacks such as low enantioselectivity,
a long reaction time, the use of additives, and the use of
expensive and toxic chiral ligands that require multiple
steps to synthesize. In addition, the synthesis of chiral li-
gands requires harsh synthetic conditions, which limit their
applications. In 1994, Kobayashi et al. reported the use of
(R)-(+)-1,1Ј-bi-2-naphthol [(R)-(+)-BINOL], Sc(OTf)3 or
Yb(OTf)3, and tertiary amines as an efficient catalyst for an
asymmetric Diels–Alder reaction.[16] Subsequently, Hou et
al. developed the same catalytic protocol for an ARO reac-
tion using (R)-(+)-BINOL, Yb(OTf)3, and tertiary amines
as the catalyst, which provided up to 80%ee for an aliphatic
epoxide and only 18%ee for an aromatic epoxide.[15a] The
major drawbacks of this protocol were the need to carry
out the reaction at –78 °C, the low enantioselectivities for
A number of valuable products could be synthesized
through a catalytic asymmetric reaction of a meso-epoxide
with various nucleophiles such as azides,[7] cyanides,[8]
alcohols,[9] water,[10] thiols,[11] selenols,[12] indoles,[13,11d] and
carboxylic acids.[14] Several reports have appeared for the
synthesis of β-amino alcohols through the asymmetric ring
[a] Department of Chemistry, Institute of Chemical Technology,
Matunga, Mumbai 400019, India
E-mail: bm.bhanage@gmail.com
bm.bhanage@ictmumbai.edu.in
www.ictmumbai.edu.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300818.
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G. V. More, B. M. Bhanage
FULL PAPER
aromatic epoxides, and the limited substrate scope. It
should be noted that the application of (R)-(+)-BINOL and
Sc(OTf)3 with tertiary amines has been well explored for
various enantioselective organic transformations.[17,2c]
Therefore, this present work involves the search for an
efficient catalytic system for an epoxide ring-opening reac-
tion that proceeds enantioselectively. These efforts are a
continuation of our previous work on the synthesis of race-
mic β-amino alcohols through the ring opening of epoxides
with anilines.[18] Herein, we report the asymmetric ring-
opening reaction of a meso-epoxide with aniline and substi-
tuted anilines. This reaction, which is catalyzed by (R)-(+)-
BINOL-Sc(OTf)3-N-methylmorpholine and is carried out
at 0 °C for 12 h, afforded optically enriched β-amino
alcohols in high yields (up to 89%) and with excellent enan-
tiomeric excess values (up to 94%ee).
Figure 3. Comparison of the fluorescence spectrum of (R)-(+)-
BINOL and chiral scandium complex in CH2Cl2.
When Sc(OTf)3 was added to the solution of (R)-(+)-
BINOL, the fluorescence intensity of (R)-(+)-BINOL was
somewhat quenched with a decrease in the wavelength and
maximum emission (λ = 368 nm). Again, the addition of
NMM to the solution of (R)-(+)-BINOL and Sc(OTf)3 re-
sulted in a dramatic decrease in the fluorescence intensity
without any shift to the wavelength (λ = 368 nm), which is
probably a result of a ligand to metal energy or electron
transfer process[20] and indicates the formation of a com-
plex. The extreme quenching of the fluorescence behavior
in the presence of the prepared chiral scandium complex
was probably a result of the formation of excited hydrogen-
bonded complexes and excited-state proton transfer com-
plexes as shown in Figure 2. The specularity of the titration
profiles clearly indicates that the formation of a complex
with the phenolic moiety affects the quenching of the fluo-
rescence and decreases the delocalization of (R)-(+)-BINOL
with a red shift (λex ≈ 400 nm) as shown in Figure 3.
Results and Discussion
The chiral scandium complex was prepared according to
a reported procedure.[19] To a stirred solution of (R)-(+)-
BINOL (0.12 equiv.) in CH2Cl2 (2.0 mL) under nitrogen
was added Sc(OTf)3 (0.10 equiv.), and the resulting mixture
was cooled to 0 °C. N-methylmorpholine (NMM,
0.24 equiv.) was subsequently added to the reaction mix-
ture, which was then stirred at 0 °C for 30 min. The unique
structure of the catalyst is shown in Figure 2.
Using this new chiral scandium catalyst, we optimized
the reaction conditions for the asymmetric ring-opening re-
action of a meso-epoxide with aniline and substituted anil-
ines. Our preliminary experiments showed that 10 mol-%
of the chiral scandium complex can effectively catalyze the
aminolysis of meso-epoxides with aniline in high yields and
with up to 94%ee. To further optimize the reaction condi-
tions, we chose cis-stilbene oxide and aniline for the model
reaction along with (R)-(+)-BINOL-Sc(OTf)3 and N,N-di-
isopropylethylamine (DIPEA) as the in situ generated cata-
lyst. The influence of various reaction parameters such as
Figure 2. Preparation of chiral scandium complex from (R)-(+)-
BINOL.
The existence of hydrogen bonds between the phenolic solvent, the amine, molecular sieves, temperature, and time
hydrogens of (R)-(+)-BINOL and the nitrogens of the terti- (see Table 1) were examined.
ary amines is the most characteristic detail of this catalyst.
The influence of the solvent on the asymmetric ring-
In this chiral catalyst, the axial chirality of (R)-(+)-BINOL opening reaction was investigated (see Table 1, Entries 1–5).
is transferred through the hydrogen bonds to the amine Solvents such as tetrahydrofuran (THF), dichloroethane,
moiety, and, therefore, the amine plays an important role toluene, diethyl ether, and dichloromethane were screened.
in the enantioselectivity of the desired product. The chiral The activity along with the enantioselectivity was signifi-
scandium complex was studied by fluorescence spec- cantly higher in polar solvents such as dichloromethane
troscopy, and the fluorescence behavior of (R)-(+)-BINOL (54%ee), and, therefore, it was used for further studies. The
is shown in Figure 3. (R)-(+)-BINOL shows maximum chiral scandium complex with the tertiary amines plays an
fluorescence intensity at 372 nm (λex = 342 nm).
important role in the enantioselectivity of the desired com-
2
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Asymmetric Ring Opening of meso-Epoxides with Aromatic Amines
Table 1. Effect of reaction parameters on the asymmetric ring-opening reaction of meso-stilbene oxide with aniline.[a]
[a] Reagents and conditions: (R)-(+)-BINOL (12 mol-%), Sc(OTf)3 (10 mol-%), NMM (24 mol-%), MS (4 Å, 125 mg), meso-stilbene oxide
(0.5 mmol), aniline (0.6 mmol), dichloromethane (DCM, 2 mL). [b] MS: molecular sieves. [c] Isolated yield. [d] Determined by chiral
HPLC analysis on a Chiralcel OD-H column.
pounds. Therefore, various amines such as diisopropylethyl- meric excess value of the desired product marginally de-
amine (54%ee), triethylamine (59%ee), 2,2,6,6-tetrameth- creased. Very good catalytic activity was obtained by using
ylpiperidine (43%ee), 1,8-diazabicyclo[5.4.0]undec-7-ene 4 Å molecular sieves, and it was therefore used in further
(DBU, 60%ee), 1,4-diazabicyclo[2.2.2]octane (DABCO, studies.
62%ee), 1-methylimidazole (37%ee), 1,2-dimethylimid-
Subsequently, we studied the effect of the catalyst load-
azole (56%ee), 1,2,2,6,6-pentamethylpiperidine (59%ee), ing on the enantioselectivity of the β-amino alcohols. The
and NMM (80%ee) were screened (see Table 1, Entries 6– catalyst loading was screened in a range from 5–15 mol-%
14). The reaction did not proceed in the absence of amine, (see Table 2 Entries 1–6). The best results were obtained by
and further experiments were carried out using NMM as using 10 mol-% of the catalyst, which provided the desired
the tertiary amine.
product in 89% yield and with 80%ee. The reaction was
Next, we screened the role of the molecular sieves (see unsuccessful in the absence in any one of the components
Table 1, Entries 15–18). Better results were obtained when of the chiral scandium complex, that is, (R)-(+)-BINOL,
the amine was used with 4 Å molecular sieves (80%ee) than Sc(OTf)3, and NMM. The reaction was also sluggish in the
with either 3 Å (76%ee) or 5 Å molecular sieves (71%ee). presence of only Sc(OTf)3 and NMM [without (R)-(+)-BI-
In the absence of molecular sieves, the yield and enantio- NOL] and gave a racemic compound.
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Table 2. Effect of catalyst loading on the asymmetric ring-opening and β-naphthylamines smoothly underwent the reaction to
reaction of meso-epoxide with aniline.[a]
provide the desired product in very good yield with enantio-
selectivities of 74 and 81%ee, respectively (see Table 3, En-
tries 9 and 10). The aliphatic epoxide cyclohexane oxide
also furnished a good yield (96%) but a poor enantiomeric
excess value (22%ee) when it underwent the reaction with
aniline.
Table 3. Enantioselective ring-opening reaction of meso-stilbene
oxide with aromatic amines.[a]
Entry Catalyst loading
X [mol-%] Y [mol-%] Z [mol-%]
% Yield[b] % ee[c]
1
2
3
4
5
6
18
12
6
–
12
12
15
10
5
10
–
10
36
24
12
24
24
–
91
89
68
23
–
76
80
74
racemic
–
–
–
[a] Reagents and conditions: meso-stilbene oxide (0.5 mmol), anil-
ine (0.6 mmol), MS (4 Å, 125 mg), DCM (2 mL), r.t., 24 h. [b] Iso-
lated yield. [c] Determined by chiral HPLC analysis on a Chiralcel
OD-H column.
Encouraged by these results, we attempted to improve
the enantioselectivity of desired products by studying the
effect of temperature, and, hence, different reactions were
carried out at various temperatures that ranged from room
temperature to –15 °C (see Table 1, Entries 19–21). At room
temperature, the enantioselectivity of the product was low,
whereas decreasing the temperature to 0 °C increased the
enantioselectivity up to 94%ee along with same yield of the
desired product as that obtained at room temperature. A
further decrease in the temperature to –15 °C did not have
a profound effect on the yield of the product, but the
enantioselectivity decreased to 79%ee.
Next, we examined the effect of time on the model reac-
tion (see Table 1, Entries 22–25). After 12 h, the maximum
yield and enantioselectivity was obtained for the desired
product. Hence, the optimized reaction parameters for the
asymmetric ring-opening reaction included cis-stilbene ox-
ide (0.5 mmol), aniline (0.6 mmol), the chiral scandium cat-
alyst (10 mol-%), MS (4 Å, 125 mg), and dichloromethane
(2 mL) at 0 °C for 12 h.
With these optimized conditions in hand, we screened
the reaction between cis-stilbene oxide and different aro-
matic aniline derivatives as the nucleophile (see Table 3, En-
tries 1–10). In all of the cases, the desired β-amino alcohol
was obtained with high enantioselectivity. Among the vari-
ous nucleophiles employed, para-substituted anilines (i.e., 4-
methylaniline, 4-methoxyaniline, 3-fluoro-4-methoxyaniline,
and 4-bromoaniline) afforded the desired amino alcohols
with ee values above 82% with the exception of 4-bromoan-
iline, which gave 68%ee (see Table 3, Entries 3 and 5–7).
On the other hand, 2-methylaniline and 2-methoxyaniline
gave the desired chiral β-amino alcohols in 76 and 67%ee,
respectively (see Table 3, Entries 2 and 4). These results im-
ply that the steric interactions from the ortho-substituted
nucleophile disfavors a high enantioselectivity. The steri-
cally hindered aniline 2,4,6-trimethylaniline maintained a
[a] Reagents and conditions: (R)-(+)-BINOL (12 mol-%), Sc(OTf)3
(10 mol-%), NMM (24 mol-%), MS (4 Å, 125 mg), meso-stilbene
oxide (0.5 mmol), aniline derivative (0.6 mmol), DCM (2 mL), r.t.,
24 h. [b] Isolated yield. [c] Determined by chiral HPLC analysis on
a Chiralcel OD-H column.
Conclusions
In this work, we have developed a simple and efficient
chiral scandium catalyst for the synthesis of β-amino
alcohols. The enantioselective ring-opening reaction of
meso-epoxide with aniline derivatives gave enantiomerically
pure β-amino alcohols in high yields and with excellent
enantioselectivities (up to 94%ee) when conducted at 0 °C
for 12 h. This reaction proceeded under mild conditions
using simple and inexpensive starting materials such as the
(R)-(+)-BINOL catalyst, meso-stilbene oxide, aniline deriv-
atives, and 4 Å molecular sieves. Obviously, this new and
versatile catalytic system has competitive advantages such
as short reaction times, no additives, and no expensive chi-
ral ligands that require a multistep synthesis under harsh
reaction conditions. This inexpensive and effective chiral
catalyst system is particularly attractive with a bright future
in industrial-scale applications.
Experimental Section
General Methods: All chemicals were purchased from M/S Sigma
good yield and led to 64%ee (see Table 3, Entry 8). The α- Aldrich, S. D. Fine Chemicals, and commercial suppliers. All sol-
4
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Asymmetric Ring Opening of meso-Epoxides with Aromatic Amines
vents were distilled before use. The experiments were carried out
under nitrogen. The progress of the reaction was monitored by thin
layer chromatography using Merck silica gel 60 F254 plates. Prod-
ucts were purified by column chromatography on silica gel (60–
120 mesh). The 1H and 13C NMR spectroscopic data were recorded
with a Varian Inova 400 MHz spectrometer in either CDCl3 or
[D6]DMSO. Chemical shifts are reported in parts per million (δ)
relative to tetramethylsilane as the internal standard. The coupling
constants (J) are reported in Hz, and the splitting patterns of the
proton signals are described as s (singlet), d (doublet), t (triplet),
and m (multiplet). The IR spectra were recorded with an FTIR
(Perkin–Elmer). Optical rotations were measured by using a polari-
meter (Rudolph instrument). The enantiomeric excess values (ee)
of the products were determined by HPLC analysis with an Ag-
ilent-HPLC on Daicel Chiralpak-IB and Chiralcel OD-H chiral
columns using propan-2-ol/hexane as the eluent. Racemic com-
pounds were prepared by using racemic 1,1-binaphthol.
raphy (petroleum ether/ethyl acetate, 80:20). HPLC analysis (Daicel
Chiralpak IB column; hexane/iPrOH, 90:10; flow rate: 0.5 mL/
min): tR = 19.5 min (minor), tR = 21.1 min (major); 82%ee. IR: ν
˜
= 3403, 3042, 3028, 2922, 2851, 1618, 1518, 1453, 1046, 754,
1
699 cm–1. H NMR (400 MHz, [D6]DMSO): δ = 7.32–7.09 (m, 10
H), 6.72 (d, J = 10.8 Hz, 2 H), 6.4 (d, J = 11.2 Hz, 2 H), 5.71 (d,
J = 9.6 Hz, 1 H), 5.63 (d, J = 6.4 Hz, 1 H), 4.72 (t, J = 6.4 Hz, 1
H), 4.43 (t, J = 8.8 Hz, 1 H), 2.04 (s, 3 H) ppm. LC–MS: m/z =
304 [M + H]+.
(1R,2R)-2-[(2-Methoxyphenyl)amino]-1,2-diphenylethanol:[15e] See
Table 3, Entry 4. The title compound was purified by silica gel
chromatography (petroleum ether/ethyl acetate, 80:20). HPLC
analysis (Daicel Chiralpak IB column; hexane/iPrOH, 80:20; flow
rate: 1 mL/min): tR = 6.7 min (major), tR = 18.8 min (minor);
67%ee. IR: ν = 3410, 3052, 3029, 2924, 2853, 1601, 1511, 144,
˜
1
1429, 1364, 1225, 1176, 1125, 1027, 768, 738, 700 cm–1. H NMR
(400 MHz, [D6]DMSO): δ = 7.34–7.16 (m, 10 H), 6.75 (t, J =
8.4 Hz, 1 H), 6.47 (m, 2 H), 6.13 (d, J = 10 Hz, 1 H), 5.86 (d, J =
6.4 Hz, 1 H), 5.51 (d, J = 8 Hz, 1 H), 4.75 (t, J = 6 Hz, 1 H), 4.45
(t, J = 7.6 Hz, 1 H), 3.82 (s, 3 H) ppm. LC–MS: m/z = 320 [M +
H]+.
(1R,2R)-2-[(4-Methoxyphenyl)amino]-1,2-diphenylethanol:[15k] See
Table 3, Entry 5. The title compound was purified by silica gel
chromatography (petroleum ether/ethyl acetate, 80:20). HPLC
analysis (Daicel Chiralcel OD-H column; hexane/iPrOH, 90:10;
flow rate: 1 mL/min): tR = 33.2 min (minor), tR = 40.3 min (major);
General Procedure for the Asymmetric Ring-Opening Reaction of
meso-Epoxide with Aniline Derivatives: To a stirred solution of mo-
lecular sieves (4 Å, 125 mg) in CH2Cl2 (2.0 mL) under nitrogen
were added (R)-(+)-BINOL (0.12 mmol) and Sc(OTf)3
(0.10 mmol). The resulting mixture was cooled to 0 °C. NMM
(0.24 mmol) was added, and the reaction mixture was stirred at
0 °C for 0.5 h. The epoxide (0.5 mmol) and the aniline derivative
(0.6 mmol) were then subsequently added to the mixture, which
was stirred at 0 °C until the starting materials disappeared (moni-
tored by TLC). The reaction mixture was then filtered through a
plug of silica gel, which was washed with CH2Cl2 (25 mL). The
filtrate was dried with anhydrous NaSO4 and concentrated under
reduced pressure (rotary evaporator). The resulting residue was
purified by silica gel column chromatography (hexane/ethyl acetate)
to give the desired β-amino alcohol. All products were charac-
terized by appropriate spectroscopic techniques, and the data were
in agreement with reported values.
88%ee. IR: ν = 3434, 3056, 3032, 2924, 2852, 1624, 1522, 1454,
˜
1
1246, 1040, 756, 699 cm–1. H NMR (400 MHz, [D6]DMSO): δ =
7.31–7.09 (m, 10 H), 6.56 (d, J = 12 Hz, 2 H), 6.44 (d, J = 11.6 Hz,
2 H), 5.63 (d, J = 6.4 Hz, 1 H), 5.56 (d, J = 9.2 Hz, 1 H), 4.70 (t,
J = 6.8 Hz, 1 H), 4.39 (t, J = 8.4 Hz, 1 H), 3.54 (s, 3 H) ppm. LC–
MS: m/z = 320 [M + H]+.
(1R,2R)-2-[(3-Fluoro-4-methoxyphenyl)amino]-1,2-diphenylethanol:
See Table 3, Entry 6. The title compound was purified by silica gel
chromatography (petroleum ether/ethyl acetate, 80:20). HPLC
analysis (Daicel Chiralcel OD-H column; hexane/iPrOH, 90:10;
flow rate: 1 mL/min): tR = 22.4 min (minor), tR = 25.1 min (major);
(1R,2R)-1,2-Diphenyl-2-(phenylamino)ethanol:[15e] See Table 3, En-
try 1. The title compound was purified by silica gel chromatog-
raphy (petroleum ether/ethyl acetate, 80:20). HPLC analysis (Daicel
Chiralcel OD-H column; hexane/iPrOH, 90:10; flow rate: 1 mL/
min): tR = 15.7 min (major), tR = 20.9 min (minor); 94%ee. [α]2D5
83%ee. IR: ν = 3417, 3028, 2923, 2852, 1631, 1518, 1454, 1227,
˜
1
1027, 759, 700 cm–1. H NMR (400 MHz, CDCl3): δ = 7.27–7.17
= 40.0 (c = 0.10, CH Cl ). IR: ν = 3399, 3048, 3027, 2920, 2850,
˜
2
2
(m, 12 H), 6.71–6.67 (m, 1 H), 6.32–6.29 (m, 1 H), 6.22–6.20 (m,
1 H), 4.82 (d, J = 7 Hz, 1 H), 4.34 (d, J = 6 Hz, 1 H), 3.72 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 142.54, 142.45, 140.61,
140.05, 128.76, 128.43, 128.14, 127.80, 127.44, 126.72, 116.31,
115.76, 109.52, 109.49, 103.50, 103.28, 78.20, 65.64, 57.55 ppm.
LC–MS: m/z = 338 [M + H]+.
1
1601, 1503, 1453, 1430, 1317, 1263, 1049, 752, 699 cm–1. H NMR
(400 MHz, [D6]DMSO): δ = 7.34–7.10 (m, 10 H), 6.91 (t, J =
10 Hz, 2 H), 6.49 (d, J = 10.8 Hz, 2 H), 6.41 (t, J = 9.6 Hz, 1 H),
5.94 (d, J = 9.6 Hz, 1 H), 5.66 (d, J = 6.8 Hz, 1 H), 4.74 (t, J =
6.4 Hz, 1 H), 4.47 (t, J = 8.8 Hz, 1 H) ppm. D2O exchange 1H
NMR (400 MHz, [D6]DMSO): δ = 7.34–7.10 (m, 10 H), 6.91 (t, J
= 10 Hz, 2 H), 6.49 (d, J = 10.8 Hz, 2 H), 6.41 (t, J = 9.6 Hz, 1
H), 4.74 (d, J = 6.4 Hz, 1 H), 4.47 (d, J = 8.8 Hz, 1 H) ppm. LC–
MS: m/z = 290 [M + H]+.
(1R,2R)-2-[(4-Bromophenyl)amino]-1,2-diphenylethanol:[15k]
See
Table 3, Entry 7. The title compound was purified by silica gel
chromatography (petroleum ether/ethyl acetate, 80:20). HPLC
analysis (Daicel Chiralcel OD-H column; hexane/iPrOH, 90:10;
flow rate: 0.8 mL/min): tR = 23.1 min (minor), tR = 25.3 min
(1R,2R)-1,2-Diphenyl-2-(o-tolylamino)ethanol:[15k] See Table 3, En-
try 2. The title compound was purified by silica gel chromatog-
raphy (petroleum ether/ethyl acetate, 80:20). HPLC analysis (Daicel
Chiralpak IB column; hexane/iPrOH, 90:10; flow rate: 0.8 mL/
(major); 68%ee. IR: ν = 3435, 3058, 3026, 2924, 2851, 1595, 1348,
˜
1
1353, 1018, 769, 700 cm–1. H NMR (400 MHz, [D6]DMSO): δ =
7.35–7.11 (m, 10 H), 7.03 (d, J = 11.2 Hz, 2 H), 6.47 (d, J =
11.6 Hz, 2 H), 6.27 (d, J = 9.6 Hz, 1 H), 5.67 (d, J = 6.4 Hz, 1 H),
4.75 (t, J = 6 Hz, 1 H), 4.46 (t, J = 9.6 Hz, 1 H) ppm. LC–MS: m/z
= 368 [M + H]+.
min): tR = 14.1 min (major), tR = 21.6 min (minor); 76%ee. IR: ν
˜
= 3412, 3058, 3032, 2921, 2851, 1606, 1509, 1452, 1240, 1048, 748,
1
699 cm–1. H NMR (400 MHz, [D6]DMSO): δ = 7.36–7.13 (m, 10
H), 6.92 (d, J = 9.6 Hz, 1 H), 6.75, (t, J = 10 Hz, 1 H), 6.40 (t, J
= 9.6 Hz, 1 H), 6.13 (d, J = 10.8 Hz, 1 H), 5.87 (d, J = 6.8 Hz, 1
H), 5.03 (d, J = 8 Hz, 1 H), 4.80 (t, J = 6.4 Hz, 1 H), 4.48 (t, J =
7.2 Hz, 1 H), 2.1 (s, 3 H) ppm. LC–MS: m/z = 304 [M + H]+.
(1R,2R)-2-(Mesitylamino)-1,2-diphenylethanol: See Table 3, En-
try 8. The title compound was purified by silica gel chromatog-
raphy (petroleum ether/ethyl acetate, 80:20). HPLC analysis (Daicel
Chiralpak-IB column; hexane/iPrOH, 20:80; flow rate: 1 mL/min):
(1R,2R)-1,2-Diphenyl-2-(p-tolylamino)ethanol:[15k] See Table 3, En- tR = 6.0 min (minor), tR = 6.5 min (major); 64%ee. IR: ν = 3439,
try 3. The title compound was purified by silica gel chromatog-
˜
1
3048, 3027, 2922, 2853, 1483, 1440, 1223, 1055, 758, 699 cm–1. H
Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O30818
/KAP1
Date: 03-09-13 17:42:04
Pages: 8
G. V. More, B. M. Bhanage
FULL PAPER
[4]
[5]
[6]
a) P. O’Brien, Angew. Chem. 1999, 111, 339; Angew. Chem. Int.
Ed. 1999, 38, 326–329; b) G. Li, H. Chang, K. B. Sharpless,
Angew. Chem. 1996, 108, 449; Angew. Chem. Int. Ed. Engl.
1996, 35, 451–454.
a) A. Cordova, W. Notz, G. Zhong, J. M. Betancort, C. F.
Barbas, J. Am. Chem. Soc. 2002, 124, 1842–1843; b) B. List, J.
Am. Chem. Soc. 2000, 122, 9336–9337; c) B. M. Trost, L. R.
Terrell, J. Am. Chem. Soc. 2003, 125, 338–339.
a) G. Bartoli, M. Bosco, A. Carlone, M. Locatelli, P. Mel-
chiorre, L. Sambr, Org. Lett. 2004, 6, 3973–3975; b) S. K. Kim,
E. N. Jacobsen, Angew. Chem. 2004, 116, 4042; Angew. Chem.
Int. Ed. 2004, 43, 3952–3954; c) G. Bartoli, M. Bosco, A. Car-
lone, M. Locatelli, M. Massaccesi, P. Melchiorre, L. Sambri,
Org. Lett. 2004, 6, 2173–2176.
a) W. A. Nugent, J. Am. Chem. Soc. 1992, 114, 2768–2769; b)
L. E. Martinez, J. L. Leighton, D. H. Carsten, E. N. Jacobsen,
J. Am. Chem. Soc. 1995, 117, 5897–5898; c) for a review, see:
E. N. Jacobsen, Acc. Chem. Res. 2000, 33, 421–431.
a) B. M. Cole, K. D. Shimizu, C. A. Krueger, J. A. Harrity,
M. L. Snapper, A. H. Hoveyda, Angew. Chem. 1996, 108, 1776;
Angew. Chem. Int. Ed. Engl. 1996, 35, 1668–1671; b) K. D. Shi-
mizu, B. M. Cole, C. A. Krueger, K. W. Kuntz, M. L. Snapper,
A. H. Hoveyda, Angew. Chem. 1997, 109, 1782; Angew. Chem.
Int. Ed. Engl. 1997, 36, 1704–1707; c) Z. Pakulski, K. M. Pie-
trusiewicz, Tetrahedron: Asymmetry 2004, 15, 41–45; d) S. E.
Schaus, E. N. Jacobsen, Org. Lett. 2000, 2, 1001–1004.
a) T. Iida, N. Yamamoto, S. Matsunaga, H. Woo, M. Shiba-
saki, Angew. Chem. 1998, 110, 2383; Angew. Chem. Int. Ed.
1998, 37, 2223–2226; b) C. Schneider, A. R. Sreekanth, E. Mai,
Angew. Chem. 2004, 116, 5809; Angew. Chem. Int. Ed. 2004,
43, 5691–5694; c) S. Matsunaga, J. Das, J. Roels, E. M. Vogl,
N. Yamamoto, T. Iida, K. Yamaguchi, M. Shibasaki, J. Am.
Chem. Soc. 2000, 122, 2252–2260.
For highly enantiomerically pure 1,2-diols through the desym-
metrization of meso-epoxides using an enzymatic method, see:
a) L. Zhao, B. Han, Z. Huang, M. Miller, H. Huang, D. S.
Malashock, Z. Zhu, A. Milan, D. E. Robertson, D. P. Weiner,
M. J. Burk, J. Am. Chem. Soc. 2004, 126, 11156–11157; b) J. M.
Ready, E. N. Jacobsen, J. Am. Chem. Soc. 2001, 123, 2687–
2688.
a) C. Ogawa, N. Wang, S. Kobayashi, Chem. Lett. 2007, 36,
34–35; b) T. Iida, N. Yamamoto, H. Sasai, M. Shibasaki, J.
Am. Chem. Soc. 1997, 119, 4783–4784; c) M. H. Wu, E. N. Ja-
cobsen, J. Org. Chem. 1998, 63, 5252–5254; d) M. Boudou,
C. Ogawa, S. Kobayashia, Adv. Synth. Catal. 2006, 348, 2585–
2589.
a) M. Yang, C. Zhu, F. Yuan, Y. Huang, Y. Pan, Org. Lett.
2005, 7, 1927–1930; b) A. Tschop, M. V. Nandakumar, O. Pav-
lyuk, C. Schneider, Tetrahedron Lett. 2008, 49, 1030–1033; c) J.
Sun, M. Yang, F. Yuan, X. Jia, X. Yang, Y. Pan, C. Zhua, Adv.
Synth. Catal. 2009, 351, 920–930.
NMR (400 MHz, CDCl3): δ = 7.25–7.14 (m, 10 H), 7.01–6.99 (m,
2 H), 6.70 (s, 2 H), 5.03 (d, J = 9 Hz, 1 H), 4.10 (d, J = 9 Hz, 1
H), 2.16 (s, 3 H), 2.08 (s, 6 H) ppm. 13C NMR (100 MHz): δ =
140.95, 140.86, 140.57, 131.92, 130.03, 129.77, 128.50, 128.19,
127.95, 127.76, 127.72, 127.15, 76.68, 69.56, 20.66, 19.18 ppm. LC–
MS: m/z = 332 [M + H]+.
(1R,2R)-2-(Naphthalen-1-ylamino)-1,2-diphenylethanol:[15e]
See
Table 3, Entry 9. The title compound was purified by silica gel
chromatography (petroleum ether/ethyl acetate, 80:20). HPLC
analysis (Daicel Chiralcel OD-H column; hexane/iPrOH, 90:10;
flow rate: 1 mL/min): tR = 20.8 min (major), tR = 42.8 min (minor);
74%ee. IR: ν = 3410, 3052, 3032, 2921, 2851, 1860, 1528, 1281,
˜
1051, 766, 699 cm–1.
[7]
[8]
(1R,2R)-2-(Naphthalen-2-ylamino)-1,2-diphenylethanol:[15p]
See
Table 3, Entry 10. The title compound was purified by silica gel
chromatography (petroleum ether/ethyl acetate, 80:20). HPLC
analysis (Daicel Chiralcel OD-H column; hexane/iPrOH, 90:10;
flow rate: 1 mL/min): tR = 28.8 min (major), tR = 32.2 min (minor);
81%ee. IR: ν = 3401, 3044, 3028, 2923, 2853, 1630, 1602, 1519,
˜
1483, 1396, 1342, 1272, 1226, 1180, 1045, 831, 744, 700 cm–1. 1H
NMR (400 MHz, [D6]DMSO): δ = 7.56–7.45 (m, 2 H), 7.34–7.11
(m, 13 H), 7.02 (t, J = 9.6 Hz, 1 H), 6.48 (s, 1 H), 6.34 (d, J =
10.4 Hz, 1 H), 5.70, (d, J = 6.4 Hz, 1 H), 4.81 (t, J = 6.4 Hz, 1 H),
4.63 (t, J = 9.6 Hz, 1 H) ppm. LC–MS: m/z = 340 [M + H]+.
[9]
(1R,2R)-2-(Phenylamino)cyclohexanol:[15e] The title compound was
purified by silica gel chromatography (petroleum ether/ethyl acet-
ate, 80:20). HPLC analysis (Daicel Chiralcel OD-H column; hex-
ane/iPrOH, 85:15; flow rate: 1 mL/min): tR = 8.2 min (major), tR
= 9.4 min (minor); 22%ee. GC–MS (70 eV): m/z (%) = 106 (36.4),
[10]
[11]
118 (23.5), 132 (100), 148 (12.5), 191 (47.5). IR: ν = 3394, 3052,
˜
3025, 2938, 2923, 1917, 1600, 1514, 1497, 1322, 1259, 1152, 1100,
1056, 864, 799, 690 cm–1.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra and the HPLC chro-
matograms of the β-amino alcohol products.
Acknowledgments
G. V. M. thanks the (Council of Scientific and Industrial Research
(CSIR), New Delhi) for providing a research fellowship. The au-
thors also thank the Department of Science and Technology
(DST)-SERB, India (project file NO.SR/S1/OC-09-2012) for finan-
cial support.
[12]
[13]
a) M. Bandini, P. G. Cozzi, P. Melchiorre, A. Umani-Ronchi,
Angew. Chem. 2004, 116, 86; Angew. Chem. Int. Ed. 2004, 43,
84–87; b) M. Kokubo, T. Naito, S. Kobayashi, Tetrahedron
2010, 66, 1111–1118.
E. N. Jacobsen, F. Kakiuchi, R. G. Konsler, J. F. Larrow, M.
Tokunaga, Tetrahedron Lett. 1997, 38, 773–776.
a) X. Hou, J. Wu, L. Dai, L. Xia, M. Tang, Tetrahedron: Asym-
metry 1998, 9, 1747–1752; b) S. Sagawa, H. Abe, Y. Hase, T.
Inaba, J. Org. Chem. 1999, 64, 4962–4965; c) A. Sekine, T.
Ohshima, M. Shibasaki, Tetrahedron 2002, 58, 75–82; d) F.
Carree, R. Gil, J. Collin, Org. Lett. 2005, 7, 1023–1026; e) S.
Azoulay, K. Manabe, S. Kobayashi, Org. Lett. 2005, 7, 4593–
4595; f) R. I. Kureshy, S. Singh, N. H. Khan, S. R. Abdi, E.
Suresh, R. V. Jasra, Eur. J. Org. Chem. 2006, 1303–1309; g) K.
Arai, M. M. Salter, Y. Yamashita, S. Kobayashi, Angew. Chem.
2007, 119, 973; Angew. Chem. Int. Ed. 2007, 46, 955–957; h) E.
Mai, C. Schneider, Chem. Eur. J. 2007, 13, 2729–2741; i) K.
Arai, S. Lucarini, M. M. Salter, K. Ohta, Y. Yamashita, S. Ko-
bayashi, J. Am. Chem. Soc. 2007, 129, 8103–8111; j) E. Mai,
[1] a) S. C. Bergmeier, Tetrahedron 2000, 56, 2561–2576; b) E. J.
Corey, F. Y. Zhang, Angew. Chem. 1999, 111, 2057; Angew.
Chem. Int. Ed. 1999, 38, 1931–1934; c) C. W. Johannes, M. S.
Visser, G. S. Weatherhead, A. H. Hoveyda, J. Am. Chem. Soc.
1998, 120, 8340–8347; d) R. Noyori, M. Kitamura, Angew.
Chem. 1991, 103, 34; Angew. Chem. Int. Ed. Engl. 1991, 30,
49–69; e) G. A. Rogers, S. M. Parsons, D. C. Anderson, L. M.
Nilsson, B. A. Bahr, W. D. Kornreich, R. Kaufman, R. S. Ja-
cobs, B. Kirtmant, J. Med. Chem. 1989, 32, 1217–1230.
[2] a) D. J. Ager, I. Prakash, D. R. Schaad, Chem. Rev. 1996, 96,
835–875; b) D. E. Frantz, R. Fassler, E. M. Carreira, J. Am.
Chem. Soc. 2000, 122, 1806–1807; c) S. Kobayashi, M. Sugiura,
H. Kitagawa, W. L. Lam, Chem. Rev. 2002, 102, 2227–2302; d)
C. Schneider, Synthesis 2006, 3919–3944; e) L. P. C. Nielsen,
E. N. Jacobsen, in: Aziridines and Epoxides in Organic Synthesis
(Ed.: A. K. Yudin), Wiley-VCH, Weinheim, Germany, 2006,
ch. 7, p. 229–269.
[14]
[15]
[3] S. L. Schreiber, Science 2000, 287, 1964–1969.
6
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Asymmetric Ring Opening of meso-Epoxides with Aromatic Amines
C. Schneider, Synlett 2007, 2136–2138; k) B. Gao, Y. Wen, Z.
Yang, X. Huang, X. Liu, X. Feng, Adv. Synth. Catal. 2008,
350, 385–390; l) H. Bao, J. Zhou, Z. Wang, Y. Guo, T. You,
K. Ding, J. Am. Chem. Soc. 2008, 130, 10116–10127; m) R. I.
Kureshy, K. J. Prathap, S. Agrawal, N. H. Khan, S. R. Abdi,
R. V. Jasra, Eur. J. Org. Chem. 2008, 3118–3128; n) H. Bao, J.
Wu, H. Li, Z. Wang, T. You, K. Ding, Eur. J. Org. Chem. 2010,
1998, 120, 5840–5841; c) S. Kobayashi, M. Araki, I. Hachiya,
J. Org. Chem. 1994, 59, 3758–3759; d) M. Kawamura, S. Ko-
bayashi, Tetrahedron Lett. 1999, 40, 3213–3216.
[18] M. J. Bhanushali, N. S. Nandurkar, M. D. Bhor, B. M. Bhan-
age, Tetrahedron Lett. 2008, 49, 3672–3676.
[19] S. Kobayashi, I. Hachiya, H. Ishitani, M. Araki, Tetrahedron
Lett. 1993, 34, 4535–4538.
6722–6726; o) M. Martin, A. E. Hellani, J. Yang, J. Collin, S. [20] a) L. Pu, Acc. Chem. Res. 2012, 45, 150–163; b) P. K. Mohapa-
Bezzenine-Lafollee, J. Org. Chem. 2011, 76, 9801–9808; p) B.
Plancq, T. Ollevier, Chem. Commun. 2012, 48, 3806–3808.
[16] S. Kobayashi, H. Ishitani, I. Hachiya, M. Araki, Tetrahedron
1994, 50, 11623–11636.
[17] a) S. Kobayashi, H. Ishitani, J. Am. Chem. Soc. 1994, 116,
4083–4084; b) S. Kobayashi, M. Kawamura, J. Am. Chem. Soc.
tra, M. Iqbal, D. R. Raut, W. Verboom, J. Huskensb, S. V.
Godbole, Dalton Trans. 2012, 41, 360–363; c) J. R. Lakowicz,
Principles of Fluorescence Spectroscopy, 3rd ed., Springer, New
York, 2006.
Received: June 3, 2013
Published Online: ᭿
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Job/Unit: O30818
/KAP1
Date: 03-09-13 17:42:04
Pages: 8
G. V. More, B. M. Bhanage
FULL PAPER
Epoxide Ring Opening
G. V. More, B. M. Bhanage* ............. 1–8
Asymmetric Ring Opening of meso-Epox-
ides with Aromatic Amines Using (R)-(+)-
BINOL-Sc(OTf)3-NMM Complex as an
Efficient Catalyst
A simple and efficient protocol was devel-
oped for the asymmetric ring opening of a
meso-epoxide with various amines using a
chiral scandium complex. The system was
optimized with respect to various reaction
parameters. Under mild conditions, the re-
action afforded a wide variety of enantiom-
erically pure β-amino alcohols in high
yields and with excellent enantioselec-
tivities.
Keywords: Synthetic methods / Asymmetric
catalysis / Enantioselectivity / Epoxides /
Amines / Amino alcohols
8
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