Vanadium-salan catalyzed enantioselective ring opening of meso-epoxides with aromatic amines

Article abstract of DOI:10.1055/s-2008-1067109

The first example of enantioselective ring-opening of meso-epoxides catalyzed by chiral oxovanadium(V) - salan complexes is reported. The reaction furnished 1,2-aminoalcohols in good yields and moderate to high enantioselectivities (up to 87%). Thieme Stu

Full text of DOI:10.1055/s-2008-1067109

2100
PAPER
Vanadium–Salan Catalyzed Enantioselective Ring Opening of meso-Epoxides
with Aromatic Amines
E
nantiosel
i
e
ctive
a
n
ing of meso
-
g
a
School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, P. R. of China
Fax +86(21)51903505; E-mail: jtsun@sundia.com
b
c
d
Department of Chemistry, Sundia Meditech (Shanghai) Co, Ltd, Shanghai 201203, P. R. of China
School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. of China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai
200032, P. R. of China
Received 25 March 2008; revised 18 April 2008
cles in water,6a–c Kobayashi and co-workers developed an
efficient catalytic system using a niobium–multidentate
binol ligand in the reaction with good yields, excellent
enantioselectivities and broad substrate generality.6d,e
Abstract: The first example of enantioselective ring-opening of
meso-epoxides catalyzed by chiral oxovanadium(V)–salan com-
plexes is reported. The reaction furnished 1,2-aminoalcohols in
good yields and moderate to high enantioselectivities (up to 87%).
Key words: amine, asymmetric catalysis, epoxides, ring-opening, Vanadium compounds have been widely employed as ef-
fective catalysts in various organic reactions,8 and enan-
vanadium
tioselective reactions catalyzed by vanadium complexes
are of particular interest in asymmetric synthesis.9 To
date, however, its applications have mainly focused on
oxidation reactions, such as asymmetric sulfoxid-
ation,9a–e,10a asymmetric epoxidation,11 and a few others.12
To our knowledge, no examples of asymmetric ring-open-
ing reactions catalyzed by vanadium complexes have
been published. On the other hand, the applications of
chiral salan [N,N¢-alkyl bis(salicylamine)] ligands in
enantioselective reactions have attracted more interest re-
cently. Our previous studies investigated salan as effec-
tive ligands in asymmetric sulfoxidation,10a the Biginelli
reaction10b and pinacol coupling reactions.10c At the same
time, Katsuki and co-workers reported the successful ap-
plication of titanium–salan in asymmetric epoxidation11
and iron–salan in asymmetric sulfoxidation,9e respective-
ly, with excellent results.
Chiral b-amino alcohols are useful molecules both as
building blocks for biologically active compounds and as
chiral auxiliaries or ligands in asymmetric synthesis.1
Various methods for catalytic, enantioselective synthesis
of b-amino alcohols have been developed over the past
decades2 and the catalytic enantioselective ring-opening
of meso-epoxides with amines affords a valuable route to
b-amino alcohols with high enantioselectivities.3,4 Hou,3a
Inaba,3b Shibasaki,3c Collin3d,e and Feng3f reported their
independent investigations on the ring-opening of meso-
epoxides with good yields and moderate to high enanti-
oselectivities. In addition, the aminolytic kinetic resolu-
tion of aromatic epoxides remains an efficient method for
obtaining optically active b-aminols.7 Recently,
Schneider and co-workers used scandium–bipyridine and
indium–pyridine in the reaction and reported good yields
and high enantioselectivities.5 After the successful utiliza-
tion of scandium–bipyridine in the enantioselective ring-
opening of meso-epoxides with anilines and N-heterocy-
Herein, we wish to report our studies on the enantioselec-
tive desymmetrization of meso-epoxides with anilines
catalyzed by a vanadium–salan complex, which affords
R1
R1
N
N
N
N
R3
OH
R3
OH
HO
R3
HO
R3
R2
R2
R2
R2
1e: R2 = R3 = H
1a: R1 = R2 = R3 = H
1b: R1 = H, R2 = R3 = t-Bu
1c: R1 = Me, R2 = R3 = H
1d: R1 = Bn, R2 = R3 = H
1f: R2 = R3 = t-Bu
Figure 1
SYNTHESIS 2008, No. 13, pp 2100–2104
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x.
x
x
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2
0
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Advanced online publication: 21.05.2008
DOI: 10.1055/s-2008-1067109; Art ID: F07608SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Enantioselective Ring-Opening of meso-Epoxides
2101
Table 1 Vanadium–Salan Catalyzed Aminolysis of Cyclohexene
Oxide (2a) with Anilinea
Table 2 VO(Oi-Pr)3–Salan Catalyzed Asymmetric Addition of
Aniline to Cyclohexene Oxidea
1c (15 mol%)
1a–f (15 mol%)
OH
VXn (10 mol%)
PhNH2
+
O
CH2Cl2, 0 °C
NHPh
Me
Me
N
N
2a
3a
4a
Entry
VXn
Ligand Time (h) Yield (%)b ee (%)c
HO
OH
OH
PhNH2
O
+
1
2
VO(acac)2
VCl3
1c
1c
1c
24
5
47
90
93
86
87
84
82
84
85
57
43
36
12
27
45
28
62
17
33
55
<5
<5
VO(Oi-Pr)3 (10 mol%)
NHPh
2a
3a
4a
3
VOCl3
5
Entry
Solvent
CH2Cl2
CHCl3
hexane
THF
Temp (°C)
Yield (%)b
ee (%)c
62
4
VO(OEt)2Cl 1c
VO(OEt)Cl2 1c
24
24
24
24
24
24
24
24
1
2
3
4
5
6
7
0
0
84
78
57
43
80
87
41
5
36
6
VO(Oi-Pr)3
VO(Oi-Pr)3
VO(Oi-Pr)3
VO(Oi-Pr)3
VO(Oi-Pr)3
VO(Oi-Pr)3
1c
1a
1b
1d
1e
1f
0
12
7
0
21
8
Toluene
CH2Cl2
CH2Cl2
0
33
9
25
–40
38
10
11
67
a Reaction conditions: VO(Oi-Pr)3/1c/aniline/cyclohexene oxide =
0.1:0.15:1:1 for 24 h.
a Reaction conditions: vanadium/ligand/aniline/cyclohexene
oxide = 0.1:0.15:1:1 in CH2Cl2.
b Isolated yield.
c Determined by HPLC with a Daicel Chiralcel OD column.
b Isolated yield.
c Determined by HPLC with a Daicel Chiralcel OD column.
they gave both poor reactivities and selectivities (Table 1,
entries 10 and 11). These results indicate that chiral
ligands with the salan skeleton are more enantioselective
in the reaction than those with the salen framework. Al-
though the structure of VO(Oi-Pr)3–1c is not clear at this
stage, the results shown above indicate that the tetraden-
tate salan may wrap in a well-defined way around the
metal, thus providing better site discrimination than that
of salen.
the 1,2-aminoalcohols in good yields and moderate to
high enantioselectivities.
Chiral salan ligand 1a–d (Figure 1) could easily be pre-
pared from the corresponding Schiff base ligand.10a We
used these ligands combined with vanadium in the asym-
metric addition of anilines to meso-epoxides.
In order to screen the vanadium compounds, we initially
applied chiral salan 1c to the ring-opening of cyclohexene
oxide (2a) using aniline (3a) as the nucleophile. Treat-
ment of cyclohexene oxide with aniline in dichlo-
romethane at 0 °C gave rise to the formation of 1,2-
aminoalcohol 4a in moderate to excellent yields in most
cases (Table 1). Among the six vanadium compounds,
Using VO(Oi-Pr)3–1c as catalyst, the reaction conditions
were then further optimized as outlined in Table 2.
Among the five solvents investigated, dichloromethane
proved to be best in terms of yields and enantioselectivity
(Table 2, entry 1), while chloroform and toluene gave
good yields but poor enantioselectivities (Table 2, entries
2 and 5). When hexane and THF were employed as sol-
vent, lower yields and poor selectivities were obtained
(Table 2, entries 3 and 4). Increasing the reaction temper-
ature from 0 °C to 25 °C caused a slight increase in yields
but a sharp decrease in ee value (38% ee; Table 2, entry
6). The highest ee value (67%) was observed when the re-
action was conducted at –40 °C, however a sharp decrease
in the yield (41%) was also noted (Table 2, entry 7). We
therefore chose dichloromethane as solvent and 0 °C as
the preferred reaction temperature for further investiga-
tion.
13
VCl3, VOCl3, VO(OEt)2Cl and VO(OEt)Cl2 displayed
high catalytic activities but poor selectivities in the reac-
tion (Table 1, entries 2–5), whereas VO(acac)2 gave both
poor reactivity and selectivity (Table 1, entry 1). When
VO(Oi-Pr)3–1c was employed, 4a was obtained in good
yield and moderate enantiomeric excess (entry 6). Further
screening of four salan ligands (1a–d) in combination
with VO(Oi-Pr)3 in the reaction indicated that 1c had the
best enantioselectivity (Table 1, entries 6–9).
For comparison, chiral salen ligands 1e and 1f have also
been examined in this ring-opening reaction. However,
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2102
J. Sun et al.
PAPER
Table 3 Vanadium–1c Catalyzed Aminolysis of meso-Epoxides 2a
1c (15 mol%)
Me
Me
N
N
HO
OH
R
R
OH
R
R
ArNH2
+
O
Ar
VO(Oi-Pr)3 (10 mol%)
CH2Cl2, 0 °C, 24 h
N
H
2
3
4
Entry
1
ArNH2
Product
Yield (%)b
84
ee (%)c
62
OH
PhNH2
3a
NHPh
OH
4a
4b
PhNH2
3a
2
3
4
5
6
7
59
87
62
73
45
87
71
80
77
51
36
77
NHPh
OH
PhNH2
3a
NHPh
OH
4c
Ph
PhNH2
3a
Ph
NHPh
4d
OH
PhNH2
3a
NHPh
4e
4f
OH
PhNH2
3a
NHPh
OH
4-MeOC6H4NH2
3b
NHC6H4(4-OMe)
OH
4g
4h
4-MeOC6H4NH2
3b
8
9
90
89
77
71
83
87
82
45
NHC6H4(4-OMe)
OH
4-MeOC6H4NH2
3b
NHC6H4(4-OMe)
4i
OH
Ph
4-MeOC6H4NH2
3b
10
11
Ph
NHC6H4(4-OMe)
4j
OH
2-MeC6H4NH2
3c
NHC6H4(2-Me)
4k
Synthesis 2008, No. 13, 2100–2104 © Thieme Stuttgart · New York

PAPER
Enantioselective Ring-Opening of meso-Epoxides
2103
Table 3 Vanadium–1c Catalyzed Aminolysis of meso-Epoxides 2a (continued)
1c (15 mol%)
Me
Me
N
N
HO
OH
R
R
OH
R
R
ArNH2
+
O
Ar
VO(Oi-Pr)3 (10 mol%)
CH2Cl2, 0 °C, 24 h
N
H
2
3
4
Entry
12
ArNH2
Product
Yield (%)b
82
ee (%)c
67
OH
4-MeC6H4NH2
3d
NHTol
4l
OH
4-ClC6H4NH2
3e
13
78
55
NHC6H4(4-Cl)
4m
a Reaction conditions: VO(Oi-Pr)3/1c/anilines/epoxide = 0.1:0.15:1:1, CH2Cl2, 0 °C, 24 h.
b Isolated yield.
c Determined by HPLC with a Daicel Chiralcel OD column.
Based on these results, the scope of the reaction was in- Elemental analyses were carried out on a Perkin-Elmer 240C ele-
1
mental analyzer. H NMR data were recorded on a Bruker AMX-
vestigated using a variety of meso-epoxides and anilines.
Accordingly, meso-epoxides were allowed to react with a
range of substituted anilines in the presence of 10 mol%
VO(Oi-Pr)3 and 15 mol% 1c under the conditions de-
300 spectrometer with chemical shifts referenced to SiMe4 as inter-
nal standard. Electrospray ionization mass spectra were recorded on
a Finnigan LCQ Electrospray mass spectrometer. Optical rotations
were recorded on a Perkin Elemer 241 polarimeter. Enantiomeric
scribed above. The results showed that the catalytic activ-
ity was general for a wide range of meso-epoxides and
anilines bearing an electron-withdrawing or an electron-
donating group. Addition of aniline (3a) or p-anisidine
(3b) to a range of meso-epoxides furnished the corre-
sponding 1,2-aminoalcohols in good yields and moderate
to high enantioselectivities in all cases except with the
seven-membered cyclic epoxide 4f (Table 3, entry 6). For
the ortho-substituted aniline 3c, however, the reaction
gave lower yield and poor selectivity (Table 3, entry 11).
The aniline 3e, bearing an electron-withdrawing group at
the para position, also gave the product in a slightly lower
yield and lower enantioselectivity (Table 3, entry 13).
Moreover, para-substituted anilines with an electron-
donating group reacted with cyclohexene oxide (2a) to af-
ford the products with higher enantioselectivities
(Table 3, entries 7 and 12 versus 1, 11 and 13). In partic-
ular, when the same substrate 2a was reacted with a range
of anilines, p-anisidine 3b afforded the ring-opened prod-
uct with the highest yield (87%) and the highest ee value
(77% ee) (Table 3, entry 7).
excess values were determined by a Perkin-Elmer 200 HPLC on a
chiral Chiralcel OD-H with UV detection at 254 or 247 nm. All sol-
vents were distilled from the corresponding drying agents. All re-
agents were obtained from commercial suppliers and used without
further purification unless otherwise stated. All reactions were car-
ried out under argon. All catalytic reactions were carried out in
Schlenk tubes. Ligands 1a, 1b and 1c were prepared according the
literature.10a Analytical and spectroscopic analysis of all products
were in agreement with literature values: 4a,3a,d 4b,3d 4c,3d 4d,5c
4e,6e 4f,5c 4g–i,3d 4j–m.5c
(R,R)-N,N¢-Dibenzyl- N,N¢-bis(2-hydroxyphenyl)-1,2-cyclohex-
anediamine (1d)
Under argon, a mixture of NaH (60% dispersion in mineral oil; 1.5
g, 25 mmol) in THF (15 mL) was added anhyd DMF (1.5 mL) at r.t.
After stirring for 10 min, 1a (1.62 g, 5 mmol) was added and the
mixture was stirred for another 30 min. Then BnBr (1.3 mL, 11
mmol) was added dropwise. The reaction mixture was heated at re-
flux for 8 h and then cooled to r.t. H2O (5 mL) was added to quench
the reaction. The mixture was extracted with Et2O and the organic
layer was separated, dried (Na2SO4), filtered, and the solvent was
removed under reduced pressure to give the crude product as an oil.
Purification by column chromatography on silica gel (PE–EtOAc,
20
3:1) gave 1d as a yellow solid (1.16 g, 46%). [a]D –3.9 (c 0.2,
CH2Cl2).
In summary, we have developed an efficient catalytic sys-
tem [VO(Oi-Pr)–1c] for the enantioselective ring-opening
of meso-epoxides, providing 1,2-aminoalcohols in good
yields (up to 90%) and moderate to high enantioselectivi-
ties (up to 87% ee). We are currently extending the appli-
cation of vanadium–salan to other asymmetric reactions
and studying their synthetic applications.
1H NMR (300 MHz, CDCl3): d = 1.10–1.37 (m, 4 H), 1.69–1.82 (m,
2 H), 2.07–2.10 (m, 1 H), 2.23–2.29 (m, 1 H), 2.60 (s, 2 H), 3.41–
3.46 (m, 1 H), 3.55–3.59 (m, 1 H), 3.75–3.82 (m, 3 H), 3.98–4.02
(m, 1 H), 4.96–5.11 (m, 4 H), 6.91–6.93 (m, 4 H), 7.21–7.27 (m, 3
H), 7.29–7.34 (m, 3 H), 7.40–7.47 (m, 10 H).
Synthesis 2008, No. 13, 2100–2104 © Thieme Stuttgart · New York

2104
J. Sun et al.
PAPER
MS (EI): m/z = 505 [M – 1] (16), 399 (26), 294 (5), 213 (3), 197
(17), 107 (4), 106 (2), 91 (100), 65 (2).
(4) For the regioselective ring-opening of meso-epoxides with
anilines and amines, see: (a) Sabitha, G.; Reddy, G. S. K.
K.; Reddy, K. B.; Yadav, J. S. Synthesis 2003, 2298.
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Synthesis 2001, 831. (c) Zhao, P. Q.; Xu, L. W.; Xia, C. G.
Synlett 2004, 846. (d) Kamal, A.; Mohd, R. R.; Azhar, A.;
Khanna, G. B. R. Tetrahedron Lett. 2005, 46, 2675.
(e) Placzek, A. T.; Donelson, J. L.; Trivedi, R.; Gibbs, R. A.;
De S, K. Tetrahedron Lett. 2005, 46, 9029.
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Anal. Calcd for C34H38N2O2: C, 80.52; H, 7.50. Found: C, 80.68; H,
7.36.
Enantioselective Ring-Opening of meso-Epoxides; Typical Pro-
cedure
A solution of VO(Oi-Pr)3 (0.1 mmol) and chiral salan ligand 1c
(0.15 mmol) in CH2Cl2 (2 mL) was stirred for 10 min at 0 °C under
nitrogen. Subsequently, cyclohexene oxide (1 mmol) and aniline (1
mmol) were added and the solution was stirred at 0 °C for 24 h. The
solvents were removed under reduced pressure and the crude prod-
uct was purified by flash chromatography on silica gel column (PE–
EtOAc, 4:1) to afford 1,2-aminoalcohol (4a) in 84% yield. HPLC
analysis (Chiralcel-OD-H; n-hexane–isopropanol, 85:15; flow rate:
1 mL/min): 62% ee.
Acknowledgment
We gratefully acknowledge the National Natural Science Founda-
tion of China, the 863 High Technology Program, Science Founda-
tion of Jiangsu Province and the Key Laboratory of Fine
Petrochemical Technology of Jiangsu Province for their finacial
support.
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Synthesis 2008, No. 13, 2100–2104 © Thieme Stuttgart · New York