Enantioselective syntheses of β-amino alcohols catalyzed by recyclable chiral Fe(III) metal complex

Article abstract of DOI:10.1039/c5ra23600b

An efficient asymmetric desymmetrization of meso-epoxides with anilines catalysed by a series of simple and environmentally benign in situ generated Fe(iii) complexes based on chiral tridentate ligands L₁-L₇ with achiral and chiral l

Full text of DOI:10.1039/c5ra23600b

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Enantioselective syntheses of β-amino alcohols catalyzed by
recyclable chiral Fe(III) metal complex
Rajkumar Taka,b, Manish Kumara,c, Rukhsana I. Kureshy*a,b, Manoj Kumar Choudharya,b, Noor-ul H.
Khana,b, Sayed H. R. Abdia,b and Hari C. Bajaja,b
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient asymmetric desymmetrization of meso-epoxides with anilines catalysed by
a series of simple and
environmentally benign in situ generated Fe(III) complexes based on chiral tridentate ligands L1-L7 having achiral and chiral
linkers (methylene, piperazine, R/S Binol and diethyl tartrate) was carried out at rt. The in situ generated iron metal
complex based on ligand L5a emerged as improved (low catalyst loading) catalyst for asymmetric desymmetrization of
meso-epoxides with anilines giving high enantioselectivity (up to 99%) and high yield (95%) of enantiopure β-amino
alcohols in 14 h. While excellent results for ARO of cyclic as well as aliphatic epoxides with anilines was achieved with in
situ generated complex from the ligand L4h and Fe(III) chloride, the catalyst was recoverable and recyclable (five times)
DOI: 10.1039/x0xx00000x
www.rsc.org/
with
retention
of
its
performance.
Introduction
first time the use of a very simple experimental procedure for
The desymmetrization of meso-epoxides by the anilines is a the synthesis of chiral syn-β-amino alcohols by ARO of
simple, precise and straight forward strategy for the synthesis aromatic meso-epoxides with anilines/indoles using Fe(II)
of chiral β-amino alcohols.1,2 The enantiopure β-amino Bolm’s bipyridine complexes as catalysts.10 Excellent yields and
alcohols are important key structural units found in many enantioselectivities of β-amino alcohols were achieved with
biologically active compounds and are also used for the these complexes at higher catalyst loading (5 mol %) with no
preparation of fine chemicals, synthetic drugs and amino recyclability data. In the present study we have developed a
acids.3 In recent years, chiral amino alcohols alone4 or in the new and efficient dinuclear Fe(III) based catalytic systems for
presence of a metal ion5 have been used efficiently to catalyse ARO of aromatic meso as well as aliphatic/cyclic epoxides with
various asymmetric organic transformations. On the principle anilines. The synthesized chiral tridentate Schiff base ligands
of electrophilic activation of epoxide ring, various efficient
(L1-L7) having diverse stereogenic centres due to the different
catalytic methods have been reported for the asymmetric ring chiral/achiral linkers (R)/(S)-BINOL, diethyl D-(-)-tartrate,
opening (ARO)
of
meso-epoxides
with
alkyl/aryl methylene and piperazine with various iron metal source have
amines/indoles, using various transition metal ions6-13 and rare been used to comprehend their catalytic efficiency (low
earth metal ions14 with fair success in term of yield and catalyst loading) in the asymmetric ARO reaction of meso-
enantioselectivity of β-amino alcohols. Among them, stilbene oxide 5, cis-butene oxide 7 and cyclohexene oxide 8
recyclable Ti(IV)-catalyzed ARO reaction of meso-epoxides with with amines 6a-l. Among all the ligands screened, we are
anilines using (S)-BINOL5a, (1R,2S)-(-)-2-aminodiphenyl ethanol pleased to find out that the ligand L5a derived from (R)-BINOL
derived Schiff bases6a, chiral polymeric salen6b and dinuclear with
(1S,2R)-2-amino-1,2-diphenylethanol
worked
aminoindanol5b derived ligands with chiral linker have shown synergistically with Fe(acac)3 giving very high enantioselectivity
better performance over organo-catalytic systems15 in terms (>99%) and very good yield (95%) in the ARO reaction of meso-
of low temperature, high catalyst loading, long reaction time, stilbene oxide
5 with aniline 6a at low catalyst loading (2.5 mol
and use of inorganic and organic bases as co-catalyst. Hence it %) while ligand L4h in combination with Fe(III) chloride gave β-
is utmost importance that the metal ion should be amino alcohols of aliphatic and cyclic epoxide with anilines
environmental friendly, non-toxic and the resulting complex yield (up to 96%) with excellent ee (up to 99%). The in situ
should also be recyclable. Ollevier et al. demonstrated for the generated catalysts were found to be stable and were easily
separated from the catalytic reaction mixture and reused
several times.
Results and Discussion
Inclusion of an extra element of chirality and catalytic sites
while designing a chiral catalyst often helps in improving the
catalyst performance.5b,6c Keeping this fact in mind
achiral/chiral linker with diverse diastereomeric combinations
of amino alcohols based ligands L1-L7 were synthesised in two
steps. In the first step achiral linker (methylene
a
, piperazine
) were
b
) and chiral linker (diethyltartrate c, (S)/(R)-BINOL d
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Linkers
H2
C
N
N
N
OH
OH
a
b
OH
H2C
O O
OH
OH
O
(R)
HO
O
(R)
OH
OH
N
L1= Methylene,(1R,2S)Aminoindanol
L2= Piperazine(1R,2S)Aminoindanol
c
L1
d
N
OH
OH
N
OH
OH
OH
OH
O HO
OH O
O
N
N
tBu
O
tBu
OH
O
OH
N
tBu
OH
N
Cl
Linker
L4a-L4g
L2
L4a= (S)-Binol,(1R,2S)Aminoindanol
L4b= (S)-Binol,(1S,2S)Aminoindanol
L4c= (S)-Binol,(1S,2R)Aminoindanol
N
OH
OH
L d= ( )-Binol (1 2 )Aminoindanol
R, R
S
,
4
OH
L4e= (R)-Binol,(1R,2R)Aminoindanol
L4f= (R)-Binol,(1R,2S)Aminoindanol
L4g= (R)-Binol,(1S,2S)Aminoindanol
L4h= (R)-Binol,(1S,2R)Aminoindanol
O
(R)
O
O
O
O
(R)
O
OH
N
L =Diethyl L-tartrate,(1 2 )Aminoindanol
R, S
3
N
OH
OH
OH
N
OH
O
N
OH
OH
O
O
OH
O
OH
N
OH
N
OH
(R,S)-L7
L7 =(1R,2S)Aminoindanol
L5a= (R)-Binol,(1S,2R)Diphenyl aminoalcohol
L5b= (S)-Binol,(1R,2S)Diphenyl aminoalcohol
L6 =(S)-Binol,(S)-Valinol
Scheme 1. Structure of the ligands L1- L7
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reacted with 3-t-Bu-5-(chloromethyl)-2-hydroxybenzaldehyde
to get dialdehydes which on condensation with (1R,2S),
(1S,2S), (1S,2R), (1R,2R) amino alcohols gave tridentate
ligands L1-L7 (Scheme 1).5b At the very beginning, to
determine the effect of various linkers on the activity of
catalysts formed by the reaction of chiral tridentate ligands
L1-L4a (5 mol %) with Fe(acac)3 (1:1) were examined for ARO
Table 2 Optimization of iron metal salts for ARO reaction of meso-stilbene oxide 5 with
aniline 6a using the in situ generated catalyst from ligand L4a[a]
Entry
Metal source
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
FeCl3
60
65
68
40
70
72
68
69
45
40
51
48
30
25
33
23
reaction of meso-stilbene oxide
5 as a model substrate and
FeBr3
aniline 6a as a nucleophile in DCM at rt for 20 h (Table 1,
entries 1-4). The outcome of these reactions were
encouraging particularly with the ligand L4a where we got the
ring opened product syn-β amino alcohol in good yield (68%)
and enantioselectivity (ee, 51%; entry 4) which reflects that
inclusion of (S)-BINOL as an additional element of chirality has
distinct advantage. These observations are in consonance
Fe(acac)3
Fe(acac)2
Fe(ClO4)3
Fe(ClO4)2
Fe(CF3SO3)3
Fe(CF3SO3)2
with
transformations.16 To further ascertain this finding we used
ligand 7, which is a simpler version of L4a (having no BINOL
our
earlier
results
on
different
organic
L
linker) and the results were inferior to L4a.Moreover, the
complex derived from L7 was not recyclable due to its high
solubility in most organic solvents.
[a]
Conditions: Meso-stilbene oxide 5 (0.2 mmol), Aniline 6a (0.22 mmol),
Chiral ligand L4a (0.01 mmol), iron salts (0.01 mmol) in CH2Cl2 at rt for 20 h.
[c]
[b] Isolated yield after flash chromatograph. ee determined on Chiralcel AD
Table 1 Optimization of linkers for ARO reaction of meso-stilbene oxide 5 with aniline
column.
[a]
6a using the in situ generated catalyst from ligand L1-L4a and Fe(acac)3
It is well known in literature that a catalytically active metal
complex when generated in situ from a ligand and a metal
source, their molar ratios of the two distinctly influence the
yield and enantioselectivity of the product.5a,5b,5c,5g This may be
due to the varying degree of complexation occurring in the
solution during catalysis. Therefore, we gradually increased
the
HO HN
NH2
Ligand + Fe(acac)3
20 h, rt, DCM
O
+
5
6a
6'a
Entry
Ligand
L1
Yield [b] [%]
ee[c] [%]
18
1
2
3
4
40
45
50
68
L2
22
L3
28
L4a
51
[a]
Conditions: Meso-stilbene oxide 5 (0.2 mmol), Aniline 6a (0.22 mmol),
Chiral ligand L1- L4a (0.01 mmol), Fe(acac)3 (0.01 mmol ). [b] Isolated yield after
flash chromatography. [c] ee determined on Chiralcel AD column.
Encouraged by the preliminary results with the optimized
catalyst generated in situ and to ascertain the role of effective
metal complex for the catalytic reaction, we carried out
systematic screening of various iron salts (both divalent and
trivalent) with the chiral ligand L4a (most active and
enantioselective). The rationale behind this is based on the
concept that iron sources with different counter ions are
known to form structurally different complexes with a given
ligand, hence strongly affect the catalytic activity. Therefore,
we screened different metal salts viz., iron(III) chloride, iron(III)
bromide, iron(III) triflate, iron(III) perchlorate, iron(II) triflate,
iron(II) perchlorate and iron(II) acetylacetonate (5 mol %) (1:1)
to see the performance of ligand L4a as catalyst precursor in
Figure 1 Variation of ligand metal ratio for the synthesis of syn β-amino alcohols
ligand to metal ratio from 1:1 to 1:3 for carrying out the ARO
reaction of
5 with 6a in presence of L4a and Fe(acac)3 and data
is given as Figure 1. It is evident from the data (Figure 1) that
the ditopic ligand L4a and Fe(acac)3 (1:2) gave best results in
term of the product yield 80% with ee 75% of syn-β amino
alcohol due to the presence of two catalytically active centres.
An increase in the metal content (M:L,3:1) caused some
enhancement in the product yield with a reduction in the ee,
possibly due to the presence of excess free metal working as a
catalyst to produce racemic product thereby bringing down
the overall enantioselectivity.
the ARO of meso-stilbene oxide
5 as a model substrate with
aniline 6a as a nucleophile under the above mentioned
reaction condition. Among the different iron salts screened
iron(III) acetylacetonate worked well to give good yield (68%)
and enantioselectivity (ee, 51%; Table 2, entry 3) of syn-β
amino alcohol. We have also observed that trivalent iron salts
give better results than divalent iron possibly due to higher
Lewis acidity of the trivalent iron.
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To ascertain the in situ formation of active complex with M:L (95%) and ee (>99%). These results are superior in terms of
yield of syn-β-amino alcohol and enantioselectivity using lower
catalyst loading (2.5 mol %) than the previously reported chiral
Ti(IV) systems, which needed higher catalyst loading (15 mol
%) at rt with the same ligand5b and Fe(II) Bolm’s bipyridine
complex (5 mol %).10 Interestingly the configuration of the
(2:1) we have performed UV-Vis titration using Job’s method,
where we varied the concentration of [Fe(acac)3] against the
ligand L4a using 1x10-3M concentration in CH2Cl2.
The absorbance maximum at 551 nm was measured and
(Figure S-1)
plotted against the concentration of molar equivalent of product syn-β-amino alcohol is directly dependent on the
configuration of indanol collar irrespective of the configuration
of BINOL. Hence it is possible to get the desired configuration
in the product by selecting appropriate configuration of the
catalyst itself. In the present case, the iron complex based on
the ligand L5a provided (1S,2S)-configuration and on changing
the iron catalyst to the L5b we observed (1R,2R)-configuration
of the product. It is important to note that in ligand system
having diverse asymmetric centre, each chirality element
contributes significantly towards enantioselectivity of the
product and in the catalyst L5a only specific combination of
chirality of BINOL (R) with diphenyl aminoalcohol (1S,2R) was
found to be more suitable. This observation is in agreement
with our earlier reports in other organic transformations.16b,16c
Further, in order to understand the structure of the in situ
formed complex, [Fe2L5a(acac)2], incorporating the ligand L5a
and Fe(acac)3 was prepared and characterized by different
techniques, such as IR, UV-visible, ESI-MS and MALDI-TOF. A
Fe(acac)3 to get parabolic curve (Figure 2). It is evident from
the plot that absorbance maxima obtained at M:L molar ratio
of 2:1 suggesting the formation of dinuclear complex.
molecular peak at m/z
=
1362.89 attributable to
[Fe2L5a(acac)2] and 1361 assigned to [Fe2L5a(acac)2-H] in ESI-
MS and Matrix-assisted Laser deposition/ionization (MALDI)
spectra confirm the formation [Fe2L5a(acac)2], which is in
consonance with other analytical data (data is given in
supporting information). Our repeated attempts to get single
crystal of the complex, suitable for the X-ray analysis failed. To
find out the general applicability of the catalyst, [Fe2L5a(acac)2]
the above optimized reaction condition was further used for
Figure 2. Job’s plot drawn between ligand L4a and Fe(acac)3 (1x10-3) from UV-visible
spectral data based on the absorbance obtained from λmax = 551 nm.
In order to further improve the results we optimized other
reaction parameters like catalyst loading, solvent variation and
temperature. First we assessed the catalyst (derived from L4a
with L:M ratio 1:2) loading from 1-10 mol % with respect to
the substrate meso-stilbene oxide
5 with aniline 6a (Table 3,
the asymmetric ARO reaction meso-stilbene oxide
variety of different amines 6a-l
5 with a
entries 1-5). It was found that 2.5 mol % of catalyst loading is
sufficient to give 79% yield of β-amino alcohol with 75% ee
(entry 2). Next we screened different solvents viz., toluene,
THF, ACN, CHCl3 and DCE (Table 3, entries 6-10) for
asymmetric ARO reaction keeping other optimized reaction
parameters constant (as per entry 2). Among the various
solvents DCM showed promishing result (entry 2) and choosen
as the solvent of choice in our subsequent studies.The reaction
was further subjected to temperature variation (entries 10-
12). The data suggest that rt is the optimum temperature to
carry out ARO reaction (entry 2) because on lowering the
reaction temperature below rt the results were adversely
effected, particularly the product yield while enantioselectivity
remained unchanged. This protocol has shown similar
.
Table 3 Optimization of reaction conditions for ARO reaction of meso-stilbene
oxide 5 with aniline 6a using the in situ generated catalyst from ligand L4a with
[a]
Fe(acac)3
Catal.
mol %
Solvent
Temperature Time
Yield[b]
[%]
ee[c]
[%]
Entry
1
oC
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
10
0
[h]
14
14
14
14
12
16
10
18
14
15
20
25
12
1.0
2.5
5
DCM
DCM
DCM
DCM
DCM
Toluene
THF
68
79
80
85
89
90
78
70
91
87
70
65
79
70
75
75
74
70
72
74
60
68
66
75
77
75
2
3
4
7.5
10
5
6
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
7
performance for the formation of syn-β-amino alcohol even at
8
ACN
relatively higher scale (10 mmol) in 12 h (Table 3, entry 13). To
further improve the results, the optimal reaction conditions as
established above (Table 3, entry 2) was then extended to all
9
CHCl3
DCE
10
11
12
13[d]
DCM
DCM
DCM
the 8 diastereomers of ligand
and 7 derived from (R/S)-BINOL backbone in combination with
various diastereomeric forms of amino alcohols such as 1-
amino-2,3-dihydro-1H-inden-2-ol, 2-amino-1,2-
L4 as well as to ligands L5a, L5b, L6
L
rt
[a] Conditions: Meso-stilbene oxide 5 (0.2 mmol), Aniline 6a (0.22 mmol).
[b] Isolated yield after flash chromatography. [c] ee determined on Chiralcel AD
column. [d] Reaction performed at 10 mmol scale keeping other conditions as
per entry 2
diphenylethanol and (S)-valinol to generate active complex
with Fe(acac)3 for the enantioselective epoxide ring opening
reaction of meso-stilbene oxide
nucleophile. In the entire matrix of results, the complex
generated from ligand L5a (Figure 3) was found to be the best
for the ring opening reactions of meso-stilbene oxide 5 with
aniline 6a to give the product amino alcohols in high yield
5 with aniline 6a as a
In most of the cases, the active dinuclear [Fe2L5a(acac)2]
catalyst smoothly catalyzed the reaction with good to excellent
yield (up to 95 %) with high enantioinduction (up to 99%)
(Table 4). 4-Substituted anilines viz., 4-Me, 4-Et, 4-OMe, 4-Cl
4 | J. Name., 2012, 00, 1-3
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Entry
Amines
Time [h]
14
Yield[b] [%]
ee[c] [%]
99
except 4-NO2 aniline were found to be more reactive with
better enantioselectivity in the product than with 2-
substituted anilines (entries 1-8), possibly due to the steric
interaction arising from ortho substitution on the nucleophile
which disfavours higher enantioselectivity (entries 5,7).
1
2
Aniline 6a
95
90
94
90
30
89
20
trace
-
4-Me aniline 6b
4-Et aniline 6c
4-MeO aniline 6d
2-OMe-aniline 6e
4-Cl aniline 6f
2-Cl-aniline 6g
4-NO2 aniline 6h
Butyl amine 6i
Isopropyl amine 6j
Morpholine 6k
Pyrrolidine 6l
14
98
3
18
90
4
14
95
5
18
28
6
24
90
7
24
38
8
30
Nd
Nd
Nd
Nd
Nd
9
30
10
11
12
30
-
30
-
30
-
[a]
Conditions: Meso-stilbene oxide 5 (0.2 mmol), amines 6a-l (0.22 mmol),
[b]
chiral ligand L5a (0.005 mmol), Fe(acac)3 (0.01 mmol ), in CH2Cl2 at rt.
Isolated yield after flash chromatography. [c] ee determined on Chiralcel AD,
OD, OJ HPLC columns.
Further, due to the less reactivity of 4-NO2-aniline we got the
product in trace amount (entry 8). Moreover, the use of
aliphatic amines such as butyl amine 6i, isopropyl amine 6j
morpholine 6k and pyrrolidine 6l (Table 4, entries 9-12) were
unable to open the ring of meso-stilbene oxide even after
,
5
prolonged reaction time possibly due to higher basicity of
these amines causing blockage of acidic sites of the metal
catalyst leaving behind the epoxide un-activated.15
Figure 3. Optimization of ligands L4-L7 for ARO reaction of meso-stilbene oxide 5 with
aniline 6a
After successful optimization of iron catalyst derived from the
ligand L5a for aromatic ring opening reaction, we also explored
the same protocol for ARO reaction of aliphatic epoxide (cis-
Table 4 Product yield and ee values of ARO of meso-stilbene oxide 5 with different
amines 6a-l as nucleophile catalyzed by in-situ generated Fe-complex based on L5a
ligand under the optimized reaction conditions[a]
butene oxide 7) and cyclic epoxide (cyclohexene oxide 8) with
various anilines but unfortunately we got unsatisfactory
results. So we thought of screening our previously used ligands
R1
(Figure 3) for the ARO of cis-butene oxide
7 and cyclic epoxide
NH2
HO
HN
R2
O
5
Ligand (2.5 mol%) +
Fe(acac)3 (5 mol%)
R1
8 with different anilines (Table 5, entries 1-10). Fortunately,
+
fair success in terms of yield (89-96%) and ee (62-99%) was
achieved with ligand L4h using FeCl3 as a source of metal as
catalyst and substituted anilines (entries 2-4). Noticeably, with
aniline as a nucleophile only moderate enantioselectivity
(entry 1) was obtained. Here again, 4-NO2-aniline was unable
to open the epoxide ring of aliphatic substrates due to its poor
nucleophilicity (entries 5 and 10). These observations are in
agreement with the earlier metal based and organocatalyzed
ARO reaction of epoxides with amines.5b,15
RT, DCM
R2
6'a-l
6a-I
6b: R1 = H, R2 = Me
6a: R1 = H, R2 = H;
6c: R1 = H, R2 = Et;
6e: R1 = OMe, R2 = H;
6g: R1 = Cl, R2 =H;
6i: Butyl amine;
6d: R1 = H, R2 = OMe
6f: R1 = H, R2 = Cl
6h: R1 = H, R2 = NO2
6j: Isopropyl amine
6I: Pyrrolidine
6k: Morpholine;
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Table 5 Product yield and ee values of ARO of different meso-epoxides 7-8 with
different anilines as nucleophile by in-situ generated Fe-complex based on L4h ligand[a]
Entry
Epoxide
Amines
Time
[h]
Yield[b] ee[c]
[%]
96
90
89
[%]
62
99
90
1
2
3
Aniline 6a
14
Cis-butene
4-Me aniline 6b
4-Et aniline 6c
14
oxide
14
18
24
15
15
15
24
30
7
4
5
2-Cl aniline 6g
4-NO2 aniline 6h
Aniline 6a
80
trace
97
85
nd
63
85
95
80
nd
6
Cyclohexene
7
4-Me aniline 6b
4-Et aniline 6c
2-Cl aniline 6g
4-NO2 aniline 6h
90
oxide
8
87
8
9
78
10
trace
[a] Conditions: epoxide 7-8 (0.2 mmol), anilines 6a-c,g,h (0.22 mmol), chiral ligand
L4a(0.005 mmol), FeCl3 (0.01 mmol ), in CH2Cl2 at rt. [b] Isolated yield after flash
chromatography. [c] ee determined on Chiralcel AD, OD, OJ columns.
Scheme 2. Plausible transition state of complex
Based on experimental results a working model can be
proposed for the possible transition state (Scheme 2). In the
catalytic cycle, epoxide is activated through weak interaction
of its oxygen atom to Lewis acid centre (iron). The attack of
aniline to thus activated epoxide (by iron center) gives the
product syn β-amino alcohol. To further strengthen the
probable mechanism a stepwise UV-visible spectral study was
A (Ligand)
B (Fe(III)-complex)
C (Fe(III) com-Epoxide)
D (Fe(lII) com--Epoxide and Aniline)
2
carried out with meso-stilbene oxide
5 (0.2 mmol) as substrate
and aniline 6a (0.22 mmol) as nucleophile in DCM (0.8 ml) as
solvent at rt (Figure 4). The UV-Vis spectrum of ligand L5a
(0.005 mmol) has n–π* transition at 334 nm which showed
red-shift (bathochromic) to higher wavelength (354 nm as
LMCT band) after addition of Fe(acac)3 (0.01 mmol),
confirming the formation of in situ generated [Fe2L5a(acac)2]
complex with a new band at 539 nm assigned to d–d
0
300
400
500
600
700
800
Wavelength (nm)
Figure 4. Stepwise UV-Vis spectra recorded in DCM (A) Ligand (0.005 mmol), (B)
transition.17 After addition of substrate to the solution of the Complex (L:M 0.005:0.01), (C) Complex & Epoxide (0.2 mmol), (D) Complex, Epoxide &
aniline (0.22 mmol), (after 1h).
complex [Fe2L5a(acac)2] both the LMCT and d-d bands showed
isosbestic points at ~393 nm & ~588 nm. These observations
FeCl3 for the ring opening of cis-butene oxide
7 with 4-methyl
confirm the direct co-ordination of the substrate to Fe(III)
complex through the lone pair of the oxygen atom of the
aniline 6b at 1 mmol level under the optimized reaction
conditions (Table 5, entry 2). After completion of the catalytic
reaction, the catalyst was precipitated with n-hexane and
retrieved quantitatively. The product β-amino alcohol was
recovered from the organic layer and separated by column
chromatography. The recovered complex was dried in vacuum
and was used as such for the subsequent catalytic runs, which
worked well up to 4 catalytic runs with retention of reactivity
and enantioselectivity. From the recycling experiments it is
evident that the in situ formed catalyst is fairly stable and do
not deteriorate during the course of ARO reaction (Figure 5). In
order to confirm the stability of the recovered catalyst during
epoxide 5. The generation of the isosbestic points may be due
to the changes in the geometry of the iron complex on
interaction of substrate to the iron. On further addition of the
aniline to the reaction mixture we did not observe
considerable change in an isosbestic points confirming no
further change in the geometry of the iron complex. The
interesting feature of these Fe(III) complexes is in their
inherent tendency to precipitate out in non-polar solvents like
hexane due to their higher molecular weight and lower
solubility. Hence, the recyclability of the catalyst was checked
for the in situ generated complex with ligand L4h in
combination with
6 | J. Name., 2012, 00, 1-3
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ARTICLE
MHz and are referenced internally with TMS. Enantiomeric
excess (ee) were determined by HPLC using Daicel Chiralpak
OD, OJ and AD chiral columns with 2-propanol/hexane as
eluent. FTIR spectra were carried out using KBr. Optical
rotations were determined by automatic polarimeter (Digipol
781). Leaching of the metal was determined by inductively
coupled plasma (ICP) spectrometer (Perkin- Elmer, Optima
2000 DV) and by using TGA (Mettler Toledo) with detection
limit. For the product purification flash chromatography was
performed using silica gel 100-200 mesh. Thus, in a stepwise
manner, 3-tert-butyl salicylaldehyde was chloromethylated to
the ARO reaction, the IR spectra (Figure 6) were recorded both
for fresh catalyst and recovered catalyst which matched well
suggesting that no major structural changes had taken place
during the course of post-catalytic workup. To further check
the Leaching of the metal from the isolated complex after first
use, the filtrate obtained at the time of isolating the complex
was subjected to ICP which does not show the trace of metal.
99
90
99
89
99
89
99
88
99
88
100
80
give
3-tert-butyl-5-(chloromethyl)-2-hydroxybenzaldehyde
which on reaction with (R)/(S)-BINOL, diethyl D-(-)-tartrate,
methylene and piperazine gave dialdehydes.5b
Preparation of Ligands
Yield
Ee
60
The dialdehydes of different linkers a-d were dissolved in dry
THF to which two equimolar quantity of (1R,2S)-1-amino-2,3-
dihydro-1H-inden-2-ol/(1R,2R)-1-amino-2,3-dihydro-1H-inden-
2-ol/(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol/(1S,2S)-1-
amino-2,3-dihydro-1H-inden-2-ol (S)-2-amino-3-methylbutan-
1-ol/ (1R,2S)-(-)-2-amino1,2-diphenylamino alcohols and L-
valinol was added slowly under nitrogen atmosphere. The
resulting solution was stirred for 4 h at rt (TLC checked) and
the solvent was partially removed from the reaction mixture
on a rotary evaporator that gave yellow precipitate. The solid
obtained after filtration was washed with hexane: DCM (50:1)
to get the yellow colour desired ligands L1-L7.
40
%
20
0
1
2
3
4
5
Catalytic run
Figure 5. Recyclability study of the catalytic system using cis-butene oxide
4-methyl aniline 6b as model substrate.
7 and
Typical experimental procedure for ring opening of epoxides
To a 5 ml round bottom flask fitted with rubber septum and
equipped with a magnetic stirring bar, a solution of chiral
ligands L1-L7 (0.005 mmol) in DCM, 0.8 ml and iron salts (0.01
mmol) were charged and the resulting solution was allowed to
stir at room temperature (27±2 °C) for 1 h. Subsequently, an
Recycled complex
60
3837
3731
3054
749
55
1388
2359
2954
3430
Fresh complex
1618
% T
50
appropriate epoxide viz., meso-stilbene oxide
5/ cis-butene
3839
3731
oxide 7/cyclohexene oxide 8 (0.2 mmol) was added to the
above stirring solution and after a gap of 10 min., appropriate
amines 6a-l (0.22 mmol) was added and the reaction mixture
was allowed to stir for the specified time. The progress of the
reaction was checked on TLC using hexane/ethyl acetate (8:2)
as mobile phase. After the completion of reaction, solvent was
removed under vacuum and the product was purified by
column chromatography using silica gel 100-200 mesh as
stationary phase and hexane/ethyl acetate (8:2) as mobile
phase. All the products were characterized by appropriate
spectroscopic techniques, microanalysis, LCMS and optical
rotation which were found to be in consonance with the
reported values.5b
2357
45
3051
748
1386
2952
3431
1618
40
4000 3600 3200 2800 2400 2000 1600 1200 800
cm-1
400
Figure 6. IR spectra of fresh and recycled catalyst
Experimental Section
(S)-BINOL) / (R)-BINOL), iron metal salts viz., iron(III) chloride,
iron(III) bromide, iron(III) triflate, iron (III) perchlorate, iron(II)
triflate, iron(II) perchlorate and iron(II) acetylacetonate,
anilines like 4-methyl, 4-ethyl-, 4-methoxy, 4-chloro, 4-NO2
aniline, butyl amine, isopropyl amine, morpholine, pyrrolidine
Conclusion
In the present manuscript we have revealed the use of Fe(III)
chiral metal complexes derived from tridentate ligands
possessing achiral and chiral linkers in ARO of meso-, aliphatic
and cyclic epoxides with anilines to give corresponding
enantioenriched β-amino alcohols (ee up to >99%) with high
6a-l, and meso-epoxides namely meso-stilbene oxide
5, cis-
butene oxide 7, cyclohexene oxide 8 were purchased from
Aldrich Chemicals and were used as received. All the solvents
used in the present study were dried by known purification
technique. NMR spectra were obtained with 500 MHz /200
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ARTICLE
Journal Name
R. I. Kureshy, M. Kumar, S. Agrawal, N. H. Khan, B. Dangi,
S. H. R. Abdi and H. C. Bajaj, Chirality, 2011, 23, 76; c) M.
Kumar, R. I. Kureshy, A. K. Shah, A. Das, N. H. Khan, S. H.
R. Abdi and H. C. Bajaj, J. Org. Chem., 2013, 78, 9076.
yield (up to 95%) at low catalyst loading. The ligand L5a with
iron(III) acetylacetonate and L4h with iron(III) chloride were
found to be the best combination for ARO reaction of
aromatic/ aliphatic and cyclic epoxides with anilines
respectively. The products from the ARO of cis-butene oxide
with 4-Me-aniline viz. syn-β-amino alcohols (ee, 99 %) were
efficiently separated from the catalyst by precipitation with
hexane and the recovered catalyst worked very well up to five
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Acknowledgements
(CSMCRI Communication No.106 /2015). Rajkumar Tak and RIK
are thankful to DST, UGC and CSIR-Indus Magic Project
CSC0123 for financial assistance. Rajkumar Tak is thankful to
AcSIR for Ph. D. Registration. Authors are also thankful to
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8 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5RA23600B
Enantioselective syntheses of βꢀamino alcohols catalyzed by recyclable chiral
Fe(III) metal complex
Rajkumar Taka,b, Manish Kumara,c, Rukhsana I. Kureshy*a,b, Manoj Kumar Choudharya,b, Noor-
ul H. Khana,b, Sayed H. R. Abdia,b and Hari C. Bajaja,b
aDiscipline of Inorganic Materials and Catalysis, CSIRꢀCentral Salt and Marine Chemicals Research Institute.
bAcademy of Scientific and Innovative Research, Central Salt and Marine Chemicals Research Institute
(CSMCRI), Council of Scientific & Industrial Research (CSIR), G. B. Marg, Bhavnagarꢀ 364 002, Gujarat,
India.
cRuᵭer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia.
Eꢀmail: rukhsana93@yahoo.co.in
N
OH
OH
O
O
Fe(III)
OH
OH
N