Conformationally rigid chiral ferrocene derivative: Synthesis, resolution and stereochemical assignment

Article abstract of DOI:10.1016/j.tetasy.2017.05.006

A conformationally rigid chiral molecule LB-I with Lewis basic site has been designed and synthesized in racemic form from ferrocene via Lewis acid mediated diastereoselective cyclization of hydroxy lactam. Both isomers were successfully obtained in enantiomerically pure form through classical resolution using dibenzoyl-D-tartaric acid as the chiral resolving agent in acetone. The nature of the diastereomeric salt formed in the resolution process was investigated by single crystal X-ray crystallographic studies. The absolute configuration of (+)-LB-I was unambiguously assigned as (S,R_p) by single crystal analysis of the salt I obtained from precipitate fraction containing (+)-LB-I and dibenzoyl-D-tartaric acid.

Full text of DOI:10.1016/j.tetasy.2017.05.006

Tetrahedron: Asymmetry 28 (2017) 830–836
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Conformationally rigid chiral ferrocene derivative: Synthesis,
resolution and stereochemical assignment
⇑
Kamsali Murali Mohan Achari, Chinnasamy Ramaraj Ramanathan
Department of Chemistry, Pondicherry University, Puducherry 605 014, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A conformationally rigid chiral molecule LB-I with Lewis basic site has been designed and synthesized in
racemic form from ferrocene via Lewis acid mediated diastereoselective cyclization of hydroxy lactam.
Both isomers were successfully obtained in enantiomerically pure form through classical resolution using
dibenzoyl-D-tartaric acid as the chiral resolving agent in acetone. The nature of the diastereomeric salt
formed in the resolution process was investigated by single crystal X-ray crystallographic studies. The
Received 5 April 2017
Revised 7 May 2017
Accepted 10 May 2017
Available online 29 May 2017
absolute configuration of (+)-LB-I was unambiguously assigned as (S,Rp) by single crystal analysis of
the salt I obtained from precipitate fraction containing (+)-LB-I and dibenzoyl-D-tartaric acid.
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
Due to the rigidity and presence of steric hindrance, the chiral
molecule LB may display good stereoselectivity in asymmetric
organic transformations. The planar chirality on ferrocene nucleus
is usually introduced by either ortholithiation of Ugi’s amine5 or
using ortho-directing units such as acetals,6 oxazolines7 or
sulphoxides.8 The direct introduction of both central and planar
chirality on ferrocene skeleton in a single reaction sequence has
not been reported so far.
Ferrocene derivatives with one or more heteroatoms are impor-
tant in organic synthesis as they are suitable ligands capable of
coordinating transition metal ions to provide complexes displaying
potential applications as catalysts in different synthetic transfor-
mations.1 Due to their availability, steric and electronic properties,
unique stereochemical aspects and wide variety of coordination
modes, these ligands have been successfully employed in a wide
variety of stereoselective transformations.2 Ferrocene derivatives
containing nitrogen heterocycles, tertiary phosphines and amines
(Lewis bases) are known to catalyze a variety of chemical reactions
through their nucleophilic reactivity. Hence, the development of
new ferrocene based chiral molecules for asymmetric catalysis
has attracted much attention in recent years. Very few chiral cata-
lysts have been reported in this field, amongst which the planar
chiral ferrocene DMAP developed by Fu et al. has proven to be a
very effective catalyst in variety of asymmetric transformations,
such as additions of alcohols or amines to ketenes, rearrangements
of O-acylated enolates, asymmetric [2+2] cycloadditions of aldehy-
des and ketenes and acylations of alcohols and silylated enolates
by anhydrides.3 The combination of both planar and central chiral-
ity usually display good enantioselectivity.4
2. Results and discussion
Isoindoloisoquinolinones can be efficiently synthesized through
6-exo-trig cyclization of phenethylphthalimides in presence of
either Lewis acid or Brønsted acid.9 Based on our experience, retro
synthetically, the target molecule ( )-L can be obtained from imide
5. Imide 5 could be realized from ferrocenecarboxaldehyde 1 by
nitroaldol condensation, and reduction of the double bond as well
as nitro group followed by condensation of the amine with phthalic
anhydride.
As illustrated in Scheme 1, condensation of ferrocenecarbox-
aldehyde 1, which was prepared from ferrocene,10 with nitro-
methane in presence of ammonium acetate and
a catalytic
amount of acetic acid under sonication afforded 2 in 82% yield.11
The reduction of the double bond in 2 was achieved using NaBH4
and silica gel combination in an isopropanol and chloroform sol-
vent mixture to furnish 3 in 83% yield.9 Catalytic hydrogenation
of nitro alkane 3 with 10% Pd/C in methanol provided amine 4.12
Refluxing the toluene solution of 4 and phthalic anhydride produced
water molecules, which were removed azeotropically using a
Dean-Stark set up to afford 2-ferrocenylethylisoindoline-1,3-dione 5
Hence, a conformationally rigid skeleton, ( )-L, a hybrid unit
visualized from isoindoloisoquinolinone and ferrocene, has been
designed with both central and planar chirality (Fig. 1). Further
modification of this molecule may lead to the Lewis base, ( )-LB.
⇑
Corresponding author.
E-mail address: crrnath.che@pondiuni.edu.in (C.R. Ramanathan).
http://dx.doi.org/10.1016/j.tetasy.2017.05.006
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.

K. M. M. Achari, C. R. Ramanathan / Tetrahedron: Asymmetry 28 (2017) 830–836
831
O
N
N
B
C
A
replacing benzene
B
*
N
C
ring A with ferrocene
O
planar
Fe
D
Fe
*
chirality
D
central chirality
=
*
( )-L
( )-LB
Figure 1. Novel chimeric molecule ( )-L hypothesized from isoindoloisoquinolinone.
O
CHO
NO2
NO2
N
(i)
(ii)
(iii), (iv)
Fe
Fe
Fe
Fe
O
1
2, 82%
3, 83%
5, 75%
Scheme 1. Synthesis of imide 5. Reagents and conditions: (i) CH3NO2, AcONH4/AcOH, sonication, 3.5 h; (ii) NaBH4/SiO2, CHCl3/iPrOH, rt, 5 h; (iii) 10% Pd/C, H2 gas, MeOH,
24 h; (iv) phthalic anhydride, toluene, reflux, 5 h.
in 75% yield.13 Partial reduction of imide 5 using NaBH4 and a
O
N
methanol system followed by cyclization using BF3ꢀOEt2 generated
the cyclized lactam L in 79% yield (Scheme 2).14 Unfortunately,
lactam L underwent aerial oxidation while purifying through
either column chromatography or through recrystallization (see
Supporting information). The aerial oxidation problem may be alle-
viated by introducing an alkyl group. Accordingly, the ethyl group
was introduced by treating imide 5 with ethylmagnesium bromide
followed by cyclization of the resulting hydroxy lactam 6b using
Lewis acid (Scheme 2).15
N
LiAlH4
Fe
Fe
THF, reflux, 24 h
( )-LB-I, 70%
L-I
Scheme 3. Synthesis of ( )-LB-I.
The reduction of lactam L-I was accomplished with lithium alu-
minium hydride (LiAlH4) to provide the target Lewis base LB-I in
racemic form with 70% yield (Scheme 3).16 The structure of
( )-LB-I was characterized and confirmed by using spectroscopic
techniques such as IR, 1H NMR, 13C NMR, HRMS along with single
crystal X-ray crystallography (Fig. 2).
The hydroxy lactam 6a or 6b upon cyclization is supposed to
furnish a pair of diastereomers due to the creation of both central
and planar chiral components in the resulting molecule. This reac-
tion furnished only an enantiomeric pair in a highly diastereoselec-
tive fashion. This may be due to the exo-selective SEAr reaction of
the ferrocene ring with electrophilic iminium ion as depicted in
the Figure 3. The advantage of this method is the capability of
introducing both planar and central chirality on L or L-I in a single
reaction.
During the development of new chiral molecules for asymmet-
ric transformations,17 we have successfully employed the classical
resolution technique involving diastereomeric salt formation
between a racemic base with a chiral acid as well as a racemic acid
with a chiral base.18 Therefore, the resolution of ( )-LB-I was car-
ried out with L-tartaric acid (1.0 equiv.) in different solvents such
as methanol, chloroform, acetonitrile and acetone. Although the
diastereomeric salt formation was observed in acetonitrile as well
Figure 2. ORTEP representation of the X-ray crystal structure of ( )-LB-I with 50%
probability ellipsoids.
O
O
N
O
N
R
N
Fe
(b)
(a)
Fe
Fe
R
HO
O
5
R = H, L, 79%
R = H, 6a, 94%
R = Et, 6b, 86%
R = Et, L-I, 88%
Scheme 2. Synthesis of ( )-L and ( )-L-I. Reagents and conditions: For 6a (a) NaBH4/MeOH, ꢁ40 °C, 1 h, ꢁ20 °C, 5 h; for 6b (a) EtMgBr, THF, ꢁ70 °C, 0.5 h, rt, 3 h; for L (b)
BF3ꢀOEt2, CH2Cl2, 0 °C – rt, 48 h; for L-I (b) BF3ꢀOEt2, CH2Cl2, 0 °C – rt, 4 h.

832
K. M. M. Achari, C. R. Ramanathan / Tetrahedron: Asymmetry 28 (2017) 830–836
R
hydrogen bonded homochiral or heterochiral aggregates (achiral
O
N
acids).19 This methodology prompted us to enrich the scalemic
(ꢁ)-LB-I using available achiral acids. Following this methodology,
(method B) the scalemic (ꢁ)-LB-I (93% ee) was treated with 1.0
equivalent of achiral acids, such as oxalic acid, malonic acid and
phthalic acid. Among these achiral acids, oxalic acid afforded
enantiomerically pure (ꢁ)-LB-I in 31% yield from the precipitate
fraction; this may be because of the predominant formation of
homochiral aggregates in the precipitate fraction (Scheme 4).
The enantiomeric excess of enantiomerically pure (+)-LB-I and
(ꢁ)-LB-I were further confirmed by NMR studies using chiral
solvating agent (R)-(ꢁ)-BINOL-phosphoric acid20 in CDCl3 (see
Supporting information).
N
O
R
Fe
Fe
Unfavored
Favored
Figure 3. The exo-selective cyclization of ferrocene with iminium ion.
as in acetone solvents at room temperature, the compound LB-I
liberated from the precipitate fractions failed to show a specific
rotation. This observation prompted us to resolve ( )-LB-I using
(+)-O,O0-dibenzoyl tartaric acid (
(pKa = 1.85) than
Hence, the resolution of ( )-LB-I was carried out with a 1:1 mix-
ture of ( )-LB-I and -DBTA in solvents such as methanol, acetone
D
-DBTA), which is a stronger acid
L
-tartaric acid (pKa1 = 2.98, pKa2 = 4.34).
After the successful resolution of ( )-LB-I, we focused our atten-
tion on assigning the configurations in chiral molecule (+)-LB-I
using crystallographic analysis of a single crystal obtained from
the precipitate I. Single crystal was obtained by recrystallization
of the precipitate I in ethanol (dissolving the precipitate I by heat-
ing at 50 °C for 15 min and then allowed to stand at room temper-
D
or acetonitrile at room temperature. Except in methanol, both in
acetone and in acetonitrile, the precipitation was realized (Table 1,
entries 1–3). For example, ( )-LB-I and D-DBTA were dissolved in
ature). The crystal structure (Figure 4)21 reveals that the
D-DBTA
acetone and allowed to stir at room temperature for 15 min, fol-
lowed by standing at room temperature for 1 h (Table 1, entry 2)
to furnish the precipitate, which was filtered and washed with cold
acetone. After digestion of the precipitate fraction with a 1:1 mix-
ture of CH2Cl2/aq K2CO3, (+)-LB-I was obtained in 43% yield with
99% ee. The filtrate, upon evaporation and digestion with a CH2Cl2/aq
K2CO3 mixture, afforded (ꢁ)-LB-I isomer in 48% yield and with
93% ee (Scheme 4). When using acetonitrile as the solvent,
(+)-LB-I was obtained in 41% yield and with 97% ee from the
precipitate, and (ꢁ)-LB-I in 43% yield and with 90% ee from the fil-
trate (Table 1, entry 3). Based on these observations, acetone was
considered as a good solvent for the resolution of ( )-LB-I using
was crystallized with one molecule of (+)-LB-I. Furthermore, the
CAO bond lengths (C33AO5 = 1.251 Å and C33AO6 = 1.250 Å) of
one of the two carboxylic acid groups of
be nearly equal; this indicates that the substrate and
D
-DBTA were found to
-DBTA
D
formed a diastereomeric ammonium salt I. The configuration of
the C13 stereogenic center and the planar chirality of (+)-LB-I were
assigned relative to the (2S,3S)-(+)-dibenzoyl tartaric acid. Based
on this relative configuration, it was found that the configurations
of the stereogenic center C13 and the planar chirality in (+)-LB-I
are (S) and (Rp) respectively. Hence, the stereogenic center C13
and planar chirality in (ꢁ)-LB-I are (R) and (Sp), respectively.
1.0 equiv of
of the isomers of LB-I, the experiments were carried out with
( )-LB-I using 1.0 equiv of -DBTA in acetone by varying the
D-DBTA. To improve the enantiomeric purity and yields
3. Conclusion
D
precipitation time and the results are shown in Table 1 (entries 2, 4).
The yields and enantiomeric purity of the product from both the
precipitate and the filtrate fractions did not change with precipita-
tion time. Therefore, the optimum time for the resolution of
In conclusion, a new ferrocene based conformationally rigid chi-
ral molecule with a Lewis base site has been designed and synthe-
sized in racemic form. We have developed
economical method for the resolution of ( )-LB-I using commer-
cially available dibenzoyl- -tartaric acid. Enrichment of scalemic
a simple and
( )-LB-I was found to be stirring of ( )-LB-I with
D-DBTA
D
(1.0 equiv) for 15 min followed by standing at room temperature
for 1 h. Decreasing the number of equivalents of chiral resolving
agent from 1.0 equiv to 0.5 equiv with respect to ( )-LB-I
decreased the yield of (+)-LB-I from 43% to 31% with no change
in the enantiomeric excess and a decrease in the enantiomeric
excess of (ꢁ)-LB-I from 93% to 85% with an increase in the yield
from 48% to 55% (Table 1, entry 5).
(ꢁ)-LB-I was accomplished by using an achiral acid, i.e. oxalic acid.
The absolute configurations in (+)-LB-I were determined by using
single crystal X-ray crystallographic analysis. Further investiga-
tions into the structural modification and scope of those molecules
as chiral catalysts in asymmetric transformations are currently in
progress.
Based on these studies, the optimized conditions for the resolu-
tion of ( )-LB-I were found to be stirring ( )-LB-I with D-DBTA
4. Experimental
4.1. General
(1.0 equiv) in acetone at room temperature for 15 min, then stand-
ing at the same temperature for 1 h. The isomer (+)-LB-I from pre-
cipitate was obtained in 43% yield and with 99% ee, while the other
isomer (ꢁ)-LB-I was obtained from filtrate in 48% yield and with
93% ee (Scheme 4). To enrich the enantiomeric purity of (+)-LB-I,
the precipitate I formed in the reaction between ( )-LB-I and
All reactions were performed in an oven-dried round bottom
flasks. Stainless steel syringes or cannulae were used to transfer
air and moisture sensitive liquids. Melting points are uncorrected
and were determined using a Buchi Melting Point M-560, Switzer-
land. Infrared spectra were recorded on Thermo Nicolet iS10 FT-IR
Spectrophotometer and are reported in frequency of absorption
(cmꢁ1). Mass spectra were measured with Agilent-6530 B Q-TOF
(ESI-HRMS), 1H and 13C NMR were recorded on Brucker AVANCE
400 spectrometer. NMR spectra for all the samples were measured
in CDCl3 using TMS as an internal standard. The chemical shifts are
expressed in d ppm downfield from the signal of internal TMS. Data
are represented as follows: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, dd = doublet of doublet,
ddd = doublet of doublet of doublet, td = triplet of doublet,
m = multiplet), coupling constants in Hertz (Hz) and integration.
Solvents used for the reactions were dried using standard
D
-DBTA (1.0 equiv) in acetone was recrystallized from a mixture
of methanol and acetonitrile (8:2) to afford the enantiomerically
pure isomer (+)-LB-I in 36% yield (Scheme 4). The enrichment of
enantiomeric purity of (ꢁ)-LB-I (93% ee) was carried out using
two different methods. In method A, (ꢁ)-LB-I was stirred with
L
-DBTA (1.0 equiv) in acetone at room temperature for 15 min
and then standing at room temperature for 1 h, which afforded
(ꢁ)-LB-I in 41% yield and with >99% ee from the precipitate
fraction (Scheme 4).
Periasamy et al. developed a methodology for the enrichment of
the enantiomeric purity of partially resolved (non-racemic) amino
alcohols and a diamine via the preparation of the corresponding

K. M. M. Achari, C. R. Ramanathan / Tetrahedron: Asymmetry 28 (2017) 830–836
833
Table 1
Optimization conditions for resolution of ( )-LB-Ia
Entry
Solvent
Reaction time (t)
Precipitation time (t)
Precipitate
Filtrate
D-DBTA (equiv.)
%Yieldb
%eec
%Yieldb
%eec
—
1
2
3
4
5
1.0
1.0
1.0
1.0
0.5
MeOH
Acetone
CH3CN
Acetone
Acetone
15 min
15 min
15 min
15 min
15 min
1 h
1 h
1 h
2 h
1 h
—
—
—
43
41
41
31
(+)-99
(+)-97
(+)-99
>99 (+)
48
43
46
55
(ꢁ)-93
(ꢁ)-90
(ꢁ)-90
(ꢁ)-85
a
b
c
In all experiments, ( )-LB-I (178 mg, 0.5 mmol) and
Yields are of isolated scalemic LB-I [(+)-LB-I from precipitate and (ꢁ)-LB-I from filtrate fractions].
Enantiomeric excess of the regenerated samples were determined by chiral HPLC analysis (Chiral stationary phase: Diacel-Chiralcel OD, Mobile phase: hexane and
D-DBTA were dissolved in solvent (8 mL).
isopropyl alcohol (99.5:0.5), 0.5 mL/min, tR = 15.02 min [(+)-LB-I], tR = 16.69 min [(ꢁ)-LB-I]).
N
Fe
(
)-LB-I
(+)-O,O'-DBTA (1.0 equiv.), acetone, rt, 15
min (stir) and 1 h (stand)
CH2Cl2/ aq. K2CO3
(+)-LB-I
Filtrate I
CH2Cl2/ aq. K2CO3
Precipitate I
99% ee
CH2Cl2/ aq. K2CO3
(-)-LB-I
Method-B
Precipitate III
31%, >99% ee
Recrystallization
MeOH/CH3CN (8:2)
Oxalic acid (1.0 equiv.)
Toluene, rt, 6 h
(-)-LB-I
48%, 93% ee
5 oC, 24 h
CH2Cl2/ aq. K2CO3
(-)-LB-I
Filtrate III
(-)-O,O'-DBTA
14%, 75% ee
Precipitate II
Filtrate II
(1.0 equiv.), acetone, rt
Method-A
15 min (stir) and 1 h (stand)
CH2Cl2/ aq. K2CO3
CH2Cl2/ aq. K2CO3
(+)-LB-I
5%, 90% ee
(+)-LB-I
36%, >99% ee
Filtrate III
Precipitate III
CH2Cl2/ aq. K2CO3
CH2Cl2/ aq. K2CO3
(-)-LB-I
(-)-LB-I
41%, >99% ee
7%, 14% ee
Scheme 4. Optimization conditions for the resolution of ( )-LB-I.
H
N
Ph
C13
O
O
O
O
OH
O
F
e
O
O
(S,Rp)
Ph
I
Figure 4. ORTEP diagram of diastereomeric salt I with 50% probability (hydrogen atoms are omitted for clarity except on nitrogen atom N1, C30 and C32 in D-DBTA).
procedures.22 For syntheses, the chemicals such as ferrocene,
sodium borohydride, boron trifluoride etherate and lithium
aluminium hydride were supplied by Aldrich, USA. The remaining
reagents were from Avra, RANKEM and Sd Fine Chemicals were
used. Column chromatography was performed on Merck silica
gel 100–200 mesh, and TLC analyses were facilitated using
phosphomolybdic acid stain in addition to UV light with Merck
60 GF254 pre-coated silica plates. X-ray crystal data were collected
on Oxford Diffraction Xcalibur diffractometer with Mo-K
radiation (k = 0.71073 Å). Empirical absorption correction using
spherical harmonics, implemented in SCALE3 ABSPACK scaling
algorithm, were applied. Structure solution and refinement were
a

834
K. M. M. Achari, C. R. Ramanathan / Tetrahedron: Asymmetry 28 (2017) 830–836
performed with SHELX-97.23 Optical rotations were measured in
an AUTOPOL-IV automatic polarimeter. Enantiomeric excess of
the samples were determined on a Shimadzu HPLC systems using
the Daicel-Chiralcel OD column.
hexane as eluent to give 2-nitro-1-ferrocenylethane 3 in 83% yield
(16.72 g) as a yellow solid. (mp: 99 °C); IR (KBr, cmꢁ1): 3096, 2916,
1645, 1559, 1447, 1380; 1H NMR (400 MHz, CDCl3): dH 4.50
(t, J = 7.2 Hz, 2H), 4.14 (s, 5H), 4.12–4.09 (m, 4H), 3.06
(t, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): dC 82.63, 76.38,
68.86, 68.25, 68.18, 27.95; HRMS-ESI (m/z): [M] Found 259.0296
and calculated 259.0296 for C12H13FeNO2.
4.2. Preparation of ferrocenecarboxaldehyde 1
Ferrocenecarboxaldehyde was prepared from ferrocene accord-
ing to the literature.10 Phosphorus oxychloride (50 mL, 536 mmol)
was added dropwise to the dimethylformamide (39.0 g, 536 mmol)
at 0 °C and the resulting mixture was stirred for 30 min at this tem-
perature under a nitrogen atmosphere. Next ferrocene (50.0 g,
268 mmol) in dry chloroform (250 mL) was added dropwise to
the mixture for 30 min at 0 °C. After completion of the addition,
the reaction mixture was kept stirring for 28 h with heating at
55–60 °C on an oil bath, taking care that the temperature did not
exceed 60 °C. The reaction mixture was then cooled to room
temperature and neutralized carefully with an aqueous saturated
Na2CO3 solution and then extracted repeatedly with the dichloro-
methane. The combined organic layer was dried over anhydrous
Na2SO4, filtered and the solvent was evaporated under reduced
pressure. The residue was purified through silica gel column chro-
matography using hexane/ethyl acetate mixture (95:05) as eluent
to give ferrocenecarboxaldehyde 1 in 55% yield (31.7 g) as a red-
dish brown solid. (mp: 122 °C, lit.10 123 °C); IR (KBr, cmꢁ1): 3093,
2837, 2760, 1683, 1447; 1H NMR (400 MHz, CDCl3): dH 9.95 (s,
1H); 4.80–4.60 (m, 4H), 4.27 (s, 5H); 13C NMR (100 MHz, CDCl3):
dC 193.63, 79.49, 73.33, 69.78; HRMS-ESI (m/z): [M+H]+ Found
215.0157 and calculated 215.0159 for C11H11FeO.
4.5. Preparation of 2-amino-1-ferrocenylethane 4
A mixture of 2-nitro-1-ferrocenylethane 3 (20.0 g, 77 mmol)
and 10% Pd/C (0.82 g, 7.7 mmol) in methanol was stirred under
1 atm. H2 gas for 24 h. The reaction mixture was then filtered
through a pad of Celite and washed with methanol. The solvent
was removed under reduced pressure to give 2-amino-1-ferro-
cenylethane 4 in 92% yield (16.27 g) as a dark red viscous oil. Com-
pound 4 was used for next step without further purification. IR
(KBr, cmꢁ1): 3428, 3087, 2922, 2849, 1642, 1574, 1468; 1H NMR
(400 MHz, CDCl3): dH 4.09 (s, 5H), 4.06–4.05 (m, 4H), 2.79
(t, J = 6.8 Hz, 2H), 2.47 (t, J = 6.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3): dC 86.22, 68.62, 68.46, 67.50, 43.47, 33.91; HRMS-ESI
(m/z): [M] Found 229.0554 and calculated 229.0554 for C12H15FeN.
4.6. Preparation of 2-ferrocenylethylisoindoline-1,3-dione 5
2-Amino-1-ferrocenylethane 4 (18.0 g, 78.2 mmol) and phthalic
anhydride (15.06 g, 101.7 mmol) were refluxed in toluene
(200 mL) at 130 °C. The water formed in this reaction was removed
from the mixture using Dean-Stark apparatus and the reaction was
continued for 5 h. The reaction mixture was cooled to room tem-
perature and toluene was evaporated under vacuum. This reaction
mixture was dissolved in dichloromethane and washed with 2 M
NaOH. The organic layer was separated, dried over anhydrous
Na2SO4 and the solvent was evaporated under reduced pressure.
The crude material was purified through silica gel column
chromatography using hexane/ethyl acetate (95:05) as eluent to
4.3. Preparation of 2-nitro-1-ferrocenylethylene 2
To a solution of ferrocenecarboxaldehyde 1 (10.0 g, 46.6 mmol)
in nitromethane (30 mL, 560 mmol) were added acetic acid
(2.7 mL, 46.6 mmol) and ammonium acetate (9.0 g, 116 mmol).
The reaction mixture was then subjected to ultrasound (sonica-
tion) for 3.5 h. The crude mixture was extracted with dichloro-
methane. The combined organic layer was washed with brine
solution, dried over anhydrous Na2SO4, filtered and the solvent
was evaporated under reduced pressure. The residue was purified
through silica gel column chromatography using hexane/ethyl
acetate mixture (97:03) as eluent to give 2-nitro-1-ferro-
cenylethylene 2 in 82% yield (9.85 g) as a purple solid. (mp:
138 °C, lit.24 139–140 °C); IR (KBr, cmꢁ1): 3102, 3084, 3043, 2919,
1627, 1495; 1H NMR (400 MHz, CDCl3): dH 7.98 (d, J = 13.2 Hz,
1H), 7.26 (d, J = 13.2 Hz, 1H), 4.61 (t, J = 2.0 Hz, 2H), 4.55 (t,
J = 2.0 Hz, 2H) 4.23 (s, 5H); 13C NMR (100 MHz, CDCl3): dC 142.17,
133.34, 73.70, 72.94, 70.33, 69.86; HRMS-ESI (m/z): [M] Found
257.0143 and calculated 257.0217 for C12H11FeNO2.
give 2-ferrocenylethylisoindoline-1,3-dione
5
in 75% yield
(21.13 g) as a yellow solid. (mp: 156–157 °C); IR (KBr, cmꢁ1):
3084, 2977, 2939, 1771, 1716, 1610, 1517; 1H NMR (400 MHz,
CDCl3): dH 7.84 (dd, J = 5.2, 3.2 Hz, 2H), 7.71 (dd, J = 5.2, 3.2 Hz,
2H), 4.14 (s, 5H), 4.11–4.09 (m, 2H), 4.07–4.06 (m, 2H), 3.87–3.83
(m, 2H), 2.72–2.68 (m, 2H); 13C NMR (100 MHz, CDCl3): dC
168.35, 134.04, 132.28, 123.34, 84.69, 68.72, 68.29, 67.75, 38.99,
28.64; HRMS-ESI (m/z): [M] Found 359.0609 and calculated
359.0609 for C20H17FeNO2.
4.7. Preparation of 3-hydroxy-2-ferrocenethylisoindolin-1-one
6a
At first, NaBH4 (1.42 g, 37.5 mmol) was added portionwise at
ꢁ40 °C for 1 h to a solution of imide 5 (3.0 g, 8.3 mmol) in a mix-
ture of MeOH (40 mL) and CH2Cl2 (60 mL) under a nitrogen atmo-
sphere. The reaction mixture was warmed to ꢁ20 °C and stirred at
this temperature for 5 h. The reaction was quenched by the addi-
tion of water. The aqueous phase was extracted with CH2Cl2 and
the combined organic extracts were dried over anhydrous Na2SO4
and the solvent was evaporated under reduced pressure. This
crude material was purified through silica gel column chromatog-
raphy using hexane/ethyl acetate (70:30) as eluent to give 6a in
94% yield (2.84 g) as a yellow solid. (mp: 103–104 °C); IR (KBr,
cmꢁ1): 3540, 3272, 3075, 2922, 2846, 1668, 1618, 1471; 1H NMR
(400 MHz, CDCl3): dH 7.64–7.63 (m, 1H), 7.56 (dd, J = 5.2, 1.2 Hz,
2H), 7.49–7.42 (m, 1H), 5.57 (d, J = 12.0 Hz, 1H), 4.11 (s, 5H), 4.07
(s, 2H), 4.04–4.02 (m, 2H), 3.65–3.58 (m, 1H), 3.48–3.41 (m, 1H),
4.4. Preparation of 2-nitro-1-ferrocenylethane 3
To an efficiently stirred mixture of 2-nitro-1-ferrocenylethylene
2 (20.0 g, 77.5 mmol), silica gel (193.0 g, 2.5 g/mmol), isopropanol
(290 mL, 1.5 mL/g of SiO2) and chloroform (1.55 L, 8 mL/g of SiO2)
was added NaBH4 (11.73 g, 310 mmol) in 1 g portion over a period
of 1 h and the reaction mixture was stirred for 5 h at room temper-
ature. The disappearance of the pink color of 2-nitrovinylferrocene
indicates the completion of the reaction and the excess NaBH4 was
decomposed using dil. HCl after which the mixture was filtered.
The silica gel was washed with chloroform. The combined filtrate
was washed with brine, dried over anhydrous Na2SO4, filtered
and the solvent was evaporated under reduced pressure. The crude
material was purified through silica gel chromatography using

K. M. M. Achari, C. R. Ramanathan / Tetrahedron: Asymmetry 28 (2017) 830–836
835
3.13 (d, J = 11.6 Hz, 1H), 2.68–2.64 (m, 2H); 13C NMR (100 MHz,
CDCl3): dC 167.45, 144.03, 132.31, 131.69, 129.90, 123.42, 123.30,
85.51, 82.33, 68.81, 68.54, 68.21, 67.85, 67.80, 40.81, 28.51;
HRMS-ESI (m/z): [M] Found 361.0765 and calculated 361.0765
for C20H19FeNO2.
give 6b in 86% yield (18.8 g) as a yellow solid. (mp: 146–147 °C);
IR (KBr, cmꢁ1): 3261, 2975, 2942, 1674, 1616, 1471, 1443, 1418;
1H NMR (400 MHz, CDCl3): dH 7.75–7.72 (m, 1H), 7.57–7.53 (m,
1H), 7.48–7.44 (m, 2H), 4.14 (s, 6H), 4.08 (s, 1H), 4.04–4.02 (m,
2H), 3.76 (ddd, J = 13.8, 9.5, 4.4 Hz, 1H), 3.26 (ddd, J = 13.6, 9.2,
7.4 Hz, 1H), 2.93 (ddd, J = 14.0, 9.5, 7.4 Hz, 1H), 2.67
(ddd, J = 13.8, 9.3, 4.4 Hz, 1H), 2.33 (s, 1H) 2.17–1.98 (m, 2H),
0.49 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): dC 167.55,
146.55, 132.36, 131.74, 129.67, 123.20, 121.78, 91.93, 86.05,
68.85, 68.49, 68.35, 67.90, 67.76, 40.26, 29.21, 28.53, 7.98;
HRMS-ESI (m/z): [M] Found 389.1078 and calculated 389.1078
for C22H23FeNO2.
4.8. Preparation of ferroceno[1,2-a]-3,10b-dihydropyrido[2,1-a]
isoindol-6(4H)-one L
The hydroxy lactam 6a (0.100 g, 0.276 mmol) was dissolved in
dry dichloromethane under a nitrogen atmosphere. To this solu-
tion was added BF3ꢀEt2O (0.42 mL, 3.314 mmol) at 0 °C and the
reaction mixture was allowed to warm to room temperature with
stirring. Stirring was continued for 48 h at room temperature. The
reaction was quenched with aqueous saturated NaHCO3 solution
and the organic layer was separated. The aqueous layer was
extracted with dichloromethane (3 x 15 mL). The organic layers
were combined, washed with brine solution, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure to give L
in 79% yield (0.075 g) as a yellow solid. (mp: 175 °C); IR (KBr,
cmꢁ1): 3040, 2939, 2913, 1684, 1463, 1415; 1H NMR (400 MHz,
CDCl3): dH 8.00 (d, J = 7.6 Hz, 1H), 7.67–7.66 (m, 2H), 7.60–7.55
(m, 1H), 5.26 (s, 1H), 4.66–4.60 (m, 1H), 4.23–4.20 (m, 2H), 4.09
(t, J = 2.4 Hz, 1H), 3.46 (s, 5H), 3.14 (td, J = 12.0, 5.4 Hz, 1H), 3.06–
2.97 (m, 1H), 2.52–2.46 (m, 1H); 13C NMR (100 MHz, CDCl3): dC
167.35, 146.64, 132.80, 131.42, 128.56, 124.00, 122.62, 85.62,
81.72, 69.49, 66.48, 66.07, 63.18, 57.50, 37.01, 24.43; HRMS-ESI
(m/z): [MꢁH] Found 342.0582 and calculated 342.0581 for
4.11.
Preparation
of
10b-ethyl-ferroceno[1,2-a]-3,10b-
dihydropyrido[2,1-a]isoindol-6(4H)-one L-I
The hydroxy lactam 6b (0.389 g, 1 mmol) was dissolved in dry
dichloromethane. To this solution was added BF3ꢀEt2O (1.5 mL,
12 mmol) at 0 °C and the reaction mixture was allowed to warm
to room temperature with stirring. Stirring was continued for 4 h
at room temperature. The reaction was quenched with an aqueous
saturated NaHCO3 solution and the organic layer was separated.
The aqueous layer was extracted with dichloromethane
(3 ꢂ 15 mL). Organic layers were combined, washed with brine
solution, dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. This crude material was purified through
silica gel column chromatography using hexane/ ethyl acetate
(80:20) as eluent to give L-I in 88% yield (0.326 g) as a yellow solid.
(mp: 172–173 °C); IR (KBr, cmꢁ1): 3101, 3046, 2963, 2929, 1685,
1465, 1403; 1H NMR (400 MHz, CDCl3): dH 8.00–7.98 (m, 1H),
7.67 (td, J = 7.5, 1.1 Hz, 1H), 7.61–7.59 (m, 1H), 7.54 (td, J = 7.4,
1.0 Hz, 1H), 4.62–4.52 (m, 1H), 4.15–4.14 (m, 2H), 4.04 (t,
J = 2.4 Hz, 1H), 3.40 (s, 5H), 3.07–2.98 (m, 2H), 2.50–2.41 (m, 1H),
2.09–1.99 (m, 2H), 0.47 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): dC 167.76, 150.20, 132.58, 131.35, 128.21, 123.73, 121.38,
91.12, 80.69, 69.52, 66.03, 65.68, 65.54, 62.88, 33.58, 32.84,
24.02, 8.19; HRMS-ESI (m/z): [M] Found 371.0977 and calculated
371.0973 for C22H21FeNO.
C20H16FeNO. The crude sample of L (0.075 g) was purified through
silica gel column chromatography using hexane/ethyl acetate
(80:20) as eluent to give compound 7 in 0.072 g (91%) instead of L.
4.9. Purification of L
Compound L (0.100 g, 0.29 mmol) was dissolved in dry dichlor-
omethane and the solution was left at room temperature for
recrystallization. The formed yellow crystals were washed with
cold hexane to give 10b-hydroxy-ferroceno[1,2-a]-3,10b-dihy-
dropyrido[2,1-a]isoindol-6(4H)-one 7 in 0.096 g (92%) instead of
L. (mp: 201–202 °C); IR (KBr, cmꢁ1): 3267, 2943, 2922, 1678,
1470, 1414; 1H NMR (400 MHz, CDCl3): dH 7.88–7.84 (m, 2H),
7.72 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 4.45 (s, 1H), 4.27–
4.23 (m, 2H), 4.12 (s, 1H), 3.42 (s, 5H), 3.38 (d, J = 5.6 Hz, 1H),
3.29 (td, J = 12.8, 5.2 Hz, 1H), 3.04–2.95 (m, 1H), 2.49 (dd,
J = 16.0, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): dC 166.36,
148.92, 132.33, 130.84, 129.70, 123.69, 122.09, 99.94, 87.63,
85.77, 70.20, 67.50, 66.73, 64.25, 33.55, 24.18; HRMS-ESI (m/z):
[M] Found 359.0606 and calculated 359.0609 for C20H17FeNO2.
4.12. Preparation of 10b-ethyl-ferroceno[1,2-a]-3,4,6,10b-
tetrahydropyrido[2,1-a]isoindole LB-I
Lithium aluminium hydride (0.51 g, 13.5 mmol) weighed into a
pre-dried schlenk round bottom flask containing compound L-I
(1.0 g, 2.7 mmol). Anhydrous THF was added to the reaction mix-
ture at 0 °C and the reaction mixture was heated at reflux for
24 h. After complete conversion of starting material, monitored
by TLC, tert-butyl methyl ether (25 mL) was added and the reaction
mixture was quenched by the careful addition of saturated aque-
ous sodium potassium tartrate solution. The mixture was stirred
for 1 h before the addition of anhydrous Na2SO4 and then filtered
through a Celite pad. The filtrate was evaporated under reduced
pressure. This crude material was purified through silica gel col-
umn chromatography using hexane/ethyl acetate (90:10) as eluent
to give LB-I in 70% yield (0.672 g) as yellow solid. (mp: 133–
134 °C); IR (KBr, cmꢁ1): 3102, 3078, 2971, 2932, 2911, 2876,
2785, 1462, 1437, 1353; 1H NMR (400 MHz, CDCl3): dH 7.36–7.35
(m, 1H), 7.34–7.33 (m, 1H), 7.32–7.31 (m, 1H), 7.29–7.27 (m,
1H), 4.43 (d, J = 13.2 Hz, 1H), 4.35 (d, J = 13.2 Hz, 1H), 4.10 (dd,
J = 2.0 Hz, 1.2 Hz, 1H), 3.99–3.97 (m, 2H), 3.46 (s, 5H), 3.20–3.15
(m, 1H), 2.99–2.87 (m, 2H), 2.22–2.18 (m, 1H), 1.87–1.69 (m,
2H), 0.67 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): dC
148.54, 141.67, 139.57, 126.84, 126.69, 122.58, 122.49, 91.30,
82.99, 69.41, 65.06, 64.96, 62.39, 55.99, 44.42, 34.74, 20.71, 9.64;
HRMS-ESI (m/z): [M+H] Found 358.1257 and calculated 358.1258
for C22H23FeN.
4.10. Preparation of 3-ethyl-3-hydroxy-2-ferrocenethyli-
soindolin-1-one 6b
Ethylmagnesium bromide was prepared from bromoethane
(12.0 g, 111.11 mmol) and magnesium turnings (2.70 g,
111.11 mmol) and small amount of iodine in THF (15 mL). This
solution of Grignard reagent was added dropwise via syringe to a
stirred solution of 2-phthalimido-1-ferrocenylethane 5 (20.0 g) in
degassed THF (250 mL) at ꢁ70 °C under a nitrogen atmosphere.
The solution was stirred at ꢁ70 °C for 0.5 h and then allowed to
warm to room temperature and stirring was continued for 3 h.
The reaction was quenched by the addition of saturated aqueous
NH4Cl (10 mL). The reaction mixture was extracted with CH2Cl2
(3 ꢂ 50 mL). The combined organic extracts were dried over anhy-
drous Na2SO4 and the solvent was evaporated under reduced pres-
sure. This crude material was purified through silica gel column
chromatography using hexane/ethyl acetate (70:30) as eluent to

836
K. M. M. Achari, C. R. Ramanathan / Tetrahedron: Asymmetry 28 (2017) 830–836
4.13. Resolution of ( )-LB-I
The organic layer was separated and the aqueous layer was
extracted with dichloromethane. The combined extracts were
dried over anhydrous Na2SO4, filtered and evaporated to obtain
crude (ꢁ)-LB-I. The crude material was purified through silica gel
column chromatography (hexanes/ethyl acetate = 90:10) to afford
(+)-Dibenzoyl-D-tartaric acid (358 mg, 1.0 mmol) and ( )-LB-I
(357 mg, 1.0 mmol) were taken in acetone (16 mL) and the con-
tents were stirred for 15 minutes and then left to stand for 1 h at
room temperature. The obtained precipitate I was filtered and
washed with cold acetone (10 mL). The precipitate I was recrystal-
lized from a mixture of methanol and acetonitrile (8:2) (10 mL).
The formed precipitate II fraction was suspended and stirred in a
mixture of dichloromethane (20 mL) and 10% aqueous K2CO3
(20 mL) until complete dissolution occurred. The organic layer
was separated and the aqueous layer was extracted with dichloro-
methane. The combined extracts were dried over anhydrous
Na2SO4, filtered and evaporated to obtain crude (+)-LB-I. The crude
material was purified through silica gel column chromatography
(hexanes/ethyl acetate = 90:10) to afford (+)-LB-I as a yellow solid
(ꢁ)-LB-I as a yellow solid (31%, >99% ee), [
a]
25 = ꢁ208.5 (c 1,
D
CHCl3); mp: 107–108 °C. Enantiomeric excesses of the optically
active compounds were determined by chiral HPLC analysis (Chiral
stationary phase: Diacel-Chiralcel OD, Mobile phase: hexane and
isopropyl alcohol (99.5:0.5), 0.5 mL/min, tR = 15.02 min [(+)-LB-I],
tR = 16.69 min [(ꢁ)-LB-I]).
Acknowledgements
We thank DST and CSIR, New Delhi, India for financial support.
K.M.M.A. thank UGC, New Delhi for SRF. We thank Dr. Binoy K.
Saha and Mr. S. V. Ganesh for solving crystal data. We gratefully
acknowledge the CIF, Pondicherry University for NMR/IR data.
DST-FIST programme and UGC-SAP (DSA) awarded to Department
of Chemistry, Pondicherry University are gratefully acknowledged
for XRD, HRMS and HPLC data.
(36%, >99% ee), [a]
25 = +208.5 (c 1, CHCl3); mp: 107–108 °C.
D
Enantiomeric excesses of the optically active compounds were
determined by chiral HPLC analysis (Chiral stationary phase:
Diacel-Chiralcel OD, Mobile phase: hexane and isopropyl alcohol
(99.5:0.5), 0.5 mL/min, tR = 15.02 min [(+)-LB-I], tR = 16.69 min
[(ꢁ)-LB-I]).
The filtrate I was evaporated and the residue was suspended
and stirred in a mixture of dichloromethane (20 mL) and 10% aque-
ous K2CO3 (20 mL) until complete dissolution occurred. The
organic layer was separated and aqueous layer was extracted with
dichloromethane. The combined extracts were dried over anhy-
drous Na2SO4, filtered and evaporated to obtain crude (ꢁ)-LB-I.
The crude material was purified through silica gel column chro-
matography (hexanes/ethylacetate = 90:10) to afford (ꢁ)-LB-I as
yellow solid (48%, 93% ee). Enantiomeric excesses of the optically
active compounds were determined by chiral HPLC analysis (Chiral
stationary phase: Diacel-Chiralcel OD, Mobile phase: hexane and
isopropyl alcohol (99.5:0.5), 0.5 mL/min, tR = 15.02 min [(+)-LB-I],
tR = 16.69 min [(ꢁ)-LB-I]).
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.05.
006.
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(ꢁ)-Dibenzoyl- -tartaric acid (179 mg, 0.5 mmol) and scalemic
L
(ꢁ)-LB-I (93% ee, 178 mg, 0.5 mmol) were taken in acetone
(8 mL) and the contents were stirred for 15 minutes and then left
to stand for 1 h at room temperature. The formed precipitate III
was suspended and stirred in a mixture of dichloromethane
(20 mL) and 10% aqueous K2CO3 (20 mL) until dissolution occurred.
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extracted with dichloromethane. The combined extracts were
dried over anhydrous Na2SO4, filtered and evaporated to obtain
crude (ꢁ)-LB-I. The crude material was purified through silicagel
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a
]
25 = ꢁ208.5 (c 1,
D
CHCl3); mp: 107–108 °C]. Enantiomeric excesses of the optically
active compounds were determined by chiral HPLC analysis (Chiral
stationary phase: Diacel-Chiralcel OD, Mobile phase: hexane and
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(20 mL) and 10% aqueous K2CO3 (20 mL) until dissolution occurred.