Enantioselective synthesis of new dimeric chromene derivatives by a ferrocene-copper catalyst system

Article abstract of DOI:10.3184/174751915X14279896539656

Novel 2-iminochromene dimers were prepared in excellent yields (93-99%) and with high to excellent enantioselectivities (89-97% ee) by a simple and efficient method. The precursor 2-[(3-cyano-2H-chromen-2-ylidene)amino]acetates and both racemic and enantioselective 2-iminochromene dimers were disclosed and characterised for the first time.

Full text of DOI:10.3184/174751915X14279896539656

226 RESEARCH PAPER
VOL. 39 APRIL, 226–229
JOURNAL OF CHEMICAL RESEARCH 2015
Enantioselective synthesis of new dimeric chromene derivatives by a
ferrocene-copper catalyst system
Di Xu, Li Dai, Lan Li, Zhiming Zhou and Jun Zhang*
R&D Center for Pharmaceuticals, School of Chemical Engineering and the Environment, Beijing Institute of Technology, Beijing 100081, P.R. China
Novel 2-iminochromene dimers were prepared in excellent yields (93−99%) and with high to excellent enantioselectivities (89−97% ee) by
a simple and efficient method. The precursor 2-[(3-cyano-2H-chromen-2-ylidene)amino]acetates and both racemic and enantioselective
2-iminochromene dimers were disclosed and characterised for the first time.
Keywords: 2-iminochromene dimer, enantioselective, ferrocene
Iminochromene derivatives are an important class of
compounds, widely present in nature.1-3 Numerous chromene-
based structures are used as antibiotics,4 fungicides,5 and
anti-inflammatory,6 anticoagulant7 and antitumor agents.8
Because of their high fluorescence properties, many synthetic
analogues have been made over the years.9-13 They are widely
used as brighteners, optical whitening agents, laser dyes and
also as fluorescent probes in medical science.14,15 The 2-imino
analogues comprise a very important class of protein tyrosine
kinase (PTK) inhibitors with low molecular weight.16,17 As a
new development, the synthesis of chiral dimeric chromene
derivatives is an important target as a novel modification of
existing therapeutic compounds. We have recently reported the
synthesisofasiloxane-substitutedferrocenyloxazolinephosphine
(FOXAP) ligand L(f) (Fig. 1) and successfully used it in the
enantioselective 1,3-dipolar cycloaddition of azomethine ylides
with alkylidene malonates.18
of 2-[(3-cyano-2H-chromen-2-ylidene)amino)acetates with
excellent enantioselectivity.
Results and discussion
Our three-step synthesis of chiral dimeric chromene derivatives
is shown in Scheme 1. Compounds 3a and 3b are known
compounds and were synthesised by a literature method19 and
then reacted with glycine ethyl (or t-butyl) ester hydrochloride 4
(1.0 equiv.) in CH2Cl2 to give iminoesters 5a–d.
For the optimisation of the final step of the synthesis,
the asymmetric self-Michael addition reaction, we chose
5a as the model compound, and the yields of compound 6a
using various bases, two copper salts and three ligands are
shown in Table 1. In a single experiment with PPh3/Et3N and
CuClO4, a moderate yield of 72% was obtained (entry 1). An
organocatalyst such as cinchonine was tried, but the yield was
low (entry 2). Next, several metal complexes and salts such
as CuClO4·4CH3CN, Cu(OAc)2·H2O, and Cu(ClO4)2·6H2O
were examined in combination with the ligand L(f). We
found that Cu(ClO4)2·6H2O/L(f) gave the best result in THF
at room temperature in the presence of Et3N as a base and 4Å
molecular sieves as water absorbent under the protection of N2
for the standard time of 24 h (entry 5). At 0 oC, under the same
conditions, a higher ee value was obtained, but the yield was
lower (entry 6).
We now report a novel synthesis of chiral dimeric chromene
derivatives catalysed by a combination of copper(II) salts
and L(f), in good yields and excellent enantioselectivities.
This is a preliminary report of copper/siloxane-substituted
FOXAP complexes that catalyse the self-Michael addition
O
PPh2
Fe
Then, the effect of the base was investigated. As shown in
Table 1, Cu(ClO4)2·6H2O/L(f) performed well with Et3N,
while reactions with bases such as KOBut, K2CO3, and
diisopropanolamine (DIPEA) gave lower yields or lower
enantioselectivities (entries 7–9).
OTMS
N
On the basis of the results reported above, the optimised
reaction conditions were set as follows: 10 mol% of
Fig. 1 Stucture of siloxane-substitued ferrocenyloxazolinephosphine
(FOXAP) L(f).
NH
(4)
ROOCCH2 2`HCl
CHO
CN
NH
piperidine
X
+
X
NC
CN
EtOH,
r.t.30 min
12 h
CH2Cl2
,
r.t.,
OH
O
1
2
:
:
=
3a
3b
X
X
H
=
6-Br
X
O
X
Copper/Ligand,
4A
CN
NC
ROOC
:
:
=
=
=
R
6a
6b
X
X
X
X
R
R
6-Br,
6-Br,
tBu
Et
=
H,
H,
MS
24 h
base,
THF,
2
=
=
=
N
:
:
6c
6d
temp.,
tBu
N
O
COOR
=
tBu
∗
CN
=
Et
R
:
:
:
:
=
5a
5b
5c
5d
X
X
X
X
R
R
6-Br,
6-Br,
H,
H,
X
=
=
=
=
Et
=
R
R
tBu
Et
N
H
O
COOR
=
Scheme 1 Catalytic enantioselective synthesis of 2-iminochromene dimmers.
* Correspondent. E-mail: zhangjun603@bit.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2015 227
Table 1 Yields and ee values obtained in the optimisation of the reaction conditions (catalyst, ligand, base) for the conversion of iminoester 5a by
asymmetric self-Michael addition into chiral dimeric chromene derivative 6a (Scheme 1)a
Entry
Metal
CuClO4·4CH3CN
−
CuClO4·4CH3CN
Cu(OAc)2·H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Ligand
PPh3
Cinchonine
L(f)
Base
Et3N
−
Et3N
Et3N
Et3N
Et3N
t-BuOK
K2CO3
DIPEA
Temperature /oC
Yield /%b
eec /%
−
ND
87.0
75.2
91.2
93.7
90.6
88.4
92.5
1
2
3
4
5
6
7
8
9
0
72
15
77
86
98
93
98
95
RT
RT
RT
RT
0
RT
RT
RT
L(f)
L(f)
L(f)
L(f)
L(f)
L(f)
89
aReaction conditions: 5a (0.25 mmol), base (0.025 mmol), metal (0.025 mmol), 4Å molecular sieves (two particles) and ligand (0.028 mmol) in THF (3.0 mL).
bIsolated yield.
cDetermined by chiral HPLC analysis (Daicel OD-H, hexane/i-propane = 87/13, 1.0 mL min-1).
ND, not determined; RT, room temperature.
Table 2 Yields and ee values, under the optimised conditions, for the conversion of iminoesters 5a–d into chiral dimeric chromene derivatives 6a–d
(Scheme 1)a
Entry
R
tBu
Et
tBu
Et
X
H
H
6-Br
6-Br
Product
6a
6b
6c
6d
Yieldb (%)
eec (%)
91.2
88.7
97.4
1
2
3
4
98
93
99
96
89.1
aReaction conditions: 5 (0.25 mmol), EtN3 (0.025 mmol), Cu(ClO4)2·6H2O (0.025 mmol), 4Å molecular sieves (two particles) and L(f) (0.028 mmol) in THF (3.0 mL).
bIsolated yield.
cDetermined by chiral HPLC analysis (Daicel OD-H, hexane/i-propane).
Å molecular sieves under nitrogen. Flash column chromatography was
carried out on Liang Chen Gui Yuan Silica Gel 200–300 mesh and TLC
on Yan Tai Jiang You plates. NMR spectra were obtained on a Bruker
Avance-400 spectrometer (1H NMR at 400 Hz, 13C NMR at 100 Hz)
in CDCl3 using the solvent as internal reference (7.26 and 77.00 ppm,
Cu(ClO4)2·6H2O and L(f) as the catalyst, Et3N as the base, THF
as the solvent with a substrate concentration of 0.08 M at room
temperature.
Then, we applied the optimised experimental conditions to
several more substrates by varying the substituents of compound 5
(Table 2). The reactions proceeded well in all cases (entries 1–4).
Bulky substituents α to N (imine) impacted the results positively,
due to steric hindrance (entry 1 versus entry 2; entry 3 versus
entry 4). With bromine as the substituent, the substrates gave
higher conversions and enantioselectivities (entry 3 99% yield and
97% ee versus entry 1; entry 4 versus entry 2). Overall, the new
products were formed virtually quantitatively under the optimised
conditions.
1
respectively for H and 13C). Chemical shifts (δ) are given in ppm and
coupling constants (J) in Hz. Melting points were determined with an XT4
microscope electrothermal apparatus and are uncorrected. Enantiomeric
excess values were determined with a Knauer S1050 HPLC instrument.
Electron impact mass spectra (m/z, relative intensity (%)) were determined
with an Agilent Technologies instrument working at 70 eV ionisation
energy. IR spectra were recorded using a Bruker Alpha spectrophotometer
with a ATR-Ge device. Elemental analyses were obtained on an Elementar
Vario MICRO CUBE (Germany) elemental analyser.
Examples of HPLC traces of the product 6a are shown in Fig. 2.
The optimised HPLC resolution condition for 6a is Daicel OD-H
column, hexane/i-propane (87/13) as eluent, 1.0 mL min-1 flow rate
at room temperature.
Synthesis of substituted 2-imino-2H-chromene-3-carbonitriles 3; general
procedure 19
In an ice bath, malononitrile 2 (1.0 equiv.) was added to a solution of the
aldehyde 1 (5.0 mmol) in EtOH (5.0 mL), and piperidine (one drop) was
then added. The mixture was stirred at room temperature. Within 10 min,
a pale yellow solid started to precipitate from the reaction mixture. Stirring
was continued for a further 20 min. The yellow solid was filtered off and
washed with petrol ether to give the pure products. 3a: M.p. 162 oC (petrol
ether) (lit.20 160–162 oC ). 3b: m.p. 198 oC (petrol ether) (lit.19 198–199 oC).
The proposed reaction pathway is outlined in Scheme 2.
Iminocoumarins 3 were prepared by Knoevenagel condensation
in one-pot reactions from 2-hydroxybenzaldehyde derivatives
1 and malononitrile 2 in the presence of a catalytic amount of
piperidine. The spontaneous cyclisation between the o-hydroxy
group and the side chain cyano group of a transient intermediate
led to the iminocoumarin derivatives 3. The aldehydeamines
5 were obtained by the condensation of the imines 3 and the
amino acid hydrochlorides 4, with the precipitation of NH4Cl.
The 2-[(3-cyano-2H-chromen-2-ylidene)amino)acetates 5 then
undergo a base catalysed intermolecular self-Michael-type reaction
by attack of the α-C to N (imine) of one molecule onto the olefinic
group of the other, to yield the 2-iminochromene dimers 6. The
enantioselectivity was generated from steric hindrance, which
resulted from the coordination between the CuII/L(f) catalyst and
the N (imine) atom and the ester group of 5.
Synthesis of substituted 2-[(3-cyano-2H-chromen-2-ylidene)amino)
acetates 5; general procedure
2-Imino-2H-chromene-3-carbonitrile 3 (1.5 mmol) was suspended in
CH2Cl2 (40 mL). Glycine ester hydrochloride 4 (1.0 equiv.) was then
added, and the reaction mixture became clear almost immediately but
became cloudy after 1 h. The reaction was stirred at room temperature for
a further 11 h. NH4Cl was filtered off and the filtrate was concentrated and
purified by flash column chromatography. Eluent: petrol ether/EtOAc =
5/1. Compounds 5 were obtained as white solids.
Synthesis of racemic/enantioselective substituted dimeric chromene
Experimental
derivatives 6; general procedure
THF (3.0 mL) was added to a Schlenck-type flask, containing
Cu(ClO4)2·6H2O (9.3 mg, 0.025 mmol) and ligand (for racemic product
Most of the starting materials were commercially available and were
used without further purification. Solvents were dried and stored over 4

228 JOURNAL OF CHEMICAL RESEARCH 2015
O
NC
BuOtOC
N
CN
rac-
6a
O
N
H
COOtBu
O
NC
BuOtOC
N
∗
CN
6a
COOtBu
O
N
H
Fig. 2 HPLC traces of 6a.
H
O
NH2
ROOCCH2
HCl
`
CN
NH
CHO
CN
CN
piperidine
4
( )
X
X
X
+
NC
CN
O
OH
1
2
3
H
X
CN
N
X
O
CN
NC
O
COOR
H+
H
X
N
ROOC
+
:Base-
-
H
N
O
COOR
∗
CN
5
6
X
N
H
O
COOR
Scheme 2 Proposed reaction pathway for chiral 2-iminochromene dimmers.
6, PPh3 13.1 mg, 0.050 mmol; for enantioselective product 6, ferrocene
ligand 15.6 mg, 0.028 mmol) under nitrogen. The catalyst was formed
in situ after stirring for 15 min at room temperature. 2-[(3-cyano-
2H-chromen-2-ylidene)amino]acetate 5 (0.250 mmol) and Et3N (4
μL, 0.025 mmol) were added. The reaction mixture was stirred under
nitrogen at room temperature for 24 h, and then allowed to warm to
room temperature. The solvent was removed under reduced pressure
and the resulting residue was purified by flash chromatography on
silica gel using mixtures of petrol ether-EtOAc as eluent.
t-Butyl-2-[(3-cyano-2H-chromen-2-ylidene)amino]acetate (5a): White
solid; yield 97%; m.p. 105 oC (petrol ether); IR (KBr cm-1): ν 2232, 1736,
1662, 1604 cm-1; 1H NMR: δ 7.73 (1H, s), 7.31–7.30 (1H, m), 7.11–7.09 (1H,
m), 6.80–6.77 (2H, m), 3.80 (2H, s), 1.25 (9H, s); 13C NMR: δ 172.6, 154.1,
151.9, 136.0, 133.2, 129.5, 124.8, 121.3, 116.5, 110.6, 97.1, 82.4, 57.6, 26.5
(3C); MS (EI, 70eV): M+ m/z 285. Anal. calcd for C16H16N2O3: C, 67.59; H,
5.67; N, 9.85; found: C, 67.32; H, 5.86; N, 9.73%.
Ethyl-2-[(3-cyano-2H-chromen-2-ylidene)amino]acetate (5b): White
o
solid; yield 56%; m.p. 99 C (petrol ether); IR (KBr cm-1): 2231, 1736,

JOURNAL OF CHEMICAL RESEARCH 2015 229
1
o
1664; H NMR: δ 7.74 (1H, s), 7.32–7.31 (1H, m), 7.11–7.09 (1H, m),
acetate (6d): Yellow solid; yield 96%; m.p. 146 C (petrol ether); IR
6.81–6.79 (2H, m), 4.37 (2H, s), 4.23 (2H, q, J = 7.1 Hz), 1.29 (3H, t,
J = 7.1 Hz); 13C NMR: δ 171.4, 153.6, 151.9, 136.7, 131.6, 129. 5, 122.7,
120.0, 116.4, 109.1, 97.0, 61.3, 49.2, 14.2; MS (EI, 70eV): M+ m/z 257.
Anal. calcd for C14H12N2O3: C, 65.62; H, 4.72; N, 10.93; found: C,
65.33; H, 4.79; N, 11.02%.
(KBr cm-1): ν 2204, 1735, 1650, 1623 cm-1; 1H NMR: δ 8.22 (1H, s), 7.66
(2H, s), 7.61 (1H, d, J = 8.8 Hz), 7.53 (1H, s), 7.28 (1H, s), 7.06-7.04 (2H,
m), 4.37 (4H, s), 4.28-4.23 (4H, q, J = 7.0 Hz), 1.33-1.28 (6H, t, J = 7.1
Hz); 13C NMR: δ 173.9, 171.5, 155.6, 153.6, 152.9, 146.0, 139.4, 135.4,
134.2, 132.1, 129.8, 123.7, 121.3, 121.4, 121.1, 120.2, 119.6, 118.1, 109.5,
97.6, 71.7, 64.2, 61.7, 61.1, 45.6, 41.6, 14.7, 14.6; MS (EI, 70eV): M+ m/z
671. Anal. calcd for C28H22Br2N4O6: C, 50.17; H, 3.31; N, 8.36; found: C,
50.09; H, 3.26; N, 8.41%; HPLC (Daicel OD-H, hexane/iPrOH = 92/8,
1.0 mL min-1, 215 nm) t1 = 27 min (major), t2 = 36 min (minor).
t-Butyl-2-[(6-bromo-3-cyano-2H-chromen-2-ylidene)amino]
o
acetate (5c): Pale yellow solid; yield 98%; m.p. 143 C (petrol ether);
IR (KBr cm-1): ν 2235, 1737, 1663, 1598; 1H NMR: δ 7.65 (1H, s), 7.59
(1H, dd, J = 8.8, 2.3 Hz), 7.52 (1H, d, J = 2.3 Hz), 7.02 (1H, d, J = 8.8
Hz), 4.28 (2H, s), 1.50 (9H, s); 13C NMR: δ 168.5, 152.6, 147.5, 142.4,
136.2, 131.0, 119.1, 117.7, 117.0, 114.0, 108.0, 81.5, 49.7, 28.1 (3C); MS
(EI, 70eV): M+ m/z 363. Anal. calcd for C16H15BrN2O3: C, 52.91; H,
4.16; N, 7.71; found: C, 52.80; H, 4.27; N, 7.66%.
Conclusions
In summary, new 2-iminochromene dimers were successfully
prepared under mild condition. In addition, siloxane-
substituted FOXAP ligand L(f) was successfully applied in the
enantioselective self-Michael reactions of 5 with satisfactory
yields (up to 99%) and excellent ee values (up to 97% ee).
Further investigation of the range of the substrate, the absolute
configuration of the product, and the application of the dimers
are underway.
Ethyl-2-[(6-bromo-3-cyano-2H-chromen-2-ylidene)amino]acetate
(5d): Pale yellow solid; yield 83%; m.p. 128 oC (petrol ether); IR (KBr
cm-1): ν 2233, 1737, 1670, 1190; 1H NMR: δ 7.68 (1H, s), 7.59 (1H, dd,
J = 8.8, 2.3 Hz), 7.53 (1H, d, J = 2.2 Hz), 7.04 (1H, d, J = 8.8 Hz), 4.36
(2H, s), 4.23 (2H, q, J = 7.1 Hz), 1.30 (3H, t, J = 7.1 Hz); 13C NMR:
δ 169.5, 152.6, 147.6, 142.7, 136.3, 131.1, 119.1, 117.7, 117.1, 114.0,
107.9, 61.1, 48.9, 14.2; MS (EI, 70eV): M+ m/z 335. Anal. calcd for
C14H11BrN2O3: C, 50.17; H, 3.31; N, 8.36; found: C, 50.05; H, 3.44; N,
3.26%.
t-Butyl-2-(2-[(2-(t-butoxy)-2-oxoethyl)amino]-3-cyano-4H-
chromen-4-yl)-2-[(3-cyano-2H-chromen-2-ylidene)amino]acetate
(6a): White solid; yield 98%; m.p. 138 oC (petrol ether); IR (KBr cm-1):
ν 2209, 1736, 1657, 1620 cm-1; 1H NMR: δ 8.46 (1H, br s), 8.29 (1H, s),
7.71–7.55 (2H, m), 7.50–7.45 (2H, m), 7.33–7.17 (2H, m), 7.16–6.96
(2H, m), 4.55 (2H, s), 4.22–4.09 (1H, m), 2.33–2.21 (1H, m), 1.49 (9H,
s), 1.30 (9H, s); 13C NMR: δ 175.9, 168.1, 157.2, 155.4, 152.2, 145.8,
138.5, 133.3, 132.6, 128.3, 126.8, 126.2, 123.1, 121.0, 120.7, 118.4,
117.4, 117.2, 109.6, 98.3, 81.9, 81.6, 70.7, 65.4, 45.8, 42.0, 28.4 (6C);
MS (EI, 70eV): M+ m/z 569. Anal. calcd for C32H32N4O6: C, 67.59; H,
5.67; N, 9.85; found: C, 66.98; H, 5.73; N, 9.81%; HPLC (Daicel OD-H,
hexane/iPrOH = 87/13, 1.0 mL min-1, 215 nm) t1 = 17 min (major), t2 =
21 min (minor).
The authors acknowledge financial assistance from the
National Natural Science Foundation of China (Grant no.
KZ200610011006), and the National Technological Project
of the Manufacture and Innovation of Key New Drugs
(2009ZX09103-143).
Received 6 March 2015; accepted 23 March 2015
Paper 1503235 doi: 10.3184/174751915X14279896539656
Published online: 13 April 2015
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Ethyl-2-(3-cyano-2-[(2-ethoxy-2-oxoethyl)amino]-4H-chromen-4-
yl)-2-[(3-cyano-2H-chromen-2-ylidene)amino]acetate (6b): White
solid; yield 93%; m.p. 131 oC (petrol ether). IR (KBr cm-1): ν 2212, 1733,
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t-Butyl-2-(6-bromo-2-[(2-(t-butoxy)-2-oxoethyl]amino)-3-cyano-
4H-chromen-4-yl)-2-[(6-bromo-3-cyano-2H-chromen-2-ylidene)
amino]acetate (6c): Yellow solid; yield 99%; m.p. 152 oC (petrol
ether); IR (KBr cm-1): ν 2210, 1732, 1654, 1619 cm-1. 1H NMR: δ
8.01 (1H, s), 7.66 (1H, s), 7.58–7.54 (2H, m), 7.47 (1H, d, J = 2.1
Hz), 7.31–7.29 (1H, m), 6.98–6.86 (2H, m), 4.46 (1H, d, J = 2.6 Hz),
4.21–4.03 (2H, m), 2.05 (1H, s), 1.49 (9H, s), 1.44 (9H, s); 13C NMR:
δ 170.4, 167.3, 156.7, 154.6, 152.1, 147.0, 139.8, 135.4, 134.2, 132.1,
129.1, 122.4, 121.5, 121.2, 121.1, 120.8, 118.8, 117.6, 109.5, 98.5, 82.0,
81.2, 71.0, 64.3, 45.2, 41.0, 29.1, 28.41 (6C); MS (EI, 70eV): M+ m/z
725. Anal. calcd for C32H30Br2N4O6: C, 52.91; H, 4.16; N, 7.71; found:
C, 52.66; H, 4.03; N, 7.82%; HPLC (Daicel OD-H, hexane/iPrOH =
90/10, 1.0 mL min-1, 215 nm) t1 = 25 min (major), t2 = 32 min (minor).
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chromen-4-yl)-2-[(6-bromo-3-cyano-2H-chromen-2-ylidene)amino]
3
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