Enantioselective synthesis of 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitriles from 2-iminochromenes

Article abstract of DOI:10.1080/00397911.2016.1177728

A series of medicinally important 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitriles were synthesized using enantioselective conjugate addition of nitromethane to 2-iminochromenes. The reactions were performed using L8-Cu (II) catalytic system and moderate to good enantioselectivities (62–88%) and yields (66–96%) were obtained.

Full text of DOI:10.1080/00397911.2016.1177728

Synthetic Communications
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Enantioselective Synthesis of 2-Amino-4-
(Nitromethyl)-4H-Chromene-3-Carbonitriles from
2-Iminochromenes
Gamze Koz, Omer Koz & Necdet Coskun
To cite this article: Gamze Koz, Omer Koz & Necdet Coskun (2016): Enantioselective Synthesis
of 2-Amino-4-(Nitromethyl)-4H-Chromene-3-Carbonitriles from 2-Iminochromenes, Synthetic
Communications, DOI: 10.1080/00397911.2016.1177728
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1177728
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Date: 26 April 2016, At: 21:16

Enantioselective Synthesis of 2-Amino-4-(Nitromethyl)-4H-Chromene-3-
Carbonitriles from 2-Iminochromenes
1
1
2
Gamze Koz , Omer Koz , Necdet Coskun
1
2
Department of Chemistry, Bursa Technical University, Bursa, Turkey, Department of
Chemistry, Uludag University, Bursa, Turkey
Corresponding author: E-mail: gamzedkoz@gmail.com
Abstract
A series of medicinally important 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitriles
were synthesized using enantioselective conjugate addition of nitromethane to 2-
iminochromenes. The reactions were performed using L8-Cu (II) catalytic system and
moderate to good enantioselectivities (62-88%) and yields (66-96%) were obtained.
KEYWORDS: 2-iminochromene, amino alcohol catalyst, nitromethane, enantioselective
conjugate addition
INTRODUCTION
1

Chromene derivatives are an important class of heterocyclic compounds, widely
distributed in natural products. Among a variety of chromene derivatives, 2-amino-4H-
chromenes are particularly important since they are recognized as ‘privileged medicinal
[
1,2]
scaffolds’ . In recent years, functionalized 2-amino-4H-chromenes have demonstrated
[
3]
a wide range of biological properties, such as antimicrobial and antifungal ,
[
4]
[5]
[6]
[7]
antioxidant , antitumor and anticancer , anti-HIV , antiproliferation , and
[
8]
antiinflammatory . For example, ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-
oxoethyl)-4H-chromene-3-carboxylate (HA 14-1) and related compounds are early Bcl-2
antagonists and have been shown to synergize with various anticancer therapies of
diverse mechanisms of action. 2-Amino-3-cyano-4H-chromene bearing a 3-bromo-4,5-
dimethoxyphenyl at the 4-position (MX58151) represents a promising class of
proapoptotic small-molecule agents with multiple action modes against the breast cancer
[
9]
cell lines (Scheme 1).
There are a number of methods reported for the synthesis of racemic 2-amino-3-nitrile-
[
10]
chromenes . Given the fact that enantiomers often indicate distinct biological activity,
the efficient access to optically pure 2-amino-3-nitrile-chromenes would be extremely
desirable to further study the correlation between the chirality and their propensities for
biological activities to acquire more potent and appropriate pharmaceutical candidates.
Although there are a few papers on the asymmetric conjugate additions of nitroalkanes to
[
11]
unsaturated systems , examples on the enantioselective assembly of 2-amino-4-
nitromethyl)-4H-chromene-3-carbonitrile structures are still rather scarce and general
(
approach for their synthesis is via a cascade Michael-cyclization sequence of 2-(E)-2-
2

[
12]
nitrovinylphenols and malononitrile. Recently, Wang et al. reported the
enantioselective conjugate addition of nitroalkanes to 2-iminochromenes catalyzed by
[
13]
hydrogen bonding catalysts such as quinine-thiourea derivatives. However, there is
still a limited number of chiral catalysts which are active in the conjugate addition
reactions to 2-iminochromenes. Herein, we report an alternative catalytic method for the
enantioselective synthesis of 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitriles using
a simple amino alcohol derived ligand L8 and Cu (II) ions.
RESULTS AND DISCUSSION
2
-iminochromenes (1a-f) were synthesized and characterized by previously reported
[
14]
methods . Our initial investigation commenced with screening catalytic activities of a
variety of (L)-amino acids, L1-6, L-aspartic acid derived amino alcohol L7 and its Schiff
base derivative L8, which were reported by our group and applied successfully in the
[
15]
asymmetric Henry reactions of aromatic aldehydes . None of the catalysts worked well
as an organocatalyst with regard to the enantioselectivity and we obtained the products as
a racemic mixture. Then we performed the reactions using L-Cu(II) catalytic system. The
screening results of L1-8 in a model asymmetric conjugate addition reaction between
nitromethane (1.5 equiv) and 1a (1 equiv) using L (20 mol %) and copper (II) acetate (20
mol %) in ethanol at room temperature, are summarized in Table 1.
The best ligand L8 was selected for further optimization of the reaction conditions and
optimizations mainly focused on the effects of solvents. The results are given in Table 2
3

All solvents provided moderate to excellent conversions however enantioselectivities
were slightly lower in alcohols then the other organic solvents (entry 1-5). Best yields
and enantioselectivities were obtained in acetonitrile (entry 7) and toluene (entry 10). In a
final optimization reaction we used 40 mol% Cu(OAc)
2 2
nH O (L8:Cu(II) ratio was 1:2) in
toluene and obtained 88% ee and 91% yield (entry 11).
With the optimized reaction conditions in hand, we assessed the scope of the asymmetric
conjugate addition of nitromethane to various 2-iminochromenes (2a-f). All the reactions
proceeded with moderate to good stereochemical control (88% ee max) and good yields
(96% max) (Table 3). Most of the reactions were completed within 48 h, although longer
reaction times were required for the conjugate addition to 2c and 2d. The opposite
enantiomer was obtained excessively in the reaction of 2e with nitromethane.
The mechanism and the asymmetric induction of this transformation can be rationalized
as in Scheme 2.
The initial step of this conjugate addition reaction is the formation of intermediate 3 in
the presence of L8 – Cu (II) catalytic system. We propose that the multiple hydrogen
bonds and coordination to copper atom lower the HOMO−LUMO energy gap of
nitroalkane and 1a resulting in the formation of the addition product. Enantioselectivities
obtained in this reaction depends on the chiral and steric environment of intermediate 3.
The result of 1,4-addition is the formation of 4 and in the final step of the reaction, 4
undergoes a proton shift to generate the desired addition product 2a.
4

EXPERIMENTAL
General
All reagents were obtained from commercial sources and were used without further
purification. Silica gel F254 (Merck 5554) precoated plates were used for thin layer
1
13
chromatography. HNMR and CNMR spectra were carried out using a 400 MHz Bruker
NMR spectrometer at ambient temperature. Melting points were recorded with an electro
thermal digital melting points apparatus. Kromasil column was used for chiral HPLC
analysis. 2-iminochromenes (1a-f) were synthesized by previously reported methods and
[
13]
characterized by reported spectroscopic data and melting points
.
General Procedure For The Conjugate Addition Of Nitromethane To 2-
Iminochromenes
The corresponding 2-iminochromene (1a-f) (0.30 mmol) was added to the mixture of L
2 2
(0.06 mmol), Cu(OAc) nH O (0.12 mmol) and nitromethane (0.90 mmol) in appropriate
solvent (5 mL). The resulting suspension was stirred at room temperature until the
addition was completed. The solvent was removed under vacuum and the product was
2 4
extracted with dichloromethane:water. The organic phase was dried with Na SO and
filtered, and the dichloromethane fraction was evaporated under vacuum. The crude
product was purified with column chromatography (1:3 ethyl acetate:hexane) to give the
addition product. The racemic samples for HPLC analysis were prepared using DBU
catalyzed conjugate addition of nitromethane to 2-iminochromenes in methanol.
5

[
12,13]
2
2
a-f were characterized using previously reported spectroscopic data
d was fully characterized as it was not previously reported.
except for 2d.
(
S)-2-Amino-6-Hydroxy-4-(Nitromethyl)-4H-Chromene-3-Carbonitrile (2d)
1
White crystal; 66% yield; mp 165 C (decomp.); HNMR (400 MHz, DMSO-d
6
): (ppm)
9
1
1
1
3
.45 (s, 1H), 7.01 (s, 2H), 6.87-6.84 (d, J= 8.8 Hz, 1H), 6.71-6.68 (dd, J= 2.8, 8.8 Hz,
H), 6.65 (d, J= 2.8 Hz, 1H), 4.74-4.69 (dd, J= 5.2, 12.4 Hz, 1H), 4.63-4.58 (dd, J= 5.6,
13
2.4 Hz, 1H), 4.22-4.19 (t, J=5.2 Hz, 1H). CNMR (400 MHz, DMSO-d
6
): (ppm)
62.4, 153.9, 142.1, 120.0, 119.9, 116.8, 115.8, 113.5, 80.7, 49.5, 34.9. IR (KBr): 3450,
–1
333, 2190, 1652, 1615, 1580, 1539, 1498, 1427, 1220 cm . Anal. Calcd. for:
C
11
H
9
N
3
O
4
(%): C, 53.44; H, 3.67; N, 17.00, Found: C, 53.42.; H, 3.68; N, 16.99.
CONCLUSION
In summary, we have successfully applied L8-Cu(II) catalytic system in the
enantioselective conjugate addition of nitromethane to electrophilic 2-iminochromenes
with good yields (66-96%) and ee (62-88 %) values. This is the first Cu (II) catalyzed
method for the asymmetric synthesis of 2-amino-4-(nitromethyl)-4H-chromene-3-
carbonitriles. The method is operationally simple and tolerates substantial variation in the
two reacting partners. On the other hand, L-(+)-aspartic acid-derived Schiff base ligand is
an advantageous catalyst as it can be prepared from cheap and easily accessible starting
materials in an easy 3-step procedure.
ACKNOWLEDGEMENTS
6

G. K. acknowledges a BIDEB 2218-Postdoctoral Fellowship from the Turkish Scientific
and Technological Research Council (TUBITAK). G. K. gratefully acknowledges Prof.
Osman Kopmaz for providing the opportunity to study at research laboratories of Bursa
Technical University. Prof. Stephen T. Astley is gratefully acknowledged for the careful
reading of the manuscript.
1
13
Full experimental detail, H and C NMR spectra of all known compounds and 2d,
HPLC chromatograms, optical rotations. This material can be found via the
“
Supplementary Content” section of this article’s webpage.
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1
0

Table 1. Screening of L1-8 – Cu(II) in the asymmetric conjugate addition of
nitromethane to 2-iminochromene (1a) as model reaction
a
b
Catalyst
L1
Yield (%)
ee (%)
76
77
56
72
76
81
88
6
L2
-
L3
-
L4
-
L5
-
L6
10
10
12
L7
L8
93
a
b
Isolated yield. Determined by HPLC.
1
1

Table 2. Optimization of the reaction conditions
a
b
No
1
Solvent
Time (h)
24
Yield (%)
ee (%)
Methanol
94
92
93
91
93
72
84
66
69
90
91
-
2
Methanol:Water
Ethanol
18
-
3
24
12
22
59
70
72
64
70
74
88
4
2-Propanol
t-Butanol
24
5
24
6
Ethylacetate
Acetonitrile
Dichloromethane
THF
48
7
48
8
72
9
48
1
0
1
Toluene
48
c
1
Toluene
48
a
b
Isolated yield. Determined by HPLC. The absolute configuration was assigned by
c
comparison of the specific rotation value with the reported data in Ref. 11c,d. 40 mol%
2 2
Cu(OAc) .nH O was used.
1
2

Table 3. Scope of the asymmetric conjugate addition to electrophilic 2-iminochromenes
a
b
No
Product
Time (h)
48
Yield (%) ee (%)
2
a
91
88
2
b
48
96
62
2
2
2
c
d
e
72
96
48
80
66
81
85
c
-
84
80
2
f
48
87
a
b
Isolated yield. Determined by HPLC. The absolute configuration was assigned by
c
comparison of the specific rotation value with the reported data in Ref. 11c,d. We were
not able to determine ee% with Kromasil column for 2d.
1
3

Scheme 1. Biologically active 2-amino-4H-chromenes.
1
4

Scheme 2. Proposed reaction mechanism
1
5