Organocatalyzed enantioselective synthesis of 2-amino-5-oxo-5,6,7,8- tetrahydro-4H-chromene-3-carboxylates

Article abstract of DOI:10.1016/j.tetlet.2011.10.040

The organocatalyzed enantioselective synthesis of biologically active 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate derivatives was achieved using bifunctional cinchona alkaloids as the catalysts. Using quinine thiourea as the catalyst, the t

Full text of DOI:10.1016/j.tetlet.2011.10.040

Tetrahedron Letters 52 (2011) 6792–6795
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalyzed enantioselective synthesis of
2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylates
⇑
Naresh Ramireddy, Santhi Abbaraju, Cong-Gui Zhao
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-0698, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The organocatalyzed enantioselective synthesis of biologically active 2-amino-5-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carboxylate derivatives was achieved using bifunctional cinchona alkaloids as the cata-
lysts. Using quinine thiourea as the catalyst, the tandem Michael addition–cyclization reaction between
1,3-cyclohexanediones and alkylidenecyanoacetate derivatives gives the desired products in high yields
(up to 92%) and good ee values (up to 82%).
Received 14 September 2011
Revised 5 October 2011
Accepted 7 October 2011
Available online 15 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
4H-Chromene
Tandem reaction
Organocatalysis
Cinchona thiourea
Enantioselective
1,3-Cyclohexanedione
Polyfunctionalized chromene derivatives are an important class
of heterocyclic compounds that frequently show biological and
pharmacological activities, such as, anticancer, anticoagulant, spas-
molytic, diuretic, anti-anaphylactic, antibacterial, and fungicidal
activities.1 Some of these compounds may also be used as pig-
ments and biodegradable agrochemicals.2 2H-Chromene and 4H-
chromene are also important structural motifs that may be found
in many natural products.3 Among the chromene derivatives, 2-
amino-4H-chromenes are favorite compounds for medicinal chem-
ists due to their potential biomedical applications. A few exem-
plary biologically active 2-amino-4H-chromene derivatives are
collected in Figure 1. 2-Amino-4H-chromene-3-carbonitrile deriva-
tive 1 was reported to possess antibacterial activity.1e A similar
compound 2 exhibits nanomolar inhibitory activity against human
excitatory amino acid transporter subtype 1 (EAAT1) and with
more than 400-fold selectivity over EAAT2 and EAAT3.1f On the
other hand, 2-amino-4H-chromene-3-carboxylate compound 3
(HA 14–1) is a tumor antagonist and can induce apoptosis of hu-
man acute myeloid leukemia cells.1g Pyranopyrazole derivative 4
was found to be an inhibitor of the human Chk1 kinase.1h
oped the first enantioselective syntheses of 2-amino-4H-
chromene derivatives on the basis of a Michael addition in
2008.5a They later also reported a synthesis based on a Friedel–
Craft reaction.5b In 2009, Xie and co-workers reported asymmetric
synthetic method involving an organocatalyzed double Michael
addition reaction.5c Wang’s group recently reported a tandem Mi-
chael–Mannich reaction for the enantioselective synthesis of 2,4-
OMe
O
Ph
O
O
CN
CN
NH2
O
NH2
1
2
OH
OH
Due to their usefulness, their synthesis has attracted a lot of
attention. Many methods have been developed for the synthesis
of racemic 2-amino-4H-chromene derivatives.4 Nonetheless, their
asymmetric synthesis is not much explored.5,6 The reported asym-
metric syntheses are summarized as follows: Zhao’s group devel-
EtO2C
CN
Br
CO2Et
NH2
CN
O
HN
N
O
NH2
3
4
⇑
Corresponding author. Tel.: +1 210 458 5432; fax: +1 210 458 7428.
E-mail address: cong.zhao@utsa.edu (C.-G. Zhao).
Figure 1. Biological active 2-amino-4H-chromene derivatives.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.040

N. Ramireddy et al. / Tetrahedron Letters 52 (2011) 6792–6795
6793
Table 1
diamino-4H-chromene derivatives using an indane–amine thio-
Catalyst screening and reaction condition optimizationsa
urea catalyst.5d Most recently, an asymmetric synthesis of 2-ami-
no-5-oxo-tetrahydro-4H-chromene-3-carboxylates using a salen-
cobalt(II) complex was reported by Feng’s group.5e
O
CO2Et
O
OEt
Catalyst
Since it is well known that individual enantiomers of a given
molecule often possess different biological activities, we are inter-
ested in developing asymmetric syntheses of these useful hetero-
cyclic molecules using organocatalytic methods.6 In this regard,
our group recently reported the first enantioselective synthesis of
6-amino-5-cyanodihydropyrano[2,3-c]pyrazoles6a and 2-amino-8-
oxo-tetrahydro-4H-chromene-3-carbonitriles6b on the basis of a
tandem7 Michael addition–cyclization reaction using chiral bifunc-
tional cinchona catalysts.8 Since we have demonstrated that
bifunctional cinchona alkaloids can catalyze a tandem Michael
addition–cyclization reaction between 1,2-cyclohexanediones and
benzylidenemalononitriles,6b we reasoned that a similar reaction
can be carried out between 1,3-cyclohexanediones and ben-
zylidenecyanoacetate derivatives for the synthesis of 2-amino-5-
CN
*
O
O
13a
O
NH2
14a
15a
Entry
Solvent
Catalyst
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15e
16f
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
Benzene
DME
5
6
7
8
1
1
1
1
1
1
1
1
94
91
92
93
90
91
90
84
91
90
86
85
90
93
92
74
22
14
72
72
70
62d
66d
57
71
70
71
70
68
62
79
77
9
10
11
12
7
7
7
oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate
derivatives
1
1
1
using these organocatalysts. Although Feng and co-workers have
reported a transitionmetal-catalyzed synthesis,5e an organocata-
lyzed synthesis of these important chromene derivatives is still
lacking. Herein we wish to report a quinine thiourea-catalyzed
asymmetric synthesis of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carboxylates.
Et2O
7
1
THF
7
1
CH2Cl2
Toluene
Toluene
7
7
7
1
4.5
4.5
Initially, 5,5-dimethylcyclohexane-1,3-dione (13a) and ethyl
(E)-2-cyano-3-phenylacrylate (14a) were adopted as the model
substrates and toluene as the solvent to screen some readily avail-
able cinchona alkaloid catalysts. The structures of these catalysts
(5–12) are shown in Figure 2. The results of this screen are summa-
rized in Table 1. As shown by the data in Table 1, when quinine (5)
was used as the catalyst at room temperature, the desired product
15a was obtained in high yield (94%, entry 1). The formation of
product 15a was confirmed by comparing its 1H and 13C NMR spec-
troscopic data with those reported data.5e,9 Similarly, cupreine (6)
is also highly reactive and led to a high yield of 15a (entry 2). Nev-
ertheless, low enantioselectivities were obtained for the desired
product 15a with these two catalysts (entries 1 and 2). In contrast,
when quinine-derived thiourea 7 was used as the catalyst, the ee
value of the desired product was much improved (72% ee). Also
a
Unless otherwise specified, all reactions were conducted with 5,5-dimethyl-
cyclohexane-1,3-dione (13a, 0.1 mmol), ethyl (E)-2-cyano-3-phenylacrylate (14a,
0.12 mmol), and the catalyst (0.01 mmol, 10 mol %) in the specified solvent (0.5 mL)
at room temperature.
b
Yield of isolated product after column chromatography.
Determined by HPLC analysis on a ChiralCel OD-H column.
c
d
The opposite enantiomer was obtained in excess.
The reaction was conducted at 0 °C.
The reaction was conducted at À15 °C.
e
f
excellent yield of 15a was obtained (92%, entry 3). These results
indicate that the thiourea moiety is essential for achieving good
enantioselectivity in this reaction. Similar results were also ob-
tained with the dihydroquinine-derived thiourea 8 (entry 4) and
cinchonidine thiourea 9 (entry 5). Quinidine thiourea (10) and cin-
chonine thiourea (11), the pseudo-enantiomers of 7 and 9, respec-
tively, were also screened under these conditions, and slightly
lower ee values were obtained for the opposite enantiomeric prod-
uct (entries 7 and 8). Similarly, Takemoto thiourea10 12 also led to
lower ee value of 15a (57% ee, entry 9). Thus, this screen identified
quinine thiourea (7) and dihyroquinine thiourea (8) as the best cat-
alysts for this reaction. Since 7 is more easily accessible than 8, it
was adopted for further reaction condition optimizations.
Firstly, the effects of solvent on the reaction were evaluated. It
was found that, besides toluene, similar but slightly diminished
enantioselectivities may also be obtained in xylene, benzene,
DME, and ether (entries 9–12). Other common organic solvents,
such as THF (entry 13) and CH2Cl2 (entry 14) led to slightly inferior
ee values of the product (entries 11 and 12). Additionally, slightly
lower product yields were obtained in ethereal solvents like DME
and Et2O (entries 11 and 12). Thus, toluene was identified as the
best solvent for this reaction.
Secondly, the temperature influences on this reaction were
investigated. When the reaction was performed at 0 °C, the ee va-
lue was improved to 79% at a slight expense of the reaction rate
(entry 15). Further decrease in the reaction temperature to
À15 °C showed no enhancement in the ee value, but with a further
decrease of the reaction rate (entry 16).
With the optimized reaction conditions at hand, we then stud-
ied the substrate scope of this reaction and the results are com-
piled in Table 2. As the results in Table 2 show, different ester
CF3
S
OH
N
HN
N
H
CF3
H
N
N
R2
H
N
RO
R1
R1 = OMe; R2 = -CH=CH2
5
R = Me
R = H
7
6
8 R1 = OMe; R2 = -CH2-CH3
9 R1 = H;
R2 = -CH=CH2
CF3
CF3
S
N
S
NH
F3C
N
H
N
N
H
N
H
CF3
N
H
R
12
10
R = OMe
11 R = H
Figure 2. Bifunctional cinchona alkaloid catalysts used in the study.

6794
N. Ramireddy et al. / Tetrahedron Letters 52 (2011) 6792–6795
Table 2
tion (entry 17). As the results show, the two methyl groups at
the C-5 of the dione has some beneficial effects on the enantiose-
lectivity but not on the reactivity (entry 3 vs entry 17). It should
be noted that extending the reaction times may result in slightly
lower ee values of the products. For example, compound 15j (Ta-
ble 2, entry 10) was obtained in 76% ee and 88% yield if the reaction
was conducted for 8.5 h. This is most likely due to a slow racemi-
zation of the stereogenic center under the reaction conditions.11
In summary, we have developed an organocatalyzed asymmet-
ric synthesis of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carboxylates using quinine-derived thiourea as the catalyst.
The tandem Michael-cyclization reaction of 1,3-cyclohexanediones
and alkylidenecyanoacetates yields the title compounds in high
yields (up to 92%) and good enantioselectivities (up to 82% ee).
Enantioselective synthesis of 2-amino-5-oxo-5, 6, 7, 8-tetrahydro-4H-chromene-3-
carboxylatesa
R1
R1
O
R2 OR3
O
CO2R3
CN
7
*
O
toluene, 0 °C
R1
R1
R2
O
NH2
O
13
14
15
Entry
R1
R2
R3
15
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Ph
Ph
Ph
Et
a
b
c
d
e
f
g
h
i
4.5
4
4.5
4
4
4.5
3
2.5
4.5
6.5
4.5
3.5
6.5
6.5
7.5
92
90
85
88
85
91
75
72
85
84
90
85
86
82
81
67
83
79
69
80
74
76
75
Me
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
3-BrC6H4
2-BrC6H4
3-MeOC6H4
2-MeOC6H4
1-Napthyl
2-Thienyl
Ph
Acknowledgments
66d
65d
82d
80
This research was financially supported by the Welch Founda-
tion (Grant No. AX-1593) and partially by the NIH/NIGMS (Grant
No. SC1GM082718), for which the authors are very grateful.
j
l
74
k
n
m
o
p
q
20d
74
Supplementary data
51d
65d
76d
70d
Supplementary data (detailed experimental procedure, com-
pound spectroscopic data, copy of NMR spectra and HPLC analysis
chromatograms) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2011.10.040.
11
4.5
a
Unless otherwise specified, all reactions were conducted with cyclohexane-1,3-
dione (13, 0.1 mmol), alkylidenecyanoacetate (14, 0.12 mmol), and catalyst
(0.01 mmol, 10 mol %) in toluene (0.5 mL) at 0 °C.
7
References and notes
b
Yield of isolated product after column chromatography.
Determined by HPLC analysis on a ChiralCel OD-H column.
Determined by HPLC analysis on a ChiralPak AD-H column.
c
d
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alkyl groups on the benzylidenecyanoacetates (14) have some ef-
fects on the enantioselectivity of this reaction: The ee value of
the product 15 increases from 69% to 80% when the ester alkyl
group is changed from a methyl to an isopropyl group (entries
1–3). These increases are most likely due to the steric effects. Since
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substituent on the phenyl ring of 14 influences the enantioselectiv-
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electron-withdrawing capacity of the substituent, the lower the
product ee value (entries 4–8). Strong electron-withdrawing
groups, such as the cyano and nitro groups, also lead to diminished
product yields (entries 7 and 8). In contrast, electron-donating
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subject it to
a less stereoselective catalyst under the optimized reaction
conditions also led to reduced ee value of the product.