Enantioselective synthesis of functionalized 2-amino-4H-chromenes via the o-quinone methides generated from 2-(1-tosylalkyl)phenols

Article abstract of DOI:10.1016/j.tetlet.2015.05.076

An efficient bifunctional squaramide-catalyzed Michael addition/cyclization reaction of o-quinone methides generated in situ from 2-(1-tosylalkyl)phenols with active methylene compounds bearing a cyano group has been realized to synthesize chiral 2-amino-

Full text of DOI:10.1016/j.tetlet.2015.05.076

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
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Enantioselective synthesis of functionalized 2-amino-4H-chromenes
via the o-quinone methides generated from 2-(1-tosylalkyl)phenols
Bo Wu a, Xiang Gao a, Zhong Yan a, Wen-Xue Huang a, Yong-Gui Zhou a,b,
⇑
a State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient bifunctional squaramide-catalyzed Michael addition/cyclization reaction of o-quinone
methides generated in situ from 2-(1-tosylalkyl)phenols with active methylene compounds bearing a
cyano group has been realized to synthesize chiral 2-amino-4H-chromenes with excellent enantioselec-
tivities and broad substrate scope.
Received 20 April 2015
Revised 19 May 2015
Accepted 21 May 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
2-Amino-4H-chromenes
o-Quinone methides
2-(1-Tosylalkyl)phenols
Chromenes occupy a prominent position in modern hetero-cyc-
lic chemistry attributing to their extraordinary significance in bio-
logically active molecules, natural products, and synthetic drugs.1
Among the diverse types of chromenes, 2-amino-4H-chromenes
are recognized to be particularly important as they belong to ‘priv-
ileged medicinal scaffolds’.2 For instance, the tumor antagonist
HA14-1 and related substituted alkyl (4H-chromen-4-yl)cyanoac-
etates are a new class of small molecules that exhibit a binding
activity for the surface pocket of cancer implicated Bcl-2 protein
and induce apoptosis or programmed cell death in tumor cells.2f
Crolibulin (EPC2407) is a microtubulin inhibitor currently in
phase I/II clinical trials as anticancer agent and apoptosis inducer
for the treatment of anaplastic thyroid cancer.2j IRSP inhibitor acts
as an insulin-regulated aminopeptidase inhibitor which is useful
in therapeutic application including enhancing memory and
learning functions2k (Fig. 1). Due to the remarkable importance
of 2-amino-4H-chromene frameworks, their syntheses are of
contemporary interest. Despite various methods for the
construction of racemic 2-amino-4H-chromenes been reported,3
asymmetric syntheses of these structures are still limited. In 2008,
Zhao group disclosed the first asymmetric synthesis of 2-amino-
4H-chromenes by bifunctional thiourea catalyzed tandem addi-
Mannich cyclization/tautomerization cascade sequences,5 three-
component cascade reaction,6 and conjugate addition of nitroalka-
nes to 2-iminochro-menes.7 In these organocatalytic strategies, cin-
chona derivatives, bifunctional thiourea and squaramide were
found to be efficient catalysts. In contrast, only two examples of
metal complex catalyzed asymmetric synthesis have emerged in
recent years. In 2011, Feng group reported enantioselective con-
struction of 2-amino-4H-chromenes using salen–cobalt(II) complex
or N,N0-dioxide-Zn(II) complex.8 In spite of these considerable
advances, there are still some drawbacks involving low catalytic
efficacy, poor stereoselectivity, and unsatisfactory substrate scope.
Hence, developing a facile method for the synthesis of chiral
2-amino-4H-chromenes with high enantioselectivities and broad
substrate scope is still highly desirable.
o-Quinone methides (o-QMs) are a crucial class of intermediates
in various biological processes9 and have been regarded as highly
reactive chemical motifs.10 Despite the wide application of o-QMs,
only few organocatalytic enantioselective settings of o-QMs have
been reported owing to their high reactivity and instability.11
Organocatalytic formal [4+2] cycloaddition of o-QMs with active
methylene compounds bearing the cyano group is also a stream-
lined method for the synthesis of optically active 2-amino-4H-chro-
menes. Recently, Han group reported quinine-catalyzed annulation
of the electron-rich and stable o-QMs with malononitrile to provide
4-arylvinyl, 4-aryl, and 4-vinyl 2-amino-3-cyano-4H-chromenes
with excellent yields and enantioselectivities. However, the sub-
strate scope was limited.11u As our continuing efforts to the
employment of o-QMs,11r,12 we focused on bifunctional
organocatalytic reactions of in situ generated o-QMs. In our
tion/cyclization reactions of 2-naphthols and
a,a-dicyanoolefins
with moderate enantioselectivities.4a Subsequently, several
organocatalytic syntheses of chiral 2-amino-4H-chromenes have
been developed, including tandem Michael addition/cyclization,4
⇑
Corresponding author. Tel./fax: +86 411 84379220.
E-mail address: ygzhou@dicp.ac.cn (Y.-G. Zhou).
http://dx.doi.org/10.1016/j.tetlet.2015.05.076
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wu, B.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.05.076

2
B. Wu et al. / Tetrahedron Letters xxx (2015) xxx–xxx
OMe
MeO
Br
O
N
CN
CO2Et
EtO
Br
CN
CO2Et
O
NH2
H2N
O
NH2
HO
O
NHAc
NH2
Crolibulin (EPC2407)
Figure 1. Bioactive 2-amino-4H-chromene derivatives.
HA14-1
IRSP inhibitor
Table 1
Condition Optimizationa
Ph
Ph
CN
NH2
Ts
OH
1a
CN
CN
Organocatalyst 4
+
Base, Solvent, T
O
2a
3a
MeO
MeO
N
S
N
N
S
Ar
Ar
N
H
N
H
OH
N
H
N
H
N
N
N
4a
4b
4c
Ar = 3,5-(CF3)2C6H3
Et
Ar = 3,5-(CF3)2C6H3
MeO
MeO
O
O
N
N
Ph
Ph
O
O
S
Me2N
HN
N
H
N
H
Ar
HN
Ar
HN
HN Ar
N
N
4d
4e
4f
Ar = 3,5-(CF3)2C6H3
Ar = 3,5-(CF3)2C6H3
Ar = 3,5-(CF3)2C6H3
Entry
Cat.
Base
Solvent
t (h)
Yieldb (%)
Eec (%)
1
—
K2CO3
PhMe
2
80
—
2
3
4
5
6
7
8
9
10
11
12
13
14d
15e
16f
—
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
NaHCO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DCM
THF
p-Xylene
p-Xylene
p-Xylene
p-Xylene
2
Trace
83
80
87
80
83
83
83
Trace
93
—
4a
4b
4c
4d
4e
4f
4e
4e
4e
4e
4e
4e
4e
4e
24
24
24
72
24
24
4
24
24
24
24
6
56
94
95
97
97
ꢀ95
67
—
93
24
96
97
96
96
90
97
97
97
4
1
43
a
1a (0.10 mmol), 2a (0.12 mmol), cat. (0.01 mmol), base (0.12 mmol), solvent (1.5 mL), 25 °C.
Isolated yields.
Determined by chiral HPLC.
40 °C.
60 °C.
80 °C.
b
c
d
e
f
previous work, we reported the thiourea catalyzed enantioselective
conditions may furnish racemic products as a result of an obvious
background reaction. Considering active methylene compounds
bearing the cyano group had been broadly employed as
nucleophilic reagents in asymmetric organocatalytic additions,13
amination of o-QMs with aqueous ammonia in 33% ee.12d Low
enantioselectivity possibly attributes to the fact that the o-QMs
generated in situ from 2-(1-tosylalkyl)phenols under basic
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B. Wu et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
R'
R'
Michael Addition
R
Cyclization
Inorganic Base
∗
Ts
OH
R'
R
O
O
NH2
Bifunctional
+
Organocatalyst
via
R
C
N
C
N
H
N
O
O
R
R'
O
H
H
N
N
Inorganic base generates the o-QMs
*
Inorganic base doesn't promote Michael addition
C
N
R
Wide substrate scope and high enantioselectivity
Scheme 1. New strategy for enantioselective synthesis of functionalized 2-amino-4H-chromenes.
R1
R1
O
R
R
Cat. 4e
Na2CO3, p-xylene, 40 o
C
Ts
OH
R2
R2
+
CN
NH2
1
2
3
Me
Me
Me
CN
CN
CN
CN
O
NH2
O
NH2
O
NH2
O
NH2
3a
3b
3c
94% yield, 97% ee
3d
97% yield, 97% ee
97% yield, 97% ee
94% yield, 98% ee
F
Me
CN
CN
CN
NH2
CN
NH2
O
NH2
O
NH2
O
O
3e
97% yield, 97% ee
3fa
3ga
3ha
96% yield, 92% ee
88% yield, 92% ee
96% yield, 92% ee
Me
F
CN
NH2 MeO
CN
CN MeO
NH2
CN
NH2
MeO
O
O
NH2 MeO
O
O
3ia
3ja
3ka
3la
96% yield, 90% ee
97% yield, 91% ee
93% yield, 91% ee
96% yield, 93% ee
Ph
Ph
Ph
Ph
i
MeO
MeO
CN
CN
CO2 Pr
COPh
NH2
O
NH2
O
NH2 MeO
O
NH2
O
3ma
3na
3oa
71% yield, 91% ee
3pa
97% yield, 94% ee
96% yield, 84% ee
97% yield, 90% ee
Ph
Ph
Ts
SO2Ph
O
NH2
O
NH2
3qa
95% yield, 98% ee
3ra
93% yield, 98% ee
Scheme 2. Substrate scope. Reaction conditions: 1 (0.10 mmol), 2 (0.12 mmol), 4e (0.01 mmol), Na2CO3 (0.12 mmol), p-xylene (1.5 mL), 40 °C. a60 °C.
Please cite this article in press as: Wu, B.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.05.076

4
B. Wu et al. / Tetrahedron Letters xxx (2015) xxx–xxx
temperature to 60 °C. Additionally, the methoxyl substituent was
tolerated and the corresponding adducts were achieved in almost
quantitative yields from 90% to 94% ee. The reaction of 2-(phenyl(-
tosyl)methyl)phenol with malononitrile could also deliver product
3n with 84% ee. Furthermore, a series of active methylene com-
pounds bearing the cyano group transformed successfully, good
yields and excellent enantioselectivities were observed. The abso-
lute configuration of the product, 2-amino-4-phenyl-4H-benzo[h]-
chromene-3-carbonitrile (3a; which can be increased to 99% ee by
a simple recrystallization with dichloromethane), was unambigu-
ously determined to be S by X-ray crystallographic analysis
(Fig. 2).14
In summary, we have developed a highly efficient asymmetric
bifunctional squaramide-catalyzed Michael addition/cyclization
reaction of o-quinone methides generated in situ from 2-(1-tosy-
lalkyl)phenols with active methylene compounds bearing the
cyano group under basic conditions for the preparation of struc-
turally important chiral 2-amino-4H-chromene compounds with
broad substrate scope.15 Further explorations on the extension of
this strategy to synthesize other compounds are ongoing in our
laboratory.
(S)
CN
NH2
O
Figure 2. X-ray single crystal structure of 2-amino-4H-chromene 3a.
we envisioned the combination of 2-(1-tosylalkyl)phenols and
active methylene compounds bearing the cyano group for synthesis
of chiral 2-amino-4H-chromenes in the presence of inorganic bases
and bifunctional organocatalysts. The key for this tandem reaction is
a suitable option of bifunctional organocatalysts and inorganic
bases. The bifunctional organocatalysts could be used for deproto-
nation of active methylene compounds bearing the cyano group to
produce the nucleophilic species in the chiral environment. The
inorganic bases should not promote the following Michael addition
to effectively weaken background reaction and guarantee the con-
trol of high enantioselectivities by the organocatalysts. Herein, we
reported bifunctional squaramide-catalyzed Michael addition/cy-
clization of o-quinone methides generated in situ from the
2-(1-tosylalkyl)phenols with active methylene compounds bearing
the cyano group for the synthesis of 2-amino-4H-chromenes
with excellent enantioselectivities and broad substrate scope
(Scheme 1).
Acknowledgments
This work was financially supported by the National Natural
Science Foundation of China (21125208 & 21372220).
Supplementary data
To begin our study, 2-(1-tosylalkyl)naphthol 1a and malononi-
trile 2a were chosen as model substrates. The background reaction
was firstly investigated. In the absence of organocatalysts, the reac-
tion occurred smoothly to provide racemic product within 2 h in
80% yield using K2CO3 as inorganic base, whereas trace product
was obtained with the utility of Na2CO3 indicating that using
Na2CO3 as inorganic base could weaken background reaction
(Table 1, entries 1–2). Subsequently, organocatalysts were exten-
sively examined. In the case of quinine catalyst 4a, the desired pro-
duct was delivered in good yield and moderate 56% of
enantioselectivity (entry 3). Bifunctional thiourea or squaramide
catalysts gave higher enantioselectivity and dihydroquinine-based
squaramide catalyst 4e was the best catalyst in terms of 97% ee
(entries 4–8). In accordance with our prediction, inorganic bases
played a vital role on reactivity and enantioselectivity. Using stron-
ger base K2CO3 led to lower enantioselectivity albeit with higher
reactivity due to inevitable background reaction (entry 9).
Moreover, a weaker base like NaHCO3 shut down the reaction
(entry 10). Among all the tested solvents, p-xylene was proved to
be the most favorable solvent with respect to excellent yield and
enantioselectivity (entries 11–13). Finally, the temperature was
also evaluated. Increasing the reaction temperature, the rate of
the reaction was accelerated and the enantioselectivity could be
maintained. However, when the reaction temperature was
increased to 80 °C, only moderate yield was obtained. Therefore,
the optimal reaction conditions were established: using 4e as cat-
alyst, Na2CO3 as base, and p-xylene as solvent to perform the reac-
tion at 40 °C.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.05.
076.
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of 2-amino-4H-chromenes by using our previous reported strategy appeared:
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Bernardi, L. Chem.-Eur. J. 2015, 21, 6037. Both Fochi’s group and we reported
bifunctional squaramide-catalyzed reaction of o-quinone methides with active
methylene compounds bearing cyano group for synthesis of chiral 2-amino-
4H-chromenes. Fochi’s group used the water–oil biphase system to weaken
background reaction and ensure high enantioselectivity. Four aryl substituted
substrates could react with malononitrile and moderate yield with up to
94% ee were obtained. We chosen suitable inorganic base to weaken
background reaction and guarantee excellent enantioselectivity. Good yield
and up to 98% ee were achieved by using our strategy. Additionally, alkyl
substituted substrates were also suitable reaction partners and a series of
active methylene compounds bearing cyano group including malononitrile,
benzoylacetonitrile, phenylsulfonylacetonitrile conducted the reaction
smoothly with excellent enantioselectivity.
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Please cite this article in press as: Wu, B.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.05.076