Expeditious assembly of a 2-Amino-4H-chromene skeleton by using an enantioselective Mannich intramolecular ring cyclization-tautomerization cascade sequence

Article abstract of DOI:10.1002/chem.201100927

Easy to assemble! An enantioselective cascade Mannich intramolecular ring cyclization-tautomerization reaction of malononitrile with 2-hydroxyl N-protected α-amido sulfone is described (see scheme), which provides a new route to the synthesis of the privi

Full text of DOI:10.1002/chem.201100927

COMMUNICATION
DOI: 10.1002/chem.201100927
Expeditious Assembly of a 2-Amino-4H-chromene Skeleton by Using an
Enantioselective Mannich Intramolecular Ring Cyclization–Tautomerization
Cascade Sequence
Qiao Ren,[a] Woon-Yew Siau,[a] Zhiyun Du,[b] Kun Zhang,[b] and Jian Wang*[a]
The concept of a “privileged medicinal scaffold” has
emerged as one of the most guiding principles in the process
of drug discovery.[1] The privileged scaffold commonly con-
sists of a rigid hetero-ring system that assigns a well-defined
orientation of appended functionalities for target recogni-
tion.[2] In the light of this, the accessibility of convenient
methods for the diversification of privileged scaffold func-
tionalities impacts on the success in seeking potential drugs.
Undoubtedly, the discovery of novel synthetic methodolo-
gies to facilitate the preparation of compound libraries is a
pivotal focal point in modern medicinal chemistry.[3]
Chromene, as one of the privileged scaffolds, often ap-
pears as an important structural component in both biologi-
cally active and natural compounds. It has widely appeared
in natural alkaloids, tocopherols, flavonoids, and anthocya-
nins.[4] Moreover, in recent years functionalized chromenes
have played an ever-increasing role in the field of synthetic
and medicinal chemistry.[5] Among the diverse chromene
systems, 2-amino-4H-chromenes are particularly privileged
medicinal scaffolds for the generation of small-molecule-
based ligands with highly pronounced spasmolytic, diuretic,
anticoagulant, and antianaphylactic activities.[6] In particular,
the current interest in 2-amino-4H-chromene derivatives
with a nitrile functionality arises from their potential appli-
cation in the treatment of human inflammatory tumor ne-
crosis factor (TNF)a-mediated diseases, such as rheumatoid
and psoriatic arthritis.[7]
The corresponding cyano-functionalized benzopyranopyri-
dine (inhibitor of MK-2) originating from the 2-amino-4H-
chromene scaffold was found to inhibit mitogen-activated
protein kinase (MAPK)-activated protein kinase 2 (MK-2)
and suppress the expression of TNFa in U937 cells.[7a] In the
case of cancer therapy, the tumor antagonist HA14-1 and a
family of related alkyl (4H-chromen-4-yl)cyanoacetates are
a new class of small molecules that exhibit a binding activity
for the surface pocket of the cancer-implicated Bcl-2 protein
and induce apoptosis or programmed cell death in follicular
lymphoma B cells and leukemia HL-60 cells.[7b] The 2-
amino-3-cyano-4H-chromene MX58151, with a 3-bromo-4,5-
dimethoxyphenyl substituent at the 4-position, represents a
promising class of proapoptotic small-molecule agents with
multiple action modes against the breast cancer cell line
T47D, the lung cancer cell line H1299, and the colorectal
cancer cell line DLD-1.[7c,f] It induces caspase-mediated
apoptosis in tumor cells and is about as potent as or slightly
more potent than the commonly prescribed anticancer alka-
loids Vinblastine and Paclitaxel in the caspase activation
assay.[7f] Furthermore, compound MX58151 might have an
advantage for the treatment of the drug-resistant cancers as
it retains activity in tumor cells resistant towards current an-
timitotic agents, taxanes (including Taxol and Taxotere), and
the Vinca alkaloids.[7c,f] The inhibition of tubuline polymeri-
zation and disruption of preformed endothelial cell capillary
tubules constitute other significant activities of 2-amino-3-
cyano-4-aryl-4H-chromenes of type 3 that can place them in
the row of effective anticancer therapeutics with an analo-
gous mode of action.[7c,f] Most recently, another 2-amino-4-
aryl-4H-chromene compound (IRSP inhibitor) has been dis-
covered as an insulin-regulated aminopeptidase inhibitor. In
particular, this inhibitor is maybe useful in therapeutic appli-
cation including enhancing memory and learning func-
tions.[7g]
[a] Q. Ren, W.-Y. Siau, Prof. Dr. J. Wang
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543
Fax : (+65)6516-1691
E-mail: chmwangj@nus.edu.sg
[b] Prof. Dr. Z. Du, Prof. Dr. K. Zhang
Faculty of Engineering and Light Industry
Guang Dong University of Technology
Guang Dong, 510006 (P.R. China)
In view of the significance of this framework, efficient
syntheses of 2-amino-4H-chromenes are of great interest.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100927.
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Despite the fact that asymmetric organocatalysis has
evolved as a powerful tool for the preparation of enantio-
merically enriched compound,[8] organocatalytic methods to
generate optically pure 2-amino-4H-chromenes are still
absent. Recently, hydrogen-bonding-mediated catalysis for
quential reactions to generate the undesired compound b.
To avoid these side reactions, we decided to introduce a
poor leaving group (X=tert-butoxycarbonyl (Boc)) with a
less electron-withdrawing character into the imine structure.
To our knowledge, N-Boc protected imine is an ideal choice.
Unfortunately, we failed to seek a successful method to syn-
thesize 2-hydroxyl N-Boc imine (Scheme 1). Instead, a N-
Boc a-amido sulfone,[11] one of the precursors of N-Boc
imine, was used to react with malononitrile. Gratifyingly, the
investigation showed only desired compound c was afforded
(Scheme 1, a/b/c=0:0:100).
With the initial experiments in hand, we then went on to
probe the asymmetric catalytic feasibility of this reaction.
tert-Butyl (2-hydroxyphenyl)(phenylsulfonyl) methylcarba-
mate (1a) was treated with malononitrile 2 in the presence
of catalyst VII (quinine–thiourea), which was developed by
the Soꢁs, Dixon, and Connon groups, respectively
(Scheme 2).[12] As shown in Table 1, catalyst VII gave a
43% yield in 10 min with a 16% ee (Table 1, entry 7). The
Takemoto thiourea catalyst VI also only offered a 46%
yield with a 42% ee (Table 1, entry 6). Consequently, the
À
C C bond formation has been discovered as a powerful new
tool and synthetic method for the efficient construction of
molecular architectures.[9] In particular, there was a remark-
able development and application on chiral bifunctional thi-
ourea catalysis.[10] The utilization of inexpensive and readily
synthesized chiral thiourea catalysts has attracted considera-
ble interest and proved to be effective in several asymmetric
transformations. Herein, we document a novel strategy for
the preparation of chiral 2-amino-4H-chromenes through a
hydrogen-bonding-mediated enantioselective cascade pro-
cess. To date, such a progress has not been described. Signif-
icantly, this strategy allowed a quick construction of diverse-
ly functionalized 2-amino-4H-chromenes under mild reac-
tion conditions and with good to high enantioselectivities
(74–89% enantiomeric excess (ee)) and high to excellent
yields (81–94%) could be achieved. In this context, we
sought to extent the usage of the indane catalytic system for
the construction of novel and useful complexes based on the
several successful examples disclosed by our research group.
We began our investigation by examining the organic
base catalyzed reaction of a-substituted ketones with b,g-un-
saturated ketoesters. The initial experiment results showed
that the use of a catalytic amount of quinine enabled a reac-
tion between 2-hydroxy imine and malononitrile. Surprising-
ly, if a phenyl group was introduced to 2-hydroxy imine, a
mixture of undesired compounds a and b were generated in
10 min (Scheme 1, a/b=10:90). Then, we tried a stronger
electron-withdrawing group involved 2-hydroxy N-Ts imine
(Scheme 1, X=tosyl, (Ts)). However, only compound b was
finally produced (Scheme 1, a/b=0:100). Based on above
experimental results, we deduced that both strong electron-
withdrawing groups and good leaving groups on the 2-hy-
droxyl imine might assist the Knoevenagel-type reaction to
form intermediate a. Then, intermediate a trigged the se-
Scheme 2. Bifunctional chiral organocatalysts.
Table 1. Evaluation of different bifunctional chiral organocatalysts.[a]
Entry
Catalyst
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
I
II
38
43
50
48
61
46
43
29
9
III
IV
V
VI
VII
77
30
44
42
16
[a] Reaction conditions: CH2Cl2 (0.2 mL), tert-butyl (2-hydroxyphenyl)(-
phenylsulfonyl) methylcarbamate (1a, 0.1 mmol, 1.0 equiv), malononitrile
2 (0.11 mmol, 1.1 equiv), Na2CO3 solution (0.1m, 0.12 mmol, 1.2 equiv),
and catalyst (10 mol%) at RT. [b] Yield of isolated product after column
chromatography. [c] Enantiomeric excess (ee) was determined by HPLC.
Scheme 1. Investigation of 2-hydroxyimines.
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Chem. Eur. J. 2011, 17, 7781 – 7785

Expeditious Assembly of 2-Amino-4H-chromene Skeleton
COMMUNICATION
discovery of a novel and active chiral catalyst that could
promote this reaction with both high efficiency and excel-
lent stereocontrol became our main focus. In this context,
we sought to extent the usage of the indane-amine–thiourea
catalytic system based on several successful examples dis-
closed by our research group.[13] Undoubtedly, bifunctional
indane-amine–thiourea organocatalysts demonstrated some
unique aspects, such as higher activity, excellent stereocon-
(Table 2, entries, 4, 5, 7, and 8). Use of solid Na2CO3 (no
water) decreased the reaction rate and ee value (Table 2,
entry 2, 720 min, 52% ee). A slightly weaker base Li2CO3
improved the reaction conversion and maintained the ee
value (Table 2, entry 3, 88% yield, 77% ee). A slow conver-
sion was observed when NaHCO3 was used (Table 2,
entry 9). This evidence prompted us to select aqueous
Li2CO3 as the base media of choice and the further optimi-
zation of the standard reaction parameters was carried out.
For further optimization, solvent, as well as reaction tem-
perature, were examined (Table 3). The initial solvent
trol, and
a flexible skeleton. Catalyst I, II, and IV
(Scheme 2) exhibited high stereoselectivity in several Mi-
chael addition reaction-triggered cascade processes. Un-
fortunately, catalyst I gave a poor result in this catalytic pro-
cess (Table 1, 38% yield, 29% ee). Catalyst III, a similar an-
alogue of catalyst I but with a switch of amine and thiourea
functional groups, showed good enantioselectivity (Table 1,
50% yield, 77% ee). While the further improvements were
ongoing, we noticed that the dihedral angle between the two
functional groups on the catalyst was a critical factor in con-
trolling the stereochemistry. Consequently, catalysts II and
IV (Scheme 2) were synthesized with the amine and thiour-
ea group anti to each other. In contrast to the structure of
catalysts I and III, catalysts II and IV just have a chiral in-
version on the amine part, respectively, but maintain all the
other features. Results showed that catalysts II and IV were
not the best catalysts (Table 1, entries 2 and 4, 9 and
30% ee, respectively). Meanwhile, we examined catalyst V,
a l-tert-leucine derivative; however, only a moderate result
was generated (Table 1, entry 5, 61% yield, 44% ee).
Having failed to find a catalyst more promising than III, a
base screen was then performed.
Table 3. Evaluation of other parameters.[a]
Entry
Solvent
T
c
A
t
Yield
[%][c]
ee
[b]
[oC]
[molLÀ1
]
[min]
[%][d]
1
2
3
4
5
6
7
8
CH2Cl2
C2H2Cl2
Toluene
PhCF3
Anisole
iPrOH
DMSO
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
RT
RT
RT
RT
RT
RT
RT
0
0
0
0
À10
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
10
10
60
60
60
60
60
10
10
30
120
180
88
78
72
80
67
67
77
89
90
94
94
92
77
71
76
72
78
27
3
79
83
88
83
83
9
0.1
10
11
12
0.05
0.025
0.05
Optimization studies highlighted the ability of a range of
bases, either solid or an aqueous solution (Table 2), to gen-
erate the N-Boc imine in situ. Stronger aqueous bases
K2CO3, Cs2CO3, LiOH, or KOH, did increase the conversion
to the desired product, but did not increase the ee value
[a] Reaction conditions: tert-butyl (2-hydroxyphenyl)(phenylsulfonyl)
methylcarbamate (1a, 0.1 mmol, 1.0 equiv), malononitrile 2 (0.11 mmol,
1.1 equiv), Li2CO3 (0.1m, 0.12 mmol, 1.2 equiv), and catalyst III
(10 mol%). [b] Concentration. [c] Yield of isolated product after column
chromatography. [d] Enantiomeric excess (ee) was determined by HPLC.
Table 2. Base effect.[a]
screen was performed at room temperature. In general, less
polar solvents are crucial for obtaining good enantioselectiv-
ities at room temperature (Table 3, entries 1–5, 71–78% ee).
For high polar solvents, relatively lower enantioselectivities
were obtained due to the potential removal of the hydro-
gen-bonding interaction between the substrates and the cat-
alyst (Table 3, entries 6 and 7, 20 and 45% ee, respectively).
Finally, CH2Cl2 gave the best results with respect to reaction
rate, yield and ee value (Table 3, entry 1). To further opti-
mize the reaction, we varied the reaction temperature and
the concentration of Li2CO3. The results showed that the
enantioselectivity can be enhanced by an appropriate tem-
perature and base concentration (Table 3, entry 10, 30 min,
94% yield, 88% ee).
Under the optimized reaction conditions, the generality of
our cascade process was examined by using various in situ
generated aromatic N-carbamoyl a-imino ethyl glyoxylates
1a–i (Scheme 3). Aromatic N-carbamoyl a-imino ethyl
glyoxylates having both electron-withdrawing (Scheme 3,
3b–d, 82–87% yield, 83–85% ee) and electron-donating sub-
Entry[a]
Base
t
Yield
[%][b]
ee
A
[%][c]
1
Na2CO3
Na2CO3
Li2CO3
K2CO3
10
720
10
10
10
30
2
50
74
88
70
77
86
71
82
85
77
52
77
76
74
74
73
71
68
2[d]
3
4
5
Cs2CO3
6
ACHTUNGTRENNUNG(NH4)2CO3
7
LiOH
8
9
NaOH
NaHCO3
2
180
[a] Reaction conditions: tert-butyl (2-hydroxyphenyl)(phenylsulfonyl)
methylcarbamate (1a, 0.1 mmol, 1.0 equiv), malononitrile 2 (0.11 mmol,
1.1 equiv), base (0.1m, 0.12 mmol, 1.2 equiv), and catalyst III (10 mol%)
in CH2Cl2 (0.2 mL) at RT. [b] Yield of isolated product after column
chromatography. [c] Enantiomeric excess (ee) was determined by HPLC.
[d] 0.12 mmol of dry Na2CO3 was used.
Chem. Eur. J. 2011, 17, 7781 – 7785
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J. Wang et al.
Scheme 3. Substrate scope under the optimized conditions; see Table 3,
entry 10.
Scheme 4. Proposed catalytic cycle.
stituents (Scheme 3, 3e–h, 81–89% yield, 74–89% ee) could
be applied to this transformation; the substitution pattern of
the arene had limited influence on the enantioselectivity of
the reaction. In addition, it was possible to use carbobenzy-
loxy (Cbz) as protecting group in this reaction (Scheme 3,
3i, 82% yield, 84% ee). The absolute configuration of the
products was determined by single-crystal X-ray analysis of
3d (Figure 1).[14]
egy demonstrated here could be applied to other asymmet-
ric transformations to efficiently assemble chiral materials
with complex structures. Further elaboration of the products
to other types of biologically active compounds and the po-
tential application of the catalytic system are now ongoing
in our group.
Experimental Section
General procedure: To a solution of tert-butyl (2-hydroxyphenyl) (phe-
nylsulfonyl)methylcarbamate 1a (0.1 mmol, 1.0 equiv), malononitrile 2
(0.11 mmol, 1.1 equiv) and catalyst III (0.01 mmol) in CH2Cl2 (2.0 mL) at
08C, was added chilled lithium carbonate aqueous solution (0.1m,
0.12 mmol, 1.2 equiv) in one portion. The resulting biphasic reaction mix-
ture was kept stirring at 08C for 0.5 h. Then the reaction mixture was di-
luted with water (2 mL) and extracted with ethyl acetate (5 mL, three
times). Organic layers were combined, washed with brine (6 mL), dried
over anhydrous sodium sulfate, and concentrated under reduced pressure.
Crude product was purified by silica gel flash chromatography, eluted by
hexane/EtOAc=3:1 to afford the desired product 3a as white solid
(27.0 mg, 94% yield). 1H NMR (500 MHz, CDCl3): d=7.49 (s, 1H),
7.33–7.22 (m, 1H), 7.16 (t, J=7.5 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 5.64
(d, J=7.9 Hz, 1H), 4.94 (d, J=7.9 Hz, 1H), 4.87 (m, 2H), 1.46 ppm (s,
9H); 13C NMR (125 MHz, CDCl3): d=160.57, 155.07, 148.38, 129.18,
129.11, 125.35, 121.35, 118.96, 116.13, 80.00, 58.56, 43.90, 28.30 ppm;
HRMS (ESI): m/z: calcd for C15H17N3O3Na: 310.1162 [M+Na+]; found
310.1169. HPLC (Chiralpak IA, isopropanol/hexane=20:80, flow rate:
1.0 mLminÀ1, l=254 nm): Rt (major)=7.7 min, Rt (minor)=14.7 min;
ee=88%; [a]2D5 =À63.2 (c=0.79 in acetone).
Figure 1. X-ray crystal structure of 3d.
Our postulated reaction pathways are summarized in
Scheme 4. In the initial step, an elimination of compound 1a
causes formation of the intermediate imine A under the
presence of Li2CO3. The subsequent Mannich reaction of in-
termediate A with malononitrile 2 forms the intermediate B
catalyzed by indane-amine–thiourea III. Then, the intramo-
lecular oxa-nucleophilic addition of nitrile group leads to
the intermediate C. Finally, intermediate C undergoes a tau-
tomerization to offer the desired compound 3a.
In summary, we have developed an efficient and conven-
ient cascade process for the synthesis of 2-amino-4H-chro-
menes in high to excellent yields (81–94%) and with good
to high enantioselectivities (74–89% ee). This protocol pro-
ceeded through a Mannich cyclization–tautomerization cas-
cade sequence. We hope that the catalytic system and strat-
Acknowledgements
The authors acknowledge the National University of Singapore for finan-
cial support (Academic Research Grant, nos: R143000408133,
R143000408733 and R143000443112).
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Expeditious Assembly of 2-Amino-4H-chromene Skeleton
COMMUNICATION
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Keywords: asymmetric catalysis
chromene · indane · organocatalysis · thiourea
·
cascade reaction
·
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[14] CCDC-818689 (3d) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
Received: March 26, 2011
Revised: April 28, 2011
Published online: May 25, 2011
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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