C-H Oxidation/Michael Addition/Cyclization Cascade for Enantioselective Synthesis of Functionalized 2-Amino-4H-chromenes

Article abstract of DOI:10.1021/acs.orglett.5b03148

A streamlined method for the enantioselective synthesis of 2-amino-4H-chromenes from readily available 2-alkyl-substituted phenols and active methylene compounds bearing a cyano group with up to 97% ee is presented. This reaction is a cascade procedure including manganese dioxide mediated C-H oxidation for the generation of o-quinone methides and bifunctional squaramide-catalyzed Michael addition/cyclization.

Full text of DOI:10.1021/acs.orglett.5b03148

Letter
pubs.acs.org/OrgLett
C−H Oxidation/Michael Addition/Cyclization Cascade for
Enantioselective Synthesis of Functionalized 2‑Amino‑4H‑chromenes
†
†
†
†
,†,‡
Bo Wu, Xiang Gao, Zhong Yan, Mu-Wang Chen, and Yong-Gui Zhou*
†State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, P. R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
*
S Supporting Information
ABSTRACT: A streamlined method for the enantioselective synthesis
of 2-amino-4H-chromenes from readily available 2-alkyl-substituted
phenols and active methylene compounds bearing a cyano group with
up to 97% ee is presented. This reaction is a cascade procedure
including manganese dioxide mediated C−H oxidation for the
generation of o-quinone methides and bifunctional squaramide-
catalyzed Michael addition/cyclization.
he development of efficient and novel chemical reactions
with malononitrile, giving 2-amino-3-cyano-4H-chromenes with
excellent enantioselectivity (eq 1, Scheme 1).
12m
T
that allow the rapid and direct construction of complex
and diversified molecules from available and inexpensive
starting materials stands at the forefront of synthetic chemistry,
Scheme 1. Synthesis of Chiral 2-Amino-4H-chromenes via o-
Quinone Methides
1
and it also has impressive significance in industrial processes.
One of the most powerful methods to realize these goals is the
application of cascade reactions which carry out multiple
transformations in a single step, accompanied by undeniable
benefits including atom economy, economy of labor, and
2
sustainability of resources. In particular, these cascade
strategies are useful and effective in the total synthesis of
2c−e,3
natural products and bioactive molecules.
The significant
importance of the 2-amino-4H-chromene scaffold in bio-
logically active molecules, natural products, and synthetic
4
drugs has motivated chemists to develop various methods for
the asymmetric synthesis of 2-amino-4H-chromenes, involving
5
organocatalytic tandem Michael addition/cyclization, Mannich
6
cyclization/tautomerization cascade sequences, three-compo-
7
nent cascade reaction, conjugate addition of nitroalkanes to 2-
8
iminochromenes, and metal complex catalyzed cascade
9
reactions. Although considerable progress has been made in
the formation of chiral 2-amino-4H-chromenes, there are
several disadvantages including low catalytic efficacy, poor
stereoselectivity, and unsatisfactory substrate scope. Hence, the
development of facile and enantioselective approaches to such
scaffolds with a broad substrate scope is still highly desirable.
o-Quinone methides (o-QMs) are a prominent class of
However, the substrate scope was limited. Fochi’s group and
our groups independently described a similar bifunctional
squaramide-catalyzed reaction of o-QMs generated in situ from
2-(1-arylsulfonyl-alkyl)phenols with active methylene com-
pounds bearing a cyano group under basic conditions for the
preparation of chiral 2-amino-4H-chromenes (eq 2, Scheme
10
intermediates in a large number of biological processes and
1
1
are recognized as a highly reactive chemical species. In this
decade, a series of organocatalytic enantioselective reactions of
12n,o
1
).
2
1
2,13
-Alkyl-substituted phenol derivatives are easily available and
o-QMs
have been reported due to their inherent reactivity.
14
can be oxidized to generate o-QM intermediates. Addition-
ally, we have also disclosed that o-QM intermediates could be
Organocatalytic formal [4 + 2] cycloaddition of o-QMs with
active methylene compounds bearing a cyano group is also a
concise method for the synthesis of chiral 2-amino-4H-
chromenes. Recently, the Han group reported quinine-
catalyzed annulation of the electron-rich and stable o-QMs
Received: October 30, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03148
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
generated in situ from 2-alkyl-substituted phenol derivatives by
metal oxidant mediated oxidation, which could be rapidly
trapped by the sulfur ylides to allow stereoselective synthesis of
Table 1. Optimization of Reaction Conditions
14g
trans-2,3-dihydrobenzofurans.
Therefore, we envisioned a
metal oxidant mediating the C−H oxidation of 2-alkyl-
substituted phenol derivatives to produce the o-QM inter-
mediates that underwent asymmetric Michael addition with
active methylene compounds bearing a cyano group via an
organocatalytic system followed by cyclization for the
construction of optical active 2-amino-4H-chromenes. The
combination of a metal oxidant and organocatalyst in this
cascade reaction could effectively impede background reactions
and ensure high enantioselectivity. Generally, a simple
combination of metal oxidant and organocatalyst remains
challenging in organic chemistry. Organocatalysts experience
15
difficulty in tolerating highly oxidizing conditions. Moreover,
a metal oxidant might bind tightly with the organocatalyst,
16
which causes the deactivation of the organocatalyst. Herein,
we reported cascade C−H oxidation/Michael addition/
cyclization reactions with the combination of a metal oxidant
and an organocatalyst for the enantioselective synthesis of 2-
amino-4H-chromenes (eq 3, Scheme 1).
At the outset, 2-alkyl-substituted phenol 1a and malononi-
trile 2a (1.2 equiv) were chosen as model substrates. The
oxidant had a significant influence in the reaction and triggered
the generation of o-QM intermediates. In this respect, we
initially turned our attention to the evaluation of oxidants. To
our delight, the anticipated product 2-amino-4H-chromene 3a
was obtained in 81% isolated yield and 78% ee in the presence
of silver oxide and a catalytic amount of quinine (Table 1, entry
b
c
entry
cat.
oxidant
solvent
yield (%) ee (%)
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
Ag O
2
CH Cl2
81
28
25
91
97
91
75
72
75
63
97
94
97
97
94
97
78
10
72
78
82
75
82
82
81
28
68
47
91
89
81
94
2
AgOAc
CH Cl2
2
K Fe(CN)6
3
CH Cl2
2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
CH Cl2
2
CHCl3
ClCH CH Cl
2
2
benzene
toluene
p-xylene
THF
10
11
12
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
1
). However, other metal oxidants, AgOAc and K Fe(CN) ,
3 6
13
exhibited lower reactivity (Table 1, entries 2 and 3). Organic
oxidants such as DDQ and PhI(OAc)2 afforded mixed
products. Additionally, the yield could be further improved,
1
4
15
d
1
6
4d
and the enantioselectivity was maintained by using MnO as the
a
2
Conditions: 1a (0.10 mmol), 2a (0.12 mmol), cat. (0.01 mmol),
oxidant (2.0 equiv), while MnO was used in 4.0 equiv, solvent (1.5
oxidant (Table 1, entry 4). Subsequently, various solvents were
extensively examined, and it was found that solvent effect
played a crucial role in the reactivity and enantioselectivity.
2
b
c
d
mL), 30 °C. Isolated yields. Determined by chiral HPLC. Catalyst
loading was reduced to 5 mol %.
Among them, CHCl proved to be a suitable solvent in view of
3
the excellent yield and good enantioselectivity (Table 1, entries
1m could also be oxidized to generate o-QMs and reacted with
malononitrile to afford the corresponding adducts in high yield
and enantioselectivity. Furthermore, a train of active methylene
compounds bearing a cyano group proceeded successfully,
achieving moderate to good yields and excellent enantiose-
lectivities. It is worth noting that when the substituents R were
alkyl groups, mixed products were obtained. The absolute
configuration of compounds 3a and 3k was determined to be S
by comparison of the specific rotations with the reported
5
−10). Next, a series of organocatalysts were explored.
Cinchona alkaloid-based thiourea catalysts 4b and 4c provided
disappointing results with moderate enantioselectivity (Table 1,
entries 11 and 12). Gratifyingly, quinine-based squaramide
catalyst 4d gave the best enantioselectivity (91% ee) (Table 1,
entry 13). Satisfactorily, no decrease in enantioselectivity and
yield was observed when the catalyst loading was reduced to 5
mol % (Table 1, entry 16).
12m,o
With the aforementioned optimal reaction conditions, we
next explored the substrate scope of the current cascade
reaction between 2-alkyl-substituted phenols 1 and active
methylene compounds bearing a cyano group 2. As
summarized in Scheme 2, in all cases, the reaction performed
very well, delivering the corresponding chiral 2-amino-4H-
chromenes in good yields and high enantioselectivities. For 2-
alkyl substituted sesamols 1a−1g, electronic and steric
properties had no obvious influence on the enantioinduction.
Notably, vinyl substrates 1h and 1j were favorable reaction
partners, and the reaction proceeded smoothly with good
enantioselectivities and moderate yields. In addition, 2-alkyl-
substituted 4,5-dimethoxyphenol substrates 1i−k were em-
ployed in the cascade reaction with excellent enantiocontrol.
Interestingly, 2-alkyl-substituted 4-methoxynaphthols 1l and
literature data (see the Supporting Information).
Considering that both amino and cyano groups are versatile
functional groups, further derivatizations were conducted for
the production of biologically active molecules. The reaction of
(S)-6-amino-8-(4-methoxyphenyl)-8H-[1,3]dioxolo[4,5-g]-
chromene-7-carbonitrile 3a with cyclohexanone afforded
polycyclic compound 5 in 63% yield with 89% ee in the
presence of aluminum chloride according to the known
17
literature method (Scheme 3), which is a tacrine analogue
and acts as a potential drug for the treatment of Alzheimer’s
17b
disease.
In conclusion, we have developed a streamlined method for
the asymmetric synthesis of chiral 2-amino-4H-chromenes from
readily available 2-alkyl-substituted phenols and active methyl-
ene compounds bearing a cyano group with excellent
B
DOI: 10.1021/acs.orglett.5b03148
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Scope for the Synthesis of 2-Amino-4H-
Notes
chromenes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the financial support from National Natural
Science Foundation of China (21372220 and 21532006).
■
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AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: ygzhou@dicp.ac.cn.
C
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