Enantioselective dearomative [3+2] cycloaddition of 2-nitrobenzofurans with aldehyde-derived Morita-Baylis-Hillman carbonates

Article abstract of DOI:10.1039/c9cc04542b

The phosphine-catalyzed asymmetric dearomative [3+2] cycloaddition of 2-nitrobenzofurans with aldehyde-derived Morita-Baylis-Hillman (MBH) carbonates or allenoate was developed. The reaction with MBH carbonates resulted in a series of cyclopentabenzofurans containing three contiguous stereocenters with good to high yields, diastereoselectivities and enantioselectivities. The use of allenoate also gave the target product with moderate enantioselectivity.

Full text of DOI:10.1039/c9cc04542b

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DOI: 10.1039/C9CC04542B
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Enantioselective Dearomative [3+2] Cycloaddition of 2-
Nitrobenzofurans with Aldehyde-Derived Morita−Baylis−Hillman
Carbonates
Received 00th January 20xx,
Accepted 00th January 20xx
Xin-He Yang, Jian-Ping Li, Dong-Chao Wang,* Ming-Sheng Xie, Gui-Rong Qu and Hai-Ming Guo*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The phosphine-catalyzed asymmetric dearomative [3+2] dihydrobenzofuran motif. Very recently, Yuan and co-workers
cycloaddition of 2-nitrobenzofurans with aldehyde-derived developed the β-isocupreidine-catalyzed dearomative [3+2]
Scheme 1. Dearomative [3+2] Cycloaddition of 2-Nitrobenzofurans
with MBH Carbonates and Allenoates
Morita−Baylis−Hillman carbonates or allenoate was developed.
The reaction with MBH carbonates resulted in a series of
cyclopentabenzofurans containing three contiguous stereocenters
with good to high yields, diastereoselectivities and
enantioselectivities. The use of allenoate also gave the target
product with moderate enantioselectivity.
Me
Me
Et
N
Ph
N
O
O
O
CO2Et
H
BocO
CO2Et
N
(A)
Yuan (2019)
(ref. 7)
N
O
NR3*
NO2
NO2
Ph2P
O
Catalytic asymmetric dearomatization (CADA) reactions are a
powerful tool for the rapid assembly of enantio-enriched
three-dimensional polycyclic molecules from readily available
aromatic substrates.1 The CADA reactions of electron-rich
heteroarenes (e.g. indole, pyrrole, furan, etc) have been
CO2tBu
O
H
BocO
CO2tBu
N
H
But
(B) Zhang (2019)
(ref. 8)
PR3*
O
NO2
(C) This work
Ar
H
Ar
CO2Et
successfully
nucleophilicity.2
developed
based
on
their
inherent
nitro-
CO2Et
BocO
O
However, electron-deficient
C6
NO2
P
Ph
or
CO2Bn
NO2
O
+
or
DIOP
C1
heteroarenes are the challenging substrates for CADA
reaction. Since Arai3a and Trost3b reported the asymmetric
dearomative cycloadditions of nitroarenes in 2014, the CADA
reactions of nitro-substituted-indoles were well devloped.4
Meanwhile, the dearomative cycloadditions of 2-
nitrobenzofurans were beginning to get attention. In 2017,
You and co-workers5 described the asymmetric dearomative
[3+2] cycloaddition of 2-nitrobenzofurans with epoxybutene
CO2Bn
H
*
C6
*
O
NO2
cycloadditon of 2-nitrobenzofurans with isatin-derived
Morita−Baylis−Hillman (MBH) carbonates (Scheme 1A).7
Additionally, the group of Zhang demonstrated the phosphine-
catalyzed asymmetric dearomative [3+2] cycloaddition of 2-
nitrobenzofurans with formaldehyde-derived MBH carbonates
(Scheme 1B).8 However, under Zhang’s reaction conditions,
the substituted MBH carbonates and allenoates were not
compatible with the dearomative [3+2] cycloaddition of 2-
nitrobenzofurans. Yuan and co-workers9 also reported the
Ph2PMe-catalyzed dearomative [3+2] annulation of 2-
nitrobenzofurans with allenoates. The cycloadditon reactions
of MBH adducts have emerged as one of the most-powerful
strategies used to prepare functionalized carbo- and
heterocycle.10 However, substituted MBH carbonates and
allenoates remain the challenging substrates for the
phosphine-catalyzed enantioselective dearomative [3+2]
cycloaddition of 2-nitrobenzofurans.
for
the
straightforward
construction
of
chiral
tetrahydrofurobenzofurans for the first time. Later, Yuan and
co-workers6 investigated the CADA reaction of 2-
nitrobenzofurans with 3-isothiocyanato oxindoles for the
preparation
of
spirooxindoles
containing
a
2,3-
Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Key
Laboratory of Green Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine
Chemicals, School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan Province 453007, China.
E-mail: wangdc@htu.edu.cn; ghm@htu.edu.cn.
Electronic Supplementary Information (ESI) available: Experimental procedures,
spectral data of new compounds, original NMR spectra HPLC copies, and
crystallographic data. CCDC 1919097 for 3ad, 1919015 for 3ao. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/x0xx00000x
Benzo-fused polycyclic heterocyclic units are the core
structures commonly found in various natural products,
bioactive molecules, and drugs.11 In this context, searching for
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by 1H NMR analysis of the crude reaction mixture. cDetermined by chiral HPLC
the efficient synthesis routes to construct this type of scaffold
is in great demand. In recent years, our group has been
exploring the dearomative cycloaddition reactions of
heteroarenes.12 We have recently reported the Cu(I)-catalyzed
asymmetric dearomative 1,3-dipolar cycloaddition of 2-
nitrobenzofurans with azomethine ylides for the synthesis of
pyrrole-fused hydrobenzofurans.12e Herein, we report the
synthesis of chiral cyclopentabenzofurans via the asymmetric
dearomative [3+2] cycloaddition of 2-nitrobenzofurans with
aromatic aldehyde-derived MBH carbonates or allenoates
(Scheme 1C).
Initially, 2-nitrobenzofuran 1a and benzaldehyde-derived
MBH carbonates 2a were employed as the model substrates
for the optimization of reaction conditions. As shown in Table
1, diverse chiral phosphine catalysts were first examined.
When biphosphine catalysts C1-C4 were used as the catalysts
in CH2Cl2 at room temperature, the dearomatized adduct 3aa
View Article Online
analysis. d2a (0.15 mmol). e2a (0.12 mmol). fC6 (7.5 mol%). gC6 (5 mol%).
DOI: 10.1039/C9CC04542B
was obtained in 14-77% yields but with poor
enantioselectivities (Table 1, entries 1-4). The use of
bifunctional phosphine catalyst C5 afforded the product 3aa
with moderate enantioselectivity, but low yield (Table 1, entry
5). The spirocyclic phosphine catalyst C6 exhibited the highest
catalytic activity and gave the desired product in 84% yield and
91% ee (Table 1, entry 6). Ferrocene phosphine catalyst C7
could hardly catalyze the desired cycloaddition reaction (Table
1, entry 7). Subsequently, the screening of solvents and
temperatures (Table 1, entries 8–13) showed that the isolation
of the desired product 3aa could be achieved in 93% yield and
o
97% ee (Table 1, entry 12) when CHCl3 was employed at 0 C.
When the amount of catalyst or MBH carbonates 2a was
reduced, the ee value of the product remained unchanged but
the yield was decreased (Table 1, entries 14-17). Finally, the
following optimal reaction conditions were obtained: 10 mol%
of C6, 1.0 equivalent of 1a, and 2.0 equivalents of 2a in CHCl3
at 0 oC (Table 1, entry 12).
Table 1. Optimization of Reaction Conditionsa
Ph
Ph
H
O
catalyst (10 mol %)
solvent., N2, T, 12 h
CO2Et
CO2Et
NO2
+
BocO
O
Scheme 2. Substrate Scope for MBH carbonates a
NO2
3aa
1a
2a
R2
Ph
P
OCH3
Ph
H
Ph2P
PPh2
OBoc
Ph
C6
(10 mol%), CHCl3
N2, 0 oC, 12 h
CO2R1
NO2
+
R1O2C
P
R2
O
O
P
O
Ph2P
PPh2
P
O
NO2
3aa-3ao
Me
Ph
Ph
H3CO
Ph
1a
2a-2o
C1
C4
C2
C3
PPh2
N
PPh2
O
HN
O
P
Ph
H
H
H
Fe
CO2Et
CO2Me
CO2Bn
H
CO2Me
O
O
O
F3C
CF3
NO2
NO2
3ab
NO2
O
NO2
3ad
C7
C5
C6
3aa
3ac
93% yield, 97% ee
(87% yield, 97% ee)b
92% yield, 94% ee
(89% yield, 94% ee)b
88% yield, 93% ee
92% yield, 94% ee
Entry
Cat.
C1
C2
C3
C4
C5
C6
C7
C6
C6
C6
C6
C6
C6
C6
C6
C6
C6
C6
C6
C6
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
T
rt
MS
Yieldb (%)
14
eec (%)
41
22
-31
5
F
Cl
Br
CN
1
-
2
rt
-
77
H
H
H
H
CO2Me
CO2Me
CO2Me
CO2Me
3
rt
-
36
O
O
NO2
4
rt
-
33
O
O
NO2
NO2
3af
NO2
3ah
5
rt
-
15
61
91
--
3ae
3ag
86% yield, 97% ee
86% yield, 96% ee
87% yield, 94% ee
88% yield, 96% ee
(88% yield, 95% ee)b
6
rt
-
84
NO2
Cl
Cl
Cl
7
rt
-
NR
82
8
rt
-
91
93
90
92
97
96
96
96
95
94
95
97
94
Cl
CO2Me
H
H
H
H
CO2Me
CO2Me
CO2Me
9
CHCl3
THF
rt
-
89
O
O
O
O
NO2
NO2
NO2
3al
NO2
10
11
12
13
14
15
16
17d
18e
19f
20g
rt
-
79
3aj
3ai
3ak
Toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
rt
0 oC
-
74
88% yield, 96% ee
85% yield, 96% ee
92% yield, 94% ee
90% yield, 96% ee
(88% yield, 96% ee)b
Me
Me
-
93
-20 oC
0 oC
0 oC
0 oC
0 oC
0 oC
0 oC
0 oC
-
3 Å
4 Å
5 Å
-
48
H
H
CO2Me
CO2t-Bu
H
91
CO2Me
O
O
NO2
NO2
89
O
NO2
93
3am
3an
96% yield, 95% ee
3ao
90% yield, 97% ee
94% yield, 96% ee
72
aReaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), and catalyst (10 mol%) in
CHCl3 (1.0 mL), N2, 12 h, and 0 oC. Yields of isolated product. For all products, d.r.
value was >20:1, as determined by 1H NMR analysis of the crude reaction
mixture. The ee values were determined by chiral HPLC analysis. bThe reaction
was performed on 0.3 mmol scale.
-
51
-
74
-
39
aUnless otherwise noted, reaction conditions were: 1a (0.1 mmol), 2a (0.2 mmol),
and catalyst (10 mol%) in solvent (1.0 mL), N2, and 12 h at the corresponding
temperature. bYields of isolated product. The d.r. value was >20:1, as determined
Under the optimal reaction conditions, various aromatic
aldehyde-derived MBH carbonates 2a-2m, were tested by
2 | J. Name., 2012, 00, 1-3
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reacting with 2-nitrobenzofuran 1a (Scheme 2). Different ester product 5 with 38% yield and up to 72% ee was obtained when
View Article Online
o
DOI: 10.1039/C9CC04542B
groups had slight effect, and the corresponding reactions gave C1 and 4 Å MS in PhCH3 at 0 C were employed (Scheme 4). As
the desired products with excellent yields and suggested by reviewer, the reaction on 0.5 mmol scale was
enantioselectivities (88-93% yields and 93-97% ee, Scheme 2, performed and resulted in product 5 with 36% yield and up to
3aa-3ac). The effect of the groups at the para position of 70% ee. The structure of product 5 was assigned according to
benzene ring (3ad-3ai) was subsequently investigated. Both the literature.9a
the electron-rich and electron-deficient substituents could
The transformations of the optically pure product 3aa were
tolerate the reaction, therefore resulted in the corresponding carried out according to the literature methods.5a,6 Firstly, the
adducts with excellent yields (85-92%) and ee values (94-97%). denitrated compound 6a was obtained in 73% yield and 94%
The reaction of 2-chloro and 3-chloro-substituted MBH ee (Scheme 5A). After that, by using ruthenium trichloride and
carbonates 2j and 2k gave the desired products 3aj (88% yield, sodium periodate, the dihydroxylation of 3aa afforded the
96% ee) and 3ak (88% yield, 96% ee). The reaction of corresponding product 6b in 51% yield and 96% ee, which is
disubstituted MBH carbonates 2l and 2m proceeded smoothly considered a virtually pure stereoisomer (Scheme 5B).
with 2-nitrobenzofurans 1a, generating the desired products
3al and 3am with excellent yields and enantioselectivities.
Moreover, formaldehyde-derived MBH carbonates 2n and 2o
also gave the corresponding compounds with excellent results
Scheme 4. Dearomative [3+2] Cycloaddition of 2-Nitrobenzofurans
with Allenoate.
CO2Bn
H
C1
(20 mol%), 4 Å MS (80 mg)
NO2
*
•
CO2Bn
(3an with 96% yield and 95% ee, 3ao with 94% yield and 96%
ee). Unambiguously, the absolute configurations of the
products 3ad and 3ao, determined by single-crystal X-ray
diffraction analysis, were (1R,3aR,8bR) and (3aR,8bR),
respectively.13
Subsequently, reactions of 2-nitrobenzofurans 1 containing
diverse groups were carried out under the optimal reaction
conditions. As shown in Scheme 3, 2-nitrobenzofurans 1
bearing various substituents, either with electron-withdrawing
or electron-donating group, could react smoothly with 2a to
afford the corresponding cycloadducts 3ba-3ha in good yields
(67-94%) and excellent enantioselectivity (90-99% ee).
toluene (2.0 mL), 0 oC, N2, 12 h
*
O
O
NO2
4
5
1a
l
0.2 mmol scale: 38% yield, 72% ee
0.5 mmol scale: 36% yield, 70% ee
Scheme 5. Transformation Reactions of Dearomatized Products
Ph
Ph
H
H
Bu3SnH (3.0 eq), AIBN (1.5 eq)
toluene, 80 oC, 30 min
CO2Et
CO2Et
(A)
O
O
H
NO2
6a
73% yield, 94% ee
3aa
0.2 mmol, 97% ee
Ph
Ph
H
H
OH
RuCl3·3H2O (10 mol %), NaIO4 (2.0 eq)
EA/CH3CN/H2O, 30 min
CO2Et
(B)
CO2Et
O
O
OH
NO2
NO2
3aa
Scheme 3. Substrate Scope for 2-Nitrobenzofuran Derivatives.a
6b
51% yield, 3:1 dr, 96% ee
0.2 mmol, 97% ee
Ph
H
OBoc
Ph
C6
(10 mol%), CHCl3
N2, 0 oC, 12 h
R3
CO2Et
Conclusions
R3
NO2
+
EtO2C
O
O
NO2
In summary, we have successfully developed a highly
enantioselective dearomative [3+2] cycloaddition reaction of
2-nirtobenzofurans with aldehyde-derived MBH carbonates.
Using 10 mol% (S)-SITCP as a catalyst, various 2,3-fused
1b-1h
H3CO
3ba-3ha
2a
Ph
Ph
Ph
F
O2N
H
H
O
H
CO2Et
CO2Et
CO2Et
O
O
NO2
3ba
72% yield, 94% ee
NO2
NO2
cyclopentannulated
dihydrobenzofurans
with
three
3da
3ca
continuous stereocenters were obtained in good yields with
high enantioselectivities. The reaction features a general scope
for both MBH carbonates and 2-nitrobenzofurans.
Furthermore, the use of allenoates in the dearomative [3+2]
cycloaddition reaction of 2-nirtobenzofurans also resulted in
the target products with moderate enantioselectivity.
We are grateful for the financial support from the National
Natural Science Foundation of China (21672055 and
U1604283), the 111 Project (D17007), and the Key Scientific
Research Projects in University of Henan Province
(18A150007).
67% yield, 90% ee
CO2Et
84% yield, 95% ee
(85% yield, 95% ee)b
Ph
Ph
H
H
CO2Et
H3CO
H3C
O
O
NO2
NO2
3ea
73% yield, 96% ee
3fa
78% yield, 90% ee
Ph
H
Ph
H
CO2Et
CO2Et
O
O
NO2
NO2
H3CO
Br
3ga
3ha
94% yield, >99% ee
81% yield, 97% ee
aReaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), and catalyst (10 mol%) in
CHCl3 (1.0 mL), N2, 12 h, and 0 oC. Yields of isolated product. For all products, d.r.
value was >20:1, as determined by 1H NMR analysis of the crude reaction
mixture. The ee values were determined by chiral HPLC analysis. bThe reaction
was performed on 0.3 mmol scale
Conflicts of interest
There are no conflicts to declare.
We also extended the use of the enantioselective
dearomative [3+2] cycloaddition of 2-nitrobenzofurans to the
challenging substrate allenoate 4. After screening of various
solvents and chiral phosphine catalysts (see Table S1 in SI), a
ORICD
Dong-Chao Wang: 0000-0002-5037-4727
Ming-Sheng Xie: 0000-0003-4113-2168
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Hai-Ming Guo: 0000-0003-0629-4524
Notes and references
1
For a book, see: (a)S.-L. You, Asymmetric Dearomatization
Reactions, Wiley-VCH, Weinheim, 2016; for selected recent
reviews, see: (b) C.-X. Zhuo, W. Zhang and S.-L. You, Angew.
Chem., Int. Ed., 2012, 51, 12662; (c) C.-X. Zhuo, C. Zheng and
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S.-L. You, Chem, 2016, 1, 830; (e) W.-T. Wu, L. Zhang and S.-L.
You, Chem. Soc. Rev., 2016, 45, 1570; (f) Q. Ding, X. Zhou and
R. Fan, Org. Biomol. Chem., 2014, 12, 4807; (g) W. Sun, G. Li,
L. Hong and R. Wang, Org. Biomol. Chem., 2016, 14, 2164. for
selected recent examples, see: (h) Q. Cheng, Y. Wang and S.-
L. You, Angew. Chem., Int. Ed., 2016, 55, 3496; (i) F. Jiang, D.
Zhao, X. Yang, F.-R. Yuan, G.-J. Mei and F. Shi, ACS Catal.,
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Nemoto, J. Am. Chem. Soc., 2017, 139, 10188; (k) Y. Xu, F.
Chang, W. Cao, X. Liu and X. Feng, ACS Catal., 2018, 8, 10261;
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W. Hernandez, U. Klöckner, J. Pospech, L. Hauss and D.
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5
6
7
8
9
2
For selected recent examples, see: (a) C. Shen, R.-R. Liu, R.-J.
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13 CCDC 1919097 (3ad), 1919015 (3ao) contain 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.ac.uk/data_request/cif.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9CC04542B
Enantioselective Dearomative [3+2] Cycloaddition of
2-Nitrobenzofurans with Aldehyde-Derived Morita−Baylis−Hillman
Carbonates
Xin-He Yang, Jian-Ping Li, Dong-Chao Wang,* Ming-Sheng Xie, Gui-Rong Qu and Hai-Ming
Guo*
Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Key Laboratory of
Green Chemical Media and Reactions, Ministry of Education, Collaborative Innovation Center of
Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical
Engineering, Henan Normal University, Xinxiang, Henan Province 453007, China.
E-mail: wangdc@htu.edu.cn; ghm@htu.edu.cn.
The phosphine-catalyzed asymmetric dearomative [3+2] cycloaddition of 2-nitrobenzofurans with
aldehyde-derived MBH carbonates or allenoate was developed.
Ar
H
Ar
R
CO2Et
CO2Et
BocO
+
O
NO2
or
23 examples
up to 96% yield
up to >99% ee
PR3*
or
CO2Bn
R
NO2
O
CO2Bn
H
*
*
O
NO2