Phosphine-Catalyzed Enantioselective Dearomative [3+2]-Cycloaddition of 3-Nitroindoles and 2-Nitrobenzofurans

Article abstract of DOI:10.1002/anie.201900036

Over the past years, the metal-catalyzed dearomative cycloaddition of 3-nitroindoles and 2-nitrobenzofurans have emerged as a powerful protocol to construct chiral fused heterocyclic rings. However, organocatalytic dearomative reaction of these two classe

Full text of DOI:10.1002/anie.201900036

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Accepted Article
Title: Phosphine-Catalyzed Enantioselective Dearomative [3 + 2]-
Cycloaddition of 3-Nitroindoles and 2-Nitrobenzofurans
Authors: Junliang Zhang, Huamin Wang, Junyou Zhang, and Youshao
Tu
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10.1002/anie.201900036
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Phosphine-Catalyzed Enantioselective Dearomative [3 + 2]-
Cycloaddition of 3-Nitroindoles and 2-Nitrobenzofurans
Huamin Wang+, Junyou Zhang+, Youshao Tu, and Junliang Zhang*
Abstract: Over past years, the metal-catalyzed dearomative
cycloaddition of 3-nitroindoles and 2-nitrobenzofurans have emerged
as a powerful protocol to construct chiral fused heterocyclic rings.
However, organocatalytic dearomative reaction of these two classes
of heteroarenes has become a long-standing challenging task.
Herein, we reported the first example of phosphine-catalyzed
asymmetric dearomative 3-nitroindoles and 2-nitrobenzofurans was
realized, which provide a new, facile, and efficient protocol for the
synthesis of chiral 2,3-fused cyclopentannulated indolines and
dihydrobenzofurans by reacting with allenoates and MBH
carbonates, respectively via dearomative [3 + 2]-cycloaddition.
atalytic
asymmetric
dearomatization
(CADA)
of
Cheteroarenes have emerged as one of the simple and
powerful strategies to access enantio-enriched polycyclic
frameworks.[1] Compared with the now well-received electron-
rich heteroarenes,[2] the CADA reactions of electron-deficient
nitro-heteroarenes was still very limited. In 2014, Arai et al.
reported the first example of asymmetric dearomative 1,3-dipolar
cycloaddition of electron-deficient indoles under the catalysis of
copper complex (Scheme 1a).[3] Later, Trost and co-workers[4]
Scheme 1. Asymmetric dearomatizative cycloaddition of 3-nitroindoles and 2-
nitrobenzofurans.
developed
a palladium/phosphoramidite catalyst system to
achieve the asymmtric dearomative [3C+2C]-cycloaddition
reaction of 3-nitroindole with trimethylenemethane (Scheme 1b).
The group of Yuan investigated a series of enantioselective
dearomative cycloaddition reactions of 3-nitroindoles and 2-
nitrobenzofurans (Scheme 1c and 1d).[5] Recently, You and co-
workers[6] disclosed a highly stereoselective palladium-catalyzed
asymmetric dearomative [3+2]-cycloaddition of nitrobenzofurans
with vinyl oxiranes (Scheme 1e). Shortly after, You,[7] Hou[8],
Shi[9] and Wang[10] independently realized the palladium-
catalyzed asymmetric dearomatization [3+2]-cycloaddition
reaction of 3-nitroindoles with vinyl oxiranes, vinylazirdines and
vinylcylopropanes (Scheme 1f). Despite these advances, reports
for organocatalytic asymmetric dearomative cycloadditions of 3-
nitroindoles and 2-nitrobenzofurans remain rare,[5a,5c] and
therefore is still highly desirable.
Figure 1. Relevant natural products and bioactive moleculars.
nitroindoles or 2-nitrobenzofurans has not been realized so far.
This may be attributed to: (1) the high energetic barrier in
dearomative cycloaddition;[14] (2) regioselectivity outcome of the
cycloaddition;
and
(3)
control
of
diastereo-
and
enantioselectivities. With regard to the high importance of chiral
indolines and benzodihydrofurans (Figure 1)[15] and in
continuation of our research program on asymmetric phosphine
catalysis,[16] we became interest in the phosphine-catalyzed
asymmetric dearomative cycloaddition of electron-deficient
heteroarenes such as 3-nitroindoles and 2-nitrobenzofurans. We
envisioned that zwitterionic intermediate (A or B), generated
from the addition of phosphine to allenoate 2, might react with 3-
nitroindoles 1 via consecutive conjugate addition−α- or γ-
addition, thereby leading to dearomative cycloaddition products
(Scheme 2). Herein we present the first example of phosphine-
catalyzed asymmetric dearomative [3+2]-cycloaddition of 3-
nitroindoles and 2-nitrobenzofurans with allenoates and MBH
carbonates, respectively, for highly enantioselective synthesis of
chiral indolines and benzodihydrofurans (Scheme 1g).
Over the past decades, asymmetric phosphine-catalysis have
emerged as a powerful tool for the construction of diverse chiral
skeletons.[11-13] However, to the best of our knowledge,
phosphine catalytic asymmetric dearomative cycloaddition of 3-
[*] H. Wang, J. Zhang, Prof. Dr. J. Zhang*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
School of Chemistry and Molecular Engineering, East China Normal
University
Shanghai, 200062 (P. R. China)
Prof. Dr. J. Zhang*
Department of Chemistry
Fudan University
2005 Songhu Road, Shanghai, 200438 (P. R. China)
Y. Tu
College of Chemistry and Life Science, Advanced Institute of Materials
Science, Changchun University of Technology,
2055 N. Yan'an Avenue, Changchun 130012 (P. R. China)
[+] These authors contributed equally to this work.
E-mail: junliangzhang@fudan.edu.cn
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
Scheme 2. Designed phosphine-catalyzed dearomative cycloaddition.
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10.1002/anie.201900036
Angewandte Chemie International Edition
COMMUNICATION
single-crystal X-ray diffraction analysis.[17] However, ester-
substituted nitroindole (1l) was less ideal, and the yield of the
reaction dropped dramatically (3l, 46%). In addition, the
allenoates bearing various ester group, namely methyl (2b),
benzyl (2c) and phenethyl (2d), were well applicabe to the
reaction, furnishing the cycloadducts 3n-3p in 75-98% yields
with 89-93% ees.
To test the above hypothesis, we investigated the reaction of
1-tert-butyloxycarbonyl-3-nitroindole 1a and allenoate 2a in
toluene with 15 mol% of chiral phosphine catalyst at room
temperature. When chiral sulfinamide derived Xiao-Phos P1-
P3[16a,c] were used as the catalyst, the desired dearomatization
product 2a could be obtained in 20-34% NMR yields and with
poor enantioselectivities (Table 1, entries 1-3). With the use of
Peng-Phos P4[16e] bearing a 3,5-bis(trifluoromethyl)benzamide
moiety as the catalyst, the yield and ee were elevated to 71%
yield and 51% ee, respectively (Table 1, entry 4). Chiral
dipeptidic phosphines P5-P7 could deliver better yield and ee
(Table 1, entries 5-7). With the use of P7, a systematic
screening of solvent, additives, reaction temperature and
catalyst loading was carried out (Table 1, entries 8-19). Finally,
the best reaction conditions were determined: 15 mol% P7,
mesitylene, 4 ÅMS, 0 °C, delivering 93% yield of 3a with 95% ee
(Table 1, entry 19).
Table 1. Optimization of reaction conditions[a]
Scheme 3. Substrate scope for cycloaddition of 3-nitroindoles with allenoates.
All reactions were carried on 0.1 mmol scale in mesitylene (1.0 mL) and used
2.0 equiv of 2, 15 mol% P7, 50 mg of 4 Å MS under N2, 0 oC; Isolated yields
were reported; Ee values were determined by chiral HPLC analysis.
Entry
1
Cat.
P1
P2
P3
P4
P5
P6
P7
P7
P7
P7
P7
P7
P7
P7
P7
P7
P7
P7
P7
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
Yield (%)[b]
20
Ee (%)[c]
19
-3
2
30
3
34
0
4
70
51
78
87
89
65
41
90
89
90
--
5
82
6
87
7
80
8
78
9
THF
50
10
11
12
13
14
15
16
17[d]
18[e]
19[e,f]
mesitylene
o-xylene
m-xylene
p-xylene
cumene
acetone
CHCl3
90
45
66
N.R.
N.R.
N.R.
65
Inspired by the above result, we then tried to extend this
phosphine-catalyzed asymmetric dearomative [3+2]-cyclo-
addition to the 2-nitrobenzofuran 4a, but failed (eq. 1). After
many attempts, we finally realized the phosphine catalyzed
asymmetric dearomative [3+2]-cycloaddition of 2-nitrobenzo-
furan 4a by the use of MBH carbonate 5a as the 3C-component
(eq. 2). The reaction scope was then investigated via variation of
2-nitrobenzofuran component under the catalysis of P3
(Scheme 4). In general, 2-nitrobenzofurans bearing electron-
donating and electron-withdrawing groups could undergo
dearomative cycloaddition smoothly to afford the corresponding
products 6b-6p in 81-98% yields with 95-98% ees. The absolute
configuration of the product was determined by X-ray crystal
structural analysis of 3b.[17] The variation of the ester moiety of
MBH carbonates was also investigated and the isopropyl MBH
carbonate still could deliver good result (6r, 96% ee), but the
corresponding methyl or benzyl MBH carbonates gave only
moderate yield of the products with relatively lower ee (6q and
--
--
69
89
91
95
mesitylene
mesitylene
mesitylene
15
50
93
[a] Unless otherwise specified, all reactions were carried on 0.1 mmol scale in
solvent (1.0 mL) and used 2.0 equiv of 2a, 15 mol% catalyst under N2, rt. [b]
Determined by 1H NMR. [c] Determined by HPLC analysis using a chiral
stationary. [d] 10 mol % catalyst used. [e] at 0 oC. [f] 50 mg of 4 Å MS.
The scope of this phosphine-catalyzed asymmetric
dearomative [3+2]-cycloaddition was then investigated (Scheme
3). Halogens (1b-3d, 3g) or electron-donating groups (1e-1k,
1m) at different positions on the indole ring are compatible,
delivering the desired products in 77-96% yields with up to 95%
ee. The absolute configuration of product 3f was determined via
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10.1002/anie.201900036
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COMMUNICATION
6s). Unfortunately, the substituted MBH carbonates could not be
compatible with this transformation under various conditions.
Scheme 5. Scaled-Up version of the dearomative [3+2] annulation and
transformation of the product 3a. a) TFA, DCM; b) Zn, TMSCl, MeOH; c) 1)
LiOH,THF/H2O; 2) 2-Aminonaphthalene, EDCl, DMAP, DCM; d) NiCl2, NaBH4,
MeOH; e) NaBH4, EtOH, 0 oC; f) NaBH4, EtOH, 0 oC to rt.
Scheme 4. Study the reaction scope. All reactions were carried on 0.2 mmol
scale in dichloroethane (2.0 mL) and used 1.5 equiv of 5, 10 mol% P3 under
N2, rt.; Isolated yields were reported; Ee values were determined by chiral
HPLC analysis.
A gram-scale reaction under the catalysis of 7.5 mol% P3 was
then performed, delivering 1.33 g of 6a (88% yield) with 97% ee
(see the SI). Synthetic transformations of 3a were then
conducted (Scheme 5). The nitro group of 3a was efficiently
reduced with Zn/HCl, delivering compound 7a in 90% yield with
94% ee. The deprotection of Boc group with TFA in DCM could
produce 8a in 95% yield. In addition, amide 9a was obtained by
hydrolysis and amidation in 64% overall yield and 94% ee via a
two-step procedure. The denitronation reaction was realized by
treatment with NiCl2/NaBH4 in MeOH, furnishing the product 10a
was attained in 76% yield with 93% ee. Treating compound 3a
with NaBH4 in EtOH could selectively furnish 11a or 12a by
adjusting the reaction temperature.
According to the above results and literatures,[11-13] two
plausible mechanisms and transition state stereoinduction
models are depicted in Scheme 6. In the cycloaddition of 3-
nitroindole/allenoate (cycle I), the conjugate addition of P7 to
allenoate 2a would generate phosphonium intermediate IA,
which upon subsequent conjugate addition to 1a via the -
position to form advanced intermediate IB. Subsequent
cyclization affords the intermediate IC, which then regenerates
catalyst P7 via elimination to give product 3a. In the
cycloaddition of 2-nitrobenzofuran/MBH carbonate (cycle II), the
conjugated addition of allylic phosphonium ylide ID, in-situ
generated from P3 and MBH carbonate, to 4a generates
intermediate IE, which upon Michael addition to generate
intermediate IF. Finally, the elimination of P3 affords product 6a.
Meanwhile, we reasoned that the hydrogen-bonding interaction
between the amide NH and the nitroarene facilitates a significant
decrease the LUMO energy of the aromatic partner[18] and
makes cycloaddition process smoothly.
Scheme 6. Possible reaction mechanism and proposed transition states.
In summary, we have developed the first phosphine-catalyzed
asymmetric dearomative [3 + 2]-cycloaddition of 3-nitroindoles
and 2-nitrobenzofurans with allenoates and MBH carbonates,
respectively, which provides a new, facile, and efficient protocol
for the synthesis of chiral 2,3-fused cyclopentannulated indolines
and dihydrobenzofurans in moderate to excellent yields with
high enantioselectivities. Notably, to the best of knowledge, this
work represents the first example of phosphine-catalyzed
asymmetric dearomative cycloaddition reaction. Synthetic
transformations of product were also showcased. The strategy
disclosed in this report affords a new approach to synthetically
valued chiral polycyclic structures, which might be potentially
useful for organic synthesis and medicinal chemistry.
Acknowledgements
We are grateful to 973 Programs (2015CB856600), National
Natural Science Foundation of China (21425205) and
Changjiang Scholars and Innovative Research Team in
University (PCSIRT) for financial supports.
Keywords: phosphine catalysis• dearomatization• cycloaddition•
CADA• nitro-heteroarenes
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10.1002/anie.201900036
Angewandte Chemie International Edition
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H. Wang, J. Zhang, Y. Tu, J. Zhang*
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Phosphine-Catalyzed
Enantioselective Dearomative [3 + 2]-
Cycloaddition of 3-Nitroindoles and 2-
Nitrobenzofurans
The first example of phosphine-catalyzed asymmetric dearomative [3 + 2]-cycloaddition of 3-
nitroindoles and 2-nitrobenzofurans was realized, which provides a new, facile, and efficient
protocol for the synthesis of chiral 2,3-fused cyclopentannulated indolines and
dihydrobenzofurans by reacting with allenoates and MBH carbonates, respectively
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