Facile synthesis of chiral [2,3]-fused hydrobenzofuran: Via asymmetric Cu(i)-catalyzed dearomative 1,3-dipolar cycloaddition

Article abstract of DOI:10.1039/c8cc09226e

Intermolecular asymmetric dearomative 1,3-dipolar cycloaddition of 2-nitrobenzofurans with azomethine ylides was enabled by using a chiral Cu(i)/(S,S_p)-ⁱPr-Phosferrox catalyst. As a result, a series of highly stereoselective chiral [2,3]-fused hydrobenzofurans possessing four contiguous stereogenic centers were obtained with good to high yields, diastereoselectivities and enantioselectivities. The reaction has broad substrate scope tolerating various functional groups.

Full text of DOI:10.1039/c8cc09226e

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Facile synthesis of chiral [2,3]-fused
hydrobenzofuran via asymmetric Cu(I)-catalyzed
dearomative 1,3-dipolar cycloaddition†
Cite this: Chem. Commun., 2019,
55, 553
Received 20th November 2018,
Accepted 8th December 2018
a
Lei Liang,
Hong-Ying Niu,b Dong-Chao Wang, *c Xin-He Yang,c
Gui-Rong Quc and Hai-Ming Guo
*
ac
DOI: 10.1039/c8cc09226e
rsc.li/chemcomm
Intermolecular asymmetric dearomative 1,3-dipolar cycloaddition
of 2-nitrobenzofurans with azomethine ylides was enabled by using
a chiral Cu(I)/(S,Sp)-iPr-Phosferrox catalyst. As a result, a series of
highly stereoselective chiral [2,3]-fused hydrobenzofurans possessing
four contiguous stereogenic centers were obtained with good to high
yields, diastereoselectivities and enantioselectivities. The reaction has
broad substrate scope tolerating various functional groups.
Fig. 1 Representative examples of natural products containing fused
polycyclic hydrobenzofuran scaffolds.
The fused polycyclic hydrobenzofurans are naturally prevalent
molecules, some of which exhibit a broad range of biological
activities.1 For example (Fig. 1), rocaglamide is a naturally occurring On the contrary, studies on the dearomatization of electron-
complex molecule that possesses a tricyclic hydrobenzofuran deficient arenes as electrophiles remain relatively scarce.8,9
scaffold and exhibits potent anticancer, anti-inflammatory and Recently, several dearomatization reactions based on the electro-
neuroprotective activities.2 (+)-Gynunone isolated from the roots philicity of nitro-substituted arenes were reported. In 2017, You
of Gynura elliptica possesses anti-platelet aggregation activity.3 and co-workers9a developed a method for the straightforward
As a member of the [2,3]-fused hydrobenzofurans, CID755673, construction of chiral tetrahydrofurobenzofurans via palladium-
which was found in a marine sponge, contains a benzofuro[2,3- catalyzed dearomative [3+2] cycloaddition of nitrobenzofurans
c]azepin core and is a highly selective protein kinase inhibitor.4 with epoxybutene. Later, Yuan and co-workers9b reported the
Moreover, azonazine, a novel dipeptide from Aspergillus insulicola, CADA reaction of nitrobenzofurans with 3-isothiocyanato oxindoles
exhibits anti-inflammatory activity by inhibiting NF-kB luciferase by using bis(oxazoline)/Zn(OTf)2 as a catalyst (Scheme 1A). Despite
and nitrite production.5 In this context, the exploration of an this elegant progress, the one-step construction of chiral hydro-
efficient synthesis route for constructing this type of scaffold can benzofuran molecules containing multiple chiral centers and
be highly valuable.
functional groups remains a challenging task. In recent years,
The catalytic asymmetric dearomatization (CADA) reactions catalytic asymmetric 1,3-dipolar cycloaddition of azomethine
have emerged as a powerful tool for the rapid assembly of ylides with electron deficient CQC bonds has provided a direct
enantio-enriched three-dimensional polycyclic molecules from route to highly substituted pyrrolidines with multiple stereo-
readily available aromatic substrates.6 The dearomatization of genic centers.10 However, the merging of CADA reaction with
electron-rich arenes (naphthol, indole, pyrrole, etc.) has been cycloaddition of azomethine ylides to construct chiral-fused
successfully developed based on their inherent nucleophilicity.7 polycyclic compounds is rare.8h Herein, we report the straight-
forward construction of new chiral core structures of hydrobenzo-
furan enabled by copper-catalyzed asymmetric dearomative 1,3-
dipolar cycloaddition of 2-nitrobenzofurans with azomethine
ylides (Scheme 1B).
Initially, we investigated the 1,3-dipolar reaction of 2-nitro-
benzofuran 1a with N-benzylidene glycine methyl ester 2a by
using Cs2CO3 as the base in MTBE and Cu(MeCN)4ClO4/rac-
BINAP-L1 complex as the catalyst at 0 1C. Gratifyingly, the reaction
a School of Environment, Henan Normal University, Xinxiang, Henan province,
453007, P. R. China. E-mail: ghm@htu.edu.cn
b School of Chemistry and Chemical Engineering, Henan Institute of Science and
Technology, Xinxiang, Henan Province 453003, P. R. China
c Henan Key Laboratory of Organic Functional Molecules and Drug Innovation,
School of Chemistry and Chemical Engineering, Henan Normal University,
Xinxiang, Henan Province 453007, P. R. China. E-mail: wangdc@htu.edu.cn
† Electronic supplementary information (ESI) available. CCDC 1864355 (3ah). For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8cc09226e proceeded well, delivering the desired racemic dearomatized
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Table 1 Optimization of reaction conditionsa
Scheme 1 Different synthetic routes to chiral [2,3]-fused hydrobenzo-
furan compounds.
Entry
MX
L
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
CuCl
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L8
L8
L8
73
75
69
63
55
80
63
83
76
80
81
65
77
21
8 : 1
8 : 1
10 : 1
9 : 1
8 : 1
9 : 1
7 : 1
9 : 1
8 : 1
9 : 1
7 : 1
6 : 1
7 : 1
1 : 3
23
45
5
product 3aa with a moderate yield (Table 1, entry 1). With such
an effective method for synthesizing racemic products, we then
turned our attention to chiral ligands (entries 2–11). The axially
chiral bidentate phosphine ligands including (R)-BINAP-L2
and (R)-segphos-L3 were first examined. The cycloaddition
proceeded well, resulting in 3aa as a major product with good
yield, however, with poor-to-moderate enantioselectivities
(Table 1, entries 2 and 3). The enantioselectivity of this reaction
was further improved by screening different types of commercially
available chiral ligands, such as (R)-Ph-BOX-L4, (R)-Ph-pybox-L5,
(R)-Ph-PHOX-L6, (R,R)-DIOP-L7 and a series of phosferrox ligands
L8–L11 (entries 4–13). As shown in Table 1, L4–L5 led to poor
enantioselectivities (entries 4 and 5). When (R)-Ph-PHOX-L6 and
(R,R)-DIOP-L7 were used as ligands, the chiral cycloaddition
product was obtained with moderate results (entries 6 and 7).
3
53
56
98
83
89
78
93
91
92
9
10
11
12
13
14
Cu(OTf)2
AgCO2CF3
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), Cu(MeCN)4ClO4
(5 mol%), L (5.5 mol%) and Cs2CO3 (10 mol%) in MTBE (2.0 mL), 0 1C,
N2, 12 h. Yields of isolated product. Determined by 1H NMR analysis
of the crude mixture. Determined by chiral HPLC analysis.
b
c
d
We further focused on the screening of phosferrox ligands with the desired products with good yields and diastereoselectivities,
different substituents, among which, the (S,Sp)-iPr-phosferrox-L8 and excellent enantioselectivities (up to 73% yield, 5 : 1 dr and
was the most promising ligand, generating the desired product 97% ee). Moreover, the 2-thienyl- and 2-naphthyl-substituted
3aa with 82% yield, 98% ee and 9 : 1 dr (entries 8–11). In the a-iminoesters (2i and 2j) also delivered the corresponding
presence of (S,Sp)-iPr-phosferrox-L8, the catalyst Cu(MeCN)4ClO4 compounds 3ai and 3aj with good results. Delightfully, a-imino-
was changed to CuCl, Cu(OTf)2 and AgCO2CF3. These central ester 2k derived from an aliphatic aldehyde and a-iminoester 2l
metals failed to further improve the enantioselectivity or dia- with an alkenyl substituent were also successfully employed
stereoselectivity under identical reaction conditions (entries under the same reaction conditions, and the targeted chiral
12–14). Furthermore, the screening of other solvents and bases [2,3]-fused benzofuranpyrrolidines 3ak and 3al were obtained
also did not show better results (see Table S1, ESI†).
with excellent enantioselectivities (up to 96% ee).
Finally, the optimal reaction conditions were obtained as
Subsequently, we focused on the groups on the benzofuran
follows: 5 mol% of Cu(MeCN)4ClO4, 5.5 mol% of L8 and 10 mol% ring. A wider variety of nitrobenzofurans were prepared and
of Cs2CO3 in MTBE at 0 1C (entry 8). evaluated (Scheme 3). The reaction proceeded smoothly with
Under the optimal reaction conditions, various azomethine N-benzylidene glycine methyl ester 2a, furnishing the respective
ylide precursors, a-iminoesters 2a–2l, were tested by reacting cycloadducts with excellent results (3ba–3la). Substrates bearing
with 2-nitrobenzofuran 1a using the asymmetric dearomative various substituents, either with electron-withdrawing or electron-
[3+2] reaction (Scheme 2). The effect of the group at the para donating groups, at the 5 position (1b–1g) led to the corresponding
position of the benzene ring (3ab–3af) was firstly investigated. dearomatized products with good yields (74–82%) and diastereo-
Both the electron-rich and electron-deficient substituents were selectivities (6: 1–15 :1 dr), and excellent enantioselectivities
well tolerated and led to the corresponding adducts with good (94–99% ee). A similar trend was also observed when substituting
yields (75–85%) and dr values (up to 10 : 1 dr), and excellent ee values at the 6 or 7 position (Br, Me, MeO) (3ha–3ka). Notably, the
(98–99%). The reaction proceeded smoothly with a-iminoesters highest enantioselectivities were observed in 5-nitro, 6-methyl or
containing an aryl ring with meta substituents (2g, 2h), generating 6-methoxy nitrobenzofuran (1g, 1i and 1j). Furthermore, 4-chloro
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Fig. 2 The absolute configuration of the cycloadduct 3ah.
Scheme 2 Substrate scope for azomethine ylides. Reaction conditions:
1a (0.2 mmol), 2a (0.3 mmol), Cu(MeCN)4ClO4 (5 mol%), L8 (5.5 mol%) and
Cs2CO3 (10 mol%) in MTBE (2.0 mL), 0 1C, N2, 12 h. Yields of isolated
product. The dr ratios were determined by 1H NMR analysis of the crude
mixture. The ee values were determined by chiral HPLC analysis.
Scheme 4 Gram-scale synthesis and transformation.
The absolute configuration of [2,3]-fused benzofuranpyrrolidine
product 3ah (Fig. 2), determined by single-crystal X-ray diffraction
analysis, was unambiguously found to be (1S,3S,3aS,8bS).
To further explore the prospective use of this methodology,
the gram-scale synthesis of [2,3]-fused benzofuranpyrrolidine
was carried out. As shown in Scheme 4A, 3ja was obtained, with
79% yield, 10 : 1 dr, and 99% ee, by treating 5.0 mmol 2-nitro-6-
methoxy-benzofuran 1j with N-benzylidene glycine methyl ester
2a in the presences of 5 mol% Cu(MeCN)4ClO4 and 5.5 mol%
(S,Sp)-iPr-Phosferrox-L8. The transformations of [2,3]-fused benzo-
furanpyrrolidine products were carried out. Firstly, zinc dust in a
methanolic hydrogen chloride solution was used to reduce the
nitro group to the respective amine 4aa (Scheme 4B). After that,
the ester group was selectively reduced using LiAlH4 (2 equiv.)
as a reducing agent, and the corresponding product containing
a hydroxyl group 4ja was obtained with good results (Scheme 4C).
Additionally, the phenyl group was attached to the aromatic ring via
the Suzuki–Miyaura cross coupling of 3fa with phenylboronic acid,
and 5-phenyl substituted nitrobenzofuranpyrrolidine 4fa was
Scheme 3 Substrate scope for variously functionalized 2-nitrobenzofurans.
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), Cu(MeCN)4ClO4 (5 mol%),
L8 (5.5 mol%) and Cs2CO3 (10 mol%) in MTBE (2.0 mL), 0 1C, N2, 12 h. Yields of
isolated product. The dr ratios were determined by 1H NMR analysis of the
crude mixture. The ee values were determined by chiral HPLC analysis.
nitrobenzofuran was employed under the same reaction conditions, obtained with 88% yield and 95% ee (Scheme 4D).
and the reaction proceeded to deliver the chiral tricyclic product In summary, we successfully developed a highly enantio-
3la with good results, but with slightly lower enantioselectivity selective dearomative 1,3-dipolar cycloaddition reaction of nirto-
(92% ee).
benzofurans with iminoesters. Using Cu(I)/iPr-phosferrox complex
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We are grateful for the financial support from the National
Natural Science Foundation of China (21672055 and U1604283),
and the 111 Project (D17007) for support.
Conflicts of interest
There are no conflicts to declare.
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