Palladium-Catalyzed Highly Stereoselective Dearomative [3 + 2] Cycloaddition of Nitrobenzofurans

Article abstract of DOI:10.1016/j.chempr.2017.06.015

Stereoselective construction of highly functionalized heterocyclic molecules is an ongoing concern for the chemical community. Among the various strategies developed with this goal, catalytic asymmetric dearomatization, an attractive method for constucting cyclic molecules with multiple stereocenters from readily available aromatic compounds, has received extensive attention in recent years. Here, we report a highly stereoselective construction of tetrahydrofurobenzofurans and tetrahydrofurobenzothiophenes via palladium-catalyzed dearomative [3 + 2] cycloaddition of nitrobenzofurans and nitrobenzothiophenes, respectively. Good to excellent yields (63%–92%), diastereoselectivity (13/1 → >20/1 dr), and enantioselectivity (75%–95% ee) were obtained, leading to products with vicinal stereogenic carbon centers. The reaction features wide substrate scope and diverse transformations of the products.

Full text of DOI:10.1016/j.chempr.2017.06.015

Article
Palladium-Catalyzed Highly Stereoselective
Dearomative [3 + 2] Cycloaddition of
Nitrobenzofurans
Qiang Cheng, Hui-Jun Zhang,
Wen-Jun Yue, Shu-Li You
slyou@sioc.ac.cn
HIGHLIGHTS
High diastereo- and
enantioselectivity enabled by a
fine-tuned palladium catalyst
Direct construction of
tetrahydrofurobenzofurans via
dearomatization reactions
Straightforward construction of
vicinal chiral quaternary carbon
centers
You and colleagues have developed a method for the straightforward construction
of tetrahydrofurobenzofurans, core structures of a series of natural products and
biologically active compounds, via palladium-catalyzed dearomative [3 + 2]
cycloaddition reactions. Good to excellent diastereo- and enantioselectivities with
broad substrate scope and high functional-group compatibility were enabled via
fine-tuning of chiral PHOX ligands. In addition, this method could also provide
dearomatized products with vicinal chiral quaternary carbon centers, a general
challenge in synthetic chemistry.
Cheng et al., Chem 3, 428–436
September 14, 2017 ª 2017 Elsevier Inc.
http://dx.doi.org/10.1016/j.chempr.2017.06.015

Article
Palladium-Catalyzed Highly
Stereoselective Dearomative [3 + 2]
Cycloaddition of Nitrobenzofurans
Qiang Cheng,1 Hui-Jun Zhang,1 Wen-Jun Yue,1 and Shu-Li You1,2,3,
*
SUMMARY
The Bigger Picture
There has been an increasing
demand for chiral compounds,
which find wide applications in
areas of biological science and
pharmaceuticals because of the
different performance of the two
enantiomers in living organisms.
Asymmetric catalysis appears to
be the most productive method
among chiral technologies for
access to enantiopure
Stereoselective construction of highly functionalized heterocyclic molecules is
an ongoing concern for the chemical community. Among the various strategies
developed with this goal, catalytic asymmetric dearomatization, an attractive
method for constucting cyclic molecules with multiple stereocenters from
readily available aromatic compounds, has received extensive attention in
recent years. Here, we report a highly stereoselective construction of tetrahy-
drofurobenzofurans and tetrahydrofurobenzothiophenes via palladium-cata-
lyzed dearomative [3 + 2] cycloaddition of nitrobenzofurans and nitrobenzothio-
phenes, respectively. Good to excellent yields (63%–92%), diastereoselectivity
(13/1 / >20/1 dr), and enantioselectivity (75%–95% ee) were obtained, leading
to products with vicinal stereogenic carbon centers. The reaction features wide
substrate scope and diverse transformations of the products.
compounds. In this regard,
catalytic asymmetric
dearomatization has emerged as a
highly efficient strategy for the
construction of complex chiral
molecules from planar aromatic
compounds.
INTRODUCTION
Tetrahydrofurobenzofuran occurs as a well-known structural core for many natural
products isolated from herbal plants (Figure 1).1–5 In recent years, modification of
this unique structure has been implemented to obtain more pharmaceutically rele-
vant compounds.6–9 However, to date, most synthetic strategies for the construction
of tetrahydrofurobenzofuran, especially those bearing continuous chiral carbon ster-
eogenic centers, have been based on stepwise ring-closing processes.6–8 Therefore,
a convenient one-step construction of this tricyclic ring system appears to be more
attractive.
Tetrahydrofurobenzofurans are
the core structures of many
biologically active natural
products and pharmaceuticals.
Thus, developing a new method
for the rapid construction of these
structures is particularly attractive.
Here, we report a highly
Palladium-catalyzed formal [3 + 2] cycloaddition reaction10–12 between electron-
deficient alkenes and epoxybutenes13 is a powerful and atom-economic tool for
the synthesis of substituted tetrahydrofurans.14–21 Unfortunately, control of the
enantioselectivity and diastereoselectivity of this kind of reaction remains chal-
lenging because of the long distance between the reactive site and the chiral catalyst
in the stereoselectivity-determining transition state.22 Limited successful examples
using specific substrates have been reported.20,23–27 To figure out a more general
methodology for highly stereoselective [3 + 2] ring formation reactions is still urgent.
stereoselective construction of
tetrahydrofurobenzofurans via
palladium-catalyzed dearomative
[3 + 2] cycloaddition of
nitrobenzofurans.
The catalytic asymmetric dearomatization (CADA) reaction plays a significant role in
the synthesis of complex organic compounds by disruption of structurally simple
arenes.28–31 Dearomatization of electron-rich arenes such as indole, pyrrole, phenol,
or naphthol usually relies on their inherent nucleophilicity.32–55 By turning these
electron-rich arenes into electrophiles, which can be done by decorating an elec-
tron-withdrawing group on the arene, novel types of reactions are expected.
428 Chem 3, 428–436, September 14, 2017 ª 2017 Elsevier Inc.

Figure 1. Selected Natural Products with the Core Structure of Tetrahydrofurobenzofuran
Interestingly, merging dearomatization of polarity-inversed benzofurans with cata-
lytic [3 + 2] cycloaddition reaction leads to direct construction of tetrahydrofuroben-
zofurans. Undoubtedly, these reactions have to confront the challenge of breaking
aromaticity.56–58 Here, we report a highly stereoselective palladium-catalyzed dear-
omative [3 + 2] cycloaddition of nitrobenzofurans and nitrobenzothiophenes.53,59–64
RESULTS AND DISCUSSION
We initiated our studies with 2-nitrobenzofuran 1a as the substrate, given the ready
availability and diverse transformation of the nitro group. When 1a was mixed with
simple epoxybutene 2a under the catalysis of chiral palladium catalyst, to our disap-
pointment, no reaction occurred with either the Trost ligand L1 or the Feringa ligand
L2 (Table 1, entries 1 and 2). Then we turned our attention to phosphinooxazoline
(PHOX) ligands, another type of ligand often used in asymmetric allylic substitution
reactions.65–67 Gratifyingly, when L3 was used, dearomatized product 3aa was ob-
tained with moderate results (65% yield, 5.9/1 dr, 53% ee; Table 1, entry 3). To
realize full conversion of substrate 1a, we screened several additives and found
Cs2CO3 to be the best (see Table 1, entry 4, and Table S1 for details). Further
screening of the conditions proved that this reaction should be performed in toluene
at room temperature, although only moderate selectivity was obtained (see Table 1,
entry 5, and Table S1 for details).
Next, we focused on screening PHOX ligands with different skeletons or substituents
(see Tables 1 and S2 for all details).68–74 Although comparable reactivity and enan-
tioselectivity were obtained for L3 and L4, planar chirality on the ligands had a detri-
mental influence on diastereoselectivity (Table 1, entries 5 and 6). After investigation
of the substituents on the oxazoline ring, we found that the tert-butyl group on the
chiral center of the ligands had the highest dr value, albeit with moderate enantio-
selectivity (Table 1, entries 6–8). Next, the chemical environment around the phos-
phine center was adjusted via modification of the phenyl rings (L7–L12). These
results showed that more electron-withdrawing and sterically bulky groups on the
phenyl ring resulted in better enantioselectivity (Table 1, entries 9–14). We noted
that a severely electron-deficient phosphine center might cause weak binding to
palladium, leading to low conversion of substrate 1a (Table 1, entry 14). Finally,
ligand L11 was found to be the best.
1State Key Laboratory of Organometallic
Chemistry, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, China
With the optimized reaction conditions (5 mol % Pd2dba3, 11 mol % (S)-L11, 1 equiv
of 1a, 2 equiv of 2a, 1 equiv of Cs2CO3 in toluene [0.1 M] at room temperature) in
hand, we further explored the scope of the substrate. To our delight, nitrobenzofur-
ans with different steric and electronic constraints underwent dearomatization
smoothly (Table 2; see also Figures S1–S79 and S106–S124). For instance, substrates
2Collaborative Innovation Center of Chemical
Science and Engineering, Tianjin 300071, China
t
3Lead Contact
bearing varied substituents at the 5 position (Me, MeO, Bu, Ph, F, Cl, Br, CO2Me,
*Correspondence: slyou@sioc.ac.cn
http://dx.doi.org/10.1016/j.chempr.2017.06.015
NO2) provided 3ba–3ja with good yields (73%–93%) and excellent diastereoselectiv-
ity (>20/1 dr) and enantioselectivity (87%–94% ee) (Table 2, entries 2–10). Notably,
Chem 3, 428–436, September 14, 2017 429

Table 1. Ligand Investigation for Dearomatization of Nitrobenzofuran 1a
Entry
1d
2d
3d
4f
L
Conversion (%)a
Yield (%)b
dra
ee (%)c
ND
ND
53
L1
L2e
L3
L3
L3
L4
L5
L6
L7
L8
L9
L10
L11
L12
<5
0
ND
<5
0
ND
78
65
73
78
83
42
82
87
87
75
80
82
50
5.9/1
6.7/1
6.9/1
18.8/1
9.1/1
11.1/1
14.0/1
>20/1
18.0/1
14.2/1
>20/1
>20/1
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
62
5
62
6
68
7
33
8
60
9
72
10
11
12
13
14
77
84
84
85
86
Reaction conditions: 5 mol % Pd2dba3, 11 mol % L, 0.1 mmol of 1a, 0.2 mmol of 2a, and 0.1 mmol of Cs2CO3 in toluene (1 mL) in a sealed tube at room temper-
ature. ND, not detected. See also Tables S1 and S2.
aDetermined by 1H NMR of the crude reaction mixture with CH2Br2 as internal standard.
bIsolated yield of 3aa with both diastereoisomers.
cDetermined by high-performance liquid chromatography (HPLC) analysis of the major diastereoisomer.
dConducted at 50ꢀC without Cs2CO3.
e22 mol % L2 was used.
fConducted at 50ꢀC.
1i with an ester group and 1j with a nitro group were tolerated, indicating a broad
scope of this reaction. Furthermore, benzofurans with substituent at the 6 or 7 posi-
tion bearing groups with varied electronic properties (6-MeO, 6-Br, 6-Ph, 6-phenyl-
ethynyl, 7-MeO, 7-Me, 7-allyl) were converted successfully in good to excellent
yields and selectivity (Table 2, entries 11–17). Alkene and alkyne were also inte-
grated under these reaction conditions (Table 2, entries 14 and 17). To our surprise,
most halides (Table 2, entries 6–8, 12, and 18–19), and the even more reactive
430 Chem 3, 428–436, September 14, 2017

Table 2. Substrate Scope of Nitrobenzofuran
Entry
1
1 (R)
Time (hr)
24
32
20
32
24
20
30
7
3
Yield (%)a
82 (75)c
80
ee (%)b
85 (85)c
93
1a (H)
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
2
1b (5-Me)
1c (5-MeO)
1d (5-tBu)
1e (5-Ph)
3
74
92
4
73
94
5
74
94
6
1f (5-F)
82
90
7
1g (5-Cl)
84
90
8
1h (5-Br)
79
92
9
1i (5-CO2Me)
1j (5-NO2)
1k (6-MeO)
1l (6-Br)
7
93
88
10
11d
12e
13
14
15
16
17
18f
19
12
48
7
3ja
82
87
3ka
3la
63
86
90
83
1m (6-Ph)
1n (6-phenylethynyl)
1o (7-MeO)
1p (7-Me)
1q (7-allyl)
1r (4-F)
20
4
3ma
3na
3oa
3pa
3qa
3ra
3sa
83
82
92
85
24
32
12
20
4
85
91
79
87
79
91
88
75
1s (5,7-(Cl)2)
85
92
Reaction conditions: 5 mol % Pd2dba3, 11 mol % (S)-L11, 0.2 mmol of 1, 0.4 mmol of 2a, and 0.2 mmol of
Cs2CO3 in toluene (2 mL) in a sealed tube at room temperature. All dr > 20/1 except where otherwise
noted.
aIsolated yield of 3 with both diastereoisomers.
bDetermined by HPLC analysis of the major diastereoisomer.
c2 mmol of 1a was used.
ddr = 14/1.
edr = 16/1.
fdr = 13/1.
bromide group, survived under this palladium-catalyzed process, which might be
attributed to the electronic deficiency of the metal center, although 4-F-substituted
benzofuran 1r displayed moderate selective control. In addition, the absolute
configuration of 3fa was determined as 3R,3aS,8bS by X-ray crystallographic analysis
of a single crystal of the enantiopure sample (see also Figure S136).
We also applied this reaction to different substituted vinyl epoxides to further
demonstrate the generality of this method (Table 3; see also Figures S84–S97 and
S127–S132). Interestingly, compared with 2-vinyl-oxirane 2a, various substituted vi-
nyl-oxirane substrates showed better selectivity (>20/1 dr, 85%–95% ee). Methyl,
phenyl, and substituted phenyl groups with various electronic properties were all
endured, resulting in products bearing vicinal quaternary carbon centers. At the
same time, the absolute configuration of 3fb was determined as 3R,3aS,8bS by
Chem 3, 428–436, September 14, 2017 431

Table 3. Substrate Scope of Substituted Epoxybutene
Entry
2 (R0)
Time (hr)
3
Yield (%)a
ee (%)b
85
1
2
3
4
5
6
7c
2a (H)
24
24
18
12
20
24
18
3aa
3ab
3ac
3ad
3ae
3af
3fb
82
74
77
91
61
70
92
2b (Me)
87
2c (Ph)
92
2d (4-F-C6H4)
2e (4-Ph-C6H4)
2f (3-MeO-C6H4)
2b (Me)
94
95
93
85
Reaction conditions: 5 mol % Pd2dba3, 11 mol % (S)-L11, 0.2 mmol of 1a, 0.4 mmol of 2, and 0.2 mmol of
Cs2CO3 in toluene (2 mL) in a sealed tube at room temperature.
aIsolated yield of 3 with both diastereoisomers.
bDetermined by HPLC analysis of the major diastereoisomer.
c0.2 mmol of 1f was used.
X-ray crystallographic analysis of a single crystal of the enantiopure sample (see also
Figure S137).
Interestingly, this method could be extended to the dearomatization of nitrobenzo-
thiophene without any modification of the reaction conditions (Scheme 1; see also
Figures S80–S83, S125, and S126). Both 2-nitrobenzothiophene and 3-nitrobenzo-
thiophene underwent the [3 + 2] dearomative cycloaddition with vinyl-oxirane 2a
smoothly in reasonable yields, and diastereo- and enantioselectivity despite the
presence of a sulfur atom, a potentially harmful ligating center for many metals.75
To our delight, when 2 mmol of 1a was used in this reaction, 75% yield of 3aa was
obtained without erosion of the enantiomeric excess value (Table 2, entry 1).
Furthermore, several transformations of the products were carried out to show the
potential application of this method. When product 3aa was used under the condi-
tions of the cross-metathesis process with methyl acrylate, 4 was isolated in 88%
yield and 82% ee (Scheme 2, equation 1; see also Figures S98, S99, and S133).
The nitro group could be easily eliminated through radical reduction by Bu3SnH in
1 hr (Scheme 2, equation 2; see also Figures S100, S101, and S134). In addition,
the bromide group in 3ha could be readily transformed into an aryl group via the Su-
zuki-Miyaura cross-coupling reaction; no stereocenters were influenced (Scheme 2,
equation 3; see also Figures S102, S103, and S135).
A plausible catalytic cycle was proposed for this highly stereoselective dearomatiza-
tion reaction (Scheme 3A). Coordination and oxidative addition of a palladium cata-
lyst to the epoxybutene 2a lead to ring-opened intermediate B. A catalyst-controlled
dearomative addition of the alcohol anion with a pending p-allylpalladium complex
to substrate 1a could deliver C. The following quick cyclization affords the desired
product 3aa. A plausible model for the stereocontrol of the cycloaddition process
was also postulated according to the report by Kollmar et al.76,77 (Scheme 3B).
The reaction occurs in the smallest sector divided according to the steric effect of
432 Chem 3, 428–436, September 14, 2017

Scheme 1. Dearomatization of Nitrobenzothiophenes
the PHOX ligand. The configuration of the resulting product was in accordance with
that of the major product.
In summary, we have developed a method for the synthesis of tetrahydrofurobenzo-
furans with high stereoselectivity by dearomatization of nitrobenzofurans via palla-
dium-catalyzed asymmetric formal [3 + 2] cycloaddition reaction. Fine-tuning of
the electronic and steric characteristic of PHOX ligands contributed crucially to
the success of this reaction. The wide scope for both substrates and easily transform-
able functional groups on the products make this methodology potentially useful for
organic synthesis and medicinal chemistry. Further investigation of the mechanistic
details and application of this method to other heteroarenes for the construction of
different kinds of interesting fused-ring systems are ongoing in our lab.
EXPERIMENTAL PROCEDURES
Representative Procedure for Catalytic Asymmetric Dearomatization of
Nitrobenzofurans and Characterization of the Products
A flame-dried sealed tube was cooled to room temperature and filled with argon.
To this flask were added Pd2dba3 (9.2 mg, 0.01 mmol, 5 mol %), (S)-L11 (14.9 mg,
11 mol %), and toluene (1 mL). The mixture was stirred at room temperature for
30 min before the addition of 1a (0.2 mmol, 1.0 equiv), Cs2CO3 (0.2 mmol, 1.0 equiv),
Scheme 2. Transformations of Products
Chem 3, 428–436, September 14, 2017 433

Scheme 3. Mechanistic Proposal
A plausible catalytic cycle (A) and a model for the stereocontrol of the cycloaddition process (B).
2a (0.4 mmol, 2.0 equiv), and toluene (1 mL). The reaction was sealed with a Teflon
plug and stirred at room temperature. After completion (monitored by thin-layer
chromatography), the mixture was filtered through celite. The solution was concen-
trated by rotary evaporation. The diastereomeric ratio was determined by 1H NMR of
the crude reaction mixture. Then the residue was purified by silica gel column chro-
matography (PE/EtOAc = 50/1) to afford the desired product 3aa. Pale-yellow solid,
m.p. = 56.1ꢀC–57.6ꢀC, 38.0 mg, 82% yield, >20/1 dr, 85% ee (Agilent 1260 Infinity
Analytical SFC system Daicel Chiralcel OJ-H [0.46 3 15 cm], CO2/2-propanol = 95/5,
v = 1.3 mL minꢁ1, l = 214 nm, t(major) = min, t(minor) = min), [a]D25 = ꢁ44.3 (c = 1.0,
CHCl3). 1H NMR (400 MHz, CDCl3) d 7.44 (dd, J = 7.2, 0.4 Hz, 1H), 7.39 (td, J = 8.0,
1.2 Hz, 1H), 7.10 (td, J = 7.6, 0.8 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 5.98 (s, 1H), 5.77
(ddd, J = 16.8, 10.0, 8.4 Hz, 1H), 5.36 (d, J = 17.2 Hz, 1H), 5.32 (d, J = 10.8 Hz, 1H),
4.18–4.10 (m, 2H), 3.37 (dd, J = 14.8, 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 159.1,
131.9, 129.6, 126.2, 125.3, 123.7, 123.3, 122.2, 111.2, 87.9, 73.0, 55.4. IR (thin film):
nmax (cmꢁ1) = 2998, 2958, 2926, 2897, 2873, 1618, 1596, 1561, 1466, 1368, 1354,
1328, 1284, 1235, 1210, 1187, 1144, 1118, 1090, 1050, 1011, 937, 818, 792, 753,
728, 713, 684. HRMS (EI) calcd for C12H11NO4 [M]+: 233.0688; found: 233.0685.
ACCESSION NUMBERS
The structures of products 3fa and 3fb in this article have been deposited in
the Cambridge Crystallographic Data Center under accession numbers CCDC:
1552486 and 1552485, respectively.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures, 137
figures, 4 tables, and 2 data files and can be found with this article online at
http://dx.doi.org/10.1016/j.chempr.2017.06.015.
AUTHOR CONTRIBUTIONS
Methodology, Q.C. and S.-L.Y.; Investigation, Q.C., H.-J.Z., and W.-J.Y.; Writing –
Original Draft, Q.C.; Writing – Review & Editing, S.-L.Y.; Supervision, S.-L.Y.
ACKNOWLEDGMENTS
We thank the National Basic Research Program of China from the Ministry of Science
and Technology (2015CB856600 and 2016YFA0202900), the National Natural Sci-
ence Foundation of China (21332009 and 21421091), and the Chinese Academy
of Sciences (XDB20000000 and QYZDY-SSW-SLH012) for generous financial
support.
434 Chem 3, 428–436, September 14, 2017

Received: April 18, 2017
Revised: June 9, 2017
Accepted: June 21, 2017
Published: September 14, 2017
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