Catalytic Asymmetric Synthesis of Chiral Dihydrobenzofurans through a Formal [4+1] Annulation Reaction of Sulfur Ylides and In Situ Generated ortho-Quinone Methides

Article abstract of DOI:10.1002/ejoc.201601186

The first example of a catalytic asymmetric formal [4+1] annulation reaction between sulfur ylides and in situ generated ortho-quinone methides (o-QMs) is reported in this work. A C2-symmetric chiral urea was identified to be the best H-bonding catalyst, affording a wide range of chiral 2,3-dihydrobenzofurans in high yields and moderate enantioselectivities [70–98 % yields, up to 89:11 e.r. (enantiomeric ratio)].

Full text of DOI:10.1002/ejoc.201601186

A Journal of
Accepted Article
Title: Catalytic Asymmetric Synthesis of Chiral Dihydrobenzofurans via A For-
mal [4+1] Annulation Reaction of Sulfur Ylides and In Situ-Generated ortho-
Quinone Methides
Authors: Qing-Qing Yang; Wen-Jing Xiao
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601186
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601186
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COMMUNICATION
Catalytic Asymmetric Synthesis of Chiral Dihydrobenzofurans via
A Formal [4+1] Annulation Reaction of Sulfur Ylides and In Situ-
Generated ortho-Quinone Methides
Qing-Qing Yang*[a,b] and Wen-Jing Xiao[b]
Abstract: The first example of catalytic asymmetric formal [4+1]
Figure 1. Naturally occurring chiral 2,3-dihydrobenzofurans.
annulation reaction between sulfur ylides and in situ-generated
ortho-quinone methides was reported in this work. A C2-symmetric
chiral urea was identified to be the best H-bonding catalyst, affording
Recently, we disclosed an asymmetric [4+1] annulation of
chiral sulfur ylides[8,9] and in-situ generated o-azaxylylenes,
a wide range of chiral dihydrobenzofurans in high yields and
moderate enantioselectivities (70-98% yields, up to 89:11 e.r.).
affording chiral indolines in good yields and good
enantioselectivities[10d] (Scheme 1A, up to 93% yield, 95.5:4.5
e.r.). Thereafter, we turned our attention to the synthesis of
chiral
Introduction
Chiral dihydrobenzofurans occupy a very important position in
heterocycles due to their prevalence in natural products and
synthetic drugs with diverse bioactivities.[1-5] For example,
natural product megapodiol can be used as
a potential
antileukemic agent;[2] (-)-tremetone and (-)-hydroxytremetone,
isolated from Eupatorium urticaefolium (Compositae), show
insecticidal properties.[3] Moreover, annullatin A exhibits potent
agonistic activity toward the cannabinoid receptors CB1 and
CB2,[5] and annullatin B displays CB1-agonistic activity and
inverse agonistic activity toward CB2 (Figure 1).[5] Given their
diverse bioactivities, chiral 2,3-dihydrobenzofurans have drawn
increasing research interests from synthetic chemists.[6] Many
efficient methods have been developed for the synthesis of
chiral dihydrobenzofurans, including the kinetic resolution,[4,7a]
asymmetric synthesis from chiral reagents,[7b] or asymmetric
catalysis.[7c-l] Despite these advances, the further development
of alternative methods to rapidly synthesize chiral 2,3-
dihydrobenzofurans is still in demand.
Scheme 1. Strategies for the enantioselective [4+1] annulations of sulfur ylides and
in situ-generated highly reactive intermediates.
dihydrobenzofurans from sulfur ylides and ortho-quinone
methides (o-QMs), which can be in-situ generated from phenol
derivatives.[11] Notably, o-QMs are recognized as highly useful
intermediates which were widely used in the synthesis of 5-, 6-
or 7-membered oxa-heterocyles.[12] During our research, the
group of Zhou, Osyanin and Sun reported a formal [4+1]
annulation reaction of o-QMs intermediates and sulfur ylides,
affording the 2,3-dihydrobenzofuran products.[13,14] However, the
known camphor derived chiral sulfonium salts were used to
realize the enantioselective synthesis of the corresponding
products.[13b,d] And three results were obtained, in which 63% ee
was the best but only in 25% yield.[13d] Herein, for the first time,
we developed the enantioselective synthesis of 2,3-
dihydrobenzofuran via an asymmetric [4+1] annulation reaction
of acyl-substituted sulfur ylides and o-QMs intermediates
(Scheme 1B). This success lied on the cooperative catalysis
strategy of multiple H-bonding catalysts,[15] which has been well
developed in our previous work on the annulation reactions of
sulfur ylides with unsaturated keto-esters[10a] and nitroolefins.[10c]
[a]
[b]
Q.-Q. Yang
College of Materials and Chemical Engineering, China Three
Gorges University
8 Daxue Road, Yichang, Hubei 443002 (China)
Q.-Q. Yang, Prof. Dr. W.-J. Xiao
Results and Discussion
Key Laboratory of Pesticide & Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (China)
E-mail: loveqq59@sina.com
The feasibility of this planned [4+1] annulation reaction was
examined using TBS-protected phenol substrates 1a (1.0 equiv.)
and sulfur ylide 2a (1.2 equiv.) in toluene at room temperature,
providing the desired product in 90% yield (Table 1, Entry 1).[16]
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
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COMMUNICATION
Then we turned our attention to the asymmetric catalysis. As
shown in Table 1, our investigation started with the screening of
chiral multiple H-bonding catalysts (entries 2-5) at 20 mol%
catalyst loading in toluene for the reaction of tert-
butyldimethylsilyl (TBS)-protected phenol substrate 1a and sulfur
ylide 2a in the presence of CsF (1.0 equiv.) and 18-Crown ether-
6 (1.0 equiv.). As highlighted in Table 1, the urea catalyst III
induced the chiral cycloadduct 3aa in excellent yield with
promising enantiomeric ratio (93% yield, 60:20 e.r., Table 1,
entry 4). Further optimization of the reaction media revealed that
toluene was still the best solvent (Table 1, entries 6-7 vs entry 4).
Additional efforts to improve the enantioselectivity were made by
lowering the reaction temperature (Table 1, entries 8-9 vs entry
4). When the reaction was implemented at -20 oC, the
enatiomeric ratio of 3aa was significantly increased to 85:15
(Table 1, entry 9). Finally, carrying out the reaction under higher
dilution[16] can further increase the enantiomeric ratio to 89:11
(Table 1, entry 10).
dihydrobenzofurans in excellent yields and moderate
enantiomeric ratio (80-98% yields, 79:21-89:11 e.r.). The
electronic property of benzene ring did not affect the yield much
and generally, good stereoselectivities were achieved (Table 2,
entries 1-6). Furthermore, disubstituted phenol derivative 1g
could readily participate in this reaction, providing the
corresponding benzofuran 3ga with good results (Table 2, entry
7). While in the absence of 18-Crown ether-6, the reaction at -20
oC was too slow to consume the starting materials completely.
And the enantioslectivity of 3ga was decreased to 69:19 e.r.[16]
As summarised in Table 3, this asymmetric [4+1] annulation
was also general with respect to sulfur ylides. For example, for
most arylacyl-substituted sulfur ylides, regardless of their
substitution pattern and electronic property system of benzene
ring, reactions could perform well to give the corresponding
products in generally high yields with moderate to good
Table 2. Scope of TBS-protected phenol substrates 1.[a]
Table 1. Optimisation of reaction conditions.[a]
Entry
1, R1
3
Yield[b]
96%
80%
96%
98%
96%
98%
98%
e.r.[c]
89:11
85:15
89:11
78:22
83:17
85:15
86:14
1
2
3
4
5
6
7
1a, H
3aa
3ba
3ca
3da
3ea
3fa
3ga
1b, 4-OMe
1c, 4-Me
1d, 4-F
Entry
Cat.
-
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
THF
Temp.
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
0 oC
t
Yield[b]
90%
60%
95%
93%
94%
96%
95%
95%
93%
96%
e.r.[c]
-
1e, 4-Cl
1f, 4-Br
1g, 4,6-Br2
1
2 h
2
I
1.5 h
1.5 h
1.5 h
2.5 h
1.5 h
1.5 h
2 h
51:49
50:50
60:40
54:46
59:41
54:46
78:22
85:15
89:11
3
II
4
III
IV
III
III
III
III
III
[a] Unless noted, reactions were performed with 1 (0.2 mmol), 2a (0.24 mmol),
catalyst III (20 mol%), CsF (0.2 mmol), 18-Crown ether-6 (0.2 mmol) in toluene
(4.0 mL, 0.05 M). [b] Isolated yield. [c] Determined by chiral HPLC.
5
6
Table 3. Scope of sulfur ylide components.[a]
7
8
Toluene
Toluene
Toluene
9
-20 oC
-20 oC
36 h
36 h
Entry
1
2, R2
3
Yield[b]
95%
e.r.[c]
10[d]
2b, p-MeC6H4
2c, p-OMeC6H4
2d, p-FC6H4
2e, p-ClC6H4
2f, m-ClC6H4
3ab
3ac
3ad
3ae
3af
89:11
83:17
83:17
77:23
84:16
[a] Unless noted, reactions were performed with 1a (0.1 mmol), 2a (0.12
mmol), catalyst (20 mol%), CsF (0.1 mmol), 18-Crown ether-6 (0.1 mmol) in
the indicated solvent (1.0 mL, 0.1 M). [b] Isolated yield. [c] Determined by
chiral HPLC. [d] 2 mL of toluene (0.05 M).
2
3
4
5
93%
96%
After establishing satisfactory reaction conditions,[16] we
started to probe the scope of TBS-protected phenol components
firstly. As shown in Table 2, various phenol substrates
proceeded smoothly in this asymmetric formal [4+1] annulation
96%
98%
reaction,
affording
the
corresponding
2-benzoyl-2,3-
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European Journal of Organic Chemistry
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COMMUNICATION
6
2g, m-BrC6H4
2h, 2,4-F2-C6H3
2i, 2-thienyl
2j, 2-furyl
3ag
3ah
3ai
98%
96%
97%
70%
98%
70%
90%
86:14
52:48
73:27
72:28
75:25
70:30
75:25
7
8
9
3aj
10[d]
11[d]
12[d]
2k, tBu
3ak
3al
2l, CH2=CH2Ph
2m, NEt2
3am
[a] Unless noted, reactions were performed with 1a (0.2 mmol), 2 (0.24 mmol),
catalyst III (20 mol%), CsF (0.2 mmol), 18-Crown ether-6 (0.2 mmol) in toluene
(4.0 mL, 0.05 M). [b] Isolated yield. [c] Determined by chiral HPLC. [d] 2 (0.4
mmol, 2,0 equiv.) was used.
enantioselectivity (Table 3, entries 1-7). While, sulfur ylide 2h
with difluoro-substituents gave
a poor enantiomeric ratio
probably due to the electronic effect of sulfur ylide (Table 3,
entry 7). Note that the heteroaromatic groups, such as furyl and
thienyl, were also well tolerated (Table 3, entries 8-9). Moreover,
the scope of sulfur ylides could be significantly extended to alkyl-
, alkenyl- and amino-substituted acyl sulfur ylides, providing the
corresponding products in 70-98% yields and 70:30 to 75:25 e.r.
(Table 3, entries 10-12). Additionally, TBS-protected phenol
substrates with substituents at the benzylic position were also
used in the reactions. Unfortunately, racemic 2,3-disubstituted
dihydrobenzofurans were obtained during the transformations
probably due to the steric effect.
Scheme 2. Proposed reaction mechanism.
Conclusions
In conclusion, we have developed a catalytic asymmetric [4+1]
annulation reaction of sulfur ylides and TBS-protected phenol
derivatives by using a multiple H-bonding urea catalyst. This
protocol provided a straightforward route to enantio-enriched
2,3-dihydrobenzofurans with good yields and moderate
enantiomeric ratios. Further exploitation of annulation reactions
with sulfur ylides are currently on going in our laboratory.
To better understand this reaction, a possible catalytic cycle
involving Michael addition-SN2 displacement cascade was
depicted in Scheme 2. We presumed that the exposure of sulfur
ylide 2a to multiple H-bonding catalyst III would afford complex
A.[10a,c] Then, the formed complex A incorporated with o-QMs 5a,
which was generated in situ from TBS-protected phenol
substrate 1a in the presence of CsF,[12c] to give complex B.
Possibly, in this complex the catalyst III governed the orientation
of both substrates by the H-bonding interaction and an
asymmetric Michael addition occurred to provide complex C.
Finally, the intramolecular SN2 displacement of the complex C
delivered the chiral cycloadduct 3aa with the release of catalyst
III for the next catalytic cycle.
Experimental Section
General procedure: To a 10 mL schlenk tube equipped with a magnetic
stir bar were added sulfur ylide 2a (0.22 mmol), catalyst III (0.04 mmol),
18-crown ether-6 (0.2 mmol), CsF (0.2 mmol) and dry toluene (3.0 mL).
Then the reaction mixture was stirred under -20 oC for half an hour. Later,
the solution of TBS-protected phenol substrate 1a (0.2 mmol) in toluene
(1.0 mL) was added dropwise to the above reaction mixture. Upon
consumption of the starting materials monitored by TLC, the reaction
mixture was purified by flash chromatography on silica gel (ethyl acetate :
petroleum ether = 1:10) to give the desired product 3aa as a white solid
in 96% yield, 89:11 e.r..
Acknowledgements
We are grateful to China Three Gorges University, the National
Natural Science Foundation of China (Nos. 21232003,
21202053, and 21272087) and the National Basic Research
Program of China (2011CB808603) for support of this research..
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European Journal of Organic Chemistry
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Keywords: asymmetric catalysis • H-bonding catalysis •
dihydrobenzofuran • sulfur ylides • [4+1] annulation
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This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
COMMUNICATION
10.1002/ejoc.201601186
SHORT COMMUNICATION
Organocatalysis
Qing-Qing Yang* and Wen-Jing Xiao
Page No. – Page No.
Catalytic Asymmetric Synthesis of
Chiral Dihydrobenzofurans via A
Formal [4+1] Annulation Reaction of
Sulfur Ylides and In Situ-Generated
ortho-Quinone Methides
The title H-bonding catalytic asymmetric [4+1] annulations of sulfur ylides with in
situ-generated ortho-quinone methides enable for the enantioselective synthesis of
chiral 2,3-dihydrobenzofurans in good results.
This article is protected by copyright. All rights reserved