A mild method for generation of o-quinone methides under basic conditions. the facile synthesis of trans-2,3-dihydrobenzofurans

Article abstract of DOI:10.1039/c3cc37800d

A novel and efficient method for the generation of o-quinone methide intermediates was developed from the readily available 2-tosylalkylphenols under the mild basic conditions, and their reactions with sulfur ylides were investigated for the stereoselective synthesis of trans-2,3-dihydrobenzofurans. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc37800d

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A mild method for generation of o-quinone methides
under basic conditions. The facile synthesis of
trans-2,3-dihydrobenzofurans†
Mu-Wang Chen,a Liang-Liang Cao,ab Zhi-Shi Ye,a Guo-Fang Jiangb and
Yong-Gui Zhou*a
Cite this: Chem. Commun., 2013,
49, 1660
Received 27th October 2012,
Accepted 7th January 2013
DOI: 10.1039/c3cc37800d
www.rsc.org/chemcomm
A novel and efficient method for the generation of o-quinone
On the other hand, 2,3-dihydrobenzofuran derivatives are
methide intermediates was developed from the readily available unique structural skeletons in many biologically active mole-
2-tosylalkylphenols under the mild basic conditions, and their cules and natural products.10 They are present in molecules
reactions with sulfur ylides were investigated for the stereo- acting as potent inducers of the anticarcinogenic marker
selective synthesis of trans-2,3-dihydrobenzofurans.
enzyme, quinone reductase,10c anti-multi drug resistant
agents,10e insecticidal, antifungal, and anti-trypanosomal
o-Quinone methides (o-QMs) are powerful intermediates in agents.10f Although some approaches for the synthesis of the
organic synthesis, drug chemistry and material chemistry.1 2,3-dihydrobenzofuran ring system have been described,11
Moreover, they have been implicated as the ultimate cytotoxins most of these methods have the drawbacks of poor chemo-
responsible for the functions of such agents as antitumor and/or stereoselectivities, impeding their wider application.
drugs, antibiotics, and DNA alkylators in biological chemistry.2 Thus, the development of an efficient, mild and convenient
As a consequence, some strategies have been successfully method for the preparation of these derivatives has important
developed for generating o-QMs.3 In the past decade, the significance and still remains a great challenge.
most popular methods were photochemical initiation4a–g of
Recently, as a good leaving group under basic conditions or
o-(a-phenyl) substituted phenols or thermal4h–j initiation of with acidic reagents (Lewis type), an arylsulfonyl group has been
various substituents on the benzene ring of o-methyl eneace- used in organic synthesis.12 We envisioned that the sulfonyl
toxy-phenols. Lewis acid,5a–c base5d–g and chemical oxidants5h moiety at the benzylic position of 2-substituted phenol would
were also used to generate o-QMs. In 2003, Ohwada’s group also serve as a good leaving group, and the o-QM intermediates
reported the retro-Diels–Alder reaction of 4H-1,2-benzoxazines can be generated in situ under mild basic conditions. Ylides13 act
to generate o-QMs.6 Subsequently, the fluoride induced desily- as a nucleophile under basic conditions, meanwhile, ylides could
lation of silyl derivatives of o-hydroxybenzyl bromine (or iodide) react with o-QMs to give the intermediate, followed by intra-
and o-hydroxybenzyl nitrate was also described.7 Very recently, molecular nucleophilic attack of the oxygen anion on the carbon
Bharate and co-workers developed Knoevenagel-type condensa- atom of ylides to furnish 2,3-dihydrobenzofuran derivatives
tion to furnish o-QMs.8a In addition, some efficient methods for (Scheme 1). In this process, a base has dual functions, generating
generating o-QMs8b,c involving the use of transition-metal both o-QM intermediates and ylides. Herein, we report an
complexes were also successfully documented. Considering efficient approach for generation of o-QM intermediates under
the importance of o-QMs as active intermediates and the mild basic conditions which further underwent the reaction with
instability of o-QMs due to dimerization as well as short life- sulfur ylides to synthesize trans-2,3-dihydrobenzofurans.
time,9 developing a mild and efficient method for o-QMs
generation from the commercially available starting materials
would be very desirable in organic synthesis and drug research.
a State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China.
E-mail: ygzhou@dicp.ac.cn; Web: http://www.lac.dicp.ac.cn/
b College of Chemistry and Chemical Engineering, Hunan University, Changsha
410082, China
† Electronic supplementary information (ESI) available: CCDC 876688. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3cc37800d
Scheme 1 General strategy for the mild generation of o-quinone methides and
synthesis of trans-2,3-dihydrobenzofurans.
c
1660 Chem. Commun., 2013, 49, 1660--1662
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Table 2 Substrate scope for the reaction of 2-(1-tosylalkyl)phenols 1 with
sulfonium salt 2a
2-(1-Tosylalkyl)phenols can be conveniently synthesized from the
commercially available 2-hydroxybenzaldehydes, Grignard reagents
and the p-toluenesulfinic acid sodium salt (eqn (1)). Reactions of
2-hydroxybenzaldehydes with Grignard reagents gave the 2-hydro-
xyalkylphenols, followed by the acid-mediated substitution with the
p-toluenesulfinic acid sodium salt to afford the desired 2-(1-tosyl-
methyl)phenols in moderate to excellent yields (35–86%).
Entry
R1
R2
R
Yieldb (%)
1
2
3
4
5
6
7
8
Ph
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
4-CF3C6H4
4-FC6H4
Ph
Ph
CH3
Et
Bu
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
5-Br
5-OMe
H
H
H
H
H
H
H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Me
CO2Bn
COPh
CONEt2
H
99 (3a)
98 (3b)
91 (3c)
98 (3d)
98 (3e)
91 (3f)
93 (3g)
99 (3h)
90 (3i)
80 (3j)
77 (3k)
82 (3l)
94 (3m)
67 (3n)
95 (3o)
90 (3p)
95 (3q)
(1)
In our initial research, we performed the reaction between
2-(phenyl(tosyl)methyl)phenol 1a and sulfonium salt 2a
(1.5 equiv.) at room temperature, using K2CO3 (4 equiv.) as the
base and CH2Cl2 as the solvent, respectively. To our delight,
2,3-dihydrobenzofuran 3a was isolated in 93% yield and excellent 13
diastereoselectivity with the ratio of more than 20 : 1 (trans/cis)
9
10
11
12
14
15
(entry 1, Table 1). The anionic base played a vital role in this
16
reaction, that it not only assists elimination of arenesulfinic 17c
H
acid to form the o-QM intermediate, but also promote sulfur
a
1 (0.2 mmol), 2 (0.24 mmol), Cs2CO3 (2.5 equiv.), CH2Cl2 (3 mL), room
b
ylides to participate in the nucleophilic reaction subsequently
temperature, 12 h. Isolated yields and all of the dr >20 : 1.
c
(entries 2–6). KOH and KOtBu were not effective (entries 3
Trimethylsulfoxonium iodide was used instead of sulfonium salts.
and 6), while K3PO4, NaOH and K2CO3 gave moderate to good
yields (entries 1, 2 and 4), and Cs2CO3 gave the excellent yield
and diastereoselectivity (entry 5). Then several common sol-
vents such as CH3CN, THF and toluene all led to the formation
of the product 3a in good yields and excellent diastereoselec-
tivities except DMSO (entries 6–10), and CH2Cl2 gave the best
result in terms of yield and trans/cis selectivity (98% yield and
>20 : 1 dr) (entry 5). While decreasing the amounts of base to
2.5 equiv. and sulfonium salt to 1.1 equiv. did not affect the
yield and the diastereoselectivity. Finally, we established the
optimal reaction conditions for this reaction: using Cs2CO3 as
the base and CH2Cl2 as the solvent to perform the reaction at
room temperature. The structure and stereochemistry of 3 were
well characterized by the combination of NMR, HRMS spectro-
scopy, and single-crystal X-ray analysis (see ESI†).
Under the optimized reaction conditions, a variety of
2-(1-tosylalkyl)phenols and sulfonium salts were explored to
examine the generality of the reaction (Table 2). Various
2-(1-tosylalkyl)phenols underwent the reaction smoothly and
gave the corresponding products with good to excellent yields
and diastereoselectivities (>20 : 1). As to the substituents R1, the
aryl substituents showed better reactivity than alkyl substituents
(entries 1–12). Although the steric and electronic nature of the
aryl substituents had a little influence on the outcome of the
reaction, generally high yields and diastereoselectivities were
obtained (entries 1–7). The effect of substituents of the phenol
did not inhibit the reaction (entries 8–9). Thereafter, various
kinds of sulfur ylides were also tested; good yields and excellent
diastereoselectivities were obtained (entries 13–16). Further-
more, the unstable ylide trimethylsulfoxonium iodide reacted
well with 1a to afford 3-phenyl-2,3-dihydrobenzofuran (3q) in
95% yield (entry 17). Subsequently, the synthesis of enantiomeri-
cally pure 2,3-dihydrobenzofuran was also tried. Using the
known camphor derived chiral sulfonium salts developed by
Dai and Tang14,15 instead of sulfonium salt 2a, only moderate
enantioselectivity (37% ee) and 99% yield were obtained.
Based on the above experimental results and stereochemis-
try of the products, a plausible mechanism was proposed as
illustrated in Scheme 2. Firstly, the reaction was initiated by the
formation of the o-QM intermediate A in the presence of a base,
then intermediate A reacts with sulfur ylides B to give the
intermediate C, followed by trans-elimination–cyclization to
afford the product trans-dihydrobenzofurans 3.
Table 1 Optimizing the conditions for the reaction of 2-(phenyl(tosyl)-methyl)-
phenol 1a with sulfonium salt 2aa
Entry
Solvent
Base
Yieldb (%)
drc
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
K2CO3
NaOH
KOH
93
81
>20 : 1
>20 : 1
n.d.
>20 : 1
>20 : 1
n.d.
>20 : 1
>20 : 1
>20 : 1
12 : 1
>20 : 1
o5
K3PO4
Cs2CO3
KOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
33
98
o5
85
94
94
10
99
9
Toluene
DMSO
CH2Cl2
10
11d
a
1a (0.2 mmol), 2a (0.3 mmol), base (4.0 equiv.), solvents (3 mL), room
temperature, 12 h. Isolated yields. Determined by 1H NMR. 2a
b
c
d
In summary, we have successfully developed a novel and
efficient method for generation of o-QM intermediates from the
(0.24 mmol), base (2.5 equiv.).
c
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Scheme 2 Plausible
mechanism
for the
formation of
trans-2,3-
dihydrobenzofurans.
readily available 2-tosylalkylphenol under mild basic conditions,
and their reactions with sulfur ylides for the stereoselective synth-
esis of 2,3-dihydrobenzofuran derivatives were investigated.16 This
methodology features cheap starting materials, mild reaction
conditions, high yields and high stereoselectivity. Further studies
on the application of o-QM intermediates in organic synthesis and
the asymmetric version of the reactions are in progress.
This work was financially supported by National Natural
Science Foundation of China (21032003 and 21125208).
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1662 Chem. Commun., 2013, 49, 1660--1662
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