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Radical Addition Cascade Cyclization of 1,6-Enynes with DMSO to Access Methylsulfonylated and Carbonylated Benzofurans under Transition-Metal-Free Conditions Jie Zhang, Shijing Cheng, Zhiqiang Cai, Ping Liu, and Peipei Sun J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01265 • Publication Date (Web): 03 Jul 2018 Downloaded from http://pubs.acs.org on July 3, 2018
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The Journal of Organic Chemistry
Radical Addition Cascade Cyclization of 1,6-Enynes with DMSO to Access Methylsulfonylated and Carbonylated Benzofurans under Transition-Metal-Free Conditions Jie Zhang, Shijing Cheng, Zhiqiang Cai, Ping Liu,* and Peipei Sun* School of Chemistry and Materials Science, Jiangsu Provincial Key Laboratory of Material Cycle Processes and Pollution Control, Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Nanjing Normal University, Nanjing 210023, China
[email protected];
[email protected] ABSTRACT: A mild and direct addition/cyclization cascade to construct methylsulfonylated and carbonylated benzofurans was accomplished using oxygen-linked 1,6-enynes as the starting materials. The interaction of NH4I and DMSO promoted the generation of sulfur-containing radical and initiated the radical addition to the C=C double bond of 1,6-enynes cascade intramolecular 5-exo-dig cyclization. A wide range of oxygen-linked 1,6-enynes bearing various substituents were found to be suitable in this cascade process, providing benzofurans with dual functional groups in moderate to high yields. This method could also be utilized to synthesize benzothiophenes from sulfur-linked 1,6-enynes.
■ INTRODUCTION Benzofuran ring containing compounds are prevalent in many biologically active natural products, pharmaceutical and material molecules.1 For example, methoxsalen is a natural product found in many seed plants, and may be useful in facilitating smoking cessation as a CYP2A6 inhibitor (Figure 1).2 Amiodarone is an antiarrhythmic agent used to treat and prevent a series of irregular
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heartbeats.3 Benzbromarone structurally related to the amiodarone, is a uricosuric agent used for the treatment of primary chronic gout.4 Benzofuran derivatives are also often found in antifungal agents,5 antitubercular agents6 and psychoactive substances,7 etc.
Figure 1. Representative pharmaceutical molecules based on benzofuran.
Substantial efforts have been devoted to develop the versatile methods for the synthesis of benzofurans in the past decades.8 Among them, cascade cyclization strategy has become an attractive approach in recent years since it enables access to fused heterocycles in only a few steps and can simultaneously introduce some important functional groups.9 Radical cascade of 1,n-enynes is a very powerful synthetic methodology to construct carbocycles10 and heterocycles,11 and has been recently reviewed by Studer et al.12 In 2012, Tanaka and co-workers disclosed the intramolecular cyclization reactions of phenol-linked 1,6-enynes to produce vinylbenzofurans through the sequential cleavage and formation of sp2 C−O bonds in the presence of a cationic RhI catalyst.13 A radical cascade initiated by intermolecular addition of TEMPO or NO2 radical to C=C double bond of phenol-linked 1,6-enynes was reported by Li et al., who obtained two types of carbonylated benzofurans using tBuNO2 under air (Scheme 1).14 Afterwards, the group of Kumar15 and Jiang16 used the Langlois’ reagent (CF3SO2Na) and sodium sulfinate as precursor for trifluoromethyl and sulfonyl radicals in a similar cascade respectively. Despite these significant advances made for the construction of functionalized benzofurans, introducing useful groups with convenient methods to prepare diverse benzofuran derivatives are still highly desirable.
Scheme 1. Radical Cascade of 1,6-Enynes to Produce Difunctionalized Benzofurans
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The Journal of Organic Chemistry
Previous work Li, 2015
O
14
TEMPO R1
DMF, 40 o C t
R1 O R2 O
BuNO2 , air
H
O
R2
R1
O
H 2O
R2
EtOAc, r.t. Kumar, 2017
NO2
O R1
R2
CF 3SO 2Na visible light , PQ
R1 R2 O
CH3 CN/H 2O
O Jiang, 2017
O
15
16
R1
O
R3 SO2 Na AgNO 3, K 2S 2 O8
R2
R1 R2
CH3 CN, 85 o C
O
CF3
O
S O O R3
O
This work
R1
R1 NH4I (4.0 equiv)
R2
DMSO/H2 O, 130 o C, air O
R2 O
S O
O
Dimethyl sulfoxide (DMSO) is a useful high-boiling polar solvent for organic reactions because of its relative stability, low toxicity and low cost. In recent years, chemists have employed DMSO as versatile building blocks in organic transformations and made numerous important achievements.17 Our group described DMSO as the sources of methylthio group (MeS-) for the para-methylthiolation of arylamines and methylene group (-CH2-) for the methylene-bridged arylamines or imidazoheterocycles.18 Heterocycles bearing methylsulfonyl moiety (MeSO2-) are present in various medicinal compounds and show diverse biological activities.19 The application of DMSO as the source of methylsulfonyl was also reported by several groups.20 Our current research interest targets radical cascades by merging some readily available radical resources with unsaturated substrates to construct heterocyclic products under transition-metal-free conditions.21 Herein, we report a radical cascade of oxygen- or sulfur-linked 1,6-enynes with DMSO to access methylsulfonylated and carbonylated benzofurans or benzothiophenes. Initially, we tested the cascade reaction of 1-(phenylethynyl)-2-(vinyloxy)benzene (1a) in DMSO in the presence of NH4I (4.0 equiv) at 130 °C under air, and the desired product (2-((methylsulfonyl)methyl)benzofuran-3-yl)(phenyl)methanone (2a) was isolated in 20% yield (Table1, entry 1). We discovered that the chemical transformation was obviously influenced by the
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addition of co-solvent water (entries 2−7). The controlled experiments showed that a 4:1 volume ratio of DMSO and H2O was the best and resulted in 2a in 75% yield (entry 5). In the absence of the promoter NH4I, the reaction could not take place at all (entry 8). The addition of various other halides, such as a series of iodides (KI, HI, I2, TBAI (tetrabutylammonium iodide)), bromides (NH4Br, TBAB (tetrabutylammonium bromide)) or chloride (NH4Cl) instead of NH4I led to very slight conversion of 1a (entries 9−15). Changing the loading of NH4I did not improve the yield of 2a (entries 16−17). In addition, the reaction temperature and time were important parameters for the cascade process (entries 18−21). The yield of 2a dramatically decreased when the temperature was changed to 120°C or 100°C (entries 18−19), and a 30% yield was obtained when the time was shortened to 12 h (entry 20). A slightly lower yield of 2a was obtained under Ar atmosphere, which indicated that the cascade reaction did not need strict control to the reaction atmosphere (entry 22). In addition, when the reaction was performed using 5 equiv DMSO in DMF/H2O, a low yield of 12% was obtained (entry 23).
Table 1. Optimization of Reaction Conditionsa O
+ O
O S
promoter solvent, 130 oC, air
O
S O O
2a
1a
entry
promoter (equiv)
solvent (ratio)
T (℃)
yield (%)b
1
NH4I (4)
DMSO
130
20
2
NH4I (4)
DMSO/H2O (1:1)
130
55
3
NH4I (4)
DMSO/H2O (2:1)
130
60
4
NH4I (4)
DMSO/H2O (3:1)
130
68
5
NH4I (4)
DMSO/H2O (4:1)
130
75
6
NH4I (4)
DMSO/H2O (5:1)
130
66
7
NH4I (4)
DMSO/H2O (1:2)
130
32
8
−
DMSO
130
0
9
KI (4)
DMSO/H2O (4:1)
130
trace
10
HI (4)
DMSO/H2O (4:1)
130
