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Synthesis of Functionalized Benzo[b]furans via Oxidative Cyclization of o-Cinnamyl Phenols Mohammad Rehan, Rajender Nallagonda, Braja Gopal Das, Tannu Meena, and Prasanta Ghorai J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02752 • Publication Date (Web): 02 Mar 2017 Downloaded from http://pubs.acs.org on March 2, 2017
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The Journal of Organic Chemistry
Synthesis of Functionalized Benzo[b]furans via Oxidative Cyclization of o-Cinnamyl Phenols Mohammad Rehan, Rajender Nallagonda, Braja Gopal Das, Tannu Meena and Prasanta Ghorai* Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhauri, Bhopal462066, India.
ABSTRACT: Disclosed herein an efficient synthetic route for the synthesis of functionalized 2-benzyl benzo[b]furans via a regioselective 5-exo-trig intramolecular oxidative cyclization of ortho-cinnamyl phenols using [PdCl2(CH3CN)2] as catalyst and benzoquinone as an oxidant. Further, a sequential orthocinnamyaltion of phenols using cinnamyl alcohols catalyzed by Re2O7 followed by an oxidative cyclization using the above Pd-catalyst is performed. The reaction showed broad substrate scope with good to excellent yields. INTRODUCTION Benzo[b]furan is a common structural motif found in natural products, pharmaceuticals and agrochemicals.1 Derivatives of benzo[b]furans are acting, for examples, as antitumor2/anticancer-agents,3 5lipoxygenase4/mTOR signaling5a/angiotensin-inhibitors,5b and immunosuppressive activitors.6 The intriguing biological properties, medicinal applications and molecular architecture of benzo[b]furan based natural products continue to draw a challenge and motivation for their synthesis. Various efficient synthetic method has been developed;7 the traditional strategies for accessing the functionalized benzofurans relied mainly on the transition-metal catalyzed inter- or intra-molecular heteroannulation of prefunctionalized substrates (such as ortho-halo8 or ortho-alkynyl9 phenols). Recently, efforts have been directed towards the synthesis of benzo[b]furans via ortho C–H activation/functionalization of phenols (Scheme 1).10-15 Notably, highly substituted benzo[b]furan motifs are also present in various leading drugs and organic materials. In particular, a significant number of natural products and synthetic compounds contain the 2-benzyl 3-aryl/alkyl benzo[b]furan core (see Figure 1).16 Despite the significant advances in the synthesis of benzo[b]furans, selective synthesis of 2-benzyl 3-aryl/alkyl benzo[b]furan motifs from readily accessible phenols still remains a daunting challenge. Notably, among the above mentioned methods, only the ortho-propargylation/annulation strategy successfully provided such moiety, albeit with limited substrate scope.13,17 Therefore, the development of a method to synthesize the
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above mentioned benzo[b]furans from readily available substrates with broad substrate scope would be significantly rewarding.
Figure 1. Bioactive 2-benzyl benzo[b]furans Inspired by the oxidative-annulation strategy,18 our group has a long-standing interest in the Pdcatalysed oxidative cycloannulation of various cinnamyl-substituted building blocks, which has been proven to be an important strategy for the synthesis of many hetrocycles.19 For instances, ocinnamylanilines have been utilized for the synthesis of 2-benzyl indoles19a and 2-aryl quinolines19b. More recently, the synthesis of 2-benzyl furans also have been developed from 2-cinnamyl-1,3dicarbonyls.19c Here, we sought for the synthesis of functionalized 2-benzyl 3-aryl/alkyl benzo[b]furan via an intramolecular oxidative cyclization of o-cinnamylphenols.20 Ar
Previous reports:
Ar
or R
Ar O
R2 R1
HO 2C
(Ref .10) O
OH
[M]
R
CO 2R 2
R1
(Ref.11)
(Ref.13)
Ar2
R1
R1
O
HO
(Ref.12)
OH O
R
Ar 1
CO 2R 2 R
R2
Ar 2
R
Ar 1 R Ar 2
O
Ar1 This work: FC ort ho-cinnamylation/oxidative cycloisomerization FG
R HO
FC Re
FG
OC R
FG
O2
OH Ar Re
Pd
OH Ar o-Cinnamy lphenol
R
Pd
Ar O
one-pot
Scheme 1. Synthesis of Functionalized Benzo[b]furans from Phenol
2
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The Journal of Organic Chemistry
Further, a simple and effecient one-pot protocol for the synthesis of functionalized 2-benzyl benzo[b]furan via a sequential o-cinnamylation of phenol followed by oxidative cyclization has also been demonstrated. An easy avaiablility of the cinnamyl alcohols compared to the propargyl alcohol might provide a broader synthetic utility of the current methodology.
RESULTS AND DISCUSSION The reaction optimization studies for the oxidative cyclization of the model substrate o-cinnamylphenol (1a), which was prepared via a Friedel-Crafts alkylation of cinnamylalcohol with phenols using Re2O7 catalyst in acetonitrile as solvent (for details, see Supporting Information), is summarised in Table 1. When 1a was stirred in 1,4-dioxane at 80 oC in the presence of a 5 mol% of various palladium catlysts (such as Pd(OAc)2, [Pd(PPh3)2Cl2], Pd(OTFA)2, PdCl2 and [PdCl2(CH3CN)2], entries 1-5, respectively), it was observed that [PdCl2(CH3CN)2] provided the desired 2-benzyl-5-methyl-3-phenyl benzo[b]furan 3a (entry 5) in 38% isolated yield in the presence of O2 ballon as an oxidant. Table 1. Catalyst optimizationa H3C OH Ph Ph 1a (0.2 mmol)
Ph
H3C
catalyst (5 mol %) Oxidant
O
80 oC
Ph
3a
entry
Catalyst
Oxidant
Solvent
Yield (%)b
1
Pd(OAc)2
O2
toluene
28
2
Pd(PPh3)2Cl2
O2
toluene
trace
3
Pd(OTFA)2
O2
toluene
17
4
PdCl2
O2
toluene
23
5
PdCl2(CH3CN)2
O2
toluene
38
6
PdCl2(CH3CN)2
BQ
toluene
66
7
PdCl2(CH3CN)2
BQ
1,4-dioxane
85
8
PdCl2(CH3CN)2
BQ
Other solventsc
