Palladium(II)-Catalyzed C-H Bond Activation/C-C and C-O Bond Formation Reaction Cascade: Direct Synthesis of Coumestans

Article abstract of DOI:10.1021/acs.joc.6b01966

A palladium catalyzed cascade reaction of 4-hydroxycoumarins and in situ generated arynes has been developed for the direct synthesis of coumestans. This cascade strategy proceeds via C-H bond activation/C-O and C-C bond formations in a single reaction vessel. This methodology affords moderate to good yields of coumestans and is tolerant of a variety of functional groups including halide. The methodology was applied to the synthesis of natural product flemichapparin C.

Full text of DOI:10.1021/acs.joc.6b01966

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Note
Palladium(II)-Catalyzed C-H Bond Activation/C-C and C-O Bond
Formation Reaction Cascade: Direct Synthesis of Coumestans
Kashmiri Neog, Ashwini Borah, and Pranjal Gogoi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01966 • Publication Date (Web): 09 Nov 2016
Downloaded from http://pubs.acs.org on November 10, 2016
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The Journal of Organic Chemistry
Palladium(II)-Catalyzed C-H Bond Activation/C-C and
C-O Bond Formation Reaction Cascade: Direct Synthesis of
Coumestans
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Kashmiri Neog, Ashwini Borah and Pranjal Gogoi*
Applied Organic Chemistry Group, Chemical Science and Technology Division,
CSIR-North East Institute of Science and Technology, Assam, Jorhat 785006, India
Eꢀmail: gogoipranj@yahoo.co.uk
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ABSTRACT: A palladium catalyzed cascade reaction of 4ꢀhydroxycoumarins and in situ
generated arynes has been developed for the direct synthesis of coumestans. This cascade
strategy proceeds via CꢀH bond activation/CꢀO and CꢀC bond formations in a single reaction
vessel. This methodology affords moderate to good yields of coumestans and is tolerant of a
variety of functional groups including halide. The methodology was applied to the synthesis
of natural product flemichapparin C.
Coumestan constitutes the central core unit of a variety of natural polycyclic lactones1 with
2
important biological activities including anticancer, antibacterial, antifungal, antimyotoxic,
and phytoalexine effects. Most importantly, they are known as nonꢀsteroidal "dietary
estrogens". Some of the coumestans have the same binding affinity for the ERꢀβ estrogen
receptor as 17βꢀestradiol.3 Figure 1 shows some of the naturally occurring biologically active
coumestans such as coumestrol, wedelolactone, medicagol and psoralidin. Due to wide range
of biological properties make coumestans an interesting synthetic target for chemist.
Figure 1. Examples of some naturally occurring coumestans
The total syntheses of coumestans particularly coumestrol, wedelolactone, psoralidin,
and flemichapparin have been reported by several groups using quite different approaches
with modest overall yields.1d,4 Because of impressive biological activities, particularly
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The Journal of Organic Chemistry
Page 2 of 14
estrogenic, it is highly desirable to develop more efficient and general synthetic methods for
the synthesis of coumestans and their derivatives. In this regard, a number of synthetic
methods have been developed for the construction of this privileged structural unit. For
example, Pdꢀcatalyzed CꢀS activation followed by intramolecular transesterification of 2ꢀ
(methylthio)benzofuranꢀ3ꢀcarboxylates and 2ꢀhydroxyphenylboronic acid,5a iodocyclization
and Pdꢀcatalyzed intramolecular lactonization of acetoxyꢀcontaining 2ꢀ(1ꢀalkynyl)anisoles,5b
baseꢀcatalyzed condensation of phenyl acetic acid methyl ester with benzoylchloride
followed by intramolecular cyclization,5c LDAꢀinduced migration of heterobiaryl Oꢀ
carbamates,5d Ag2CO3/Celite mediated construction of furan ring from 1,3ꢀdicarbonyl
compounds and vinyl sulfides followed by dehydrogenation,5e aerobic ironꢀbased crossꢀ
dehydrogenative coupling of βꢀketoesters and phenols have been reported for the syntheses of
coumestan derivatives.5f In addition to these, derivatives of 4ꢀhydroxycoumarins have also
been extensively used to lead to diversified coumestan derivatives. In this regard, FeCl3ꢀ
mediated intramolecular oxidative annulation of 4ꢀhydroxyꢀ3ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone
derivatives,6a Pdꢀcatalyzed intramolecular arylation of 4ꢀ(aryloxy)ꢀ3ꢀhalocoumarins,6b
double CꢀH activations of 4ꢀphenoxyꢀ2ꢀcoumarins,6c and intramolecular CꢀH bond
functionalization6d,e are the notable examples (Figure 2). However, in all the cases, preꢀ
functionalizations of 4ꢀhydroxycoumarins are required to get the starting materials. Detsi et
al. has reported the use of enzyme peroxidase from onion solid waste for the synthesis of
coumestans from catechols and 4ꢀhydroxycoumarins in satisfactory yields.7 While there are
presently a number of useful synthetic procedures to prepare these compounds, there remain
several limitations as well. (i) Most of the reported procedures involve multiple steps with
moderate overall yield. (ii) The starting materials are often not very readily available. (iii)
Harsh reaction conditions are usually required. In view of these limitations, the development
of efficient strategy for the synthesis of coumestan is highly desirable.
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Figure 2. Some synthetic approaches to coumestans
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The Journal of Organic Chemistry
Arynes have been successfully used for the development of several useful synthetic
methodologies8 and demonstrated as versatile intermediate for the synthesis of natural
products.9 There are several methods for the generation of aryne,10 however Kobayashi’s
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10a
protocol
using oꢀsilyl aryl triflate and a fluoride source provides an excellent opportunity
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to demonstrate the application of arynes in various useful synthetic methodologies. In
addition, palladiumꢀcatalyzed C−H activation/C−C bond formation has emerged as a
powerful tool for chemical synthesis.11 This synthetic strategy is attractive from the
viewpoint of synthetic simplicity and step economy. Recently, Xu12 et al. reported a
palladiumꢀcatalyzed oxidative annulation of acrylamides with benzyne precursors for the
synthesis of quinolinones via N−H activation/Heck reaction strategy. Much progress has been
achieved in terms of synthesis efficiency and atom economy in the highly selective
functionalization of C−H bonds involving directing substituents. In this regard, we envisaged
here the Pdꢀcatalyzed CꢀH activation of 4ꢀhydroxycoumarins followed by CꢀC and CꢀO bond
formations with reactive intermediate arynes to access synthetically useful and biologically
important coumestan derivatives.
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To achieve this challenging transformation, we optimized our reaction conditions
employing 4ꢀhydroxycoumarin 1a and benzyne precursor 2a as model substrates (Table 1).
After a detailed investigation, the oxidative annulation of 1a with 2a gave coumestan 3a in
81% yield under the optimized conditions (Table 1, entry 4).
Table 1. Optimization Studies a
Entry
Catalyst
Oxidant
Fluoride
Source
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
Base
Solvent Isolated Yield
3a (%)b
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Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
ꢀꢀ
Cu(OAc)2
Air
K2CO3 CH3CN
K2CO3 CH3CN
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trace
trace
81
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
ꢀꢀ
CH3CN
NaOAc CH3CN
NaOAc CH3CN
NaOAc CH3CN
NaOAc CH3CN
NaOAc CH3CN
NaOAc CH3CN
NaOAc CH3CN
NaOAc DMSO
ND
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39
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15
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Pd(PPh3)4
[Cp*RhCl2]2
[RuCl2(pꢀCymene)]2 Cu(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
ꢀꢀ
K2S2O8
Ag2O
CsF
CsF
CsF
CsF
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
ꢀꢀ
NaOAc
NaOAc Dioxane
DMF
59
CsF
60
39
22
ND
TBAF NaOAc CH3CN
KF
CsF
NaOAc CH3CN
ꢀꢀ CH3CN
a Conditions: 4ꢀHydroxy coumarin (1.0 mmol), oꢀSilyl aryl triflate (1.5 mmol), Catalyst (5 mol%), Oxidant (1.2
o
b
mmol); Fluoride source (2 mmol); Base (1.2 mmol), CH3CN (5 mL) stirred in Ace pressure tube at 120 C;
isolated yield; ND: Not detected.
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