Double Sonogashira Research Articles

Total Synthesis Confirms Laetirobin as a Formal Diels-Alder Adduct

Laetirobin, isolated from a parasitic fungus host-plant relationship, was synthesized in six practical steps with an overall yield of 12% from commercially available 2,4-dihydroxyacetophenone. Because the product is a pseudosymmetric tetramer of benzo[b]furans, each step of the synthesis was designed to involve tandem operations. Highlights include: 1) the double Sonogashira reaction of a bis(alkyne), 2) the practical copper(I)-mediated formation of a bis(benzo[b]furan), and 3) the biomimetic [4+2] dimerization and unexpected cationic [5+2] annulation of gem-diaryl alkene precursors. Preliminary structure-activity relationship data between the isomeric [4+2] and [5+2] tetramers revealed only the natural product to possess promising anticancer potential. Specifically, laetirobin is capable of blocking tumor cell division (mitosis) and invoking programmed cell death (apoptosis).

Microwave-Assisted Selective Synthesis of 2H-Indazoles via Double Sonogashira Coupling of 3,4-Diiodopyrazoles and Bergman–Masamune Cycloaromatization

The microwave-assisted double Sonogashira coupling of 3,4-diiodo-1-trityl and 1-phenylpyrazole with terminal acetylene took only three minutes. Dialkynylpyrazoles, the coupling products, were heated at 240 °C in the presence of 1,4-cyclohexadiene to obtain 2H-2-trityl and 2-phenylindazoles, respectively. This synthetic route to 2H-indazole, which was achieved via cyclization to form the 6-membered ring of dialkynylpyrazole, is a novel procedure.

Synthesis and EPR studies of 2'-deoxyuridines with alkynyl, rodlike linkages.

Sonogashira coupling of diacetyl 5-ethynyl-2'-deoxyuridine with diacetyl 5-iodo-2'-deoxyuridine gave the acylated ethynediyl-linked 2'-deoxyuridine dimer (3 b; 63%), which was deprotected with ammonia/methanol to give ethynediyl-linked 2'-deoxyuridines (3 a; 79%). Treatment of 5-ethynyl-2'-deoxyuridine (1 a) with 5-iodo-2'-deoxyuridine gave the furopyrimidine linked to 2'-deoxyuridine (78%). Catalytic oxidative coupling of 1 a (O(2), CuI, Pd/C, N,N-dimethylformamide) gave butadiynediyl-linked 2'-deoxyuridines (4; 84 %). Double Sonogashira coupling of 5-iodo-2'-deoxyuridine with 1,4-diethynylbenzene gave 1,4-phenylenediethynediyl-bridged 2'-deoxyuridines (5; 83%). Cu-catalyzed cycloisomerization of dimers 4 and 5 gave their furopyrimidine derivatives. One-electron addition to 1 a, 3 a, and 4 gave the anion radical, the EPR spectra of which showed that the unpaired electron is largely localized at C6 of one uracil ring (17 G doublet) at 77 K. The EPR spectra of the one-electron-oxidized derivatives of ethynediyl- and butadiynediyl-linked uridines 3 a and 4 at 77 K showed that the unpaired electron is delocalized over both rings. Therefore, structures 3 a and 4 provide an efficient electronic link for hole conduction between the uracil rings. However, for the excess electron, an activation barrier prevents coupling to both rings. These dimeric structures could provide a gate that would separate hole transfer from electron transport between strands in DNA systems. In the crystal structure of acylated dimer 3 b, the bases were found in the anti position relative to each other across the ethynyl link, and similar anti conformation was preserved in the derived furopyrimidine-deoxyuridine dinucleoside.

The first asymmetric Sonogashira coupling for the enantioselective generation of planar chirality in paracyclophanes

The double Sonogashira coupling of diiodoparacyclophanes with alkynes proceeded to give planarly chiral dialkynylparacyclophanes; a chiral Pd catalyst, which was prepared in situ from PdCl(2)(CH(3)CN)(2) and Taniaphos, realized the first asymmetric Sonogashira coupling with up to ca. 80% ee.

Palladium‐Catalyzed Efficient and One‐Pot Synthesis of Diarylacetylenes from the Reaction of Aryl Chlorides with 2‐Methyl‐3‐butyn‐2‐ol

AbstractAn efficient and practical synthetic method has been developed for the preparation of symmetrical diarylacetylenes from the direct reaction of aryl chlorides with 2‐methyl‐3‐butyn‐2‐ol catalyzed by palladium(II) chloride‐bis(tricyclohexylphosphine) [PdCl2(PCy3)2] under mild reaction conditions. Unsymmetrical diarylated acetylenes could be also obtained by using two different aryl chlorides simultaneously. The catalytic procedure includes a novel one‐pot palladium‐catalyzed, double Sonogashira coupling of inactivated aryl chlorides without use of copper(I) as co‐catalyst.

Methods for the Synthesis of 5,6,7,8-Tetrahydro-1,8-naphthyridine Fragments for αVβ3 Integrin Antagonists

The preparation of 3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propan-1-amine 2a and 3-[(7R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl]propan-1-amine 2b, key intermediates in the synthesis of alpha(V)beta(3) antagonists, is described. The syntheses rely on the efficient double Sonogashira reactions of 2,5-dibromopyridine 3 with acetylenic alcohols 4a/4b and protected propargylamines 10a-e followed by Chichibabin cyclizations of 3,3'-pyridine-2,5-diyldipropan-1-amines 9a/9b.

Synthesis and analysis of polyethylene glycol linked P-glycoprotein-specific homodimers based on (−)-stipiamide

A series of five homodimeric polyethylene glycol (PEG) linked homodimers based on the multidrug resistance reversal agent (−)-stipiamide were made and tested for their ability to interact with P-glycoprotein, the protein responsible for multidrug resistance, using ATPase and photoaffinity displacement assays. Key reactions include a new alkoxide-mesylate displacement for the assembly of the PEG linkers and a double Sonogashira coupling reaction.