[3+2] Cycloaddition of Alkynyl Boronates and in†situ Generated Azomethine Ylide.

Scalable [3+2] cycloaddition of alkynyl boronates and in situ generated unstabilized azomethine ylide is reported for the first time. The selective formation of either 1 : 1 or 1 : 2 cycloaddition products was achieved by carefully optimizing the reaction conditions, mainly by controlling the reactant stoichiometry, catalyst loading, and internal temperature. The developed protocol tolerated many valuable functional groups, including TMS, protected alcohol (as ether or THP derivatives), or aldehyde (as acetal). Further common C-C and C-heteroatom bond-forming reactions, as well as scaled-up procedures demonstrate the utility of the prepared compounds as building blocks for organic synthesis and drug discovery.

Chemoselective Reactions of Functionalized Sulfonyl Halides.

Chemoselective transformations of functionalized sulfonyl fluorides and chlorides are surveyed comprehensively. It is shown that sulfonyl fluorides provide an excellent selectivity control in their reactions. Thus, numerous conditions are tolerated by the SO2 F group - from amide and ester formation to directed ortho-lithiation and transition-metal-catalyzed cross-couplings. Meanwhile, sulfur (VI) fluoride exchange (SuFEx) is also compatible with numerous functional groups, thus confirming its title of "another click reaction". On the contrary, with a few exceptions, most transformations of functionalized sulfonyl chlorides typically occur at the SO2 Cl moiety.

Photochemical [2+2] Cycloaddition of Alkynyl Boronates.

A photochemical [2+2] cycloaddition of alkynyl boronates and maleimides is reported. The developed protocol provided 35-70 % yield of maleimide-derived cyclobutenyl boronates and demonstrated wide compatibility with various functional groups. The synthetic utility of the prepared building blocks was demonstrated for a range of transformations, including Suzuki cross-coupling, catalytic or metal-hydride reduction, oxidation, and cycloaddition reactions. With aryl-substituted alkynyl boronates, the products of double [2+2] cycloaddition were obtained predominantly. Using the developed protocol, a cyclobutene-derived analogue of Thalidomide was prepared in one step. Mechanistic studies supported the participation of the triplet-excited state maleimides and ground state alkynyl boronates in the key step of the process.

Synthesis of 3-Borylated Pyrrolidines by 1,3-Dipolar Cycloaddition of Alkenyl Boronates and Azomethine Ylide.

A scalable and efficient process for the preparation of 3-borylated pyrrolidines by 1,3-dipolar cycloaddition of N-benzyl azomethine ylide generated in situ has been developed. The optimized method included the use of LiF in DMSO at 110 °C and was suitable for α-mono-, α,ß-di-, and α,ß,ß-trialkyl-, ß,ß-(hetera)cycloalkylidene-, CO2 Et-, as well as most ß-(het)aryl-substituted alkenyl boropinacolates. The 1,3-dipolar reaction proceeded on a multigram scale providing 3-borylated pyrrolidines with diverse substitution patterns (including fused and spirocyclic ones) in a diastereoselective manner. The Pd(OH)2 -mediated N-debenzylation of pyrrolidine hydrochlorides was successfully performed to give the corresponding bifunctional building blocks on an up to 130 g scale, thus providing a substantial expansion of the synthetic and medicinal chemist's toolbox. Other reactions included the preparation of trifluoroborates, Zweifel-Aggarwal sp3 -sp2 coupling, and oxidative deborylation as an example of C-heteroatom bond formation.

Regioselective synthesis of isoxazole and 1,2,4-oxadiazole-derived phosphonates via [3 + 2] cycloaddition.

The results of the study on reactions of halogenoximes bearing (protected) functional groups or fluorinated substituents with various phosphorus-containing dipolarophiles are described. To control the regioselectivity of the reaction, vinylphosphonates bearing a leaving group (i.e. bromine or dialkylamino group) in the α or ß position were used; 3,5- and 3,4-disubstituted isoxazoles were obtained in 47-80% and 63-75% yields, respectively. The reaction was also effective for the parent vinyl phosphonate and cyanophosphonate; in this case, the corresponding isoxazoline- and 1,2,4-oxadiazole-derived phosphonates were isolated in 55-69% and 34-73% yields, respectively. The utility of the products obtained was demonstrated by the preparation of direct conformationally restricted analogues of phosphohistidine.