Synthesis and Rh-catalyzed reductive cyclization of 1,6-enynes and 1,6-diynes containing alkynylboronate termini

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Abstract

Ir-catalyzed dehydrogenative borylation of terminal alkynes (DHBTA) has been used to borylate the C(sp)-H bond in a series of 1,6-enynes and 1,6-diynes. Ir catalysts based on the diarylamido/bis(phosphine) PNP ligands proved to be capable of performing DHBTA on these substrates. The alkynylboronate products were then explored as substrates in reductive cyclization reactions designed to yield five-membered carbocycles and heterocycles with preservation of the carbon-boron bond. The reductive cyclization of enynes with H2 was carried out using cationic Rh catalysts (after the work of Krische et al.) supported by bidentate phosphine ligands, of which BINAP proved to be the generally best performing. Reductive cyclization of borylated enynes typically resulted in mixtures of isomeric products. Attempts to optimize the reductive cyclization of borylated 1,6-enynes to yield a single product were not successful; in addition, the distribution of products in these reactions was poorly reproducible. On the other hand, reductive cyclization of 1,6-diynes with the same Rh catalysts was better behaved, allowing for selectivity and reproducibility. In particular, alkynylboronate derivatives of bis(propargyl)amine underwent smooth reductive cyclization to 3,4-substituted pyrroles. The influence of substituents and conditions on the product distribution was explored and representative reactions utilizing new borylated heterocycles in Suzuki coupling reactions were carried out.

Introduction

Organoboronic esters have proven to be versatile building blocks that can undergo a number of transformations [1]. Most notably they are used as substrates in Suzuki coupling [2], but numerous transformations can be performed with these compounds to access a number of functionalities [3]. Due to the versatility of organoboronic esters, new methodologies for incorporating C–B bonds into molecules are of great interest. Our group has been focused on developing the dehydrogenative borylation of terminal alkynes (DHBTA) using pincer-ligated iridium [4,5] and palladium catalysts [6]. Other catalysts for the dehydrogenative borylation of terminal alkynes have recently been reported by the Tsuchimoto [7], Bertrand [8], Darcel [9], and Ingleson groups [10]. Our second generation Ir catalysts Ir2 and Ir3 (Scheme 1) have shown remarkable reactivity and substrate scope and have outperformed our first generation DHBTA catalyst Ir1. These complexes have allowed us to explore more sophisticated substrates such as 1,6-enynes and 1,6-diynes.

The use of 1,6-eynes and 1,6-diynes in cyclization reactions is a well-developed area of chemistry [11], but there are only a few reports of reactions using the borylated substrates. The benefit of using alkynylboronates in cyclization reactions is that the resulting cyclic compound will have a versatile C–B linkage preinstalled. This benefit has prompted other chemists to pursue cyclizations with alkynylboronates. For instance, Renaud et al. showed that borylated 1,6-enynes could undergo enyne metathesis using ruthenium catalysts (Scheme 2, top) [12]. The Aubert group has also conducted cobalt-mediated [2 + 2+2] cycloadditions with alkynylboronates and borylated α,ω-diynes [13,14]. Borylated monoynes however, are more frequently used in cyclization reactions [15]. Gandon and Aubert have used rhodium-catalyzed [2 + 2+2] cycloadditions of alkynylboronates followed by selective Suzuki coupling in order to synthesize a series of oligoaryls (Scheme 2, bottom) [16]. The Harrity group has also used numerous cyclization reactions with alkynylboronates to synthesize borylated cyclic compounds such as pyrazoles [17], pyridones [18], arenes [19], and a number of other cyclic compounds [20]. Recently, alkynylboronates have also been used as substrates for regioselective Pauson-Khand reactions [21]. The alkynylboron reagents used in these reactions were all synthesized via the use of a stoichiometric strong base and anhydrous acidic work up developed by Brown [22].

For this publication, we were inspired by the work of the Krische group [23] to investigate the use of cationic rhodium catalysts to perform reductive cyclization with borylated 1,6-enynes and 1,6-diynes. This reaction uses dihydrogen as a terminal reductant to form a five-membered exocyclic alkene from a 1,6-enyne or a five-membered exocyclic diene from a 1,6-diyne (Scheme 3). Reductive cyclization is a useful way of synthesizing five-membered rings, and has been used in the total synthesis of daphnane diterpene orthoesters [24] and lucentamycin A [25]. The benefit of extending this reaction to use alkynylboronates is that the resulting five-membered ring will form with a Csp2-B preinstalled and be ready for further functionalization. Alternatively, boranes can be used as a reductant in cyclization reactions with 1,6-enynes and 1,6-diynes to synthesize cyclic compounds with C–B bonds. Enynes have been shown to undergo borylative cyclization reactions such as the palladium-catalyzed borylative cyclization to exocyclic alkenylboronates [26], or the rhodium-catalyzed hydroborylation-cyclization reactions to form exocyclic alkyenylboronates [27]. Recently the Lu group has also used cobalt catalysts to perform hydroboration/cyclization of 1,6-enynes [28]. In addition to using dihydrogen or boranes as reductants, other reducing agents such as silanes [29] and aldehydes [30] have been used.

Herein, we describe a method of borylating 1,6-enynes and 1,6-diynes through DHBTA, and using these products in reductive cyclization with cationic rhodium complexes (Scheme 3). In our experience, borylated 1,6-enynes underwent reductive cyclization and then an olefin isomerization, which usually resulted in a mixture of endocyclic alkenes and exocyclic alkenes. Borylated 1,6-diynes could also undergo a similar isomerization, and borylated 1,6-diynes with amine linkers were shown to form 3,4-bis(methylpinacolborane)-substituted pyrroles. By combining DHBTA with reductive cyclization, we have developed an atom economical method of developing pyrroles with C–B bonds preinstalled. Pyrroles in general are valuable target molecules due to their presence in pharmaceuticals [31], and a lot of attention has been devoted to developing new synthetic routes [[32], [33], [34]].

Section snippets

DHBTA of 1,6-enynes

We have previously shown that Ir3 is capable of borylating N-allyl-N-propargyl toluenesulfonamide, and dimethyl 2-allyl-2-propargylmalonate at 0.1% catalyst loading using 2 eq. of pinacolborane (HBpin) [5]. We have expanded this substrate scope by investigating additional 1,6-enynes tethered by an amine or ether functionality and investigated their reactivity with HBpin (results described in Table 1). Ir3 performed well with all of the substrates using 0.1 mol% catalyst loading. Diethyl

Conclusion

We have expanded the substrate scope of Ir-catalyzed DHBTA to include a number of 1,6-enynes and 1,6-diynes. These species are capable of undergoing rhodium-catalyzed reductive cyclization. However, the pinacolboryl substituent seems to promote an alkene isomerization with heteroatom-tethered enynes and diynes. This double bond isomerization was difficult to control with 1,6-enynes, and these reactions usually resulted in a mixture of products. However, the reductive cyclization of 1,6-diynes

Data statement

The data underlying this manuscript include experimental procedures, and characterization of chemical compounds by NMR spectroscopy and mass-spectrometry. These data can be found in the supplementary information for this manuscript.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We are thankful for the support of this work by the US National Science Foundation (grants CHE-1300299 and CHE-1565923). We are grateful to Yanyan Wang and Prof. Donald J. Darensbourg for their assistance with automated flash column chromatography, Ruth Ann Gholson for assistance with the formatting of the manuscript, and Bryan J. Foley for assistance with accessing and collecting some of the data.

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      In 2015, we reported on tandem catalysis of the conversion of terminal alkynes into triborylalkenes by the Ir complexes supported by the SiNN ligand [25]. The first step of the transformation is the dehydrogenative borylation of terminal alkynes (DHBTA), on which we and others extensively reported separately [26–36]. DHBTA results in the formation of alkynylboronates which are diborated in the second step to yield triborylalkenes by a (SiNN)Ir catalysts modified by the addition of CO.

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