Formal anti-Markovnikov Hydroamination of Terminal Aryl Alkynes with Pinacolborane and Hydroxylamines via Zr/Cu Sequential Catalysis

Abstract

We have developed sequential Zr/Cu catalysis involving regioselective hydroboration and electrophilic amination for the formal anti-Markovnikov hydroamination of terminal aryl alkynes. The reaction system can provide a facile access to enamines from terminal acetylenes with high regioselectivity under mild conditions.Enamines are important building blocks in organic synthesis because of their versatile reactivity directed toward alkylations, cycloadditions, and some related bond-forming reactions for heterocycle synthesis.1 In general, enamines are prepared by condensation of the corresponding aldehydes or ketones and amines in the presence of Brønsted acids or Lewis acids. However, due to relatively harsh reaction conditions, the above processes sometimes suffer from low functional compatibility. On the other hand, transition-metal-catalyzed hydroamination of alkynes with amines has recently received significant attention because it can complement the traditional condensation methodology and provide functional-group-tolerant approach to the target enamines. To date, a variety of catalyst systems have been reported. 3 However, in view of regioselectivity and efficiency, there still remains some room for the anti-Markovnikov hydroamination of terminal alkynes. Although 4 Ru-, 5 and Zrbased 6 catalysts have been successfully employed, 7 most of them require elevated temperature.8 Thus, further developments appear to be desired.Meanwhile, our group 9 and others 10 have recently focused on the unique reactivity of chloramines and hydroxylamine derivatives and succeeded in the catalytic CN bond formation through an electrophilic amination. In this context, we envisioned that a combination of regioselective hydroboration of terminal alkynes and electrophilic amination of preformed alkenylborane intermediates could be a good alternative to the above hydroamination protocols. Here, we report sequential Zr/ Cu catalysis for a formal anti-Markovnikov hydroamination of terminal aryl alkynes. The process involves Zr-catalyzed hydroboration with pinacolborane and Cu-catalyzed electrophilic amination with O-benzoylhydroxylamines, leading to the corresponding enamines regioselectively under very mild conditions (Scheme 1). 11To establish the second electrophilic amination step shown in Scheme 1, we first chose (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (0.25 mmol) and O-benzoyl-N,N-diethylhydroxylamine (1a, 0.30 mmol) as model substrates and extensively screened various reaction parameters such as catalysts, bases, and solvents. It was found that the reaction proceeded in THF smoothly even at room temperature in the presence of a catalytic amount of Cu(OAc) 2 ¢OH 2 together with several phosphorous ligands using LiOt-Bu as the base (Scheme 2).Among the phosphorus ligands we tested, P(OEt) 3 , PPh 3 , and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) showed better activity, and the corresponding enamine 2a was obtained in 5965% yields, as judged by 1 H NMR. In the case of P(OEt) 3 , when 1a was used as...

Copper-Catalyzed Electrophilic Amination of sp2 and sp3 C−H Bonds

“…We were interested in O-acylhydroxylamines as an electrophilic nitrogen source, inspired by the pioneering work on electrophilic aminations between organometallic reagents and Oacylhydroxylamines. [45][46][47][48][49][50][51][52][53][54][55][56][57][58] Simultaneously, we envisioned that various Oacylhydroxylamines could also act as an electrophilic acylating agent [48][49]51 toward zinc enolates and lead to the alternative formation of 1,3-dicarbonyl compounds. Such dual reactivity of O-acylhydroxylamines is valuable and useful, providing a powerful and divergent strategy for direct and selective access to α-amino carbonyl and 1,3-dicarbonyl compounds, highly desirable motifs in organic synthesis and pharmaceuticals.…”

“…[35][36][37][38][39][40][41][42][43][44] The key to these amination reactions is the use of [NR 2 ] + synthons as the nitrogen source. Many electrophilic aminations have been achieved using various organometallic reagents, [45][46][47][48][49][50][51][52][53][54][55][56][57][58] while significant advances have also been achieved via C−H functionalization. [59][60][61][62][63][64] Most of these transformations leverage the use of transition metals to facilitate the formation of the C−N bond.…”

“…These include oxaziridines, 97 N-haloamines, [98][99][100][101][102] and O-substituted hydroxylamines. [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][103][104][105][106][107][108] Of the various electrophilic aminating reagents, O-acylhydroxylamine derivatives occupy a prominent position in the development of umpolung C−N bond construction. 35 In particular, O-benzoylhydroxylamines have become increasingly popular for the synthesis of alkyl and aryl amines.…”

“…35 In particular, O-benzoylhydroxylamines have become increasingly popular for the synthesis of alkyl and aryl amines. [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][103][104][105][106][107][108] They are easily prepared via oxidation of primary or secondary amines with benzoyl peroxide or the benzoylation of hydroxylamines to give stable, often crystalline, compounds (Scheme 1). 48 Due to the labile nature of the N−O bond of O-benzoylhydroxylamines, electrophilic amination of different nucleophilic species is often achieved via transition metal catalysis.…”

“…48 Due to the labile nature of the N−O bond of O-benzoylhydroxylamines, electrophilic amination of different nucleophilic species is often achieved via transition metal catalysis. [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][103][104][105][106][107][108] [45][46][47][48] Grignard reagents, 49 organoboron compounds, [50][51][52][53][54] organosilicon reagents, [55][56] organolithiums, 57 and organozirconium reagents. 58 Generally amination reactions of organometallics with O-benzoylhydroxylamines utilize transition metals such as copper or nickel to cleave the N−O bond and promote the formation of C−N bonds.…”