Umpolung of Hemiaminals: Titanocene‐Catalyzed Dehydroxylative Radical Coupling Reactions with Activated Alkenes

Abstract

Bis(cyclopentadienyl)titanium(III) chloride (Nugents reagent) [1] is an efficient single-electron reductant and has been used as a versatile tool in organic synthesis, [2,3] owing to the ease of handling, its functional-group compatibility, and a broad array of reactions that can be effected under relatively mild conditions. Today, [Cp 2 TiCl] is used as a catalyst for several types of radical reactions by employing a catalytic amount of [Cp 2 TiCl 2 ] as a catalyst precursor and a metal (such as Mn, Zn, Al, In, Mg, and Sm) [4] as a coreductant in the presence of TMSCl or protic acids. Among the [Cp 2 TiCl]-catalyzed radical reactions, reductive epoxide opening reaction, [5] first demonstrated by Nugent and Rajan-Babu, [1] then by Gansäuer et al., [5b,c] has been the subject of intensive studies and found applications in natural product synthesis. [6] In this reaction, a [Cp 2 TiCl]-initialized homolysis of CÀO bonds is involved. As an extension of this feature, Barrero and co-workers recently described a deoxygenation of alcohols usually mediated by a stoichiometric amount of [Cp 2 TiCl]. In addition, catalytic examples have also been reported. [7] In view of these precedents, the [Cp 2 TiCl]catalyzed dehydroxylative coupling reactions of alcohols and other hydroxy-containing compounds, such as sugars, hemiacetals, and hemiaminals seemed possible.It is known that umpolung of hemiaminals can provide radical carbon intermediates in a position to amino groups through dehydroxylation and one-electron reduction of the corresponding carbenium ions. [8] We have recently developed a SmI 2 -mediated dehydroxylative radical cross-coupling reaction of hemiaminals with activated alkenes [Scheme 1, Eq. (1)], [9] which was assumed to proceed through a SmI 2based single-electron reduction of N-acyliminium ions. This methodology provides a useful and efficient strategy for C À C bond formation at the carbon atoms in a position to amino groups, and can be employed for the synthesis of alkaloids and other pharmaceuticals. [10] Based on these considerations, it would be particularly interesting and valuable to develop transition-metal-catalyzed dehydroxylative radical coupling reactions of hemiaminals under mild conditions, which have not been reported so far. We envisioned that the singular ability of [Cp 2 TiCl] to cleave a CÀO bond might help us to achieve this goal.Herein we report titanocene-catalyzed dehydroxylative radical coupling reactions of hemiaminals with activated alkenes [Scheme 1, Eq. (2)]. This novel reaction was performed by using a [Cp 2 TiCl 2 ] (cat.)/Mg/TMSCl reduction system [11] in the presence of tert-butanol. An application of this radical methodology has been demonstrated by an efficient synthesis of (AE)-9,10-diepi-stemoamide.We began our study with the treatment of hemiaminal 1 [12] and methyl acrylate (2.0 equiv) with [Cp 2 TiCl 2 ] (0.025 equiv), Mg powder (2.0 equiv), and TMSCl (2.0 equiv); the desired cross-coupling product 2 a was obtained in 54 % yield (Table 1, entry 1). The influence of othe...

Metal‐Catalyzed β‐Functionalization of Michael Acceptors through Reductive Radical Addition Reactions

“…[28] Hemiaminals were employed, which acted as masked aminoalkyl halides,a nd were formed in situ with Me 3 SiCl. [28] Hemiaminals were employed, which acted as masked aminoalkyl halides,a nd were formed in situ with Me 3 SiCl.…”

“…Ti III catalysis was also found to be suitable for achieving radical addition reactions of a-aminoalkyl radicals,w hich were generated by af ormal cleavage of CÀOH bonds as the initiation step (Scheme 6). [28] Hemiaminals were employed, which acted as masked aminoalkyl halides,a nd were formed in situ with Me 3 SiCl. Furthermore,c atalytic amounts of [Cp 2 TiCl 2 ]w ere used in combination with Me 3 SiCl, tertbutanol, and Mg. Thea uthors proposed that the hemiaminal was first transformed into the aminoalkyl chloride.S ingleelectron reduction would then afford the aminoalkyl radical, which would subsequently attack the Michael acceptor.T i III catalysis gave superior results compared to the earlier SmI 2 -mediated procedure.…”

“…Ti III catalysis was also found to be suitable for achieving radical addition reactions of α‐aminoalkyl radicals, which were generated by a formal cleavage of COH bonds as the initiation step (Scheme ) 28. Hemiaminals were employed, which acted as masked aminoalkyl halides, and were formed in situ with Me 3 SiCl.…”

Reductive Umpolung Reactions with Low-Valent Titanium Catalysts

“…More recently, a related reductive umpolung of hemiaminals was published by Zheng et al., which represented an advancement of a previously published electrochemically induced or SmI 2 ‐mediated process (Figure ) . This way, cyclic 5‐hydroxypyrrolidin‐2‐ones were coupled under mild reaction conditions and the scope of the Michael acceptor coupling partner was significantly broader than in other Ti III ‐catalyzed cross‐couplings.…”

Concise Diastereoselective Total Synthesis of (±)-Parvistemonine A

“…In contrast, reduction by borane at -20 °C afforded the desired alcohol 10 in good yield. 7 Next, sequential mesylation and iodination proceeded smoothly to give iodide 4 (Scheme 3). 8…”