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. 2018 Nov 7;140(44):14836-14843.
doi: 10.1021/jacs.8b08605. Epub 2018 Oct 26.

Ti-Catalyzed Radical Alkylation of Secondary and Tertiary Alkyl Chlorides Using Michael Acceptors

Xiangyu Wu  1 , Wei Hao  1 , Ke-Yin Ye  1 , Binyang Jiang  1 , Gisselle Pombar  1 , Zhidong Song  1 , Song Lin  1
Affiliations

Ti-Catalyzed Radical Alkylation of Secondary and Tertiary Alkyl Chlorides Using Michael Acceptors

Xiangyu Wu et al. J Am Chem Soc. .

Abstract

Alkyl chlorides are common functional groups in synthetic organic chemistry. However, the engagement of unactivated alkyl chlorides, especially tertiary alkyl chlorides, in transition-metal-catalyzed C-C bond formation remains challenging. Herein, we describe the development of a TiIII-catalyzed radical addition of 2° and 3° alkyl chlorides to electron-deficient alkenes. Mechanistic data are consistent with inner-sphere activation of the C-Cl bond featuring TiIII-mediated Cl atom abstraction. Evidence suggests that the active TiIII catalyst is generated from the TiIV precursor in a Lewis-acid-assisted electron transfer process.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Reduction of Cp*TiCl3 by Mn in the presence or absence of AlCl3. Top: UV–vis spectra showing the reduction in the presence of AlCl3; the peaks at 450 and 330 nm are assigned to Cp*TiCl3 and its corresponding reduced form, respectively. Bottom: Change in absorption at 450 nm showing the reduction of Cp*TiCl3.
Figure 2.
Figure 2.
Cyclic voltammetry of Cp*TiCl3 (2 mM) and tBuCl (2 mM) in DCM (0.2 M BU4NPF6) with a scan rate of 100 mV/s.
Scheme 1.
Scheme 1.
Ti-Catalyzed Alkylation of Unactivated Alkyl Chlorides: Challenges and Rationale
Scheme 2.
Scheme 2.
Rationale for Catalyst Optimization
Scheme 3.
Scheme 3.
Synthetic Scale (1 mmol or Greater) Preparation and Ti-Catalyzed Alkylation of Alkyl Chlorides
Scheme 4.
Scheme 4.
Spin Trapping Experiments
Scheme 5.
Scheme 5.
Proposed Catalytic Cycle
See this image and copyright information in PMC

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