Chlorodifluoromethane as a C1 Synthon in the Assembly of N-Containing Compounds

摘要

class="head no_bottom_margin" id="sec1title">IntroductionThe C1 chemistry has emerged as an elegant strategy for efficient preparation of homologous compounds, which added one extra carbon in modern chemical transformations (, , , , , , ). There are ample significance and a plethora of characteristics for C1 chemistry, for instance, carbon chain increasing (), construction of importance functional groups (carboxylic or carbonyl groups) (, ), incorporation of two or more organic small molecules to yield important products (), and modification of the pharmaceutical or natural products for value-added bulk (, ). Among all known C1 synthons, CO2, CO, and formic acid are the most famous ones, which have been widely used in various reaction processes, and many beautiful transformations have been developed with them, which further attracted more and more chemists devoted to this field (, , href="#bib1" rid="bib1" class=" bibr popnode">Aresta et al., 2014, href="#bib17" rid="bib17" class=" bibr popnode">Huang et al., 2011, href="#bib5" rid="bib5" class=" bibr popnode">Cokoja et al., 2011, href="#bib29" rid="bib29" class=" bibr popnode">Oh and Hu, 2013, href="#bib37" rid="bib37" class=" bibr popnode">Sordakis et al., 2018, href="#bib11" rid="bib11" class=" bibr popnode">Gibson, 1969, href="#bib7" rid="bib7" class=" bibr popnode">Enthaler et al., 2010). Despite the significance and great advance of C1 chemistry, the search for C1 synthons that display unique reactivity, complement to the current C1 sources, and add more value to C1 chemistry is still highly desirable. Thus, direct introduction of one extra carbon from cheap and available materials under mild conditions to provide a cost-efficient, pragmatic, and valuable alternative avenue would be popular in the field of synthetic and pharmaceutical communities, which might have deep impact on industry as well.Chlorodifluoromethane (ClCF2H) is well known as an inexpensive and abundant industrial raw material (href="#bib18" rid="bib18" class=" bibr popnode">Hudlicky and Pavlath, 1995) for the construction of various fluorinated compounds (href="#bib40" rid="bib40" class=" bibr popnode">Wang et al., 2014, href="#bib9" rid="bib9" class=" bibr popnode">Fier and Hartwig, 2012, href="#bib13" rid="bib13" class=" bibr popnode">Gu et al., 2014, href="#bib44" rid="bib44" class=" bibr popnode">Yu et al., 2017, href="#bib41" rid="bib41" class=" bibr popnode">Wu et al., 2019, href="#bib26" rid="bib26" class=" bibr popnode">Miao et al., 2018, href="#bib46" rid="bib46" class=" bibr popnode">Zhang et al., 2019), featuring thermodynamic stability and kinetic inertness as well as atomic economy as fluorine source. Therefore, efficient transformations of this easily accessible raw material to create valuable chemicals have deservedly gained great attention. The most common transformation of ClCF2H involves the formation of difluorocarbene (:CF2) by the cleavage of both C-Cl and C-H bonds (href="/pmc/articles/PMC6658997/figure/fig1/" target="figure" class="fig-table-link figpopup" rid-figpopup="fig1" rid-ob="ob-fig1" co-legend-rid="lgnd_fig1">Figure 1Aa) (href="#bib8" rid="bib8" class=" bibr popnode">Feng et al., 2017), usually under basic conditions with heteroatom nucleophiles, rendering the corresponding difluoromethylated heteroatom compounds (href="#bib14" rid="bib14" class=" bibr popnode">Hine and Porter, 1957, href="#bib28" rid="bib28" class=" bibr popnode">Nawrot and Jonczyk, 2007). Pyrolysis of ClCF2H at high temperature or pressure leads to the important raw industrial material tetrafluoroethylene (href="#bib18" rid="bib18" class=" bibr popnode">Hudlicky and Pavlath, 1995, href="#bib38" rid="bib38" class=" bibr popnode">Sung et al., 2004). Very recently a reaction by palladium-catalyzed cross-coupling between arylboronic acids and ClCF2H via a metal-difluorocarbene intermediate has been reported (href="#bib8" rid="bib8" class=" bibr popnode">Feng et al., 2017, href="#bib45" rid="bib45" class=" bibr popnode">Yu et al., 2019), representing the catalytic transformation of ClCF2H. Other conversion processes that do not involve difluorocarbene species were still difluoromethylation-related ones in which only one C-Cl bond was broken through a difluoromethyl radical pathway (href="/pmc/articles/PMC6658997/figure/fig1/" target="figure" class="fig-table-link figpopup" rid-figpopup="fig1" rid-ob="ob-fig1" co-legend-rid="lgnd_fig1">Figure 1Ab) (href="#bib42" rid="bib42" class=" bibr popnode">Xu et al., 2018). Trifluoromethyl anion (CF3⁻) is readily derived from the difluorocarbene species and external fluorine source via double cleavage of ClCF2H (href="/pmc/articles/PMC6658997/figure/fig1/" target="figure" class="fig-table-link figpopup" rid-figpopup="fig1" rid-ob="ob-fig1" co-legend-rid="lgnd_fig1">Figure 1Ac) (href="#bib48" rid="bib48" class=" bibr popnode">Zheng et al., 2015). Intriguingly and surprisingly, quadruple cleavage of ClCF2H to provide versatile C1 synthons, by breaking one C-Cl bond, two stable C-F bonds, and one C-H bond orderly in a single-vessel reaction (href="/pmc/articles/PMC6658997/figure/fig1/" target="figure" class="fig-table-link figpopup" rid-figpopup="fig1" rid-ob="ob-fig1" co-legend-rid="lgnd_fig1">Figure 1B), has never been reported to date, probably mainly because of the high BDE of C(sp³)-F bonds (the bond dissociation energy of a single C-F bond: 485 KJ/mol) (href="#bib30" rid="bib30" class=" bibr popnode">O'Hagan, 2008).href="/pmc/articles/PMC6658997/figure/fig1/" target="figure" rid-figpopup="fig1" rid-ob="ob-fig1">class="inline_block ts_canvas" href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=6658997_gr1.jpg" target="tileshopwindow">target="object" href="/pmc/articles/PMC6658997/figure/fig1/?report=objectonly">Open in a separate windowclass="figpopup" href="/pmc/articles/PMC6658997/figure/fig1/" target="figure" rid-figpopup="fig1" rid-ob="ob-fig1">Figure 1Various Transformations of ClCF2H(A) Known transformations of ClCF2H.(a) Double cleavage of ClCF2H to lead to difluorocarbene species.(b) Single cleavage of ClCF2H to lead to difluoromethyl radical.(c) Double cleavage of ClCF2H with external F⁻ to lead to trifluoromethyl anion.(B) Our work.(d) Quadruple cleavage of ClCF2H as a C1 source.