Unexpected Substituent Effects in Spiro-Compound Formation: Steering N-Aryl Propynamides and DMSO toward Site-Specific Sulfination in Quinolin-2-ones or Spiro[4,5]trienones

Abstract

A highly substituent-dependent rearrangement allows for the novel and SOCl 2 -induced divergent synthesis of 3-methylthioquinolin-2-ones and 3-methylthiospiro[4.5]trienones through intramolecular electrophilic cyclization of N -aryl propyamides. DMSO acts as both solvent and sulfur source, and use of DMSO- h 6 / d 6 enables the incorporation of SCH 3 or SCD 3 moieties to the 3-position of the heterocyclic framework. Different para -substituents trigger divergent reaction pathways leading to the formation of quinolin-2-ones for mild substituents and spiro[4,5]trienones for both electron-withdrawing and -donating substituents, respectively. On the basis of both computational and experimental results, a new mechanism has been put forward that accounts for the exclusive spirolization/defluorination process and the surprising substituent effects.

Synthesis of 3‐Halogenated Quinolin‐2‐Ones from N‐Arylpropynamides via Hypervalent Iodine(III)−Mediated Umpolung Process

“…On the basis of the previous reports [5a,g,14a,16] as well as the experimental results achieved above, we proposed a possible pathway for this electrophilic intramolecular cyclization/halogenation process (Scheme 5). First, the reactive hypervalent iodine species A is generated through the ligand exchange between LiBr and PIDA [14] .…”

“…However, for the substrates bearing a methoxy or fluoro substitituent at the para-position of the aniline ring, the reaction underwent the alternative spiro cyclization/halogenation process to afford the halogen-ated spiro [4,5]trienones with good yield (Scheme 2). With reference to the previous reports, [16] it was the presence of the exceptional methoxy and fluoro substituent at the para position of the aniline moiety in the substrate that diverted the reaction to undergo an alternative spirolization pathway.…”

“…Next, the reactive species A is converted to iodonium intermediate B , which possesses unique reactivity [5g] . After that, the electrophilic addition of iodonium B to the triple bond of substrate 1 a affords spiro cation intermediate C , which undergoes rearrangement, through a transition intermediate D , to give intermediate E [16,17] . Finally, deprotonative rearomatization occurs in E to afford intermediate F , which undergoes reductive elimination of PhI to deliver the title product 2 a (Scheme 5, path a).…”

“…[14] Next, the reactive species A is converted to iodonium intermediate B, which possesses unique reactivity. [5g] After that, the electrophilic addition of iodonium B to the triple bond of substrate 1 a affords spiro cation intermediate C, which undergoes rearrangement, through a transition intermediate D, to give intermediate E. [16,17] To test whether the reaction could be carried out in an organic catalytic pattern by using aryliodide as catalyst and peracetic acid as terminal oxidant, we subjected substrate 1 a to the conditions of phenyliodide (0.2 equiv. ), LiBr (2.4 equiv.…”

Application of DMSO as a methylthiolating reagent in organic synthesis

“…Recently, Du's group developed an unexpected substituent effects method for the synthesis of 3-methylthioquinolin-2-ones 57a and 3-methylthiospiro [4.5]trienones 57b from the N-aryl propynamides 56 via an electrophilic intramolecular cyclization under the DMSO/SOCl 2 system. 60 In this protocol, the remarkable substituent effect was described in detail by quantum chemical methods, and the synthetic outcome could be conveniently steered to or away from the spiro compounds, thus revealing a range of analogous but until now poorly understood spiro-forming cyclization reactions. Altogether, the methylthiolation strategy realized by DMSO/SOCl 2 possesses striking desirable features such as the ready availability of substrates, mild reaction conditions, and remarkably simple workup procedure (Scheme 13).…”