Synthesis of Angularly Fused Aromatic Compounds from Alkenyl Enediynes by a Tandem Radical Cyclization Process

Abstract

The synthetic potential of the Bergman cyclization (BC) [1] has not been greatly explored despite remarkable progress in the understanding of the reaction mechanism [2] and the mode of biological action of enediynes.[3] The radicals within the 1,4-diradical generated during the BC are distally oriented, thus preventing self-quenching, which can lead to a highly strained bicyclo system, and are spinpaired by an external quencher.[4] The 1,4-diradical can undergo polymerization, [5] which causes the usual low yield of cyclized products. BC and related reactions involve the formation of benzenoid frameworks and, hence, are attractive for the synthesis of polyaromatic and benzannulated compounds. John and Tour [6] reported the formation of polyphenylenes using BC, while Grissom and Calkins [7] demonstrated the tandem radical cyclization of enediynes with diverse alkenyl acceptors. Diradicals generated in a porphyrin network have been trapped with a neighboring aromatic ring (Smith and co-workers, [8a] and Zaleski and coworkers [8b] ). Taking a cue from these results and the ortho effect reported by Alabugin and coworkers, [9] we studied the reactivity of aryl exomethylene N-substituted cyclic enediynes of type A (Scheme 1). The initial intention was to explore the effect the p cloud of an aromatic ring [10] positioned above one of the alkynes of an enediyne framework would have on the BC. We did observe some interesting variations in reactivity depending on the R substituent present on the aromatic ring. However, the more important aspect is the synthesis of the angularly fused polyaromatic compounds [4]helicenes (C) [11] in high yields. The process, which involves the BC as the key step of an unprecedented tandem radical reaction, offers a general route to these compounds and also expands the synthetic potential of the BC.The aryl enediynes 1 required for our study were prepared from o-iodo propargyl amine 2 [12] by using a six-step protocol. A Sonogashira coupling [13] with trimethylsilyl acetylene followed by a desilylation produced the enediyne 4. Another coupling reaction with the Z-iodo alkene (obtained by a haloWittig reaction) [14] followed by THP removal furnished the acyclic enediyne 7. This was converted into the mesylate 8, which on treatment with K 2 CO 3 in anhydrous DMF [15] produced the cyclic enediyne 1 (Scheme 2). NOESY spectra (see the Supporting Information) confirmed the positioning of the aryl ring to be above the enediyne alkyne.As a test study, enediyne 1 was dissolved in [D 6 ]DMSO and kept at 90 8C (Scheme 3). The reaction was monitored by recording the 1 H NMR spectra at different times. There was a gradual decrease in the signals for the substrate accompanied [*] Dr.

10-Membered Azaenediyne Fused to a Benzothiophene through the Nicholas Macrocyclization: Synthesis and DNA Cleavage Ability

“…Hence a high-yielded aza-Nicholas macrocyclization step and choosing the right solvent for a TBAF-promoted decomplexation allowed target azaenediyne to be obtained within six synthetic steps in 18% overall yield, which is higher than the overall yields for benzothiophene-fused Oenediyne 2 (11%) 44 and C-enediyne 3 (13%) 43 synthesized previously. Moreover, in all previous examples of 10-membered azaenediynes synthesized by alkylation [28][29][30]35,36,[38][39][40] or by the Mitsunobu reaction 31,32,36 an enediyne system was either nonfused or annulated with a benzene ring. One could hypothesize that these macrocyclization techniques could be unsuitable for such highly strained 10-membered benzothiophene enediynes.…”

“…[29][30][31][32][33][34][35][36] In all examples of enediyne synthesized except one 33 the nitrogen atom is in a homopropargylic position, therefore the Nicholas reaction could be a suitable method for a macrocyclization step. 37 However, two other general types of reactions has been used for the construction of these azaenediynes: N-alkylation [28][29][30]35,36,[38][39][40] (Scheme 1, A) and the Mitsunobu reaction (Scheme 1, B). 31,32,36 Only single example of the Nozaki cyclization has been also reported for the azaenediyne system fused to a -lactam ring.…”

Highly Reactive Cyclic Monoaryl Iodoniums Tuned as Carbene Generators Couple with Nucleophiles under Metal-Free Conditions

“…While a carbonyl group was installed to stabilize the iodine charge, various R groups were taken into consideration to test its impact on chemical properties, including alkyl (1a), aryl (1b), halogen (1c), and hydrogen (1d). After the preparation of precursors 1′ of cMAVIs (see Supplemental Information ) ( Ho et al., 2007 ; Puri et al, 2014 ; Roy et al., 2011 ), cMAVIs 1a-1d were obtained in good yields using the procedure for the synthesis of cDAIs ( Zhu et al., 2013 ). The crystal X-ray diffraction unambiguously verified the structure of 1a.…”

Synthesis and reactivity of anthracenyl-substituted arenediynes

“…12,[14][15][16] Moreover, the photophysical properties of polycyclic aromatic hydrocarbons containing the 5-membered ring are unusual compared to the analogous molecules with 6-membered rings. 3,[5][6][7][8][9][10][11][12][13]15 It is thus of interest to develop a better understanding of the structure-property relationships of the 5-membered ring containing polycyclic aromatic hydrocarbons. Cyclization of arylsubstituted arenediynes proceeds via C 1 -C 5 cyclization (5-membered cyclic product) or C 1 -C 6 Bergman cyclization (6-membered cyclic product) pathway that can be modulated by the sterics and electronics of aryl substituents.…”