Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Iodide as a Nucleophilic Trigger in Aryne Three-Component Coupling for the Synthesis of 2‑Iodobenzyl Alcohols Subrata Bhattacharjee, Avishek Guin, Rahul N. Gaykar, and Akkattu T. Biju* Department of Organic Chemistry, Indian Institute of Science, Bangalore-560012, India
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ABSTRACT: The synthetic potential of KI as the iodide source in aryne three-component coupling has been demonstrated using aldehydes as the third component. This mild and transition-metalfree coupling reaction allowed the straightforward synthesis of 2iodobenzyl alcohols in moderate to good yields with good functional group compatibility. Moreover, KBr and KCl could be used as the nucleophilic trigger in this aryne multicomponent coupling (MCC) and N-methylisatin and CO2 could be used as the electrophilic third components.
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arenes, which can easily be functionalized to valuable compounds. It is important to note in this context that the use of halides as electrophilic source in aryne MCCs has been uncovered by the groups of Yoshida,15 Wang,16 and Hu.17 Moreover, the reaction of arynes with an electrophilic iodide source for the iodoalkynylation of arynes was demonstrated by Hamura, Suzuki and co-workers.18 Herein, we report the use of KI as the iodide source for the aryne MCCs using aldehydes as the third component for the transition-metal-free and mild synthesis of 2-iodobenzyl alcohols (eq 2). Inspired by the potential of aryne MCCs triggered by nucleophilic species, the present study was initiated by treating 4-nitrobenzaldehyde 1a with the Kobayashi aryne precursor 2a19 and KI. When the aryne was generated using the combination of KF/18-crown-6 in THF at 25 °C, the 2iodobenzyl alcohol 3a was formed in 64% yield (Table 1, entry 1). Compared to KI, other iodide sources such as NaI and tetrabutylammonium iodide (TBAI) furnished a reduced yield of 3a (entries 2, 3). Moreover, the fluoride sources such as CsF and tetrabutylammonium fluoride (TBAF) returned a diminished yield of 3a (entries 4,5). The reaction temperature was found to be optimal at 25 °C as the reaction provided a lower yield of 3a when performed at 50 °C and at 0 °C (entries 6, 7). The reaction performed in DME afforded 53% of 3a (entry 8). Interestingly, the product was formed in 67% yield when the concentration was doubled (entry 9). Increasing the amount of aryne precursor 2a slightly increased the yield of 3a (entry 10). Finally, performing the reaction using 2.5 equiv of KI resulted in the formation of 3a in 70% isolated yield (entry 11).20 With the optimized reaction conditions in hand, we then evaluated the scope and limitations of this transition-metal-free reaction. A series of aromatic aldehydes having electron-neutral
ulticomponent coupling (MCC) involving arynes has been widely used for the convenient synthesis of versatile and structurally complex 1,2-disubstituted benzenes.1,2 In a typical aryne MCC, the nucleophile having no acidic hydrogen atoms adds to the highly electrophilic aryne generating the aryl anion intermediate, which is subsequently intercepted by the electrophilic coupling partner leading to the formation of 1,2-disubstituted arenes (the nucleophile and electrophile are separate entities).1b,d The commonly used nucleophiles in aryne MCCs include isocyanides,3 amines,4 imines,5 nitrogen heterocycles (such as pyridine,6 (iso)quinoline,7 and aziridines),8 phosphines,9 and solvents such as DMF,10 DMSO,11 and THF (Scheme 1, eq 1).12 The Scheme 1. Transition-Metal-Free Aryne MCCs
electrophilic third components usually employed are aldehydes, activated ketones, and CO2.13 Although a series of nucleophilic species can initiate the aryne MCCs, the use of halides as the nucleophilic trigger has received only scant attention,14 and employing iodide for the aryne MCCs is not known to the best of our knowledge. Notably, the use of iodide as the trigger could result in the synthesis of 2-iodo substituted © XXXX American Chemical Society
Received: May 7, 2019
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DOI: 10.1021/acs.orglett.9b01621 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
entry
variation of standard conditions
yield of 3a (%)b
1 2 3 4c 5 6 7 8 9 10d 11e
none NaI instead of KI TBAI instead of KI CsF instead of KF/18-crown-6 TBAF instead of KF/18-crown-6 50 °C instead of 25 °C 0 °C instead of 25 °C DME instead of THF 1.0 mL of THF instead of 2.0 mL 2.5 equiv of 2a in 1.0 mL of THF 2.5 equiv of KI in 1.0 mL of THF
64
