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Fig. 3. Reaction scope of Ir(III)-catalyzed intramolecular amidation. is indicated in parentheses; the data are reported as percent isolated yields. Downloaded from
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on March 1, 2018
(A) Functionalization of benzylic, tertiary, secondary, and primary C(sp )–H *10 mol % catalyst was used. †Run at 80°C for 48 hours. ‡Run at 40°C for
bonds. (B) Examination of chemo- and regioselectivity. (C) Functionalization 12 hours followed by 80°C for 24 hours. §5 mol % catalyst was used.
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of aromatic C(sp )–H bonds. Unless otherwise indicated, reactions were run ||Hexafluoro-2-propanol was used as solvent. ¶Run at room temperature.
F
with 2 mol % of catalyst and NaBAr 4 at 40°C for 12 hours.The Ir catalyst used #Run at 60°C. d.r., diastereomeric ratio; e.e., enantiomeric excess.
product in 99% yield. Whereas a b-methyl substit- insertion mechanism (see below). Finally, ami- aziridine formation (27–29). Olefin isomerization
uent gave rise to excellent reactivity and diaster- dation of nonactivated secondary C–Hbonds of was not observed during the formation of lactam
eoselectivity (14, >20:1), the amination of an n-butyl (23), cyclopentyl (24), and adamantyl 28. Similarly, dioxazolones bearing g-propargylic
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a-substituted substrate gave a mixture of syn- (25) groups was successful, and primary C(sp )– C–H bonds underwent lactamization in high yields
and anti-inserted products without a bias (15, H bonds also underwent reaction, albeit in mod- (30–32), allowing for efficient access to key pre-
15′, 1:0.8). When dioxazolones prepared from erate yield (26). cursors in the total synthesis of (–)-stemoamide
benzoic acids were used, 3-substituted isoindolin- The high reactivity of the Ir catalyst motivated derivatives (29). Considering that intramolecular
1-ones (16, 17) were obtained in high yields. us to examine the selectivity trends when multiple amidation has frequently suffered from related
Heterocycles such as benzofuran (18)orthio- reactive sites were embedded in the same mole- aziridination reactions caused by electron-rich p
phene (19) were also tolerated under the reaction cule (Fig. 3B). Preferential chemo- and regioselec- functionality (28, 30, 31), theremarkablechemo-
conditions. Themethodalsotransformed tertiary tivity patterns often provide clues to the reaction selectivity observed in this system is intriguing
C–H bonds, thereby introducing quaternary mechanism and have been widely used to under- (32). Next, we designed substrates having non-
carbon centers (3, 20) and an azaspirocyclic stand microscopic insertion pathways (28). When equivalent g and g′ C–H bonds to qualitatively
scaffold (21). The desired lactamization pro- g-allylic C–H bonds that potentially undergo olefin rank the reactivity toward distinctive C–Hbonds.
ceeded in a stereospecific manner when g-chiral aziridination were tested, insertion products were Benzylic C–H bonds were favored over nonacti-
dioxazolone was used (22), providing a clue to the observed exclusively with no detectable sign of vated secondary C–Hbonds (33,12.6:1) butwere

Hong et al., Science 359, 1016–1021 (2018) 2 March 2018 4of6