Organic Letters
Letter
previously found that the reaction of the isoxazole with alkyne
proceeded via tautomerization from the O-enolate intermedi-
ate, which is structurally relevant to the complex C in Scheme
7, to the corresponding C-enolate (Scheme 8, top). Therefore,
the isoxazoles selectively produced the 1:3 coupling products.
In sharp contrast, this is not the case for the isothiazoles, since
the formation of C-thioenolate (thioketone) species is
thermodynamically quite unfavorable (Scheme 8, bottom).14
Accordingly, the 1:2 coupling products are considered to be
dominant for the reaction of the isothiazoles.
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
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ORCID
In order to gain some insight into this speculation, we
conducted a computational study (Figure 1).15 The phenyl
groups on the isoquinoline ring were omitted to simplify the
calculation. In both cases of isoxazole (Figure 1a) and
isothiazole (Figure 1b), the most stable configurations were
isoquinoline-coordinated six-membered enol complexes E-1.
Without the coordination of the nitrogen atom, two metastable
states K-2 (for C-enolate and C-thio-enolate) and E-2 (for O-
enolate and S-thio-enolate) were obtained. For the isoxazole,
the C-enolate (K-2) exhibited a lower ΔH (+9.6 kcal/mol) as
compared to that of O-enolate (E-2, ΔH = +15.8 kcal/mol). In
sharp contrast, for the isothiazole, the C-enolate (K-2, ΔH =
+33.4 kcal/mol) was of much higher energy content than the
S-thioenolate species (E-2, ΔH = +23.1 kcal/mol). Addition-
ally, we calculated the activation enthalpies of the following
C−H bond cleavage reactions via the concerted metalation
deprotonation (CMD) mechanism from the intermediates K-2
and E-2. The activation barriers for the isoxazole were,
respectively, 20.1 kcal/mol in the keto pathway (K-2 → K-TS
→ K-3) and 20.8 kcal/mol in the enol pathway (E-2 → E-TS
→ E-3). Since there was no significant difference between the
activation energies, it is reasonable to conclude that the
reaction outcome is mainly directed by the relative stability of
the intermediates (E-2 vs K-2), being consistent with the
explanation in Scheme 8. In a similar manner, the barriers for
the isothiazole were estimated as 9.0 kcal/mol in the keto
pathway and 9.4 kcal/mol in the enol pathway. The enthalpies
obtained herein were high considering the fact that the
reaction proceeded even at 40 °C (Table 1, entry 12). This is
probably because the stabilization effect of isoquinoline
coordination is overestimated due to the omission of the
phenyl substituents.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was supported by JSPS KAKENHI Grant No. JP
19K15586 (Grant-in-Aid for Young Scientists) to Y.N. and JP
17H06092 (Grant-in-Aid for Specially Promoted Research) to
M.M. The numerical calculations were carried out on the
TSUBAME3.0 supercomputer at the Tokyo Institute of
Technology, Tokyo, Japan, and on the supercomputer at the
Research Center for Computational Science, Okazaki, Japan.
This computational work was supported by JSPS KAKENHI
Grant No. JP 17K17720 (Grant-in-Aid for Young Scientists
(B)) to Y.H. and a JST CREST Grant No. JPMJCR1522 to
S.K.
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ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge at
Detailed experimental procedures, spectroscopic data,
and copy of NMR spectra (PDF)
Atomic coordinates of all calculated molecules (XYZ)
́
T. J.; Chedotal, H.; Meyer, C.; Cossy, J. Org. Lett. 2019, 21, 8364.
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Accession Codes
mentary crystallographic data for this paper. These data can be
D
Org. Lett. XXXX, XXX, XXX−XXX