Organic Letters
Letter
We have also used DFT calculations to probe aspects of the
mechanism (cf. Figure 2) of this unusual transformation (Figure
3). The benzothietene 20 is the [2 + 2] adduct between benzyne
and the thiocarbonyl group in 6a. This was observed to be similar
infreeenergytotheisomeric, ring-opened, polarized thioquinone
methide 21, and both were considerably more stable than the
reactant pair. We did not attempt to locate transition structures
for any processes interconverting benzyne and 6awith 20 or of 20
with 21. We explored possible pathways for the unimolecular
isomerization of 21 to the product 25. This was fruitful once we
allowed for the nonintuitive possibility of hydrogen atom removal
by the basic sulfur atom from the iminium ion methyl group trans
to the thiolated arene (cf. MeE in 21 and HE in 22-TS). This
produces the azomethine ylide 23; 22-TS was the only transition
structure that we could identify for this step. This TS lies ca. 30
kcal·mol−1 higher in energy than 21, which places that step in the
category of being “feasible.” A very rapid (and highly exergonic)
progression from 23 is computed to ensue. We could not identify
animiniumthiolate likeE(Figure1)asastableentity. Instead, the
TS 24-TS collapsed directly to 25. A related, thiolate-mediated
proton shift via an azomethine ylide like 23 was described both
experimentally and computationally by Seidel, Houk, and co-
workers.13
including copies of 1H and 13C NMR spectra; and
computed (DFT) geometries and energies of benzyne
intermediates and transition states (PDF)
AUTHOR INFORMATION
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Corresponding Author
ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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Support for this research was provided by the National Institutes
of General Medical Sciences of the U.S. Department of Health
and Human Services (GM65597). V.P. appreciates support from
a Gleysteen−Heisig fellowship for undergraduate students. Some
of the NMR data were obtained with an instrument acquired with
funds from the NIH Shared Instrumentation Grant program
(S10OD011952).
REFERENCES
We then carried out a deuterium labeling experiment to probe
the mechanism experimentally (Figure 4). Triyne 4 was heated
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Figure 4. Mono-CD3-labeled thioamide 6ad shows preference for 1,3-
3
migration of the H- over D-atom.
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(11) These reactions were typically not further explored (and,
therefore, are not shown in Table 2) largely for pragmatic reasons. In
some instances the product(s) coeluted with unreacted thioamide; in
others, mixtures of products from regioisomeric modes of trapping (cf.
entries 6 and 7) of the benzyne complicated the purification.
(12) We studied several aliphatic thioamides; the presence of an acidic
α-proton diverted the reaction course to provide a benzothiophene, a
process involving spontaneous (air?) oxidation. For example:
with the trideuterated thiobenzamide 6ad to give a mixture of the
3
products 26a and 26b in a ratio of 6:1. This clearly shows that a
net, intramolecular 1,3-hydrogen migration is involved in this
transformation and that it is most likely the rate-determining step
(protium is preferentially transferred over deuterium) of the
trappingsequencethatconverts 5into26. Wedidnotobserve any
appreciable amount of the di- or the tetradeuterated analog of 16,
which supports the view of the proton transfer as an intra-
molecular event, not requiring an external proton shuttle.
In conclusion, aromatic thioamides react with (thermally
generated) benzynes to form dihydrobenzothiazine derivatives
that we propose arise by an unusual, thiolate-assisted, 1,3-
hydrogen atom migration. These mechanistic views are
supported by a deuterium labeling experiment and DFT
calculations. A wide range of thioamides participate in such a
transformation to produce structurally diverse dihydrobenzo-
thiazines in a regio- and diastereoselective manner.
ASSOCIATED CONTENT
* Supporting Information
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TheSupportingInformationisavailablefreeofchargeontheACS
(13) Jarvis, C. L.; Richers, M. T.; Breugst, M.; Houk, K. N.; Seidel, D.
Org. Lett. 2014, 16, 3556−3559.
Experimental details for the preparation of new com-
pounds; spectroscopic data for their characterization,
D
Org. Lett. XXXX, XXX, XXX−XXX