Organic Letters
Letter
undergo a radical pathway. Despite the similar reaction
conditions, the etherification strategy using aryl methyl
sulfoxides and alcohols was not significantly interfered by
radical scavengers.8 Moreover, methylsulfinate anion 7 or its
oxidized product 8 was identified as the leaving group by
HRMS. The ambient light exerted a negligible effect on the
excluding the photoinduced radical initiation process.15
Diphenyl sulfone (1q) could couple with 2a to give 3aa in
64% yield under the standard conditions, implying the α-anion
Based on the related literature reports,16 we proposed the
dimsyl anion, which was generated from the depronation of
DMSO by KOtBu, acted as the electron donor to initiate the
Catalysis, Southern University of Science and Technology,
Peiyuan Yu − Shenzhen Grubbs Institute, Department of
Chemistry and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Qingchao Liu − Department of Pharmaceutical Engineering,
College of Chemical Engineering, Northwest University, Xi’an,
Authors
Jixiang Bai − Department of Pharmaceutical Engineering,
College of Chemical Engineering, Northwest University, Xi’an,
Shanxi 710069, P.R. China; Shenzhen Grubbs Institute,
Department of Chemistry and Guangdong Provincial Key
Laboratory of Catalysis, Southern University of Science and
Technology, Guangdong 518055, P.R. China
Tianxin Wang − Shenzhen Grubbs Institute, Department of
Chemistry and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Guangdong 518055, P.R. China
Botao Dai − Shenzhen Grubbs Institute, Department of
Chemistry and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Guangdong 518055, P.R. China
To unveil the origin of the chemoselectivity favoring Csp2−S
bond cleavage, density functional theory (DFT) calculations
were performed (Figure 1). For the chain propagation process,
two different pathways were investigated: the cleavage of
Csp2−S or Csp3−S bond followed by the nucleophilic addition
of alkoxide anion to the phenyl or methyl radical (shown in
black or blue, respectively). The computed free energy barriers
for the first step suggest that the cleavage of the Csp2−S bond
(TS1, 11.0 kcal/mol) is slightly more difficult than that of the
Csp3−S bond (TS3, 9.8 kcal/mol). As a result, the generation
of phenyl radical from C is less favorable, in agreement of the
BDE calculations shown in Figure S1. However, for the second
step, nucleophilic attack of potassium alkoxide E to the phenyl
radical via TS2 (8.6 kcal/mol) is much lower in energy than to
the methyl radical via TS4 (13.5 kcal/mol). In TS2, there is a
stabilizing interaction between the potassium and the phenyl
carbon (2.83 Å), which is absent in TS4. In addition, the
phenyl group can stabilize the radical anion generated (F), by
allocating the unpaired electron in its relatively low-lying π*
orbital (Figure 1, top right). This effect is exemplified by the
relative energies of radical anions F and 13. Once F is formed,
a single electron transfer to 1a will result in the final product
3aa and regenerate C, to close the radical propagation cycle.
In summary, we have developed an unprecedented formal
cross-coupling of aryl methyl sulfones and alkyl alcohols to
prepare alkyl aryl ethers. Two marketed antitubercular drugs
(Etocarlide and Isoxyl) were concisely prepared using the
formal coupling as the key step. The mechanistic studies reveal
an SRN1 pathway as the major component, in which the dimsyl
anion initiates the chain process. Computational study suggests
the preference of aryl methyl sulfones served as Csp2
electrophiles is due to the stabilization of radical anion F, in
addition to the favorable interaction between the phenyl
carbon and the potassium cation in TS2.
Complete contact information is available at:
Author Contributions
§J.B., T.W., and B.D. contributed equally to this work. T.J.
designed and supervised the project. J.B. and T.W. performed
the experiments. P.Y. directed the computational study. B.D.
carried out the computational study. T.J., Q.L., and P.Y.
analyzed the results. T.J. and P.Y. wrote the paper.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Science and Technology Innovation Commis-
sion of Shenzhen Municipality (JCYJ20180302180256215),
Shenzhen Nobel Prize Scientists Laboratory Project
(C17783101), and Guangdong Provincial Key Laboratory of
Catalysis (2020B121201002) for funding. Q.L. acknowledges
the Foundation of Shaanxi Educational Committee
(15JK1717) and the National Natural Science Foundation of
China (22078263) for financial support. SUSTech is greatly
acknowledged for providing startup funds to T.J.
(Y01216129). We are also very grateful to Dr. Yang Yu
(SUSTech) for HRMS. Computational work was supported by
Center for Computational Science and Engineering at
Southern University of Science and Technology.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
Experimental procedures, characterization data, NMR
spectra of new compounds, detailed computational
study, and calculated structures (PDF)
REFERENCES
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(1) (a) Patai, S.; Rappoport, Z.; Stirling, C. The Chemistry of
Sulphones and Sulfoxides; John Wiley & Sons, 1988. (b) Simpkins, N.
S. Sulphones in Organic Synthesis; Pergamon Press, 1993.
2013, 42, 599−621. (b) Modha, S. G.; Mehta, V. P.; van der Eycken,
AUTHOR INFORMATION
Corresponding Authors
■
Tiezheng Jia − Shenzhen Grubbs Institute, Department of
Chemistry and Guangdong Provincial Key Laboratory of
5764
Org. Lett. 2021, 23, 5761−5765