Purpose(s)
1.Skeletal reorganization is a type of process involving multiple bonds cleavage and formation for molecule framework reassembly (Fig.1). the skeletal reorganization process has attracted considerable attention and also
been widely applied in organic synthesis toward diverse carbocyclic and heterocyclic compounds.
2.The four-membered sulfur-containing heterocycles, such as thiete sulfones, thietane sulfones and thietanes, are strained small ring compounds which have found wide applications in the discovery of dye, drug and pesticide.(Fig.2).
we hypothesized that the deprotonation at the α-position of sulfonyl moiety of Nsulfonyl ynamides might initiate an anionic 4-exo-dig or 5-endo-dig cyclization to deliver cyclic sulfonamides which are privileged structures in medicinal chemistry
(Fig.3)
Method(s)
General procedure for the synthesis of thiete sulfones 2.
An oven-dried schlenk tube equipped with a magnetic stirrer bar was purged with argon three times. Ynamide 1 (0.2 mmol) was dissolved in 2 mL anhydrous THF and added by a syringe. The mixture was cooled to -40 °C and LDA (2 mol/L in THF, 0.15 mL, 0.3 mmol) was added dropwise. The reaction was stirred at -40 °C for another 1 h. MeOH (0.1 mL) was added to quench the reaction and then the mixture was concentrated under vacuum to obtain the residue, which was further purified by silica gel column chromatography using ethyl acetate/petroleum ether as eluent to give thiete sulfones 2.
General procedure for the synthesis of propargyl sulphonamides 3.
An oven-dried schlenk tube equipped with a magnetic stirrer bar was purged with argon three times. Ynamide 1 (0.2 mmol) was dissolved in 2 mL anhydrous THF and added by a syringe. DMPU (62 μL, 1 mmol) was added and the mixture was cooled to -40 °C. Subsequently, LDA (2 mol/L in THF, 0.15 mL, 0.3 mmol) was added dropwise. The reaction was stirred at -40 °C for another 1 h, and then MeOH (0.1 mL) was added to quench the reaction. The mixture was concentrated under vacuum to obtain the residue, which was further purified by silica gel column chromatography using ethyl acetate/petroleum ether as eluent to give propargyl sulphonamides 3.
Result(s)
1. our study by using N-sulfonyl ynamide 1a and lithium base to investigate this reaction.
Through optimizing the reaction, we found that LDA was superior to give 2a in 72% yield (entry 2),but the utilization of DMPU as ligand would exclusively give 3a in good yield (entry 12, 82% yield). Therefore, the skeletal reorganization is divergent and could be controlled by ligand(Fig.4).
2. With the optimized reaction conditions in hand, we next tested the substrate scope of this skeletal reorganization divergence. The starting material N-sulfonyl ynamides could be easily prepared by coupling of sulfonamides and alkynyl bromides(Fig.5). Moreover, the scope for another skeletal reorganization toward propargyl sulfonamide was also investigated(Fig.6).
3. Synthetic applications and mechanism study (Fig.7).
a. Gram-scale reaction of ynamide 1a.
b. Electrophilic reagents-quenched reorganization toward N-functionalized thiete sulfones 4.
c. MeI-quenched reorganization toward N-methyl propargyl sulfonamide 5.
d. Crossover reaction.
e. α-Methylation experiment.
f. 13C-Labelled experiment.
Conclusion(s)
In summary, we have discovered a skeletal reorganization divergence of N-sulfonyl ynamides.
1.Upon treatment with lithium base, the N-sulfonyl ynamides could undergo lithiation/cyclization and the sequential ligand-determining 1,3-sulfony migration or β-elimination to deliver thiete sulfones or propargyl sulphonamides.
2. This skeletal reorganization divergence features broad substrate scope and scalability. Mechanistic experiments and DFT calculations are conducted to verify the rationality of proposed mechanism.
3.this protocol not only represents a new skeletal reorganization mode, but also provides facile and selective access to privileged molecules from the easily accessible ynamides.