Skeletal reorganization divergence of N-sulfonyl ynamides

Skeletal reorganization is a type of intriguing processes because of their interesting mechanism, high atom-economy and synthetic versatility. Herein, we describe an unusual, divergent skeletal reorganization of N-sulfonyl ynamides. Upon treatment with lithium diisopropylamine (LDA), N-sulfonyl ynamides undergo a skeletal reorganization to deliver thiete sulfones, while the additional use of 1,3-dimethyl-tetrahydropyrimidin-2(1H)-one (DMPU) shifts the process to furnish propargyl sulfonamides. This skeletal reorganization divergence features broad substrate scope and scalability. Mechanistically, experimental and computational studies reveal that these processes may initiate from a lithiation/4-exo-dig cyclization cascade, and the following ligand-dependent 1,3-sulfonyl migration or β-elimination would control the chemodivergence. This protocol additionally provides a facile access to a variety of privileged molecules from easily accessible ynamides.

S keletal reorganization is a type of process involving multiple bond cleavage and formation for molecule framework reassembly ( Fig. 1a) 1,2 . Owing to the intriguing reaction mechanism, high atom-economy property and capability of accessing complex and synthetically challenging molecules, the skeletal reorganization process has attracted considerable attention and also been widely applied in organic synthesis toward diverse carbocyclic and heterocyclic compounds [3][4][5] . For example, a variety of transition-metal-catalysed skeletal reorganizations of enynes have been explored for efficient synthesis of polycyclic compounds [6][7][8][9][10] . Recently, Sun and co-workers discovered an unusual skeletal reorganization of oxetane for the synthesis of 1,2-dihydroquinolines (Fig. 1b) 11 . Meanwhile, Liu and co-workers established a skeletal reorganization protocol of olefine via a radicalinitiated cyclization/1,n (n = 3, 4, 5) vinyl migration cascade for accessing medium-and large-sized cycles, which are ubiquitous structural motifs in natural products and pharmaceutical agents (Fig. 1c) 12 . Very recently, Zhu and co-workers reported a novel skeletal reorganization of kojic acid-or maltol-derived alkynes under Indium catalysis, which provided an expeditious access to valuable hydroxylated benzofurans (Fig. 1d) 13 . Despite these advances, the investigation of skeletal reorganizations toward synthetically challenging and biologically interesting molecules remains continuously interesting and important.

Results
Reaction optimization. We commenced our study by using Nsulfonyl ynamide 1a and lithium base to investigate this reaction. As shown in Table 1, we initially treated 1a with n-BuLi at −40°C for 1 h and then quenched with MeOH; a new major product 2a and a minor product 3a were isolated (entry 1). The standard analysis, including 1 H nuclear magnetic resonance (NMR), 13 C NMR and mass spectroscopy, was not able to identify these compounds. Gratifyingly, the X-ray analysis showed that 2a was a thiete sulfone and 3a was a propargyl sulfonamide (  trimethylamine as base showed inferior to shut down the reactivity even at room temperature, and 1a was recovered (entries 6-8).

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When LDA was used as base and the temperature was varied to 0°C or −78°C, the yield of 2a would slightly decrease (entries 9-10). Considering that lithiation was involved in this process, we tried to add ligands to increase the yield. Next, using of N,N,N',N'tetramethylethylenediamine as ligand showed no improvement (entry 11). Interestingly, the utilization of 1,3-dimethyl-tetrahydropyrimidin-2(1H)-one (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.
Reaction scope study. 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. As shown in Fig. 4, various ynamides 1 could participate well in this skeletal reorganization, leading to the corresponding thiete sulfones 2 in moderate-to-good yields. Diverse substitutions on the amino group of ynamides, including n-butyl, benzyl, i-propyl, cyclopentanyl and thiophene-2-ethyl, were found tolerable in this process (2b-2d). The (S)-1-phenylethyl amine-derived ynamide 1g could also engage in this reaction to give the chiral moiety tethered thiete sulfone 2g in 77% yield.
Other functional groups, such as alkene and protected alcohol, were also compatible in this reorganization process to give the corresponding products (2h and 2i), which might offer ample opportunities for the further derivatization. In addition, the aniline-derived ynamide (1j) was also applicable to deliver the desired product 2j in an excellent 92% yield. The structure of 2j was further confirmed by X-ray diffraction (for more details, see Supplementary Fig. 10). For the variation of sulfonyl groups, a variety of substitutions were also tested and found amenable in this process to access functionalized thiete sulfones (2k-2q). In detail, N-methylsulfonyl and N-benzylsulfonyl ynamides could reorganize to corresponding thiete sulfones in moderate yield (2k-2m), and the structure of 2k was confirmed by X-ray diffraction (for more details, see Supplementary Fig. 11). When N-cycloalkylsulfonyl ynamides like N-cyclopentanylsulfonyl ynamides and N-cyclohexanylsulfonyl ynamides were used, the skeletal reorganization could deliver spiro-fused thiete sulfones in moderate-to-good yields (2n-2q), and the structure of 2q was also verified by X-ray diffraction (for more details, see Supplementary Fig. 12). With respect of the substitution at the β-position of ynamides, a set of aryl groups functionalized with 2-chloro, 3-methyl, 4-methyl, 4-pentyl, 4-methoxy, 4-fluoro or 4-chloro were tolerable to furnish the corresponding products in good yields (2r-2x), and these substituents did not show any significant electronic and steric effects with the yields. Other aryl groups, including 2-naphthyl, 3-pyridinyl and thiophene-2-yl, were suitable in this process to produce the products successfully (2y-2a'), and the structure of 2a' was confirmed by X-ray analysis (for more details, see Supplementary Fig. 13). Meanwhile, the cyclohexenyl-substituted ynamide 1d' could smoothly transform to the corresponding product 2b' in 62% yield. Notably, silyl substitution was compatible with the process as well. For example, the TIPS-substituted ynamide 1e' could reorganize to product 2c' in 58% yield with retention of the TIPS group, while the TMSsubstituted ynamide 1f' could transform to product 2d' in a remarkable 94% yield accompanied with TMS desilylation. Unfortunately, β-alkyl-substituted and terminal ynamides were not applicable in this process (2e'-2f'). Since the aminocontaining full-substituted thiete sulfones are synthetically challenging 66 , this skeletal reorganization of ynamides provides a robust and efficient approach toward these molecules with the achievement of structural diversity and molecule complexity. Next, the scope for another skeletal reorganization toward propargyl sulfonamide was also investigated. As shown in Fig. 5, a variety of ynamides were treated with LDA and DMPU toward the formation of propargyl sulfonamides, and the amino substitutions like n-butyl, cyclopentanyl, thiophene-3-ethyl and protected alcohol were compatible with this process (3b-3e).
With respect to the sulfonyl substitutions, the cyclopentanyl and cyclohexanyl were applicable in the process to deliver the corresponding products in good yields (3f-3i). Meanwhile, alkynes with substitution on the aryl ring, including 2-fluoro, 2chloro, 3-methyl, 4-methyl, 4-pentyl and 4-fluoro, could well engage in this skeletal reorganization process to give the corresponding propargyl sulfonamides in good yields (3j-3o). The naphthyl and pyridinyl groups were also applicable to furnish the products smoothly (3p-3q). In terms of the structure of products, this skeletal reorganization involves an interesting 1,3alkyne migration from N-atom to C-atom. Propargyl sulfonamide is a versatile synthon and their synthesis is challenging by conventional methods. Thus this protocol provides a simple and efficient method to synthesize these molecules from readily available materials along with the fascinating process.
Synthetic applications and mechanism study. To demonstrate the synthetic utility of this skeletal reorganization divergence, an 8 mmol scale reaction was conducted (Fig. 6a). Under the standard reaction conditions, 1a could be selectively transformed to 2a and 3a in gram-scale, indicating that these skeletal reorganization processes were practical. Considering that these processes may involve lithium intermediates that could offer opportunities for divergent functionalization of products, the derivatization was carried out. As shown in Fig. 6b reorganization process of ynamide 1a was quenched with MeI, an N-methyl propargyl sulfonamide product 5 was obtained in good yield (Fig. 6c). This experiment suggested the existence of sulfonamide anion intermediate after this skeletal reorganization process.
In order to view more insights into the reaction, the mechanism exploration was conducted. First, the crossover reaction was carried out to further explore the molecular reaction mode of this skeleton reorganization. As shown in Fig. 6d, when ynamide 1r and 1x were subjected in one pot under the standard reaction condition, 2q and 2v were exclusively formed in 79 and 73% yields, respectively. This result excluded the possibility of intermolecular group exchange and verified this reaction is an intramolecular process. Besides, treating the mixture of 1c and MeI with LDA could exclusively deliver the α-methylation product 6 in an excellent 91% yield (Fig. 6e). This outcome disclosed that the α-lithiation was the initial step of the skeleton reorganization. Meanwhile, isotope-labelling experiment was conducted to probe the skeleton reorganization processes. As shown in Fig. 6f, (β-13 C)-1a was prepared and subjected to the standard reactions. 13 C-2a and 13 C-3a could be formed smoothly under standard conditions. The position of 13 C-labelled carbon atom in the products was identified, which indicated that phenyl migration did not occur in these skeleton reorganization processes.
Moreover, we conducted density functional theory (DFT) calculations at the level of M06 using the Gaussian 09 suite of computational programs. The 6-31G(d,p) basis set was applied for the C, H, O, N, S and Li atoms. In the LDA-mediated process, there are three possible cyclizations after α-lithiation (Fig. 7). In paths 1 and 2, Li species Int-A may undergo a 4-exo-dig cyclization to deliver isometric Int-B or Int-C via transition state TS 1 or TS 2 with a barrier of 17.6 or 18.4 kcal/mol, respectively. In path 3, Int-A undergoes a 5-endo-dig cyclization to give Int-D by TS 3 with a higher barrier of 20.4 kcal/mol. Similarly, in the presence of DMPU, the formed Li species Int-E may undergo three types of cyclizations as well (Fig. 8). In paths 4 and 5, Int-E may transform to Int-F or Int-G via TS 4 or TS 5 with a barrier of 22.5 or 23.7 kcal/mol. However, in path 6, Int-E needs a higher barrier of 25.2 kcal/mol to initiate a 5-endo-cyclization to deliver Int-H. The relative lower barrier of paths 1 and 4 suggests that 4exo-dig cyclization/cis addition is more favoured in these two skeleton reorganization processes.
Based on experimental and computational studies, a plausible reaction mechanism for this skeletal reorganization divergence is proposed (Fig. 9). Initially, the α-position of sulfonyl group would undergo lithiation upon treatment with LDA to deliver A and then a 4-exo-dig cyclization would occur to generate fourmembered β-sultam intermediate B 63,64,67,68 . Subsequently, B presumably undergoes a 1,3-sulfonyl migration to form lithium thiete sulfone intermediate C 69,70 , which could be protonated by MeOH to deliver product 2. When MeOH was replaced by other electrophilic reagents, intermediate C could be functionalized directly to obtain N-substituted thiete sulfone products. In the presence of DMPU, α-lithiation of 1 could deliver Li species D, which undergoes a 4-exo-dig cyclization to form intermediate E.  probably due to the addition of DMPU that dissociates the intermolecular or intramolecular interaction of Li species and change the reactivity. The following protonation would furnish product 3.

Discussion
In summary, we have discovered a skeletal reorganization divergence of N-sulfonyl ynamides. Upon treatment with lithium base, the Nsulfonyl ynamides could undergo lithiation/cyclization and the sequential ligand-determining 1,3-sulfonyl migration or βelimination to deliver thiete sulfones or propargyl sulfonamides. This skeletal reorganization divergence features broad substrate scope and scalability. Mechanistic experiments and DFT calculations are conducted to verify the rationality of the proposed mechanism. Therefore, 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.

Methods
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 tetrahydrofuran (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 sulfonamides 3. An ovendried 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 sulfonamides 3.

Data availability
All data generated and analysed during this study are included in this article and its Supplementary Information and also available from the authors upon reasonable request. The X-ray crystallographic coordinates for structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 1999861 (2a), 1999862 (2b), 1999863 (2j), 1999864 (2k), 1999865 (2q) and 1999866 (2a'). These data can be obtained free of charge via https://www.ccdc.cam. ac.uk/structures/.