ARTICLE

https://doi.org/10.1038/s41467-020-19467-5 OPEN Skeletal reorganization divergence of N-sulfonyl ynamides ✉ Linwei Zeng1, Yuxin Lin 1, Jiaming Li1, Hironao Sajiki 2, Hujun Xie3 & Sunliang Cui 1

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 dii- N 1234567890():,; sopropylamine (LDA), -sulfonyl ynamides undergo a skeletal reorganization to deliver thiete , while the additional use of 1,3-dimethyl-tetrahydropyrimidin-2(1H)-one (DMPU) shifts the process to furnish propargyl . This skeletal reorganization divergence features broad substrate scope and scalability. Mechanistically, experimental and computa- tional 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.

1 Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, 310058 Hangzhou, China. 2 Laboratory of Organic Chemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan. 3 School of Food Science and Biotechnology, Zhejiang Gongshang ✉ University, 310018 Hangzhou, China. email: [email protected]

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keletal reorganization is a type of process involving multiple investigated in C–H functionalization to establish axially chiral bond cleavage and formation for molecule framework molecules and macrocyclic compounds25,26. However, the con- S 1,2 reassembly (Fig. 1a) . Owing to the intriguing reaction ventional synthesis of thiete sulfones relies on multi-step routes mechanism, high atom-economy property and capability of and also suffers from narrow scope27–32. Therefore, it would be accessing complex and synthetically challenging molecules, the interesting to explore a distinct and efficient approach to func- skeletal reorganization process has attracted considerable attention tionalized thiete sulfones. and also been widely applied in organic synthesis toward diverse Ynamides are a type of N-substituted electron-rich that carbocyclic and heterocyclic compounds3–5. For example, a variety exhibit unique chemical properties and serve as versatile synthons of transition-metal-catalysed skeletal reorganizations of enynes in organic synthesis33–42. For example, ynamides could act as have been explored for efficient synthesis of polycyclic com- flexible cyclization partners in heterocycle synthesis43–45, pounds6–10. Recently, Sun and co-workers discovered an unusual precursors46–49 and enamide precursors50,51, racemization-free skeletal reorganization of oxetane for the synthesis of 1,2-dihy- coupling reagents for peptide and macrolide synthesis52–54 and C2 droquinolines (Fig. 1b)11. Meanwhile, Liu and co-workers estab- building blocks of multicomponent reactions)55–57. In recent lished a skeletal reorganization protocol of olefine via a radical- years, the intramolecular cyclizations of ynamides, including initiated cyclization/1,n (n = 3, 4, 5) vinyl migration cascade for transition-metal-catalysed and Brønsted acid-catalysed nucleo- accessing medium- and large-sized cycles, which are ubiquitous philic cyclizations, anionic cyclizations and radical cyclizations, structural motifs in natural products and pharmaceutical agents have been extensively investigated for the synthesis of N-hetero- (Fig. 1c)12. Very recently, Zhu and co-workers reported a novel cycles (Fig. 3a)58–61. However, the skeletal reorganization of skeletal reorganization of kojic acid- or maltol-derived alkynes ynamides is rarely reported. In 2012, Evano and co-workers under Indium catalysis, which provided an expeditious access to reported an s-BuLi-mediated skeletal reorganization of N-Boc valuable hydroxylated benzofurans (Fig. 1d)13. Despite these ynamides for de novo synthesis of 1,4-dihydropyridines and advances, the investigation of skeletal reorganizations toward , which invoked a process of carbonyl-directed depro- synthetically challenging and biologically interesting molecules tonation and anionic 6-endo-dig cyclization (Fig. 3b)62. Encour- remains continuously interesting and important. aged by these, we hypothesized that the deprotonation at the α- The four-membered -containing heterocycles, such as position of sulfonyl moiety of N-sulfonyl ynamides might initiate thiete sulfones, thietane sulfones and thietanes, are strained small an anionic 4-exo-dig or 5-endo-dig cyclization to deliver cyclic ring compounds that have found wide applications in the dis- sulfonamides, which are privileged structures in medicinal covery of dye, drug and pesticide (Fig. 2)14–19. Typically, the chemistry (Fig. 3c)63,64. In continuation of our interests in yna- unsaturated thiete sulfones showed valuable synthetic utility in mide chemistry55–57,65, herein we would like to report a skeletal organic synthesis. For example, thiete sulfones could be used as reorganization divergence of N-sulfonyl ynamides for selective dienophiles in the Diels–Alder reaction with tetraphenyl cyclo- entry to thiete sulfones and propargyl sulfonamides (Fig. 3d). pentadienones or isobenzofurans for accessing bridged and fused- – ring compounds20 22. Moreover, they could participate in [3 + 2] Results cycloadditions with diazo compounds or oxides for the Reaction optimization. We commenced our study by using N- synthesis of heterocycles23,24. Recently, thiete sulfones have been sulfonyl ynamide 1a and lithium base to investigate this reaction.

a Bond cleavage and formation Molecule framework reassembly

b c R 2 R2 R R 8-14 Rf • N HO O N In(OTf) O 3 Xn R1 R1 Xn R3 Rf 3 R X = C, O; n = 1~3

d 4 1 5 R O R O R O HO 4 O 5 R In(OTf)3 R R1 R6 R3 R6 R3 O R2 O OH R2 Kojic acid derived Maltol derived Hydroxylated benzofurans

O • • O • Aldol reaction 5-endo-dig • H2O O • Aromatization O • • In O • In

Fig. 1 Skeletal reorganization. a Scheme of a skeletal reorganization in molecules. b In-catalysed skeletal reorganization of oxetanes. c Radical-initiated skeletal reorganization of olefines. d In-catalysed skeletal reorganization of kojic acid- or maltol-derived alkynes.

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Et Me O N O Me N O S

S S O S OCF2H O O N Me S O OMe Et O Cyanine dye Antidepressant agent Phosphodiesterase inhibitor

HO O OH HO O S O Boc Boc Cl Me Me N NH O NH O H Ph Ph O S O S H H Cl HO HO OBz HO HO OBz N CF O 3 Taxol derivatives Pesticide

Fig. 2 Sulfur-containing four-membered ring in useful molecules. Some representative cases are listed.

a R Nu Transition metal Nu Radical cyclization Nu R or 1 1 1 N R N R N N R   Brønsted acid 1 N 1 EWG EWG R EWG R EWG EWG

(EWG = electron-withdrawing group)

b Boc t-BuO O t-BuO O t-BuO O Boc N N N s-BuLi N Li N N or 1 1 2 R 1 1 1 R R 2 R R Li R Li 1 2 R TMEDA 2 2 2 R R R R R R3 3 3 R R3 R3 R3 R 6-endo-dig

c O R3 S O N 1 3 R R2 R3 R O O 4-exo-dig H S Deprotonation S O R1 N R1 N O R3 R2 R2 5-endo-dig O R1 S O N R2

d O O 2 Skeletal reorganization divergence S SO2NHR O S LDA O LDA R1 N Unusual outcome 2 1 2 R DMPU R NHR Broad substrate scope R1

Fig. 3 Skeletal reorganization of ynamides. a Intramolecular cyclizations of ynamides. b Skeletal reorganization of N-Boc ynamides. c Our initial hypothesis. d This work: Skeletal reorganization divergence of N-sulfonyl ynamides.

As shown in Table 1, we initially treated 1a with n-BuLi at −40 °C occurrence of skeletal reorganization. This unexpected outcome for 1 h and then quenched with MeOH; a new major product 2a prompted us to optimize the reaction. The next survey of lithium and a minor product 3a were isolated (entry 1). The standard bases showed that lithium diisopropylamine (LDA) was superior analysis, including 1H nuclear magnetic resonance (NMR), 13C to give 2a in 72% yield (entry 2), while the utilization of lithium NMR and mass spectroscopy, was not able to identify these bis(trimethylsilyl) would decrease the yield to 31% (entry 3). compounds. Gratifyingly, the X-ray analysis showed that 2a was a The use of sodium bis(trimethylsilyl)amide and potassium bis thiete and 3a was a propargyl (for more (trimethylsilyl)amide as base could only give 3a in very low yield details, see Supplementary Figs. 8 and 9), indicating an unusual (entries 4–5). Using NaH, 1,8-diazabicyclo[5.4.0]undec-7-ene or

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Table 1 Reaction optimizationa.

Me O Me Me SO NHn-Pr O 2 O S Me Me S Reaction condition Me O + Ph N n-Pr Ph NHn-Pr Ph 1a 2a 3a

Entry Base Additive Solvent T (°C) Yield of 2a (%)b Yield of 3a (%)b 1 n-BuLi None THF −40 60 19 2 LDA None THF −40 72 18 3 LiHMDS None THF −40 31 0 4 NaHMDS None THF −40 0 14 5 KHMDS None THF −40 0 16 6 NaH None THF 25 0 0 7 DBU None THF 25 0 0 8 TEA None THF 25 0 0 9 LDA None THF 0 68 19 10 LDA None THF −78 65 21 11 LDA TMEDA THF −40 63 16 12 LDA DMPU THF −40 Trace 82

LDA lithium diisopropylamine, LiHMDS lithium bis(trimethylsilyl)amide, NaHMDS sodium bis(trimethylsilyl)amide, KHMDS potassium bis(trimethylsilyl)amide, DBU 1,8-diazabicyclo[5.4.0]undec-7-ene, TEA trimethylamine, TMEDA N,N,N’,N’-tetramethylethylenediamine, DMPU 1,3-dimethyl-tetrahydropyrimidin-2(1H)-one. aReaction conditions: 1a (0.2 mmol), base (0.3 mmol), additive (1 mmol), THF (2 mL), 1 h, then MeOH (0.1 mL). bIsolated yields. trimethylamine as base showed inferior to shut down the reactivity detail, N-methylsulfonyl and N-benzylsulfonyl ynamides could even at room temperature, and 1a was recovered (entries 6–8). reorganize to corresponding thiete sulfones in moderate yield When LDA was used as base and the temperature was varied to (2k–2m), and the structure of 2k was confirmed by X-ray 0°Cor −78 °C, the yield of 2a would slightly decrease (entries diffraction (for more details, see Supplementary Fig. 11). When 9–10). Considering that lithiation was involved in this process, we N-cycloalkylsulfonyl ynamides like N-cyclopentanylsulfonyl tried to add ligands to increase the yield. Next, using of N,N,N’,N’- ynamides and N-cyclohexanylsulfonyl ynamides were used, the tetramethylethylenediamine as ligand showed no improvement skeletal reorganization could deliver spiro-fused thiete sulfones in (entry 11). Interestingly, the utilization of 1,3-dimethyl-tetra- moderate-to-good yields (2n–2q), and the structure of 2q hydropyrimidin-2(1H)-one (DMPU) as ligand would exclusively was also verified by X-ray diffraction (for more details, see give 3a in good yield (entry 12, 82% yield). Therefore, the skeletal Supplementary Fig. 12). With respect of the substitution at the reorganization is divergent and could be controlled by ligand. 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 Reaction scope study. With the optimized reaction conditions in good yields (2r–2x), and these did not show any hand, we next tested the substrate scope of this skeletal reorga- significant electronic and steric effects with the yields. Other aryl nization divergence. The starting material N-sulfonyl ynamides groups, including 2-naphthyl, 3-pyridinyl and thiophene-2-yl, could be easily prepared by coupling of sulfonamides and alkynyl were suitable in this process to produce the products successfully bromides. As shown in Fig. 4, various ynamides 1 could parti- (2y–2a’), and the structure of 2a’ was confirmed by X-ray analysis cipate well in this skeletal reorganization, leading to the corre- (for more details, see Supplementary Fig. 13). Meanwhile, the sponding thiete sulfones 2 in moderate-to-good yields. Diverse cyclohexenyl-substituted ynamide 1d’ could smoothly transform substitutions on the amino group of ynamides, including n-butyl, to the corresponding product 2b’ in 62% yield. Notably, silyl benzyl, i-propyl, cyclopentanyl and thiophene-2-ethyl, were substitution was compatible with the process as well. For exam- found tolerable in this process (2b–2d). The (S)-1-phenylethyl ple, the TIPS-substituted ynamide 1e’ could reorganize to product -derived ynamide 1g could also engage in this reaction to 2c’ in 58% yield with retention of the TIPS group, while the TMS- give the chiral moiety tethered thiete sulfone 2g in 77% yield. substituted ynamide 1f’ could transform to product 2d’ in a Other functional groups, such as and protected , remarkable 94% yield accompanied with TMS desilylation. were also compatible in this reorganization process to give the Unfortunately, β--substituted and terminal ynamides were corresponding products (2h and 2i), which might offer ample not applicable in this process (2e’–2f’). Since the amino- opportunities for the further derivatization. In addition, the containing full-substituted thiete sulfones are synthetically chal- aniline-derived ynamide (1j) was also applicable to deliver the lenging66, this skeletal reorganization of ynamides provides a desired product 2j in an excellent 92% yield. The structure of 2j robust and efficient approach toward these molecules with the was further confirmed by X-ray diffraction (for more details, see achievement of structural diversity and molecule complexity. Supplementary Fig. 10). For the variation of sulfonyl groups, a Next, the scope for another skeletal reorganization toward variety of substitutions were also tested and found amenable in propargyl sulfonamide was also investigated. As shown in Fig. 5,a this process to access functionalized thiete sulfones (2k–2q). In variety of ynamides were treated with LDA and DMPU toward

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O O S LDA (1.5 equiv.), –40 oC, THF O S O R1 N 1 2 R2 R NHR 1 2 Scope of amine

O Me O Me O Me O Me O Me O Me O S Me O S Me O S Me O S Me O S Me O S Me Me n-Bu Bn i-Pr () Ph N Ph N Ph N Ph N Ph N 2 Ph N H H H H H H Ph 2b, 70% 2c, 85% 2d, 83% 2e, 74% 2f, 84% S 2g, 77%

Scope of sulfonyl C16

Q2 Q1 O Me C15 O Me O Me C14 C17 O H S1

O S Me C9 O S Me Q2 C12 O S Me C13 Q1 O S H C7 S1 C5 C3 C4

C6 C8 C1 Ph N Ph C5 C2 Ph N C11 C10 Me Ph N C3 H C6 Ph N N1 H H C4 N1 C1 C10 H C2 C9 OTBS C7 C8 2h, 78% 2i, 81% 2j, 92% 2j 2k, 54%a 2k

O H O Ph O O O O O S H O S O S O S O S O S

n-Bu Bn n-Bu Bn Ph N Ph N Ph N Ph N Ph N n-Bu Ph N Bn H H H H H H 2l, 55%a 2m, 47%a 2n, 43% 2o, 81% 2p, 34% 2q, 74%

Q1 Scope of Q2

C15 S1 C2 O Me C3 O Me O Me C1

C16 C14 Q2 C3 C4 C4 O Me O S Me C13 C1 C6 O S Me O S Me Q1 C5 C2 C5 S1 C7 O S Me S2

C15 C8 N1 C14 C9 Bn Bn Bn C16 N C12 N1 N N C11 C12 C11 C10 C22 H C17 Bn H H C18 N C7 C6 C10 C21 S C20 H C19 C8 2q N C9 R 2y, 80% 2z, 85% 2a',85% 2a'

2r, R = 2-Cl, 86% O Me O Me O Me O Me O Me 2s, R = 3-Me, 74% O S Me O S Me 2t, R = 4-Me, 79% O S Me O S Me O S Me 2u, R = 4-pentyl, 74% Bn N H N 2v, R = 4-OMe, 70% H TIPS N Bn H THPO N Bn H N Bn H H H 2w, R = 4-F, 78% Me 2x, R = 4-Cl, 85% 2b', 62% 2c', 58% 2d', 94%b 2e', 0 2f', 0c

Fig. 4 Scope of thiete sulfones. Standard condition: 1 (0.2 mmol), LDA (0.3 mmol), THF (2 mL), −40 °C, 1 h, then treated with MeOH (0.1 mL). Yields refer to isolated products. a0.6 mmol LDA was used. bProduct of desilylation. cFrom the terminal ynamide.

the formation of propargyl sulfonamides, and the amino Synthetic applications and mechanism study. To demonstrate substitutions like n-butyl, cyclopentanyl, thiophene-3-ethyl and the synthetic utility of this skeletal reorganization divergence, an protected alcohol were compatible with this process (3b–3e). 8 mmol scale reaction was conducted (Fig. 6a). Under the stan- With respect to the sulfonyl substitutions, the cyclopentanyl and dard reaction conditions, 1a could be selectively transformed to cyclohexanyl were applicable in the process to deliver the 2a and 3a in gram-scale, indicating that these skeletal reorgani- corresponding products in good yields (3f–3i). Meanwhile, zation processes were practical. Considering that these processes alkynes with substitution on the aryl ring, including 2-fluoro, 2- may involve lithium intermediates that could offer opportunities chloro, 3-methyl, 4-methyl, 4-pentyl and 4-fluoro, could well for divergent functionalization of products, the derivatization was engage in this skeletal reorganization process to give the carried out. As shown in Fig. 6b, when various electrophilic corresponding propargyl sulfonamides in good yields (3j–3o). reagents instead of MeOH were used to quench the reaction after The naphthyl and pyridinyl groups were also applicable to furnish treating ynamide 1 with LDA, corresponding electrophilic the products smoothly (3p–3q). In terms of the structure of groups, such as methyl, allyl, propargyl, protected ethanol-2-yl, products, this skeletal reorganization involves an interesting 1,3- acetate and acetyl, were successfully installed in the amino group alkyne migration from N-atom to C-atom. Propargyl sulfonamide of products, leading to a series of functionalized thiete sulfones is a versatile synthon and their synthesis is challenging by (4a–4f). This result not only confirmed that a lithium amino conventional methods. Thus this protocol provides a simple and intermediate is involved in the reorganization process but also efficient method to synthesize these molecules from readily offered a vast potential for further derivatization of thiete sulfone available materials along with the fascinating process. skeletons. Similarly, when the LDA/DMPU-mediated skeletal

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2 O SO2NHR S O LDA (1.5 equiv.), DMPU (5 equiv.) R1 N o R2 –40 C, THF R1 1 3 Scope of amine

O O O O O n-Bu O O O Me S Me S Me S ( ) N N N 2 Me S N H H H S H OTBS Me Me Me Me

Ph 3b, 89% 3c, 72% Ph 3d, 46% Ph 3e, 44% Ph

Scope of sulfonyl

O O O O O n-Bu O n-Bu O n-Bu O n-Bu S S S N N N S N H H H H F

3f, 82% Ph 3g, 85% 3h, 84% Ph 3i, 84%

F Scope of alkyne

O O O O n-Bu O n-Bu O n-Bu Me S Me S N 3j, R = 2-F, 72% N Me S N H 3k, R = 2-Cl, 86% H H Me 3l, R = 3-Me, 66% Me Me R 3m, R = 4-Me, 64% 3n, R = 4-pentyl, 81% 3o, R = 4-F, 70% 3p, 86% 3q, 66% N

Fig. 5 Scope of propargyl sulfonamides. Standard condition: 1 (0.2 mmol), LDA (0.3 mmol), DMPU (1 mmol), THF (2 mL), −40 °C, 1 h, then treated with MeOH (0.1 mL). Yields refer to isolated products. reorganization process of ynamide 1a was quenched with MeI, an there are three possible cyclizations after α-lithiation (Fig. 7). In N-methyl propargyl sulfonamide product 5 was obtained in good paths 1 and 2, Li species Int-A may undergo a 4-exo-dig yield (Fig. 6c). This experiment suggested the existence of sulfo- cyclization to deliver isometric Int-B or Int-C via transition state namide anion intermediate after this skeletal reorganization TS1 or TS2 with a barrier of 17.6 or 18.4 kcal/mol, respectively. In process. path 3, Int-A undergoes a 5-endo-dig cyclization to give Int-D by In order to view more insights into the reaction, the TS3 with a higher barrier of 20.4 kcal/mol. Similarly, in the mechanism exploration was conducted. First, the crossover presence of DMPU, the formed Li species Int-E may undergo reaction was carried out to further explore the molecular reaction three types of cyclizations as well (Fig. 8). In paths 4 and 5, Int-E mode of this skeleton reorganization. As shown in Fig. 6d, when may transform to Int-F or Int-G via TS4 or TS5 with a barrier of ynamide 1r and 1x were subjected in one pot under the standard 22.5 or 23.7 kcal/mol. However, in path 6, Int-E needs a higher reaction condition, 2q and 2v were exclusively formed in 79 and barrier of 25.2 kcal/mol to initiate a 5-endo-cyclization to deliver 73% yields, respectively. This result excluded the possibility of Int-H. The relative lower barrier of paths 1 and 4 suggests that 4- intermolecular group exchange and verified this reaction is an exo-dig cyclization/cis addition is more favoured in these two intramolecular process. Besides, treating the mixture of 1c and skeleton reorganization processes. MeI with LDA could exclusively deliver the α-methylation Based on experimental and computational studies, a plausible product 6 in an excellent 91% yield (Fig. 6e). This outcome reaction mechanism for this skeletal reorganization divergence is disclosed that the α-lithiation was the initial step of the skeleton proposed (Fig. 9). Initially, the α-position of would reorganization. Meanwhile, isotope-labelling experiment was undergo lithiation upon treatment with LDA to deliver A and conducted to probe the skeleton reorganization processes. As then a 4-exo-dig cyclization would occur to generate four- shown in Fig. 6f, (β-13C)-1a was prepared and subjected to the membered β-sultam intermediate B63,64,67,68. Subsequently, B standard reactions. 13C-2a and 13C-3a could be formed smoothly presumably undergoes a 1,3-sulfonyl migration to form lithium under standard conditions. The position of 13C-labelled carbon thiete sulfone intermediate C69,70, which could be protonated by atom in the products was identified, which indicated that phenyl MeOH to deliver product 2. When MeOH was replaced by other migration did not occur in these skeleton reorganization electrophilic reagents, intermediate C could be functionalized processes. directly to obtain N-substituted thiete sulfone products. In the Moreover, we conducted density functional theory (DFT) presence of DMPU, α-lithiation of 1 could deliver Li species D, calculations at the level of M06 using the Gaussian 09 suite of which undergoes a 4-exo-dig cyclization to form intermediate E. computational programs. The 6-31G(d,p) basis set was applied Unlike intermediate B, intermediate E may undergo a β- for the C, H, O, N, S and Li atoms. In the LDA-mediated process, elimination to generate lithium propargyl sulfonamide F,

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a O Me d O O S Me LDA O O S S o Ph NHn-Pr O Me –40 C 2a Ph N Ph NHBn O 2q, 79% 74% (1.57 g) 1r Bn Me S LDA O + Ph N + Me –40 oC, THF O Me n-Pr Me SO2NHn-Pr O O S Me 1a LDA Me S Me O MeO N DMPU NHBn o –40 C Ph Bn 3a 1x 75% (1.59 g) 2v, 73% MeO

b O e O o Me Me Me LDA , –40 C, THF O S Me S O Me O O O LDA R1 N Me S Me S Li S + 1 E THF O 2 E R N O O Ph N R Ph N + MeI Ph N 1 4 R2 o Bn –40 C Bn Bn 1c 6, 91% α-Lithiation O Me O Me O Me O Me O S Me O S Me O S Me O S Me

R Ac Ph N Ph N Ph N Ot-Bu Ph N Bn Bn Bn Bn TBSO O f O Me 4a, R = Me, 71% 4d, 60% 4e, 72% 4f, 56% LDA O S Me 13 4b, R = allyl, 58% Me –40 oC C Ph N n-Pr 4c, R = propargyl, 55% O H Me S O 13C-2a, 70% Ph 13C N c Me n-Pr O O Me O n-Pr β 13 LDA Me o Me S N ( - C)-1a 13 Me S LDA, DMPU, –40 C, THF Ph C O O DMPU Ph N Me S Me o n-PrHN –40 C O n-Pr MeI Ph 1a 5, 73% 13C-3a, 79%

Fig. 6 Synthetic applications and mechanistic experiments. 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.

THF THF TS3 THF Ph Δ Li THF G (kcal/mol) THF Me Li Me Li Ph Ph Me TS Me 2 THF n-Pr N N S O N S O Me n-Pr S 1a n-Pr O O O Me TS1 O

LDA TS1 TS2 TS3 THF 17.6 18.4 20.4 –40 oC THF THF THF Ph Li THF THF Ph Me Li THF Me Li Ph Ph Me Me THF n-Pr N THF N S O Li N S O Me n-Pr S n-Pr O N Me O O Me n-Pr S O Me Int-C O O 0.0 Int-B Int-D Int-A –7.2 –10.9 –27.4 Int-B

Int-C Path 1 (red): 4-exo-dig cyclization/cis addition Path 2 (blue): 4-exo-dig cyclization/trans addition Path 3 (green): 5-endo-dig cyclization Int-D

Fig. 7 DFT calculations for the LDA-mediated cyclization in the skeleton reorganization. Free energy profiles (kcal/mol) of three possible cyclizations from Int-A. path 1 (red): 4-exo-dig cyclization/cis addition leading to Int-B (via TS1), path 2 (blue): 4-exo-dig cyclization/trans addition leading to Int-C (via TS2), path 3 (green): 5-endo-dig cyclization leading to Int-D (via TS3).

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TS6 ΔG (kcal/mol)

TS5 DMPU DMPU DMPU

TS4 Li Ph Li Me Me Ph Ph Li Me Me n-Pr N N S O N S O S Me n-Pr n-Pr O Me O O O 1a TS TS5 TS LDA 4 6 DMPU 22.5 23.7 25.2 THF DMPU DMPU –40 oC Li DMPU Ph Me Li Ph Me Ph Ph Me Li Me DMPU n-Pr N N S O N S O S Me n-Pr Li O n-Pr O Me O O N Me Int-F Int-G Int-H n-Pr S Me O O 0.0 –8.2 –8.6 –19.3

Int-E

Int-F Path 4 (red): 4-exo-dig cyclization/cis addition Int-G Path 5 (blue): 4-exo-dig cyclization/trans addition Path 6 (green): 5-endo-dig cyclization Int-H

Fig. 8 DFT calculations for the LDA/DMPU-mediated cyclization in the skeleton reorganization. Free energy profiles (kcal/mol) of three possible cyclizations from Int-E. path 4 (red): 4-exo-dig cyclization/cis addition leading to Int-F (via TS4), path 5 (blue): 4-exo-dig cyclization/trans addition leading to Int-G (via TS5), path 6 (green): 5-endo-dig cyclization leading to Int-H (via TS6).

R1 O THF O O S O 1,3-Sulfonyl THF 4-exo-dig O S MeOH O S N migration Li Li 2 R 2 R2 LDA N R1 N R R1 N THF R2 S THF R1 Li H O O THF THF A B C THF 2 O S O R1 N 1 R2 R O 1 SO NR2 SO NHR2 L S O 2 2 LDA Li 4-exo-dig β-elimination Li MeOH DMPU N N Li R2 R2 L THF S 1 1 R 1 O O L R R D (L = DMPU) E F 3

Fig. 9 Plausible mechanism. Possible reaction mechanism of the skeletal reorganization divergence. probably due to the addition of DMPU that dissociates the Methods intermolecular or intramolecular interaction of Li species and General procedure for the synthesis of thiete sulfones 2. An oven-dried change the reactivity. The following protonation would furnish 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 product 3. (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 Discussion −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 In summary, we have discovered a skeletal reorganization divergence further purified by silica gel column chromatography using ethyl acetate/petroleum of N-sulfonyl ynamides. Upon treatment with lithium base, the N- as eluent to give thiete sulfones 2. sulfonyl ynamides could undergo lithiation/cyclization and the sequential ligand-determining 1,3-sulfonyl migration or β- General procedure for the synthesis of propargyl sulfonamides 3.Anoven- elimination to deliver thiete sulfones or propargyl sulfonamides. dried Schlenk tube equipped with a magnetic stirrer bar was purged with argon three This skeletal reorganization divergence features broad substrate scope times. Ynamide 1 (0.2 mmol) was dissolved in 2 mL anhydrous THF and added by a and scalability. Mechanistic experiments and DFT calculations are syringe. DMPU (62 μL, 1 mmol) was added and the mixture was cooled to −40 °C. conducted to verify the rationality of the proposed mechanism. 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 Therefore, this protocol not only represents a new skeletal reorga- quench the reaction. The mixture was concentrated under vacuum to obtain the resi- nization mode but also provides facile and selective access to privi- due, which was further purified by silica gel column chromatography using ethyl leged molecules from the easily accessible ynamides. acetate/petroleum ether as eluent to give propargyl sulfonamides 3.

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53. Yang, J., Wang, C., Xu, S. & Zhao, J. Ynamide-mediated thiopeptide synthesis. Acknowledgements Angew. Chem. Int. Ed. 58, 1382–1386 (2019). We are grateful for the financial support by the National Natural Science Foundation of China 54. Yang, M., Wang, X. & Zhao, J. Ynamide-mediated macrolactonization. ACS (21971222), Leading Talent of “Ten Thousand Plan”-National High-Level Talents Special Catal. 10, 5230–5235 (2020). Support Plan. We thank Dr. Zhenjun Mao (Department of Chemistry, Zhejiang University) 55. Huang, B., Zeng, L., Shen, Y. & Cui, S. One-pot multicomponent synthesis of and Jianyang Pan (Research and Service Center, College of Pharmaceutical Sciences, Zhejiang β-amino . Angew. Chem. Int. Ed. 56, 4565–4568 (2017). University) for performing NMR spectrometry for structure elucidation. 56. Shen, Y., Huang, B., Zeng, L. & Cui, S. Single reactant replacement approach β of passerini reaction: one-pot synthesis of -acyloxyamides and phthalides. Author contributions Org. 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The Baldwin rules: revised and extended. Wires Comput. Mol. Sci. 6, 487–514 (2016). Reprints and permission information is available at http://www.nature.com/reprints 64. Gilmore, K. & Alabugin, I. V. Cyclizations of alkynes: revisiting baldwin’s ’ rules for ring closure. Chem. Rev. 111, 6513–6556 (2011). Publisher s note Springer Nature remains neutral with regard to jurisdictional claims in fi 65. Chen, R., Zeng, L., Huang, B., Shen, Y. & Cui, S. Decarbonylative coupling of published maps and institutional af liations. α-keto acids and ynamides for synthesis of β-keto . Org. Lett. 20, 3377–3380 (2018). 66. Hasek, R. H., Meen, R. H. & Martin, J. C. Reactions of alkanesulfonyl chlorides Open Access This article is licensed under a Creative Commons Attri- with ketene N,N- and O,N-. J. Org. Chem. 30, 1495–1498 (1965). bution 4.0 International License, which permits use, sharing, adaptation, 67. Bailey, W. F. & Aspris, P. H. Facile preparation of alkenylidenecycloalkanes by distribution and reproduction in any medium or format, as long as you give appropriate cyclization of acetylenic alkyllithiums bearing a propargylic leaving group. J. credit to the original author(s) and the source, provide a link to the Creative Commons – Org. Chem. 60, 754 757 (1995). license, and indicate if changes were made. The images or other third party material in this 68. Bailey, W. F. & Ovaska, T. V. Cyclization of acetylenic alkyllithiums. J. Am. article are included in the article’s Creative Commons license, unless indicated otherwise in – Chem. Soc. 115, 3080 3090 (1993). a credit line to the material. If material is not included in the article’sCreativeCommons 69. Flynn, A. J., Ford, A. & Maguire, A. R. Synthetic and mechanistic aspects of license and your intended use is not permitted by statutory regulation or exceeds the – sulfonyl migrations. Org. Biomol. 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