SOMOphilic Alkynylation of Unreactive Alkenes Enabled by Iron-Catalyzed Hydrogen Atom Transfer

We report an efficient and practical iron-catalyzed hydrogen atom transfer protocol for assembling acetylenic motifs into functional alkenes. Diversities of internal alkynes could be obtained from readily available alkenes and acetylenic sulfones with excellent Markovnikov selectivity. An iron hydride hydrogen atom transfer catalytic cycle was described to clarify the mechanism of this reaction.


Results
To start our investigation, we probed the reaction employing alkene 1a (0.3 mmol) and acetylenic sulfone 2a (0.2 mmol) as model substrates in the presence of Fe(acac) 3 (30 mol%), PhSiH 3 (2.0 equiv) in a mixed solvent. As expected, the desired internal alkyne 3a bearing a quaternary carbon center could be obtained with 81% yield (Table 1, Entry 1). Some other acetylenic sulfones 2a -2a were investigated, and worse results were obtained (Table 1, Entries 2-Entries 6). Additionally, only 62% yield of 3a was generated if the reaction was operated in EtOH without the addition of (CH 2 OH) 2 , which showed that (CH 2 OH) 2 played an irreplaceable role contributing to the high efficiency of the transformation (Table 1, Entry 7), because it could suppress the formation of PhSi(OEt) 3 [46]. Additionally, the yield of desired product 3a was reduced to 60% with the amount of Fe(acac) 3 decreasing to 20 mol% (Table 1, Entry 8). After screening of other catalysts including In(acac) 3 , Co(acac) 3 and FeCl 3 , it was shown that In(acac) 3 and Co(acac) 3 were completely ineffective and FeCl 3 was of modest efficiency, resulting in the alkyne product 3a with a 45% yield (Table 1, Entries 9-Entries 11). Notably, an apparent decrease in the yield was observed when alkene 1a (0.2 mmol) and acetylenic sulfone 2a (0.3 mmol) participated in the reaction (Table 1, Entry 12). was less explored. In 2006, Renaud and coworkers disclosed a radical-mediated alkynylation of alkenes to yield internal alkynes under the initiation of di-tert-butylhyponitrite, wherein the in situ hydroboration of the alkenes contributed to the excellent anti-Markovnikov selectivity (Scheme 1c) [68]. Herein, we developed an iron-catalyzed strategy to synthesize the internal alkynes with Markovnikov selectivity from readily available alkenes via a MHAT process (Scheme 1d).

Results
To start our investigation, we probed the reaction employing alkene 1a (0.3 mmol) and acetylenic sulfone 2a (0.2 mmol) as model substrates in the presence of Fe(acac)3 (30 mol%), PhSiH3 (2.0 equiv) in a mixed solvent. As expected, the desired internal alkyne 3a bearing a quaternary carbon center could be obtained with 81% yield ( Table 1, Entry 1). Some other acetylenic sulfones 2a'-2a''''' were investigated, and worse results were obtained (Table 1, Entries 2-Entries 6). Additionally, only 62% yield of 3a was generated if the reaction was operated in EtOH without the addition of (CH2OH)2, which showed that (CH2OH)2 played an irreplaceable role contributing to the high efficiency of the transformation (Table 1, Entry 7), because it could suppress the formation of PhSi(OEt)3 [46]. Additionally, the yield of desired product 3a was reduced to 60% with the amount of Fe(acac)3 decreasing to 20 mol% ( Table 1, Entry 8). After screening of other catalysts including In(acac)3, Co(acac)3 and FeCl3, it was shown that In(acac)3 and Co(acac)3 were completely ineffective and FeCl3 was of modest efficiency, resulting in the alkyne product 3a with a 45% yield ( With the optimal conditions in hand, we then examined the scope of iron-catalyzed SOMOphilic alkynylation, keeping 2a and 2b as radical acceptors, which is presented in Figure 1. These simple and mild conditions turned out to be compatible with a wide range of alkenes with exquisite functional group tolerance. β-methyl alkenes were investigated as suitable substrates to react with 2a, affording the substituted alkynes 3a-3d bearing quaternary carbons in modest to good yields. Moreover, alkenes bearing bulky groups also worked well to provide the corresponding alkynes 3e-3f in satisfactory yields. Since this reaction's conditions were gentle, alkenes bearing a wide of functional groups such as phenyl (1g), carbonyl (1h), ester (1i), amide (1j, 1k), amine (1l), hydroxyl (1m), carboxyl (1n), silicon (1o) groups underwent the MHAT-promoted alkynylation in 55% to 84% yields. Notably, although the reactions were operated in mixed alcohols, the alkenes bearing halide atoms performed well, generating desired alkynes 3p-3q in good yields, which could be applied for the further transformations. In addition, the reactions of internal alkenes with alkyne reagent 2a were operated smoothly, leading to the formation of the alkynylation products 3r-3u in 50% to 86% yields. The styrene derivatives could also be treated as suitable candidates under the optimized conditions to provide the alkynes 3v-3x in medium yields with excellent selectivity.
GC-MS using dodecane as the internal standard. c Isolated yield in parentheses.
With the optimal conditions in hand, we then examined the scope of iron-catalyzed SOMOphilic alkynylation, keeping 2a and 2b as radical acceptors, which is presented in Figure 1. These simple and mild conditions turned out to be compatible with a wide range of alkenes with exquisite functional group tolerance. β-methyl alkenes were investigated as suitable substrates to react with 2a, affording the substituted alkynes 3a-3d bearing quaternary carbons in modest to good yields. Moreover, alkenes bearing bulky groups also worked well to provide the corresponding alkynes 3e-3f in satisfactory yields. Since this reaction's conditions were gentle, alkenes bearing a wide of functional groups such as phenyl (1g), carbonyl (1h), ester (1i), amide (1j, 1k), amine (1l), hydroxyl (1m), carboxyl (1n), silicon (1o) groups underwent the MHAT-promoted alkynylation in 55% to 84% yields. Notably, although the reactions were operated in mixed alcohols, the alkenes bearing halide atoms performed well, generating desired alkynes 3p-3q in good yields, which could be applied for the further transformations. In addition, the reactions of internal alkenes with alkyne reagent 2a were operated smoothly, leading to the formation of the alkynylation products 3r-3u in 50% to 86% yields. The styrene derivatives could also be treated as suitable candidates under the optimized conditions to provide the alkynes 3v-3x in medium yields with excellent selectivity. Encouraged by the results of variable alkenes, we continued to investigate the scope of alkyne sources utilizing alkene 1m as a radical precursor under the optimal conditions. Diversities of acetylenic sulfones were prepared and participated in the reaction system. As shown in Figure 2, the electron-donating groups, electron-withdrawing groups and halide atoms on the phenyl rings were tolerated. As examples, acetylenic sulfones with methyl, methoxyl, phenyl, fluoro, chloro, bromo and trifluoromethyl groups engage in the reactions, yielding the corresponding products 4a-4g in 71% to 85% yields. Importantly, triisopropylsilacetylene-derived sulfone demonstrated an excellent performance, yielding the product 4h with a 92% yield, which could be converted into the terminal alkyne under desiliconization conditions.
Encouraged by the results of variable alkenes, we continued to investigate the scope of alkyne sources utilizing alkene 1m as a radical precursor under the optimal conditions. Diversities of acetylenic sulfones were prepared and participated in the reaction system. As shown in Figure 2, the electron-donating groups, electron-withdrawing groups and halide atoms on the phenyl rings were tolerated. As examples, acetylenic sulfones with methyl, methoxyl, phenyl, fluoro, chloro, bromo and trifluoromethyl groups engage in the reactions, yielding the corresponding products 4a-4g in 71% to 85% yields. Importantly, triisopropylsilacetylene-derived sulfone demonstrated an excellent performance, yielding the product 4h with a 92% yield, which could be converted into the terminal alkyne under desiliconization conditions. A tentative mechanism of this SOMOphilic alkynylation of alkenes is depicted in Scheme 2 according to the reported iron-catalyzed hydrofunctionalizations of alkenes via the MHAT process [40] and radical-mediated alkynylation [68]. Initially, Fe III (acac)3 was converted into the HFe III (acac)2 species with the interaction of PhSiH3 in alcohol. Then, MHAT occurred between HFe III (acac)2 and non-activated alkenes 1, acting as a rate-determining step [69], affording carbon-centered radical A with excellent Markovnikov selectivity as well as Fe II (acac)2. Subsequently, anti-Michael addition of A onto acetylenic sulfone 2a generated enyl radical intermediates B, followed by the radical-mediated desulfonation to afford the desired alkyne products 3 with a release of sulfonyl radical, achieving the alkynyl functionalization with the realization of sulfonyl radical C. Finally, the sulfonyl radical C oxidized Fe II (acac)2 to Fe III (acac)3 to fulfill the catalytic cycle, generating a sulfinic acid E [70], which was detected in HRMS ( Figure S1 in Supplementary Materials). A tentative mechanism of this SOMOphilic alkynylation of alkenes is depicted in Scheme 2 according to the reported iron-catalyzed hydrofunctionalizations of alkenes via the MHAT process [40] and radical-mediated alkynylation [68]. Initially, Fe III (acac) 3 was converted into the HFe III (acac) 2 species with the interaction of PhSiH 3 in alcohol. Then, MHAT occurred between HFe III (acac) 2 and non-activated alkenes 1, acting as a ratedetermining step [69], affording carbon-centered radical A with excellent Markovnikov selectivity as well as Fe II (acac) 2 . Subsequently, anti-Michael addition of A onto acetylenic sulfone 2a generated enyl radical intermediates B, followed by the radical-mediated desulfonation to afford the desired alkyne products 3 with a release of sulfonyl radical, achieving the alkynyl functionalization with the realization of sulfonyl radical C. Finally, the sulfonyl radical C oxidized Fe II (acac) 2 to Fe III (acac) 3 to fulfill the catalytic cycle, generating a sulfinic acid E [70], which was detected in HRMS ( Figure S1 in Supplementary Materials).

Discussion
In conclusion, we developed an iron-catalyzed SOMOphilic alkynylation of non-activated alkenes with acetylenic sulfone with Markovnikov selectivity. A wide range of Scheme 2. Plausible mechanism.

Discussion
In conclusion, we developed an iron-catalyzed SOMOphilic alkynylation of nonactivated alkenes with acetylenic sulfone with Markovnikov selectivity. A wide range of secondary and tertiary alkynes bearing variable functional and sensitive groups could be obtained from readily available and easily prepared starting materials by this efficient and mild MHAT strategy. Additional applications in the synthesis and modification of complex molecules or bioactive compounds are under investigation in our laboratory.

General Information
Unless otherwise noted, all reactions were performed under an argon atmosphere using flame-dried glassware. All new compounds were fully characterized. NMR-spectra were recorded on Bruker ARX-400 MHz or ARX-600 Associated. 1 H NMR spectra data were reported as δ values in ppm relative to chloroform (δ 7.26) if collected in CDCl 3 . 13 C NMR spectra data were reported as δ values in ppm relative to chloroform (δ 77.00). 1 H NMR coupling constants were reported in Hz, and multiplicity was indicated as follows: s (singlet); d (doublet); t (triplet); q (quartet); quint (quintet); m (multiplet); dd (doublet of doublets); ddd (doublet of doublet of doublets); dddd (doublet of doublet of doublet of doublets); dt (doublet of triplets); td (triplet of doublets); ddt (doublet of doublet of triplets); dq (doublet of quartets); app (apparent); and br (broad). Mass spectra were obtained using a Micromass Q-Tof instrument (ESI) and Agilent Technologies 5973N (EI). All reactions were carried out in flame-dried 25 mL Schlenk tubes with Teflon screw caps under an argon atmosphere. Unless otherwise noted, materials obtained from commercial suppliers were used without further purification. Acetylenic sulfones 2 were prepared according to the reported procedures [29,71].

General Procedures of Iron-Catalyzed SOMOphilic Alkynylation
Flame-dried 10 mL Schlenk tube filled with N 2 , acetylenic sulfones 2 (0.2 mmol, 1.0 equiv) and Fe(acac) 3 (21.2 mg, 0.06 mmol, 30 mol%) were added under N 2 , evacuated and purged with N 2 three times. Afterwards, PhSiH 3 (43.2 mg, 0.4 mmol, 2 equiv), nonactivted alkenes 1 (33.1 mg, 0.3 mmol, 1.5 equiv) and ethanol (0.8 mL) and ethylene glycol (0.2 mL) were added via syringe. The formed mixture was stirred at 35 • C under N 2 for 12 h, as monitored by TLC. The solution was then cooled to room temperature, and the solution was diluted with ethyl acetate and transferred to a round bottom flask. The concentrated residue was purified by column chromatography using ethyl acetate/petroleum ether as an eluent to afford the corresponding products and 3 and 4.      Figure S1: HRMS spectra of sulfinic acid E; 1H NMR, 13 C NMR and 19 F NMR spectra of starting materials and products.

Data Availability Statement:
The data presented in this study are available on request from the corresponding authors.