Nickel-Catalyzed Kumada Cross-Coupling Reactions of Benzylic Sulfonamides

Herein, we report a Kumada cross-coupling reaction of benzylic sulfonamides. The scope of the transformation includes acyclic and cyclic sulfonamide precursors that cleanly produce highly substituted acyclic fragments. Preliminary data are consistent with a stereospecific mechanism that allows for a diastereoselective reaction.

Ring-strain-promoted XC of aziridines has been accomplished [20]. Early stoichiometric work by Hillhouse established that aziridines undergo facile oxidative addition with nickel complexes [21]. Catalytic Negishi reactions of sulfonylaziridines have subsequently been established. The Doyle laboratory reported a regioselective Negishi XC reaction of styrenyl aziridines with alkylzinc reagents with substitution at the benzylic position (Scheme 1a) [22,23]. Key to their success was the use of an electron deficient fumarate ligand. Shortly thereafter, the Doyle and Jamison groups independently described a regioselective Negishi XC reaction of alkyl aziridines with alkylzinc reagents to forge the desired carbon-carbon bond (Scheme 1b,c) [24,25]. The differing regioselectivity of these reactions can be explained by comparing the oxidative addition events of the C-N bonds. Styrenyl aziridines preferentially undergo oxidative addition at the benzylic center to afford a η 3 -benzylnickel complex. In contrast, alkyl aziridines, which do not contain an aromatic ring to direct the nickel complex, preferentially undergo oxidative addition at the less hindered position [21]. These reports demonstrate the ability to activate the C-N bond in strained rings.
Development of XC reactions of acyclic benzylamine derivatives has relied upon formation of highly reactive electrophiles (i.e., charged ammonium salts) [26,27]. For example, the Watson laboratory demonstrated that benzylic trimethylammonium salts are competent electrophiles in Suzuki-Miyaura XC reactions with aryl and vinylboronic acids (Scheme 2a) [28,29]. Similarly, the Wang laboratory disclosed the XC reaction of benzylic trimethylammonium salts with organoaluminum reagents to forge the desired carboncarbon bond (Scheme 2b) [30]. The use of Katritzky salts to activate amines has proven to be sufficient for activation of benzylic and alkyl amines for Suzuki-Miyaura and Negishi XC reactions. Previously, it has been observed that Katritzky salts participate in SN2, radical, and Minisci-type reactions, and in recent years, many transition-metal catalyzed reactions have been developed [31][32][33][34][35][36][37][38][39][40]. The Watson laboratory hypothesized that these air and moisture stable salts would be suitable electrophiles in a XC reaction [41]. To test their hypothesis, primary amines were converted to Katritzky salts via a condensation reaction with 2,4,6-triphenylpyrylium tetrafluoroborate and the corresponding salts were subjected to Suzuki-Miyaura XC reactions with aryl boronic acids. The desired cross-coupled products were obtained in good yields (Scheme 3a) [42]. This strategy was amenable to the coupling of primary benzylic Katritzky salts as well (Scheme 3b) [43]. Additionally, vinyl boranes and alkylborane reagents, generated in situ by hydroboration of alkenes, participated in XC with Katritzky salts (Scheme 3c,d) [44,45]. This strategy has been extended beyond Suzuki-Miyaura reactions to include Negishi XC reactions with alkylzinc reagents (Scheme 3e) [46]. The use of Katritzky salts to activate amines has proven to be sufficient for activation of benzylic and alkyl amines for Suzuki-Miyaura and Negishi XC reactions. Previously, it has been observed that Katritzky salts participate in S N 2, radical, and Minisci-type reactions, and in recent years, many transition-metal catalyzed reactions have been developed [31][32][33][34][35][36][37][38][39][40]. The Watson laboratory hypothesized that these air and moisture stable salts would be suitable electrophiles in a XC reaction [41]. To test their hypothesis, primary amines were converted to Katritzky salts via a condensation reaction with 2,4,6-triphenylpyrylium tetrafluoroborate and the corresponding salts were subjected to Suzuki-Miyaura XC reactions with aryl boronic acids. The desired cross-coupled products were obtained in good yields (Scheme 3a) [42]. This strategy was amenable to the coupling of primary benzylic Katritzky salts as well (Scheme 3b) [43]. Additionally, vinyl boranes and alkylborane reagents, generated in situ by hydroboration of alkenes, participated in XC with Katritzky salts (Scheme 3c,d) [44,45]. This strategy has been extended beyond Suzuki-Miyaura reactions to include Negishi XC reactions with alkylzinc reagents (Scheme 3e) [46].
These methods establish strain-and charge-based strategies to activate amines for use as the electrophilic partner in XC reactions; however, the requirement for aziridines or functionalization as highly reactive ammonium salts remains a major limitation in broad application of these methods. In this manuscript, we report the first nickel-catalyzed Kumada XC reaction of simple benzylic sulfonamides with methylmagnesium iodide (Scheme 4). Previously, the Jarvo laboratory disclosed the Kumada XC reaction of benzylic ethers which proceeded in excellent yields, and enantio-and diastereoselectivity [12,47,48]. Building on this work, we aimed to develop an analogous reaction that employed benzylic sulfonamides. Ethers and sulfonamides have similar leaving group abilities, as the conjugate bases have similar pK a 's, and we hypothesized sulfonamides would behave similarly to ethers in a XC reaction [49,50]. In addition, these moieties are appealing because they are common functional groups in synthesis. Furthermore, we demonstrate that sulfonamides undergo stereospecific XC reactions, in contrast to the stereoablative reactivity typically observed with styrenyl aziridines and Katritzky salts [22,[36][37][38][39][40][51][52][53][54]. This stereospecific improve the yield of 2 (entries 4-7).
We next investigated an alternative precatalyst. Previously, the Jarvo laboratory reported the cross-electrophile coupling (XEC) reaction of benzylic and allylic sulfonamides which employed a BINAP-ligated nickel (II) precatalyst [50,57,58]. Utilizing these conditions, with 15 mol % of catalyst, we were delighted to observe the desired product in 54% yield and 40% yield of styrene 3 (entry 8). We elected to proceed with the nickel (II) precatalyst as it provided the desired product in the highest yield.

Entry
Nickel Catalyst Ligand Yield 2 (%) 1 Yield 3 (%) 1 RSM 1 (%) 1 1 2 Ni(cod)2 rac-BINAP 25  With optimized conditions in hand, we evaluated the scope of the Kumada XC reaction (Scheme 5). Naphthyl substrates were well tolerated under the standard reaction conditions and product 4 was observed in 84% yield. Notably, products such as 5 and 6 with branching at the β-position provided good yields of cross-coupled products with lesser amounts of styrenes formed from β-hydride elimination (20-30%) when compared to product 2. We hypothesized that this increase in steric bulk destabilized the conformation necessary for β-hydride elimination to proceed. We next investigated an alternative precatalyst. Previously, the Jarvo laboratory reported the cross-electrophile coupling (XEC) reaction of benzylic and allylic sulfonamides which employed a BINAP-ligated nickel (II) precatalyst [50,57,58]. Utilizing these conditions, with 15 mol % of catalyst, we were delighted to observe the desired product in 54% yield and 40% yield of styrene 3 (entry 8). We elected to proceed with the nickel (II) precatalyst as it provided the desired product in the highest yield.
With optimized conditions in hand, we evaluated the scope of the Kumada XC reaction (Scheme 5). Naphthyl substrates were well tolerated under the standard reaction conditions and product 4 was observed in 84% yield. Notably, products such as 5 and 6 with branching at the β-position provided good yields of cross-coupled products with lesser amounts of styrenes formed from β-hydride elimination (20-30%) when compared to product 2. We hypothesized that this increase in steric bulk destabilized the conformation necessary for β-hydride elimination to proceed. We also sought to evaluate a series of arylpiperidines, with the expectation that a stereospecific XC reaction at the benzylic position would provide synthetic access to highly substituted acyclic fragments. Furthermore, products would bear a pendant sulfonamide moiety, available for subsequent functionalization [50]. Rapid synthesis of the requisite cyclic sulfonamides was achieved by hetero Diels-Alder (HDA) cycloadditions or aza-Prins reactions [59][60][61]. For substrates with alkyl substituents in the 4-position, [4+2] HDA reactions provided the requisite starting materials (Scheme 6a). For substrates bearing ether groups in the 4-position, an aza-Prins reaction provided the requisite 2-aryl-4-hydroxylpiperidine that could be subsequently methylated or benzylated. (Scheme 6b).
We also sought to evaluate a series of arylpiperidines, with the expectation that a stereospecific XC reaction at the benzylic position would provide synthetic access to highly substituted acyclic fragments. Furthermore, products would bear a pendant sulfonamide moiety, available for subsequent functionalization [50]. Rapid synthesis of the requisite cyclic sulfonamides was achieved by hetero Diels-Alder (HDA) cycloadditions or aza-Prins reactions [59][60][61]. For substrates with alkyl substituents in the 4-position, [4+2] HDA reactions provided the requisite starting materials (Scheme 6a). For substrates bearing ether groups in the 4-position, an aza-Prins reaction provided the requisite 2-aryl-4-hydroxylpiperidine that could be subsequently methylated or benzylated. (Scheme 6b). With rapid and diastereoselective access to the desired piperidines, we examined these cyclic substrates in ring-opening Kumada XC reactions (Scheme 7). Phenyl and methyl substituents (products 7 and 8) were well tolerated and minimal amounts (<5%) of βhydride elimination were observed. Methylated and benzylated ethers were well tolerated and provided the desired products in good yields (9, 10, and 11) [62]. It is important to note that the diastereomeric ratio observed in the products is consistent with the diastereomeric ratio of the starting material (See Materials and Methods Section). Therefore, preliminary data support a stereospecific Kumada XC reaction. With rapid and diastereoselective access to the desired piperidines, we examined these cyclic substrates in ring-opening Kumada XC reactions (Scheme 7). Phenyl and methyl substituents (products 7 and 8) were well tolerated and minimal amounts (<5%) of βhydride elimination were observed. Methylated and benzylated ethers were well tolerated and provided the desired products in good yields (9, 10, and 11) [62]. It is important to note that the diastereomeric ratio observed in the products is consistent with the diastereomeric ratio of the starting material (See Materials and Methods Section). Therefore, preliminary data support a stereospecific Kumada XC reaction. To further develop the potential scope of this reaction, we sought to establish a ringopening of a sulfonyl piperidine with an aryl Grignard reagent (Scheme 8). Such transformations would provide synthetic access to diarylalkanes bearing pendant sulfonamides, including rapid assembly of stereochemically-rich analogs of ATPase inhibitor 14 [63][64][65][66][67]. We have previously observed that in Kumada XC reactions of benzylic ethers employing aryl Grignard reagents, the optimal nickel catalyst is ligated by dppe [68]. We were pleased to see that this trend applied to benzylic sulfonamides: employing the commercially available precatalyst, (dppe)NiCl2, the XC reaction proceeded smoothly to provide the desired product 13 in 58% isolated yield [69]. To further develop the potential scope of this reaction, we sought to establish a ring-opening of a sulfonyl piperidine with an aryl Grignard reagent (Scheme 8). Such transformations would provide synthetic access to diarylalkanes bearing pendant sulfonamides, including rapid assembly of stereochemically-rich analogs of ATPase inhibitor 14 [63][64][65][66][67]. We have previously observed that in Kumada XC reactions of benzylic ethers employing aryl Grignard reagents, the optimal nickel catalyst is ligated by dppe [68]. We were pleased to see that this trend applied to benzylic sulfonamides: employing the commercially available precatalyst, (dppe)NiCl 2 , the XC reaction proceeded smoothly to provide the desired product 13 in 58% isolated yield [69]. mations would provide synthetic access to diarylalkanes bearing pendant sulfonamides, including rapid assembly of stereochemically-rich analogs of ATPase inhibitor 14 [63][64][65][66][67]. We have previously observed that in Kumada XC reactions of benzylic ethers employing aryl Grignard reagents, the optimal nickel catalyst is ligated by dppe [68]. We were pleased to see that this trend applied to benzylic sulfonamides: employing the commercially available precatalyst, (dppe)NiCl2, the XC reaction proceeded smoothly to provide the desired product 13 in 58% isolated yield [69]. We propose the following catalytic cycle for the Kumada XC reaction based on related mechanisms for the Kumada XC reaction of benzylic ethers and the XEC reaction of benzylic sulfonamides (Scheme 9) [50,70]. First, reduction of the nickel(II) precatalyst with the Grignard reagent provides the active Ni(0) catalyst 15. Next, oxidative addition of the benzylic sulfonamide affords the Ni(II) intermediate 16. Based on the calculated reaction coordinate diagram and transition state energies for related transformations, we hypothesize that rate-determining oxidative addition occurs with inversion of the benzylic carbon [12,47,48,70]. This step is facilitated by Lewis acidic magnesium salts that activate the sulfonamide moiety. Transmetallation with the Grignard reagent provides alkylnickel complex 17. Subsequent reductive elimination, which occurs with retention at the benzylic center, affords the desired product and turns over the catalyst. Alternatively, intermediate 16 can undergo β-hydride elimination to afford the observed styrene by-product. We propose the following catalytic cycle for the Kumada XC reaction based on related mechanisms for the Kumada XC reaction of benzylic ethers and the XEC reaction of benzylic sulfonamides (Scheme 9) [50,70]. First, reduction of the nickel(II) precatalyst with the Grignard reagent provides the active Ni(0) catalyst 15. Next, oxidative addition of the benzylic sulfonamide affords the Ni(II) intermediate 16. Based on the calculated reaction coordinate diagram and transition state energies for related transformations, we hypothesize that rate-determining oxidative addition occurs with inversion of the benzylic carbon [12,47,48,70]. This step is facilitated by Lewis acidic magnesium salts that activate the sulfonamide moiety. Transmetallation with the Grignard reagent provides alkylnickel complex 17. Subsequent reductive elimination, which occurs with retention at the benzylic center, affords the desired product and turns over the catalyst. Alternatively, intermediate 16 can undergo β-hydride elimination to afford the observed styrene by-product.

General Procedures
All reactions were carried out under an atmosphere of N2, or Ar when noted. All glassware was oven-or flame-dried prior to use. Tetrahydrofuran (THF), diethyl ether (Et2O), dichloromethane (CH2Cl2), and toluene (PhMe) were degassed with Ar and then passed through two 4 × 36 inch columns of anhydrous neutral A-2 alumina (8 × 14 mesh; LaRoche Chemicals; activated under a flow of argon at 350 °C for 12 h) to remove H2O [71]. All other solvents utilized were purchased anhydrous commercially, or purified as described. 1

General Procedures
All reactions were carried out under an atmosphere of N 2 , or Ar when noted. All glassware was oven-or flame-dried prior to use. Tetrahydrofuran (THF), diethyl ether (Et 2 O), dichloromethane (CH 2 Cl 2 ), and toluene (PhMe) were degassed with Ar and then passed through two 4 × 36 inch columns of anhydrous neutral A-2 alumina (8 × 14 mesh; LaRoche Chemicals; activated under a flow of argon at 350 • C for 12 h) to remove H 2 O [71]. All other solvents utilized were purchased anhydrous commercially, or purified as described. 1  , doublet of doublet of triplet (ddt), doublet of triplet of doublet (dtd), triplet (t), broad triplet (br t), triplet of doublet (td), triplet of doublet of doublet (tdd), triplet of triplet (tt), quartet (q), quartet of doublet (qd), quartet of doublet of doublets (qdd), quintet (quint), apparent quintet (appar quint), sextet, apparent sextet (appar sextet), multiplet (m)]. coupling constants [Hz], integration). Carbon chemical shifts are reported in ppm (δ) relative to TMS with the respective solvent resonance as the internal standard (CDCl 3 , δ 77.16 ppm). Unless otherwise indicated, NMR data were collected at 25 • C. Infrared (IR) spectra were obtained on a Thermo Scientific Nicolet iS5 spectrometer with an iD5 ATR tip (neat) and are reported in terms of frequency of absorption (cm −1 ). Analytical thin-layer chromatography (TLC) was performed using Silica Gel 60 F 254 precoated plates (0.25 mm thickness). Visualization was accomplished by irradiation with a UV lamp and/or staining with KMnO 4 or CAM. Flash chromatography was performed using SiliaFlash F60 (40-63 µm, 60 Å) from SiliCycle. Automated chromatography was carried out on a Teledyne Isco CombiFlash Rf Plus. Melting points (m.p.) were obtained using a Mel-Temp melting point apparatus and are uncorrected. High resolution mass spectrometry was performed by the University of California, Irvine Mass Spectrometry Center. See the 1 H, 13 C, COSY and NOE NMR detailed data in the Supplementary Materials.
Bis(1,5-cyclooctadiene)nickel was purchased from Strem, stored in a glove box freezer (-20 • C) under an atmosphere of N 2 and used as received. All ligands were purchased from Strem or Sigma Aldrich and were stored in a glovebox and used as received. The methylmagnesium iodide was titrated with iodine prior to use [72]. All other chemicals were purchased commercially and used as received, unless otherwise noted.

General Kumada Cross-Coupling Reaction Procedures Method A: Kumada Cross-Coupling Reaction
In a glovebox, a flame-dried 7 mL vial equipped with a stir bar was charged with sulfonamide substrate (1.0 equiv), nickel precatalyst (15 mol %) and PhMe (0.10-0.20 M in substrate). The Grignard reagent (2.0 equiv) was then added dropwise via a syringe. After 24 h, the reaction was removed from the glovebox, quenched with methanol, filtered through a plug of silica gel eluting with 100% Et 2 O and concentrated in vacuo. Phenyltrimethylsilane (PhTMS; 8.6 µL, 0.050 mmol) was added and the yield was determined by 1 H NMR based on comparison to PhTMS as internal standard before purification by column chromatography.
For reactions in which 1.0 equiv of MgI 2 is added, the vial is wrapped in aluminum foil for the duration of the reaction due to the light sensitivity of MgI 2 .
(1) Preparation of Grignard Reagent Under a N 2 atmosphere, a three-necked flask equipped with a stir bar, reflux condenser, and Schlenk filtration apparatus was charged with magnesium turnings (1.  [72] and could be stored, sealed under N 2 atmosphere or in a glovebox, for up to 4 weeks. (2) Preparation of (R-BINAP)NiCl 2 This method was adapted from a procedure reported by Jamison [57]. To a flame-dried 50 mL round bottom flask equipped with a stir bar was added NiCl 2 ·6H 2 O (0.24 g, 1.0 mmol, 1.0 equiv). The flask was placed under vacuum and flame-dried until nearly all of the nickel compound had turned from emerald green to yellow-orange. Some of the green hexahydrate is necessary for the reaction to proceed. The flask was allowed to cool to room temperature then (R-BINAP) (0.62 g, 1.0 mmol, 1.0 equiv) was added. The flask was then equipped with a reflux condenser and was evacuated and backfilled with N 2 . Then the solids were dissolved in MeCN (20 mL, 0.05 M) and the reaction mixture was allowed to reflux for 24 h. Upon completion, the reaction was cooled to room temperature and the black crystalline precipitate was filtered under vacuum to yield a fine black powder (0.53 g, 0.71 mmol, 71% yield).

Characterization Data for Kumada Cross-Coupled Products
nesium turnings were washed with Et2O (2 × 1.0 mL) then the Schlenk flask was sealed, removed, and placed under an N2 atmosphere. The resulting methylmagnesium iodide was typically between 2.4 and 3.0 M as titrated by Knochel's method [72] and could be stored, sealed under N2 atmosphere or in a glovebox, for up to 4 weeks. (2) Preparation of (R-BINAP)NiCl2 This method was adapted from a procedure reported by Jamison [57]. To a flame-dried 50 mL round bottom flask equipped with a stir bar was added NiCl2·6H2O (0.24 g, 1.0 mmol, 1.0 equiv). The flask was placed under vacuum and flame-dried until nearly all of the nickel compound had turned from emerald green to yellow-orange. Some of the green hexahydrate is necessary for the reaction to proceed. The flask was allowed to cool to room temperature then (R-BINAP) (0.62 g, 1.0 mmol, 1.0 equiv) was added. The flask was then equipped with a reflux condenser and was evacuated and backfilled with N2. Then the solids were dissolved in MeCN (20 mL, 0.05 M) and the reaction mixture was allowed to reflux for 24 h. Upon completion, the reaction was cooled to room temperature and the black crystalline precipitate was filtered under vacuum to yield a fine black powder (0.53 g, 0.71 mmol, 71% yield).  internal standard. The residue was purified by flash chromatography (0-5% EtOAc/hexanes) to yield a mixture of the title compound and styrene 3. To separate the major product and the styrene, an Upjohn dihydroxylation was performed [60,61]. The following amounts of reagents were used: substrate (30 mg, 0.12 mmol, 1.0 equiv), OsO4 (7.6 μL, 1.   (

Method C: Methylation of Sulfonamide with Methyl Iodide
This method was adapted from a procedure reported by Jarvo [12,47,48]. To a suspension of NaH (1.3 equiv) in THF (0. 10 M) was added a solution of sulfonamide (1.0 equiv) in THF (0.15 M) at 0 °C. The mixture was warmed to rt and allow to stir for 1 h before the addition of iodomethane (1.1 equiv). The reaction was allowed to stir overnight at rt. The excess NaH was quenched with sat. NH4Cl and the solution was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by flash column chromatography.

Method D: Fe-Catalyzed Formal [4+2] Cycloaddition
This method was adapted from a procedure reported by Matsubara [59]. To a flamedried round-bottom flask equipped with a stir bar was added imine (1.0 equiv), FeCl3 (5.0 mol%), and PhMe (0. 1 M). Once the solution was homogenous, diene (2.0 equiv) was added. The reaction mixture was allowed to stir at rt overnight. After completion, the reaction mixture was filtered through a short pad of silica, washed with excess ethyl acetate, and concentrated in vacuo.

Method E: Pd/C Reduction of Alkenes
A flame-dried round-bottom flask with stir bar was charged with palladium on carbon (1.0 mg/3.5 mmol of substrate), flushed with N2, and capped with septum. Slowly, DCM was added, until Pd/C was fully submerged. Then MeOH (0.2 M in substrate), and alkene (1.0 equiv) were added. Vacuum was pulled on the flask until the solvent began to bubble, at which point the flask was backfilled with N2 (×3). An H2 balloon was added and This method was adapted from a procedure reported by Ruano et al. [73]. A flame-dried two-neck flask equipped with a stir bar, condenser, septum and N 2 inlet was charged with aldehyde (1.0 equiv), and p-toluenesulfonamide (1.0 equiv) and CH 2 Cl 2 (330 mL). Then Ti(OEt) 4 (2.0 equiv) was added dropwise. The deep orange solution was brought to reflux (~45 • C) and allowed to stir for 48 h. The solution was cooled to room temperature and was quenched with H 2 O. The mixture was vacuum filtered and the filtrate was concentrated in vacuo. This method was adapted from a procedure reported by Ruano et al. [73]. A flamedried two-neck flask equipped with a stir bar, condenser, septum and N2 inlet was charged with aldehyde (1.0 equiv), and p-toluenesulfonamide (1.0 equiv) and CH2Cl2 (330 mL). Then Ti(OEt)4 (2.0 equiv) was added dropwise. The deep orange solution was brought to reflux (~45 °C) and allowed to stir for 48 h. The solution was cooled to room temperature and was quenched with H2O. The mixture was vacuum filtered and the filtrate was concentrated in vacuo.

Method C: Methylation of Sulfonamide with Methyl Iodide
This method was adapted from a procedure reported by Jarvo [12,47,48]. To a suspension of NaH (1.3 equiv) in THF (0.10 M) was added a solution of sulfonamide (1.0 equiv) in THF (0.15 M) at 0 °C. The mixture was warmed to rt and allow to stir for 1 h before the addition of iodomethane (1.1 equiv). The reaction was allowed to stir overnight at rt. The excess NaH was quenched with sat. NH4Cl and the solution was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by flash column chromatography.

Method D: Fe-Catalyzed Formal [4+2] Cycloaddition
This method was adapted from a procedure reported by Matsubara [59]. To a flamedried round-bottom flask equipped with a stir bar was added imine (1.0 equiv), FeCl3 (5.0 mol%), and PhMe (0. 1 M). Once the solution was homogenous, diene (2.0 equiv) was added. The reaction mixture was allowed to stir at rt overnight. After completion, the reaction mixture was filtered through a short pad of silica, washed with excess ethyl acetate, and concentrated in vacuo.

Method E: Pd/C Reduction of Alkenes
A flame-dried round-bottom flask with stir bar was charged with palladium on carbon (1.0 mg/3.5 mmol of substrate), flushed with N2, and capped with septum. Slowly, DCM was added, until Pd/C was fully submerged. Then MeOH (0.2 M in substrate), and alkene (1.0 equiv) were added. Vacuum was pulled on the flask until the solvent began to bubble, at which point the flask was backfilled with N2 (×3). An H2 balloon was added and This method was adapted from a procedure reported by Jarvo [12,47,48]. To a suspension of NaH (1.3 equiv) in THF (0.10 M) was added a solution of sulfonamide (1.0 equiv) in THF (0. 15 M) at 0 • C. The mixture was warmed to rt and allow to stir for 1 h before the addition of iodomethane (1.1 equiv). The reaction was allowed to stir overnight at rt. The excess NaH was quenched with sat. NH 4 Cl and the solution was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated in vacuo, and purified by flash column chromatography. This method was adapted from a procedure reported by Ruano et al. [73]. A flamedried two-neck flask equipped with a stir bar, condenser, septum and N2 inlet was charged with aldehyde (1.0 equiv), and p-toluenesulfonamide (1.0 equiv) and CH2Cl2 (330 mL). Then Ti(OEt)4 (2.0 equiv) was added dropwise. The deep orange solution was brought to reflux (~45 °C) and allowed to stir for 48 h. The solution was cooled to room temperature and was quenched with H2O. The mixture was vacuum filtered and the filtrate was concentrated in vacuo.

Method C: Methylation of Sulfonamide with Methyl Iodide
This method was adapted from a procedure reported by Jarvo [12,47,48]. To a suspension of NaH (1.3 equiv) in THF (0.10 M) was added a solution of sulfonamide (1.0 equiv) in THF (0.15 M) at 0 °C. The mixture was warmed to rt and allow to stir for 1 h before the addition of iodomethane (1.1 equiv). The reaction was allowed to stir overnight at rt. The excess NaH was quenched with sat. NH4Cl and the solution was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by flash column chromatography.

Method D: Fe-Catalyzed Formal [4+2] Cycloaddition
This method was adapted from a procedure reported by Matsubara [59]. To a flamedried round-bottom flask equipped with a stir bar was added imine (1.0 equiv), FeCl3 (5.0 mol%), and PhMe (0. 1 M). Once the solution was homogenous, diene (2.0 equiv) was added. The reaction mixture was allowed to stir at rt overnight. After completion, the reaction mixture was filtered through a short pad of silica, washed with excess ethyl acetate, and concentrated in vacuo.

Method E: Pd/C Reduction of Alkenes
A flame-dried round-bottom flask with stir bar was charged with palladium on carbon (1.0 mg/3.5 mmol of substrate), flushed with N2, and capped with septum. Slowly, DCM was added, until Pd/C was fully submerged. Then MeOH (0.2 M in substrate), and alkene (1.0 equiv) were added. Vacuum was pulled on the flask until the solvent began to This method was adapted from a procedure reported by Matsubara [59]. To a flame-dried round-bottom flask equipped with a stir bar was added imine (1.0 equiv), FeCl 3 (5.0 mol%), and PhMe (0. 1 M). Once the solution was homogenous, diene (2.0 equiv) was added. The reaction mixture was allowed to stir at rt overnight. After completion, the reaction mixture was filtered through a short pad of silica, washed with excess ethyl acetate, and concentrated in vacuo. This method was adapted from a procedure reported by Ruano et al. [73]. A flamedried two-neck flask equipped with a stir bar, condenser, septum and N2 inlet was charged with aldehyde (1.0 equiv), and p-toluenesulfonamide (1.0 equiv) and CH2Cl2 (330 mL). Then Ti(OEt)4 (2.0 equiv) was added dropwise. The deep orange solution was brought to reflux (~45 °C) and allowed to stir for 48 h. The solution was cooled to room temperature and was quenched with H2O. The mixture was vacuum filtered and the filtrate was concentrated in vacuo.

Method C: Methylation of Sulfonamide with Methyl Iodide
This method was adapted from a procedure reported by Jarvo [12,47,48]. To a suspension of NaH (1.3 equiv) in THF (0.10 M) was added a solution of sulfonamide (1.0 equiv) in THF (0.15 M) at 0 °C. The mixture was warmed to rt and allow to stir for 1 h before the addition of iodomethane (1.1 equiv). The reaction was allowed to stir overnight at rt. The excess NaH was quenched with sat. NH4Cl and the solution was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by flash column chromatography.

Method D: Fe-Catalyzed Formal [4+2] Cycloaddition
This method was adapted from a procedure reported by Matsubara [59]. To a flamedried round-bottom flask equipped with a stir bar was added imine (1.0 equiv), FeCl3 (5.0 mol%), and PhMe (0. 1 M). Once the solution was homogenous, diene (2.0 equiv) was added. The reaction mixture was allowed to stir at rt overnight. After completion, the reaction mixture was filtered through a short pad of silica, washed with excess ethyl acetate, and concentrated in vacuo.

Method E: Pd/C Reduction of Alkenes
A flame-dried round-bottom flask with stir bar was charged with palladium on carbon (1.0 mg/3.5 mmol of substrate), flushed with N2, and capped with septum. Slowly, DCM was added, until Pd/C was fully submerged. Then MeOH (0.2 M in substrate), and alkene (1.0 equiv) were added. Vacuum was pulled on the flask until the solvent began to A flame-dried round-bottom flask with stir bar was charged with palladium on carbon (1.0 mg/3.5 mmol of substrate), flushed with N 2 , and capped with septum. Slowly, DCM was added, until Pd/C was fully submerged. Then MeOH (0.2 M in substrate), and alkene (1.0 equiv) were added. Vacuum was pulled on the flask until the solvent began to bubble, at which point the flask was backfilled with N 2 (×3). An H 2 balloon was added and the reaction mixture was allowed to stir vigorously until complete by 1 H NMR. The balloon was then removed, and the flask was purged with N 2 for 30 min. The septum was removed, and the reaction mixture was filtered through Celite using MeOH (100 mL). The collected solvent was then concentrated in vacuo. This method was adapted from a procedure reported by Sabitha [60,61]. To a flamedried pressure tube equipped with a stir bar was added aldehyde (1.0 equiv), homoallylic sulfonamide 33 (1.1 equiv), and CH2Cl2 (0. 10 M). Then trifluoroacetic acid (10.0 equiv) was added slowly via syringe. The solution was warmed to 60 °C and allowed to stir for 72 h. The solution was then cooled to rt and quenched with saturated aq. NaHCO3. Then the pH was adjusted to >7 by the addition of Et3N. The solution was transferred to a separatory funnel, and the aqueous layer was extracted with CH2Cl2 (×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then redissolved in MeOH, and K2CO3 (3.5 equiv) was added to the flask and the slurry was allowed to stir at rt for 3 h. The solvent was removed under reduced pressure, then H2O was added and the residue was transferred to a separatory funnel. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo.

Method G: Alkylation of Secondary Alcohol
This method was adapted from a procedure reported by Yang [74]. In a glovebox, to a flame-dried round bottom flask equipped with a stir bar was added NaH (2.2 equiv). The flask was removed from the glovebox and NaH was dissolved in THF (0. 2 M). Alcohol (1.0 equiv) was added dropwise as a solution in THF (0.3 M) and the reaction mixture was allowed to stir at rt for 1 h. Methyl iodide or benzyl bromide was then added dropwise to the stirring slurry and the reaction mixture was allowed to stir at rt overnight. The reaction was then quenched with saturated aq. NH4Cl and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. This method was adapted from a procedure reported by Sabitha [60,61]. To a flamedried pressure tube equipped with a stir bar was added aldehyde (1.0 equiv), homoallylic sulfonamide 33 (1.1 equiv), and CH 2 Cl 2 (0. 10 M). Then trifluoroacetic acid (10.0 equiv) was added slowly via syringe. The solution was warmed to 60 • C and allowed to stir for 72 h. The solution was then cooled to rt and quenched with saturated aq. NaHCO 3 . Then the pH was adjusted to >7 by the addition of Et 3 N. The solution was transferred to a separatory funnel, and the aqueous layer was extracted with CH 2 Cl 2 (×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was then redissolved in MeOH, and K 2 CO 3 (3.5 equiv) was added to the flask and the slurry was allowed to stir at rt for 3 h. The solvent was removed under reduced pressure, then H 2 O was added and the residue was transferred to a separatory funnel. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. This method was adapted from a procedure reported by Sabitha [60,61]. To a flamedried pressure tube equipped with a stir bar was added aldehyde (1.0 equiv), homoallylic sulfonamide 33 (1.1 equiv), and CH2Cl2 (0. 10 M). Then trifluoroacetic acid (10.0 equiv) was added slowly via syringe. The solution was warmed to 60 °C and allowed to stir for 72 h. The solution was then cooled to rt and quenched with saturated aq. NaHCO3. Then the pH was adjusted to >7 by the addition of Et3N. The solution was transferred to a separatory funnel, and the aqueous layer was extracted with CH2Cl2 (×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then redissolved in MeOH, and K2CO3 (3.5 equiv) was added to the flask and the slurry was allowed to stir at rt for 3 h. The solvent was removed under reduced pressure, then H2O was added and the residue was transferred to a separatory funnel. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo.

Method G: Alkylation of Secondary Alcohol
This method was adapted from a procedure reported by Yang [74]. In a glovebox, to a flame-dried round bottom flask equipped with a stir bar was added NaH (2.2 equiv). The flask was removed from the glovebox and NaH was dissolved in THF (0. 2 M). Alcohol (1.0 equiv) was added dropwise as a solution in THF (0.3 M) and the reaction mixture was allowed to stir at rt for 1 h. Methyl iodide or benzyl bromide was then added dropwise to the stirring slurry and the reaction mixture was allowed to stir at rt overnight. The reaction was then quenched with saturated aq. NH4Cl and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. This method was adapted from a procedure reported by Yang [74]. In a glovebox, to a flame-dried round bottom flask equipped with a stir bar was added NaH (2.2 equiv). The flask was removed from the glovebox and NaH was dissolved in THF (0. 2 M). Alcohol (1.0 equiv) was added dropwise as a solution in THF (0.3 M) and the reaction mixture was allowed to stir at rt for 1 h. Methyl iodide or benzyl bromide was then added dropwise to the stirring slurry and the reaction mixture was allowed to stir at rt overnight. The reaction was then quenched with saturated aq. NH 4 Cl and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. This method was adapted from a procedure reported by Sabitha [60,61]. To a flamedried pressure tube equipped with a stir bar was added aldehyde (1.0 equiv), homoallylic sulfonamide 33 (1.1 equiv), and CH2Cl2 (0. 10 M). Then trifluoroacetic acid (10.0 equiv) was added slowly via syringe. The solution was warmed to 60 °C and allowed to stir for 72 h. The solution was then cooled to rt and quenched with saturated aq. NaHCO3. Then the pH was adjusted to >7 by the addition of Et3N. The solution was transferred to a separatory funnel, and the aqueous layer was extracted with CH2Cl2 (×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then redissolved in MeOH, and K2CO3 (3.5 equiv) was added to the flask and the slurry was allowed to stir at rt for 3 h. The solvent was removed under reduced pressure, then H2O was added and the residue was transferred to a separatory funnel. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo.

Method G: Alkylation of Secondary Alcohol
This method was adapted from a procedure reported by Yang [74]. In a glovebox, to a flame-dried round bottom flask equipped with a stir bar was added NaH (2.2 equiv). The flask was removed from the glovebox and NaH was dissolved in THF (0. 2 M). Alcohol (1.0 equiv) was added dropwise as a solution in THF (0.3 M) and the reaction mixture was allowed to stir at rt for 1 h. Methyl iodide or benzyl bromide was then added dropwise to the stirring slurry and the reaction mixture was allowed to stir at rt overnight. The reaction was then quenched with saturated aq. NH4Cl and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. (28) was prepared according to Method B. The following amounts of reagents were used: benzo[b]thiophene-2-carbaldehyde (3.2 g, 20. mmol, 1.0 equiv), p-toluenesulfonamide (3.1 g, 20. mmol, 1.0 equiv), Ti(OEt)4 (8.4 mL, 40. mmol, 2.0 equiv), and CH2Cl2 (330 mL). The residue was purified by flash column chromatography (5-25% EtOAc/hexanes) to yield the title compound as a pale yellow solid (5.0 g, 16 (

Conclusions
In conclusion, we have developed a Kumada XC reaction of benzylic sulfonamides with Grignard reagents including methylmagnesium iodide and arylmagnesium iodide. This reaction utilizes readily available starting materials that are not activated prior to the XC reaction. We have demonstrated that increasing the steric bulk adjacent to the reactive center destabilizes the conformation necessary for β-hydride elimination to occur. A stereospecific ring opening Kumada XC reaction has been established to synthesize highly substituted acyclic fragments. This work provides a basis for the XC reaction of simple benzylic sulfonamides.
Supplementary Materials: The following are available online, 1 H, 13 C, COSY and NOE NMR data are available online.

Informed Consent Statement: Not application.
Data Availability Statement: Data sharing not applicable.