Synthesis of Sulfilimines Enabled by Copper-Catalyzed S-Arylation of Sulfenamides.

Herein, an unprecedented synthetic route to sulfilimines via a copper-catalyzed Chan-Lam-type coupling of sulfenamides is presented. A key to success in this novel transformation is the chemoselective S-arylation of S(II) sulfenamides to form S(IV) sulfilimines, overriding the competitive, and more thermodynamically favored, C-N bond formation that does not require a change in the sulfur oxidation state. Computations reveal that the selectivity arises from a selective transmetallation event where bidentate sulfenamide coordination through the sulfur and oxygen atoms favors the S-arylation pathway. The mild and environmentally benign catalytic conditions enable broad functional group compatibility, allowing a variety of diaryl or alkyl aryl sulfilimines to be efficiently prepared. The Chan-Lam coupling procedure could also tolerate alkenylboronic acids as coupling partners to afford alkenyl aryl sulfilimines, a class of scaffolds that cannot be directly synthesized via conventional imination strategies. The benzoyl-protecting groups could be conveniently removed from the product, which, in turn, could be readily transformed into several S(IV) and S(VI) derivatives.


Introduction
Sul limines, the aza-analogues of sulfoxides, are a class of unique tetravalent sulfur-derived compounds. They nd widespread applications in organic chemistry, serving as versatile intermediates, nitrene transfer reagents, directing groups, among others. [1][2][3] Chiral sul limines have also been developed as ligands for enantioselective transition-metal catalysis. 4,5 Recently, the biological signi cance of sul limines has drawn much attention. In 2009, Hudson and coworkers revealed that hydroxylysine-211 and methionine-93 in collagen IV was covalently cross-linked by a sul limine bond, which represents the rst sul limine group identi ed in biomolecules. 6,7 This novel bond, which is an evolutionary adaptation to mechanical stress in metazoan evolution, is believed to play an important role in stabilizing the network of the basement membrane. In the eld of chemical biology, Chang, Toste and coworkers have introduced a seminal methionine bioconjugation protocol by transforming methionines to the corresponding sul limine derivatives using oxaziridines under biocompatible conditions. 8,9 This powerful tagging method allows access to antibody-drug conjugates as well as identi cation of reactive methionine residues in whole proteomes.
Owing to the signi cant roles of sul limines in chemistry and biology, much effort has been devoted to their synthesis. 10 Conventionally, sul limines are prepared from the corresponding sul des via a oxidative imination strategy wherein a sulfur-nitrogen double bond is generated (Scheme 1a). 10 This imination strategy suffers from limited compability with functional groups due to the requisite oxidation conditions. In addition, some commonly used imination reagents, such as the azide, are potentially explosive which jeopardizes their applications, especially in industry. Inspired by sulfur transferases, the Zhao group reported an elegant [2,3]-sigmatropic rearrangement of oxyacetamide derivatives to afford orthosul liminyl phenols (Scheme 1b). 11,12 This strategy again forms the sulfur-nitrogen double bond. To date, this novel strategy has not been expanded beyond the synthesis of ortho-hydroxylaryl sul limines. Willis and coworkers disclosed an innovative consecutive addition of two Grignard reagents to a bespoke sul nylamine to afford sul limines (Scheme 1c). 13 While a redox neutral process, the application of this approach is limited to substrates that can tolerate the reactive Grignard regents employed. Therefore, the development of mild and e cient synthetic methods to access to sul limines with broad functional groups tolerance remains a challenge.
Copper-catalyzed Chan-Lam coupling has emerged as one of the most powerful tools to construct C-N, C-O and C-S bonds in the past decades, attributed to cheap and abundant catalysts, an absence of elaborate ligands, mild and environmentally benign reaction conditions, as well as the excellent functional group compability. 14,15 Very recently, our group reported an unprecedented photoredox dehydrogenative Chan-Lam coupling of diaryl sulfoximines under external-oxidant-free conditions. 16 We envisioned that sulfenamides (R-S-NH-R'), a class of stable and easily accessible sulfur(II)-derived molecules, 17 could undergo rearrangement to yield sul liminyl species, which could be utilized as a key intermediate to generate sul limines via a highly chemoselective S-arylation strategy. To the best of our knowledge, the S-arylation of sulfenamides has not been explored previously, most likely due to competitive reaction on the more nucleophilic nitrogen atom. Herein, we report a novel copper-catalyzed Chan-Lam-type S-arylation of sulfenamides and arylboronic acids to provide a facile access to diverse sul limines (Scheme 1d). In this process, S(II) compounds are converted to S(IV) compounds using only oxygen as the oxidant. In contrast to other oxidative routes (Scheme 1a-b), the substrate herein begins with an S-N single bond and the method creates a new S-C double bond.

Results
Reaction development. We chose readily accessible sulfenamide (1a) and commercially available phenylboronic acid (2a) as the model substrates to optimize the catalytic conditions (Table 1). After the extensive studies, the optimal conditions were determined to be: sulfenamide (1a) as the limiting reagent, Substrate scope. Having the optimal reaction conditions in hand, the scope of arylboronic acids in the coupling was investigated using 1a ( Table 2). The parent phenylboronic acid (2a) coupled successfully with 1a to furnish 3aa in 94% yield on small scale and was similarly effective on gram scale (4.1 mmol, 1.0 g) providing the product in 85% yield. Arylboronic acids bearing electron-donating groups, such as 4-Me (2b) or 4-OMe (2c), were compatible with the reaction conditions, providing 3ab and 3ac in 92% and 77% yield respectively. Electron-withdrawing groups, such as 4-F (2d), 4-Cl (2e), 4-Br (2f), or 4-CF 3 (2g), were well tolerated using the same conditions, and the corresponding products (3ad-g) were synthesized in yields ranging from 65% to 96%. The connectivity was unambiguously determined by X-ray crystallography of 3ae (see SI for details). The sterically hindered 2-methylphenylboronic acid (2h) was also tolerated, affording 3ah in 65% yield. 3-Substituted arylboronic acids were competent coupling partners, as evidenced by the formation of 3ai in 79% yield. In accord with the mild reaction conditions, an array of functional groups could be incorporated on the arylboronic acid component. Aldehyde (2j), ketone (2k), ester (2l), unprotected hydroxyl (2m), and vinyl (2n) groups were well tolerated by our coupling protocol to provide the corresponding products (3aj−n) in 50−77% yields. Heteroarylboronic acids also exhibited good compability under the coupling conditions, and N-arylated products of the unprotected indolyl (3ao), 5-benzofuranyl (3ap) and 5-benzothiophenyl (3aq) sul limines were prepared in 42-89% yields. This method afforded novel sul limine-modi ed tyrosine (3ar), albeit in modest yield (63%). The coupling reactions of arylboronic acids bearing unprotected phenol (2m), free indole (2o), and secondary amide (2r) are particularly impressive, since they are known to afford the corresponding Oor N-arylated products by Chan-Lam couplings. 14,15 Of note, alkenyl aryl sul limines are challenging to prepare via the classical imination of sul des, due to competitive addition of nitrenes to alkenes. 18 Remarkably, the couplings with vinylboronic acids formed of desired products (3as-v) in synthetically useful yields (33-55%), highlighting the power of this protocol.
Subsequently, we turned our attention to varying the sulfur substrate component coupling with phenylboronic acid 2a ( Table 2). The parent phenyl sulfenamide (1b) reacted successfully with 2a to give 4ba in excellent yield. Aryl sulfenamides bearing electron-donating groups were amendable substrates for the coupling reaction, as evidenced by the formation of 4ca in 84% yield. The electron-withdrawing groups appended on aryl sulfenamides, such as 4-F (1d), 4-Cl (1e), or 4-NO 2 (1f), were well tolerated, providing 4da-fa in good yields. This coupling procedure also exhibited excellent compability with steric demanding 2-substituted aryl sulfenamides, and 4ga-ja were prepared in 73-87% yield. The chemistry also accommodated aryl sulfenamides with 3-substituents, with 4ka and 4la being obtained in 80% and 64% yield, respectively. The coupling reaction between 2,4-di uorophenylboronic acids 1m and 2a proceeded smoothly to give 4ma in 71% yield. A 2-thiophenyl substrate provided heteroaryl sul limine 4na in moderate yield.
To determin if alkyl aryl sul limines could be formed, S-alkyl sulfenamides were evaluated ( Table 2). The S-alkyl sulfenamides coupled very sluggishly when O 2 was employed as an oxidant. As such, we hypothesize that a stronger oxidant and higher temperatures would be effective. In line with this reasoning, 80 o C and DTBP as oxidant provided the product from linear n-heptyl sulfenamide (1o) in 81% yield (5oa). S-Alkyl sulfenamides bearing aromatic substituents could couple successfully with 2a, exempli ed by 5pa (57%). The coupling procedure exhibited excellent compability toward S-alkyl sulfenamides containing a range of functional groups, including ester (1q, 1r), nitrile (1s), ketone (1t) or amide (1u), with the corresponding products 5qa-ua forming in 47-77% yield. The chemistry also accommodated sulfenamides bearing cyclic substituents leading to the formation of 5va and 5wa in 84% and 51% yield, respectively.
At the outset of this work, the mechanism for the transformation of a sulfenamide to sul limine was uncertain, and the factors that allowed S-coupling vs N-coupling were especially unclear. Several mechanisms were thus surveyed computationally. The initial ground states of the copper(II) species were surveyed using B3LYP/6-31G(d), Cu:SDD 19,20 and pathways were calculated with PCM-DCE-M06-gd3/6-311+G(3d,p), Cu:SDD//B3LYP-GD3/6-311+G(3d,p), Cu:SDD 21-24 using Gaussian 16. 25 All graphics were made with Cylview. 26 The bimolecular reductive elimination proposed by Stahl and coworkers 27 was investigated initially. In this proposed mechanism, the initial copper(I) is oxidized by O 2 which is followed by transmetalation with an arylboronic acid. Disproportionation with CuX 2 is invoked to generate a Cu(III) species along with a Cu(I) byproduct. A six-membered transition state can then be envisioned where the sulfur forms a carbon bond and the N-H hydrogen is abstracted by one of the X-groups on copper. Despite signi cant exploration, such a transition state could not be located computationally.
As such, we turned to possible pathways based on the proposed mechanism by Watson ( Figure 1a ). 28 Here, ligand exchange of the sulfenamide onto Cu(II) is followed by transmetallation of the arylboronic acid. Disproportionation with Cu(TFA) 2 is proposed to generate a Cu(III) species along with a Cu(I) byproduct. Reductive elimination then forms the S-C bond. Finally, the Cu(I) is reoxidized to Cu(II) by O 2 .
To begin exploring this pathway, the binding patterns for the deprotonated sulfenamide and Cu(II)OH species was investigated with different numbers of water molecules as ligands. To simplify calculations, a phenyl was used for Ar 1 /Ar 2 and N-acetyl was used in place of N-benzoyl. The two lowest energy geometries included copper complexes coordinating the sulfenamide at the nitrogen or at the sulfur (SI Scheme S2).
Notably, the initial complex binding through sulfur (I) is lower in energy than binding through nitrogen (VI) (Figure 1b). The structure of I is a more ideal square planar complex than VI contributing to the lower energy of that complex. Transmetallation of these initial complexes gave rise to III and VIII via transition states II and VII, respectively. Disproportionation with another Cu(II) provides to Cu(III) complexes IV and IX, along with copper(I) tri uoroacetate. Reductive elimination from these Cu(III) intermediates then forms aryl-heteroatom bond via transition states V and X.
For these pathways, the possible spin states for the disproportionation intermediates (IV and IX) and reductive elimination transition states (V and X) were explored since Cu(III) can exist as a singlet or triplet. 29,30 The triplet spin state for the nitrogen-bonded compounds IX and X was over 20 kcal/mol higher in energy than the singlet. No triplet reductive elimination transition state for the sulfur pathway would optimize. As such, the singlets became the focus and are shown in Figure 1b.
The reductive elimination transition state energy is lower for the C-N bond forming reaction (X) and proceeds through a classic three-membered transition state. In contrast, the C-S bond forming transition state (V) is 6.6 kcal/mol higher is energy. The hard Cu(III) avoids directly bonding with the soft sulfur center. Rather, the transition state involves coordination through the oxygen of the carbonyl while the sulfur adds to the carbon center via a six-membered transition.
Overall, the selectivity of the process appears to be determined during the transmetallation event which is the rate limiting step. Speci cally, the S-transmetalation transition state (II) is 2.1 kcal/mol lower in energy than the N-transmetalation transition state (VII) accounting for the chemoselectivity observed in the reaction. The factor that leads to the lower energy of I vs VI and hence II vs VII appears to be the bidentate S,O-coordination. Similar bidentate coordination modes were higher in energy in the N-bonded complexes. The zwitterionic version illustrated in I better represents the computed charges and is consistent with the prior reports for similar compounds. 31 According to the above calculations, the protecting group on nitrogen plays a key role by both stabilizing the negative charge on nitrogen via resonance and by coordinating the copper center. As such, other Nacyl groups which would be expected to exhibit a similar pro le were explored (table 2c). Notably, the coupling reactions proceeded very well employing N-acyl sulfenamides as nucleophiles and led to the formation of 6xa-za in good yields. The benzoxycarbamate was also well tolerated to produce 6baa in modest yield under slightly modi ed conditions. On the other hand, phenyl (1bb) or 4-nitrophenyl protecting groups (1bc) on nitrogen were ineffective in the reaction consistent with our mechanistic proposal. While this group would stabilize a negative charge on nitrogen as required the above mechanism, it would not be able to chelate which is also required the above mechanism.
Synthetic applications. To show the potential utility of our copper-catalyzed Chan-Lam coupling, deprotection of N-Bz-diphenyl sul limine 4ba was performed. Treatment with sulfuric acid for 6 h readily generated the NH-diphenyl sul limine 7a in 76% yield (condition a, Scheme2). This free sul limine, is a versatile building block and allows access to diverse derivatives (Scheme 2). Oxidation of 7a with PhI(OAc) 2 to afforded free sulfoximine 8a, 32 a prevalent scaffold in medicinal chemistry (condition b). 33 Imination of 7a by means of chloramine-T and TsNHNa generated sulfondiimine 8b, 34 which represents a category of underexplored sulfur(VI)-derived compounds (condition c). 35 Leveraging the nucleophilicity of the free sul limine, 7a could be subjected into Michael-type additions to either alkene (condition d) or alkyne (condition e) substrates, leading to the formation of 8c and 8d in 78% and 62% yield, respectively. 36,37 As an example of sul limines which cannot be directly constructed by our Chan-Lam coupling procedure, 8e could be easily prepared by installation of Boc group on 7a in 87% yield (condition f). 38 Free sul limine 7a could also be utilized as coupling partner with aryl iodide in palladium-catalyzed Buchwald-Hartwig amination, providing the arylated product 8f in 85% yield (condition g). 39 Conclusion In summary, we have developed a novel synthetic approach to form sul limines from stable and readily available sulfenamides and arylboronic acids via a copper-catalyzed Chan-Lam-type coupling strategy. A simple copper catalyst [Cu(TFA) 2 ·H 2 O] e ciently promotes the chemoselective S-arylation of sulfonamides, and a variety of diaryl, alkyl aryl, and even alkenyl aryl sul limines could be e ciently produced. Calculations indicate that the selectivity arises from a selective transmetallation event where bidentate sulfenamide coordination through the sufur and oxygen atoms is key to the selectivity. This unprecedented protocol features excellent chemoselectivity, mild and environmentally benign conditions, broad functional group compability, and does not require an elaborate ligand or acid/base additives. The product is an entry point for a range of S(IV) and S(VI) product, further highlighting the strengths of this transformation. The concepts described herein also provide a basis for the development of novel methodologies to construct other organosulfur compounds, which are currently under investigation in our laboratory.

Methods
General Procedure for Catalysis. To an oven-dried microwave vial equipped with a stir bar was added N-(p-tolylthio)benzamide (1a) (24.3 mg, 0.10 mmol), phenylboronic acid (2a) (14.6 mg, 0.12 mmol), and Cu(TFA) 2 ·H 2 O (2.9 mg, 10 mol %). Then, the microwave vial was sealed with a cap. Oxygen was purged/vacuumed three times through a three-way valve, and the microwave tube became an oxygen atmosphere. DCE (0.5 mL) was added to the microwave vial via syringe. The microwave vial was heated to 60 °C in an oil bath and stirred for 12 hours. Upon completion of the reaction, the sealed vial was cooled to room temperature, and opened to air. The reaction solution was concentrated under reduced pressure. The crude product was puri ed by ash chromatography to afford the pure product.

Data availability
Experimental procedure and characterization data of new compounds are available within Supplementary Information. Any further relevant data are available from the authors upon reasonable request.