Thiazol-2-ylidenes: Versatile N-Heterocyclic Carbene Ligands with Enhanced Electrophilicity for Transition-Metal-Catalysis

. Over the last 20 years, N-heterocyclic carbenes (NHCs) have emerged as a dominant direction in ligand development in transition-metal-catalysis. In particular, strong  -donation in combination with tunable steric environment make NHCs to be among the most common ligands used for C – C and C – heteroatom bond formation. Thus far, NHC ligand development has been almost exclusively limited to N-aryl-imidazolylidenes, such as IPr, prepared by deprotonation of symmetrical imidazolium salts. However, the molecular structure of imidazolylidene systems is constrained by the substitution with two nitrogen atoms, a limitation that prohibits the development of more active carbene

analogues.Herein, we report the first study on steric and electronic properties of thiazol-2-ylidenes.We demonstrate that the ring dissymmetry and enhanced -electrophilicity result in a class of highly active carbene ligands for electrophilic cyclization reactions to form valuable oxazoline heterocycles.The evaluation of steric, electron-donating and -accepting properties as well as structural characterization and coordination chemistry is presented.This mode of catalysis can be applied to late-stage drug functionalization to furnish attractive building blocks for medicinal chemistry.Considering the key role of N-heterocyclic ligands, we anticipate that N-aryl thiazol-2-ylidenes will be of broad interest as ligands in modern chemical synthesis.
Article.Since the first successful isolation in 1991 1 and the first use in catalysis in 1995, 2 Nheterocyclic carbenes (NHCs) have emerged as a powerful class of ligands in transition-metalcatalysis. 3,4 The tremendous utility of NHCs hinges on strong σ-donation 5 in combination with tunable steric environment, 6 supercharging the catalytic activity of transition metals beyond other ligands.The most remarkable impact is in the development of Ru-catalyzed olefin metathesis 7 and Pd-catalyzed cross-couplings, 8 where the strong σ-donation and high stability of M-C(NHC) bond render NHCs superior to the more ubiquitous phosphine ligands.Thus far, NHC ligand development in transitionmetal-catalysis has been almost exclusively limited to N-aryl-imidazolylidenes A, [4][5][6][7][8] such as IPr, 9 prepared by deprotonation of symmetrical imidazolium salts (Figure 1).This is presumably due to enhanced electronic and steric stabilization of the carbene center by two nitrogen atoms as well as two N-Ar wingtip substituents, which render N-aryl-imidazolylidenes more stable and easier to handle. 10e pioneering studies by Bertrand and co-workers established that cyclic carbene systems with a marked decrease of heteroatom stabilization, such as CAACs B (cyclic (alkyl)amino)carbenes), 11 are readily available, showing unique reactivity as supporting ligands in transition-metal-catalysis.More reactive and less stabilized systems, such as diamidocarbenes C, 12 mesoionic carbenes D 13 and remote carbenes E, 14   In this context, N-aryl thiazol-2-ylidenes F are an intriguing class of N-heterocyclic carbenes (Figure 1).Following the isolation of a stable thiazol-2-ylidene by Arduengo in 1997, 16 this class of ligands stayed dormant until 2008, when Grubbs demonstrated the unique reactivity of Ru-based thiazol-2ylidene olefin metathesis catalysts. 17To our knowledge, this is the only application of N-aryl thiazol-2ylidene ligands in transition-metal-catalysis reported to date. 18More recently, there has been a resurgence of organocatalyzed radical relays and decarboxylative couplings made possible through the persistent radical stabilization by thiazol-2-ylidenes. 19In the meantime, studies by Boydston demonstrated organocatalyzed anodic oxidation of aldehydes through in situ generation of electroauxiliaries of thiazol-2-ylidenes, 20 while the first characterization of elusive Breslow intermediates from thiazol-2-ylidenes by spectroscopic and crystallographic methods has been reported. 21ologically, thiazol-2-ylidenes are key intermediates in biochemical transformations of vitamin B1, 22 including pyruvate decarboxylase, transketolase and dehydrogenase, a fact that spurred the interest in the burgeoning area of umpolung carbene reactivity. 23ometrically, replacement of one of the nitrogen atoms in imidazol-2-ylidene systems with sulfur in thiazol-2-ylidenes results in disrupting the symmetrical ring geometry of imidazolylidenes. 24At the same time, there is a strong electronic effect in decreasing stabilization of the carbene center through diminished π donation from sulfur. 256][7][8]24 These geometrical and electronic factors might explain why, with exception of the report by Grubbs, 17 N-aryl thiazol-2-ylidenes have been unexplored as NHC ligands in transition-metal-catalysis.
In terms of electronics, the diminished π donation from sulfur due to unsymmetrical ring geometry and large sulfur radius is expected to result in more electrophilic carbenes than traditional imidazol-2ylidene systems, while maintaining strong donor ability (Figure 1). 25 In terms of geometry, the effect of typical NHC ligands on M-C(NHC) bond is defined as "umbrella" shaped, in contrast to cone shaped phosphines (Figure 1). 6The combination of a nitrogen atom with a quaternary carbon in CAACs renders these ligands as "wall-shaped" with regard to the M-C(NHC) bond. 11The steric properties of N-aryl thiazol-2-ylidenes render these ligands "half umbrella" shaped with the nitrogen N-wingtip oriented toward the M-C(NHC) bond and lack of substitution on the sulfur atom.
As a part of our interest in NHC catalysis, 26 herein, we report the first study on steric and electronic properties of thiazol-2-ylidenes.Most importantly, we demonstrate that the ring dissymmetry and enhanced π-electrophilicity result in a class of highly active carbene ligands that supersede imidazol-2-ylidenes.We present the evaluation of steric, electron-donating and π-accepting properties as well as structural characterization and coordination chemistry.Considering the key role of N-heterocyclic ligands, we envision that N-aryl thiazol-2-ylidenes will be of broad interest as ligands in chemical synthesis.
With structural and electronic characterization of N-aryl thiazol-2-ylidenes, we next evaluated the activity of Ag(I)-thiazol-2-ylidene complexes in catalysis (Table 1, and Schemes 4-5).As stated above, we selected Ag(I)-NHC complexes because Ag(I) complexes have been much less explored in catalysis than other group 11 metals 27 as well as to probe electrophilic π-activation of the ligands.Electrophilic O-cyclization of N-propargylic amides was selected as a model reaction due to the importance of the product oxazoline heterocycles in medicinal chemistry research. 33As shown, the reaction proceeds under very mild conditions using bis-NHC-Ag(I) salts 4a-d (5-10 mol%) in the presence of AcOH in CH2Cl2 at room temperature (Table 1, entries 1-8, see SI for details).AcOH is required as an additive (vide infra). 34Likewise, no reaction takes place in the absence of N-aryl thiazol-2-ylidene Ag(I) complexes (Table 1, entries 9-10).Out of the complexes 4a-d, the cycloheptyl complex [Ag( 7 IPrS)2](ClO4) showed the highest reactivity and was selected for scope studies.The loading could be further decreased to 1 mol% with excellent efficiency (>95%) (  Having established the optimal conditions for electrophilic cyclization using N-aryl-thiazol-2ylidene-Ag(I) complexes, next the scope was examined (Scheme 4).
Furthermore, substitution at the methylene carbon adjacent to the nitrogen to deliver 4-substitued oxazolines is also compatible (9x-9aa), increasing the overall synthetic utility of the process.Further, substitution of the alkyne is tolerated without loss in reaction efficiency (9ab-9ad), furnishing fully substituted oxazolines.The product 9ad was crystalline and the structure was confirmed by x-ray crystallography, indicating (Z)-geometry of the double bond (dr > 98:2).This result is consistent with an anti-attack of the amide bond oxygen on the Ag(I)-NHC-π-activated alkyne (vide infra).Most crucially, the mild reaction conditions enabled by the N-aryl thiazol-2-ylidene ligands permit this mode of catalysis to be applied to late-stage functionalization to furnish attractive heterocyclic building blocks for medicinal chemistry and agrochemistry research (Scheme 5).Thus, electrophilic cyclization of propargylic amides from acifluorfen (9af, protoporphyrinogen oxidase inhibitor), piperonylic acid (9ag, trans-cinnamate hydroxylase inhibitor), dicamba (9ah, broad spectrum herbicide), febuxostat (9ai, antigout) and probenecid (9aj, antihyperuricemic) delivered cyclization products in good to high yields without modification of the reaction conditions.This successful late-stage diversification highlights the mild conditions of the present protocol with tolerance to an array of sensitive functional groups (halides, cyano, nitro, sulfonamide, aryl ethers, S-heterocycles), demonstrating prospective impact on medicinal chemistry research.To gain insight into the reaction mechanism of this intriguing transformation, catalytic cycle was studied by DFT computations (Figure 4).Based on the previous work, 34 our calculation results show that the catalytic cycles for these processes are comprised of three key steps.In the first step, L2Ag will give active catalyst 1' in the presence of AcOH.The free energy of activation for this step is 20.1 kcal/mol for TS1 (Figure 4).After formation of active catalyst  See SI for computational details.
To further evaluate the effect of nitrogen to sulfur replacement in N-aryl thiazol-2-ylidenes, HOMO and LUMO energy levels of carbenes Me IPrS, 6 IPrS, 7 IPrS and Me IMesS were determined at the B3LYP 6-311++g(d,p) level (Figure 5 and SI).It is now recognized that the donating ability of carbenes is closely associated with the HOMO orbital, while the electron acceptance is associated with the LUMO orbital. 5,11,30Computation of frontier orbitals represents the most accurate evaluation of nucleophilicity (higher HOMO) and electrophilicity (lower LUMO) of NHC ligands, 5,11,30 while the comparison must be available at the same level of theory.

Methods
General procedure for the synthesis of Ag(I) Complexes.An oven-dried vial equipped with a stir bar was charged with N-Aryl thiazol-2-ylidenes carbene precursors (1.0 equiv), (typically, 0.5 equiv) and NaCl (typically, 2.0 equiv).The reaction mixture was placed under a positive pressure of argon and subjected to three evacuation/backfilling cycles under high vacuum.DCM (typically, 0.04 M) was added and the reaction mixture was stirred away from light overnight at room temperature.The reaction mixture was filtered through Celite with DCM as eluent and concentrated under reduced pressure, and dried under high vacuum to afford silver(I) complex General procedure for the cyclisation of propargylic amides.An oven-dried vial equipped with a stir bar was charged with propargylic amides (1.0 equiv), Ag catalyst 4c (typically, 1.0 mol%).The reaction was placed under a positive pressure of argon and subjected to three evacuation/backfilling cycles under high vacuum.Then AcOH (typically, 1.0 equiv) and DCM (typically, 1.0 M) was added and the reaction mixture was stirred at room temperature for 8 h.The volatiles were removed in vacuo and the products were purified by column chromatography on silica gel (EtOAc/hexanes).
have been developed, each class showing varying degrees of heteroatom stabilization and distinctive promise in transition-metal-catalysis.15

Figure 3 .
Figure 3. (a) X-ray crystal structure of complex 5a.Hydrogen atoms have been omitted for clarity.

Table 1 .
Optimization of Ag-NHC-Catalyzed Cyclization of N-Propargylic Amides a 1, the ligand exchange between AcO -and amide Re would give intermediate 2 with a free energy release of -6.7 kcal/mol.In second step, 2' would generate putative vinyl-silver intermediate 3' by a 5-exo-dig cyclisation.The free energy of activation for TS2 (Z) and TS22 (E) is 12.7 and 19.6 kcal/mol, respectively.This calculation result for Z/E selectivity is fully consistent with the experiments results.The final step involves a 1,4-H shift that leads to the final product P1.First, two-and three-molecule HOAc-assisted 1,4-H shift (TS31 and TS32) were calculated.The calculated activation free energy of TS31 and TS32 is high (27.4 and 24.5 kcal/mol, page S142, SI) to occur under the experimental conditions.Another possible pathway involves HOAc and ligand assisted 1,4-H shift.In this pathway, coordination of HOAc and ligand with 3' would generate intermediate 4' with a free energy release of -10.0 kcal/mol.The protodemetallation step would form the product P1 and regenerate the silver catalyst and HOAc.This step is exergonic by -30.6 kcal/mol and the free energy barrier is 15.8 kcal/mol.