Synthesis of ( − )-Verbenone-Derived Triazolium Salts and Their Application in Enantioselective Intramolecular Stetter Reaction

: Two novel chiral verbenone-derived triazolium salts have been synthesized from readily available ( − )-verbenone and found to be efﬁcient for the enantioselective intramolecular Stetter reaction. The approach, based on the intramolecular annulation between acyl anion equivalents and Michael acceptors, beneﬁts from broad substrate scope, high chemical and stereochemical efﬁciency, and operational simplicity. Mono-, and disubstituded chromanone derivatives have been obtained in excellent yields and in a highly stereochemical manner.

In recent years, N-heterocyclic carbenes (NHCs) catalysis proved to be one kind of the most reliable organocatalyst and versatile platform in organocatalysis, and plenty of complex carbo-and heterocycles have been constructed via various umpolung or non-umpolung strategies [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Many kinds of chiral NHCs have been developed to catalyze stereochemical reactions, in which one of the most popular and effective structural scaffolds proved to be the aminoindanol skeleton. In 2008, the You group demonstrated the first synthesis and application of camphor-derived triazolium salts as carbene precursors. Those catalysts from a readily available chiral source proved to be highly effective and stereoselective in the synthesis of various chiral compounds [31][32][33][34][35]. With our ongoing interest in the development of new N-heterocyclic carbene catalysts, especially from those readily available natural chiral sources [36][37][38][39][40], we envisioned that verbenone might be an efficient chiral scaffold for N-heterocyclic carbene catalysts. Herein, we report our studies on the synthesis of novel chiral triazolium salts from (−)-verbenone and their application to the asymmetric catalytic intramolecular Stetter reaction.

Results and Discussion
Triazolium salts 1 were synthesized from (1S)-(−)-verbenone as outlined in Scheme 1. The synthesis commences with catalytic hydrogenation of (1S)-(−)-verbenone 2 giving highly diastereoselective cis-verbanone 3 with an excellent yield of 99%. Then, 3 was transformed into through crystallization at the ketoxime stage failed. Hence, we decided to reduce the carbonyl group by treatment of 4 with sodium borohydride in ethanol. Gratifyingly, crystallization of the crude 5 gave the enantiomerically pure hydroxyoxime 5 in 99% ee. Stereoselective reduction of 5 with lithium aluminium hydride afforded the amino alcohol 6 in 63% yield, which was immediately used to the next step without further purification. The lactam 8 was prepared by previously reported two-step procedure involving the formation of chloroamide 7, followed by the cyclization reaction with the use of potassium tert-butoxide. Finally, a one-pot procedure was used for the three-step conversion into triazolium salts 1A-B. The NHC precatalyst 1B could be easily and cleanly isolated as a tetraphenyl borate salt. For the salt 1A, preparation does not require chromatographic purification. Evaporation of the solvent followed by washing with diethyl ether provided a pure product that was air-and water-stable solid. With the new (1S)-(−)-verbenone-derived triazolium salts 1A-B in hand, our studies began with testing their activity in the intramolecular Stetter reaction of 9a. As summarized in Table 1, when the triazolium salt 1A (10 mol %) was used together with triethylamine (10 mol %), only a trace amount of desired chromanone 10a was observed (Table 1, entry 1). To our great delight, under the same conditions, triazolium salt 1A bearing pentafluorophenyl moiety showed an excellent reactivity and high level of enantioinduction (92% yield, 89% ee). It is well known that NC6F5 NHC substituents give to lead to the irreversible Breslow intermediate (acyl anion equivalent) that undergoes the nucleophilic attack to the electrophilic Michael acceptor. Lowering the catalyst loading from 10 to 5 mol % and reaction, the temperature also gave high enantiocontrol of the desired annulation products, albeit small decrease of the yields were observed. With the new (1S)-(−)-verbenone-derived triazolium salts 1A-B in hand, our studies began with testing their activity in the intramolecular Stetter reaction of 9a. As summarized in Table 1, when the triazolium salt 1A (10 mol %) was used together with triethylamine (10 mol %), only a trace amount of desired chromanone 10a was observed (Table 1, entry 1). To our great delight, under the same conditions, triazolium salt 1A bearing pentafluorophenyl moiety showed an excellent reactivity and high level of enantioinduction (92% yield, 89% ee). It is well known that N-C 6 F 5 NHC substituents give to lead to the irreversible Breslow intermediate (acyl anion equivalent) that undergoes the nucleophilic attack to the electrophilic Michael acceptor. Lowering the catalyst loading from 10 to 5 mol % and reaction, the temperature also gave high enantiocontrol of the desired annulation products, albeit small decrease of the yields were observed.
Encouraged by this result, different organic bases were screened. All tested bases were found tolerable ( Table 2. Entries 1-10) and diisopropylethylamine was optimal in terms of both yield and enantiomeric excess of the product ( Table 2, Entry 1). conditions, triazolium salt 1A bearing pentafluorophenyl moiety showed an excellent reactivity and high level of enantioinduction (92% yield, 89% ee). It is well known that NC6F5 NHC substituents give to lead to the irreversible Breslow intermediate (acyl anion equivalent) that undergoes the nucleophilic attack to the electrophilic Michael acceptor. Lowering the catalyst loading from 10 to 5 mol % and reaction, the temperature also gave high enantiocontrol of the desired annulation products, albeit small decrease of the yields were observed.  Encouraged by this result, different organic bases were screened. All tested bases were found tolerable ( Table 2. Entries 1-10) and diisopropylethylamine was optimal in terms of both yield and enantiomeric excess of the product ( Table 2, Entry 1). Further examination of the solvents led to the following optimized reaction condition, that is, with 10 mol % prior generated carbene at a substrate concentration of 0.1 M in cyclohexane at room temperature (Table 3, Entry 7). With the reaction condition optimized, the substrate scope of the annulation reaction was explored by employing a variety of salicylaldehyde-derived substrates.  12  TolueneToluene DIPEANEt 3  2020  9692  9089  3  Toluene  DCyEA  20  95  89  4  Toluene  DBU  20  93  86  5  Toluene  DMAP  20  81  88  6  Toluene  DABCO  20  82  86  7  Toluene  TBD  20  85  87  8  Toluene  P 2 -Et  20  92  88  9  Toluene  KHMDS  20  94  89  10 Toluene t-BuOK 20 92 90 a Unless otherwise noted, all reactions were carried out with the 9a (0.1 mmol), base 10 mol %, toluene 1 mL (0.1 M). b Isolated yields. c Determined by HPLC analysis using a chiral stationary phase. TBD: 1,5,7-Triazabicyclo[4.4.0]dec-5-ene; Phosphazene base P 2 -Et: Tetramethyl (tris(dimethyl-amino) phosphoranylidene) phosphorictriamid-Et-imin.
Further examination of the solvents led to the following optimized reaction condition, that is, with 10 mol % prior generated carbene at a substrate concentration of 0.1 M in cyclohexane at room temperature (Table 3, Entry 7). With the reaction condition optimized, the substrate scope of the annulation reaction was explored by employing a variety of salicylaldehyde-derived substrates.
As shown in Table 4, all tested substrates bearing either electron-donating (Table 4, products 10b-e) or electron-withdrawing (Table 4, 10f-l) substituents on the phenyl ring were well tolerated, giving the corresponding chromanone derivatives in excellent yields and generally high enantiocontrol of the cyclization process. It is worth noting, that the position and electronic properties of the substituents on the phenyl ring did not influence the outcome of the reaction. Remarkably, satisfied results could also be obtained for the salicylaldehyde-derived substrate possessing two substituents in different positions was successfully accomplished (Table 4, 10l). The absolute configuration of the Stetter products was determined to be S by comparison of its optical rotation. Further examination of the solvents led to the following optimized reaction condition, that is, with 10 mol % prior generated carbene at a substrate concentration of 0.1 M in cyclohexane at room temperature (Table 3, Entry 7). With the reaction condition optimized, the substrate scope of the annulation reaction was explored by employing a variety of salicylaldehyde-derived substrates.   90  89  3  THF  DIPEA  20  93  89  4  CMPE  DIPEA  20  92  90  5  MTBE  DIPEA  20  81  90  6  TAME  DIPEA  20  82  89  7  Cyclohexane  DIPEA  20  96  91 a Unless otherwise noted, all reactions were carried out with the 9a (0.1 mmol), Diisopropylethylamine 10 mol %, solvent 1 mL (0.1 M). b Isolated yields. c Determined by HPLC analysis using a chiral stationary phase.
As shown in Table 4, all tested substrates bearing either electron-donating (Table 4, products 10b-e) or electron-withdrawing (Table 4, 10f-l) substituents on the phenyl ring were well tolerated, giving the corresponding chromanone derivatives in excellent yields and generally high enantiocontrol of the cyclization process. It is worth noting, that the position and electronic properties of the substituents on the phenyl ring did not influence the outcome of the reaction. Remarkably, satisfied results could also be obtained for the salicylaldehyde-derived substrate possessing two substituents in different positions was successfully accomplished (Table 4, 10l). The absolute configuration of the Stetter products was determined to be S by comparison of its optical rotation.

Materials and Methods
a Unless otherwise noted, all reactions were carried out with the 9a-l (0.2 mmol), Diisopropylethylamine 10 mol %, cyclohexane 2 mL (0.1 M). b Isolated yields. c Determined by HPLC analysis using a chiral stationary phase.

General Information
Reactions involving moisture sensitive reagents were carried out under an argon atmosphere using standard vacuum line techniques. All glassware used were flame dried and cooled under vacuum. All solvents were dried using an Innovative Technologies PureSolv Solvent Purification System (INERT) and degassed via three freeze-pump-thaw cycles. All other commercial reagents were used as supplied without further purification unless stated otherwise. The crude compounds were purified by a Combiflash Rf chromatography system (Teledyne Technologies, Inc., Thousand Oaks, CA, USA) unless specified otherwise. Analytical thin layer chromatography was performed on pre-coated aluminum plates (Kieselgel 60 F254silica). TLC visualization was carried out with ultraviolet light (254 nm), followed by staining with a 1% aqueous KMnO 4 solution. NMR spectra were recorded on a Bruker AMX 400 and 700 spectrometers (Bruker, Karlsruhe, Germany) and referenced to the solvent residual peak. Melting points were obtained in open capillary tubes using a Stuart SMP50 melting point apparatus (Cole Palmer, Stone (Staffordshire), UK) and were uncorrected. Elemental analyses were performed on a Vario MACRO CHN analyzer (Elementar Analysensysteme GmbH, Langenselbold, Germany). Optical rotations ([α] D ) were measured on a PolAAr 3000 polarimeter (Optical Activity LTD, Cambridgeshire, UK). IR spectra were recorded on Bruker Alpha (Bruker, Karlsruhe, Germany) and are reported in terms of frequency of absorption cm −1 . Mass spectra were collected on a Shimadzu High Performance Liquid Chromatograph/Mass Spectrometer LCMS-8030 (Shimadzu, Kyoto, Japan), (ESI, operating both in positive and negative modes). Enantiomeric excesses were determined by HPLC analysis on chiral stationary phase using 4.6 mm × 250 mm Phenomenex Lux Cellulose-1 or Daicel Chiralcel OJ with n-hexane, 2-propanol as eluent. The (1S)-(−)-verbenone that was purchased from Sigma-Aldrich (Poznań, Poland) was of 94% chemical purity, and an optical purity of 56% was determined GC (Shimadzu GC-2010 Plus, Shimadzu, Kyoto, Japan) with a chiral stationary phase (Supelco Beta-DEX tm 325, 30 m, 0.25mm ID, 0.25 µm film). All other reagents were purchased from commercial suppliers. Salicylaldehyde-derived substrates 9a-l were prepared according to the known procedures [36]. The spectra of NMR and HPLC is in the Supplementary Materials.

(−)-Cis-verbanone 3
The catalytic hydrogenation of (−)-verbenone [41] 2 (50 g, 0.37 mol) with Pd/C (10%, 0.5 g) in 50 mL cyclohexane at room temperature and 30 atm was completed after 20 h. The reaction mixture was filtered, and concentrated to give (−)-cis-verbanone 3 (49.9 g, 0.37 mol, 99% yield A three-necked flask, equipped with a dropping funnel and a magnetic stirring bar, was charged with tert-butanol (312 mL) and potassium tert-butoxide (28.3 g, 319 mmol). After dissolution of the precipitate, the mixture was cooled below 10 • C and (−)-cis-verbanone 3 (40.5 g, 266 mmol) was slowly added with vigorous stirring. After 30 minutes, isoamyl nitrite (42.9 mL, 432 mmol) was slowly added, keeping the reaction temperature below 10 • C. After stirring the mixture for 30 minutes at this temperature, 80 mL of petroleum ether was added, and stirring was continued additionally for 4 h. Next, petroleum ether (200 mL) and water (80 mL) was added, then biphasic solution was transferred to a separatory funnel, the water phase was separated and the organic phase was extracted with water. The combined waters were acidified with acetic acid. The precipitate was filtered and dried to a yield of 42.0 g, 232 mmol, (87%) of crude product 4 in high purity. The 4 (15.8 g, 87.1 mmol) was dissolved in anhydrous ethanol (158 mL), then the mixture was cooled to 0 • C and treated with a small portion of sodium borohydride (9.1 g, 240 mmol). The reaction mixture was stirred at the same temperature for 2 h. After this time, the solvent was evaporated, and water was added. The resulting mixture was then extracted with ethyl acetate, washed with brine, dried (MgSO 4 ), and concentrated to provide the product as a white solid. The crystallization from the n-heptane/chloroform gave enantiomerically pure hydroxyoxime 5 (99% ee [Daicel Chiralpak OJ, hexanes/2-propanol, 90:10, v = 0.7 mL/min −1 , λ = 220 nm, t (major) =  To a suspension of LiAlH 4 (2.6 g, 68.5 mmol) in 46 mL of anhydrous diethyl ether was added dropwise, a solution of 5 (4.3 g, 22.8 mmol) in 46 mL of anhydrous diethyl ether at room temperature over 45 minutes. The mixture was then heated under reflux for 24 h. The reaction mixture was then carefully hydrolyzed with 4N NaOH solution (20 mL) and water (20 mL). The precipitate was filtered off and washed with ether (3 × 100 mL). The combined organic layers were concentrated under vacuum to give aminoalcohol 6 (2.4 g, 63%) as a colorless oil, and was used in the next step without further purification. To a solution of 6 (2.2 g, 12.7 mmol) in CH 2 Cl 2 (50 mL) was added a 0.5M aqueous solution of NaOH (200 mL). The resulting solution was cooled in an ice-water slush bath and a solution of chloroacetyl chloride (4.3 mL, 52.1 mmol, 1.2 eq.) in CH 2 Cl 2 (100 mL) was added over a 45 minutes period. The ice bath was removed, and the resulting mixture was stirred vigorously for 16 h. The layers were separated, and the aqueous phase extracted three times with dichloromethane. The combined organic extract was washed with 10% NaHCO 3 , brine and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The crude product was purified by column chromatography to afford the title compound 6 (2.0 g, 8 A flame-dried 50 mL round-bottomed flask was charged with morpholinone 8 (0.44 g, 2.1 mmol) and dry dichloromethane (22 mL). Trimethyloxonium tetrafluoroborate (0.31 g, 13.5 mmol, 1.0 eq.) was added and stirred under an atmosphere of argon for 20 h. The phenylhydrazine was added (0.23 mL, 2.1 mmol, 1eq.) and stirred at an ambient temperature until the starting material was consumed as visualized by TLC (ca. 24 h). After the time, the solvent was evaporated and the triethyl orthoformate (5 mL) and chlorobenzene (5 mL) were added. The mixture was then heated to 110 • C and stirred at this temperature for 24 h. After completion, the solvent was removed in vacuum and the crude triazolium salt 1A was washed by diethyl ether and toluene to give pure NHC pre-catalyst (0.  13  A flame-dried 50 mL round-bottomed flask was charged with morpholinone 8 (0.44 g, 2.1 mmol) and dichloromethane (22 mL). Trimethyloxonium tetrafluoroborate (0.31 g, 2.1 mmol, 1.0 eq.) was added and stirred under atmosphere of Ar for 12 h. The pentafluorophenylhydrazine was added (0.42 g, 2.1 mmol, 1eq.) and stirred at an ambient temperature until the starting material was consumed as visualized by TLC (ca. 16 h). After this time, the solvent was evaporated and the triethyl orthoformate (5 mL) and chlorobenzene (5 mL) were added. The mixture was then heated to 110 • C and stirred at this temperature for 24 h. After completion, the solvent was removed in vacuum. The crude product was dissolved in methanol (5 mL) and the sodium tetraphenylborate (3.1 g, 9.0 mmol) was added, and the reaction mixture was allowed to stir for 12 hours at room temperature. The formed precipitate was filtered and washed with cold methanol (

General Procedure for Enantioselective Intramolecular Stetter Reaction
A flame dried round bottom flask was charged with triazolium salt 1B (14.4 mg, 0.02 mmol, 10 mol %) and 2.0 mL of cyclohexane. Then to this solution was added DIPEA (3.5 µL, 0.02 mmol, 10 mol %) via syringe and the solution was allowed to stir at ambient temperature for 20 minutes. After then, a substrate (0.2 mmol) was added, and the resulting solution was allowed to stir at an ambient temperature and monitored by TLC. The reaction mixture was placed directly onto a silica gel column and eluted with a suitable solution of hexane and ethyl acetate (80:20). Evaporation of a solvent afforded an analytically pure product.
Ethyl ( to be efficient for intramolecular Stetter reaction, affording the desired mono-, and disubstituted chromanones in excellent yields and high enantiomeric excesses. Structural diversity of enantiomerically pure monoterpenes, often an access to both enantiomeric forms, commercial availability, and a relatively low cost of monoterpenes give opportunities in terms of structural selection and modification of future catalysts. Further applications of these (−)-verbenone-derived triazolium salts in asymmetric catalysis are currently under way.

Patents
The synthesis of the triazolium salts 1A-B is the subject of a Polish patent application nr. P.428214 (WIPO ST 10/C PL428214).