Next Article in Journal
Hybridization of Nanodiamond and CuFe-LDH as Heterogeneous Photoactivator for Visible-Light Driven Photo-Fenton Reaction: Photocatalytic Activity and Mechanism
Previous Article in Journal
Switchable Access to Amines and Imines from Reductive Coupling of Nitroarenes with Alcohols Catalyzed by Biomass-Derived Cobalt Nanoparticles
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Catalysts
Volume 9
Issue 2
10.3390/catal9020117
catalysts-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
Zbigniew Rafiński
* and
Marek P. Krzemiński
Chair of Organic Chemistry, Faculty of Chemistry, Nicolaus Copernicus University in Toruń, 7 Gagarin Street, 87-100 Toruń, Poland
*
Author to whom correspondence should be addressed.
†
Dedication to Professor Marek Zaidlewicz on the Occasion of his 80th Birthday.
Catalysts 2019, 9(2), 117; https://doi.org/10.3390/catal9020117
Submission received: 5 January 2019 / Revised: 24 January 2019 / Accepted: 28 January 2019 / Published: 29 January 2019
Browse Figures
Review Reports Versions Notes

Abstract

:
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.

Graphical Abstract

1. Introduction

Chromanones and related structures are privileged natural products that possess a broad array of biological activity [1,2,3,4,5,6]. Notably, these natural products have been shown to exhibit biological activities including anti-tumor, anti-inflammatory, antimicrobial, estrogenic, and antiestrogenic properties [5]. In spite of all these interesting properties, limited strategies for the general and efficient preparation of these compounds have been investigated in a stereoselective manner thus far [7,8,9,10,11,12].
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.

2. 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 ketooxime 4 in 87% yield by treatment with isoamyl nitrite. Due to the fact, that verbenone is not commercially available in an enantiomerically pure form, attempts of enantiomeric enrichment 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.
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.
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.

3. Materials and Methods

3.1. 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 KMnO4 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-DEXtm 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.

3.2. Preparation of the Triazolium Salts 1A–B

3.2.1. (−)-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). [α]D30 – 32.5 (c 2.0; CHCl3). 1H NMR (400 MHz, CDCl3), δ (ppm): 1.03 (s, 3H, CH3); 1.19 (d, J = 7.6 Hz, 3H, CH3); 1.36 (s, 3H, CH3), 1.42 (d, J = 10.4 Hz, 1H); 2.15–2.16 (m, 1H); 2.20 (d, J = 4.8 Hz, 1H), 2.34–2.44 (m, 1H), 2.56–2.63 (m, 2H), 2,84–2,92 (m, 1H). 13C NMR (101 MHz, CDCl3), δ (ppm): 21.1, 24.6, 27.0, 28.5, 31.1, 40.2, 41.4, 47.4, 58.0, 214.4.

3.2.2. (1S,4S,5S,E)-3-(Hydroxyimino)-4,6,6-trimethylbicyclo[3.1.1]heptan-2-one 4

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. T.t. = 146–147 °C. 1H NMR (400MHz, CDCl3), δ (ppm): 1.07 (s, 3H, CH3), 1,43 (s, 3H, CH3), 1.45 (d, J = 7,2 Hz, 3H, CH3), 1.49 (s, 1H), 2.20–2.24 (m, 1H), 2.69-2.74 (m, 2H), 3.24 (dq, J = 7.2, 7.0, 2.8 Hz, 1H). 13C NMR (101 MHz, CDCl3), δ (ppm): 16.0, 24.0, 27.3, 28.3, 36.4, 42.4, 45.7, 56.3, 155.5, 199.1. IR (ATR) ṽ (cm−1): 3201, 2918, 1719, 945, 826. MS (ESI): Mass calcd for [M + Na]+ C10H15NO2Na: 204.1; found 204.1. Anal. calculated for C10H15NO2: C, 66.27; H, 8.37; found: C, 66.35; H, 8.44.

3.2.3. (1S,2R,4S,5S,E)-2-Hydroxy-4,6,6-trimethylbicyclo[3.1.1]heptan-3-one oxime 5

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 (MgSO4), 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) = 8.09 min], 7.5 g, 40.9 mmol, 47%). T.t. = 172–174 °C. [α]D30 + 5,67 (c 2.0, CHCl3). 1H NMR (400 MHz, CDCl3), δ (ppm): 0.80 (d, J = 10.8 Hz, 1H), 1.18 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.48 (d, J = 7.2 Hz, 3H, CH3), 1.91 (dt, J = 6.0, 2.8 Hz, 1H), 2.22–2.26 (m, 1H), 2.38–2.42 (m, 1H), 3,02 (dq, J = 8.0, 6.8, 3,2 Hz, 1H), 4.58 (m, 1H). 13C NMR (100.1 MHz, CDCl3), δ (ppm): 18.7, 25.2, 29.0, 30.4, 39.4, 39.8, 45.8, 47.6, 74.5, 165.0. IR (ATR) ṽ (cm−1): 3238, 2941, 1447, 934, 827. MS (ESI): Mass calcd for [M + Na]+ C10H17NO2Na: 206.1; found 206.1. Anal. calculated for C10H17NO2: C, 65.54; H, 9.35; found: C, 65.61; H, 9.44.

3.2.4. 2-Chloro-N-((1S,2R,3S,4S,5S)-2-hydroxy-4,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)acetamide 7

To a suspension of LiAlH4 (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 CH2Cl2 (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 CH2Cl2 (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% NaHCO3, 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, 8.1 mmol, 64%) as a colorless oil. [α]D30 + 15,6 (c 2.0, CHCl3). 1H NMR (400 MHz, CDCl3), δ (ppm): 1.03 (d, J = 7.7 Hz, 3H, CH3), 1.14 (s, 3H, CH3), 1.22 (d, J = 7.7 Hz, 1H), 1.25 (s, 3H, CH3), 1.98–2.01 (m, 1H), 2.24–2.26 (m, 1H), 2.31 (dt, J = 10.5, 10.5 Hz, 1H), 2.73–2.78 (m, 1H), 4.12–4.18 (m, 2H), 4.54 (dd, J = 4.2, 4.2 Hz, 1H), 4.67–4.71 (m, 1H). 13C NMR (100.1 MHz, CDCl3), δ (ppm): 16.5, 26.0, 28.4, 29.6, 38.6, 38.7, 43.8, 46.0, 48.1, 48.9, 72.9, 167.2. IR (ATR) ṽ (cm−1): 3365, 2906, 1651, 1518, 1258, 1065, 775. MS (ESI): Mass calcd for [M + Na]+ C12H20ClNO2Na: 268.1; found 268.1. Anal. calculated for C12H20ClNO2: C, 58.65; H, 8.20; found: C, 58.76; H, 8.31.

3.2.5. (4aS,5S,6S,8S,8aR)-5,7,7-Trimethylhexahydro-2H-6,8-methanobenzo[b][1,4]oxazin-3(4H)-one 8

To a solution of chloroamide 7 (1.3 g, 5.4 mmol) in 36 mL of anhydrous dichloromethane was added dropwise a solution of potassium tert-butoxide (1.2 g, 10.9 mmol) in i-propanol (36 mL) over 45 minutes at 0 °C. The solution was allowed to warm to ambient temperature and stirred for 24 h. After that time, all volatile materials were evaporated under reduced pressure. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether/ethyl acetate, 8:2) to afford lactam 8 (1.0 g, 4.8 mmol, 91%) as a colorless waxy oil. [α]D30 – 63.7 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3), δ (ppm): 1.13 (s, 3H, CH3), 1.19 (d, J = 7.7 Hz, 3H, CH3), 1.25 (s, 3H, CH3), 2.01 (dt, J = 2.8, 2.8 Hz, 1H), 2.34–2.39 (m, 3H), 2.57–2.62 (m, 1H), 3.92 (d, J = 16.1 Hz, 1H), 4.17 (t, J = 9.1 Hz, 1H), 4.27 (d, J = 16.8 Hz, 1H), 4.30 (dd, J = 4.2, 3.5 Hz, 1H). 13C NMR (100.1 MHz, CDCl3), δ (ppm): 15.0, 24.5, 26.8, 28.0, 37.4, 37.8, 44.6, 46.4, 48.0, 66.9, 76.8, 171.7. IR (ATR) ṽ (cm−1): 2904, 1671, 1111, 730. MS (ESI): Mass calcd for [M + Na]+ C12H19NO2Na: 232.1; found 232.2. Anal. calculated for C12H19NO2: C, 68.87; H, 9.15; found: C, 68.96; H, 9.26.

3.2.6. (5aR,6S,8S,9S,9aS)-7,7,9-Trimethyl-2-phenyl-5a,6,7,8,9,9a-hexahydro-4H-6,8-methanobenzo[b] [1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium tetrafluoroborate 1A

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 (0.43 g, 1.1 mmol, 52% yield) as a light brown solid. T.t = 231–233 °C. 1H NMR (400 MHz, CDCl3), δ (ppm): 1.10 (d, J = 8.0 Hz, 3H), 1.14 (s, 3H), 1,27 (d, J = 12.0 Hz, 1H), 1.28 (s, 3H), 2.16 (m, 1H), 2.29 (m, 1H), 2.48 (m, 1H), 3.36 (m, 1H), 4.71 (dd, J = 8.0, 8.0 Hz, 1H), 4.88 (d, J = 16.0 Hz, 1H), 5.20 (d, J = 16.0 Hz, 1H), 5.27 (dd, J = 12.0, 8.0 Hz, 1H), 7.52 (m, 3H), 7.90 (m, 2H), 10.29 (s, 1H). 13C NMR (100.1 MHz, CDCl3), δ (ppm): 15.4, 25.4, 26.0, 29.0, 34.6, 39.0, 44.6, 48.1, 52.5, 60.8, 120.5 (2C), 130.2 (2C), 130.7, 134.9, 140.3, 151.4. IR (ATR) ṽ (cm−1): 3040, 2979, 2930, 2872, 1667, 1563, 1052, 822. MS (ESI): Mass calcd for [M+] C19H24N3O: 310.2; found 310.2. Anal. calculated for C19H24BF4N3O: C, 57.45; H, 6.09; found: C, 57.49; H, 6.14.

3.2.7. (5aR,6S,8S,9S,9aS)-7,7,9-Trimethyl-2-(perfluorophenyl)-5a,6,7,8,9,9a-hexahydro-4H-6,8-methano- benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium tetraphenylborate 1B

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 (2 mL) to give tetraphenylborate salt 0.48 g, 0.67 mmol, (32% yield) as a light brown solid. T.t. = 184–186 °C. 1H NMR (400 MHz, CDCl3), δ (ppm): 0.77 (d, J = 8.0 Hz, 3H), 0,99 (s, 3H), 1.29 (s, 3H), 1.38 (d, J = 12.0 Hz, 1H), 2.24 (m, 1H), 2.41–2.51 (m, 2H), 3.10 (m, 1H), 3.73 (m, 1H), 4.03 (m, 1H), 4.50 (d, J = 16.0 Hz, 1H), 5.06 (d, J = 16.0 Hz, 1H), 5.90 (bs, 1H), 6.97 (m, 12H), 7.35 (m, 8H). 13C NMR (100.1 MHz, CDCl3), δ (ppm): 14.9, 24.9, 25.9, 28.8, 34.6, 39.1, 44.3, 47.7, 52.3, 60.4, 122.5 (8C), 125.9 (4C), 136.0 (8C), 146.2, 151.2, 162.9, 163.4, 163.9, 164.4. IR (ATR) ṽ (cm−1): 3043, 2989, 2925, 2872, 1599, 1527, 1478, 1072, 999, 835, 737, 706, 612, 469. MS (ESI): Mass calcd for [M+] C19H19F5N3O: 400.1; found 400.1. Anal. calculated for C43H39BF5N3O: C, 71.77; H, 5.46; found: C, 71.83; H, 5.50.

3.3. 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 (S)-2-(4-oxochroman-3-yl)acetate 10a: yellow oil, 96% yield (45 mg, 0.19 mmol), 91 ee [Daicel Chiralpak OD-H, hexanes/2-propanol, 90:10, v = 0.7 mL/min−1, λ = 254 nm, t (minor) = 15.05 min, t (major) = 26.79 min]. 1H NMR (400 MHz, CDCl3) δ 1.28 (t, J = 7.2 Hz, 3H, CH3), 2.41 (dd, J = 17.0, 8.1 Hz, 1H), 2.93 (dd, J = 17.0, 4.9 Hz, 1H), 3.33 (ddt, J = 12.0, 8.1, 5.1 Hz, 1H), 4.19 (dq, J = 7.2, 2.0 Hz, 2H), 4.30 (dd, J = 11.9, 11.4 Hz, 1H), 4.60 (dd, J = 11.2, 5.3 Hz, 1H), 6.97 (dd, J = 8.2, 0.7 Hz, 1H), 7.02 (ddd, J = 8.0, 7.1, 0.9 Hz, 1H), 7.47 (ddd, J = 8.3, 7.1, 1.8 Hz, 1H), 7.88 (dd, J = 8.0, 1.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 14.2, 30.3, 42.5, 61.0, 70.2, 117.8, 120.5, 121.5, 127.4, 136.0, 167.7, 171.3, 192.6 ppm.
Ethyl (S)-2-(7-methoxy-4-oxochroman-3-yl)acetate 10b: yellow oil, 95% yield (50 mg, 0.19 mmol), 94% ee [Phenomenex Lux Celluose-1, hexanes/2-propanol 90:10, v = 0.7 mL/min−1, λ = 254 nm, t (minor) = 36.80 min, t (major) = 68.35 min]. 1H NMR (700 MHz, CDCl3) δ 1.29 (t, J = 7.1 Hz, 3H, CH3), 2.39 (dd, J = 16.9, 8.4 Hz, 1H), 2.94 (dd, J = 16.9, 4.7 Hz, 1H), 3.27 (ddt, J = 11.6, 8.5, 5.0 Hz, 1H), 3.84 (s, 3H, CH3), 4.19 (qd, J = 7.1, 2.2 Hz, 2H), 4.28 (dd, J = 11.4, 11.4 Hz, 1H), 4.59 (dd, J = 11.1, 5.2 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.59 (dd, J = 8.4, 2.4 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 14.2, 30.4, 42.1, 55.6, 60.9, 70.6, 100.7, 110.1, 114.4, 129.1, 163.1, 166.0, 171.5, 191.2 ppm.
Methyl (S)-2-(7-methyl-4-oxochroman-3-yl)acetate 10c: yellow oil, 97% yield (45 mg, 0.19 mmol), 91% ee [Daicel Chiralpak OJ, hexanes/2-propanol, 90:10, v = 0.7 mL/min−1, λ = 254 nm, t (minor) = 26.19 min, t (major) = 20.44 min]. 1H NMR (700 MHz, CDCl3) δ 2.38 (s, 3H, CH3), 2.44 (dd, J = 16.8, 8.4 Hz, 1H), 2.96 (dd, J = 16.8, 4.9 Hz, 1H), 3.29–3.35 (m, 1H), 3.75 (s, 3H, CH3), 4.28 (dd, J = 11.2, 11.2 Hz, 1H), 4.59 (dd, J = 11.2, 4.9 Hz, 1H), 6.80 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 22.9, 31.1, 43.4, 53.0, 71.2, 118.8, 119.2, 123.9, 128.3, 145.6, 162.8, 172.9, 193.2 ppm.
Ethyl (S)-2-(6-methoxy-4-oxochroman-3-yl)acetate 10d: yellow oil, 95% yield (50 mg, 0.19 mmol), 93% ee [Phenomenex Lux Celluose-1, hexanes/2-propanol 90:10, v = 0.7 mL/min−1, λ = 254 nm, t (minor) = 19.82 min, t (major) = 24.46 min]. 1H NMR (700 MHz, CDCl3) δ 1.28 (t, J = 7.2 Hz, 3H, CH3), 2.43 (dd, J = 16.9, 8.2 Hz, 1H), 2.90 (dd, J = 16.9, 4.9 Hz, 1H), 3.30 (ddt, J = 11.7, 8.1, 5.1 Hz, 1H), 3.79 (s, 3H, CH3), 4.15–4.22 (m, 2H), 4.26 (dd, J = 11.5, 11.5 Hz, 1H), 4.56 (dd, J = 11.2, 5.3 Hz, 1H), 6.90 (d, J = 9.1 Hz, 1H), 7.08 (dd, J = 9.1, 3.1 Hz, 1H), 7.30 (d, J = 3.1 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 14.2, 30.5, 42.5, 55.8, 60.9, 70.4, 107.7, 119.1, 120.3, 125.2, 154.1, 156.4, 171.4, 192.6 ppm.
Ethyl (S)-2-(6-methyl-4-oxochroman-3-yl)acetate 10e: yellow oil, 93% yield (46 mg, 0.19 mmol), 90% ee [Daicel Chiralpak OJ, hexanes/2-propanol, 90:10, v = 0.7 mL/min−1, λ = 254 nm, t (major) = 19.71 min, t (minor) = 22.48 min]. 1H NMR (700 MHz, CDCl3) δ 1.31 (t, J = 7.1 Hz, 3H, CH3), 2.33 (s, 3H, CH3), 2.44 (dd, J = 16.8, 8.0 Hz, 1H), 2.95 (dd, J = 16.8, 4.7 Hz, 1H), 3.33 (ddt, J = 11.9, 8.2, 4.7 Hz, 1H), 4.21 (qd, J = 7.1, 5.8 Hz, 2H), 4.29 (dd, J = 11.4, 11.4 Hz, 1H), 4.59 (dd, J = 11.2, 5.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 7.30–7.33 (m, 1H), 7.70–7.71 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 14.2, 20.4, 30.4, 42.6, 61.0, 70.2, 117.6, 120.1, 126.9, 131.0, 137.1, 159.8, 171.4, 192.8 ppm.
Methyl (S)-2-(6-fluoro-4-oxochroman-3-yl)acetate 10f: yellow oil, 96% yield (46 mg, 0.19 mmol), 93% ee [Daicel Chiralpak OJ, hexanes/2-propanol, 90:10, v = 0.7 mL/min−1, λ = 254 nm, t (major) = 15.54 min, t (minor) = 13.60 min]. 1H NMR (400 MHz, CDCl3) δ 2.46 (dd, J = 17.0, 8.0 Hz, 1H), 2.94 (dd, J = 17.0, 4.8 Hz, 1H), 3.32 (ddt, J = 12.2, 8.0, 5.0 Hz, 1H), 3.75 (s, 3H, CH3), 4.30 (dd, J = 11.9, 11.5 Hz, 1H), 4.60 (dd, J = 11.3, 5.3 Hz, 1H), 6.97 (dd, J = 9.1, 4.1 Hz, 1H), 7.21 (ddd, J = 9.1, 7.7, 3.2 Hz, 1H), 7.53 (dd, J = 8.3, 3.1, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 30.0, 42.4, 52.1, 70.4, 112.3 (d, J = 23.7 Hz), 119.5 (d, J = 7.9 Hz), 120.9 (d, J = 7.1 Hz), 123.6 (d, J = 24.5 Hz), 157.0 (d, J = 191.2 Hz), 158.2 (d, J = 48.2 Hz), 171.6, 191.8 ppm.
Ethyl (S)-2-(6-chloro-4-oxochroman-3-yl)acetate 10g: yellow oil, 99% yield (51 mg, 0.20 mmol), 94% ee [Daicel Chiralpak OJ, hexanes/2-propanol, 95:5, v = 0.7 mL/min−1, λ = 254 nm, t (major) = 19.91 min, t (minor) = 22.96 min]. 1H NMR (700 MHz, CDCl3) δ 2.47 (dd, J = 17.5, 8.4 Hz, 1H), 2.95 (dd, J = 17.5, 4.9 Hz, 1H), 3.31-3.37 (m, 1H), 3.75 (s, 3H, CH3), 4.32 (dd, J = 11.2, 11.2 Hz, 1H), 4.63 (dd, J = 11.2, 4.9 Hz, 1H), 6.96 (d, J = 9.1 Hz, 1H), 7.43 (dd, J = 9.1, 2.8 Hz, 1H), 7.85 (d, J = 3.5 Hz, 1H) ppm. 13C NMR (176 MHz, CDCl3) δ 30.9, 43.3, 53.1, 71.3, 120.6, 122.2, 127.7, 128.1, 136.9, 161.2, 172.6, 192.4 ppm.
Methyl (S)-2-(6-bromo-4-oxochroman-3-yl)acetate 10h: yellow oil, 97% yield (58 mg, 0.19 mmol), 95% ee [Daicel Chiralpak OJ, hexanes/2-propanol, 95:5, v = 0.7 mL/min−1, λ = 254 nm, t (major) = 24.64 min, t (minor) = 28.35 min]. 1H NMR (700 MHz, CDCl3) δ 2.47 (dd, J = 17.5, 8.4 Hz, 1H), 2.95 (dd, J = 17.5, 4.9 Hz, 1H), 3.31–3.37 (m, 1H), 3.75 (s, 3H, CH3), 4.32 (dd, J = 11.2, 11.2 Hz, 1H), 4.63 (dd, J = 11.2, 4.9 Hz, 1H), 6.90 (d, J = 9.1 Hz, 1H), 7.54 (dd, J = 9.1, 2.8 Hz, 1H), 7.99 (d, J = 3.5 Hz, 1H) ppm. 13C NMR (176 MHz, CDCl3) δ 30.9, 43.3, 53.1, 71.3, 120.6, 122.2, 127.7, 128.1, 136.9, 161.2, 172.6, 192.4 ppm.
Methyl (S)-2-(4-oxo-6-(trifluoromethoxy)chroman-3-yl)acetate 10i: yellow oil, 94% yield (57 mg, 0.19 mmol), 96% ee [Daicel Chiralpak OJ, hexanes/2-propanol, 95:5, v = 0.7 mL/min−1, λ = 254 nm, t (major) = 27.21 min, t (minor) = 31.15 min]. 1H NMR (400 MHz, CDCl3) δ 2.47 (dd, J = 17.2, 8.0 Hz, 1H), 2.94 (dd, J = 17.2, 4.8 Hz, 1H), 3.30-3.40 (m, 1H), 3.74 (s, 3H, CH3), 4.28 (dd, J = 12.4, 11.2 Hz, 1H), 4.63 (dd, J = 11.2, 5.2 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 7.31–7.38 (m, 1H), 7.72–7.76 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 29.9, 42.3, 52.1, 70.4, 119.4, 119.6, 120.3 (q, J = 255.9 Hz), 120.8, 129.2, 143.2, 160.1, 171.6, 191.5 ppm.
Ethyl (S)-2-(8-iodo-4-oxochroman-3-yl)acetate 10j: yellow solid, m.p. 75–78 °C, 85% yield (61 mg, 0.17 mmol), 94% ee [Phenomenex Lux Celluose-1, hexanes/2-propanol 90:10, v = 0.7 mL/min−1, λ = 254 nm, t (minor) = 16.40 min, t (major) = 20.00 min]. 1H NMR (700 MHz, CDCl3) δ 1.32 (t, J = 7.1 Hz, 3H, CH3), 2.48 (dd, J = 17.0, 8.0 Hz, 1H), 2.95 (dd, J = 17.0, 5.9 Hz, 1H), 3.39 (ddt, J = 12.5, 7.7, 5.2 Hz, 1H), 4.19–4.25 (m, 2H), 4.42 (dd, J = 11.7, 11.7 Hz, 1H), 4.77 (dd, J = 11.2, 5.2 Hz, 1H), 6.86 (t, J = 7.8 Hz, 1H), 7.90–7.92 (m, 1H), 7.98–8.00 (m, 1H) ppm. 13C NMR (176 MHz, CDCl3) δ 15.2, 31.3, 43.0, 62.1, 71.8, 86.4, 122.0, 124.2, 128.8, 146.5, 161.2, 172.1, 192.9 ppm.
Ethyl (S)-2-(8-fluoro-4-oxochroman-3-yl)acetate 10k: yellow oil, 97% yield (45 mg, 0.19 mmol), 89% ee [Phenomenex Lux Celluose-1, hexanes/2-propanol 90:10, v = 0.7 mL/min−1, λ = 254 nm, t (minor) = 15.56 min, t (major) = 20.34 min]. 1H NMR (400 MHz, CDCl3) δ 1.29 (t, J = 7.2 Hz, 3H, CH3), 2.47 (dd, J = 17.0, 7.8 Hz, 1H), 2.92 (dd, J = 17.0, 4.9 Hz, 1H), 3.38 (ddt, J = 12.1, 7.9, 5.1 Hz, 1H), 4.19 (dq, J = 7.2, 1.6 Hz, 2H), 4.40 (dd, J = 12.1, 11.3 Hz, 1H), 4.71 (dd, J = 11.3, 5.3 Hz, 1H), 6.96 (td, J = 8.0, 4.4 Hz, 1H), 7.29 (ddd, J = 10.6, 8.0, 1.6 Hz, 1H), 7.66 (dt, J = 8.0, 1.4 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 14.1, 30.2, 42.5, 61.1, 70.8, 120.9 (d, J = 6.3 Hz), 121.8 (d, J = 17.4 Hz), 122.4 (d, J = 3.9 Hz), 122.6, 150.0 (d, J = 11.5 Hz), 151.5 (d, J = 247.2 Hz), 171.1, 191.6 (d, J = 3.4 Hz) ppm.
Ethyl (S)-2-(5,7-dichloro-4-oxochroman-3-yl)acetate 10l: white solid, m.p. 76–79 °C, 94% yield (57 mg, 0.19 mmol), 94% ee [Daicel Chiralpak OJ, hexanes/2-propanol, 95:5, v = 0.7 mL/min−1, λ = 254 nm, t (major) = 23.22 min, t (minor) = 27.18 min]. 1H NMR (700 MHz, CDCl3) δ 1.30 (t, J = 7.1 Hz, 3H, CH3), 2.42 (dd, J = 17.1, 7.8 Hz, 1H), 2.92 (dd, J = 17.1, 5.1 Hz, 1H), 3.35 (ddt, J = 12.2, 7.8, 5.1 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.32 (dd, J = 12.1, 11.3 Hz, 1H), 4.62 (dd, J = 11.3, 5.4 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 14.2, 30.2, 43.0, 61.1, 70.0, 116.5, 117.1, 121.4, 125.0, 135.6, 140.4, 163.1, 171.1, 189.7 ppm.

4. Conclusions

In conclusion, we have developed two novel chiral terpene triazolium salts from readily available (1S)-(−)-verbenone. The verbenone-derived triazolium salt 1B and diisopropylethylamine is found 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.

5. 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).

Supplementary Materials

The following are available online at https://www.mdpi.com/2073-4344/9/2/117/s1.

Author Contributions

Conceptualization, investigation, supervision, writing original draft: Z.R.; Methodology: M.K.

Funding

The project is co-financed by the National Science Center (Poland) as part of the SONATA BIS program (UMO-2016/22/E/ST5/00469)

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Harborne, J.B. The Flavonoids: Advances in Research since 1986; chapter 3: C-Glycosylflavonoids; Springer: Berlin/Heidelberg, Germany, 2017; ISBN 9781351410458. [Google Scholar]
  2. Dewick, P.M. Isoflavonoids. In The Flavonoids: Advances in Research since 1986; Springer: Berlin/Heidelberg, Germany, 2017; ISBN 9781351410458. [Google Scholar]
  3. Williams, C.A.; Grayer, R.J. Anthocyanins and other flavonoids. Nat. Prod. Rep. 2004, 21, 539–573. [Google Scholar] [CrossRef] [PubMed]
  4. Tringali, C. Bioactive Compounds from Natural Sources: Isolation, Characterization and Biological Properties; CRC Press: Boca Raton, FL, USA, 2001; ISBN 0203212312. [Google Scholar]
  5. Andersen, Ø.M.; Markham, K.R. Flavonoids: Chemistry, Biochemistry and Applications; CRC Press: Boca Raton, FL, USA, 2005; ISBN 9781420039443. [Google Scholar]
  6. Evans, B.E.; Rittle, K.E.; Bock, M.G.; DiPardo, R.M.; Freidinger, R.M.; Whitter, W.L.; Lundell, G.F.; Veber, D.F.; Anderson, P.S.; Chang, R.S.L.; et al. Methods for Drug Discovery: Development of Potent, Selective, Orally Effective Cholecystokinin Antagoniststs. J. Med. Chem. 1988, 31, 2235–2246. [Google Scholar] [CrossRef]
  7. Farmer, R.L.; Biddle, M.M.; Nibbs, A.E.; Huang, X.; Bergan, R.C.; Scheidt, K.A. Concise syntheses of the abyssinones and discovery of new inhibitors of prostate cancer and MMP-2 expression. ACS Med. Chem. Lett. 2010, 1, 400–405. [Google Scholar] [CrossRef] [PubMed]
  8. Shintani, R.; Yamagami, T.; Kimura, T.; Hayashi, T. Asymmetric synthesis of 2-aryl-2,3-dihydro-4-quinolones by rhodium-catalyzed 1,4-addition of arylzinc reagents in the presence of chlorotrimethylsilane. Org. Lett. 2005, 7, 5317–5319. [Google Scholar] [CrossRef] [PubMed]
  9. Chen, J.; Chen, J.; Lang, F.; Zhang, X.; Cun, L.; Zhu, J.; Deng, J.; Liao, J. A C 2-Symmetric chiral bis-sulfoxide ligand in a rhodium-catalyzed reaction: Asymmetric 1,4-addition of sodium tetraarylborates to chromenones. J. Am. Chem. Soc. 2010, 132, 4552–4553. [Google Scholar] [CrossRef] [PubMed]
  10. Ishikawa, T.; Oku, Y.; Tanaka, T.; Kumamoto, T. An approach to anti-HIV-1 active Calophyllum coumarin synthesis: An enantioselective construction of 2,3-dimethyl-4-chromanone ring by quinineassisted intramolecular Michael-type addition. Tetrahedron Lett. 1999, 40, 3777–3780. [Google Scholar] [CrossRef]
  11. Wang, H.F.; Cui, H.F.; Chai, Z.; Li, P.; Zheng, C.W.; Yang, Y.Q.; Zhao, G. Asymmetrie synthesis of fluorinated flavanone derivatives by an organocatalytic tandem intramolecular oxa-michael Addition/electrophilic fluorination reaction by using bifunctional cinchona alkaloids. Chem. A Eur. J. 2009, 15, 13299–13303. [Google Scholar] [CrossRef]
  12. Cui, H.; Li, P.; Chai, Z.; Zheng, C.; Zhao, G.; Zhu, S. Facile stereoselective synthesis of fluorinated flavanone derivatives via a one-pot tandem reaction. J. Org. Chem. 2009, 74, 1400–1402. [Google Scholar] [CrossRef]
  13. Enders, D.; Balensiefer, T. Nucleophilic carbenes in asymmetric organocatalysis. Acc. Chem. Res. 2004, 37, 534–541. [Google Scholar] [CrossRef]
  14. Enders, D.; Niemeier, O.; Henseler, A. Organocatalysis by N-heterocyclic carbenes. Chem. Rev. 2007, 107, 5606–5655. [Google Scholar] [CrossRef]
  15. Menon, R.S.; Biju, A.T.; Nair, V. Recent advances in employing homoenolates generated by N-heterocyclic carbene (NHC) catalysis in carbon-carbon bond-forming reactions. Chem. Soc. Rev. 2015, 44, 5040–5052. [Google Scholar] [CrossRef] [PubMed]
  16. Ryan, S.J.; Candish, L.; Lupton, D.W. Acyl anion free N-heterocyclic carbene organocatalysis. Chem. Soc. Rev. 2013, 42, 4906–4917. [Google Scholar] [CrossRef] [PubMed]
  17. Flanigan, D.M.; Romanov-Michailidis, F.; White, N.A.; Rovis, T. Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes. Chem. Rev. 2015, 115, 9307–9387. [Google Scholar] [CrossRef] [PubMed]
  18. Hopkinson, M.N.; Richter, C.; Schedler, M.; Glorius, F. An overview of N-heterocyclic carbenes. Nature 2014, 510, 485–496. [Google Scholar] [CrossRef] [PubMed]
  19. Marion, N.; Díez-González, S.; Nolan, S.P. N-heterocyclic carbenes as organocatalysts. Angew. Chem. Int. Ed. 2007, 46, 2988–3000. [Google Scholar] [CrossRef] [PubMed]
  20. De Sarkar, S.; Biswas, A.; Samanta, R.C.; Studer, A. Catalysis with N-heterocyclic carbenes under oxidative conditions. Chem. Eur. J. 2013, 19, 4664–4678. [Google Scholar] [CrossRef] [PubMed]
  21. Dzieszkowski, K.; Rafiński, Z. N-Heterocyclic Carbene Catalysis under Oxidizing Conditions. Catalysts 2018, 8, 549. [Google Scholar] [CrossRef]
  22. Zhang, C.; Hooper, J.F.; Lupton, D.W. N-Heterocyclic Carbene Catalysis via the α,β-Unsaturated Acyl Azolium. ACS Catal. 2017, 7, 2583–2596. [Google Scholar] [CrossRef]
  23. Ragno, D.; Di Carmine, G.; Brandolese, A.; Bortolini, O.; Giovannini, P.P.; Massi, A. Immobilization of Privileged Triazolium Carbene Catalyst for Batch and Flow Stereoselective Umpolung Processes. ACS Catal. 2017, 7, 6365–6375. [Google Scholar] [CrossRef]
  24. Ema, T.; Nanjo, Y.; Shiratori, S.; Terao, Y.; Kimura, R. Solvent-Free Benzoin and Stetter Reactions with a Small Amount of NHC Catalyst in the Liquid or Semisolid State. Org. Lett. 2016, 18, 5764–5767. [Google Scholar] [CrossRef]
  25. Soeta, T.; Tabatake, Y.; Ukaji, Y. An asymmetric intramolecular Stetter reaction catalyzed by a chiral triazolium precatalyst bearing a pyridine moiety. Tetrahedron 2012, 68, 10188–10193. [Google Scholar] [CrossRef]
  26. Jia, M.Q.; Li, Y.; Rong, Z.Q.; You, S.L. Synthesis of (1R,2R)-DPEN-derived triazolium salts and their application in asymmetric intramolecular Stetter reactions. Org. Biomol. Chem. 2011, 9, 2072–2074. [Google Scholar] [CrossRef] [PubMed]
  27. Read de Alaniz, J.; Kerr, M.S.; Moore, J.L.; Rovis, T. Scope of the Asymmetric Intramolecular Stetter Reaction Catalyzed by Chiral Nucleophilic Triazolinylidene Carbenes. J. Org. Chem. 2008, 73, 2033–2040. [Google Scholar] [CrossRef] [PubMed]
  28. Kerr, M.S.; Read de Alaniz, J.; Rovis, T. A Highly Enantioselective Catalytic Intramolecular Stetter Reaction. J. Am. Chem. Soc. 2002, 124, 10298–10299. [Google Scholar] [CrossRef] [PubMed]
  29. Enders, D.; Breuer, K.; Teles, J.H. A Novel Asymmetric Benzoin Reaction Catalyzed by a Chiral Triazolium Salt. Preliminary communication. Helv. Chim. Act. 1996, 79, 1899–1902. [Google Scholar] [CrossRef]
  30. Moore, J.L.; Silvestri, A.P.; Read de Alaniz, J.; DiRocco, D.A.; Rovis, T. Mechanistic Investigation of the Enantioselective Intramolecular Stetter Reaction: Proton Transfer Is the First Irreversible Step. Org. Lett. 2011, 13, 1742–1745. [Google Scholar] [CrossRef] [PubMed]
  31. Li, Y.; Feng, Z.; You, S.L. d-Camphor-derived triazolium salts for catalytic intramolecular crossed aldehyde-ketone benzoin reactions. Chem. Commun. 2008, 2263–2265. [Google Scholar] [CrossRef]
  32. Li, Y.; Wang, X.Q.; Zheng, C.; You, S.L. Highly enantioselective intramolecular Michael reactions by d-camphor-derived triazolium salts. Chem. Commun. 2009, 5823–5825. [Google Scholar] [CrossRef]
  33. Rong, Z.Q.; Li, Y.; Yang, G.Q.; You, S.L. d-camphor-derived triazolium salts for enantioselective intramolecular Stetter reactions. Synlett 2011, 7, 1033–1037. [Google Scholar] [CrossRef]
  34. Jia, M.Q.; Liu, C.; You, S.L. Diastereoselective and enantioselective desymmetrization of α-substituted cyclohexadienones via intramolecular stetter reaction. J. Org. Chem. 2012, 77, 10996–11001. [Google Scholar] [CrossRef]
  35. Jia, M.Q.; You, S.L. Desymmetrization of cyclohexadienones viad-camphor-derived triazolium salt catalyzed intramolecular Stetter reaction. Chem. Commun. 2012, 48, 6363–6365. [Google Scholar] [CrossRef]
  36. Rafiński, Z.; Kozakiewicz, A.; Rafińska, K. (−)-β-pinene-derived N-heterocyclic carbenes: Application to highly enantioselective intramolecular stetter reaction. ACS Catal. 2014, 4, 1404–1408. [Google Scholar] [CrossRef]
  37. Rafiński, Z.; Kozakiewicz, A. Enantioselective Synthesis of Chromanones Bearing Quaternary Substituted Stereocenters Catalyzed by (1R)-Camphor-Derived N-Heterocyclic Carbenes. J. Org. Chem. 2015, 80, 7468–7476. [Google Scholar] [CrossRef] [PubMed]
  38. Rafiński, Z. Novel (−)-β-Pinene-Derived Triazolium Salts: Synthesis and Application in the Asymmetric Stetter Reaction. ChemCatChem 2016, 8, 2599–2603. [Google Scholar] [CrossRef]
  39. Rafiński, Z.; Kozakiewicz, A.; Rafińska, K. Highly efficient synthesis of spirocyclic (1R)-camphor-derived triazolium salts: Application in the catalytic asymmetric benzoin condensation. Tetrahedron 2014, 70, 5739–5745. [Google Scholar] [CrossRef]
  40. Rafiński, Z. Enantioselective benzoin condensation catalyzed by spirocyclic terpene-based N-heterocyclic carbenes. Tetrahedron 2016, 72, 1860–1867. [Google Scholar] [CrossRef]
  41. Konopelski, J.P.; Sundararaman, P.; Barth, G.; Djerassi, C. Optical rotatory dispersion studies. 128. Octant contributions of methyl groups in 4-tert-butylcyclohexanones. J. Am. Chem. Soc. 1980, 102, 2737–2745. [Google Scholar] [CrossRef]
Catalysts 09 00117 sch001 550
Scheme 1. Synthesis of tetracyclic triazolium salts from (1S)-(−)-verbenone.
Scheme 1. Synthesis of tetracyclic triazolium salts from (1S)-(−)-verbenone.
Catalysts 09 00117 sch001
Table
Table 1. NHC catalyst screening.
Table 1. NHC catalyst screening.
Catalysts 09 00117 i001
Entry aNHC Precat.T [°C]mol %Yield (%) bee c
11ART10<5ND
21BRT109289
31B0108589
41BRT57288
a Unless otherwise noted, all reactions were carried out with the 9a (0.1 mmol), triethylamine 10 mol %, toluene 1 mL (0.1 M). b Isolated yields. c Determined by HPLC analysis using a chiral stationary phase.
Table
Table 2. Screening of bases.
Table 2. Screening of bases.
Catalysts 09 00117 i002
Entry aSolventBaseTime (h)Yield (%) bee c
12TolueneTolueneDIPEANEt3202096929089
3TolueneDCyEA209589
4TolueneDBU209386
5TolueneDMAP208188
6TolueneDABCO208286
7TolueneTBD208587
8TolueneP2-Et209288
9TolueneKHMDS209489
10Toluenet-BuOK209290
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 P2-Et: Tetramethyl(tris(dimethyl-amino)phosphoranylidene)phosphorictriamid-Et-imin.
Table
Table 3. Screening of solvents.
Table 3. Screening of solvents.
Catalysts 09 00117 i003
Entry aSolventBaseTime (h)Yield (%) bee c
1TolueneDIPEA209690
2o-XyleneDIPEA209589
3THFDIPEA209389
4CMPEDIPEA209290
5MTBEDIPEA208190
6TAMEDIPEA208289
7CyclohexaneDIPEA209691
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.
Table
Table 4. Substrate scope for enantioselective intramolecular Stetter reaction.
Table 4. Substrate scope for enantioselective intramolecular Stetter reaction.
Catalysts 09 00117 i004
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.

Share and Cite

MDPI and ACS Style

Rafiński, Z.; Krzemiński, M.P. Synthesis of (−)-Verbenone-Derived Triazolium Salts and Their Application in Enantioselective Intramolecular Stetter Reaction. Catalysts 2019, 9, 117. https://doi.org/10.3390/catal9020117

AMA Style

Rafiński Z, Krzemiński MP. Synthesis of (−)-Verbenone-Derived Triazolium Salts and Their Application in Enantioselective Intramolecular Stetter Reaction. Catalysts. 2019; 9(2):117. https://doi.org/10.3390/catal9020117

Chicago/Turabian Style

Rafiński, Zbigniew, and Marek P. Krzemiński. 2019. "Synthesis of (−)-Verbenone-Derived Triazolium Salts and Their Application in Enantioselective Intramolecular Stetter Reaction" Catalysts 9, no. 2: 117. https://doi.org/10.3390/catal9020117

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop