esolution in the asymmetrictransfer hydrogenation of 3-aryl-indanones:applications to a short synthesis of (+)-indatralineand a formal synthesis of (R)-tolterodine†
Songsoon Parkab and Hyeon-Kyu Lee *ab
Efficient kinetic resolution (KR) occurs in asymmetric transfer hydrogenation (ATH) reactions of racemic 3-
aryl-1-indanones using commercial (R,R)- or (S,S)-Ts-DENEB as a catalyst, a 1 : 5 mixture of HCO2H and
Et3N as a hydrogen source and MeOH as solvent. This process at room temperature produces near
equal yields of cis-3-arylindanols with high dr and ee, and unreacted 3-arylindanones with excellent ee.
Stereoselective transformations of 3-arylindanols and 3-arylindanones, generated by using the ATH-KR
protocol, were carried out to form (+)-indatraline and synthetically valuable (R)-6-methyl-4-
phenylcoumarine, which is a key intermediate in the preparation of (R)-tolterodine, (S)-4-aryl-3,4-
dihydroquinoline-2(1H)-one and (S)-4-aryl-3,4-dihydroisoquinoline-1(2H)-one.
Introduction
Indane frameworks are found in natural products that possessdiverse biological activities and that serve as drug candidates.1–3
Among members of this family, 3-arylindanols and 3-arylinda-nones are privileged structural components of many pharma-ceutical agents and key intermediates in the synthesis ofa variety of bioactive compounds (Fig. 1).4–7 Typical examples ofthis type are (+)-indatraline used for the treatment of depressionand cocaine addiction,8–10 the antihypertensive agent (+) irind-alone,11 the neuroprotective agent (+)-quadrangularin A,12
(+)-isopaucioral F used for the treatment of osteoporosis12 anda-diisoeugenol that has cytotoxic and antioxidant activities.13
An example of a bioactive indane bearing a 3-alkenyl group is(+)-multisianthol, which has antitumor activity.14,15 In addition,3-arylindanoles and 3-arylindanones are valuable intermediatesin routes for the synthesis medicinal agents.
Consequently, the development of methods for convenientand stereoselective syntheses of 3-arylindanol and 3-arylinda-none is an important goal in organic synthesis. Typically, enan-tioenriched 3-aryl-1-indanols are prepared by reduction7 (NaBH4
or K-selectride for 1,3-syn indanols) of enantioenriched 3-aryl-1-
tute of Chemical Technology, PO Box 107,
harmacology, University of Science and
on 305-333, Korea. E-mail: leehk@krict.
ESI) available: Experimental proceduresindanones, copies of 1H-, 13C-NMR, andall new compounds. See DOI:
the Royal Society of Chemistry
indanones. Also, Corey's oxazaborolidine-catalyzed reduction ofracemic 3-aryl-1-indanones is known to produce mixtures con-taining almost equal amount of cis- and trans-3-aryl-1-inda-nols.16,17 Furthermore, resolution of racemic 3-aryl-1-indanol hasbeen accomplished using a commercially available lipase(Novozyme 435®).18 Previous efforts have shown that enan-tioenriched 3-aryl-1-indanones can be prepared by intra-molecular Friedel–Cras acylation of enantioenriched 3,3-diarylpropanoic acids under strongly acidic conditions,19–22 or by Ir-catalysed asymmetric hydrogenation of 3-arylinden-1-ones (58–90% ee).23 Bakers' yeast-promoted conjugate reduction of 3-arylinden-1-ones to form enantioenriched 3-aryl-1-indanones hasalso been described.24,25 Recent approaches devised to generateenantioenriched 3-aryl-1-indanones rely on metal (Pd or Ni)-catalyzed asymmetric intramolecular reductive Heck reaction of20-halochalcones,7,26–28 and Rh-catalyzed asymmetric intra-molecular 1,4-addition of aryl boronates to enones.29
Asymmetric transfer hydrogenation (ATH) reactions, usinghydrogen sources other than molecular hydrogen, have provento be among the most powerful processes for asymmetricreduction of ketones to produce enantioenriched alcohols.These processes have advantages associated with operationalsimplicity, ready availability of various hydrogen sources, anduse of readily accessible and less sensitive catalysts.30–35 Indeed,stereoselective ATH of 1-indanones or 2-substituted-1-indanones to produce corresponding 1-indanols or 2-substituted-1-indanols, which utilize chiral transition metal(Ru, Rh) catalysts and a HCO2H/Et3N mixture as a hydrogensource, have already been described.36–38 However, no exampleshave been reported thus far of ATH promoted transformationsof 3-aryl-1-indanones to 3-aryl-indanols having stereogenic
Fig. 1 Examples of biologically active 3-(aryl)-substituted indanes.
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centers at C-3. This deciency encouraged us to explore thestereochemical outcome of ATH reactions of 3-aryl-indanonesusing enantioenriched chiral transition metal catalysts anda HCO2H/Et3N mixture as the hydrogen source.
Results and discussion
Previously, it was reported that ATH reaction of 3-methoxycarbonyl-1-indanone (3) with Mohar's Ru-catalyst (C4,Scheme 1d), containing benzosultam (syn-ULTAM) ligand andHCO2H/Et3N (5 : 2) as hydrogen source (40 �C, 6 h), produces cis-(1R,3S)-3-methoxycarbonyl-1-indanol with high levels of diaster-eoselectivity and enantioselectivity, owing to dynamic kineticresolution (DKR) resulting from rapid racemization of the duallyactivated C-3 hydrogen (Scheme 1a).39,40 Because Mohar's catalystC4 is not commercially available, we assessed whether the ATHreaction of 3-methoxycarbonyl-1-indanone (3) would take placeefficiently employing commercial (R,R)-Ts-DENEB (C3) instead ofC4 as catalyst under the same reaction conditions. The oxo-tethered Ru-catalysts (R,R)- and (S,S)-Ts-DENEB (C3) which weredeveloped by T. Touge and T. Ikariya et al. generally showed,among the Noyori-type chiral Ru-catalysts, enhanced catalyticperformance with excellent levels of stereoselectivity in the asym-metric transfer hydrogenation reactions of ketonic substrates.36,41
The results show that C3 also promotes ATH reaction of 3 thatforms the cis-(1R,3S)-indanol 4 with excellent levels of stereo-selectivity (95%, 99% ee) accompanying DKR (Scheme 1b). Thisnding led us to speculate that ATH reaction of the 3-arylinda-none 1s using C3 as catalyst under similar reaction conditionswould also produce the corresponding 3-arylindanol stereo-selectively, hopefully accompanying DKR.
Contrary to expectation, subjection of 3-(3,4-dichlorophenyl)-1-indanone (1s) to the same conditions used for reduction of 3-
23162 | RSC Adv., 2021, 11, 23161–23183
methoxycarbonyl-1-indanone (3) (C3 as catalyst, FA/TEA ¼ 5 : 2,40 �C) leads to incomplete reaction (72%) and formation ofa 76 : 24 mixture of cis (99% ee) and trans indanol 2s, and 28% ofenantioenriched indanone 1s (99% ee) (Scheme 1c). In anattempt to nd ATH reaction conditions which induce DKR, weemployed stronger base of DBU (pKa ¼ 24.3)42 instead of Et3N(pKa ¼ 18.8) in the ATH reaction of 1s. However, ATH of 1s withFA/DBU (5 : 2) for 24 h, otherwise under the same reactionconditions, is still incomplete (60% conversion) affording 87 : 13mixture of cis (87% ee) and trans indanol 2s, and 40% ofunreacted indanone 1s (99% ee) (Scheme 1d). When the reactiontemperature of ATH reaction of 1s with FA/DBU (5 : 2) wasincreased to 60 �C for 24 h, the conversion of the ATH reactionwas increased to 81% but, dr (cis-2s: trans 2s ¼ 73 : 27) and ee ofcis-2s (67% ee) was rapidly decrease. Therefore, since ATH reac-tion of 1s in the presence of (R,R)-Ts-DENEB (C3) and FA/Et3N(5 : 2) as hydrogen source provided cis-indanol 2s (99% ee) and ofenantioenriched indanone 1s (99% ee) in a single step wechanged our attention to ATH accompanying kinetic resolutionusing FA/Et3N rather than attempted ATH-DKR employing FA/DBU (Scheme 1c).
To uncover conditions that would make this process moreselective, ATH reaction of 1s was conducted under the samereaction conditions but at 23 �C rather than 40 �C for 24 h.Interestingly, the process was found to generate a 92 : 8 mixtureof cis (99% ee) and trans indanol 2s in 56% yield along with 44%of enantioenriched 3-arylindanone 1s (99% ee). These resultsshow that ATH reaction of 1s is not accompanied by DKR andthat it proceeds with kinetic resolution (KR) to generate nearequal amounts of enantioenriched 3-arylindanol 2s and 3-ary-lindanone 1swith excellent stereoselectivities for both of the cis-3-arylindanol 2s (99% ee) and recovered 3-arylindanone 1s (99%ee). Thus, the nature of 3-substituent governed lability of the
Scheme 1 ATH reactions of 3-methoxycarbonyl-1-indanone (3) and 3-aryl-1-indanone 1s.
Paper RSC Advances
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proton at C-3 center controls whether or not the ATH process isattended by DKR. This is further demonstrated by the obser-vation that treatment of enantioenriched (S)-3-methoxycarbonyl-1-indanone ((S)-3, 99% ee) with a 5 : 2 FA/TEA
mixture in the absence of C3, as expected, does not promoteformation of the reduction product 4 but instead leads toquantitative recovery of almost completely racemized indanone3 (1.3% ee) (Scheme 2a). In contrast, reaction of
a Reaction conditions: substrate (1 eq., 0.25 mmol), Cat. (1 mol%); FA : TEA(0.2 M); rt, under N2 atmosphere. b Determined by using 1H-NMR. c Dete
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enantioenriched (S)-3-arylindanone ((S)-1s) (99% ee) under thesame conditions generates (S)-1s quantitatively withouta noticeable decrease in enantiomeric purity (99% ee) (Scheme2b).
Because enantioenriched forms of variously substituted 3-arylindanols 2 and 3-arylindanones 1 are core motifs in manybioactive natural product and important intermediates in ster-eoselective syntheses of pharmaceuticals and biologically activecompounds, we extended our study to uncover optimal condi-tions for ATH reactions of racemic 3-arylindanones 1 to produce3-arylindanols and 3-arylindanones with high levels of stereo-selectivity. In the rst phase of this investigation, we exploredthe use of different commercially available chiral Ru-catalysts topromote ATH reaction of racemic 3-arylindanone 1s. ATHreaction of 1s (FA : TEA ¼ 5 : 2) using Noyori catalyst (R,R)-RuCl[TsDPEN](cymene) (C1) or (R,R)-RuCl[TsDPEN](mesitylene) (C2)was found to occur for 6 h to form 3-arylindanol 2s with 53–56%conversions (entries 1 and 2, Table 1), and slightly higherconversions take place when the reaction time is extended to24 h (65–77% conversion, entries 4 and 5). These processesproduce slightly lower cis/trans ratios of 2s compared with thosecatalyzed by (R,R)-Ts-DENEB (C3) but the conversions of 1s to 2sin ATH reactions using C3 are nearly time independent (6 h,
one 1sa
ol (2s)Indanone(1s)
ransb ee (%) of cis-2sc ee (%) of trans-2sc ee (%) of recovered 1sc
56% and 24 h, 57%) (entries 3 and 6). Because longer time (>24h) ATH reactions of 1s under acidic conditions provided by 5 : 2FA : TEA are accompanied by formation of small quantities ofundesired side-products (e.g., indenes resulting from dehydra-tion of indanol 2s), the process was carried out under non-acidicconditions using 1 : 1 or 1 : 5 FA : TEA mixtures and C3 ascatalyst. ATH reaction using 1 : 5 FA : TEA occurs in a 1s to 2sconversion of 53% aer 6 h, which remains almost the sameaer 24 h (55%, entries 9 and 10). Moreover, no indene side-products are detected in the crude product mixture using 1H-NMR analysis. An investigation of the inuence of solvents onthe ATH reaction of 1s (entries 11–17) shows that reactions inthe CH3CN, CH2Cl2, THF and EtOAc produce cis-indanol 2s inhigh ee (99% ee), but that the conversion of 1s to 2s is less than50% aer 6 h and the % ee of the recovered indanone 1s is nothigh (36–83% ee). However, reaction inMeOH for 6 h using 1 : 5FA/TEA and C3 as the catalyst (entry 17) leads to reduction ofonly (3R)-1s to form (1R,3R)-2s (50%, 99% ee) and recovery ofunreacted (3S)-1s (50%, 99% ee). In addition, when the time forreaction in MeOH is extended to 20 h, the yields and % ee's of(1R,3R)-2s (50%, 99% ee) and (3S)-1s (50%, 99% ee) remain thesame (entry 18).
Having identied optimal conditions (C3 catalyst, 1 : 5mixture of FA/TEA, in MeOH at rt for 6 h), the scope and limi-tations of the ATH-KR reaction were explored using variouslysubstituted 3-aryl-indanones. The requisite racemic 3-aryl-indanones used for this purpose were prepared by triic acid-catalyzed condensation reactions between the requisite of cin-namic acids and arenes (Scheme 3, Method A),43–45 or Pd-catalyzed intramolecular reductive Heck cyclization of the cor-responding 20-bromochalcones (Method B).46,47
The results show that 3-arylindanones 1, containing anassortment of electron-donating and -withdrawing substitu-ents, undergo ATH-KR reactions under the optimized condi-tions within 10 h to generate in most cases the correspondingcis-3-aryl-1-indanols (R,R)-2 and unreacted 3-aryl-1-indanones(S)-1 with excellent stereoselectivities (Table 2).
Most reactions reach to 50% conversion within 10 h at roomtemperature and produce almost equal amounts of the corre-sponding indanols and indanones. Moreover, extending thereaction times to more than 10 h does not affect the conversionratios and stereoselectivities (Table 1, entries 17 and 18).
Scheme 3 Synthesis of substituted 3-aryl-indanones 1.
However, in contrast to that of the unsubstituted analog, reac-tions of 3-arylindanones, containing electron-donating substit-uents such as Me or OMe on the indanone aromatic ring (Table2, entries 2–5 and 7), require slightly longer reaction times toattain 50% conversions but the stereoselectivities for both 3-aryl-1-indanol and unreacted 3-aryl-1-indanone formation areexcellent. Moreover, ATH-KR reactions of 4-Me-3-phenylindanone (1b, Table 2, entry 2) and 7-Me-3-phenylindanone (1e, Table 2, entry 5) which have Me substitu-ents near to carbonyl moiety or 3-phenyl substituent are notcomplete (<50% conversion) even aer 20 h. However, bycarrying out these reactions using 2 mol% of C3 as catalyst, 50%conversions are attained aer 6 h for 1b and 1e (entries 2 and 5).These observations suggest that not only electronic nature butalso steric factor of substituents on the indanone ring have aninuence on the ATH-KR process, perhaps by affecting forma-tion of the catalyst–substrate complex.
Unlike substituents on the indanone ring, the electronicnature and position of substituents on the 3-aryl ring do notnoticeably affect the times required to reach 50% conversion,and stereoselectivities of the 3-arylindanols 2 and recovered 3-arylindanones 1 products remain high. For example, ATH-KRreactions of 3-(2-Cl-phenyl), 3-(3-Cl-phenyl)-, or 3-(4-Cl-phenyl)-1-indanones (1h–1j) and 3-(2-Me-phenyl), 3-(3-Me-phenyl)-, or3-(4-Me-phenyl)-1-indanones (1k–1m) reach 50% conversionaer 7–8 h and produce the corresponding 3-arylindanols and3-arylindanones with excellent stereoselectivities (entries 8–13).ATH-KR reactions of 3-arylindanones containing diverseelectron-rich or electron-decient 3-aryl groups (1n–1q) proceedin a similar manner to form the corresponding 3-aryl-indanolsand unreacted 3-aryl-indanones aer 6–8 h with good stereo-selectivities (entries 14–17). 3-Arylindanones possessing varioussubstituents on both the indanone and 3-phenyl rings also aresuitable substrates for the ATH-KR reaction (entries 20–24). Theresults show that ATH-KR reactions of 3-arylindanones con-taining 3-furan (1y) and 3-thiophene (1z) substituents alsoproduce the corresponding 3-arylindanols and unreacted 3-arylindanones with similar efficiencies and stereoselectivities(entries 25 and 26). In addition, ATH-KR reaction of 1c underthe same conditions, except employing (S,S)-Ts-DENEB insteadof (R,R)-Ts-DENEB as catalyst, yields the antipodal (S,S)-3-ary-lindanol 2c (45%, 98% ee) and unreacted (R)-3-arylindanone 1c(47%, 99% ee) with excellent levels of stereoselectivity (entry 3).Similarly, ATH-KR reaction of 1s under the same conditionsusing (S,S)-Ts-DENEB as catalyst forms (S,S)-3-arylindanol 2s(47%, >99% ee) and unreacted (R)-3-arylindanone 1s (47%, 98%ee) (entries 19 and 27).
The absolute congurations of resulting 2a as (1R,3R) andrecovered 1a as (S) were determined by comparison of opticalrotations and NMR data with those of the knowncompounds.7,23,27 The stereochemical outcomes of the ATHreaction can be rationalized by the well-known attractive C–H/pinteraction48,49 in the transition state between h6 of (R,R)-Ts-DENEB catalyst (C3) and the aromatic ring moiety of inda-none 1a as shown in Fig. 2. The cis product of 2a might befavored as a consequence of 3-phenyl substituent of 1a keepingaway from the reaction site in the transition state.41
a Reaction conditions: substrate 1 (1 eq., 0.5 mmol), (R,R)-Ts-DENEB catalyst (1 mol%), FA : TEA (3 eq. : 15 eq.), MeOH (0.2 M, 2.5 mL), rt (23 �C)under N2 atmosphere. b Determined by using 1H NMR. c Yields correspond to isolated yields, % ee's were determined by chiral HPLC. Absolutestereochemistry was determined by comparison with optical rotation of known compounds. d 2 mol% of (R,R)-Ts-DENEB catalyst was used.e (S,S)-Ts-DENEB catalyst (1 mol%) was used.
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Highly enantiomerically enriched 3-aryl-1-indanols 2 and 3-aryl-1-indanones 1 produced in the ATH-KR reactions arevaluable intermediates for the synthesis of medicinally impor-tant compounds such as (+)-indatraline8 or (R)-tolterodine.50 Todemonstrate this assertion, (S,S)-3-(3,4-dichlorophenyl)-1-indanol (2s), formed by ATH-KR reaction of 1s, was convertedto (+)-indatraline viamesylation and subsequent reaction of theformed mesylate with methylamine in the same ask(Scheme 4a).7,18 In a route for the synthesis of (R)-tolterodine,a potent and competitive muscarinic antagonist that iscurrently used for the treatment of urinary urge incontinence,50
(R)-5-methyl-3-phenyl-1-indanone (1c) obtained from ATH-KRreaction of 1c was transformed to (R)-6-methyl-4-phenylcoumarine (5) via Baeyer–Villiger oxidation withoutdeterioration of optical purity (Scheme 4b). Because the
Fig. 2 Proposed asymmetric induction model41 in the ATH-KR of racem
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conversion of (R)-5 to (R)-tolterodine via DIBAL-H reduction toa lactol and subsequent reductive amination with diisopropyl-amine has been reported,7,51–53 this route constitutes a formalsynthesis of (R)-tolterodine (Scheme 4b). Finally, to demon-strate applications to the synthesis of quinoline derivatives,treatment of (S)-3-(3,4-dichlorophenyl)-1-indanone oxime O-tosylate (6), obtained from (S)-1s, using 1.5 equiv. of AlCl3 atroom temperature,54 produces the readily separable mixture of(S)-4-aryl-3,4-dihydroquinoline-2(1H)-one ((S)-7) and (S)-4-aryl-3,4-dihydroisoquinoline-1(2H)-one ((S)-8).
Conclusions
In summary, this effort demonstrates that efficient kineticresolution (KR) attends asymmetric transfer hydrogenation
(ATH) reactions of diverse racemic 3-aryl-1-indanones whencommercial (R,R)- or (S,S)-Ts-DENEB is employed as catalyst,a 1 : 5 mixture of HCO2H and Et3N is used as a hydrogen sourceand MeOH is utilized as solvent. These processes, carried out atroom temperature, produce near equal amounts of the corre-sponding cis-3-arylindanols and unreacted 3-arylindanoneswith excellent levels of diastereo- and enantio-selectivity. Thekey merit of the process is that it forms both highly enantio-merically enriched cis-3-arylindanols and 3-arylindanones ina single step. In addition, selected stereoselective trans-formations of 3-arylindanol and 3-arylindanones generated bythe ATH-KR process, demonstrate the usefulness of this methodin producing key intermediates for the preparation of(+)-indatraline, (R)-tolterodine, (S)-4-aryl-3,4-dihydroquinoline-2(1H)-one and (S)-4-aryl-3,4-dihydroisoquinoline-1(2H)-one.
Experimental sectionGeneral
Synthetic procedure and characterization data of starting 3-aryl-1-indanones 1a–1z are included in the ESI.† All reactionswere conducted under an inert atmosphere of nitrogen usinganhydrous solvents. Mixtures of HCO2H/Et3N (5 : 2 and 1 : 1)are commercially available and 1 : 5 mixture of HCO2H/Et3N
was prepared by adding 1 equiv. of Et3N to 5 equiv. of HCO2Hat 0 �C under a nitrogen atmosphere and used as such. Chiraltransition metal catalysts C1–C3 were purchased fromcommercial vendors. The progress of reactions was moni-tored using thin layer chromatography (TLC) and visualizedusing UV light and by staining with ethanolic phosphomo-lybdic acid (PMA) solution or ninhydrin solution followed byheating. Flash column chromatography was carried out onsilica gel (38–75 mm). Analytical thin layer chromatography(TLC) was performed on Merck silica gel 60 F254 plates.Preparative thin layer chromatography (PLC) was performedon Merck silica gel 60 F254 2 mm plates. Syntheses undermicrowave system were conducted by using CEM Discover SP.Nuclear magnetic resonance (NMR) spectra were recordedusing Bruker 500 MHz NMR instrument (1H NMR at 500 MHzand 13C NMR at 125 MHz) or Bruker 400 MHz NMR instru-ment (1H NMR at 400 MHz and 13C NMR at 101 MHz). 1HNMR data are reported as follows: chemical shi (d, ppm),multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,m ¼ multiplet, br ¼ broad), integration, coupling constants(Hz). Data for 13C NMR are reported in terms of chemical shi(d, ppm). High performance liquid chromatography (HPLC)was carried out on a Young Lin HPLC system (7725i Injector,
SDV 30 Plus Solvent Degassor & Valve Module (HeliumSparging), SP930D Solvent Delivery Pump, UV 730D Absor-bance Detector) equipped with a Chiralpak IA, IB, IC, ID orChiralpak AD-H, Chiralcel OD-H column. Specic rotationswere measured on a Rudolph Autopol IV (Automatic polar-imeter). High-resolution mass spectra and elemental analysiswere obtained from the Korea Research Institute of ChemicalTechnology. HR-MS were measured with electron impact (EI)via double focusing mass analyzer (magnetic and electricelds) or electrospray ionization (ESI) via time of ight (TOF)analyzer.
Representative procedure for the ATH of 3-phenyl-1-indanone(1a) accompanying kinetic resolution
To a solution of 3-phenyl-1-indanone (1a, 104 mg, 0.5 mmol)and triethylamine (1.06 mL, 7.5 mmol) dissolved in methanol(1.5 mL) was added formic acid (63.4 mL, 1.5 mmol) followedby (R,R)-Ts-DENEB catalyst (3.2 mg, 0.005 mmol dissolved in1.0 mL of methanol). The reaction mixture was stirred at25 �C under of N2 atmosphere. Aer the reaction time spec-ied in the Table 2 (6–14 h), the reaction mixture was dilutedwith chloroform (30 mL) and washed with water and brine (20mL) successively. The organic layer was dried with MgSO4,ltered and concentrated by rotary evaporation. The resultingmixture of 3-phenyl-1-indanol (2a) and unreacted remaining1a were easily separated by ash column chromatography(ethyl acetate : n-hexane 1 : 7). dr and ee's of the resultingindanol 2a and unreacted remaining indanone 1a weredetermined by chiral HPLC. (Racemic cis- and trans-3-phenyl-1 indanols (2a) were obtained by NaBH4 reduction of 1a inMeOH.) Absolute congurations were determined bycomparison of optical rotations and NMR data with those ofthe known compounds.
(1R,3R)-3-Phenyl-2,3-dihydro-1H-inden-1-ol (2a)
Yield 45% (46.7 mg as white solid); mp 95.2–95.9 �C; 97% ee(Chiralpak IB, 0 to 6% IPA for 7 min in n-hexane, 1 mL min�1,270 nm, tR(major) ¼ 23.2 min, tR(minor) ¼ +16.9 min); [a]24D ¼�15.6 (c 1.13, CH2Cl2). Literature values: [a]23D ¼ �11 (c 1,CHCl3 for 95% ee).27 [a]23D ¼ +16.1 (c 0.1, CH2Cl2 for 86% ee)23
Yield 43% (48.2 mg as white solid); mp 122.6–123.3 �C; 95% ee(Chiralpak IB, 0 to 6% IPA for 7 min in n-hexane, 1 mL min�1,270 nm, tR(major)¼ 16.6min, tR(minor)¼ 25.4min); [a]29D ¼�5.6 (c2.4, CH2Cl2);
Yield 47% (52.2 mg as white solid); >99% ee (Chiralpak IB,0 to 6% IPA for 7 min in n-hexane, 1 mL min�1, 270 nm,tR(major) ¼ 16.0 min, tR(minor) ¼ 15.1 min); [a]21D ¼ �29.4 (c1.7, CH2Cl2). Literature values for (S)-1c: [a]23D ¼ +28.9� (c 1.0,CHCl3 for 97% ee).7 [a]25D ¼ +20.3 (c 0.1, CH2Cl2 for 86% ee);23
Yield 49.7% (53.2 mg, brown solid); mp 54.8–55.0 �C; 94% ee(Chiralpak IB, 0 to 5% EtOH for 7 min in n-hexane, 1 mL min�1,270 nm, tR(major) ¼ 34.5 min, tR(minor) ¼ 16.4 min); [a]21D ¼�3.0 (c 2.4, CH2Cl2). Literature value for (S)-1z: [a]
Synthesis of (1R,3S)-3-(3,4-dichlorophenyl)-N-methyl-2,3-dihydro-1H-inden-1-amine, (+)-indatraline7
A solution of (1S,3S)-3-(3,4-dichlorophenyl)-2,3-dihydro-1H-inden-1-ol (2s) (87 mg, 0.3 mmol) and triethylamine (210 mL, 1.5 mmol)dissolved in anhydrous THF (3.0 mL) was cooled to �20 �C andmethananesulfonyl chloride (70 mL, 0.9 mmol) was added drop-wise. The reaction mixture was stirred at�20 �C for 1 h. Then 2 Msolution of methylamine in THF (3.75 mL 7.5 mmol) was addedslowly over 30min. The reactionmixture was allowed to warm to rtand stirred 18 hours. The solvent was removed by rotary evapora-tion, and EtOAc (10mL) andwater (10mL) were added. The phases
were separated and the aqueous layer was re-extracted with EtOAc(20 mL � 3) and the combined organic layers were washed withbrine (40 mL), dried over anhydrous MgSO4, concentrated byrotary evaporation. The crude residue was puried by silica-gelcolumn chromatography (EtOAc : Et3N ¼ 95 : 5) to give (+)-inda-traline (56.6 mg, 65%) as a yellow oil.
Yield 65% (56.6 mg as a yellow oil); [a]27D ¼ �18.6 (c 0.1, CHCl3).Literature value [a]22D ¼ �18.9 (c ¼ 1.1, CHCl3);19
Synthesis of (R)-6-methyl-4-phenylchroman-2-one [(R)-5]27
To a solution of (R)-1c (90 mg, 0.4 mmol) and p-toluenesulfonicacid (19.5 mg, 0.09 mmol) in CH2Cl2 (6 mL) was added m-CPBA(443 mg 1.76 mmol) portionwise. The solution was heated toreux for 24 hours. Aer cooling to room temperature, thereaction mixture was quenched with saturated aqueousNaHCO3 (10 mL) and Na2S2O3 (10 mL) and extracted with EtOAc(20 mL � 3). The combined organic layers were dried overanhydrous MgSO4 and concentrated by rotary evaporator. Thecrude residue was puried by ash column chromatography onsilica-gel (EtOAc : n-hexane 1 : 10) to provide (R)-5 as a whitesolid (65%, 65 mg).
Yield 65% (65 mg, as white solid); mp 85.1–85.9 �C; 99% ee(Chiralpak IB, 0 to 6% IPA for 7 min in n-hexane, 1 mL min�1,270 nm, tR(major) ¼ 18.9 min, tR(minor) ¼ 17.9 min); [a]27.6D ¼�2.36 (c 0.9, CHCl3). Literature values [a]15.8D ¼ �3.6 (c 1.0,CHCl3 for 99% ee).55 [a]20D ¼ �2.24 (c 0.35, CHCl3 for 98% ee);561H NMR (CDCl3, 400 MHz): d 7.4 (t, 2H, J ¼ 7.4 Hz), 7.3 (d, 1H, J¼ 7.2 Hz), 7.2 (d, 2H, J ¼ 7.2 Hz), 7.1–7.1 (m, 1H), 7.0 (d, 1H, J ¼8.2 Hz), 6.8–6.7 (m, 1H), 4.3–4.2 (m, 1H), 3.1–2.9 (m, 2H), 2.3 (s,
A suspension of hydroxylamine hydrochloride (144 mg, 2.1mmol) and NaOAc (212 mg, 2.6 mmol) in 80% aqueous EtOH(20 mL) was stirred at rt for 30 min. (S)-3-(3,4-dichlorophenyl)-2,3-dihydro-1H-inden-1-one ((S)-1s) (360 mg 1.3 mmol) wasadded and the reaction mixture was heated gently to reux for2 h. Aer cooling to rt, the solvent was evaporated undervacuum and the residue was diluted with EtOAc (60 mL) andwashed with water (30 mL) and brine successively. The organiclayer was dried over anhydrous MgSO4, and concentrated byrotary evaporation. The crude oxime product (ca. 353 mg) wasused in the next step without further purication. To a stirredsolution of 1-indanone oxime (300 mg, ca.1.0 mmol) and p-toluenesulfonyl chloride (225 mg, 1.1 mmol) in 3 mL of acetonewas added 4 N NaOH (0.5 mL) solution dropwise at �10 �C.Aer 5 min, the cooling bath was removed and the reactionmixture was stirred for 2 h at rt. Then the reaction mixture waspoured into 50 g of ice and extracted with EtOAc (30 mL � 3).The combined extracts were dried over anhydrous MgSO4 andconcentrated by rotary and the resulting residue was puried byash chromatography (EtOAc : n-hexane 1 : 5) on silica-gel togive (E)-indanone oxime-O-tosylate ((S)-6, 360 mg, 78%) asa white solid. To a solution of (E)-indanone oxime-O-tosylate((S)-6, 100 mg, 0.22 mmol) in CH2Cl2 (3 mL) at �40 �C wasadded AlCl3 (49 mg, 0.34 mmol) portionwise. The reactionmixture was stirred for 30 minutes at that temperature andallow to warm to rt. The reaction mixture was stirred for addi-tional 2 h. Then, water (15 mL) was added carefully forquenching, and extracted with EtOAc (30 mL � 3). Thecombined organic layers were washed with brine (40 mL), driedover anhydrous MgSO4 and concentrated by rotary evaporation.The crude residue was puried by ash column chromatog-raphy on silica-gel (EtOAc : n-hexane 1 : 3) to give (S)-7 (26.8 mg,41% yield), and (S)-8 (23.1 mg, 35% yield). Rf for (S)-7 ¼ 0.2 andRf for (S)-8 ¼ 0.1 (EtOAc : n-hexane 1 : 2).
This research was nancially supported by grants from theNational Research Foundation of Korea (2017M3A9A5051181) andKorea Research Institute of Chemical Technology (SI2151-20).
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