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Tetrahedron 69 (2013) 9322e9328

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Tetrahedron

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Synthesis of new chiral 2-functionalized-1,2,3,4-tetrahydroquinolinederivatives via asymmetric hydrogenation of substituted quinolines

Anna M. Maj a,e,*, Isabelle Suisse a,c,e, Christophe Hardouin d,Francine Agbossou-Niedercorn a,b,e,*

aUniversit�e Lille Nord de France, F-59000 Lille, FrancebCNRS, UCCS UMR 8181, F-59655 Villeneuve d’Ascq, FrancecUniversit�e Lille 1, Sciences et Technologies, F-59655 Villeneuve d’Ascq, FrancedOril Industrie, 13, rue Auguste Desgen�etais, 76210 Bolbec, Francee ENSCL, UCCS e CCM e CCCF, Av. Mendeleïev, CS90108, F-59652 Villeneuve d’Ascq, France

a r t i c l e i n f o

Article history:Received 11 June 2013Received in revised form 23 July 2013Accepted 29 July 2013Available online 3 August 2013

Keywords:Asymmetric hydrogenationHeterocyclesQuinolinesIridium

* Corresponding authors. E-mail addresses: anna.francine.agbossou@ensc-lille.fr (F. Agbossou-Niederco

0040-4020/$ e see front matter � 2013 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2013.07.090

a b s t r a c t

The asymmetric hydrogenation of a series of quinolines substituted by a variety of functionalized groupslinked to the C2 carbon atom is providing access to optically enriched 2-functionalized 1,2,3,4-tetrahydroquinolines in the presence of in situ generated catalysts from [Ir(cod)Cl]2, a bisphosphine,and iodine. The enantioselectivity levels were as high as 96% ee.

� 2013 Elsevier Ltd. All rights reserved.

1. Introduction

Chiral amines are ubiquitous building blocks found in manybioactive compounds, such as pharmaceuticals and agrochemicals.Because chiral heterocyclic compounds are structures of interestpresent in natural and synthetic products with biological, agro-chemical, and pharmaceutical properties,1 the asymmetric hydro-genation of the parent heteroaromatic derivatives has beenextensively investigated.2 Actually, chiral heterocyclic compoundsobtained from efficient asymmetric hydrogenation of quinolines,3

isoquinolines,4 quinoxalines,5 indoles,6 pyrroles,7 pyridines,8 oxa-zoles,9 furans,10 benzofurans,11 and thiophenes12 have been re-ported. The hydrogenation of quinolines was first described byZhou, who published, a decade ago, the highly efficient iridium-catalyzed asymmetric hydrogenation of 2-substituted alkyl quino-lines.3a The hydrogenation was performed with iridium catalystsgenerated from [Ir(cod)Cl]2 and the atropisomeric diphosphineMeOeBiphep. From this pioneering work, a variety of iridium cat-alysts bearing chiral ligands, such as, for example, diphosphines,3e,13

maj@ensc-lille.fr (A.M. Maj),rn).

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phosphine-phosphites,14 phosphinites,15 monodentate phospho-rous ligands,16 phosphine-phosphoramidites,17 P,N-ligands,18 butalso phosphine-free and organocatalytic systems,18 have been de-veloped for this transformation. The substrate scope comprises es-sentially 2-substituted quinolines bearing aryl, alkyl, or benzylresidues. Quinolines bearing ketone, ester, amide, or benzene sul-fonyl functionalities have also been considered. Nevertheless, theadditional functionality was generally connected to the N-hetero-aromatic unit via a methylene spacer. Regardless the excellent re-sults obtained with such type of derivatives, the substrate scopedeserves to be extended to other functionalized scaffolds eventuallydirectly connected to the C2 carbon atom in order to further increasethe potential of this methodology. As part of our ongoing researchtoward the use of catalyzed asymmetric transformations for thesynthesis of biologically relevant targets,6c,19 and taking into accountthe scarce examples of spacer free 2-functionalized tetrahy-droquinolines, we thought to investigate valuable new 2-functionalized quinoline substrates.

Herein, we report on our investigation based on Ir-catalyzedhydrogenation of a series of quinolines, which have not beenstudies yet (Fig. 1). Hydrogenations of quinoline carboxylates 2e5,hydroxymethylene quinoline 7, bromoquinoline 8, and amino-derivative 14 have been reported recently.19e

Fig. 1. 2-Functionalized quinoline substrates studied in this work.

A.M. Maj et al. / Tetrahedron 69 (2013) 9322e9328 9323

2. Results and discussion

Five of the selected substrates were commercially available (1, 2,3,10, and 11). The others were prepared easily by applying standardtransformations (Fig. 1, Scheme 1).

Scheme 1. Synthesis of the substrates.

The esters 4e6 were obtained by transesterification of the com-mercial methyl-quinolone-2-carboxylate 2 in the presence of a cat-alytic amount of cesium carbonate in the appropriate alcohol(80e90% yield). Alcohol 7 could be obtained by reduction of the ester2 with sodium borohydride (73% yield). Chloro 8 and bromo 9compounds were obtained from alcohol 7 by reaction with SOCl2and PBr3, 76 and 83% yield, respectively. The synthesis of the diBocsubstrate 14 has been carried out by reaction of 2-(bromomethyl)quinoline 9 with di-tert-butyliminodicarboxylate in the presence ofcesium carbonate (80% yield). The three substrates 12, 13, and 15were obtained from 14. Thus, the cleavage of one Boc residue of 14was performed in the presence of lithium bromide at 65 �C for 1 h,furnishing 13 in 89% yield after purification.20 The complete depro-tection of 14 into 15was carried out in acidic ethanol with 90% yield.Then, 2-aminomethylquinoline 12 was obtained in 82% yield fromreaction of 15 with sodium hydroxide. Substrate 15 could also beobtained from nitrile 10 applying a hydrogenation over Pd/C fol-lowed by a protonation in 58% overall yield21 (Scheme 1).

For our initial hydrogenation experiments, we examined thereduction of acid 1 and methyl ester 2. Hydrogenations were per-formed in the presence of [Ir(cod)Cl]2, a diphosphine (Fig. 2), I2 asan additive, in toluene under 50 bar H2 at 20 �C.3a The results arereported in Table 1.

When acid 1was hydrogenated in the presence of ligand L1, thereaction proceeded smoothly with 90% conversion within 17 h and

82% yield into the 1,2,3,4-tetrahydroquinolic acid 16 (entry 1, Table1). An enantiomeric excess of 41% was determined on the corre-sponding methyl ester 17 obtained after esterification of the hy-drogenation product 16 (SOCl2/MeOH) (entry 1). Under identicalconditions, ester 2 led to 17 in 88% yield and 66% ee (entry 2). Onthis basis, a screening of ligands was then carried out specifically onthe hydrogenation of 2. Conversions were ranging from 7 to 100%,selectivities into 17 from 2 to 98%, and ee’s from 0 to 74%. Amongthe array of ligands employed, some iridium catalysts bearingspecific atropisomeric diphosphine led to the best results in termsof conversion and enantioselectivity. Indeed, 66, 74, and 72% eewere measured in the presence of MeOeBiphep L1, Difluorphos L7,and P-Phos L8, respectively (entries 2, 8, and 9). However, SynphosMeOeCleBiphep L2 and L5 led to only 36% and 25% ee, respectively(entries 3 and 6). Low catalytic activities were noticed with BinapL3, C3-Tunephos L4, Me-Duphos L15, and the ferrocene basedTaniaphos SL-T002 L17 and SL-T001 L16 ligands (entries 4, 5,14e16). On the other side, Et-FerroTANE L14 allowed a good yield(80%) but the ee remained low (11%) (entry 13). Finally, in thepresence of CatASium�T3 L13, although the conversion and yieldare good, a poor ee was measured (11%, entry 12).

Next, we concentrated on the most appropriate ligands andapplied them in the hydrogenation of other substrates, i.e., esters3e6, quinolin-2-ylmethanol 7, and halogenated 8 and 9 (Table 2).

Except for substrate 8 (entry 16), all quinolines could be hy-drogenated selectively under the applied conditions. From thecomplex reactions mixture obtained from 8, we could identifythe dehalogenated hydrogenated product 2-methyl-1,2,3,4-tetrahydroquinoline. In the case of the ethyl ester 3, the best re-sults are obtained with the Difluorphos L7 and P-Phos L8 ligandsreaching 94 and 88% ee, respectively (entries 4 and 7). These valuesshould be compared to the results obtained with methyl ester 2: 74and 72% ee in the presence L7 and L8, respectively (entries 8 and 9,Table 1). The much higher ee obtained with the ethyl ester showsthat a slight increase of the steric hindrance on the ester residuecould affect significantly the stereoselectivity outcome of thetransformation. Nonetheless, this was not a general trend as in thepresence of the MeOeBiphep ligand L1, the ee for the ethyl ester 18hydrogenation was only 58% compared to 66% obtained for thereduction of 17 (entry 2, Table 1 vs entry 1, Table 2). A further in-crease of the steric hindrance of the ester group in going from ethylto propyl resulted in a small erosion of the enantioselectivity (entry9). A high level of enantioselectivity was obtained again during thehydrogenation of isobutyl ester 6 in the presence of P-Phos L8 li-gand at 20 �C (98% yield, 94% ee) (entry 11). By decreasing the re-action temperature to 5 �C, the enantioselectivity increased to 96%ee (entry 12). In the case of the 2-hydroxymethylquinoline 7, be-cause of the low solubility of this substrate in neat toluene, we useda mixture of toluene/iPrOH as solvent. The stereoselectivity wasinteresting with a maximum of 84% ee in the presence of Difluor-phos ligand L7 (entry 14). Finally, 2-bromomethylquinoline 9 hasbeen studied. As in the case of the chloromethylquinoline 8, 2-methyl-1,2,3,4-tetrahydroquinoline was observed as by-product(82e90% ee19e). The higher ee obtained for this side product sug-gests that the cleavage of the bromide is occurring most probablyprior to hydrogenation of the quinoline heterocycle. The bestcompromise between yield and enantioselectivity was obtained inthe presence of the ligand L8 (100% yield, 81% ee, entry 19). Hy-drogenation of ethyl ester 3 has been performed on gram scale inthe same reaction conditions (50 bar H2 and T¼20 �C) and led after17 h to 100% yield into the corresponding ester 18 and to the samelevel of enantioselectivity (92% ee).

In our preliminary communication, we reported on the hydro-genation of the N,N-diBoc-2-yl-methanamine 14 providing up to91% ee.19e We extended our study and examined the nitrogenfunctionalized substrates 10e15 in the presence of the best chiral

Fig. 2. Ligands investigated in the hydrogenation of quinoline substrates.

Table 1Asymmetric hydrogenation of acid 1 and methyl ester 2a

Entry Substrate Ligand t (h) Conv.b (%) Yieldc (%) eec (%)

1 1 L1 17 90 82 41 (R)d

2 2 L1 48e 100 88 66 (R)3 2 L2 17 75 70 36 (S)4 2 L3 17 72 63 13 (S)5 2 L4 48 45 43 29 (S)6 2 L5 17 100 98 25 (S)7 2 L6 17 76 63 43 (S)8 2 L7 17 100 95 74 (S)9 2 L8 17 94 89 72 (S)10 2 L9 17 95 87 55 (S)11 2 L10 17 64 60 10 (S)12 2 L13 48 96 72 11 (S)13 2 L14 17 97 80 11 (R)14 2 L15 17 7 2 n.d.15 2 L16 17 91 84 22 (S)16 2 L17 17 21 10 0

a All reactions were performed on a 1 mmol scale; S/Ir/L/I¼100/1/1.1/10;PH2¼50 bar; 20 �C; toluene 7 mL.

b Conversion determined by GC and NMR.c Yield and ee of 17 determined by HPLC analysis on Chiralcel OJ-H column

(hexane/iPrOH 70:30, 1 mL/min); configuration not determined. By-products havenot been identified.

d Determined on the methyl ester 17 after esterification of the tetrahydroquinolicacid 16.

e Time not optimized.

Table 2Asymmetric hydrogenation of 2-functionalized quinolines 3e9a

Entry Substrate Ligand Conv.b (%) Yieldc (%) eec (%)

1 3 L1 94 89 582 L5 100 100 643 L6 100 100 644 L7 99 94 945 L11 88 88 466d L12 83 83 377 L8 99 94 888 L10 14 12 39 4 L7 100 100 9010 5 L7 100 100 7511 6 L8 100 98 9412e L7 97 97 9613f 7 L6 100 100 8014f L7 97 97 8415f L9 100 100 7016f,g 8 L8 Mixture of products17f,g 9 L6 100 44 7918g L7 100 65 6919 L8 100 100 81

a All reactions were performed on a 1 mmol scale; S/Ir/L/I¼100/1/1.1/10;PH2¼50 bar; 20 �C; toluene 7 mL; 17 h.

b Conversion determined by GC and NMR.c Yield and ee determined by HPLC analysis: 18e21: Chiralcel OJ-H column

(hexane/iPrOH 70:30, 1 mL/min); 22: Chiralcel OD column (hexane/iPrOH 90:10,1 mL/min); 24 Chiralcel OD column (hexane/iPrOH 98:2, 1.5 mL/min); configurationnot determined.

d t¼3 days.e T¼5 �C.f Solvent: toluene/iPrOH: 7/1: 8 mL.g 2-Methyl-1,2,3,4-tetrahydroquinoline is observed as by-product.

A.M. Maj et al. / Tetrahedron 69 (2013) 9322e93289324

ligands of the series explored in this work L6, L7, and L8. The resultsare reported in Table 3.

We first examined the hydrogenation of the commercial sub-strates 10 (Table 3, entry 1). The hydrogenation of 10 led to 50%

Table 3Hydrogenation of quinoline derivatives 10e15a

Entry Substrate Ligand PH2 (bar) t (h) Conv.b (%) Yieldb (%) eec (%)

1 10 L8 50 17 50 nd d

2 11 L8 50 17 92 92 543d L7 50 17 100 100 624d L8 50 17 100 100 625 12 L7 50 24 0 d d

6 L8 70 48 20 0 d

7 L6 100 72 0 d d

8 13 L7 50 17 100 100 899 L8 50 17 100 100 8410 L6 50 17 100 100 8411 14 L7 50 17 100 100 8312 L8 50 17 100 100 8513 L6 50 17 100 100 8714d L6 50 17 100 100 9115e 15 L7 70 60 79 79 42f

16e L8 70 72 85 74 65f

17e L6 70 96 90 90 55f

a All reactions were performed on a 1 mmol substrate scale; S/Ir/L/I2¼100/1/1.1/5; 20 �C; toluene 8 mL; 17 h.

b Determined by GC and NMR.c Determined by HPLC: 26, Chiralcel OD (hexane/iPrOH 90:10, 1 mL/min),

T¼20 �C; 27, Chiralcel OD (hexane/iPrOH 98:2, 0.2 mL/min), T¼22 �C; 28: ChiralcelOJ-H (hexane/iPrOH 90:10, 1mL/min), 20 �C; 30: Chiralcel AD-H (hexane/iPrOH/DEA95:5:0.1, 1 mL/min), T¼7 �C; Configuration not determined.

d T¼0 �C.e Toluene/iPrOH: 8/1.f Cs2CO3 (0.62 mmol); determined on the amine 27 after neutralization of the

chlorohydrate 30 with sodium hydroxide 1 N.

100 100 100 100

92

8789 90 91 91

70

75

80

85

90

95

100

20 10 5 0 -5

T ( C)

Conv. (%) ee (%)

Fig. 3. Asymmetric hydrogenation of 14: influence of the temperature.

A.M. Maj et al. / Tetrahedron 69 (2013) 9322e9328 9325

conversion, several products being formed. A LCeMS analysisprobed the presence of the double hydrogenation product (C]Cand CN reduction) and remaining substrate 10. However, the hy-drogenated product was difficult to quantify. Two other productscould also be identified in the reaction mixture, i.e., the 2-quinolinemethanamine, which results from the sole reduction ofthe nitrile functionality and 2-methyl-1,2,3,4-tetrahydroquinoline,which is produced by heteroaromatic ring hydrogenation andcleavage of the amino residue. We varied some reaction conditions,i.e., the ligand (L7 and L6), the pressure (from 50 to 100 bar), thetemperature (from 20 to 70 �C), Cs2CO3 as an additive. Un-fortunately, results could not be improved.

We next studied the hydrogenation of the amide 11. This re-action has already been reported in a racemic way over Adam’scatalyst22 (PtO2, EtOH, HBraq, 20 �C) but, to our knowledge, noasymmetric version was reported. Under our reaction conditions,i.e., toluene as the solvent and (R)-P-Phos L8 as the ligand, theconversion of 11, after 17 h, was 92% with 54% ee (entry 2). Theincomplete conversion of the substrate can be attributed to therelatively poor solubility of 11 in toluene. Indeed, when usinga mixture of toluene/iPrOH, after 17 h, a complete transformationwas effectively observed with a slightly higher enantioselectivity(62% ee) (entry 3). In the presence of ligand L8, no improvement ofthe selectivity was observed (62% ee, entry 4).

In the case of the NHBoc and NBoc2 substrates (13 and 14), theconversions were complete within 17 h. The ee values were in the83e89% range (entries 8e13). We also examined the effect of thetemperature on the hydrogenation of 14 in the presence of thecatalytic system [Ir(cod)Cl]2/L6 (Fig. 3). The highest ee values weremeasured at 0 and �5 �C (91% ee, entry 14). But at �5 �C, theconversion dropped to 92%. On the other side, substrate 13 was

totally hydrogenated with 89% ee whatever the temperature be-tween 20 and �5 �C in the presence of ligand L7. No reaction oc-curred with the amine free substrate 12 (entry 5). When increasingthe pressure to 70 bar, the substrate was consumed partly, but thehydrogenated compound could not be detected in the mixture ofotherwise unidentified products (entry 6).

When the corresponding bischlorohydrate substrate 15 wasreacted in the presence of Cs2CO3, product formed very slowly asonly 79% conversion was obtained after 60 h at 20 �C under 70 barof hydrogen and with a moderate enantioselectivity (42% ee) (entry15). Results could be improved in terms of enantioselectivity in thepresence of L6 and L7 ligands (65 and 55% ee, entries 16 and 17).

3. Conclusion

In summary, chiral 2-functionalized-1,2,3,4-tetrahydro-quino-line derivatives could be obtained by catalytic asymmetric hydro-genation of the corresponding quinoline precursors in the presenceof in situ generated catalysts obtained from [Ir(cod)Cl]2, a bisphos-phine, and iodine I2. On one hand, the best results were obtainedwith the two amine protected substrates bearing NHBoc 13 andNBoc2 14 groups. Selectivities up to 91% could then be achieved. Onthe other hand, asymmetric hydrogenation of various quinolinecarboxylates has been successfully performed with levels ofenantioselectivity as high as 96%. High levels of reactivity andenantioselectivity obtained on gram scale allow to display a highpotential of this transformation for an industrial application.

4. Experimental

4.1. General information

All reactions were carried out under an inert nitrogen atmo-sphere using standard Schlenk techniques. Toluene and iso-propanol were obtained from a solvent purification systemMBraunSPS-800. Methanol was distilled over magnesium. All solvents weredegassed prior to use. 1H (300 MHz) and 13C (75 MHz) NMR spectrawere recorded using a Bruker AC 300 spectrometer. Analytical thinlayer chromatography (TLC) was carried out using commercial sil-ica gel plates (Merck 60 F 254), spots were determined with UVlight. Conversions were determined by gas chromatography ona Varian 430-GC apparatus equipped with a CP Sil 5 CB column(25 m, i.d.¼0.32 mm) and by NMR experiments. Enantiomeric ex-cesses were determined by HPLC analyses with a ThermofinniganSpectra System at 254 nm or 304 nm. The analyses were performedusing Chiralpak OJ-H, AD-H, or OD columns. Melting points weredetermined using a Barnstead Electrothermal (BI 9300) apparatusand were uncorrected. Elemental analyses were performed at theUniversity Lille Nord de France on an Elementar, Vario Micro cubeapparatus. HRMS analyses were performed on an Exactive ThermoScientific spectrometer at CUMA-Pharm. Dept., University LilleNord de-France.

A.M. Maj et al. / Tetrahedron 69 (2013) 9322e93289326

4.2. Synthesis of substrates

Propyl quinoline 2-carboxylate 4, isopropyl quinoline 2-carboxylate 5, and isobutyl quinoline 2-carboxylate 6 were ob-tained by transesterification of methyl ester 2.

General procedure: Themethyl ester 2 (1 g, 5.1mmol) was stirredin the selected alcohol (25 mL) in the presence of cesium carbonate(0.05 g, 0.15 mmol) for 24 h at ambient temperature. The progressof the reaction was followed by TLC. At the end of the trans-esterification, the solvent was evaporated, water (20 mL) wasadded and the crude residue was extracted with ethyl acetate(5�25 mL). The solution was then dried over magnesium sulfateand evaporated to dryness.

4.2.1. Propyl quinoline 2-carboxylate 4. Light yellow solid; 80%yield;mp 45 �C; 1HNMR (300MHz, CDCl3) 0.98 (3H, t, J 7.1 Hz, CH3),1.83 (2H, m, CH2), 4.38 (2H, m, CH2), 7.57 (1H, m, CHar), 7.72 (1H, m,CHar), 7.81 (1H, m, CHar), 8.10 (1H, m, CHar), 8.25 (2H, m, CHar); 13CNMR (75 MHz, CDCl3) 10.43, 22.11, 67.77, 121.09, 127.51, 128.56,129.32, 130.28, 130.86, 137.27, 147.61, 148.28, 165.51; HRMS (ESI)m/z calculated for C13H14NO2 [MþH]þ: 216.1019, found: 216.1018.

4.2.2. Isopropyl quinoline 2-carboxylate 5. Yellow oil; 80% yield; 1HNMR (300 MHz, CDCl3) 1.41 (6H, d, J 8.1 Hz, CH3), 5.34 (1H, m, CH),7.58 (1H, m, CHar), 7.71 (1H, m, CHar), 7.80 (1H, m, CHar), 8.09 (1H,m, CHar), 8.24 (2H, m, CHar); 13C NMR (75 MHz, CDCl3) 21.91, 69.89,121.02, 127.43, 128.48, 129.23, 130.10, 130.89, 137.18, 147.72, 148.63,164.86; HRMS (ESI) m/z calculated for C13H14O2N [MþH]þ:216.1019, found: 216.1017.

4.2.3. Isobutyl quinoline 2-carboxylate 6. White solid; 90% yield; 1HNMR (300 MHz, CDCl3) 1.00 (6H, d, J 7.5 Hz, CH3), 2.21 (1H, m, CH),4.28 (2H, m, CH2), 7.65 (1H, m, CHar), 7.71 (1H, m, CHar), 7.80 (1H, m,CHar), 8.09 (1H, m, CHar), 7.65 (1H, m, CHar), 7.80 (1H, m, CHar), 8.17(1H, m, CHar), 8.32 (1H, m, CHar); 13C NMR (75 MHz, CDCl3) 19.32,27.94, 72.05, 120.95, 127.55, 129.30, 130.26, 130.85, 137.34, 147.66,148.25, 165.28; HRMS (ESI) m/z calculated for C14H16O2N [MþH]þ:230.11760 found: 230.11700.

4.2.4. Quinolin-2-ylmethanol 7. Methyl quinoline 2-carboxylate 2(5 g, 26.8 mmol) in solution in THF (30 mL) was added, at roomtemperature, to a solution of NaBH4 (710 mg, 18.8 mmol) in THF(20 mL). The mixture was stirred at 35 �C for 30 min. Then, at 35 �C,methanol (2.5mL) was added followed bywarmwater (30mL), andfinally ethyl acetate (20 mL). The organic layer was washed withwater (2�30 mL). The organic phase was dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. Thecrude yellow-blue residue was purified through a silica gel columnchromatography (AcOEt/MCH: 60/40). White solid; 73% yield; mp135 �C (dec); 1H NMR (300MHz, CDCl3) 4.68 (1H, s, OH), 4.95 (2H, s,CH2), 7.31 (1H, m, CHar), 7.55 (1H, m, CHar), 7.71 (1H, m, CHar), 7.81(1H, m, CHar), 8.10 (2H, m, CHar); 13C NMR (75 MHz, CDCl3) 64.25,118.43, 126.35, 127.55, 127.69, 128.57, 129.81, 136.86, 146.72, 159.19;Anal. Calcd for C10H9NO C, 75.45; H, 5.70; N, 8.80. Found C, 75.13; H,5.56; N, 8.75.

4.2.5. 2-(Chloromethyl)quinoline 8. Quinolin-2-ylmethanol 7 (4 g,25.1 mmol) was dissolved in CH2Cl2 (40 mL). SOCl2 (1.83 mL,25.1 mmol) was carefully added at 0 �C to this solution. Themixturewas allowed to return at ambient temperature and water (30 mL)was added followed by a saturated aqueous solution of K2CO3(12 mL). The organic layer was washed with brine (2�30 mL) andconcentrated under reduced pressure. The crude residue was pu-rified through a silica gel column chromatography (AcOEt/MCH:30/70). White solid; 76% yield; 1H NMR (300MHz, DMSO) 4.96 (2H,s, CH2), 7.68 (2H, m, CHar), 7.79 (1H, m, CHar), 8.00 (2H, m, CHar),

8.42 (1H, m, CHar); 13C NMR (75 MHz, DMSO) 47.77, 121.55, 127.49,127.56, 128.37, 129.13, 130.52, 137.91, 147.33, 157.29.

4.2.6. 2-(Bromomethyl)quinoline 9. Quinolin-2-ylmethanol 7 (6 g,37.8 mmol) was dissolved in CH2Cl2 (60 mL). PBr3 (2.14 mL,22.6mmol) was carefully added at 0 �C to this solution. Themixturewas allowed to return at ambient temperature and was stirred for30 min. Water (60 mL) was then added followed by a saturatedaqueous solution of K2CO3 (40 mL) to obtain a pH¼8. The organicphase was washed with brine (2�30 mL), dried over magnesiumsulfate, and concentrated under reduced pressure. The crude resi-due was purified through a silica gel column chromatography(AcOEt/MCH: 20/80). White solid; 83% yield; mp 55 �C (dec); 1HNMR (300 MHz, DMSO) 4.86 (2H, s, CH2), 7.67 (2H, m, CHar), 7.78(1H, m, CHar), 7.99 (2H, m, CHar), 8.40 (1H, m, CHar); 13C NMR(75 MHz, DMSO) 35.67, 122.10, 127.46, 127.54, 128.34, 129.07,130.53, 138.37, 147.36, 157.67; HRMS (ESI) m/z calculated forC10H9NBr [MþH]þ: 221.99129, found: 221.991.

4.2.7. N,N-DiBoc-quinolin-2-ylmethanamine 14. HN(Boc)2 (8.84 g,40.7mmol) andK2CO3 (8.45 g, 61.1mmol)were added to a solutionof2-(bromomethyl)quinoline 9 (9 g, 40.7mmol) in acetonitrile (54mL)at 20 �C. The mixture was then heated at reflux for 2 h. After cooling,water (54mL) and ethyl acetate (30mL)were added successively. Theorganic layer was washed with water (54 mL) and concentrated un-der reduced pressure. The orange oily residue was purified througha silica gel column chromatography (AcOEt/MCH: 97/3). White solid;80%yield;mp96 �C; 1HNMR (300MHz, CDCl3) 1.44 (18H, s, CH3), 5.11(2H, s, CH2), 7.32 (1H, m, CHar), 7.52 (1H, m, CHar), 7.70 (1H, m, CHar),7.80 (1H, m, CHar), 8.04 (1H, m, CHar), 8.14 (1H, m, CHar); 13C NMR(75 MHz, CDCl3) 28.04, 51.89, 81.98, 117.99, 126.05, 127.13, 127.54,129.08, 129.52, 136.65, 147.65, 152.48, 158.40; HRMS (ESI) m/z calcu-lated for C20H27O4N2 [MþH]þ: 359.19653, found: 359.19614.

4.2.8. tert-Butyl(quinolin-2-ylmethyl)carbamate 13. To a solution ofN,N-diBoc-quinolin-2-ylmethanamine 14 (4.7 g, 13.1 mmol) inacetonitrile (50 mL), LiBr (3.41 g, 39.2 mmol) was added. The re-action mixture was heated at 65 �C for 1 h. After cooling at ambienttemperature, the mixture was evaporated to dryness and the yel-low oil was dissolved in AcOEt (20 mL) then washed with water(2�20 mL). The organic phase was dried over magnesium sulfateand the crude yellow residue was purified through a silica gelcolumn chromatography (CH2Cl2/CH3OH: 98/2þ1% Et3N). 89%yield; 1H NMR (300 MHz, CDCl3) 1.52 (9H, s, CH3), 4.6 (2H, m, CH2),5.97 (1H, s, NH), 7.39 (1H, m, CHar), 7.55 (1H, m, CHar), 7.73 (1H, m,CHar), 7.83 (1H, m, CHar), 8.15 (2H, m, CHar); 13C NMR (75 MHz,CDCl3) 28.47, 46.20, 79.55, 119.85, 126.35, 127.33, 127.63, 128.85,129.72, 136.82, 147.33, 156.07, 157.19; HRMS (ESI)m/z calculated forC15H19O2N2 [MþH]þ: 259.1441, found: 259.14396.

4.2.9. Quinolin-2-ylmethanamine bischlorohydrate 15. First method:To a solution of N,N-diBocquinolin-2-ylmethanamine 14 (5 g,14 mmol) in EtOH (25 mL), a solution of EtOH$HCl 4 N (52.5 mL,210 mmol) was added at 0 �C. The solutionwas allowed to return atambient temperature and stirred for 3 h. Then, the mixture washeated at 90 �C up to the complete disappearance of the of N,N-diBoc-quinolin-2-ylmethanamine 14 (approxim. 30 min). Themixture was evaporated to dryness to give awhite solid, which waspurified through a silica gel column chromatography (CH2Cl2/CH3OH: 95/5þ1% Et3N). 90% yield; 1H NMR (300 MHz, CDCl3) 4.47(2H, m, CH2), 7.71 (1H, m, CHar), 7.81 (1H, m, CHar), 7.94 (1H, m,CHar), 8.10 (2H, m, CHar), 8.61 (1H, m, CHar), 8.88 (2H, s large, NH),9.91 (1H, s large, NH); 13C NMR (75 MHz, CDCl3) 42.29, 120.62,126.78, 127.26, 128.22, 131.06, 139.06, 144.94, 149.37, 153.69.

Second method: Quinolin 2-carbonitrile 10 (1 g, 6.5 mmol) washydrogenated over Pd (10%) on activated carbon powder (standard,

A.M. Maj et al. / Tetrahedron 69 (2013) 9322e9328 9327

reduced, nominally 50% water) (0.1 g) in MeOH/TFA (95/5: v/v)(100 mL) under 4 bar H2 at ambient temperature for 2 h. Then, thesolution was filtered and evaporated to dryness. HCl in iPrOH 5 N(25 mL) was added to precipitate the pure chlorohydrate 15. 58%yield.

4.2.10. Quinolin-2-ylmethanamine 12. Quinolin-2-ylmethanaminebischlorohydrate 15 (0.5 g, 2.1 mmol) was neutralized drop bydrop with sodium hydroxide (1 M, 30 mL) up to pH¼10. Theaqueous phase was extracted by CH2Cl2 (4�25 mL), then dried overmagnesium sulfate, filtered, and evaporated to dryness affordingthe free amine 12. 82% yield; 1H NMR (300 MHz, CDCl3) d 1.94 (2H,s, NH2), 4.16 (2H, s, CH2), 7.42 (1H, m, CHar), 7.49 (1H, m, CHar), 7.54(1H, m, CHar), 7.68 (1H, m, CHar), 7.80 (1H, m, CHar), 8.06 (2H, m,CHar); 13C NMR (75 MHz, CDCl3) 30.72, 117.69, 123.87, 128.59,129.08, 129.64, 131.54, 132.94, 138.50, 147.43.

4.3. General procedure for the asymmetric hydrogenationreactions

A 50 mL Schlenk flask, equipped with a magnetic stir bar, wascharged with [Ir(cod)Cl]2 (3.4 mg, 5�10�3 mmol) and the selectedchiral ligand (1.1�10�2 mmol). Then, the mixture was conditionedby three vacuum/nitrogen cycles and the degassed solvent (8 mL)was added. The mixture with the precatalyst was stirred at roomtemperature for 1 h before cannula transfer into a 50 mL double-walled stainless steel autoclave containing the substrate (1 mmol)and iodine (12.7 mg, 0.05 mmol). The autoclave was purged andpressurized with molecular hydrogen and the reaction was per-formed at the specified temperature during 17 h. At the end of thereaction, the autoclave was cooled and depressurized. The mixturewas filtered through a small pad of silica gel and analyzed by GC orNMR to determine the conversions. The enantiomeric excesseswere determined by HPLC.

4.3.1. Methyl 1,2,3,4-tetrahydroquinoline 2-carboxylate 17. HPLC:Chiralcel OJ-H Hexane/iPrOH 70/30, flow 1 mL/min, l¼254 nm; t122.69 min, t2 29.43 min; 1H NMR (300 MHz, CDCl3) 2.07 (1H, m,CH2), 2.29 (1H, m, CH2), 2.81 (2H, m, CH2), 3.81 (1H, s, CH3), 4.09(1H, m, CH), 6.67 (2H, m, CHar), 7.02 (2H, m, CHar); 13C NMR(75 MHz, CDCl3) 24.69, 25.82, 52.41, 53.89, 114.60, 117.69, 120.55,127.07, 129.14, 142.92, 173.76.

4.3.2. Ethyl 1,2,3,4-tetrahydroquinoline 2-carboxylate 18. HPLC:Chiralcel OJ-H Hexane/iPrOH 70/30, flow 1 mL/min, l¼254 nm; t118.18 min, t2 29.18 min; 1H NMR (300 MHz, CDCl3) 1.32 (3H, t, J6.7 Hz, CH3), 2.02 (1H, m, CH2), 2.33 (1H, m, CH2), 2.80 (2H, m, CH2),4.07 (1H, m, CH), 4.27 (2H, q, J 6.7 Hz, CH2), 4.44 (1H, s, NH), 6.66(2H, m, CHar), 6.99 (2H, m, CHar); 13C NMR (75 MHz, CDCl3) 14.41,24.66, 25.79, 53.98, 61.44, 115.03, 118.12, 120.98, 127.10, 129.17,142.42, 173.09.

4.3.3. Propyl 1,2,3,4-tetrahydroquinoline 2-carboxylate 19. HPLC:Chiralcel OJ-H Hexane/iPrOH 70/30, flow 1 mL/min, l¼254 nm; t113.36 min, t2 20.18 min; 1H NMR (300 MHz, CDCl3) 0.96 (3H, t, J7.1 Hz, CH3), 1.64 (2H, m, CH2), 2.04 (1H, m, CH2), 2.33 (1H, m, CH2),2.79 (2H, m, CH2), 4.04 (1H, m, CH), 4.17 (2H, m, CH2), 6.63 (2H, m,CHar), 7.01 (2H, m, CHar); 13C NMR (75 MHz, CDCl3) 10.44, 22.09,24.71, 25.81, 54.20, 66.95, 114.92, 118.00, 120.87, 127.08, 128.71,142.56, 173.22. HRMS (ESI) m/z calculated for C13H18NO2 [MþH]þ:220.13321, found: 220.13291.

4.3.4. Isopropyl 1,2,3,4-tetrahydroquinoline 2-carboxylate 20. HPLC:Chiralcel OJ-H Hexane/iPrOH 70/30, flow 1 mL/min, l¼254 nm; t110.75 min, t2 14.08 min; 1H NMR (300 MHz, CDCl3) 1.28 (6H, d, J7.5 Hz, CH3), 1.99 (1H, m, CH2), 2.31 (1H, m, CH2), 2.81 (2H, m, CH2),

3.98 (1H, m, CH), 5.12 (1H, m, NH), 6.65 (2H, m, CHar), 6.90 (2H, m,CHar); 13C NMR (75 MHz, CDCl3) 21.83, 24.72, 25.85, 54.04, 68.95,114.91, 117.91, 120.88, 127.07, 129.13, 142.66, 172.64.

4.3.5. Isobutyl 1,2,3,4-tetrahydroquinoline 2-carboxylate 21. HPLC:Chiralcel OJ-H Hexane/iPrOH 70/30, flow 1 mL/min, l¼254 nm; t110.10 min, t2 14.46 min; 1H NMR (300 MHz, CDCl3) 0.95 (6H, d, J7.5 Hz, CH3), 2.00 (1H, m, CH2), 2.32 (1H, m, CH2), 2.81 (2H, m, CH2),3.78 (2H, m, CHeO), 3.98 (1H, m, CH), 5.12 (1H, m, NH), 6.64 (2H, m,CHar), 6.99 (2H, m, CHar); 13C NMR (75 MHz, CDCl3) 17.20, 22.89,23.98, 25.89, 52.04, 69.48, 112.81, 115.81, 118.90, 125.16, 127.16,140.97, 171.31.

4.3.6. 2-Hydroxymethyl-1,2,3,4-tetrahydroquinoline 22. HPLC: Chir-alcel OD Hexane/iPrOH 90/10, flow 1 mL/min, l¼254 nm; t112.90 min, t2 14.40 min; 1H NMR (300 MHz, CDCl3) 1.67 (1H, m,CH2), 1.83 (1H, m, CH2), 2.75 (2H, m, CH2), 3.25 (1H, s, OH), 3.40(1H, m, CH2), 3.52 (1H, m, CH2), 3.69 (1H, m, CH), 6.49 (1H, m,CHar), 6.60 (1H, m, CHar), 6.91 (2H, m, CHar); 13C NMR (75 MHz,CDCl3) 24.31, 25.35, 52.86, 66.65, 114.71, 117.60, 121.61, 126.91,129.24, 144.00.

4.3.7. 2-(Bromomethyl)-1,2,3,4-tetrahydroquinoline 24. HPLC: Chir-alcel OD Hexane/iPrOH 98/2, flow 1.5 mL/min, l¼254 nm; t16.54 min, t2 7.55 min; 1H NMR (300 MHz, CDCl3) 1.84 (1H, m, CH2),2.16 (1H, m, CH2), 2.84 (2H, m, CH2), 3.39 (1H, m, CH), 3.55 (2H, m,CH2), 6.41 (1H, m, CHar), 6.70 (2H, m, CHar), 7.04 (2H, m, CHar); 13CNMR (75 MHz, CDCl3) 25.56, 26.81, 38.16, 52.25, 114.62, 117.88,122.12, 127.02, 129.36, 143.65.

4.3.8. 1,2,3,4-Tetrahydroquinolin-2-carboxamide 26. HPLC: ChiralcelOD Hexane/iPrOH 90/10, flow 1 mL/min, l¼254 nm; t1 30.16 min, t236.42 min; 1H NMR (300 MHz, CDCl3) 1.86 (1H, m, CH2), 2.24 (1H,m, CH2), 2.62 (2H, m, CH2), 3.93 (1H, m, CH), 5.78 (1H, s, NH), 6.56(1H, m, CHar), 6.63 (1H, m, CHar), 6.68 (2H, s, NH2), 7.00 (2H, m,CHar); 13C NMR (75 MHz, CDCl3) 24.22, 24.75, 55.28, 114.88, 118.61,122.09, 127.18, 129.38, 141.62, 176.79. HRMS (ESI) m/z calculated forC10H13N2O [MþH]þ: 177.10224 found: 177.10247.

4.3.9. 1,2,3,4-Tetrahydroquinolin-2-ylmethanamine 27. HPLC: Chir-alcel AD-H Hexane/iPrOH/DEA 95/5/0.1, flow 1 mL/min, T¼7 �C,l¼304 nm; t1 15.87 min, t2 18.02 min; 1H NMR (300 MHz, CDCl3)1.19 (2H, s, NH2), 1.59 (1H, m, CH2), 1.86 (1H, m, CH2), 2.55e2.84(4H, m), 3.17 (1H, m, CH2), 4.25 (1H, s, NH), 6.43 (1H, m, CHar),6.57 (1H, m, CHar), 6.90 (2H, m, CHar); 13C NMR (75 MHz; CDCl3)25.97, 26.28, 47.44, 53.40, 114.44, 117.03, 121.46, 126.89, 129.26,144.61.

4.3.10. tert-Butyl((1,2,3,4-tetrahydroquinolin-2yl)methyl)-carbamate28. HPLC: Chiralcel OJ-H Hexane/iPrOH 90/10, flow 1 mL/min,l¼254 nm, t1 13.94 min, t2 20.17 min; 1H NMR (300 MHz, CDCl3)1.38 (9H, s, CH3), 1.64 (1H, m, CH2), 1.85 (1H, m, CH2), 2.71 (2H, m,CH2), 3.08 (1H, m, CH), 3.18 (1H, m, CH2), 3.35 (1H, m, CH2), 4.85(1H, s, NH), 6.50 (1H, m, CHar), 6.59 (1H, m, CHar), 6.90 (2H, m,CHar); 13C NMR (75 MHz, CDCl3) 25.20, 25.85, 28.39, 45.50, 51.69,79.73, 115.03, 118.14, 121.80, 126.94, 129.29, 143.13, 156.51; HRMS(ESI) m/z calculated for C15H23N2O2 [MþH]þ: 263.1754, found:263.17508.

4.3.11. N,N-DiBoc methylene 1,2,3,4-tetrahydroquinoline 29. HPLC:Chiralcel OD Hexane/iPrOH 98/2, flow 0.2 mL/min, l¼254 nm; t134.00 min, t2 36.21 min; 1H NMR (300 MHz, CDCl3) 1.43 (18H, s,CH3), 1.61 (1H, m, CH2), 1.87 (1H, m, CH2), 2.70 (2H, m, CH2), 3.47(1H,m, CH), 3.67 (2H, m, CH2), 6.41 (1H, m, CHar), 6.54 (1H, m, CHar),6.66 (1H, s, NH), 6.90 (2H, m, CHar); 13C NMR (75MHz, CDCl3) 25.61,25.85, 28.06, 50.95, 51.64, 82.76, 114.14, 116.89, 120.71, 126.82,

A.M. Maj et al. / Tetrahedron 69 (2013) 9322e93289328

129.16, 143.99, 153.17; HRMS (ESI) m/z calculated for C20H31N2O4[MþH]þ: 363.2278, found: 363.2274.

Acknowledgements

This work was supported by Oril Industrie (A.M.M.). The authorsthank J.-P. Lecouv�e, N. Pinault, L. Vaysse-Ludot for fruitful discus-sions. Mrs. C. M�eliet (UCCS CNRS) is thanked for helpful discussionsand elemental analyses. J. Lucet is thanked for some experiments.Mrs. N. Duhal (CUMA, Universit�e Lille Nord de France, Universit�eLille 2 is thanked for HRMS and LC-MS analyses.

Supplementary data

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.tet.2013.07.090.

References and notes

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