AND IMINES

FIELD OF THE INVENTION

The present invention relates to a catalyst composition comprising a ligand with a metal complex. More particularly, the present invention relates to a catalyst composition comprising a ligand of formula I,

Formula I

Wherein, R ¹ , R ² , R ³ and R ⁴ are described below; and a metal catalyst . Further, the present invention relates to a process for the asymmetric transfer hydrogenation of >C=0, >C=C< or >C=N catalyzed by the disclosed catalyst composition.

Background and prior art:

Catalytic asymmetric transfer hydrogenation of ketones is one of the important transformations in organic chemistry and a large number of catalytic methods are available to achieve this goal. This reduction has become subject of considerable interest from both academic as well as industrial point of view.

Article titled, "On Water and in Air: Fast and Highly Chemo selective Transfer Hydrogenation of Aldehydes with Iridium Catalysts" by Xiaofeng Wu, Jianke Liu, Xiaohong Li, Antonio Zanotti-Gerosa, Fred Hancock, Daniele Vinci, Jiwu Ruan, and Jianliang Xiao in Angew. C em. 2006, 118, 6870 -6874 reports that [(Cp*IrCl ₂ ) ₂ ] (Cp*=C ₅ Me ₅ ) in combination with monotosylated ethylenediamine is a good catalyst system for highly chemo selective transfer hydrogenation (TH) of aldehydes. The reduction works in air and appears to occur on water. Article titled, "Chiral Amino Amides for the Ruthenium (Il)-Catalyzed Asymmetric Transfer Hydrogenation Reaction of Ketones in Water" JINCHENG MAO AND JUN GUO in CHIRALITY 22: 173-181 (2010) reports that the chiral amino amide was derived from L- proline and used for the [RuCl2(p-cymene)] ₂ -catalyzed asymmetric transfer hydrogenation of prochiral ketones in water with good chemical selectivities (up to 95% yield) and enantio selectivities (up to 90% ee).

Article titled, "Ru(II) Complexes of N- Alkylated TsDPEN Ligands in Asymmetric Transfer Hydrogenation of Ketones and Imines" by Jose E. D. Martins, Guy J. Clarkson, and Martin Wills in ORGANIC LETTERS 2009 Vol. 11, No. 4 847-850 reports that N- Alkylated TsDPEN derivatives bearing a small alkyl group act as highly efficient ligands in Ru(II) complexes for the asymmetric transfer hydrogenation of imines and ketones. A larger alkyl group serves to significantly reduce the activity of the catalyst; however, high enantiomeric excesses are still obtained.

Article titled, "Asymmetric Hydrogenation of Cyclic Imines with an Ionic Cp*Rh (III) Catalyst" by Chaoqun Li and Jianliang Xiao in J. AM. CHEM. SOC. 2008, 130, 13208- 13209 reports an efficient Rh (Ill)-diamine catalyst which affords excellent enantioselectivities in asymmetric hydrogenation of imines to give bioactive tetrahydroisoquinolines and tetrahydro- ?-carbolines.

Article titled, "Applications of N' -alkylated derivatives of TsDPEN in the asymmetric transfer hydrogenation of C=0 and C=N bonds" by Jose E. D. Martins, Miguel A. Contreras Redondo, Martin Wills in Tetrahedron: Asymmetry 21 (2010) 2258-2264 reports Arene/Ru(II) complexes of (R,R)-N-alkyl-TsDPEN ligands are effective in the asymmetric transfer hydrogenation of ketones and imines in formic acid/triethylamine solution. The complex derived from the N"-Bn derivative of TsDPEN reduces monocyclic imines in up to 60% ee, whilst the N ^' -Me derivative of TsDPEN forms a more active catalyst than the non- alkylated analogue and reduces ketones in up to 97% ee.

US patent Pub. No. US 2003/0199713 Al discloses a catalyst for the asymmetric hydrogenation represented by the formula ML _a XbS _c , where M is a transition metal, to be chosen from Rh and Ru, and X is a counter ion and S is a ligand, 'a' ranges from .5 to 3, 'b' and 'c', each independently, range from 0 to 2, and L is a chiral ligand having formula (1), where C _n together with the two 2 O-atoms and the P-atom forms a substituted or non- substituted ring with 2-4 C-atoms, R ¹ and R ² each independently represent H, an optionally substituted alkyl, aryl, alkaryl or aralkyl group or. may form a (heterocyclic) ring together with the N-atom to which they are bound. It further reports a process for the asymmetric hydrogen transfer of an olefinically unsaturated compound, ketone, imine or oxime derivate in the presence of a hydrogen donor and of a catalyst, use being made of a catalyst as defined above.

One of the most significant breakthroughs in transfer hydrogenation was reported by Noyori et al with the use of chlororuthenium (II) arene precursors with chiral monoarylsulfonylated-1, 2-diamine or β-amino alcohols as ligands. The structurally well- defined [Ru ⁿ (arene) (TsDPEN)] (TsDPEN = (1R, 2R)-N-(p-tolylsulfonyl)-l,2- diphenylethylene-diamine) system enables highly effective reduction of a variety of ketones with greater than 90% ee. This key development has led to intense exploration of Ru(II)arene(monotosylated diamine) systems with the aim of designing more efficient ligands, improving catalytic activity and broadening the scope of asymmetric transfer hydrogenation reaction. The TsDPEN and TsCYDN ligands are used not only in organic media but also in water and under aerobic conditions. Xiao showed these TsDPEN ligands in combination of ruthenium, rhodium and iridium in water as media and sodium format as hydrogen donor can be effectively used for ATH of ketones with 99% conversion and more than 92% ee whereas TsCYDN are proved to be better ligands than TsDPEN, as far as rhodium catalyst is concerned, with high conversion and ee are observed within a very short time of 10 mins tolh for many ketones.

A variety of amino alcohols ligands are designed and synthetized for ATH of ketones, with different electronic and steric properties but the structurally versatile monosulfonated diamine ligands are less reported and most reports are restricted on modifying the substitution on either on sulfonamide group or on the phenyl group without disturbing the real C2 Symmetric backbone of TsDPEN or TsCYDN.

Also important is the metal complex and ligand combination, since Ru-TsDPEN shows better results than Ru-TsCYDN whereas Rh-TsCYDN shows better activity than Rh- TsDPEN. There are very few examples with the use of unsymmetrical diamine ligands with transition metal catalyst for ATH of ketones and imines. First it was Wills et. al. who synthesized new monosulfonated unsymmetrical vicinal diamines and showed that derivative derived from cis 2 amino indanol having syn orientation is also active for ATH of Ketones. Later on it was proposed that anti-substitution of amine and sulfonamide groups is important for activity and enantio selectivity.

Very recently Ming-hua-xu synthesized further analogues of unsymmetrical vicinal diamines and showed that along with one phenyl group attached to carbon bearing the sulfonamide group, a bulky substituent on the carbon bearing amine is needed for high activity and enantio selectivity for ATH of ketones. But the careful observation of these results indicates that there is no clear view on which kind of substituents are tolerated and in which position. Also both these reports were restricted to use of Ru p -cymene as the catalyst for ATH.

Structure of different monotosylated vicinal diamine with C2 symmetry

Though the catalyst systems available are good there is a need to develop new ligands to improve activity of the catalyst.

OBJECTIVE OF THE INVENTION

The main object of the present invention is to provide a catalyst composition comprising a ligand of formula I,

Formula I wherein, R ¹ , R ² , R ³ and R ⁴ are described below; and a metal catalyst.

Another object of the present invention is to provide a process for the asymmetric transfer hydrogenation of >C=0, >C=C< or >C=N catalyzed by the catalyst composition provided. SUMMARY OF THE INVENTION

Accordingly, the present invention provides a catalyst composition comprising a ligand of formula I,

Formula I

R ¹ is selected from the group consisting of phenyl, substituted phenyl, alkyl-linear or branched; R is alkyl-linear or branched; R ³ , R ⁴ are independently selected from amino, NHTs or NHCF ₃ Ts; [Ts = tosyl group

(p-tolyl sulfonyl, S0 ₂ -C ₆ H ₄ -CH ₃ ) and CF3Ts = (4-(trifluoromethyl)phenyl-l- sulfonyl, S0 ₂ - C ₆ H4-CF3)]with a metal catalyst, wherein said metal is selected from transition metals, preferably Ru, Rh or Ir. Further, in accordance with the above objective the present invention provides a process for the asymmetric transfer hydrogenation of >C=0, >C=C< or >C=N catalyzed by the disclosed catalyst composition.

DETAIL DESCRIPTION OF THE DRAWINGS Fig. 1 depicts Effect of methanol content in water on ATH of l-methyl-6,7- dimethoxy-3,4-dihydroxisoquinoline(la): 25% MeOH in water (A), 50% MeOH in water (♦), 75% MeOH in water ( ^■ ); la (0.5 mmol); HCOONa (2.5 mmol); temp: 40 C, solvent: 2 ml.

Fig.2 depicts the conversion profile of 1 -methyl- 6,7-dimethoxy-3,4- dihydroxisoquinoline(la) with regard to time with the reaction conditions of la (0.5 mmol), [Rh(Cp*)C12]2 (0.0025 mmol), (I S, 2S)-TsDPEN (0.0075 mmol), HCOONa (2.5 mmol), 40°C, solvent (2 ml), H20/ MeOH ( v/v, 1 : 1); Conv (♦), ee (( ^■ )

LIST OF ABBREVIATIONS

AP Acetophenone

ATH Asymmetric transfer hydrogenation

Boc Di-t-butyl dicarbonate

Cone. Concentration

C-T Concentration-time

Cp* Pentamethylcyclopentadiene

DABCO 1 ,4-diazabicyclo [2.2.2] octane

DMF N,N-Dimethyl foramide

ee Enantiomeric excess

Ephedrine 2-Methylamino- 1 -phenyl- 1 -propanol

FA-TEA Formic acid and triethylamine (5 :2)

FID Flame ionization detector

FTIR Fourier transform infrared

GC Gas chromatography

GC-MS Gas chromatography-Mass spectrometry

h Hour (s)

HPLC High performance Liquid Chromatograpl

HR-MS High Resolution Mass Spectrometer

IPA Isopropyl alcohol (2 -propanol)

min. Minutes

NMP N-methyl 2-pyrolidone

NMR Nuclear magnetic resonance org. Organic

Ph Phenyl

ppm Parts per million

RT Room temperature

SDS Sodium dioctyl sulfosuccinate

Temp. Temperature

THF Tetrahydrofuran

TOF Turnover frequency

TPP Triphenyl phosphine

TsCYDN 1R, 2R)-N-(p-tolylsulfonyl)-l,2-cyclohexyl,diamine]

TsDPEN N-[-2-amino-l,2-diphenylethyl]-4-methylbenzenesulfonamide

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a catalyst composition comprising a ligand of formula

Formula I wherein, R is selected from the group consisting of phenyl, substituted phenyl, alkyl- linear or branched;R ² is alkyl-linear or branched;

R ³ , R ⁴ are independently selected from amino, NHTs or NHCF ₃ Ts; with a metal catalyst, wherein said metal is selected from transition metals, preferably Ru,Rhorlr.

In view of above, the present invention further provides a process for the asymmetric transfer hydrogenation of >C=0, >C=C< or >C=N catalyzed by the disclosed catalyst composition. In an embodiment the present invention provides a catalyst composition comprising a ligand of formula I,

Formula I wherein, R ¹ , is selected from the group consisting of phenyl, substituted phenyl,alkyl- linear or branched;R is alkyl-linear or branched; R ³ , R ⁴ are independently selected from amino, NHTs or NHCF ₃ Ts; with a metal catalyst, wherein said metal is selected from transition metals, preferably Ru,RhorIr. In a preferred embodiment the present invention provides a catalyst composition wherein the Ligand is preferably selected from N-[(lR,2S)-2-amino-l-phenylpropyl]-4- methyl benzene sulfonamide^ ),

N-[(l S, 2R)-2-amino- 1 -phenylpropylj-4-methylbenzenesulfonamide (3a),

N-[(1R, 2R)-2-aniino-l-phenylpropyl]-4-methylbenzenesulfonamide (13),

N-[(1S, 2S)-2-amino-l-phenylpropyl]-4-methylbenzenesulfonamide (13a),

N-[(lR,2S)-2-amino-l-methyl-2-phenylethyl]-4-methyl-benzenes ulfonamide (7), N-[(l S,2R)-2-amino- 1 -methyl-2-phenylethyl]-4-methyl-benzenesulfonamide(7a), N-[(lS,2S)-2-amino-l-methyl-2-phenylethyl]-4-methyl-benzenes ulfonamide (14), N-[(lR,2R)-2-amino-l-methyl-2-phenylethyl]-4-methyl-benzenes ulfonamide (14a).

The following scheme 1 describes the structure of preferable ligands:

13 14

3a 7a 13a 14a

Scheme 1

In another preferred embodiment the present invention provides a catalyst composition, wherein the ^■ metal catalyst is preferably selected from Pentamethylcyclopentadienylrhodium (III) chloride dimer, [Rh (Cp*) Cl ₂ ] ₂ , Pentamethylcyclopentadienyliridium(III) chloridedimer, [Ir(Cp*)Cl ₂ ] ₂ orDichloro (p-cymene) ruthenium (II) dimer [Ru (p-cymene) Cl ₂ ] ₂ .

The following scheme 2 describes the structure of preferred metal catalyst:

Scheme 2

In another embodiment, the invention encompasses synthesis of novel ligands of formula I, preferably the synthesis of ligands 3, 7, 13 and 14 are exemplified.

In another embodiment the present invention provides a process for the asymmetric transfer hydrogenation of >C=0, >C=C< or >C=N catalyzed by the catalyst composition comprising a ligand of formula I with a metal catalyst as described above, wherein the said process comprises the steps of: a. Preparation of catalyst composition by mixing metal catalyst and ligand in the reaction solvent and stirring at a given temperature for a specified time to obtain catalyst composition comprising metal complex; b. Addition of hydrogen donor and an alkene or ketone or imine to the mixture and carry out the reaction for a specific reaction time to obtain hydrogenated alkene or ketone or imine with asymmetric transfer hydrogenation.

In an embodiment the present invention provides a process for asymmetric transfer hydrogenation of ketones in water or water-co-solvent mixture using sodium formate as a hydrogen donor. The co solvent is preferably selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, isopropanol, ethylene glycol, DMF, DMSO, NMP, 1,4- dioxane, THF, acetonitrile or combinations thereof.

In an embodiment the present invention provides a process for asymmetric transfer hydrogenation of ketones is carried out with FA/TEA (formic acidVtriethylarnine mixture)as hydrogen donor as well as solvent or with water as a solvent.

In an embodiment the present invention provides a process for asymmetric transfer hydrogenation of imines in water or water-co-solvent mixture using sodium formate as a hydrogen donor. The co solvent is preferably selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, isopropanol, ethylene glycol, DMF, DMSO, NMP, 1,4- dioxane, THF, acetonitrile or combinations thereof. The preferred co-solvents are selected from acetonitrile or methanol.

In an embodiment the present invention provides a process for asymmetric transfer hydrogenation of imines is carried out with FA/TEA as hydrogen donor with organic solvent as cnsolvent. The organic solvent is preferably selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, isopropanol, ethylene glycol, DMF, DMSO, NMP, 1,4-dioxane, THF, acetonitrile or combinations thereof. In yet another embodiment, the invention provides a solvent system that is suitable for hydrogenation of iniines asymmetric transfer hydrogenation. According to this embodiment, asymmetric transfer hydrogenation of l-methyl-6,7-dimethoxy-3,4-dihydroxisoquinoline(an imine) is carried out using [Rh(Cp*)C12]2and (1S,2S)-TSDPEN, a known ligand, with sodium formate as hydrogen donor in water and in presence of various co-solvents selected from the group consisting of water, methanol, ethanol, n-propanol, n-butanol, isopropanol, ethylene glycol, DMF, DMSO, NMP, 1,4-dioxane, THF, acetonitrile or combinations thereof as reported in tables 6 and 7. As per the data presented in tables 6 and 7, the use of methanol as co-solvent along with water in 1 : 1 ratio for asymmetric transfer hydrogenation of 1- methyl-6,7-dimethoxy-3,4-dihydroxisoquinolinesurprisingly yields the best results among other co-solvents with 97% conversion and with 95% ee in just 20 min (TOF: 295 h ^" ').The reactions were carried out in air, and excellent enantio selectivities were observed for various imine substrates.

The reaction was carried out by varying the amount of methanol in water from 25% to 75%, by keeping the total quantity of solvent constant and the results are presented in Fig. l.From the Fig. 1, it can be seen that conversion of l-methyl-6,7-dimefhoxy-3,4- dihydroxisoquinoline increased with increase in methanol concentration till 50% methanol (98% conversion in 20 min) and reaction mixture was homogeneous throughout the course of reaction. However, with further increase in methanol concentration to 75% conversion decreased considerably (92% in30 min), however, enantio selectivity was not affected by a change inmethanol concentration (94—95%). The C-T(Conversion Vs Time) profile for ATH of l-methyl-6,7-dimethoxy-3,4-dihydroxisoquinoline is shown in figure 2.

ADVANTAGES OF INVENTION THE PRESENT INVENTION a. Efficient ligands and their synthesis;

b. Highcatalytic activity;

c. Broadening the scope of asymmetric transfer hydrogenation reaction. The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. EXAMPLES Example 1: Experimental

All the experiments were carried out using oven-dried glassware in open air. The

NMR spectra were recorded on a 400 MHz Bruker spectrometer. HPLC analysis was carried out using Waters Perkin Elmer HPLC instrument with quaternary gradient pump, diode array detector and auto sampler. GC-MS analysis was carried out using Agilent 5973 instrument using HP-5 column purchased from Agilent Technologies.HR-MS analysis was done using Agilent 6520 Q-TOFinstrument.

Synthesis and characterization of unsymmetrical vicinal monotosylated diamines

Preparation of N-[(1R, 2S)-2-amino-l-phenyl-propyl]-4-methyl benzenesulfonamide (Ligand 3)

The ligand is prepared as per the scheme2. In a 3 -necked 100ml round bottom flask, 1R,2S norephedrine (3.0g, 20 mmol) compound l,triphenylphosphine (5.2g,20 mmol) and BOc protected p-toluene sulfonyl amide (5.42g,20 mmol),were stirred in of dichloromethane(60ml) and the solution was cooled to 0-5°C. To this solution DEAD (3.46g, 20 mmol) was added slowly over a period of 15 mins. The solution was brought to room temperature and stirred for another 6h.After 6 h of stirring, reaction mass was washed with mixture of IN HC1 (5ml) and water (20 ml). 4N HC1 in dioxane (20ml) was added and the reaction was heated at 50°C for 2 h. The reaction mass after heating was evaporated to dryness and dichloromethane (50 ml) and water (50 ml) was added to it. The layers were shaked vigorously and DCM layer was discarded. Aqueous layer was neutralized by slow drop wise addition of dilute NaOH (4N), till the solution pH reached 7. The white solids precipitated were allowed to digest overnight and then filtered over sinteredglass crucible. The precipitate was washed 2-3 times with about 10 ml water and was dried in oven at 60°C. Crude product was recrystalised from toluene to get pure sulfonamide ligand compound 3. (1.0 g, Yield 33%) Preparation of Ligand 3 (scheme 2)

Reaction conditions: i) DEAD, Triphenyl phosphine in DCM, ii) 4N HCl in Dioxane

1H NMR (400MHz, CHLOROFORM-d) δ ppm, 7.52 (d, J=8.0 Hz, 2H), 7.14 -7.01 (m, 7H), 4.20 (d, J=5.0 Hz, 1H), 3.20 - 3.13 (m, 1H), 2.33 (s, 3H), 0.95 (d, J=6.5 Hz, 3H); ¹³ C NMR (101MHz, CHLOROFORM-d) δ ppm,142.9, 137.5, 137.2, 129.2,

128.1,127.6,127.4,127.0,62.6, 51.0, 21.5, 20.7; FTIR (KBr, cm ^_1 )3574,3358, 2878, 1599, 1323, 162, ; HRMS calculated mass: 304.1245, measured mass: 304.1249;[a] ²⁵ _D = -64.2 (1.0.CHC13) Synthesis of N-[(lS,2R)-2-amino-l-methyl-2-phenyl-ethyl]-4-methyl-benzene sulfonamide Ligand 7

Preparation of ligand 7 (Scheme 3)

Reaction conditions: iii) Triethyl amine in t-Butyl methyl ether iv) DEAD, Triphenyl phosphine in THF, v) Sodium azide in Acetonitrile: water v) Triphenyl phosphine in THF and water i) Synthesis of N-[(1S, 2R)-2-hydroxy-l-methyl-2-phenyl-ethyl]-4-methyl- benzenesulfonamidecompound 4

In a 3 necked 100 ml round bottom flask norephedrine (15.0g, 100 mmol) was taken and tert-butyl methyl ether (50 ml) and triethyl amine (10 ml) were added to it. p- toluenesulfonyl chloride (19g, 100 mmol) dissolved in tert-butyl methyl ether (50 ml) was added drop wise to the solution containing norephedrine at 0°C. The solution was stirred at room temperature for 6 h. After 6 hours the solution was washed with 2 N HC1 (50 ml). The tert-butyl methyl ether layer was concentrated to get the crude sulfonamide, which was crystallized from tolueneto get the pure product yield (22 g, yield 72%). Compound 4

Yellowish white solid, M.P 79-8 l H NMR (400 MHz, CHLOROFORM- d) δ ppm 7.69 (d, J=7.7 Hz, 2 H),7.13 - 7.24 (m, 7 H),4.72 (d, J=3.01 Hz, 1 H),3.47 (dq, J=6.7, 3.4 Hz, 1 H),2.33 (s, 3 H), 0.74 (d, J=6.8 Hz, 3 H); ¹³ C NMR (101 MHz, CHLOROFORM-c ) δ ppm 143.5,140.4, 137.8,129.8, 128.3, 127.6, 127.1, 126.1, 75.8, 55.1, 21.614.5; FT IR (KBr,cnT'): 3500, 3278, 1494, 1326, 1159, 1088 ;HRMS calculated Mass: 305.1086, measured mass: 305.1083;[a] ²⁵ _D = -16.8 (1.0, CHC13);. ii) Synthesis of (2S, 3S)-2-methyl-3-phenyl-l-(p-tolylsulfonyl) aziridine, Compound 5 In a 100 ml 3necked flask 6.1 g (20 mmol) of compound 4 was taken and THF (50 ml) was added to it. Triphenyl phosphine (5.26g, 20 mmol) dissolved in THF (20 ml) was added to the solution. The reaction mixture was cooled to 0°C. DIAD (4.1 g, 20 mmol) was added slowly to the reaction mixture, maintaining the temperature at 0°C to 5°C. The reaction mixture was further stirred for 6h and then concentrated to remove THF. Cyclohexane (50 ml) was added to the solids and contents were heated at 50°C for lh. The resulting suspension was filtered off, and the cyclohexane layer was concentrated to get the crude tosylated aziridine. Crude product was purified by column chromatography to get pure sample (Cyclohexane: Ethyl acetate; 9:l)(5g, yield,86%) Yellow liquid H NMR (CDC1 ₃ , 400 MHz) ρηι,7.82 (d, J = 8.3 Hz, 2H), 7.25 (m,5H), 7.15 (m, 2H), 3.79 (d, J= 4.4 Hz, 1H), 2.91 (m, 1H), 2.39 (s,3H), 1.84 (d, J= 6.1 Hz, 3H); ¹³ C NMR (CDC1 ₃ , 101 MHz) <Sppm,143.9, 137.9, 135.5, 129.5, 128.5, 128.0, 127.2, 126.3, 49.2, 49.1, 21.5, 14.2,; FT IR (neat^m ^"1 ), 1321, 1159 ^; HRMS,calculated mass: 287.0980, measured mass: 287.0979; [a] ⁵ _D =60.6(1.0, CHCI3); iii) Synthesis of N-[(1S, 2R)-2-azido-l-methyl-2-phenyI-ethyl]-4-methyI- benzenesulfonamide, Compound6 compound 5 (2.87g, 10 mmol) was dissolved in acetonitrile (50 ml) and sodium azide

(1.95 g, 30mmol) in water (5ml) was added to it. The contents were stirred at 50° C for 8h.After the reaction, acetonitrile was removed under reduced pressure and contents were concentrated to ~5ml. The aqueous layer containing the solid was filtered off and washed with water (10ml x 2). The product isolated was pure enough to be used for the next step.

Off white solid , MP 80-82°C,1H NMR (400MHz, CHLOROFORM-d) δ = 7.78 (d, J=7.7 Hz, 2H), 7.38 - 7.19 (m, 7H), 4.78 (d, J=8.8 Hz, 1H), 4.69 (d, J=3.8 Hz, 1H), 3.57 (ddd, J=3.9, 6.7, 8.8 Hz, 1H), 2.43 (s, 3H), 0.90 (d, J=6.8 Hz, 3H); ¹³ C NMR (CDC1 ₃ , 101 MHz) 5ppm ,143.6, 137.8,136.3, 129.7, 128.7, 128.3, 126.9, 126.8, 69.6, 54.0, 21.5, 15.2,; FT1R (KBr cm ^_1 )3251, 2099, 1378, 1299, 1166; HRMS calculated Mass: 330.1150, measured Mass: 330.1 152 difference 0.6 ppm;[a] ²⁵ _D = -105.8 (1.0, CHC13) iv)Synthesis of N-[(1S, 2R)-2-amino-l-methyl-2-phenyl-ethyl]-4-methyl- benzenesulfonamide Ligand 7

(1.65g, 5mmol) of the compound 6 was dissolved in THF (40 ml) and triphenyl phosphine (1.3 lg 5mmoi) was added to it and the resultant mixture was stirred at 50°C for nearly 6h. After 6 h water (5ml) was added to the reaction mixture and the heating was continued for further 8h.The reaction mixture was concentrated to (~5ml) remove the THF. The aqueous layer was extracted with DCM (10ml) and concentrated to get sticky mass. Toluene (10ml) and the 4N HC1 (1ml) in dioxane were slowly added to get white precipitate of hydrochloride. The resultant solution was filtered off to get white powder of hydrochloride. Traces of toluene were removed by drying under vacuum. Water (5ml)was added to dissolve the hydrochloride and IN NaOH was slowly added till the pH reached to 7.0. The solution was extracted with ethyl acetate (10ml x2) and concentrated to get sticky mass. (1.0 g, yield=67%)

^! H NMR (400MHz, CHLOROFO M-d) δ ppm, 7.73 (d, J=8.3 Hz, 2H), 7.33 - 7.13 (m, 7H), 3.95 - 3.87 (m, 1H), 3.50 (dd, J=3.8, 6.5 Hz, 1H), 2.39 (s, 3H), 0.79 (d, J=6.8 Hz, 3H); ¹³ C NMR (101MHz, CHLOROFORM-d) δ ppm, 143.4, 141.4, 137.8, 129.8, 129.6, 129.1 , 128.5, 128.3, 127.5, 127.4, 127.1, 126.8, 59.0, 54.6, 21.6, 16.0;FT IR (KBr, cm ^" '),3288, 3230, 1598, 1328, 1151, ;HRMS calculated mass: 304.1249, measured mass: 304.1245,;[ ] ²⁵ _D = +13.4 (0.5, CHC13);

Preparation of ligands 13 and 14 (scheme 5)

Reaction Conditions: i) SOCl ₂ , ii) 4N NaOH, in Methanol, iii) Pyridine in t-butyl methyl ether iv) DABCO and TMS azide, v) Triphenyl phosphine in THF and H ₂ 0

The ligand 13 and 14 is prepared by the scheme 5 are detailed herein below, i) Synthesis of (IS, 2S)-l-chloro-l-phenyl-propan-2-amine.Compound 8 In a 3 necked round bottom flask 1R, 2S norephedrine hydrochloride(30.0g, 200 mmol) was taken and to it, thionyl chloride (70.9g 596mmol) was added drop wise. After the addition was complete the reaction mixture was stirred for 3h. Vacuum was applied to remove the excess thionyl chloride, and then acetone (50 ml) was slowly added to the slurry. The resultant solution was filtered and washed with acetone and recrystalised from methanol to obtain white solids of compound 8(22 g, yield 67%)

White solid, MP 206-208°C, ¹ H NMR(400MHz, D ₂ 0)8ppm, 7.40-7.44, ( 5H, m), 4.98-5.01(lH, d 12Hz) 3.86 (1H, m),1.07 (3H d, J= 6.4),; ¹³ C NMR(400MHz, ϋ ₂ 0)δ ppm,137.3, 128.3, 127.5, 126.1, 64.1, 52.4, 16.1, ; FTIR (KBr, cm ^"1 ), 3420, 3058, 2996, 2924, 2958, 716, 692;HRMS calculated mass: 169.0658, measured mass: 169.0656, [a] ³⁰ _D = 10.4 ,(0.1 , water) ii) Synthesis of (2R, 3R)-2-methyl-3-phenyl-aziridin-2-amine compound 9

The compound 8 (10.0 g, 50mmol) obtained from step (i) was dissolved in methanol (40 ml).2N NaOH (20 ml) was slowly added under stirring to the methanol solution. The mixture was further stirred for 4h, and then was concentrated to 20ml. The aqueous layer was cooled to get the crystals of aziridine. The solution was filtered and washed 2-3 times with water (10 ml). Light yellow crystals of aziridine compound 9 (5g,76%yield)were obtained after recrystallization from hexane.

1H NMR (400MHz, CHLOROFORM-d) δ ppm, 7.32 - 7.16 (m, 5H), 3.19 (d, J=6.5 Hz, 1H), 2.39 - 2.32 (m, 1H), 0.87 - 0.84 (m, 3H); ¹³ C NMR (101MHz, CHLOROFORM-d) δ ppm, 137.7, 127.9, 127.8, 126.7, 37.2, 32.2, 13.7;FTIR (KBr, cm ^"1 ):3226, 1612, 1485, 1062,849 HRMS calculated Mass: 133.0891 , measured Mass: 133.0895,;[a] ²⁵ _D = -75.2 ,(0.4, CHC1 ₃ ); iii) Synthesis of (2S,3R)-2-methyl-3-phenyl-aziridine; methylsulfonylbenzene compound 10

(5.3g,40 mmol) of compound 9 was dissolved in TBME(30 ml), and pyridine(5ml) was slowly added to it at 0°C. p-toluenesulfonyl chloride (7.1 g) was dissolved in TBME (30ml), and the resultant solution was added slowly to the TBME containing compound 9. The reaction mixture was stirred for 4h and then of 1 N HC1 (20 ml) and 30 ml water was added to the reaction mixture, contents were shaken vigorously and the layers were separated. Aqeouslayer was discarded and TBME layer was washed again with 30 ml of water. The TBME layer was concentrated to get the compound 10 which was crystalized from hexane to get off white crystals, (7.5 g,65% yield).

1H NMR (400MHz, CHLOROFORM-d) δ ppm, 7.89 (d, J=7.8 Hz, 2H), 7.36 - 7.19 (m, 8H), 3.93 (d, J=7.3 Hz, 1H), 3.23 - 3.15 (m, 1H), 2.43 (s, 3H), 1.02 (d, J=5.8 Hz, 3H),; ¹³ C(101MHz, CHLOROFORM-d) 5ppm,18.2, 21.6, 53.7, 69.6, 126.7, 127.7, 127.9, 128.8, 129.4 129.7, 135.6, 137.5, 143.4; FTIR (KBr, cm ^-1 ) 2984, 1596, 1320, 1161 ;HRMS calculated Mass: 287.0980, measured mass: 287.0979,;[a] ²⁵ _D = -100.1 ,(1.0, CHC1 ₃ ); iv) Synthesis of N-[(lR,2R)-2-azido-l-phenyl-propyl]-4-methyl benzene sulfonamide compound 11 and

N-[(lS^S)-2-azido-l-methyl-2-phenyl-ethyl]-4-methyl-benze ne sulfonamide compound 12

Compound 10 (5.74g 20 mmol) was dissolved in acetonitrile (40 ml) and DABCO(2.24g, 20 mmol) wasadded to it.TMS azide(2.5ml) was slowly added to the reaction mixture. The reaction mixture was heated at 50°Cfor 4h. After 4h the reaction mixture was cooled to room temperature and concentrated to remove acetonitrile. Distilled water (25ml) was added to the sticky mass and stirred vigorously. The off white solid precipitated out was filtered through cintred funnel and washed 2-3 times with water. The NMR showed approximately 60:40 ratios of regioisomers 11 and 12 (Combined yield = 6.0g, yield 90%).

Purification of the enantiomers was done by preparative HPLC, to get individually pure azideisomers. Compound 12(2. Og, theoretical yield 83%), Compound 11 (2.5g, theoretical yield 83%), Compound 11

1H NMR (CHLOROFORM-d, 400MHz): δ ppm, 7.50 (d, J=7.8 Hz, 2FI), 7.14-7.21 3H), 7.02-7.1 1 (m, 4H), 5.41 (d, J=7.3 Hz, 1H), 4.24 (dd, J=7.2, 5.4 Hz, 1H), 3.72 (dd, J=6.5, 5.5 Hz, 1H), 2.34 (s, 3H), 1.24 ppm (d, J=6.5 Hz, 3H) ; X NMR C NMR (101MHz, CHLOROFORM-d) δ = 143.0, 137.6, 137.1, 129.1, 128.3, 127.8, 126. 9, 126.9, , 61.9, 61. 7, 21.30, 16.6;FTIR ((KBr, cm ^"1 ) 3255, 2893, 21 12, 1445, 1159; HRMS calculated mass: 330.1150, measured mass: 330.1149, ; [a] ²⁵ _D = -66.3 ,(0.5, CHC1 ₃ );

Compound 12

1H NMR (400MHz, CHLOROFORM-d) δ ppm, 7.64 (d, J=8.0 Hz, 2H), 7.33 - 7.13 (m, 7H), 4.87 (d, J=7.8 Hz, 1H), 4.49 (d, J=5.8 Hz, 1H), 3.56 - 3.45 (m, 1H), 2.38 (s, 3H), 2.29 (s, 1H), 0.97 (d, J=6.8 Hz, 3H), ; ¹³ C NMR (101MHz, CHLOROFORM-d) δ = 142.4, 136.4, 134.4, 128.6, 127.7, 127.6, 126.6, 125.9, 68.5, 52.6, 20.5, 17.2,;FTIR, KBr, cm ¹ ) 3236, 1602, 1495, 1072, 849, ; HRMS calculated mass: 330.1150, measured mass: 330.1152,;[a] ²⁵ _D = +91.3 (1.0, CHC1 ₃ ); v) Synthesis of N-[(1R, 2R)-2-amino-l-phenyl-propyl]-4-methyl benzene sulfonamide Compound 13

(1.65g, 5mmol) of the compound 11 was dissolved in THF (40 ml) and triphenylphosphine (1.31g, 5mmol) was added to it and the resultant mixture was stirred at 50°C for nearly 6h. After 6 h water (5ml) was added to the reaction mixture and the heating was continued for further 8h.The reaction mixture was concentrated (~5ml)to remove the THF. The aqueous layer was extracted with DCM (10ml) and concentrated to get sticky mass. Toluene (10ml) and the 4N HC1 (1ml) in dioxane were slowly added to get white precipitate of hydrochloride. The resultant solution was filtered off to get white powder ofhydrochloride. Traces of toluene were removed by drying under vacuum. Water (5ml)was added to dissolve the hydrochloride and IN NaOH was slowly added till the pH reached to 7.0. The solution was extracted with ethyl acetate (10ml x2) and concentrated to get off white solids of ligand 13. (0.8 g, yield=53%) 1H NMR (CHLOROFORM-d, 400MHz): δ ppm, 7.51 (d, J=7.8 Hz, 2H), , 7.10-7.17

(m, 3H), 7.03-7.10 (m, 4H), 4.11 (d, J=6.0 Hz, 1H), 3.21 -3.28 (m, 2H), 2.33 (s, 3H), 1.01 ppm (d, J=6.5 Hz, 3H); ¹³ C NMR (CHLOROFORM-d, 101MHz): δ ppm ,142.7, 139.3, 137.7, 129.1, 128.3, 127.3, 127.1, 127.0, , 63.2, 51.7, 21.4, 20.6 FTIR ((KBr, cm ^"1 ) 3288, 3230; 1517, 1328, 1151;HRMS calculated Mass: 304.1245, measured mass: 304.1248 difference 1.0 ppm;[oc] ²⁵ _D = -90.7 ,(1.0, CHC1 ₃ ); vi) Synthesis of N-[(1S, 2S)-2-ammo-l-methyl-2-phenyl-ethyl]-4-methyl- benzenesulfonamideligand 14

(1.65g, 5rrrmol) of the compound 12 was dissolved in THF (40 ml) and triphenyl phosphine (1.31g, 5mmol) was added to it and the resultant mixture was stirred at 50°C for nearly 6h. After 6 h water (5ml) was added to the reaction mixture and the heating was continued for further Sh.The reaction mixture was concentrated to (~5ml) remove the THF. The aqueous layer was extracted with DCM (10ml) and concentrated to get sticky mass. Toluene (10ml) and 4N HCl (1ml) in dioxane were slowly added to get white precipitate of hydrochloride. The resultant solution was filtered off to get white powder of hydrochloride. Traces of toluene were removed by drying under vacuum. Water (5ml) was added to dissolve the hydrochloride and IN NaOH was slowly added till the pH reached to 7.0. The solution was extracted with ethyl acetate (10ml x2) and concentrated to get off white solids of ligand 14. (0.8 g, yield=53%)

1H NMR (CHLOROFORM-d, 400MHz): δ = 7.68 (d, J=8.3 Hz, 2H), 7.13-7.30 (m, 8H), 3.78 (d, J=7.3 Hz, 1H), 3.11-3.40 (m, 2H), 2.41 (s, 1H), 0.92 ppm (d, J=6.5 Hz, 3H); ¹³ C NMR (101MHz, CHLOROFORM-d) δ = 143.1, 141.8, 137.9, 137.8, 129.6, 129.1, 128. 7, 128.3, 127.7, 127.0, 127.0, 125.4, 60.39, 55.33, , 21.57, 18.81 ;FTIR ((KBr, cm ^"1 ) 3268, 3240, 1507, 1323, 1152; HRMS calculated Mass: 304.1245, measured mass: 304.1249, Example 2:

Preparation of precatalyst /catalyst and initiation of asymmetric transfer hydrogenation of ketones: The procedure described by Noyoriand Xiao et. al. is used. In a typical experiment rhodium complex (5mmol, 3.09mg) and ligand (10 mmol, 3.04mg) were mixed in water / methanol. The metal complex to ligand ratio is kept 1 : 1 throught all the experiments, unless otherwise mentioned. The contents were heated at 40°C for lh.To the same solution ketone lmmol and sodium formate 5 mmol was added and reaction was initiated. Alternate Procedure: Rhodium complex and Ligand were stirred at 25 C, for 5 minutes. in water/methanol. Ketone (lmmol) and sodium formate (5mmol)were added to water/methanol to initiate the reaction.

Example 3:

Experimental procedure for transfer hydrogenation of ketones in water/methanol using sodium formate as hydrogentransfer agent

All the reactions were carried out in a Schlenk tube. In a typical experiment, [RhCp*) Cl ₂ ] ₂ (3.04 mg, 0.005mmol) and ligand-14(3.2 mg, O.OlOmmol) was added to 2 ml methanol/water in a Schlenk tube. Acetophenone (0.12 g, lmmol) and sodium formate 0.34 g,5 mmol) were added to the Schlenk tube and temperature was kept constant to desired temperature using water circulation bath. Reaction was initiated by stirring the reaction mixture with the help of magnetic needle. Reaction was continued for 2 h and reaction sample was withdrawn and 2ml of tert butyl methyl ether was added to it. Analysis of the reaction sample was carried out by chiral HPLC using Chiracel OD-H/ or Chiracel IB column supplied by Daicel company. Formation of alcohol products was confirmed by GC-MS analysis.

ATH of ketones using FA/TEA as hydrogen transfer agent

All the reactions were carried out in a Schlenk tube. In a typical experiment, FA:TEA mixture(lml) in 0.9 :1.0 molar ratio and 1ml water is added to the Schlenk tube. Temperature was kept constant to desired temperature (25°C) using water circulation bath. [RhCp*) Cl ₂ ] ₂ (3.04 mg, 0.005mmol) and ligand-14 (3.2 mg, 0.00.010 mmol) and Acetophenone (0.12 g, lmmol) were added immediately to the FA: TEA, water solution in Schlenk tube. Reaction was initiated by stirring the reaction mixture with the help of magnetic needle. Reaction was continued for 30 minutes, and reaction sample was withdrawn and -2ml of 2-propanol was added to it. Analysis of the reaction sample was carried out by Chiral HPLC using chiracel IB column supplied by Daicel Company. Formation of alcohol products was confirmed by GC-MS analysis. Tabie 1: Screening of ligands and catalyst for ATH of ketones using sodium formate in water

Reaction conditions: Catalyst: 0.5 x 10 ^"5 mol; Ligand: 1.05 x 10 ^"5 mol, Acetophenone: 1 x 10 ^"3 mol; sodium formate: 5eqwith respect to acetophenone; water 2cm ³ ; Temperature: 25°C;

Table 2: Screening of ligands and catalyst for ATH of ketones using sodium formate in methanol

Reaction conditions:

Catalyst: 0.5 x 10 ^"5 mol; Ligand: 1.05 x Ιθ ηοΙ, Acetophenone: 1 x 10 ^"3 mol; sodium

3 0

formate: 5 eq with respect to acetophenone; methanol: 2cm ; Temperature: 25 C;

Table 3: Screening of ligands and catalyst for ATH of ketones using FA/TEA as hydrogen transfer agent in water Formic acid : TEA and water

k¾5s/ Metal/ lignad ,25°C

Reaction conditions: Catalyst: 0.5 x 10 ^" mol; Ligand: 1.05 x 10 ^" Mol, Acetophenone: 1 x 10 ^"3 mol; FA: TEA molar ratio( 0.9: 1.0)+lml water; Temperature: 25°C;

Scheme 1: Asymmetric transfer hydrogenation of imines

Example 4

Experimental procedure for ATH of imines using FA/TEA as hydrogen transfer agent as shown in scheme 1: Precatalyst solution was prepared by mixing catalyst precursor, ligand and triethylamine in 1 ml of reaction solvent and mixture was stirred for an hour at reflux temperature. The solution was cooled to 28° C and substrate imine la and FA-TEA (5:2) mixture was added to this solution. The reaction was carried out for given time. Workup was carried out by adding 0.5M Na ₂ C03 solution to the reaction mixture till it was basic and extracted with DCM, dried and concentrated to give product 2a.

Conversion was calculated by analyzing the sample on GC using HP-5 column and enantiomeric excess were determined by HPLC using Chiracel OD-H column.

Table 4: Screening of ligands and catalyst for ATH of imines using FA/TEA as hydrogen transfer agent and acetonitrile as solvent

Reaction conditions: Cat (0.0025 mmol, 2mg), Lig(0.0075 mmol, 2.28 mg), TEA(0.012mmol, 1.2mg, 2μ1), Substrate (1 mmol, 205mg) , FA-TEA 5:2 (0.5ml), MeCN (4.5 ml), Temp. 28°C

Table 5: ATH of imines using Ru-ligand 14 complex with FA-TEA as hydrogen transfer agent and acetonitrile as solvent

*

No

7

reaction

6,7-dimethoxy-l-phenyl-3,4-dihydroisoquinoline

Reaction conditions: [RuCl ₂ (r| ⁶ -p-cymene)]2: 0.0025 mmol, 2 mg; Lig 14: 0.0075 mmol, 2.28 mg; TEA: 0.012mmol, 1.2 mg, μΙ^^ίτ^: 1 mmol; FA-TEA( 5:2): 0.5ml;MeCN: 4.5 ml; Temp. 28°C

Example 5

General Procedure for asymmetric transfer hydrogenation of imines using

[Rh(Cp*)C12]2 and (I S, 2S)-TsDPEN for screening of various solvents

Round bottom flask containing a magnetic stirring bar, and [Rh(Cp*)C12]2( 1.55 mg, 0.0025 mmol) and (I S, 2S)-TsDPEN (2.75 mg, 0.007 5mmol) in distilled water (1 ml) was stirred for 1 h at 40°C to generate the pre-catalyst. To the above pre-catalyst solution imine substrate (0.5 mmol), HCOONa (0.170 g, 2.5 mmol) and MeOH (1 ml) was added. The reaction mixture was stirred at 40°C for the time indicated, then cooled to room temperature and extracted with DCM (3ml x 2). Organic phase was dried over Na ₂ S0 ₄ and solvent was removed under reduced pressure. Conversion was determined by GC and enantio selectivity was determined by Chiral HPLC. Example 6

ATH of la in water using co-solvent is depicted in scheme 6

Scheme 6

1 a

97% -yield

95 % es Co-Solvent screening for ATH of imine la

Table 6: Co-solvent screening for ATH of imine la, conversions at 30 min reaction time

Entry Co-solvent Conv ee

(%) (%)

1 MeOH ^a 98 94

2 EtOH ^a 98 94

3 n-PrOH 93 91

4 n-BuOH 94 92

5 IPA 94 92

6 Ethylene 95 80

glycol

7 DMF 88 93

8 DMSO 95 89

9 NMP 95 84

10 1 ,4-dioxane 95 83

11 THF 25 92

Reaction conditions: la (0.5 mmol), [Rh(Cp*)Cl ₂ ] ₂ (0.0025 mmol),(lS, 2S)-TsDPEN (0.0075 mmol), HCOONa (2.5 mmol), 40°C,solvent (2 ml), H ₂ 0/ co-solvent (v/v, 1 : 1), Time:30min, ^a Time: 20min

From the above table, the use of co-solvent methanol in 1 : 1 ratio with water yields the product 2a with good conversion and greater enentiomeric exess.

Table 7: Co-solvent screening for ATH of imine la, conversions at 20 min reaction time

Entry Co-solvents Conv (%)

1 MeOH 98

2 EtOH 98

3 n-PrOH 70

4 n-BuOH 71

5 IPA 89

6 Ethylene glycol 80

7 DMF 77 8 DMSO 89

9 NMP 76

10 1 ,4-dioxane 72

11 THF 16

Reaction conditions:

la (0.5 mmol), [Rh(Cp*)Cl ₂ ] ₂ (0.0025 mmol),(l S, 2S)-TsDPEN (0.0075 mmol),

HCOONa (2.5 mmol), 40°C,solvent (2 ml), H ₂ 0/ co-solvent (v/v, 1 : 1), Time: 20min

Using the above general procedure, the following compounds are prepared and characterized.

Anal tic data of products

2a

(R)-6,7-Dimethoxy-l-methyl-l,2,3,4-tetrahydroisoquinoline ³ : 97% yield, 95% ee. Ή NMR (CDC1 ₃ , 200 MHz) δ (ppm): 1.44 (d, J= 6.7 Hz, 3H), 2.19 (br, 1H), 2.10(m, 2H), 2.90- 3.03 (m, 1H), 3.17-3.28 (m, 1H), 3.83 (s, 6H), 3.97-4.07 (q, J = 6.7 Hz, 1 H), 6.55 (s, 1H), 6.60 (s, 1H); ¹³ C NMR (CDC1 ₃ , 200 MHz) δ (ppm): 22.70, 29.36, 41.67, 51.14, 55.79, 55.93, 109.05, 11 1.75, 126.67, 132.22, 147.22, 147.31, HPLC (Chiralcel OD-H, hexane:isopropanol:diethylamine = 90: 10:0.1 , flow rate 1 mL/min, 254 nm): tS = 11.76min (minor), tR = 14.86 min (major).

2b (R)-6,7-Dimethoxy-l-ethyl-l,2,3,4-tetrahydroisoquinoline ³ : 95 % yield, 94% ee ; 1H NMR (CDC1 ₃ , 200 MHz) δ (ppm): 1.01-1.03 (t, J - 7.3 Hz, 3H), 1.66-1.77 (m, 1H), 1.86- 1.97( n, 1H), 2.0 (br, 1H ), 2.63-2.70 (dt, 5.0 Hz, 16.0 Hz, 1H), 2.72-2.79 (dt, J= 5.0 Hz, 16.0 Hz, 1H), 2.93-3.0 (m, 1H), 3.20-3.26 (m, 1H), 3.85 (s, 6H), 3.92 (d, J = 2.75 Hz, 1 H), 6.57 (s, 1H), 6.62 (s, 1H); ¹³ C NMR (CDC1 ₃ , 200 MHz) δ (ppm): 10.17, 28.66, 29.07, 40.76, 55.45, 55.61, 56.35, 108.83, 111.33, 126.81, 130.79, 146.79, 146.87 HPLC (Chiralcel OD-H, hexane:isopropanol: diethylamine = 80:20:0.1, flow rate lmL/min, 280 nm): tS = 9.91 min (minor), tR = 12.50 min (major).

(R)-6,7-Dimethoxy-l-propyl-l,2,3,4-tetrahydroisoquinoIine : 94 % yield , 96% ee. Ή NMR (CDC1 ₃ , 200 MHz) δ (ppm): 0.90-0.93 (t, J = 7.3 Hz, 3H), 1.33-1.49 (m, 2H), 1.56- 1.66(m, lH), 1.68-1.76(m, 1H), 1.63 (br, 1H ), 2.56-2.63 (dt, 5.5 Hz, 16.0 Hz, 1H), 2.65-2.72 (m, 1H), 2.87-2.92 (dt, 5.0Hz, 12.3 Ηζ,ΙΗ), 3.12-3.18 (m, 1H), 3.78 (s, 3H), 3.79(s, 3H), 3.82-3.85 (dd, J = 3.2Hz, 5.0 Hz, 1 H), 6.49 (s, 1H), 6.54 (s, 1H); ¹³ C NMR (CDC1 ₃ , 200 MHz) δ (ppm): 14.21, 19.38, 29.31, 38.69, 40.98, 55.18, 55.80, 55.98, 109.17, 1 11.68, 126.95, 131.30, 147.14, 147.21, HPLC (Chiralcel OD-H, hexane:isopropanol: diethylamine = 90: 10:0.1, flow rate 1 mL/min, 280 nm): tS = 10.16 min (minor), tR = 12.66 min (major).

(R)-6,7-Dimethoxy-l-isopropyl -1,2,3,4-tetrahydroisoquinoIine ⁴ : 94 % yield , 99% ee; ^! H NMR (CDCI3, 200 MHz) δ (ppm): 0.73-0.77 (d, J = 6.8 Hz, 3H), 1.11-1.15 (d, J = 6.8 Hz, 3H), 1.85 (br, 1H ), 2.23-2.38 (m, 1H), 2.52-2.67 (m, 1H), 2.74-2.82 (m, 1H), 2.72-2.97 (m, 2H), 3.26-3.35 (m, 1H), 3.85(s, 7H, Overlapped with CH), 6.57 (s, 1H), ^' 6.65 (s, 1H); ¹³ C NMR (CDCI ₃ , 200 MHz) δ (ppm): 16.0, 20.6, 30.3, 32.8, 43.1, 56.2, 56.4, 61.0, 109.4, 1 12.1, 128.8, 131.0, 147.4, 147.6, HPLC (Chiralcel OD-H, hexane:isopropanol: diethylamine = 90:10:0.1, flow rate 0.5 mL/min, 280 nm): tS = 15.41 min (minor), tR = 17.47 min (major).

2e (R)-6,7-Dimethoxy-l-butyl -1,2,3,4-tetrahydroisoquinoIine: 94% yield, 93% ee;1H NMR (CDC1 ₃ , 200 MHz) δ (ppm): 0.88-0.95, t, 7.07 Hz, 3H; 1.29-1.49, m, 2H; 1.69-1.84, m, 2H; 2.63-2.83, m, 2H; 2.92-3.04, m, 2H; 3.18-3.30, dt, IH; 5.30Hz, 10.99Hz, IH; 3.82-3.83, s, 6H; 3.88-3.96, m, IH; 6.55, s, IH; 6.59, s, IH; ¹³ C NMR (CDCI ₃ , 200 MHz) δ (ppm): 14.01, 22.80, 28.23, 28.91, 35.94, 40.85, 55.35, 55.80, 55.99, 109.29, 111.74, 126.74, 130.66, 147.27, 147.40HPLC (Chiralcel OD-H, hexane:isopropanol: diethylamine = 90:10:0.1, flow rate 1 mL/min, 280 nm): tS = 9.06 min (minor), tR = 11.51 min (major).

2f

(R)-6,7-Dimethoxy-l-cycIopentyl-l,2,3,4-tetrahydroisoquin oline: 95 % yield , 97% ee; ^! H NMR (CDCI ₃ , 200 MHz) δ (ppm): 1.23-1.76, m, 9H; 2.26-2.43, m, IH; 2.71-2.78, m, IH; 2.94-3.06, m, IH; 3.24-3.35, m, IH, 3.82, s, 6H; 3.88-3.91, d, 6.90Hz, IH; 6.54, s, IH; 6.65, s, IH; ¹³ C NMR (CDCI ₃ , 200 MHz) δ (ppm): 24.94, 25.70, 28.30, 30.37, 40.46, 45.04, 55.75, 55.98, 58.61, 109.99, 11.55, 126.64, 129.68, 146.92, 147.48; HPLC (Chiralcel OD-H, hexanedsopropanol: diethylamine = 90:10:0.1, flow rate 1 mL/min, 280 nm): tS = 11.67 min (minor), tR = 14.41 min (major).

(R)-6,7-Dimethoxy-l-cyclohexyl-l,2,3,4-tetrahydroisoquinolin e: 94 % yield , 99% ee; Ή NMR (CDC1 ₃ , 200 MHz) δ (ppm): 1.17-1.41 (m, 6H), 1.71-1.87 (m, 5H), 2.59-2.73 (dt, J = 3.7.0 Hz, 15.4 Hz, IH), 2.87-2.99 (m, 2H), 3.36-3.44 (m, IH), 3.86-3.92 (s, 7H, overlapped with NCH), 3.98-3.99 (d, 3.79Hz, IH), 6.58 (s, IH), 6.63 (s, IH); ¹³ C NMR (CDC1 ₃ , 200 MHz) δ (ppm): 25.75, 26.51, 26.65, 27.01, 29.47, 30.84, 42.29, 43.21, 55.80, 56.09, 60.31, 109.37, 111.70, 128.15, 129.71, 147.03, 147.17, HPLC (Chiralcel OD-H, hexanedsopropanol: diethylamine = 90:10:0.1, flow rate 1 mL/min, 274 rrrn): tS = 8.74 min (minor), tR = 9.60 min (major).