Patent ID: 12251688

DETAILED DESCRIPTION

In the present description, the used terms have the following meanings. The undefined terms in this document have meanings that are given and understood by one of skill in the art in light of the best knowledge available, the present disclosure and the context of the description of the patent application. Unless otherwise stated, the following chemical terms conventions have been used in the present description that have the indicated meanings as in the definitions below:

As used herein, the term “halogen atom” represents an element selected from F, Cl, Br, I.

The term “carbene” represents a particle containing an inert carbon atom with a valence number of two and two unpaired valence electrons. The term “carbene” also includes carbene analogues in which the carbon atom is replaced with another chemical element such as boron, silicon, germanium, tin, lead, nitrogen, phosphorus, sulfur, selenium, tellurium.

The term “alkyl” refers to a saturated, linear, or branched hydrocarbon substituent with an indicated number of carbon atoms. Examples of alkyl substituent are -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl. Representative branched —(C1-C10)alkyles include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, -1-methylbutyl, -2-methylbutyl, -3-methylbutyl, -1, 1-dimethylpropyl, -1,2-dimethylpropyl, -1-methylpentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -1-ethylbutyl, -2-ethylbutyl, -3-ethylbutyl, -1,1-dimethylbutyl, -1,2-dimethylbutyl, -1,3-dimethylbutyl, -2,2-dimethylbutyl, -2,3-dimethylbutyl, -3,3-dimethylbutyl, -1-methylhexyl, -2-methylhexyl, -3-methylhexyl, -4-methylhexyl, -5-methylhexyl, -1,2-dimethylpentyl, -1,3-dimethylpentyl, -1,2-dimethylhexyl, -1,3-dimethylhexyl, -3,3-dimethylhexyl, -1,2-dimethylheptyl, -1,3-dimethylheptyl and -3,3-dimethylheptyl, and the like.

The term “alkoxy” refers to an alkyl substituent as defined above linked through an oxygen atom.

The term “perfluoroalkyl” represents an alkyl group as defined above in which all hydrogen atoms have been replaced by the same or different halogen atoms.

The term “cycloalkyl” refers to a saturated mono- or polycyclic hydrocarbon substituent with an indicated number of carbon atoms. Examples of the cycloalkyl substituent are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, cyclooktyl, -cyclononyl, -cyclodecyl, and the like.

The term “alkenyl” refers to a saturated, linear, or branched non-cyclic hydrocarbon substituent having an indicated number of carbon atoms and containing at least one carbon-carbon double bond. Examples of the alkenyl substituent are -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-di-methyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl, -3-decenyl and the like.

The term “aryl” refers to an aromatic mono- or polycyclic hydrocarbon substituent with an indicated number of carbon atoms. Examples of an aryl substituent are -phenyl, -tolyl, -silyl, -naphthyl, -2,4,6-trimethylphenyl, -2-fluorophenyl, -4-fluorophenyl, -2,4,6-trifluorophenyl, -2,6-difluorophenyl, -4-nitrophenyl and the like.

The term “aralkyl” refers to an alkyl substituent as defined above substituted with at least one aryl as defined above. Examples of aralkyl substituent are -benzyl, -diphenylmethyl, -triphenylmethyl and the like.

The term “heteroaryl” refers to an aromatic mono- or polycyclic hydrocarbon substituent with an indicated number of carbon atoms in which at least one carbon atom has been replaced by a heteroatom selected from O, N and S. Examples of a heteroaryl substituent are -furyl, -thienyl, -imidazolyl, -oxazolyl, -thiazolyl, -isoxazolyl, -triazolyl, -oxadiazolyl, -thiadiazolyl, -tetrazolyl, -pyridyl, -pyrimidyl, -triazinyl, -indolyl, -benzo[b]furyl, -benzo[b]thienyl, -indazolyl, -benzoimidazolyl, -azazolyl, -quinolyl, -isoquinolyl, -carbazolyl, and the like.

The term “heterocycle” refers to a saturated or partially unsaturated, mono- or polycyclic hydrocarbon substituent with an indicated number of carbon atoms in which at least one carbon atom has been replaced with a heteroatom selected from O, N and S. Examples of a heterocycle substituent are furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl, hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, quinolinyl, isoquinolinyl, chromonyl, coumarinyl, indolyl, indolizinyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, carbazolyl, β-carbolinyl, and the like.

The term “neutral ligand” refers to a non-charged substituent capable of coordinating with a metallic center (a ruthenium atom). Examples of such ligands can be: amines, phosphines and their oxides, alkyl and aryl phosphites and phosphates, arsines and their oxides, ethers, alkyl and aryl sulphides, coordinated hydrocarbons, alkyl halides and aryl halides.

The term “anionic ligand” refers to a substituent capable of coordinating with a metallic center (a ruthenium atom) having a charge capable of partially or completely compensating the charge of the metallic center. Examples of such ligands may be fluoride anions, chloride, bromide, iodide, cyanide, cyanate and thiocyanate anions, carboxylic acid anions, alcohol anions, phenol anions, thiols and thiophene anions, hydrocarbon anions with delocalized charge (e.g. cyclopentadiene), anions of (organo)sulfuric and (organo)phosphoric acids and their esters (such as e.g. anions of alkylsulfonic and arylsulphonic acids, anions of alkylphosphoric and arylphosphoric acids, anions of alkyl and aryl esters of sulfuric acid, anions of esters of alkyl and aryl phosphoric acids, anions of alkyl and aryl esters of alkyl phosphorus and arylphosphoric acids). Optionally the anion ligand may have L1, L2and L3groups, linked in the same way as the catechol anion, the acetylacetone anion, the salicylic aldehyde anion. Anion ligands (X1, X2) as well as neutral ligands (L1, L2, L3) can be linked to each other to form multidentate ligands, e.g. a bidentate ligand (X1-X2), a tridential ligand (X1-X2-L1), a tetradentate ligand (X1-X2-L-L2), a bidentate ligand (X1-L1), a tridential ligand (X1-L1-L2), a tetradentate ligand (X1-L-L2-L3), a bidentate ligand (L1-L2), a tridential ligand (L1-L2-L3). Examples of such ligands are: catechol anion, acetylacetone anion and salicylic aldehyde anions.

The term “heteroatom” represents an atom selected from the group of oxygen, sulfur, nitrogen, phosphorus and others.

EMBODIMENTS OF THE INVENTION

The following examples are only intended to illustrate the invention and to explain its particular aspects, without limitation, and should not be equated with its entire scope, which is defined in the appended claims. In the following examples, unless otherwise indicated, standard materials and methods used in the field were used or the manufacturers' recommendations for specific reagents and methods were followed.

The use of (pre)catalysts 1 was compared with (pre)catalysts C1-C3, structures of which are illustrated below:

Diethyl malonate (S1), ethyl undecenoate (S3), acrylonitrile and methyl stearate are commercially available compounds. Diethyl (2,2-dimethylallyl)malonate (S2) was prepared according to the procedure from literature, S1 and S3 were distilled under reduced pressure and stored over activated alumina. Acrylonitrile was dried with 4 Å molecular sieves and deoxygenated with argon. All reactions were carried out under argon. Toluene was washed with citric acid, water, dried with 4 Å molecular sieves and deoxidized with argon.

The composition of the reaction mixtures was examined by gas chromatography using a PerkinElmer Clarus 680 GC apparatus equipped with a GL Sciences InertCap 5 MS/NP capillary column.

The individual components of the reaction mixtures were identified by comparing the retention times with commercial standards or isolated from reaction mixtures for which the structure was confirmed by NMR.

Example I

Application Example: RCM Reaction of Diethyl Diallylmalonate (S1)

To a solution of S1 (0.240 g, 1.0 mmol) in toluene (10 ml) at a designated temperature a determined amount of the corresponding (pre)catalyst in toluene (50 μl) was added in one portion. At appropriate intervals, samples of the reaction mixture were taken, to which 3 drops of ethyl vinyl ether were added to deactivate the catalyst. The samples were analyzed by gas chromatography.

TABLE 1Results of RCM reaction of diethyldiallylmalonate S1 at 29° C. using 0.1 mol % (pre)catalysts.Conversion [%]Time [min]1b1d24130572631091902098993099>9960>99—

TABLE 2Results of RCM reaction of diethyl diallylmalonateS1 at 40° C. using 0.1 mol % (pre)catalysts.Conversion [%]Time [min]C21a1b1c1d2——75—415——95—8810——>99—9920————>9930—————60<116—13—

TABLE 3Results of RCM reaction of diethyl diallylmalonate S1 at 80° C.using 0.1 mol % (pre)catalysts.TimeConversion [%][min]C21a1bC11c1d1g2—20>99—13>99345—51——18—6610—77——30—90201388—1943—9930—91——47—>99602494—3352——

Example II

Application Example: RCM Reaction of (2,2-Dimethylallyl) Malonate (S2)

To a solution of S2 (0.240 g, 1.0 mmol) in toluene (10 ml) at a designated temperature a determined amount of the corresponding (pre)catalyst in toluene (50 μl) was added in one portion. At the appropriate time intervals, samples of the reaction mixture were taken, to which 3 drops of ethyl vinyl ether were added to deactivate the catalyst. The samples were analyzed by gas chromatography.

TABLE 4Results of RCM reaction of (2,2-dimethylallyl)malonate (S2) at 80° C. using 0.5 mol % (pre)catalysts.Conversion [%]Time [min]C31e309193609394

TABLE 5Results of RCM reaction of (2,2-dimethylallyl)malonate (S2) at 100° C. using 0.5 mol % (pre)catalysts.Conversion [%]Time [min]C31e308896608996

Example III

Application Example: RCM Reaction of Acrylonitrile with Ethyl Undecanoate (S3)

To a solution of S3 (1.062 g, 5.0 mmol, 1 molar equivalent), acrylonitrile (0.655 mL, 10.0 mmol, 2 molar equivalents) and methyl stearate (internal standard) in toluene (8.3 mL) at 85° C. under argon, a solution of the appropriate (pre)catalyst (100 ppm) in toluene (50 μl) was added in one portion. The reaction was stirred for 1 hour. A stream of argon was passed through the solution during the reaction. A sample was taken, into which 3 drops of ethyl vinyl ether were added to deactivate the catalyst. The sample was analyzed by gas chromatography.

TABLE 6Results of CM reaction of acrylonitrile with S3.ConversionSelectivity towards P3(pre)catalyst [Ru][%]P3 [%]D3 [%][%]1a34322941b26242921c55469841d4437784C21716194

Example IV

Application Example: Homometathesis of Ethyl Undecenoate (S3)

To S3 (3.00 g, 14.13 mmol) and methyl stearate (internal standard) at 85° C. under argon a solution of the appropriate (pre)catalyst (30 ppm) in toluene (50 μl) was added in one portion. The reaction was stirred for 1 hour. A stream of argon was passed through the solution during the reaction. A sample was taken, into which 3 drops of ethyl vinyl ether were added to deactivate the catalyst. The sample was analyzed by gas chromatography.

TABLE 7Results of homodimerization reaction of S3.Selectivity towards(pre)catalyst [Ru]Conversion [%]D3 [%]D3 [%]1a9967681b8155681c9872741d966568C2765269C1514384

The C1-C2 (pre)catalysts known in the state of the art initiate the metathesis reaction of S3 without the addition of an activator, while their activity is significantly lower than (pre)catalysts 1a-d.

Example V

To the Gru-II complex (2.000 g, 2.36 mmol, 1 molar equivalent) dry deoxygenated toluene (23 ml), benzylidene ligand 9a (0.615 g, 2.59 mmol, 1.1 molar equivalent) and CuCl (0.350 g, 3.53 mmol, 1.2 molar equivalent) was added under argon. The reaction was stirred for 20 minutes at 55° C. Than was cooled to room temperature and concentrated to dryness. The residue was dissolved in ethyl acetate, filtered through a pad of Celite and concentrated to dryness. The crude product was isolated using column chromatography on silica gel (eluent:ethyl acetate/cyclohexane 2:98→1:9). The green fraction was collected and concentrated to dryness. The residue was dissolved in methylene chloride and excess of heptane was added. Methylene chloride was slowly removed under reduced pressure. The resulting precipitate was filtered and washed with cold heptane to give a green crystalline solid—(pre)catalyst 1a (1.340 g, 81%).

1H NMR (CD2Cl2, 600 MHz): δ=18.70 (s, 1H), 7.50 (t. J=7.5 Hz. 1H), 7.31-7.23 (m, 3H), 7.19 (t, J=7.4 Hz. 1H), 7.05 (br s, 4H), 6.99 (br s, 2H), 6.90 (d, J=7.5 Hz, 1H), 6.74 (d, J=7.3 Hz, 1H), 4.10 (s, 4H), 3.90-3.00 (br m, 3H), 2.90-2.00 (br m, 19H), 1.73 (s, 3H).

13C NMR (CD2Cl2, 150 MHz): δ=313.4, 313.3, 213.4, 148.9, 139.0, 134.0, 132.6, 132.5, 131.6, 129.8, 129.1, 129.0, 128.4, 128.3, 127.3, 60.0, 43.1, 32.4, 29.6, 23.3, 21.4, 14.4.

HRMS: ESI was calculated for C37H43N3Ru [M-2Cl]2+: 315.6250; found: 315.6247. (dimer)

Example VI

To the M2 complex (1.25 g, 2.36 mmol, 1 molar equivalent) dry deoxygenated toluene (13 ml), benzylidene ligand 9b (0.495 g, 1.58 mmol, 1.2 molar equivalent) and CuCl (0.183 g, 1.84 mmol, 1.4 molar equivalent) was added under argon. The reaction was stirred for 30 minutes at 70° C. Than was cooled to room temperature and concentrated to dryness. The residue was dissolved in ethyl acetate, filtered through a pad of Celite and concentrated to dryness. The crude product was isolated using column chromatography on silica gel (eluent:ethyl acetate/cyclohexane 2:98→1:9). The green fraction was collected and concentrated to dryness. The residue was dissolved in methylene chloride and excess of heptane was added. Methylene chloride was slowly removed under reduced pressure. The resulting precipitate was filtered and washed with cold heptane to give a green crystalline solid—(pre)catalyst 1b (0.490 g, 48%).

1H NMR (CD2Cl2, 600 MHz): δ=18.61 (s, 1H), 7.60-6.30 (m, 18H), 4.60-1.50 (m, 28H).

13C NMR (CD2Cl2, 150 MHz): δ=315.3, 213.2, 149.5, 139.0, 135.4, 134.6, 132.3, 131.0, 129.9, 129.1, 127.9, 127.8, 126.1, 58.8, 34.7, 22.9, 21.3, 14.4.

HRMS: ESI was calculated for C43H47N3ClRu [M-Cl]+: 742.2502; found: 742.2493.

Example VII

To the M20-SIPr complex (2.00 g, 1.97 mmol, 1 molar equivalent) dry deoxygenated toluene (19 ml), benzylidene ligand 9a (0.468 g, 1.97 mmol, 1.0 molar equivalent) and CuCl (0.293 g, 2.96 mmol, 1.5 molar equivalent) was added under argon. The reaction was stirred for 30 minutes at 80° C. Than was cooled to room temperature and concentrated to dryness. The residue was dissolved in ethyl acetate, filtered through a pad of Celite and concentrated to dryness. The crude product was isolated using column chromatography on silica gel (eluent:ethyl acetate/cyclohexane 2:98→1:9). The green fraction was collected and concentrated to dryness. The residue was dissolved in methylene chloride and excess of heptane was added. Methylene chloride was slowly removed under reduced pressure. The resulting precipitate was filtered and washed with cold heptane to give a green crystalline solid—(pre)catalyst 1c (0.470 g, 30%).

1H NMR (CD2Cl2, 600 MHz): δ=18.61 (s, 1H), 7.70-6.70 (m, 14H), 6.57 (d, J=7.7 Hz, 1H), 4.80-2.30 (br m, 11H), 2.20-0.20 (br m, 28H).

13C NMR (CD2Cl2, 150 MHz): δ=307.0, 215.5, 149.6, 148.1, 133.9, 132.7, 131.5, 129.9, 128.9, 128.7, 128.4, 128.3, 127.5, 124.9, 60.1, 55.1, 43.6, 29.2, 27.0, 23.9.

HRMS: ESI was calculated for C45H58N4ClRu [M-Cl+CH3CN]+: 791.3397; found: 791.3391.

Example VIII

To the M20-SIPr complex (0.500 g, 0.49 mmol, 1 molar equivalent) dry deoxygenated toluene (5 mL), benzylidene ligand 9b (0.185 g, 0.59 mmol, 1.2 molar equivalent) and CuCl (0.059 g, 0.59 mmol, 1.2 molar equivalent) was added under argon. The reaction was stirred for 20 minutes at 60° C. It was cooled to room temperature and concentrated to dryness. The residue was dissolved in ethyl acetate, filtered through a pad of Celite and concentrated to dryness. The crude product was isolated using column chromatography on silica gel (eluent:ethyl acetate/cyclohexane 2:98→1:9). The green fraction was collected and concentrated to dryness. The residue was dissolved in methylene chloride and excess of heptane was added. Methylene chloride was slowly removed under reduced pressure. The resulting precipitate was filtered and washed with cold heptane to give a green crystalline solid—(pre)catalyst 1d (0.083 g, 20%).

1H NMR (CD2Cl2, 600 MHz): δ=18.33 (s, 1H), 7.80-6.95 (m, 12H), 6.95-6.30 (m, 7H), 6.05 (d, J=7.7 Hz, 1H), 4.60-2.60 (br m, 14H), 2.0-0.20 (br m, 24H).

13C NMR (CD2Cl2, 150 MHz): δ=311.0, 215.6, 148.6, 135.9, 132.8, 132.6, 130.0, 129.6, 128.6, 127.4, 127.4, 126.9, 126.4, 124.4, 62.2, 59.3, 57.4, 55.7, 32.4, 29.6, 27.8, 26.4, 23.7, 23.3, 14.4.

Example IX

To the o-Tollyl compound (0.300 g, 1.04 mmol, 1.5 molar equivalent) dry deoxygenated toluene (5 mL) was added, placed in an oil bath heated to 45° C. and then LiHMDS (1 mL, 1.04 mmol, 1.5 molar equivalent) was added. After 5 minutes of reaction, 1g (0.522 g, 0.69 mmol, 1 molar equivalent) and CuCl (0.103 g, 1.04 mmol, 1.5 molar equivalent) were added under argon. The reaction was stirred for 20 minutes at 45° C. It was cooled to room temperature and concentrated to dryness. The residue was dissolved in ethyl acetate, filtered through a pad of Celite and concentrated to dryness. The crude product was isolated using column chromatography on silica gel (eluent:ethyl acetate/cyclohexane 2:98→1:9). The green fraction was collected and concentrated to dryness. The residue was dissolved in methylene chloride and excess of heptane was added. Methylene chloride was slowly removed under reduced pressure. The resulting precipitate was filtered and washed with cold heptane to give a green crystalline solid—(pre)catalyst 1e (0.274 g, 55%).

ESI was calculated for C39H39N3ClRu [M-Cl]+: 686.1878; found: 686.1884.

To the Alk-I complex (1.00 g, 1.25 mmol, 1 molar equivalent) dry deoxygenated methylene chloride (12 ml), benzylidene ligand 9a (0.356 g, 1.50 mmol, 1.2 molar equivalent) and CuCl (0.148 g, 1.50 mmol, 1.2 molar equivalent) was added under argon. The reaction was stirred for 20 minutes at 35° C. It was cooled to room temperature and concentrated to dryness. The residue was dissolved in ethyl acetate, filtered through a pad of Celite and concentrated to dryness. The residue was dissolved in methylene chloride and excess methanol was added. Methylene chloride was slowly removed under reduced pressure. The resulting precipitate was filtered and washed with cold methanol to give a green crystalline solid—(pre)catalyst 1f (0.592 g, 70%).

1H NMR (CD2Cl2, 600 MHz): δ=19.15 (s, 1H), 7.90-6.70 (m, 9H), 4.45-4.05 (m, 2H), 2.40-2.26 (m, 3H), 2.12-1.90 (m, 8H), 1.88-1.58 (m, 16H), 1.36-1.16 (m, 11H).

13C NMR (CD2Cl2, 150 MHz): δ=295.5, 148.2, 134.3, 133.2, 132.8, 132.4, 129.9, 129.1, 128.7, 128.6, 126.5, 63.1, 43.8, 35.2 (d, J=20.3 Hz), 30.7, 28.5 (d, J=10.0 Hz), 27.0, 26.9.

31P NMR (CD2Cl2, 243 MHz): δ=35.6.

Example XI

To the Alk-I complex (1.00 g, 1.25 mmol, 1 molar equivalent) dry deoxygenated methylene chloride (12 ml), benzylidene ligand 9b (0.470 g, 1.50 mmol, 1.2 molar equivalent) and CuCl (0.148 g, 1.50 mmol, 1.2 molar equivalent) was added under argon. The reaction was stirred for 20 minutes at 35° C. It was cooled to room temperature and concentrated to dryness. The residue was dissolved in ethyl acetate, filtered through a pad of Celite and concentrated to dryness. The residue was dissolved in methylene chloride and excess methanol was added. Methylene chloride was slowly removed under reduced pressure. The resulting precipitate was filtered and washed with cold methanol to give a green crystalline solid—(pre)catalyst 1g (0.592 g, 63%).

1H NMR (CD2Cl2, 600 MHz): δ=19.14 (d, J=10.2 Hz, 1H), 8.00-6.80 (m, 14H), 4.33 (d, J=14.0 Hz, 2H), 4.20-2.90 (br m, 2H), 2.39-2.26 (m, 3H), 2.05-1.60 (m, 22H), 1.38-1.16 (m, 10H).

13C NMR (CD2Cl2, 150 MHz): δ=297.7, 148.9, 134.6, 133.0, 132.7, 129.6, 129.2, 128.6, 126.6, 60.2, 34.8 (d, J=20.3 Hz), 30.2, 28.5 (d, J=9.8 Hz), 27.0.

31P NMR (CD2Cl2, 243 MHz): δ=34.5.

Example XII

To the solution of 1,2,3,4-tetrahydroisoquinoline (26.600 g, 200.0 mmol, 2 molar equivalents) and triethylamine (10.120 g, 100.0 mmol, 1 molar equivalent) in methylene chloride (500 ml) cooled to 0° C. benzyl bromide (17.100 g, 100.0 mmol, 1 molar equivalent) was added dropwise for 10 minutes. [The mixture] was slowly warmed to room temperature and stirred overnight. It was washed with water and dried over Na2SO4. It was filtered and evaporated. It was distilled under reduced pressure. The product was collected in a fraction with a boiling point of 126-132° C. at a pressure of 1.1×10−2 mbar (colorless oil, 18.470 g, 83%).

1H NMR (CDCl3, 600 MHz): δ=7.49-7.45 (m, 2H), 7.43-7.38 (m, 2H), 7.36-7.32 (m, 1H), 7.21-7.14 (m, 3H), 7.06-7.03 (m, 1H), 3.76 (s, 2H), 3.71 (s, 2H), 2.97 (t, J=5.9 Hz, 2H), 2.82 (t, J=5.9 Hz, 2H).

13C NMR (CDCl3, 150 MHz): δ=138.4, 134.9, 134.3, 129.0, 128.6, 128.2, 127.0, 126.5, 126.0, 125.5, 62.7, 56.1, 50.6, 29.3.

HRMS: ESI was calculated for C16H18N [M+H]+: 224.1434; found: 224.1441.

To the amine, obtained in the previous step, (12.946 g, 58.0 mmol, 1 molar equivalent) in ethanol (96%, 150 ml) methyl iodide (16.460 g, 116.0 mmol, 2 molar equivalents) was added. It was stirred at 35° C. overnight. The excess of methyl iodide was evaporated under reduced pressure. NaOH (3.480 g, 87.0 mmol, 1.5 molar equivalents) was added. It was heated in reflux with condenser vigorously stirring overnight. It was cooled and concentrated to dryness. The residue was dissolved in methylene chloride, washed with water and dried over Na2SO4. Filtered and concentrate to dryness. The crude product was filtered through a thin pad of silica gel (eluent:ethyl acetate/cyclohexane 5:95). Concentrated to dryness to give a colorless oil—ligand 9a (12.711 g, 92%).

1H NMR (CDCl3, 600 MHz): δ=7.53 (dd, J=7.5; 1.6 Hz, 1H), 7.35-7.27 (m, 5H), 7.26-7.19 (m, 3H), 7.17 (dd, J=17.5; 10.9 Hz, 1H), 5.65 (dd, J=17.6; 1.5 Hz, 1H), 5.26 (dd, J=11.0; 1.5 Hz, 1H), 3.55 (s, 2H), 3.51 (s, 2H), 2.14 (s, 3H).

13C NMR (CDCl3, 150 MHz): δ=139.4, 137.7, 136.2, 134.9, 130.4, 129.0, 128.1, 127.3, 126.9, 125.6, 114.8, 62.1, 60.0, 42.0.

HRMS: ESI was calculated for C17H20N [M+H]+: 238.1590; found: 238.1596.

Example XIII

To a solution of 1,2,3,4-tetrahydroisoquinoline (1.332 g, 10.0 mmol, 1 molar equivalent) and benzyl bromide (3.590 g, 21.0 mmol, 2.1 molar equivalents) in acetonitrile (100 mL) was added K2CO3(2.073 g, 15.0 mmol, 1.5 molar equivalents). It was heated under reflux with condenser vigorously stirring for 4 hours. It was cooled, filtered and concentrated to dryness. The crude ammonium salt was dissolved in methylene chloride and excess ethyl acetate was added. Methylene chloride was slowly evaporated under reduced pressure. The precipitated product was filtered and washed with ethyl acetate. The ammonium salt was obtained as a white crystalline solid (3.880 g, 98%). The ammonium salt obtained in the previous step was dissolved in ethanol (96%, 50 ml) and NaOH (0.590 g, 14.8 mmol, 1.5 molar equivalent) was added. It was heated in reflux with stirring for 2 hours. The mixture was cooled and methanol was evaporated, yielding a yellow oil. It was dissolved in methylene chloride, washed with water. It was dried over Na2SO4, filtered and concentrated to dryness to give a slightly yellow oil (2.605 g, 84%).

1H NMR (CDCl3, 600 MHz): δ=7.56-7.52 (m, 1H), 7.50-7.46 (m, 1H), 7.43-7.39 (m, 4H), 7.38-7.34 (m, 4H), 7.31-7.25 (m, 4H), 7.05 (dd, J=17.4; 10.9 Hz, 1H), 5.64 (dd, J=17.4; 1.6 Hz, 1H), 5.25 (dd, J=10.9; 1.6 Hz, 1H), 3.64 (s, 2H), 3.57 (s, 4H).

13C NMR (CDCl3, 150 MHz): δ=139.4, 137.6, 136.4, 135.1, 130.3, 129.0, 128.1, 127.4, 127.2, 126.9, 125.6, 114.5, 58.2, 56.1, 26.9.