CN102336621A - Method for synthesizing chiral fluoroamine by palladium catalytic asymmetric hydrogenation - Google Patents

Method for synthesizing chiral fluoroamine by palladium catalytic asymmetric hydrogenation Download PDF

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CN102336621A
CN102336621A CN2010102387472A CN201010238747A CN102336621A CN 102336621 A CN102336621 A CN 102336621A CN 2010102387472 A CN2010102387472 A CN 2010102387472A CN 201010238747 A CN201010238747 A CN 201010238747A CN 102336621 A CN102336621 A CN 102336621A
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CN102336621B (en
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周永贵
陈木旺
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Dalian Institute of Chemical Physics of CAS
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Abstract

The invention discloses a method for synthesizing chiral fluoroamine by palladium catalytic asymmetric hydrogenation, wherein, the used catalysis system comprises a palladium chiral diphosphite complex. The reaction is carried out under the following conditions that: the temperature is 0-50 DEG C, the solvent is a 2,2,2-trifluoroethyl alcohol, the pressure is 1-42 atm, the ratio of the substrate to the catalyst is 50 : 1, the used metal precursor is palladium trifluoroacetate, the used chiral ligand is a chiral diphosphite ligand. The catalyst is prepared by stirring the palladium metal precursor and the chiral diphosphite ligand in acetone at room temperature, and then carrying out vacuum condensation. According to the invention, by the hydrogenation of imine containing trifluoromethyl, corresponding chiral amine containing trifluoromethyl is obtained, the enantiomeric excess can reach to 94 %; by the hydrogenation of imine containing perfluoroalkyl, corresponding chiral amine containing perfluoroalkyl is obtained, and the enantiomeric excess can reach to 86 %. The present invention has the advantages of simple and practical operation, high enantioselectivitiy, good yield, green atom economy of the reaction, and no environmental pollution.

Description

A kind of method of palladium catalysis asymmetric hydrogenation synthesis of chiral fluoroamine
Technical field
The present invention relates to a kind of method of homogeneous system height enantioselectivity catalytic hydrogenation fluoro imines synthesis of chiral fluoroamine of using palladium.
Background technology
Fluorine-containing imines is very important building block, is widely used for synthetic [a) Prakash, the G.K.S. of materials chemistry, agricultural chemicals and medicine intermediate; Yudin, A.Chem.Rev.1997,97,757-786; B) Ruano, J.L.G.; Alem á n, J.; .Catal á n, S.; Marcos, V; Monteagudo, S.; Parra, A.; Pozo, C.; Fustero, S.Angew.Chem.Int.Ed.2008,47,7941-7944.].Yet because the strong electrophilic effect of trifluoromethyl or Polyfluoroalkyl is difficult to synthetic this compounds [a) Nelson, D.W. with traditional method; Easley, R.A.; Pintea, B.N.V.Tetrahedron Lett.1999,40,25-28; B) , B.; Abid, M.; London, G.; Esquibel, J.; , M.; Mhadgut, S.C.; Yan, P.; Prakash, G.K.S.; Angew.Chem.Int.Ed2005,44,3086-3089.].We are reference [a) Uneyama, K.; Amii, H.; Katagiri, T.; Kobayashi, T.; Hosokawa, T.J.Fluor.Chem.2005,126,165-171, b) Wu, Y.-M.; Li, Y.; Deng; J.J.Fluor.Chem.2005; 125,791-795.] developed a kind of method that obtains fluorine-containing imines through the catalytic trifluoroacetyl imino-choride of palladium or Polyfluoroalkyl acetyl imino-choride and aryl or alkylboronic acids through the Suzuki-Miyaura cross-coupling.Hydrogenation through to fluorine-containing imines can obtain fluorine-containing aminated compounds.
Fluorine-containing aminated compounds is a kind of very important structural unit in the organic synthesis, because the introduction of fluorine atom usually causes the change of the physiologically active of organic cpds.The fluorine-containing aminated compounds of chirality also is building block [a) Soloshonok, V.A. (Ed.), the Fhuorine-containing Synthons of biologically active in the organic synthesis; ACS Symposium Series #911, Oxford University Press, 2005; B) Soloshonok, V.A.; Mikami, K.; Yamazaki, T.; Welch, J.T.; Honek, J. (Ed.), Currenl Fluoroorganic Chemistry.New Synthetic Directions; Technologies, Materials and Biological Applications, ACS Symposium Series #949; Oxford University Press, 2006; C) Uneyama, K.Organofluorine Chemistry; Blackwell:Oxford, 2006; D) Ma, J.-A.; Cahard, D.Chem.Rev, 2004,104,6119-6146.], be the midbody of many medicine and pesticide molecule.Yet bibliographical information mainly is through substrate for induction [Ni, C.F.; .Liu, J.; Zbang, L.J.; Hu, J.B.Angew.Chem.Int.Ed.2007,46,786-789.], catalytic asymmetric reduction [Gosselin, F.; O ' Shea, P.D.; Roy, S.; Reamer, R.A.; Chen, C.-Y.; Volante.R.P.Org.Lett.2005,7,355-358.] and asymmetric addition [Fustero, S.; Pozo, C.D.; Catal á n, S.; Alem á n, J.; Parra, A.; Marcos, V.; .Ruano, J.L.G.Org.Lett.2009,11,641-644.] synthesize this compounds, and the method through synthetic this compounds of catalysis asymmetric hydrogenation does not also have the bibliographical information mistake at present.
Advantages such as asymmetric hydrogenation has that Atom economy is good, activity of such catalysts is high, speed of response is fast, the convenient separation of product, side reaction are few.Present many chiral catalysis hydro genation system have obtained application in industry.Because the asymmetric hydrogenation of imines can access Chiral Amine, therefore, we want the method synthesis of chiral fluoroamine through asymmetric catalytic hydrogenation fluoro imines.
Summary of the invention
The purpose of this invention is to provide and a kind ofly synthesize a kind of simple fluoro imines through the catalytic Suzuki-Miyaura cross-coupling of palladium, and the method for the homogeneous system height enantioselectivity catalytic hydrogenation fluoro imines synthesis of chiral fluoroamine of using palladium.The present invention's practicality easy and simple to handle, enantioselectivity is high, and productive rate is good, and reaction has Atom economy, advantages of environment protection.
For realizing above-mentioned purpose, technical scheme of the present invention is following:
Catalystsystem is the chiral diphosphine title complex of palladium, and reaction formula and condition are following:
Figure BSA00000207638100021
In the formula:
Temperature: 0-50 ℃;
Solvent: 2,2,2 tfifluoroethyl alcohol;
Pressure: a 1-42 normal atmosphere;
Time: 15-24 hour;
Metal precursor: trifluoracetic acid palladium;
Chiral ligand: biphosphine ligand;
The Preparation of catalysts method is: the metal precursor of palladium and chiral diphosphine ligand in acetone stirring at room 0.5-1 hour, vacuum concentration was removed acetone then.Said biphosphine ligand is SynPhos, SegPhos, BINAP, MeO-BiPhep, C 4-TunePhos, Cl-MeO-BiPHep, 3,5-xyiyl-BINAP, DiflucrPhos or P-Phos.
Wherein:
Reactant and product substituent R can be C1-C10 alkyl group and aromatic yl group, and Rf can be difluoromethyl, trifluoromethyl, pentafluoroethyl group, seven fluoropropyls or ten trifluoro hexyls, and PG can be the aryl of band methyl, methoxyl group, trifluoromethyl and different halogens.
Wherein, the aromatic yl group of more excellent R is 2,3 or 4 bit strip methyl on the phenyl ring, methoxyl group, trifluoromethyl, halogen (fluorine, chlorine, bromine) and 3,5-two fluoro substituents.
The aryl of PG is 4 bit strip methyl, methoxyl group, trifluoromethyl and a halogen (fluorine, chlorine, bromine) on the phenyl ring.
Raw material fluoro imines and title complex be 25-50 in molar ratio: 1. solvent load: per 0.0025 mmole is with the trifluoroethanol of 2-3 milliliter.
The chirality fluoroamine that is obtained, its enantiomeric excess is at 69-94%.
The present invention has the following advantages
1. reactive behavior and enantioselectivity are high, react completely, and it is single-minded to generate product, and nucleus magnetic hydrogen spectrum does not detect side reaction, make the ability convenient separation can obtain the pure article of high enantiomeric excess.
2. can obtain various types of fluorine-containing amine, for example difluoromethyl, trifluoromethyl.
3. Preparation of Catalyst is convenient, and operation is simple and practical.
4. hydrogenation mild condition, room temperature just can be reacted.
5. the Chiral Amine that obtains further derivatize in natural product synthetic.
Embodiment
Through embodiment the present invention is detailed below, but the present invention is not limited to following embodiment.
Embodiment 1: the optimization of condition
In reaction flask, drop into the chiral ligand L in trifluoracetic acid palladium (0.0025 mmole, 0.85 milligram) and the below diagram 1-L 6In a kind of (0.003 mmole), add 1 milliliter of acetone behind the nitrogen replacement, stirring at room 1 hour.Vacuum concentration then; Nitrogen adds 3 milliliters of 2,2,2 tfifluoroethyl alcohols down; This solution forwarded to be placed with (35 milligrams of substrate 1a in advance; 0.125 mmole) and in the reaction kettle of
Figure BSA00000207638100031
MS molecular sieve (40 milligrams), feed 41 normal atmosphere of hydrogen, 25 ℃ of reactions 16 hours.Slow release hydrogen removes the direct column chromatography for separation in the back of desolvating and obtains pure product, and reaction formula and ligand structure are following:
Figure BSA00000207638100032
2a：(R)-4-Methoxy-N(2，2，2-trifluoro-1-phenylethyl)aniliee。99％yield，93％ee，[α] RT D＝-53.6(c0.60，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.48-7.38(m，5H)，6.77(dd，J＝8.9，2.1Hz，2H)，6.65(t，J＝8.9Hz，2H)，4.84(q，J＝7.4Hz，1H)，4.12(br?s，1H)，3.73(s，3H)； 13C?NMR(100MHz，CDCl 3)δ153.5，139.7，134.5，129.2，128.1，126.8，125.4(q，J C-F＝280Hz)，115.9，115.0，62.0(q，J C-F＝30Hz)，55.8；HPLC(AD-H，elute：Hexanes/i-PrOH＝90/10，detector：254nm，flow?rate：0.8mL/min)，t 1＝9.9min，t 2＝13.7min.
The enantiomeric excess of product is used the chirality liquid chromatogram measuring, sees table 1.
Table 1. contains the asymmetric hydrogenation of trifluoromethyl imines 1a
Figure BSA00000207638100041
Embodiment 2: palladium catalysis asymmetric hydrogenation synthesizes various chirality fluoroamines 2
In reaction flask, drop into trifluoracetic acid palladium (0.85 milligram, 0.0025 mmole) with (R)-Cl-MeO-BiPhep (2.0 milligrams, 0.003 mmole), 1 milliliter of acetone of adding behind the nitrogen replacement, stirring at room 1 hour.Vacuum concentration then; Nitrogen adds 3 milliliter 2 down; 2; The 2-trifluoroethanol is transferred to this solution in the reaction kettle that is placed with substrate 1 (0.125 mmole) and
Figure BSA00000207638100042
MS (40 milligrams) in advance, feeds hydrogen to 41 normal atmosphere; Room temperature reaction 15-24 hour, slow release hydrogen.Remove the direct column chromatography for separation in the back of desolvating and obtain pure product, reaction formula is following:
Figure BSA00000207638100043
The enantiomeric excess of product is used the chirality liquid chromatogram measuring, sees table 2.
Table 2. palladium catalysis asymmetric hydrogenation synthesizes various chirality fluoroamines 2
Figure BSA00000207638100044
Figure BSA00000207638100051
(R)-4-Methoxy-N-(2，2，2-trifluoro-1-phenylethyl)aniline(2a).99％yield，93％ee，[α] RT D＝-53.6(c?0.60，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.48-7.38(m，5H)，6.77(dd，J＝8.9，2.1Hz，2H)，6.65(t，J＝8.9Hz，2H)，4.84(q，J＝7.4Hz，1H)，4.12(br?s，1H)，3.73(s，3H)； 13C?NMR(100MHz，CDCl 3)δ153.5，139.7，134.5，129.2，128.1，126.8，125.4(q，J C-F＝280Hz)，115.9，115.0，62.0(q，J C-F＝30Hz)，55.8；HPLC(AD-H，elute：Hexanes/i-PrOH＝90/10，detector：254nm，flow?rate：0.8mL/min)，t 1＝9.9min，t 2＝13.7min.
(R)-N(2，2，2-Trifluoro-1-phenylethyl)benzenamine(2b).91％yicld，93％ee，[α] RT D＝-51.8(c0.27，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.49(d，J＝6.7Hz，2H)，7.45-7.40(m，3H)，7.20(t，J＝7.9Hz，2H)，6.81(t，J＝7.3Hz，1H)，6.67(d，J＝8.4Hz，2H)，4.96(p，J＝7.3Hz，1H)，4.36(d，J＝7.1Hz，1H)， 13CNMR(100MHz，CDCl 3)δ145.7，134.3，129.6，129.3，129.1，128.1，125.3(q，J C-F＝280Hz)，119.4，114.1，60.7(q，J C-F＝30Hz)；HPLC(AD-H，elute：Hexanes/i-PrOH＝95/5，detector：254nm，flow?rate：0.8mL/min)，t 1＝7.4min，t 2＝9.0min；
(R)-4-Methyl-N-(2，2，2-trlfluoro-1-phenylethyl)aniline(2c).＝88％yield，93％ee，[α] RT D＝-54.6(c0.43，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.487.39(m，5H)，7.00(d，J＝8.3Hz，2H)，6.58(d，J＝8.4Hz，2H)，4.90(q，J＝7.3Hz，1H)，4.23(br?s，1H)，2.24(s，3H)； 13C?NMR(100MHz，CDCl 3)δ143.4，134.4，130.0.129.2，129.1，128.7，128.1，125.4(q，J C-F＝280Hz)，114.4，61.1(q，J C-F＝30Hz)，20.5；HPLC(AD-H，elute：Hexanes/i-PrOH＝95/5，detector：254nm，flowrate：0.8mL/min)，t 1＝7.6min，t 2＝10.1min；
(R)-4-Methoxy-N-(2，2，2-trifluoro-1p-tolylethyl)aniline(2d).92％yield，92％ee，[α] RT D＝-81.8(c0.70，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.36(d，J＝7.9Hz，2H)，7.22(d，J＝7.9Hz，2H)，6.78(dd，J＝8.9，22Hz，2H)，6.64(dd，J＝8.9?2.1Hz，2H)，4.82(t，J＝6.4Hz，1H)，4.11(br?s，1H)，3.74(s，3H)，2.38(s，3H)； 13C?NMR(100MHz，CDCl 3)δ153.4，139.8，139.1，131.5，129.8，128.0，125.4(q，J C-F＝280Hz)，115.8，115.0，61.6(q，J C-F＝29Hz)，55.8，21.3；HPLC(AD-H，elute：Hexanes/i-PrOH＝95/5，detector：254nm，flow?rate：0.8mL/min)，t 1＝10.9min，t 2＝14.1min.
(R)-4-Methoxy-N-(2，2，2-trifluoro-1-m-tolylethyl)aniline(2e).95％yield，93％ee，[α] RT D＝-77.0(c?0.62，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.27-7.22(m，3H)，7.15(d，J＝6.9Hz，1H)，6.73(d，J＝8.8Hz，2H)，6.60(d，J＝8.8Hz，2H)，4.75(p，J＝7.3Hz，1H)，4.06(d，J＝7.2Hz，1H)，3.69(s，3H)，2.34(s，3H)； 13CNMR(100MHz，CDCl 3)δ153.4，139.8，138.8，134.5，130.0，128.9，128.8，125.4(q，J C-F＝280Hz)，125.2，115.8，115.0，61.9(q，J C-F＝29Hz)，55.8，21.6； 19F?NMR(377MHz，CDCl 3)δ-73.9(s，3F)；HPLC(AD-H，elute：Hexanes/i-PTOH＝99/1，detector：254nm，flow?rate：0.6mL/min)，t 1＝29.0min，t 2＝31.7min；HRMS?Calculated?For?C 16H 17NOF 3[M+H] +296.1262，found：296.1268.
(R)-4-Methoxy-N-(2，2，2-trifluoro-1-o-tolylethy1)aniline(2f).90％yield，84％ee，[α] RT D＝-48.9(c?0.60，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.51(d，J＝7.4Hz，1H)，7.28-7.23(m，3H)，6.79-6.76(m，2H)，6.63-6.60(m，2H)，5.15(s，1H)，4.09(br?s，1H)，3.73(s，3H)，2.46(s，3H)； 13C?NMR(100MHz，CDCl 3)δ153.4，139.9，137.1，133.1，131.1，128.9，127.2，126.7，125.6(q，J C-F＝251Hz)，115.5，115.0，57.4(q，J C-F＝30Hz)，55.8，199； 19F?NMR(377MHz，CDCl 3)δ-73.5(s，3F)；HPLC(AD-H，elute：Hexanes/i-PrOH＝95/5，detector：254nm，flow?rate：0.8mL/min)，t 1＝8.7min，t 2＝11.7min；HRMS?Calculated?ForC 16H 17NOF 3[M+H] +296.1262，found：296.1260.
(R)-4-Methoxy-N-(2，2，2-trifluoro-1-(4-methoxyghexyl)ethyl)aniline(2g).97％yield，92％ee，[α] RT D＝-77.7(c0.74，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.36(d，J＝8.6Hz，2H)，6.92-6.89(m，2H)，6.75-6.72(m，2H)，6.61-6.58(m，2H)，4.75(q，J＝7.3Hz，1H)，4.03(br?s，1H)，3.80(s，3H)，3.71(s，3H)； 13CNMR(100MHz，CDCl 3)δ160.3，153.4，139.8，129.3，126.4，125.4(q，J C-F＝280Hz)，115.9，115.0，114.5，61.3(q，J C-F＝30Hz)，55.8，55.5； 19F?NMR(377MHz，CDCl 3)δ-74.3(s，3F)；HPLC(AD-H，ehute：Hexanes/i-PrOH＝90/10，detector：254nm，flow?rate：0.8mL/min)，t 1＝14.6min，t 2＝20.5min；HRMSCalculated?For?C 16H 15NO 2F 3[M-H] -310.1055，found：310.1043.
(R)-4-Methoxy-N-(2，2，2-trifluoro-1(4-(trifluoromethyl)phenyl)ethyl)aniliae(2h).95％yield，93％ee，[α] RT D＝-40.2(c0.80，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.67(d，J＝8.2Hz，2H)，7.60(d，J＝8.2Hz，2H)，6.76(d，J＝8.6Hz，2H)，6.59(d，J＝8.6Hz，2H)，4.91(t，J＝6.3Hz，1H)，4.16(br?s，1H)，3.73(s，3H)； 13C?NMR(100Hz，CDCl 3)δ1538，139.1，138.5，131.7，131.4，128.7，126.1，124.9(q，J C-F＝280Hz)，116.0，115.1，61.6(q，J C-F＝30Hz)，55.8； 19FNMR(377MHz，CDCl 3)δ-62.8(s，3F)，-73.9(s，3F)；HPLC(AS-H，elute：Hexanees/i-PrOH＝95/5，detector：254nm，flow?rate：0.8mL/min)，t 1＝7.8min，t 2＝9.9min；HRMS?Calculated?For?C 16H 12NOF 6[M-H] -348.0823，found：348.0836.
(R)-N-(1-(3，5-Difluorophenyl)-2，2，2-trifluoroethyl)-4-methoxyaniline(2i).87％yield，94％ee，[α] RT D＝-38.8(c?0.44，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.02(d，J＝6.3Hz，2H)，6.85-6.74(m，3H)，6.57(d，J＝8.6Hz，2H)，4.80(t，J＝6.3Hz，1H)，4.08(br?s，1H)，3.73(s，3H)； 13C?NMR(100MHz，CDCl 3)δ163.4(q，J C-F＝12.5Hz)，153.9，138.9，138.4，124.7(q，J C-F＝280Hz)，115.9，115.2，111.4，105.0(t，J C-F＝25Hz)，61.3(q，J C-F＝30Hz)，55.8； 19F?NMR(377MHz，CDCl 3)δ-74.0(s，3F)，-108.3(s，2F)；HPLC(AS-H，elute：Hexanes/i-PrOH＝95/5，detector：254nm，flow?rate：0.8mL/min)，t 1＝7.7min，t 2＝9.0min；HRMS?Calculated?For?C 15H 11NOF 5[M-H] -316.0761，found：316.0759.
(R)-4-Methoxy-N-(1，1，1-trifluorohexan-2-yl)aniline(2j).99％yield，89％ee，[α] RT D＝+26.3(c?0.60，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ6.79(d，J＝8.8Hz，2H)，6.64(d，J＝8.8Hz，2H)，3.77(s，3H)，3.72(q，J＝6.4Hz，1H)，3.27(d，J＝8.4Hz，1H)，1.87(t，J＝4.2Hz，1H)，1.51(q，J＝9.1Hz，2H)，1.40-1.33(m，3H)，0.91(t，J＝7.1Hz，3H)； 13C?NMR(100MHz，CDCl 3)δ153.0，141.1，126.6(q，J C-F＝282Hz)，115.1，115.0，57.1(q，J C-F＝29Hz)，55.9，29.6，27.8，22.6，14.0； 19F?NMR(377MHz，CDCl 3)δ-76.0(s，3F)；HPLC(AD-H，elute：Hexanes/i-PrOH＝95/5，detector：254nm，flow?rate：0.8mL/min)，t 1＝6.1min，t 2＝6.6min；HRMS?Calculated?For?C 13H 17NOF 3[M-H] -260.1262，found：260.1254.
(R)-4-Methoxy-N-(1，1，1-trifluoro-4-phenyibutan-2-yl)aniline(2k).97％yield，92％ee，[α] RT D＝+48.1(c1.18，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.29-7.19(m，3H)，7.11(d，J＝7.6Hz，2H)，6.77(d，J＝8.8Hz，2H)，6.56(d，J＝8.8Hz，2H)，3.75(s，3H)，3.69(q，J＝6.6Hz，1H)，3.32(br?s，1H)，2.92-2.85(m，1H)，2.76-2.69(m，1H)，2.20-2.19(m，1H），1.89-1.84(m，1H)； 13C?NMR(100MHz，CDCl 3)δ153.0，140.7，140.4，128.8，128.7，126.6(q，J C-F＝282Hz)，126.5，126.2，115.3，115.0，55.9(q，J C-F＝28Hz)，31.5，31.3； 19F?NMR(377MHz，CDCl 3)δ-75.9(s，3F)；HPLC(AD-H，elute：Hexanes/i-PrOH＝95/5，detector：254nm，flow?rate：0.8mL/min)，t 1＝10.1min，t 2＝107min；HRMSCalculated?For?C 17H 17NOF 3[M-H] -308.1262，found：308.1250.
(R)-N-(2，2-Difluoro-1-phenylethyl)-4-methoxyaniline(2l)。 488％yield，69％ee，[α] RT D＝-21.7(c0.80，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.44-7.33(m，5H)，6.76-6.72(m，2H)，6.60-6.57(m，2H)，5.99(td，J＝55.9，3.2Hz，1H)，4.64(td，J＝13.2，2.7Hz，1H)，4.16(br?s，1H)，3.72(s，3H)； 13C?NMR(100MHz，CDCl 3)δ153.1，140.2，135.8，129.0，128.7，128.0，116.1(t，J C-F＝246Hz)，115.7，114.9，61.3(q，J C-F＝22Hz)，55.8； 19F?NMR(377MHz，CDCl 3)δ-125.7(q，2F)；HPLC(OD-H，elute：Hexanes/i-PrOH＝90/10，deterior：254nm，flowrate：0.8mL/min)，t 1＝11.1min，t 2＝12.7min.
(R)-4-Methoxy-N-(2，2，3，3，3-pentafluoro-1-phenylpropyl)aniline(2m).95％yield，84％ee，[α] RT D＝-54.2(c?0.92，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.41-7.37(m，5H)，6.74(t，J＝8.8Hz，2H)，6.61(t，J＝8.8Hz，2H)，4.93(q，J＝8.7Hz，1H)，4.13(br?s，1H)，3.72(s，3H)； 13C?NMR(100MHz，CDCl 3)δ153.5，139.2，133.9，129.3，129.0，128.5，128.1，118.0(q，J C-F＝285Hz)，116.0，114.5，59.8(q，J C-F＝21Hz)，55.8； 19F?NMR(377MHz，CDCl 3)δ-80.9(s，3F)，-117.8(d，1F)，-125.7(d，1F)；HPLC(OD-H，elute：Hexanes/i-PrOH＝99/1，detector：254nm，flow?rate：0.4mL/min)，t 1＝17.3min，t 2＝19.0min；HRMS?Calculated?For?C 16H 13NOF 5[M-H] -330.0917，found：330.0931.
(R)-N-(2，2，3，3，4，4，4-Heptafluoro-1-phenylbutyl)-4-methoxyaniline(2n).85％yield，84％ee，[α] RT D＝-61.5(c?0.80，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.38-7.33(m，5H)，6.71(t，J＝8.9Hz，2H)，6.58(t，J＝8.9Hz，2H)，5.98(q，J＝9.2Hz，1H)，4.11(d，J＝9.0Hz，1H)，3.68(s，3H)； 13C?NMR(100MHz，CDCl 3)δ153.5，139.1，133.9，129.3，129.0，128.6，116.0，115.0，59.8(t，J C-F＝26Hz)，55.8； 19F?NMR(377MHz，CDCl 3)δ-80.7(q，3F)，-113.9(d，1F)，-114.6(d，1F)，-124.2(m，2F)；HPLC(AD-H，elute：Hexanes/i-PrOH＝97/3，detector：254nm，flow?rate：0.7mL/min)，t 1＝8.9min，t 2＝9.8min；HRMS?CalculatedFor?C 17H 13NOF 7[M-H] -380.0885，found：380.0872.
(R)-4-Methoxy-N-(2，2，3，3，4，4，5，5，6，6，7，7，7-trideoxfluoxe-1-phenylheptyl)boezenamine(2o).97％yield，86％ee，[α] RT D＝-36.6(c1.28，CHCl 3)； 1H?NMR(400MHz，CDCl 3)δ7.41-7.34(m，5H)，6.74-6.71(m，2H)，6.61-6.58(m，2H)，5.01(q，J＝9.3Hz，1H)，4.12(br?s，1H)，3.71(s，3H)； 13C?NMR(100MHz，CDCl 3)δ153.5，139.1，133.9，129.3，129.0，128.7，116.0，115.1，60.1(q，J C-F＝21Hz)，55.8； 19F?NMR(377MHz，CDCl 3)δ-80.8(t，3F)，-113.4(s，1F)，-114.1(d，1F)，-120.2(d，2F))-121.8(m，2F)，-122.6(d，1F)，-122.8(s，1F)，-125.9(d，1F)，-126.2(s，1F)，HPLC(OD-H，elute：Hexanes/i-PrOH?＝99/1，detector：254nm，flow?rate：0.4mL/min)，t 1＝14.5min，t 2＝16.0min；HRMS?Calculated?ForC 20H 13NOF 3[M-H] -530.0790，found：530.0782.
We have realized the asymmetric hydrogenation to simple fluorine-containing imines first; We can find that PG can be the aryl of band different substituents from top form; And the R substituting group is especially regardless of being alkyl or being with the aryl of different substituents can obtain all well and good result that Rf also can be various different perfluoroalkyls.

Claims (6)

1. the method for a palladium catalysis asymmetric hydrogenation synthesis of chiral fluoroamine, its catalystsystem is the chiral diphosphine title complex of palladium, reaction formula and condition are following:
Figure FSA00000207638000011
In the formula:
Temperature: 0-50 ℃;
Solvent: 2,2,2 tfifluoroethyl alcohol;
Pressure: a 1-42 normal atmosphere;
Time: 15-24 hour;
Said catalyzer is the title complex of trifluoracetic acid palladium and biphosphine ligand;
Said reactant and product substituent R are C1-C10 alkyl group and aromatic yl group, and Rf is difluoromethyl, trifluoromethyl, pentafluoroethyl group, seven fluoropropyls or ten trifluoro hexyls, and PG is the aryl of band methyl, methoxyl group, trifluoromethyl or different halogens.
2. method according to claim 1 is characterized in that: the aromatic yl group of said R is 2,3 or 4 bit strip methyl, methoxyl group, trifluoromethyl, fluorine, chlorine, a bromine and 3 on the phenyl ring, one or more in 5-two fluoro substituents.
3. method according to claim 1 is characterized in that: the aryl of PG is the substituted aryl of 4 bit strip methyl, methoxyl group, fluorine, chlorine or bromine on the phenyl ring.
4. method according to claim 1 is characterized in that: the mol ratio of said raw material fluoro imines and title complex is 25-50: 1; Solvent load: per 0.0025 mmole raw material is with the trifluoroethanol of 2-3 milliliter.
5. method according to claim 1 is characterized in that: the Preparation of catalysts method is: N 2Under the protection, with Pd (OCOCF 3) 2With chiral diphosphine ligand in molar ratio 1: 1.1-1.3 in acetone stirring at room 0.5-1 hour, vacuum concentration was removed acetone then.
6. according to claim 1 or 5 described methods, it is characterized in that: said biphosphine ligand is SynPhos, SegPhos, BINAP, MeO-BiPhep, C 4-TunePhos, Cl-MeO-BiPhep, 3,5-xylyl-BINAP, DifluorPhos or P-Phos.
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CN109336928A (en) * 2018-10-08 2019-02-15 浙江工业大学上虞研究院有限公司 Axial chirality bidentate ligand and its application in the Asymmetric hydrogen transfer reaction of palladium chtalyst
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CN111484459B (en) * 2019-01-28 2021-11-02 中国科学院大连化学物理研究所 Method for synthesizing chiral 3-trifluoromethyl-3, 4-dihydroquinoxalinone by palladium-catalyzed asymmetric hydrogenation
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