CN102336621B - Method for synthesizing chiral fluoroamine by palladium catalytic asymmetric hydrogenation - Google Patents
Method for synthesizing chiral fluoroamine by palladium catalytic asymmetric hydrogenation Download PDFInfo
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- CN102336621B CN102336621B CN201010238747.2A CN201010238747A CN102336621B CN 102336621 B CN102336621 B CN 102336621B CN 201010238747 A CN201010238747 A CN 201010238747A CN 102336621 B CN102336621 B CN 102336621B
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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
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.].But due to the strong electron attraction of trifluoromethyl or Polyfluoroalkyl, be difficult to synthetic this compounds [a) Nelson, D.W. by 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.] develop a kind of trifluoroacetyl imino-choride by palladium catalysis or Polyfluoroalkyl acetyl imino-choride and aryl or alkylboronic acids and obtained by Suzuki-Miyaura cross-coupling the method for fluorine-containing imines.By obtaining fluorine-containing aminated compounds to the hydrogenation of fluorine-containing imines.
Fluorine-containing aminated compounds is a kind of very important structural unit in organic synthesis, because the introduction of fluorine atom usually causes the change of the physiologically active of organic compound.The fluorine-containing aminated compounds of chirality is also in organic synthesis, to have bioactive building block [a) Soloshonok, V.A. (Ed.), Fhuorine-containing Synthons, 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 intermediate of much medicine and pesticide molecule.But bibliographical information is mainly by 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 also there is no bibliographical information mistake by the method for synthetic this compounds of catalysis asymmetric hydrogenation at present.
The advantages such as asymmetric hydrogenation has that Atom economy is good, the activity of catalyzer is high, speed of response is fast, the convenient separation of product, side reaction are few.Current many chiral catalysis hydro genation system have obtained application industrial.Because the asymmetric hydrogenation of imines can obtain Chiral Amine, therefore, we want the method synthesis of chiral fluoroamine by asymmetric catalytic hydrogenation fluoro imines.
Summary of the invention
The object of this invention is to provide a kind of Suzuki-Miyaura cross-coupling by palladium catalysis and synthesize a kind of simple fluoro imines, 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 achieving the above object, technical scheme of the present invention is as follows:
Catalyst system is the chiral diphosphine title complex of palladium, and reaction formula and condition are as follows:
In 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 method of catalyzer is: the stirring at room temperature 0.5-1 hour in acetone the metal precursor of palladium and chiral diphosphine ligand, then vacuum concentration is removed acetone.Described 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 with 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 phenyl ring, methoxyl group, trifluoromethyl, halogen (fluorine, chlorine, bromine) and 3,5-, bis-fluoro substituents.
The aryl of PG is 4 bit strip methyl, methoxyl group, trifluoromethyl and halogen (fluorine, chlorine, bromine) on phenyl ring.
Fluoride for Raw Material is for imines and title complex 25-50 in molar ratio: 1. solvent load: the trifluoroethanol of 2-3 milliliter for every 0.0025 mmole.
The chirality fluoroamine obtaining, its enantiomeric excess is at 69-94%.
The present invention has the following advantages
1. reactive behavior and enantioselectivity are high, react completely, and generate product single-minded, and nucleus magnetic hydrogen spectrum does not detect side reaction, make energy convenient separation, can obtain high enantiomeric excess sterling.
2. can obtain various types of fluorine-containing amine, for example difluoromethyl, trifluoromethyl.
3. catalyzer is easy to prepare, and operation is simple and practical.
4. hydrogenation mild condition, room temperature just can be reacted.
5. the Chiral Amine obtaining further derivatize in natural product synthetic.
Embodiment
Below by embodiment in detail the present invention is described in detail, 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 below diagram
1-L
6in one (0.003 mmole), after nitrogen replacement, add 1 milliliter of acetone, stirring at room temperature 1 hour.Then vacuum concentration, adds 3 milliliters of 2,2,2 tfifluoroethyl alcohols under nitrogen, by this solution forward to be placed with in advance substrate 1a (35 milligrams, 0.125 mmole) and
in the reactor of MS molecular sieve (40 milligrams), pass into 41 normal atmosphere of hydrogen, 25 ℃ are reacted 16 hours.Slow release hydrogen, except direct column chromatography for separation after desolventizing obtains pure product, reaction formula and ligand structure are as follows:
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 measured with Chiral liquid chromatography, in table 1.
Table 1. is containing the asymmetric hydrogenation of trifluoromethyl imines 1a
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) and (R)-Cl-MeO-BiPhep (2.0 milligrams, 0.003 mmole), after nitrogen replacement, add 1 milliliter of acetone, stirring at room temperature 1 hour.Then vacuum concentration, adds 3 milliliters of 2,2,2 tfifluoroethyl alcohols under nitrogen, by this solution transfer to be placed with in advance substrate 1 (0.125 mmole) and
in the reactor of MS (40 milligrams), pass into hydrogen to 41 normal atmosphere, room temperature reaction 15-24 hour, slow release hydrogen.Except direct column chromatography for separation after desolventizing obtains pure product, reaction formula is as follows:
The enantiomeric excess of product is measured with Chiral liquid chromatography, in table 2.
Table 2. palladium catalysis asymmetric hydrogenation synthesizes various chirality fluoroamines 2
(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, from form above, we can find that PG can be the aryl with different substituents, and R substituting group is especially no matter be that alkyl or the aryl with different substituents can be obtained all well and good result, Rf can be also various different perfluoroalkyls.
Claims (4)
1. a method for palladium catalysis asymmetric hydrogenation synthesis of chiral fluoroamine, the chiral diphosphine title complex that its catalyst system is palladium, reaction formula and condition are as follows:
In formula:
Temperature: 0-50 ℃;
Solvent: 2,2,2 tfifluoroethyl alcohol;
Pressure: a 1-42 normal atmosphere;
Time: 15-24 hour;
Described catalyzer is the title complex of trifluoracetic acid palladium and biphosphine ligand;
Described 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 with methyl, methoxyl group, trifluoromethyl or different halogens;
Described biphosphine ligand is SynPhos, SegPhos, BINAP, MeO-BiPhep, C
4-TunePhos or Cl-MeO-BiPhep.
2. method according to claim 1, is characterized in that: described R is the phenyl of one or more replacements in 2,3 or 4 bit strip methyl, methoxyl group, trifluoromethyl, fluorine, chlorine, bromine and 3,5-, bis-fluoro substituents.
3. method according to claim 1, is characterized in that: described Fluoride for Raw Material is 25-50 for the mol ratio of imines and title complex: 1; Solvent load: the trifluoroethanol of 2-3 milliliter for every 0.0025 mmole raw material.
4. method according to claim 1, is characterized in that: the preparation method of catalyzer is: N
2under protection, by Pd (OCOCF
3)
2with chiral diphosphine ligand in molar ratio 1: 1.1-1.3 is stirring at room temperature 0.5-1 hour in acetone, and then vacuum concentration is removed acetone.
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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 |
| 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 |
| CN112574014B (en) * | 2019-09-29 | 2022-03-11 | 中国科学院大连化学物理研究所 | Method for synthesizing chiral beta-hydroxy ketone by palladium-catalyzed asymmetric reduction |
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| CN101260085A (en) * | 2007-03-07 | 2008-09-10 | 中国科学院大连化学物理研究所 | Catalytic asymmetric hydrogenation synthesis method for chiral gamma-sultam |
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