WO2014164801A1 - Metallorganocatalysis for asymmetric transformations - Google Patents

Metallorganocatalysis for asymmetric transformations Download PDF

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Publication number
WO2014164801A1
WO2014164801A1 PCT/US2014/023519 US2014023519W WO2014164801A1 WO 2014164801 A1 WO2014164801 A1 WO 2014164801A1 US 2014023519 W US2014023519 W US 2014023519W WO 2014164801 A1 WO2014164801 A1 WO 2014164801A1
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group
phenyl
catalyst
moiety selected
mhz
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French (fr)
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Xumu Zhang
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Rutgers State University of New Jersey
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Rutgers State University of New Jersey
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Priority to JP2016501271A priority Critical patent/JP6455893B2/en
Priority to EP14779902.7A priority patent/EP2969202A4/en
Priority to US14/775,159 priority patent/US9744528B2/en
Priority to CN201480013940.2A priority patent/CN105188926B/en
Priority to CA2901591A priority patent/CA2901591A1/en
Priority to KR1020157026724A priority patent/KR20150127632A/en
Publication of WO2014164801A1 publication Critical patent/WO2014164801A1/en
Anticipated expiration legal-status Critical
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
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    • C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers
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    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
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    • B01J31/2414—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07F17/00—Metallocenes
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    • C07F17/00—Metallocenes
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Definitions

  • each one of R crab t,. R*, and d is selected from alkyl, cycloalkyl, and aryl; bridge group is selected fr m CH 2 H; *CH(CH 3 )NH (C*,li); and *CH(C3 ⁇ 4)NH.
  • C and the organocaialyst is an organic molecule catalyst covalently bound to the bridge group, to one embodiment at least one of R, 1; J3 ⁇ 4, R e> and R d is an aryl moiety selected from phenyl; P-CH* phenyl; 3, 5-di-C3 ⁇ 4 phenyl; 3,S-di-t-butyl phenyl; 3 ?
  • At least one of a, 3 ⁇ 4 R c , and R is an alky! moiety selected from t-butyl and i-propyl.
  • at least one of R a , Rt,, c, and R d is a cycloalkyl moiety selected from cyclohexyl and cyclopentyi.
  • each one of Ra, 3 ⁇ 4 > , and 3 ⁇ 4 is selected from alkyl, cycloalkyl, and aryl;
  • the bridge group is selected from CfifeNH; *CH(C3 ⁇ 4)NH (C*,R) and *CH(C3 ⁇ 4)NH (C* S);
  • the organocaialyst is an organic molecule catalyst covalently bound to the bridge group; and
  • M is selected from Rh, Pd, Cu, Ru, Ir, Ag, Au, Zn, Ni, Co, and Fe.
  • At least one of R», Rf > , c, and 3 ⁇ 4 is an aryl moiety selected from phenyl; P-CH j phenyl; 3,5-di-CHj phenyl; 3,5-di-t-butyl phenyl; 3,5-di-CFs phenyl; 2-CH 3 phenyl; C «F$;
  • At least one of R*, 3 ⁇ 4 > , e, and R ⁇ j is an alkyl moiety selected from t-butyl and i-propyl.
  • at least one of a, 3 ⁇ 4, , and - is a cycloalkyl moiety selected from cyclohexyl and cyclopentyi.
  • a method for the asymmetric hydrogenaiion of an alkene to a corresponding alkane that includes the step of combining an alkene in a suitable solvent with an excess of hydrogen gas and a catalytic-ally effective amount of a catalyst according to the present disclosure at a temperature and pressure effective to hydrogenate the alkene.
  • the solvent includes isopropanol.
  • at least one of R a? Rt,, R*, and j in the catalyst is an aryl moiety selected from phenyl; ⁇ - €3 ⁇ 4 phenyl; 3,5-di ⁇ CI3 ⁇ 4 phenyl; 3,5-di-t-biit l phenyl; 3,5-di-CF . ; phenyl; 2-CH .; phenyl;
  • At least one of R a , R «, and R,j in the catalyst is an alky! moiety selected from t-bwty and i-propyl
  • at least one of R;,, R 3 ⁇ 4 , R c , and Rj in the Catalyst is a cycloalkyl moiety selected from cyclohexyl and cyciopentyl
  • alkyl refer to the radical of saturated aliphatic groups, including straight-chain alkyl groups and branched-chain alky I groups.
  • cycloalkyl refers to a non-aromatic mono o mu!ticyclic ring system of about 3 to 7 carbo atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobuty l, cyciopenty l, cyclohexyl and the like.
  • terra refers to any functional group or substituent derived from a simple aromatic ring, be it phenyl, thienyl, indolyS, etc. Disclosed herein is a lieand having the structure or its enaiitiomer;
  • each one of R a , R c , and R ⁇ j is selected from alkyi, cycloalkyl, and a ;
  • the bridge group is selected from C3 ⁇ 4NH; *CH(C3 ⁇ 4)NH (C* and *CH(C3 ⁇ 4)NH (C*,S); and
  • the organocatalyst is an organic molecuie catalyst covalentiy bound to the bridge group.
  • Each one of " 3 ⁇ 4! 3 ⁇ 4, R «, and 3 ⁇ 4 can be the same as or di fferent from any of the other R groups.
  • all of R il; Rtha Re, and f s are the same aryl group.
  • each one of Ra, b , R c> and R,i is a different aryl group.
  • R» and R3 ⁇ 4 are different aryl groups, while R* is an alkyi group and 13 ⁇ 4 is a cycloalkyl group.
  • Preferred aryl moieties for R » , Ri 3 ⁇ 4 and R ⁇ j include phenyl; P-C3 ⁇ 4 phenyl: 3,5-di-CI b phenyl; 3,5-di-t-butyl phenyl; 3.S-di-CF 3 phenyl; 2-CHj phenyl; QF 5 ; 2-naphthyl; and 1-naphthyl Preferred cycloalkyl moieties (e.g. "Cy”) for R 8> R ()! R c , and 3 ⁇ 4 include cyclohexyl and cyclopentyi.
  • Preferred alkyi moieties tor R3 ⁇ 4, and 13 ⁇ 4 include t-buryl and i -propyl
  • organocataiyst as used herein includes organic molecules capable of catalyzing a reaction. Suitable organocatalysts contain at least one moiety that, can be covalentiy bound to a bridge group in the Kgaiid of structure (1) or the catalyst of structure (II). Preferred organocatalysts include a thiourea moiety that can be covalentiy bound to a bridge group. Exemplary organocatalysis include, but are not limited to, the following structures designated as OCI ----- OC25:
  • Hgands are represented by the following formulas:
  • the PPhj group in any of the ligands listed above can be PR ;i R» or PR t R d , wherein each one of R a , R t , and R ⁇ s is selected from alkyl, eycloalky.l, and aryl.
  • Preferred aryl moieties for R include phenyl; P-CHb phenyl; 3,5-di-C% phenyl;
  • Preferred cycloaikyl moieties for R include cyclohexyl and cyclopeniyl
  • Preferred alkyl moieties for R include t-butyl and i-propyl.
  • R s , R b , R c , and R d ca be the same as or di fferent from any of the other R groups.
  • all of R a , R c , and R tj are the same aryl group.
  • each one of !3 ⁇ 4, R t , and 3 ⁇ 4 is a different aryl group.
  • R « and R3 ⁇ 4 are different a d groups, while is an alkyl group and 3 ⁇ 4 is a cycloalkyi group.
  • Also disclosed herein is a catalyst having the structure or its enantiomer
  • each one of R a , R 3 ⁇ 4 Struktur R,,, and 3 ⁇ 4 is selected from alkyl, eye balky I, and aryl: the bridge group is selected from C3 ⁇ 4 H; *CH(CH 3 )NH (C*,i?); and *CH(CH 3 )NH (C* ⁇ ); and the organocataiyst is an organic molecule catalyst covendingSy bound to the bridge group, in one embodiment, the bridge group is part of the organocataiyst molecule, for example, a thiourea moiety for dual hydrogen bonding.
  • Each one of « , R*, R c> and 3 ⁇ 4 can be the same as or different from any of the other R groups.
  • all of R it , R 3 ⁇ 4 , Jl C ⁇ and are the same aryl group
  • each one of R a> R3 ⁇ 4, R. c , and R «j is a different aryl group.
  • R a and R 3 ⁇ 4 are different aryl groups, while ⁇ is an alkyl group and 3 ⁇ 4 is a cycloalkyi group.
  • Preferred aryl moieties for R a , R & , R c , and R f i include phenyl; P-C3 ⁇ 4 phenyl;
  • cycloalkyi moieties for *, R3 ⁇ 4, R c , and 3 ⁇ 4 include cyclohexy! and cyciopentyl.
  • Preferred alkyl moieties for R s , Rj,, R s> and R ⁇ j include t-butyl and i-propyl.
  • the terra "organocatalyst" as used herein includes organic molecules capable of catalyzing a reaction.
  • Suitable organocatalysts contain at least one moiety that can be covalentiy bound to a ridge group in the Kgand of structure (! or the catalyst of structure (11), Preferred organocatalysts include a thiourea moiety that can be c-ovalently bound to a bridge group. Exemplary organocatalysts include, but are not limited to those listed above.
  • the catalysts disclosed herein are useful for a wide range of reactions, including, but not limited ' to, asymmetric hydrogenation, hydrofbrmylation, akiol, Diels- Aider, hetereo Diels-ASder, Mannieh, Michael addition, a!lylie alkylation, alkylation,
  • a method for the asymmetric hydrogenation of an alkene, inline, ketone, or thioketone to a corresponding alkane, amine, alcohol, or thiol which includes combining an alkene, imine, ketone, or thioketone in a suitable solvent with an excess of hydrogen gas and a catalyticaily effective amount of a catalyst disclosed herein, and at a temperature arid pressure efiective to hydrogenate the alkene, imine, ketone or thioketone, in one embodiment, asymmetric hydrogenation of ⁇ ,
  • P ⁇ disubstitutednitroalkeiies provided up to >99% conversion and 99% enantioselectivity.
  • Suitable solvents include, but are not limited to, polar organic solvents.
  • An exemplary polar organic solvent includes, but is not limited to, isopropanol A
  • caialyticaliy effective amount of a catalyst can be readily determined by one of skill in the art and includes amounts effective to convert an alkene, imine, or ketone to a
  • Ligands LI - L3 were prepared according the according the literature (Hayashi, T,, et at, Butt. Chem. Sac. Jpn. 80, 53, 1 138-1 153 ) with a slight modification: column
  • Ligands L9 ⁇ L14 were prepared according the according the literature (Zhao, Q., et a!., Or . tu 2013, 15, 4014-4017).
  • Li uds LIS - L17 were synthesized as follows: S12 was prepared according the according the literature (Zhao, Q., et al. Org. Lett. 2013, 15, 4014-4017). SI3 was prepared according the according the literature (Goto v. B., et al.. New J. Chem. 2000, 24, 597-602). Under a nitrogen atmosphere,
  • nitroalkanes were characterized as follows;
  • Rh-bisphosphine complex without a (thio)urea L9) showed very low activity and enaniiose!eeti vity (Table 6. entry 1 ⁇ .
  • Urea LI 0 provided 22% conversion and 66% ee m sharp contrast with the more acidic thiourea L14 (Table 6, entry 2 vs. 6) hl

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Abstract

A ligand having the structure or its enantiomer; (I) wherein: each one of Ra, Rb, Rc and Rd is selected from alkyl, cycloalkyl, and aryl; the bridge group is selected from CH2 NH; *CH(CH3)NH (C*,R); and the organocatalyst is an organic molecule catalyst covalently bound to the bridge group. Also, a catalyst having the structure or its enantiomer: (II) wherein: each one of Ra, Rb, Rc and Rd is selected from alkyl, cycloalkyl, and aryl; the bridge group is selected from CH2NH; *CH(CH3)NH (C*,R); and *CH(CH3)NH (C*, S); the organocatalyst is an organic molecule catalyst covalently bound to the bridge group; and M is selected from the group consisting of Rh, Pd, Cu, Ru, Ir, Ag, Au, Zn, Ni, Co, and Fe.

Description

METALLORGANOCATALYSIS FOR ASYMMETRIC TRANSFORMA TIONS
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit under 35 U.S.C. § 1 19(e) of U.S. Provisional
Application Serial No. 6.1/775,807, filed March 1, 2013, the disclosure of which is incorporated herein by reference in its entirety.
BACKGROUND
Numerous impressive catalysts have been developed in transition metal catalysis and organocatalysis with unique acti ation modes. However, the utility of such cataiysts is hampered by .inherent drawbacks like limited reaction scopes and high catalyst loading. In an effort to improve upon these limitations, the concept of combing transition metal catalysis and organocatalysis has emerged in the last few years. Strategies, including cooperative catalysis, synergistic catalysis, and sequential/relay catalysis, have been established. However, the incompatibility between catalysts, substrates, intermediates and solvents is the potential shortcoming.
SUMMARY
The present document describes a Hgand having the structure o its enantiomer:
J Bridge organocatalyst
wherein: each one of R„ t,. R*, and d is selected from alkyl, cycloalkyl, and aryl; bridge group is selected fr m CH2 H; *CH(CH3)NH (C*,li); and *CH(C¾)NH. (C: and the organocaialyst is an organic molecule catalyst covalently bound to the bridge group, to one embodiment at least one of R,1; J¾, Re> and Rd is an aryl moiety selected from phenyl; P-CH* phenyl; 3, 5-di-C¾ phenyl; 3,S-di-t-butyl phenyl; 3?5-di-CF;¾ phenyl; 2-C¾ phenyl; Cd ; 2-naphihyi; and l -naphihyl. In another embodiment, at least one of a, ¾ Rc, and R is an alky! moiety selected from t-butyl and i-propyl. In an additional embodiment, at least one of Ra, Rt,, c, and Rd is a cycloalkyl moiety selected from cyclohexyl and cyclopentyi.
Also provided is a catalyst having the structure or its enandomer:
Figure imgf000004_0001
(II) wherein: each one of Ra, ¾>, and ¾ is selected from alkyl, cycloalkyl, and aryl; the bridge group is selected from CfifeNH; *CH(C¾)NH (C*,R) and *CH(C¾)NH (C* S); the organocaialyst is an organic molecule catalyst covalently bound to the bridge group; and M is selected from Rh, Pd, Cu, Ru, Ir, Ag, Au, Zn, Ni, Co, and Fe. In one embodiment, at least one of R», Rf>, c, and ¾ is an aryl moiety selected from phenyl; P-CH j phenyl; 3,5-di-CHj phenyl; 3,5-di-t-butyl phenyl; 3,5-di-CFs phenyl; 2-CH3 phenyl; C«F$;
2-naphthy 1; and i -naphthyl In another embodiment, at least one of R*, ¾>, e, and R<j is an alkyl moiety selected from t-butyl and i-propyl. In yet another embodiment, at least one of a, ¾, , and - is a cycloalkyl moiety selected from cyclohexyl and cyclopentyi.
Also provided is a method for the asymmetric hydrogenaiion of an alkene to a corresponding alkane that includes the step of combining an alkene in a suitable solvent with an excess of hydrogen gas and a catalytic-ally effective amount of a catalyst according to the present disclosure at a temperature and pressure effective to hydrogenate the alkene. In one embodiment, the solvent includes isopropanol. In another embodiment, at least one of Ra? Rt,, R*, and j in the catalyst is an aryl moiety selected from phenyl; Ρ-€¾ phenyl; 3,5-di~CI¾ phenyl; 3,5-di-t-biit l phenyl; 3,5-di-CF.; phenyl; 2-CH.; phenyl;
Figure imgf000005_0001
2-naphihyi; and l -naphtlryl In yet another embodiment, at least one of Ra, R«, and R,j in the catalyst is an alky! moiety selected from t-bwty and i-propyl, in a further embodiment, at least one of R;,, R¾, Rc, and Rj in the Catalyst is a cycloalkyl moiety selected from cyclohexyl and cyciopentyl,
DETAILED DESCRIPTION
This document describes !igands and catalysts prepared therefrom that provide unexpected improvements in conversion and selectivity in comparison with individual metal catalysts and organocatalysis by eovalently bondin chiral bisp osphmes with organocatalysts. Metal completed with bisphosphine is a general catalyst and can lead many metal-catalyzed reactions with high tumovers. Organocatalysts activate substrates and influence selectivities. As used herein, the term "metallorganocatalysis" refers to catalysts and reactions catalyzed by a compound having a metal catalyst portion eovalently bound to an. organocaia!yst portion. The high activity derived from the metal portion and high selectivity from the organocatalyst provide a useful approach in asymmetric catalysis.
As employed above and throughout the disclosure, the following terms, unless otherwise indicated., shall be understood to have the following meanings;
The term "alkyl" refer to the radical of saturated aliphatic groups, including straight-chain alkyl groups and branched-chain alky I groups. The term "cycloalkyl" refers to a non-aromatic mono o mu!ticyclic ring system of about 3 to 7 carbo atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobuty l, cyciopenty l, cyclohexyl and the like.
The terra "aryP refers to any functional group or substituent derived from a simple aromatic ring, be it phenyl, thienyl, indolyS, etc. Disclosed herein is a lieand having the structure or its enaiitiomer;
4 Bridge organocataiyst
PRcR^
(I)
wherein: each one of Ra, Rc, and R<j is selected from alkyi, cycloalkyl, and a ; the bridge group is selected from C¾NH; *CH(C¾)NH (C* and *CH(C¾)NH (C*,S); and the organocatalyst is an organic molecuie catalyst covalentiy bound to the bridge group.
Each one of" ¾! ¾, R«, and ¾ can be the same as or di fferent from any of the other R groups. For example, in one embodiment, all of Ril; Rt„ Re, and fs are the same aryl group. In another embodiment each one of Ra, b, Rc> and R,i is a different aryl group. In yet another embodiment, R» and R¾ are different aryl groups, while R* is an alkyi group and 1¾ is a cycloalkyl group.
Preferred aryl moieties for R», Ri¾ and R<j include phenyl; P-C¾ phenyl: 3,5-di-CI b phenyl; 3,5-di-t-butyl phenyl; 3.S-di-CF3 phenyl; 2-CHj phenyl; QF5; 2-naphthyl; and 1-naphthyl Preferred cycloalkyl moieties (e.g. "Cy") for R8> R()! Rc, and ¾ include cyclohexyl and cyclopentyi. Preferred alkyi moieties tor R¾, and 1¾ include t-buryl and i -propyl
The term "organocataiyst" as used herein includes organic molecules capable of catalyzing a reaction. Suitable organocatalysts contain at least one moiety that, can be covalentiy bound to a bridge group in the Kgaiid of structure (1) or the catalyst of structure (II). Preferred organocatalysts include a thiourea moiety that can be covalentiy bound to a bridge group. Exemplary organocatalysis include, but are not limited to, the following structures designated as OCI ----- OC25:
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000008_0002
0025 ; organocijtaiysis
; units
Preferred Hgands are represented by the following formulas:
Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000010_0001
Figure imgf000011_0001
Alternatively, the PPhj group in any of the ligands listed above can be PR;iR» or PRtRd, wherein each one of Ra, Rt, and R<s is selected from alkyl, eycloalky.l, and aryl. Preferred aryl moieties for R include phenyl; P-CHb phenyl; 3,5-di-C% phenyl;
3,5-di-t-buty! phenyl; 3,5-di-CF* phenyl; 2-CH3 phenyl; Q 5; 2-naphthyl; mid 1-naphthyl, Preferred cycloaikyl moieties for R include cyclohexyl and cyclopeniyl Preferred alkyl moieties for R include t-butyl and i-propyl.
Each. one of Rs, Rb, Rc, and Rd ca be the same as or di fferent from any of the other R groups. For example, in one embodiment, all of Ra, Rc, and Rtj are the same aryl group. In another erabodiment, each one of !¾, Rt, and ¾ is a different aryl group. In yet another embodiment, R« and R¾ are different a d groups, while is an alkyl group and ¾ is a cycloalkyi group.
Also disclosed herein is a catalyst having the structure or its enantiomer;
Figure imgf000012_0001
whe.re.in; each one of Ra, R¾„ R,,, and ¾ is selected from alkyl, eye balky I, and aryl: the bridge group is selected from C¾ H; *CH(CH3)NH (C*,i?); and *CH(CH3)NH (C*^); and the organocataiyst is an organic molecule catalyst covaientSy bound to the bridge group, in one embodiment, the bridge group is part of the organocataiyst molecule, for example, a thiourea moiety for dual hydrogen bonding.
Each one of «, R*, Rc> and ¾ can be the same as or different from any of the other R groups. For example, in one embodiment, all of Rit, R¾, JlC} and are the same aryl group, In another embodiment, each one of Ra> R¾, R.c, and R«j is a different aryl group. In yet another embodiment Ra and R¾ are different aryl groups, while ^ is an alkyl group and ¾ is a cycloalkyi group.
Preferred aryl moieties for Ra, R&, Rc, and Rfi include phenyl; P-C¾ phenyl;
3,5-di-CHj phenyl; 3,5-di-t-butyI phenyl; 3,5-di-CFj phenyl; 2-€i¾ phenyl; CgF*
2-n.aphthyl; and 1-naphthyl. Preferred cycloalkyi moieties for *, R¾, Rc, and ¾ include cyclohexy! and cyciopentyl. Preferred alkyl moieties for Rs, Rj,, Rs> and R<j include t-butyl and i-propyl. The terra "organocatalyst" as used herein includes organic molecules capable of catalyzing a reaction. Suitable organocatalysts contain at least one moiety that can be covalentiy bound to a ridge group in the Kgand of structure (!) or the catalyst of structure (11), Preferred organocatalysts include a thiourea moiety that can be c-ovalently bound to a bridge group. Exemplary organocatalysts include, but are not limited to those listed above.
When a metal catalyst and an. organocatalyst are linked through a covaleni bond, cooperative interactions such as the following interaction modes offer high activities and selectivities-
Metal !orggnoca iafy si s
activation mode!
substrates dived by metal complexes
and organocatalysis
Figure imgf000014_0001
afiyfic afkyiatian Exemplary methods for preparing 'the ligands and catalysts described herein are discussed in the Examples section.
The catalysts disclosed herein are useful for a wide range of reactions, including, but not limited ' to, asymmetric hydrogenation, hydrofbrmylation, akiol, Diels- Aider, hetereo Diels-ASder, Mannieh, Michael addition, a!lylie alkylation, alkylation,
Friedel-Crafis, ene, Ba lis-Hillman, fiuomuition, and Henry reactions. In. one embodiment depicted in the Examples, a method for the asymmetric hydrogenation of an alkene, inline, ketone, or thioketone to a corresponding alkane, amine, alcohol, or thiol is provided, which includes combining an alkene, imine, ketone, or thioketone in a suitable solvent with an excess of hydrogen gas and a catalyticaily effective amount of a catalyst disclosed herein, and at a temperature arid pressure efiective to hydrogenate the alkene, imine, ketone or thioketone, in one embodiment, asymmetric hydrogenation of β,
P~disubstitutednitroalkeiies provided up to >99% conversion and 99% enantioselectivity.
Suitable solvents include, but are not limited to, polar organic solvents. An exemplary polar organic solvent includes, but is not limited to, isopropanol A
caialyticaliy effective amount of a catalyst can be readily determined by one of skill in the art and includes amounts effective to convert an alkene, imine, or ketone to a
corresponding chiral alkane, amine, or alcohol
The following non-limiting examples serves to further illustrate the present invention.
EXAMPLES
Materials and Methods
All reactions dealing with air- or moisture-sensitive compounds were carried out in a dry reaction vessel under a positive pressure of nitrogen or in a nitrogen-filled glovebox. Unless otherwise noted, all reagents and solvents were purchased from commercial suppliers without further purification. Anhydrous solvents were purchased from
Sigma-A!dfich and transferred by syringe, Pori cation of products was carried out by chromatography using silica gel from ACROS (0.06-0.20 mm) and analytical thin layer chromatography (TLC) was carried out using silica gel plates from Merck (GF254).
[Rh(COD)Ci]2> [Rh(COD)2]BF4 and [ h(COD)2]SbF6were purchased from Heraeus. The HPLC solvents were purchase from Alfa (n-Hexane) and Sigma-AIdrich (2-Propanol).
1H NMR, K,C NMR and ,f P NMR spectra were recorded on a Broker Avance (400 MHz) spectrometer with CDCI3 as the solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts are reported in parts per million (ppm, Sscale) downfield from TMS at 0,00 ppm and referenced to the CD(¾ at 7.26 ppm (for Ή NMR) or 77.0 ppm (for deuteroehlorofonn). Data are reported as: multiplicity (s~singlet, d ~ doublet, t ~: triplet, q ~: quartet, m ~: multiplet), coupling constant in hertz (Hz) and signal area integration in natural numbers. ' JC NMR and i !P NMR analyses were run with decoupling. Enantiomeric excess values '"ee") were determined by Daicel chiral column on an
Agilent 1.200 Series HPLC instrument or an Agilent 7980 Series GC instrument. ew compounds were further characterized by high resolution mass spectra (HRMS) on a Waters Q-Tof Ultima mass spectrometer wit an electrospray ionization source
(University of Illinois, SCS, Mass Spectrometry Lab). Optical rotations [ajo were measured on a PER iNELMER polariraeter 343 instrument.
All (Ε)-β, β-disubstituted nitroa!kenes were prepared according the literature. (Li, S., et &l., ,4ng w. Che . Int. Ed. 2012, 51. 8573-8576). All N-H imines were prepared according to the literature, (Hon, G.f ei a!., J. Am. Chem.. Sac. 2009, 31, 9882-9883.) The absolute configuration of products were determined by compariso of analytical data with the literature (HPLC spectra, optical rotation). The absolute configuration of others were assigned by analogy.
Example 1— Synthesis of ligauds
Figure imgf000017_0001
Ligands LI - L3 were prepared according the according the literature (Hayashi, T,, et at, Butt. Chem. Sac. Jpn. 80, 53, 1 138-1 153 ) with a slight modification: column
chromatography was performed using silica gel hexane ethyl acetate for Li and
dichloromeihane meihanoi for L2) instead f al.umi»a(hexa»e/¾enzen.e for LI and ether/ethyl acetate for L2). All the spectral data are consistent with the literature values.
Under an argon, atmosphere, 3s5-bis(irifliioromet3Tyi)phe.n l isoihiocyanate (1. lrmrtol) was added to a solution of L2(l ,0 mmoi.) in dry DCM (1.0 ml). After the reaction mixture was stirred overnight the reaction mixture was concentrated ro vacuo. The residue was purified by flash column chromatography on silica gel (hexaaeethyl acetate = 9/1 as et arif) gave L8 as yello solid (640 mg, 74%). L8 was characterized as follows'.
Figure imgf000018_0001
1H NMR {400 MHz, CDC!,,) δ 7.69 (s, 30), 7.33 -7.12 (m, 1.9H), 7. 1 - 7.01 (ra,3H), 5.53 (s, 1.H), 4.47 (d, J - 7.2 Hz, 2H), 4.28 (s, 1H), 4.18(1, - 2.3 Hz, 1.H), 3.96 (s? Hi), 3.56 (s, ill).3.45 (s, ill), 1.42 (d,J - 6. Hz, HI).
C NMR (100 MHz, CDCi. S 178.37 (s), 139.18 (s), 138.94 (dsJ- 9.6 Hz), 138.82 (d, J- 6.3 Hz), 138.04(d, J - .4 Bz), 135.55 (d, J- 5.0 Bz), 134.68 (d, J- 2.1.2 Hz), 133.71 (d, J -20..! Hz),! 33.0! (d,J- 1 .2 Hz), ! 32.20 (d, J - 17.8 Hz), 129.58 (s), 128.97■- 127.94 (ml 124.48 (s), .124.3! (s), 121.60(s), 119.16 (s), 95.36 (d,,/- 24.1 Hz), 77.63 (d, === 8.5 Hz), 75.34 (d, J- 20.4 Hz), 74.16 (d, «/==== 9.1 Hz), 73.84 (d,J- 4.9 Hz), 73.37 (d, J - 8.5 Hz), 73.10 ~ 72.50 (m), 71.97 (d,J === 2.6 Hz), 50.87 is), 21.86 (s).
3}P NMR (1 2 MHz, CDCh) 6 -17.81 (s), -25.08 (s).
[α]0 ϊ5-~237.3° (c - 0.30, CHCfe)
HRMS (ESI): [ΜΗΓ] Cak.869.1406, foirad 869.1401,
Figure imgf000018_0002
lH NMR (400 MHz, CDCls) 67.54 ($, 2H), 7.42 - 7.38 (m, 3H)57.34 - 7.14 (m, 18H), 5.1 (s, 2H), 5.13 ~ 5.07 (m, 1H), 4.48 (d, J- 1.7 Hz, 2H), 4.37 (d, J- 7.4 Hz, 2H), 4.19(4 = 8.1 Hz, 2H), 4.14 (t, J= 2.3 Hz, IH), 3.65 (s, 1H), 3.57 (s, 1H), 1.46 (d„ J- 6.7 Hz, 3H). °C NMR (100 MHz, CDC1?) 5152.34 (s), 140.51 is), 140.39 (s), 138.90 (4 J -9.7 Hz), 138.14 (4 ,/ = 9.4 Hz), 135.8 (d, ~ 8,1 Hz), 1 4.92 (d, J = 2 ; 1.2 Hz), 133.60 (d, J - 20.0 Hz), 133.06 J= 19.2 Hz), 132.44 (d, J= 18.8 Hz), 131.76 (4«/= 33.2 Hz), 129.39 (s), 128.72 (s), 128.62 - 127.96 (m), 124.55 (s), 121.84 (s), 118.11 (d, J= 3.1 Hz), 115.21 (s), 95.11 (d, J= 23.6 Hz), 77.19 (s), 75.78 (d, J~ 10.3 Hz), 75.36 (d, ,/= 19.6 Hz), 74.33 (d, J - 3,0 Hz), 73.42 - 73.18 (m), 73.1 1 (d, J - 4.5 Hz), 71.67 (d, ../
Hz), 45.48 (d, J - 7.1 Hz), 20.65 (s).
HRMS (ESl): [M+i-f] Calc. 853.1635, found 853.1644.
[a'jD 2S:::"262..! ° (c ::: 0.33, COCK).
Figure imgf000019_0001
SH N R. {400 MHz, CDCh) δ 7.44 (i, J - 7.2 Hz, 2H)5 7.40■■■· 7. 1 (m, 24H), 6.00 (s, 2H), 5.46 (s, I H), 4.60 (s, I H), 4.57 - 3.52 (m, 4H), 3.56 (d, i === 10.8 Ez, 2H), 1.35 (d, J ::: 6.6 Hz, H), 1.04 (d, J■■■■■■■■ 6.2 Hz, 3H).
C NM R (100 MHz, CDCh) 6 178.66 (s), 141.83 (s), 139.05 (d, J==== 2.9 Hz), 138.97 (s), 138.23 (d, 9.6 Hz), 136.13 (d, .7= 7.2 Hz), 134.71 (d, J = 21.0 Hz), 133.62 (d, J=== 20.1 Hz), 132.98 (d, </- 19.2 Hz), 132.55 (d, J ~ 18.6 Hz), 129.29 (s), 128.98 - 127.45 (m), 125.65 (s), 95.44 (d, .7 = 23.6 Hz), 77.17 (d, J- 8.1 Hz), 75.25 (d, J- 19.9 Hz), 74.80 (d, ,7 - 10.3 Hz), 74.08 id, J- 4.5 Hz), 73,25 (d, J = 9.0 Hz), 73.13 (s), 72.72 (d, ,/ 4.3 Hz), 72.41 (s), 71.50 (d, J ~ 2.6 Hz), 52,79 (s), 50.51 (s), 23.82 (s), 21 ,45 (s).
iS¥ NMR (162 MHz, CDCh) S -17.66 (s), -25.81 (s).
HRMS (ESi): [M- H ' j Cak. 761.1972, found 761.1972.
[α]ι>25--343.5° (c - 0.21 , CHCh).
Figure imgf000019_0002
SH NMR (400 MHz, CDCh) δ 8.21 (t, ,/= 9.1 Hz, IH), 7.59 (s, IH), 7.25 - 6.92 (m, 23H), 5,51 - 5.41 (m, IH), 4.43 - 4.38 (m, 2H), 4.29 (s, 1H)} 4.17 (s, IH), 3.70 (s, IH), 3.40 (s:, I H), 3.09 (s, I H), 2,42 <s, 6H), 1.24 (d, J = 6.9 Hz, 3H).
l3C NMR (100 MHz, CDCh) δ 178.51 (s>, 140.22 (s), 139.32 (d, J= 9.9 Hz), 138.56 (d, J- 5. Hz), 138.03 (d, J~ .7 Hz), 135.9 (s), 134.64 (d, .7= 21.2 Hz), i 33.84 (d, J - 20. Hz), 132.76 (ds ,/= 18,9 Hz), 132.08 (d, J - 17.5 Hz), 129.27 (d, J= 17.7 Hz), 128.67 (s), 128.29 - 127.92 (m), 96.88 (d, J - 24.1 Hz), 75.39 (d, «/- 22.6 Hz), 73.95 (d,J-5.3 Hz), 73.65 (d, J= 5.6 Hz), 72.98 ( .7 - 6.8 Hz), 72.81 (s), 72.56 (d, J= 3.7 Hz), 72.16 (d, </ = 3.6 Hz), 1.84 (s), 24.43 (s), 21.48 (s).
· }Ρ NMR (162 MHz, CDCh) d -17.61 (s), -25,96 (s). HRMS (ESi); [M-H-f] Calc.761.1972, found 761.1 64.
[ajD"-~21 .9° (c - 0.22, CHCK)
Figure imgf000020_0001
lH NMR (400 MHz, CD(¾) δ 8.22 (s, 11), 7.73 (d, J- 8.4 Hz, 2H), 7.71 - 7.64 (m, 1 H), 7.35- 7.13 (m, 18H), 7.08 - 7.02 (mt 4H), 5.56 - 5.46 (ra, IH), 4.45 (s, IH), 4.32 (s, IH), 4.25 (a, IH), 4.17 (tJ^lA Hz, IB), 3.72 (s,lH)} 3.50 (s, IH), 3.26 (s, IH), 1.33 (d, ,/==== 6.8 Hz, Hi).
C NMR (100 MHz, CDC!j) 5178.1 (s), 139.79 (s), 1.39.14 (d,J- 9.8 Hz), 138.63 (d,J- 5.5 Hz), 137.96 (d, ·/==== 9.4 Hz), 135.58 (d, J - 4.5 Hz), 134.68 (d, J ::: 21.2 Hz), 133.81. (d,
J- 20.3 Hz), 132.83 (d, J- 18.9 Hz), 132.22 (s), 130.27- 129.77 (m), 128.78 (s), 128.66 -
128.01 (ml 127.27 (d, .7-3,4 Hz), 125.01 (s), 95.87 (d, J -24.2 Hz), 77.59 (d,J= 8.6 Hz),
75.42 (d,j- 22.0 Hz), 73.63 (d,J- 5.2 Hz), 73.14 (d, /» 7.2 Hz), 72.83 (s), 72.08 (d, J-
3.0 Hz), 51.60 (s), 23.10 (s).
3,P NMR (162 MHz, CDOs) 6 -17.85 (s), -26.34 (s).
HRMS (ESI): [M+H ;] Calc.801.1532, found 8014538.
[afo25----239.5° (e - 0.30, CHC%)
Ligands L9 ···· L14 were prepared according the according the literature (Zhao, Q., et a!., Or . tu 2013, 15, 4014-4017).
Figure imgf000021_0001
Li uds LIS - L17 were synthesized as follows:
Figure imgf000021_0002
S12 was prepared according the according the literature (Zhao, Q., et al. Org. Lett. 2013, 15, 4014-4017). SI3 was prepared according the according the literature (Goto v. B., et al.. New J. Chem. 2000, 24, 597-602). Under a nitrogen atmosphere,
3,S-bis(ttifluoromethyi)phenyl isothioeyanate (1.1 ramo!) was added to a sohiiion of SO (.1.0 mraol) in dry DCM (1.0 ml). After the reaction mixture was stirred overnight, the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane/ethyl acetate :::: 9/1 as ehiant) gave LIS as yellow solid.
LIS Ή NMR. (400 MHz, CDCI3) 6 7.65 (s, 2H), 7.54 (s, 1 H), 7.49 - 7.40 (m, 3H), 7.35 - 7.07 (m, 18B), 6.44 (s, IH), 4.53 (d, J~ 6.0 Hz, 2H), 4.21 (d, J - 1 .6 Hz, 3H), 3.71 (s, 20), 2.50 (s, 30), 1.50 (d, J:::: 6.7 Hz, 30).
"C MR (100 MHz, CDCb) 6 180.28 (s), 141.45 (s), 138.82 (d, J™ 9,8 Hz), 138.30 (d, J- 9.8 Hz), 1.35.78 (d, J::: 7.7 Hz), 134.88 (d, J- 21.3 Hz), 133.42 (άά, J- 33.4, 19.7 Hz), 132.53 (ds J- 19.5 Hz), 131.28 (q, 33.4 Hz), 129.43 (s), 129.01 - 128.44 (m), 128.28 (d, J■=== 6.S Hz), 128.16 (s), 124.61 (s), 123.89 (s), .121.90 (s), 117.57 (s), 93.41 (d, J- 26.4 Hz), 75.47 (d,J- 18.1 Hz), 74.42 (s), 73.56 (d, J~ 5.1 Hz), 73.40 (d, J~ 4.0 Hz), 72.18 (s), 71.75 (s), 54.83 (d, J- 7.7 Hz), 31.93 (s), 15.64 (s).
, !P NMR (162 MHz, CDC53) 6 -18.09 (s), -26.79 (s).
HRMS (ESI): [M-tfT] Calc. 883.1485, found 883.1583.
S14 was -prepared according the according the literature (Zhao. Q„ et al, Org. Left 2013, 15, 4014-401 7). Under an nitrogen atmosphere, 3,5-bis(iri-iIuoroinetliyI)phenyi isothioeyanate (1. Immol) was added to a solution of S14 (1,0 mmol) in dry DCM (1 ,0 mi). After the reaction mixture was stirred overnight, the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel
(hexane/ethyl acetate :::: 9/1 as ehiant) gave LI 6 as yellow solid. L16; ¾ NMR (400 MHz, CDC¾) δ 8.07 is.1 H), 7.75 (d, J~ 10.5 Hz, Mil 6.29 (s, IB),
5,30 (sf IK), 4.26 4.15 (m, 3H), 4.08 (s, 2H), 4.03 (s, 4B), 1.60 (d, ./= 6.5 Hz, 3H).
53 C NMR (100 MHz, CDC1. δ 179.16 (s), 138.72 (s), 133.43 iclJ- 33.7 Hz)? 124.42 (s), 124.07 (s), 121,36 (s, 119.84 (s), 90.06 (s), 68.59 (d, J~ 3.6 Hz), 68.27 (s), 67.41 (s), 65.57 is), 50.14 (s), 19.99 (s), H MS (ESi); [M *] Calc.500.0444, found 500.0452.
SIS was prepared according the according the literature (Zhao, Q., et al,
2013, / s 40i4-4017aad HayasM,T.,etai., Buli. Chem, Soc, Jpri.1980,55, 1138-1151). Under a nitrogen atmosphere, 3,5-bis(tri.tluorometfeyl)phettyl isofhiocyanate (l.lmmoi) was added to a solution of $15 (1.0 mraol) in dry DCM (1.0 ml). After the reaction mixture was stirred overnight, the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane/ethyl acetate :::: 9/1 as eluawt) gave LI 7 as yellow solid.
L17; 1 H NMR (400 MHz, CDCfc) S 7.74 (s, 3H), 7.51 (s, 2H), 7.40 - 7.28 (ro, 5H), 7.22 (s, 3H),7.15- .05(m, 2H),5 9(s, 1H1 .51 (s, lH):!4.32(s, IH),3.96(s, 5.H),3.79(s, 1HK 1.46 (d, J- .7 Hz, 3 H),
C NMR {100 MHz, CDC¾) 6177.42 ($), 138.02 (s), 137.86 (d,</= 6.0 Hz. 134.85 (d,J=
4.5 Hz), 133.73 (d, J - 20.8 Hz), 131.89 (d, 33.9 Hz), 131,25 (dyJ~ 17.8 Hz), 128.51
(s)} 127.43 - 127.02 (m% 126.10 - 125.89 ( ), 123.82 (*), 123.27 (s), 120.56 (s), 118.42
(s), 118.01-117.76 (m), 93.98 (ci J - 24.2 Hz), 72. ! 6 (s), 71.07 (d, J- 4.0 Hz), 70.22 is},
68.83 (s), 68.66 (s), 50.33 (s), 2.1.26 (s).
3iP NMR (162 MHz, CDC¾> δ -24.67 (s).
HRMS (ESI): [M+H'l Calc.685.0964, found 685.0950.
Example 2 - Asymmetric hydrogenation of mtroalkenes
Figure imgf000024_0001
In a nitrogen-filled glovebox, a solution of L (2.2 eqv.) and Rh(COD)C¾ (3.0 mg,
0.006 mmol) 3.0 mL anhydrous /-PrOH was stirred, at room temperature or 30 mm, A specified amount of the resulting solution (0.25 mL)was transferred to a vial charged with la (0.1 mmol) by syringe. The vials were transferred to an autoclave, which was then charged with 5 atm of i¾ and stirred at 35 °C for 24 . The hydrogen gas was released slowly and the solution was concentrated and passed through a short column of silica gel to remove the metal complex. The product (2a) was analyzed by NM spectroscopy for conversion and chiral HPLC for ee values,
(R)-2n: Ή NMR (400 MHz, CDCU) δδ 7.38 - 7.31 (m, 2H), 7.30 - 7.20 (m, 3H), 4.58- 4.46 (m, 1H)? 3.85- 3.16 (m, IH), 1,38 (d,J~ 7.0 Hz, iH).! !C NMR (100 MHz. CD(¾) δ 140.93 (s), 128.98 (s), 127.57 (s), 126.90 (s), 81.87 (s), 38.65 (s), 18.73 (s).HPLC OD, 215 am, hexane/2-propanol - 98:2, flow rate 0.9 mL/min, % (major) =1 .4 mm, ¾ (minor)
=27.4 mm. [a] D 2 = +41.4° (o - 0.67, CHC¾).
Table 1. Study of effects of pressure, concentration, and temperature.*
Entry Solvent Rh-LS Hsfatm] V(mL) T i
/-PrOH [Rh(COD)Ci]2 5 50 0.25 25 •99 99 /-PrOH [R (COD Cl]2 1 0 0.25 35 >99 99 -PrOH [ MCOD 'ljs 200 0.25 35 97 98 /4>r ! { [Rh(COD)Cli2 400 0.25 35 90 98 /-PrOH [Rh(COD)CS]2 10 200 0.25 35 97 99
6 /-PrOH Rh(COD)C!]3 20 200 0.25 35 : 99 98 7 /-PrOH [ h(COD>Cl]2 20 400 0.25 35 95 98 8 i-PrOH [Rh(COD)Cl]2 30 400 0.25 5 98 98 9 i-PtOB [Rh(COD)(¾ 100 0.5 35 99 98 10 /-PrOH Rh(COD)CS]2 100 1.0 35 97 98 1 /-PrOH [Rh(COD)Cl] 400 0.?' 90 94
[a] Unless ortherwise mentioned, reactions were performed with l a (0.1 ramol) and a Ja /Rh/L ratio of 1 /1, 1/1.1 , [b] Conversions were determined by Ή N R spectroscopy of the crade reaction mixture and HPLC analysis, [c] Determined by HPLC analysis on a chirai stationary phase. β, p-disiibstituied nitroalkanes were prepared using the general procedure set forth above with different nitroalfcenes. Nitroalkenes with various subsiituents at the phenyl ring were tolerated. Meta and para substitutions led to excellent results whether they were electron-withdrawing or electron-donating groups. The or /io-meihoxy group resulted in a lower conversion and enantioselectivity . This catalytic system also provided
enantiotoericaily β-ethyl nitroalkane with good conversio and excellent
enantioselectivitv. The nitroalkanes were characterized as follows;
Figure imgf000025_0001
(J?)~2b: 'Ή NMR (400 MHz, CDClj) 67.39 - 6.86 (m» 5H), 4.47 - 436 (m, 2H), 3.47 - 3.49 (m, 1H>, 2.25 (s., 3H), 1.28 (d, J= 7.0 Hz, 3H).^C NMR (100 MHz, CDCk) 6 137.87 (s), 137.21 (s), 129.61 (s), 126.73 (s), 81.98 (s), 38.27 (s), 20.98 (s), 18.75 (s)..HPLC: OD5 215 nm, hexane/2-propanol - 98:2, flow rate 0.9 mL/min, t«. (major) =14.1 mir I (minor) =23.0 roin. [a] D 2 = 4-42.9° (c - 0.5 L€Η€¾ )
Figure imgf000026_0001
(R)~2c; lH NMR (400 MHz, CDCU) δ 7. j 9 - 7.1 1 (m, 2H), 6.96 - 6.84 (m, 2H), 4.52™ 4.42 (ffi, 2H), 3.79 (s, 3H), 3.66 - 3.54 (m, 1 H), 1.35 (d, J = 7.0 Hz, 3H).1:'C NMR (100 MHz, CDCh) 6 158.94 (s), 132.86 (s), 127.89 (s), 1 14.34 (s), 82.12 (s), 55.26 (s), 37.92 (s), 18.79 (s).HPLC: OD, 215 nm, hexane/2-pfopanol = 98:2, flow rate 0.9 mUmm, t& (major) =22.1 mm, ifi (minor) ::::40.6 mm.[a] j/5™ 4-35.8° (c ::: 0.51, CHC¾)
Figure imgf000026_0002
(«)-2d: lH NMR (400 MHz, CE ¾) δ 7.37 ~ 7.27 (m, 2H), 7.2 - 7.12 (m, 2H), 4.63 - 4.42 (m, 2H), 3.75 - 3.48 (mt 1 H), 1.37 (d, ../ - 7.0 Hz, 3H). !3C MR (100 MHz, CDC:¾)5 139.35 (s), 133.43 (s), 129.15 (s), 128.27 (s), 81.56 (s), 38.07 (s), Ϊ 8.71 (s).HPLC: OD, 215 nm, hexane 2-p.ropanol ::: 98:2. flow rate 0.9 mL/min, ij (major) :::;18.8 min, t (minor) -27.1 i»in.[aj ··>" " 4-39.5° (c - 0.48, CHCh)
Figure imgf000026_0003
(«)~2e: lE NMR (400 MHz, CDC!3) 67, 18 - 7.13 (m, 4H), 4.56 - 4.43 (m, 2H), 3.70 ·- 3.48 (m, i 11 ), 2.63 (q, J - 7.6 Hz, 20 ), 1 ,36 (d, J = 7,0 Hz, 3H), \ .22 (t, J - 7.6 ¾ 3H). °C NMR (100 MHz, CDCb) δ 143.58 (s), 138.10 (s), 128.43 (s), 126,83 (s), 82.01 (s), 38.30 (s), 28.42 (s), 18.75 (s), 15.42 (s}.HPLC: OD, 215 nra, hexane/
0.9 mL/tnim IR (major) =1 1 .8 min, ¾ (m or) -1.9.9 mm. [a] 0 2
Figure imgf000027_0001
(J?)-2f: 1H NMR. (400 MHz, CDC ) δ 737 - 7,32 (m, 2H), 7J 8 - 7.12 (m, 2H), 4.56 - 4,43 (m, 2H), 3.69 - 3.51 (m, I H), 1.37 (d, J- 7.0 Hz, 3H), 1.30 (s5 3H).1:'C NMR (100 MHz, CDCh) 6 150.47 (s), 137.79 (s), 126.55 (s), 125.84 (s), 81.97 (8), 38.13 (s), 34.47 (s), 31.29 (s), 18.67 (s).HPLC: OD, 2.15 tm\ hexane/2«proparioi = 98:2, flow rate 0.9 mL rain, 1R
(major) ::: 9.7 mia, t¾ (minor) :::: 18.4 min. [a] r 5= · ■· 4.1.8° (c - 1.0, CHCb )
Figure imgf000027_0002
(«)-2g:1H NMR (400 MHz, CDC¾) δ 7.30 ~ 7.22 (m, 1 E), 7.16 (dd, J = 7.6, 1.6 Hz, 1 H), 6.96 - 6.88 (m, 2H), 4.68 (dd, J■■■■■■■■ 1 1.9, 6.0 Hz, IH), 4.46 (dd,J- 1 1.9, 8.8 Hz, IH), 3.97- 3.90 (m, 1H), 3.88 (s, 3H), 1.38 (d, ./= 7.0 Hz, 3H). C NMR (100 MHz, CDCh) 6 157.06 (s), 128.82 (s), 128.5.1 (s), .127.71 (s), 3.20.86 (s), 1 1 .83 (s), 80.45 (s), 55.34 (s), 33.48 (s), 1.7.05 (s).HPLC: OD, 2 5 nm, fcexane 2~propanol ::: 98:2, flow rate 0.9 mL/min, {R (major) =I4.4min, ½ (minor) =17.0min.[a] D S= +6.9 (c -0.2, CHCI3 ).
Figure imgf000027_0003
(R)~2k: lH NMR (400 MHz, CDCI. d 7,35 - 7.27 (m, I H), 7.05 - 6,87 (ra, 3H), 4.57 - 4.45 (ra 2H), 3.69 - 3.62 (m, IH), 1.38 (d, - 7.0 Hz, 3H).UC NMR (100 MHz, CDCI.5) δ 164.33 (s), 161 .88 (s), 143,46 (d, J - 7.0 Hz), 130.57 (d, J- 8.3 Hz), 122.65 (d, J- 2.9 Hz), 1 14.59 (d /= 21.0 Hz), I I 3.96 (d, ./ = 21.8 Hz), 81.5 1 (s), 38.37 (d, J= 1.6 Hz), 18.67 (s). HPLC; OD, 215 nni, hexane/2-p.ropao.ol = 98:2, flow rate 0.9 niL/roin, hi (major) -20.0 fflin, tR (minor) -28.4 min. [a] » s +333° (c - 0.72, CHCIS).
Figure imgf000028_0001
(]?)-2i: 1 H NMR (400 MHz, CDC ) 5731 -·■ 7.21 (m5 3B), 7.12 - 7.10 (m, 1 H), 4.56 4.45
(m, 2H), 3.70 - 3.55 (m, IH), 137 (d, J- 7.0 Hz, 3H)."C NMR (100 MHz, CDCb) δ 142,94 (s), 134.83 (s), 130.26 (s), 127.84 (s), 127.17 (s), 125.18 (s), 83 .41 (s), 3833 (s), 18.65 (s).HPLC: OD, 215 n , hexane/2~propanol ~ 98:2, flow rate 0.9 mL/min, t¾ (major)
- .8 min, tR (minor) =30.5 rain, [a] D 25= +37. 1° fc - 0.58, CHCL)
Figure imgf000028_0002
(J?)-2j:1H NMR (400 MHz, CDC!,) & 7.26 (i J - 7.9 Hz, ! H), 6.96 - 6.68 (m, 3H), 4.57 - 4.44 (m, 2H), 3.80 (s, 3H), 3.66 - 3.54 (m, 1H), 1.37 (d, J= 7.0 Hz, 3H).5¾ NMR (100 MHz, CDClj) 5 160.00 (s), 142.54 (s), 130.01 (s). 1 19.11 (s), ! 13.10 fs), 12.55 (s), 8.1.79 (s), 7734 (s), 77.03 (s), 76. 1 (s), 55.23 (s), 38.66 (s), 18.70 (s). HPLC: OD, 215 nm, bexane/2-propanol ~ 95:5, flow rate 0,9 mL/min, tR (major) =29.3 min, % (minor) =52.2 m ,[a] 0 25- +40.6° (c - 0,73, CHCb)
Figure imgf000028_0003
(R)-2k: Ή NMR (400 MHz, CDCh) δ 8.08 - 7.70 (m, 3H), 7.67 (d, J- 1.0 Hz, IH), 7.56 ··- 7.40 (m, 2H), 7.35 (dd, J- 8.5, 1.8 Hz, 1 H), 4.67 - 4.54 (m, 2H), 4.02 - 3.55 (m, 1.H), 1.47 (d,J= 7.0Hz, 2H).i3C NMR .(100 MHz, CDC )§ 138.29, 133.52, 132.78, 28.85, 127.76, 127.69, 126.44, 126,08, 125.78, 124.81, 81. SO, 38.80, 18.79. HPLC; OD, 215 «m, hexane/2-propanol ~ 80:20, flow rate 0.9 mL/min, ts. (major) -1 .8 mill, tR (minor) ~5'3.5 mm. fa] D 3i- ÷36.8ft (c - 0.9, CHC )
Figure imgf000029_0001
C«)-21;5H MR (400 MHz, CDC13) δ 7.3 - 7.23 (m, 3H), 7.2! - 7.10 (m, 2H), 4.59 - 4. 1 (m, 20), 3.54 - 3.11 (m, 1H), 1.79 - 1.66 (m, 2H), 0.84 (r, ./= 7.4 Hz, 3H).13C NMR (100 MHz, CD(¾)S 139.33, 128.89, 127.56, 80.76, 46.00, 26.18, 11.49. HPLC: OD, 215 urn, hexaae/2-propaao! - 98:2, flow rate 0.9 mL/rain, t« (raajor)= !6.0 mm, t¾ (mmor)™!!
mm. [a] D 25- ÷35.5° (c - 0.54, CHCi3)
Figure imgf000029_0002
($)-2m: lU NM (400 MHz, CDC ) δ 6.26- 0.23 (m, IB), 6.05 (d,J= 3.1 Hz, IB), 4.59 (dd,J-12.2:6.6Hz, IB), 4.3 (dd, J- 12.2, 8.0 Hz, IH), 3.72 - 3.60 (ffi, IH), 1.31 (d,J- 7.0 Hz, 3H).53C NMR ( 100 MHz, CDC¼} δ 152.85 (s), 141,08 (s), 109.27 (s), 104.92 (s), 78,49 (s), 3 ,41 (s), 15.12 (s).HPLC; OD, 215 tvm, hexane/2-propanoI - 99.5:0.5, flow rate 0,9 mt tnin, ts (major) -27.5 mm, iR (minor) ::::30.7 mm.
Example 3 - Asymmetric hydtogersation of N-H iraines
All N~H iraines were prepared according the literature (Boo, G., et al., J Am. Chem. Sac.2009, 131, 9882-9883.). All the spectra! data are consistent with the literature values.
Figure imgf000030_0001
1H MR (400 MHz, CDCIs) δ 1 1.46 (s, 2H), 8.20 - 7.91 (ra, 2H), 7.78 (t,J= 7.5 Hz, IH) 7.61 (dd, J ::: 1.7.7, 9.6 Hz, 2H), 2.94 (d, J- 5.2 Hz, 3H).
,3C NMR (100 MHz, CDCI3) 5 186.36 (s), 136.95 (s), 129.92 (s), 129.35 (s), 129.33 is), 21.73 (s). General procedure: j 2CI [Rh{COP)Gik-t, H¾ ^01
*¾ i~PrO , 24 . 25 *C R,"" R2 tii a nitrogen- filled g!ovebox a solution of LI (2.2 eqv,) and [Rh(COD)CI]2 (3.0 mg, 0.006 mmol) in 6.0 niL anhydrous i-PrOH was stirred at room temperature for 30 min.
NHaCf
I f Solvent. 24 h
Figure imgf000030_0002
A specified amount of the resulting solution (I mL) was transferred to a vial charged with l a (0.1 mmol) by syringe. The vials were transferred to an autoclave, which was then charged with 10 atro of ¾ and stirred at 25 ¾C for 24 h. The resulting mixture was concentrated under vacuum and dissolved in saturated aqueous NaHCO? (5 mL). After stirring tor 10 min. the mixture was extracted with CHjCl (3 x 2 roL) arid dried over Na^SO^ To the resulting solution was added Α¾0 (300 μΙΛ and stirred for 30 min. The resulting solution, was then analyzed for conversion and e directly by GC. The product was purified b chromatography on silica gel column with,
dichioromethane methanol (90: 10). All spectral data ware consistent with the literature values (Hou, G., et al., J. Am. Chem, Soc. 2009, 131, 882-9883).
Figure imgf000030_0003
Entry Solvent Metal * 1 ;-PrOH [ (COD)Ci;|j 20 25 1 35 99 92
2 i'-PrOH |Ir(COD)Cib 20 25 1 35 90 84
3 /-PrOH Rh(COD),BF4 20 2 ! 35 93
4 -PrOH Rh(NBD >SbF« 20 25 1. 35 95 17
5 i-PrOH Pd(OAc)2 20 25 J 35 <1 NI
6 /-PrOH Pd(TFA), 20 25 I 35 30 0
7 i-PrOH [ {RuCljip-cymeiie) j ¾| 20 25 i 35 8 23
[a] Unless ortlierwise mentioned, reactions were performed with la (0.1 mmol) and a Metal/L!4 ratio of 1 /1 .1 . [b] Determined by GC analysis of the corresponding acetamides. M>::: not determined. Table 3. Study of pressure and temperature.
Entry Solvent H2[atra] S/C 'V(mL) T [ ,;'Cj Conv.[%f ee[%J
] i-PrOH 20 25 1 35 99 92
Figure imgf000031_0001
i-PrOH 20 100 1 35 99 93
4 -PrOH 10 100 1 25 99 94
5 i-PrOH 10 200 1 25 96 94
Figure imgf000031_0002
/-PrOH 20 200 1 25 97 93
8 i-PrOR 20 200 i 35 97 92
9 -PiOH 20 400 ! 35 90 93
[a] Reactions were performed with la (0.1 mmol) and a [Rh(COD)Cl]2 L14 ratio of 1/1. 1. [b] Determined by GC analysis of the corresponding acetamides.
Table 4. Study of additives.
Entry Solvent M?iatrn] S/C Addtive T [ °C| C nv.[ 1 /-PrOH 20 50 4A MS 35 67 53
O OOmg
2 i-PtOH 20 50 CF3COOH 35 99 75
(10 mmol. ¾)
3 /-PrOH 20 50 CHiCOOH 35 98 79
(10 mmoi %)
4 /-PrOH 20 50 Eh 35 63 35
(10 aimo! %)
[a] Reactions were perfomied with la (0.1 mmoi) and a [Rh(COD)G]2/'L14 ratio of 1/2.
Determined by GC analysis of the corresponding acetamides.
Table 5. Solvent study.
Eirtiy Soiveat Metal source
1 /-PrOH [ h(COD)-.|BF4 93 77
2 i-PrOH [R¼ BD)3]SbFa 95 47
3 /-PrOH f.RJh(COD ¾ 99 92
4 CH2C12 Rli(COD}C!], 91 30
5 Toluene |Rli(CQD;)C¾ 60 15
6 THF { MCOD}CIj2 76 60
7 MeOH (R (CODK¾ 99 73
8 EtOH [RMCODICI]-, 92 89
9 /-BuOH fRli(CQD)C¾ 84 91
! ( )' /-PrOH Rhf CODlC!Ji 99 93
1 lrf /-PrOH Rh(COD>Cife 99 94
12' /-PrOH [Rh(COD)C¾ 96 94
1 1'" /-PrOH |:Rli(C D}C!|, 97 93
14* /-PrOH [Rh(CQD)C% 97 92
* Unless otherwise mentioned, reactions were performed with la (0.1 mmoi) and a Rli/L/la ratio of 1/1 .1/25 ia 1.0 mL solvent at 35 °C trader 20 atm ¾.* Determined by GC analysis of the corresponding acetamides. ' S/C ::: 100, 35 °C, 20 atm H S/C - .100, 25 °C, 10 atra ¾, *$iC :=: 100, 25 °C, 10 atm H S/C - 200, 25 °C, 20 aim ¾ ¾/C - 200, 35 "C, 20 atm ¾ COD = 1 ,5-cyc!oocfadieiie, NBD = 2,5-norbornadtene. A variety of N~H .unities were tested Most substrates with meta and para substitutions on the phenyl ring afforded high yields and enantkiselectivities (96-99% yield and 90-94% ee).
Figure imgf000033_0001
Figure imgf000033_0002
However, tlie chloro group and methoxy group resuiied in an obvious decrease of the yields (2d, 2e and 2g). The ortho-m&thox group on the phenyl ring resulted in 34% yield and 84% ee (2h). Products with 1- and 2-naphthyl group were obtained with 92% ee and 93% ee respectively. Changing the R2 group had a significant effect on the outcome. When 2 was ethyl, both lower conversion and enatHioselectivity were observed (2k). As the ¾ group was changed to butyl, further loss of the conversion and enannoselectivity was observed (70% yield and 75% e, 21).
To obtain insight into this catalytic system, a series of chirai ligands were prepared and control experiments were undertaken.
Figure imgf000034_0001
Cable 6. Ligand studv.
Entrv I fiA<tids CovaW
li 55
L2 66
L3 6 11
4 L4 87 5 L5 76 90 6 L6 9 94 7 1,7 26 38 8 L8 11 9 1,9 84 so¬ L8 8
U 9 57 a Unless otherwise mentioaed, reactions were performed with la (0.1 mniol) and a RhL/ia ratio of i II .1/100 in 1.0 mL solvent at 25 °C under 10 atm H2* Determined by GC analysis of the corresponding acetamides. £ Rii/L/la/P! P ::: 1/1.1/100/2.2. " RlvL/la/thiourea:::
1/1,1/100/1,1. The Rh-bisphosphine complex without a (thio)urea L9) showed very low activity and enaniiose!eeti vity (Table 6. entry 1 }. Urea LI 0 provided 22% conversion and 66% ee m sharp contrast with the more acidic thiourea L14 (Table 6, entry 2 vs. 6) hl The CF3 group on the
3.5-(trif1 oromethyi}plieny! moiety remained important in the catalytic system (Table 6, entries 3-5). Further; several modified Sigands were prepared and screened. An N~meihylation of LI 4 led to a dramatic decrease of the conversion and enantioselectivity (Table 6, entry 7). This finding suggested that, the NO was involved in the activation of .minium salts and the stereoselectivity of hydrogenation. Furthermore, the low conversion and enantioselectivity obtained with
monodentate phosphorus Hgands implied that a bisphosphine moiety was essential (Table 6, entry 9). Importantly, neither the combination of the ehiral phosphine with the
3,5-bistrirIuororaethylphenyl thiourea, nor the combination of the chiral thiourea with the simple phosphine improved this reaction (Table 6, entry 1 vs. 1 1 , entry 8 vs. 10), which pointed to the importance of the covalent linker for high activit and enantioselectivify.
Different counterions and additives were also investigated.. When the chloride counterfoil in la was replaced with trifluoromethanesulibnate, only 20% conversion, and 53% ee was observed (Table 7, entry I), The addition of a chloride counterion increased the conversions and enantioseiectiviiies (entries 2 and 3). However, the addition of bromide and iodide counterions decreased the conversions and enantioselectivities (entries 4-6),
Table 3. Substrates study and control experiments."
Figure imgf000035_0001
fjitr I Additive Covn."(%)
1 I ra 20 53
l ill TBAC 86 94
Ira LiCl 71 93
4 la 99 94
5 la Γ.ΒΑΒ 90
6 la TBAI 32 89 β Unless otherwise mendoaed. reactions were performed with la (0.1 mmo!) and a
Rh L i a/ Additive ratio of 1/1.1/100/100 in 1.0 mL solvent. ' Determined by GC analysis of
the corresponding acetamides. "Determined by Ή NMR. TBAC ::: ietrabuiyianunonium
chloride, TBAB == ietrabutylammotitum bromide, TB = tetrabutylammomim. iodide. ND™
not detertimined.
Further information about the reaction was obtained by Ή NM R studies of mixtures generated from iigands and TBAC. The addition of varying amounts of TBAC to LI 4 in CDC1¾ resulted in downfield shifts of the NH proton signals. At 1 ,0 equivaients of TBAC, the signal for 'NH was at 9.73 ppm, but when 3.0 equivaients of TBAC were added, the NH signal appeared at 10.16 ppm. Analogous experiments employing a series of different Iigands and TBAC gave similar results. This finding was consistent with a hydrogen-bonding interaction between the catalyst's thioure and chloride ions. This observation, coupled with the fact that optimal yields and ee values involve chloride ions, led us to propose that catalytic chloride-bound intermediates are involved in the mechanism.
The present invention has been described with particular reference to the preferred embodiments, it should be understood that the foregoing descriptions and examples are only illustrat e of the invention. Various alternatives and modifications thereof can be devised by those skilled in the art without departing from the spirit and scope of the present invention, Accordingly, the present invention is intended to embrace all such alternatives, modifications, and variations that fall with the scope of the appended claims.

Claims

CLAIMS What is claimed is;
1. A ligand having the structure or its eivantionier. organocataiysf
wherein: each one of Ra, Rb, R^, and Rd is selected from the group consisting of alky!, cyeloaikyl and aryl; the bridge group is selected from the group consisting of CHs'NH; *CH(C¾)NH (C*i?): and *CH(CH.,)NH (C*SS); and
the organocataiyst is an organic molecule catalyst cova!ently bound to the bridge group.
2. The Iigand of claim L wherein at least one of % !¾,, Rc, and a is an aryl moiety selected from the group consisting of phenyl; P-CH;¾ phenyl; 355-di-C¾ phenyl; 3,5-di-r-bury! phenyl; 3,5-di-CFj phenyl; 2-CHb phenyl; C¾Fs; 2-naphlhyl; and ! -naphthyi.
3. The ligand of claim 3 , wherein at least one of Rs, ¾, Rc> and ¾ is an alky! moiety selected from the group consisting of t-b tyl and i-propy!.
4. The ligand of claim 1 , wherein at least one of R?„ R¾, Rc, and j is a eycloaSkyS moiety selected from the group consisting of cyclohexyi and eyclopentyl.
5. The Hgand of claim 1„ wherein said Hgand is selected from the group consisting of compounds represented by the following formulas:
Figure imgf000038_0001
-PR¾ - Pb ■ppt¾ LL3
Figure imgf000038_0002
LL4 LL5 LL6
Figure imgf000038_0003
6. The iigand of claim 1 , wherein said Iigand is selected from the group consistin compounds represented by the following formulas:
Figure imgf000039_0001
7, The Hgand of claim 1„ wherein said ligand is selected from the group consisting of compounds represented by the following formulas:
Figure imgf000040_0001
A catalyst havinu the structure or its enantiomer:
Figure imgf000041_0001
(0) wherein: each one of Ra, ¾>, Rc, and R<j is selected from the group consisting of alkyl, cycloalkyl, and aryl; the bridge group is selected .from the group consisting of CI¾NH; *CH(C_¾)NH (C* ): and
Figure imgf000041_0002
the organ ocatal st is an organic -molecule catalyst covalemly bound to the bridge group; and M is selected from the group consisting of Rh, Pd, Cu, Ro, Ir, Ag, Au, Zn, Ni, Co, and Fe,
9. The catalyst of claim. 8, wherein at least one of Rs, Rfe} R^, and R<i is an aryl moiety selected from the group consisting of phenyl; P-CF phenyl; 3,3~di-C¾ phenyl; 3,5-di-t~butyl phenyl; 3,5-dt-CF3 phenyl: 2-C $ phenyl; QF5; 2-naphthyl; and l~naphthyt.
10. The catalyst of claim 8, wherein at least one of Rs, Rt>, and R,i is an alkyl moiety selected from the group consisting of t-butyl and i-propyl.
! 1. The catalyst of claim 8, wherein at least one of R, Ri¾ R*, and Ra is a cycloalkyl moiety selected from the group consisting of cyclohexyl and cyci.ope.ntyi.
12, A method for the asymmetric hydrogenation of an alkene to a corresponding alkane comprising combining an alkene in suitable solvent with an excess of hydrogen gas and a eatalytica!Sy effective amount of the catalyst of claim 8 at a temperature and pressure effective to hydrogenate the alkene.
13 , The method of claim 12, wherein the sol vent comprises isopropanol.
14, The method of claim 12, wherein at least one of Ra, R¾, ^, and Rd in the catalyst is an aryl moiety selected from the group consisting of phenyl; P~C¾ phenyl; 3,5-di-CHi phenyl; 3,5~di~f~bufyl phenyl; 3,S~di~€Fi phenyl; 2-CHs phenyl; C<-,Fj; 2-naphthyl; and 1-naphth l..
15. The method of c laim 12. wherein at least one ofR«, ¾, Re., and ¾ in the catalyst is an alkyl moiety selected from the group consisting of t~butyl and i-propyl.
16. The .method of claim 12, wherein at least one of .?„ ¾, Rc, and ¾ in the catalyst is a cycloalkyl moiety selected from the group consisting of cyclohexyl and cyclopentyl.
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