The present invention relates to a process for the use of a in situ generated asymmetric palladium catalyst in an enantioselective hydroamination reaction.

Many important reactions in chemical synthesis are catalysed by palladium catalysts. One such reaction involves hydroamination by the addition of an N- H bond across a double or triple bond. This reaction furnishes valuable nitrogen containing molecules from readily available and non-hazardous precursors with 100% atom economy. Thus the hydroamination process is one of the most desirable processes, economically and environmentally.

The production of optically pure compounds such as those produced by hydroamination reactions is a particularly important target in the chemical industry. Compounds such as pharmaceuticals, agrochemicals, fragrances and flavourings are required in enantiomerically highly enriched forms and preferably as single enantiomers. The production of such optically pure compounds is particularly important for use in the medical or veterinary fields where the presence of an unwanted isomer may reduce or dilute the activity of the active enantiomer or induce harmful or unwanted side effects.

Very few catalysts can facilitate the addition of N-H double bonds with high enantioselectivity. Examples of catalysts previously used in the art include an iridium-fluoride system which promotes the addition of aniline to norbornene (24%, 91% ee), palladium-catalysed addition of primary aromatic amines to

1,3-dienes (up to 95% ee) and nickel-catalysed addition of secondary aromatic amines to alkenoyl-N-oxazolidinones (up to 90% ee). For palladium or nickel catalysed reactions, catalysts loadings of 5 mol % were employed at room

temperature. However reaction times between 40 hours to 5 days are required to achieve significant yields.

The cationic palladium complex [(R-BINAP)Pd(solvate) ₂ ] ²⁺ [TfO] ^" ₂ 1 has been investigated for the enantioselective addition of primary and secondary aromatic amines to alkenes containing electron withdrawing substituents such as alkenoyl-N-oxazolidinones. Examples of the catalytic activity of the cationic palladium complex are set out below.

up to >99% yield, >99% ee

Previously, the palladium catalysts have been synthesised, isolated and purified prior to their use in the addition reactions discussed above. For example dicationic complexes of palladium can be prepared by halide abstraction from the corresponding (diphosphine)palladium dihalide using a stoichiometric amount of a silver salt, followed by the introduction of a chiral ligand such as R-BINAP.

[

2

P-P = dppf (a), dppr (b), dippf (c), dppe (d), (R)-BINAP (e)

Thus in order to perform a palladium catalyst reaction such as the hydroamination discussed above, it is necessary to firstly perform a two step synthesis of the palladium catalyst and then to carry out the hydroamination reaction. In addition, the use of 2 equivalents of silver salt in the synthetic scheme are not favoured as silver salts are expensive and separation of the catalyst from the resulting silver triflate is difficult.

Furthermore, the production and isolation of the palladium complex does not favour the preparation and screening of palladium catalysts with new chiral ligands, thus hindering the development and identification of new asymmetric catalysts.

The synthesis, isolation and purification of the palladium catalyst currently used in the art can therefore be time consuming, laborious and expensive.

Enantioselectivity of an asymmetric process is dependent on the attainment of a kinetically-favourable transition state, which is often highly sensitive to stereoelectronic effects exerted by the ligand and substrate(s). Thus, judicious modification of a ligand' s structure is often necessary to accommodate substrate changes. Traditionally, the preparation of ligands and/or catalysts is a time-consuming procedure, and constitutes one of the major hurdles in the discovery of asymmetric catalysts.

The present invention provides a novel method of hydroamination involving the in situ generation of a palladium catalyst, which allows rapid generation of the catalyst and its use directly in an enantioselective hydroamination reaction.

The first aspect of the invention therefore relates to a process for the enantioselective addition of an amine to a compound comprising an alkene comprising: incubating Pd(OTf) ₂ with a phosphine ligand comprising one or more chiral biaryl groups to form an asymmetrical catalyst in situ; and adding an amine compound and an alkene compound to the in situ generated catalyst to form a product having a covalent bond between the amine and a carbon of the alkene.

In particular, the first aspect of the invention provides a process for the enantioselective addition of amines to a compound comprising an alkene comprising: incubating Pd(OTf) ₂ -2H ₂ O with a diphosphine ligand comprising one or more chiral biaryl groups to form an asymmetric catalyst in situ; and adding an amine compound and an alkene compound to the in situ generated catalyst, to form a product having a covalent bond between the amine and a carbon of the alkene, wherein said product has an ee equal to or greater than 90%.

For the purposes of the first aspect of the invention, the phosphine ligand contains axial chirality and can be a monophosphine, a diphosphine ligand or a triphosphine ligand. When the phosphine ligand is a diphosphine ligand it is preferably one or more of BINAP, ToI-BINAP, SYNPHOS, Cl-MeO-BIPHEP, MeO-BIPHEP, C3-Tuneρhos, Difluorphos or CTH- P-Phos. When the phosphine ligand is a monophosphine ligand it is preferably one or more of Monophos, MOP or (Bz)Monophos. The phosphine ligand can be one or more ligands as illustrated in figure 3 of the present application.

The process of the first aspect of the invention provides the in situ generation of a palladium catalyst from a mixture of Pd(OTf) ₂ .2H ₂ O and excess BINAP. For the purposes of this invention, the catalytic complex generated in situ is not limiting and includes any catalytic complex comprising palladium and BINAP, such as a bis-aqua palladium BINAP complex and/or a bis-BINAP palladium complex. The complexes produced from a mixture of Pd(OTf) ₂ .2H ₂ O and excess BINAP in solution are preferably [(BINAP) ₂ Pd(solvent) ₂ ] ²⁺ [TfO] ^~ ₂ , or

[(BINAP) ₂ Pdr i2+ ⁺ [TfO]- ₂ , more preferably [(BINAP)Pd(OH ₂ ) ₂ ] 2 ^/ + ⁺ [rTfO]- ₂ . In particular, the catalyst can comprises [(BINAP)Pd(OH ₂ ) ₂ ] ²⁺ [TfO] ^~ ₂ as illustrated below,

[(BINAP) ₂ Pd i]2 ^z + ⁺ [TfO] ^" ₂ , as illustrated below,

and/or a mixture thereof. [(BINAP) ₂ Pd] ²⁺ [TfO] ^" ₂ and [(BINAP)Pd(OH ₂ ) ₂ ] ²⁺ [TfO]- may have the 3-dimensional structures as set out in figure 1 and 2.

The hydroamination reaction, more particularly the in situ generation of the asymmetric palladium catalyst is preferably carried out in an aprotic solvent, more preferably in toluene, dichloromethane or THF.

The catalyst produced by the process of the first aspect has a minimum catalyst loading of 10% to 0.5%, preferably 5% to 1%, more preferably 2.5% to 1.5%, most preferably 2%.

The product of the hydroamination reaction is preferably produced at an ee of 90% or above, more preferably 95% or above, more preferably 99% or above.

For the purposes of the process of the first aspect of the invention the amine is preferably a compound of formula (I)

(I)

The compound comprising an alkene is a compound having a carbon-carbon double bond. The compound comprising an alkene can include a carbon- carbon double bond in combination with any other functionality. The compound comprising an alkene is preferably a compound of formula (II)

(H) wherein R ₁ and R ₂ are any group;

R ₃ is H or Ci _-12 alkyl aryl or heterocyclyl;

R ₄ is Ci _-12 alkyl aryl or heterocyclyl,

wherein the aryl or heteroaryl groups for R ₃ and R ₄ can be optionally substituted.

R ₅ is hydrogen or can form with R ₂ a 4, 5 or 6-membered ring comprising one or more heteroatom such as an oxazolidinone ring.

The identity of Rj and R ₂ are not limited and can be any group. For example, R ₁ may be a chemical moiety such as a peptide, amino acid, dipeptide, a sugar, or a polymer. R ₁ may alternatively be selected from hydrogen, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 aryl or C _3-12 heterocyclyl, optionally substituted by one or more of C _1-6 alkyl, halogen, C _1-6 haloalkyl, OR ₅ , SR ₅ , NO ₂ , CN, NR ₅ R ₅ , NR ₅ COR ₅ , NR ₅ CONR ₅ R ₅ , NR ₅ COR ₅ , NR ₅ CO ₂ R ₅ , CO ₂ R ₅ , COR ₅ , CONR ₅₂ , S(O) ₂ R ₅ , SONR ₅₂ , S(O)R ₅ , SO ₂ NR ₅ R ₅ , NR ₅ S(O) ₂ R ₅ , wherein each R ₅ may be the same or different and is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl or C _6-I2 aryl;

R ₂ can be hydrogen, C _1-12 alkyl wherein the C _1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of -O-, - N(R ₅ )-, -S(O)- and -S(O ₂ )-, or aryl or with the adjacent carboxyl group forms an amino protecting group such as a carbamate including benzyloxycarbonyl, t- butoxycarbonyl, 2-(4-biphenylyl)-isoρropoxycarbonyl, 9- fluorenylmethoxycarbonyl, wherein said alkyl or aryl group can be optionally substituted with one or more of those groups described for R ₁ .

R ₃ is hydrogen or C _1-12 alkyl.

R ₄ is aryl or heterocycyl wherein said aryl or heteroaryl group can be optionally substituted with one or more of those groups described for R ₁

R ₁ is preferably a C _1-10 alkyl group such as methyl, ethyl, or n-ρroρyl.

Preferably R ₂ is OCH ₃ or OC(CH ₃ ) ₃

R ₃ is preferably H.

R ₄ is preferably

wherein Y is H, halogen, Ci _-6 alkyl or OC _1-6 alkyl, and n is 1 to 5, preferably 1, 2 or 3. More preferably Y is H, Cl, methyl or O-methyl. The Y group may be in the ortho, meta or para position, preferably the para position.

For the purposes of this invention, alkyl relates to both straight chain and branched alkyl radicals of 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms and most preferably 1 to 4 carbon atoms including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl n-pentyl, n- hexyl, n-heptyl, n-octyl. In particular, alkyl relates to a group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The term alkyl also encompasses cycloalkyl radicals including but not limited to cyclopropyl, cyclobutyl, CH ₂ - cyclopropyl, CH ₂ -cyclobutyl, cyclopentyl or cyclohexyl. In particular, cycloalkyl relates to a group having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Cycloalkyl groups may be optionally substituted or fused to one or more carbocyclyl or heterocyclyl group. Haloalkyl relates to an alkyl radical as defined above preferably having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms substituted with one or more halide atoms for example one or more of F, Cl, Br or I, such as CH ₂ CH ₂ Br, CF ₃ or CCl ₃ .

The term "alkenyl" means a straight chain or branched alkylenyl radical of 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms and most preferably 2 to 4 carbon atoms, and containing one or more carbon-carbon double bonds and

includes but is not limited to ethylene, n-propyl-1-ene, n-propyl-2-ene, isopropylene, etc. In particular, alkenyl relates to a group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The term "alkynyl" means a straight chain or branched alkynyl radical of 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms and most preferably 2 to 4 carbon atoms, and containing one or more carbon-carbon triple bonds and includes but is not limited to ethynyl, 2- methylethynyl etc. In particular, alkynyl relates to a group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.

"Aryl" means an aromatic 3-12 membered hydrocarbon preferably a 6-12 membered hydrocarbon containing one ring or being fused to one or more saturated or unsaturated rings including but not limited to phenyl, napthyl, anthracenyl or phenanthracenyl.

"Heterocyclyl" means a 3-12 membered ring system preferably a 5-12 membered aryl containing one or more heteroatoms selected from N, O or S and includes heteroaryl. In particular, the terms "aryl", "heteroaryl" and "heterocycyl" relate to a group having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.

The heterocyclyl system can contain one ring or may be fused to one or more saturated or unsaturated rings; the heterocyclyl can be fully saturated, partially saturated or unsaturated and includes but is not limited to heteroaryl and heterocarbocyclyl. Examples of carbocyclyl or heterocyclyl groups include but are not limited to cyclohexyl, phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isoxazole, isothiazole, morpholine, napthyridine,

oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazine, phthalazine, piperazine, piperidine, pteridine, purine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline, quinoline, quinoxaline, quinazoline, quinolizine, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, triazole, or trithiane.

For the purpose of the present invention, the term "fused" includes a polycyclic compound in which one ring contains one or more atoms preferably one, two or three atoms in common with one or more other ring.

Halogen means F, Cl, Br or I, preferably Br and F.

The process may further comprises the step of: transforming the compound of Formula I to a β -amino acid; or transforming the compound of Formula I to a β-amino amide.

For the purposes of this invention, where R ₂ is a protecting group such as tBoc, the β-amino acid can be obtained under mild basic conditions and the β-amino amide can be obtained under mild acidic conditions. A mild acid or base is one which will not lead to the racemisation of the newly created stereogenic centre. The acid or base is preferably used at room temperature. Concentrations are between 0.1M and 1OM. The procedure is dependent on the nature of the R ₂ group. Transformation into an acid can be carried out by hydrolysis with NaOH or Ba(OH) ₂ or HCl in H ₂ O or MeOH.

Transformation to an amide can be carried out according to procedures known in the art. For example when R ₂ is tert-butyl, removal of R ₂ is carried out with

HCl/dioxane, or TFA/CH ₂ C1 ₂ , or HBr/AcOH, or zeolites; when R ₂ is fluorenyl, removal of R ₂ is carried out with any secondary or tertiary nitrogen base (e.g. triethylamine, piperidine, DBU); when R ₂ is benzyl, removal of R ₂ is carried out by any hydrogenation procedure (e.g. H ₂ , Pd/C); ammonia/MeOH when R ₂ is Me, removal of R ₂ is carried out with ammonia/MeOH.

In a second aspect of the invention, there is provided a method of parallel ligand screening comprising incubating Pd(OTf) ₂ -2H ₂ O with a phosphine ligand comprising one or more chiral biaryl groups to form an asymmetric catalyst in situ adding one or more amine compounds and one or more alkenes to the in situ generated catalyst to form one or more products having a covalent bond between the amine and a carbon of the former said alkene,

Preferably, the method of the second aspect comprises incubating Pd(OTf) ₂ -2H ₂ O with a diphosphine ligand comprising one or more chiral biaryl groups, wherein at least one product of the method has an ee equal to or greater than 90%.

The method may involve the use of up to 30, preferably up to 20, more preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 amines and/or alkenes.

Preferably each amine compound and alkene compound are added successively (i.e. in a sequential fashion). Alternatively two or more amine compounds and/or two or more alkenes are added simultaneously. The reactions can be carried out in series or in parallel, for example on a multiple reaction array.

The products can be separated and detected, or detected in the reaction mixture. Methods of separation include MPLC, HPLC or FPLC. Methods of detection include mass spectroscopy, UV-VIS, IR, NMR spectroscopy etc.

All preferred features of each of the aspects of the invention apply to all other aspects mutatis mutandis.

The invention may be put into practice in various ways and a number of specific embodiments will be described by way of example to illustrate the invention with reference to the accompanying drawings, in which

Figure 1 shows the X-ray crystal structure of in situ generated [(R- BINAP) ₂ Pd] ²⁺ [TfO]Y,

Figure 2 shows the X-ray crystal structure of in situ generated [(BINAP) ₂ Pd] ²⁺ [TfO] ^' ,;

Figure 3 shows various phosphine ligands for the purpose of the invention; and

Figure 4 shows the evaluation of the phosphine ligands illustrated in figure 3 for the addition of aniline to butenoyl N-imide.

The present invention will now be further illustrated by reference to one of more of the following non-limited examples.

EXAMPLES

Identification of a suitable palladium precursor

Several palladium complexes were examined in combination with (R)-BINAP, in the addition of aniline to butenoyl N-imide.

General reaction condition: 5 mol% Pd salt, 5.5 mol% of R-BIΝAP (M : L of 1 : 1.1), aromatic amine (1 equiv.), butenoyl Ν-imide (1.1 equiv.), toluene, r.t.

Table 1. Comparison of Pd precursors for the addition of aniline to butenoyl Ν- imide

Entry R ¹ [Pd] precursor Time/h Yield/%* ee/% ^c

1 Me Pd ₂ (dba) ₃ -CHC1 ₃ 18 - -

2 Me PdCl ₂ 18 - -

4 Me PdCl ₂ (NCMe) ₂ 18 - -

5 Me Pd(acac) ₂ 18 - -

6 Me Pd(OAc) ₂ 18 37 2

7 Me Pd(TFA) ₂ 18 - -

8 Me Pd(OTf) ₂ -2H ₂ O 18 97 (84/ 91

9 ^e Me Pd(OTf) ₂ -2H ₂ O 18 89 89

Hf Me Pd(OTf) ₂ -2H ₂ O 18 83 92

^Calculated by ¹ H integration, determined by chiral HPLC. ^rf Value in parenthesis corresponds to result afforded by complex 1. ^e M : L ratio of 1 : 2. ^f M : L ratio of 1 : 0.5.

None of the palladium(O) nor palladium(II) complexes containing strongly coordinating anionic ligands proved to be active (entries 1-5). Interestingly, while palladium(II) acetate produced some product formation (virtually racemic), palladium(II) trifluoroacetate was inactive (entries 6 and 7). Unexpectedly, bκ(trifluoromethanesulfonate) palladium(II) dihydrate proved to be a highly active metal precursor for the reaction (entry 8). Results obtained with the in situ generated catalyst are comparable with those obtained for [R- (BINAP)Pd(solvate) ₂ ] ²⁺ [TfO] ^' ₂ prepared by conventional methods. The catalytic activity of bw(trifluoromethanesulfonate) palladium(II) dihydrate complex is little explored and it has not previously been employed in asymmetric processes.

During the reaction, catalyst 1 forms a homogenous reaction mixture as Pd(OTf) ₂ .2H ₂ O is not entirely soluble in toluene. Consequently, the catalyst activity and selectivity were found to be maintained at M : L ratios of 1:2 and 2:1 (entries 9 and 10). The presence of excess ligand does not therefore lead to the formation of the catalytically less active complexes. In addition, the effective catalyst loading as low as 2.5 mol% can be used.

Crystal structure of in situ generated palladium catalyst

The monomeric bis-aqua. and bw-ligated complexes of 1 were isolated from a mixture of the Pd(OTf) ₂ .2H ₂ O and (R)-BINAP and both structures were verified by single crystal X-ray crystallography (figure 1). Both catalysts have been found to be catalytically active.

Use of in situ generated catalyst to catalyse the addition of aromatic amines to compounds 3 and 4

The addition of the aromatic amines to model substrates 3 and 4 were examined with the in situ generated catalyst system. The results were compared to that obtained previously with isolated complex 1 (Table 2). The enantioselectivities of the two systems proved to be largely comparable. Indeed, in certain cases, significant enhancement was observed when the catalyst was generated in situ (entries 2, 7, 16 and 18). It should be noted, the addition to N-Boc substrates 3 were conducted in a lower amine:acceptor ratio (1: 1.1) than that previously employed in the art (1: 1.5). The use of a lower amine: acceptor ratio may have contributed to the lower yields observed in entries 13-24.

Reaction conditions: Amine/Michael acceptor/Pd(OTf) ₂ /(R)-BIΝAP ratio of 1/1.1/0.05/0.55 at 25°C in toluene. Value in parenthesis corresponding to the result obtained with complex 1. For the addition to N-B oc substrates 3, previous results (parenthesis) were obtained with amine/Michael acceptor/1 ratio of 1/1.5/0.05 at 25°C in toluene.

Compound 3

Compound 4

Table 2. Catalytic activity of the complex generated in situ and the isolated complex l. ^a

Entry Substrate R ¹ Y Time/h Yield/% ^ύ ee/% ^c

1 4 Me H 18 86 (84) 91 (89)

2 4 Me Cl 18 81 (88) 81 (73)

3 4 Me Me 18 86 (81) 85 (83)

4 4 Me OMe 18 81 (70) 78 (80)

5 4 Et H 72 86 (75) 80 (63)

6 4 Et Cl 72 75 (70) 60 (54)

7 4 Et Me 72 22 (70) 79 (59)

8 4 Et OMe 72 67 (76) 52 (51)

9 4 Pr H 72 79 (69) 68 (67)

10 4 Pr Cl 72 73 (78) 54 (58)

11 4 Pr Me 72 70 (71) 68 (70)

12 4 Pr OMe 72 60 (69) 57 (55)

13 3 Me H 18 89 (>99) 97 (97)

14 3 Me Cl 18 82 (>99) >99 (>99)

15 3 Me Me 18 70 (93) 90 (92)

16 3 Me OMe 40 51 (99) 79 (73)

17 3 Et H 72 54 (98) 88 (90)

18 3 Et Cl 72 61 (92) >99 (85)

19 3 Et Me 120 59 (94) 73 (71)

20 3 Et OMe 72 31 (>99) 19 (16)

21 3 Pr H 120 50 (98) 89 (89)

22 3 Pr Cl 120 45 (90) 92 (89)

23 3 Pr Me 120 34 (83) 38 (80)

24 3 Pr OMe 120 30 (82) 9 (17) ^α Values in parenthesis corresponds to results obtained with the isolated complex 1. ^Calculated by ¹ H integration, determined by chiral HPLC (major isomer has S-configuration).

Use of in situ generated palladium catalyst in parallel screening

A particularly important advantage offered by the present system allows the performance of parallel ligand screening. The use of the in situ generated catalyst in this manner is a particular advantage of the present invention.

Pd(OTf) ₂ -2H ₂ O is mixed with the appropriate diphosphine ligand in a solvent, such as THF or toluene, and stirred at room temperature for an appropriate time to generate the catalytically active complex in situ (typically 5-30 min). The substrates (amine and the olefin) were then added successively, and the reaction mixture was stirred at room temperature until reaction is judged to be complete. The process can be performed in a parallel fashion using an multiple reaction arrays, for example a 12-place reaction carousel (Radley's Technology), Chemspeed, Stem blocks, etc. These arrays are used to perform hundreds of reactions simultaneously. The arrays can be attached to a method of analysis, such as a HPLC, such that reactions may be monitored automatically.

Twenty-four commercially available chiral ligands (as illustrated in figure 2) were evaluated for the addition of aniline to the N-imide substrate butenoyl Ν- imide. The results of these reactions are illustrated in figure 3. Reaction conditions: 5 mol % Pd salt, 5.5 mol % of R-BIΝAP (M:L of 1:1.1), aniline (1 equiv.) butenoyl N-imide (1.1 equiv.), toluene, r.t.

Ligand screening: In a glove box, Radley's reaction tubes were charged with Pd(OTf) ₂ .2H ₂ O and ligand. A magnetic stirrer was introduced into each tube, which was then fitted with a PTFE screwcap (with integrated gas inlet valve and fitted rubber septum). The reaction tubes were placed in the carousel, and purged and filled successively with dry N ₂ . Dry toluene was introduced into

each tube, and the solution of the catalytic precursor was stirred for 30 min. The temperature of the reaction block was maintained at 25 ⁰ C by means of a thermostat, before the addition of the Michael acceptor, amine and additional amount of toluene. Periodically, small amounts of reaction aliquots were extracted via syringe and analysed by ¹ H NMR spectroscopy. At the end of the reaction, the solvent was evaporated, and the residue was subjected to column chromatography.

In general, the highest product yields were attained by diphosphine ligands. Biaryl ligands are particularly selective. The reaction is fairly insensitive to electronic effects (BINAP vs ToI-BINAP, Cl-MeO-BIPHEP vs MeO-BIPHEP).

Five ligands gave enantioselectivity of > 90%: BINAP, ToI-BINAP, Diflourphos, C3-Tunephos and CTH-P-Phos. In contrast, other C ₂ -symmetric ligands without axial chirality (DIOP and Phanephos) are much less selective, although the product yields remained high. The Solvias diphosphine ligands (based on planar chirality of unsymmetrical ferrocene) offered low enantioselectivities, but the reaction yield is much more dependent on the ligand structure. For example, Josiphos and Walphos diphosphines induced the highest conversions (72-85%), but with opposite stereocontrol. The aminodiphosphines (Taniaphos) led to lower product yield (ca. 65%), while Mandyphos led to complete loss of selectivity (< 1% ee). Interestingly, the monodentate MOP ligand displayed fairly respectable values (67% yield, 38% ee). 2fe-oxazolidine and BINOL ligands, previously shown to be effective in other Lewis-acid catalysed processes, are not compatible with cationic palladium in this instance, showing little/no selectivity and low turnover.

Use of in situ generated catalyst incorporating monophosphine ligands to catalyse the addition of aromatic amines to compound 4

Scheme 1. Catalytic activity of complex 1 in enantioselective αzα-Michael

addition reactions.

Pd(OTf) ₂ .2H ₂ O (5 mol%) I] y .R-Monophps - S S

4

+ArNH ₂

Table 3. Solvent Effect for reaction of aniline with Michael acceptors 4a

(Scheme l). ^a

Entry R ¹ Solvent Time/h Yield/% ee/%

1 Me Toluene 18 49 14 (1:1.1)

^{(1 :L1)} 6 (1:2.0)

27

(1:2.0)

2 Me DCM 18 49 19 (1:1.1)

^(1:L1) 23 (1:2.0)

43

(1:2.0)

3 Me THF 18 22 6 (1:1.1)

(1:1.1) i i (i _: 2.0)

7

(1:2.0)

4 Me Acetonitrile 18 15 <1 (1 :1.1)

(1:1.1) _{16 (R)}

7 (1:2.0)

(1:2.0)

5 Me MeOH 18 24 3 (R)

(1:1.1) (1:1.1)

14 17 (R)

(1:2.0) (1:2.0)

"General reaction condition: 5 mol% Pd salt, 5.5 or 10 mol%

of R-Monophos (M : L of 1: 1.1 or 1: 2.0), aromatic amine (1

equiv.), 4a (1.1 equiv.), solvent, r.t.

Table 4. Catalytic activity of the complex generated in situ

and the isolated complex 1 (Scheme 2). ^α

Entry Substrate R ¹ Y Time/h Yield/% ee/%

Me H 18 43 23

Me Cl 18 18 63

4 Me OMe 18 49

Reaction carried out in DCM.

Scheme 3. Catalytic activity of complex 1 in enantioselective aza-Michael

addition reactions.

Pd(OTf) ₂ 2H ₂ O (5 mol%)

+ArNH ₂

S-(B z)Monophos=

Table 5. Catalytic activity of the complex generated in situ

and the isolated complex 1 (Scheme 3). ^a

Entry Substrate R ¹ Y Time/h Yield/% ee/%

1 4 Me H 18 30 5

2 4 Me Cl 18 20 42

4 4 Me OMe 18 53 8 (R)