Patent Application
20200407381
The present invention relates to the field of organic phosphorus chemistry, especially the chemistry of bulky organophosphorus compounds. The present invention provides a process for the synthesis of compound of formula (I). This process is especially useful to obtain chiral bulky phosphorus compounds. The present invention also relates to compound of formula (VII), (VIII), (IX) and (X) and their processes of manufacturing starting from a compound of formula (I).
The organic phosphorus compounds are currently used in agrochemistry, pharmacy, catalysis, materials, or as flame retardants, extracting agents for hydrometallurgy, or still as chemical reagents. In addition, the properties of organic phosphorus compounds can depend on their chirality.
Depending on their substitution, the phosphorus compounds can bear the chirality on the P-center.
In recent years the electronically bulky phosphorus ligands (bulky phosphines) bearing substituents such as t-butyl or adamantyl gave a lot of interest in catalysis because they allow the activation of weakly actived substrates. That is explained by the steric hindrance of the ligand, allowing on one hand a weakly coordination of the metal in the catalyst, which makes it more reactive in respect of a substrate, and on the other hand favoring the reductive elimination of the product of the coordination sphere.
In the field of chirality, in recent years many chiral ligands bearing bulky substituents such as t-butyl, adamantyl (Ad) or 1,1,3,3-tetramethylbutyl demonstrated their extremely enantioselectivity. Today, many of these chiral ligands are commercially available:
So far, the stereoselective synthesis of bulky phosphines could be achieved either from secondary phosphine derivatives, phosphinous acid borane complex or starting from dimethylphosphine borane complex, according to four main strategies (Scheme 1).
In the former case, P-chirogenic secondary phosphine oxides are prepared from dichlorophosphine, and via the secondary menthyl phosphinate which is diastereomerically separated by chromatography or cristallisation. Deprotonation of secondary phosphine oxide then alkylation leads to the phosphine oxides which are deoxygenated into the corresponding tertiary phosphines (Scheme 1a). Only the synthesis of t-butylphenylphosphine derivatives were described according to this strategy which requires difficult separation and deoxygenation steps.
A second route is based on the P-chirogenic phosphinous acid borane complex which is enantiomerically prepared either by chemical resolution or starting from secondary phosphine oxide. Subsequent reactions of phosphinous acid borane lead to the tertiary phosphine, via the secondary phosphine borane intermediate (Scheme 1b). Again, only the synthesis of the bulky t-butylphenylphosphine derivatives were described according to this strategy.
The more convenient methodology to synthesize bulky phosphines is based on the use of dimethylphosphine-borane (R=t-Bu, Ad, 1,1,3,3-tetramethylbutyl) prepared from the dichlorophosphine bearing R as bulky substitutent (ie t-Bu, Ad or 1,1,3,3-tetramethylbutyl) (Scheme 1 c,d). The asymmetric synthesis is based on the enantioselective deprotonation of the prochiral dimethylphosphine-borane in presence of (−)-sparteine, to afford diastereoselectively the corresponding carbanion in α-position with respect to the P-center (Scheme 1c and 1d). In a first case, the oxidative homocoupling of the anion by copper(II) salt leads then to the BisP* after decomplexation of the borane (Scheme 1c). In the second case the carbanion is oxidized by O2 then K2S2O8 in presence of RuCl3 to afford the secondary methylphosphine-borane. Thus, deprotonation of the sec-phosphine-borane with n-butyllithium and subsequent reaction with R′X affords the tertiary methylphosphines after decomplexation (Scheme 1d). This method was used to prepare commercially available ligands for asymmetric metal-based catalysis, such as QuinoxP*, BisP* and TMB-QuinoxP*.
While (−)-sparteine is the naturally occurring chiral diamine, it is possible to prepare easily the surrogate of (+)-sparteine from (−)-cystisine, and use it for the synthesis of the enantiomer of an organophosphorus compound. However, if the use of the sparteine surrogate has been only demonstrated for the synthesis of t-butylphenyl- or t-butylmethylphosphines, the efficiency of this alternative route was not demonstrated for various substituents at the P-center.
On the other hand, among the best methodologies to synthesize P-chirogenic organophosphorus compounds, the stereoselective synthesis using ephedrine as asymmetric inductor and the borane as protecting group, developed by the Applicant, continue to occupy a place of choice, due to its efficiency to prepare various classes of products in a given configuration. The ephedrine method is based on the two key steps: diastereoselective preparation of the oxazaphospholidine-borane complex and stereoselective ring-opening by reaction with organolithium reagents to afford the aminophosphine-boranes (Scheme 2). Methanolysis or HCl acidolysis of aminophosphine boranes leads to phosphinite-boranes or chlorophosphine boranes, respectively, useful electrophilic building blocks for the synthesis of numerous classes of P-chirogenic phosphines (Scheme 2).
Whereas the efficiency of the ephedrine's methodology for the synthesis of P-chirogenic phosphorus compounds was extensively exemplified, only the bulky adamantyl- and t-butylphosphine phenyl derivatives have been synthetized according to this way.
As shown above, synthesis known in the prior art to obtain chiral bulky phosphorus compounds are poorly versatile. Indeed, to date, the best stereoselective methods using sparteine or ephedrine as asymmetric inductors, allow only to prepare bulky phosphines bearing only one bulky substituent such as t-butyl, adamantyl or 1,1,3,3-tetramethylbutyl, and a phenyl or methyl, at the P-center.
Therefore, there remains a need for the development of new method of synthesis of libraries of chiral bulky organophosphorus compounds. Such methods should be versatile enough to easily lead to broad library of bulky organophosphorus compounds.
The present invention relates to a selective process of synthesis of P-chirogenic organophosphorus compounds of general formula (I), summarized in Scheme 3.
This invention thus relates to a process for manufacturing a compound of formula (I)
According to one embodiment, the amine is a mono or a diamine, preferably is selected from 1,4-diazabicyclo[2.2.2]octane (DABCO), diethylamine, triethylamine and morpholine, and more preferably 1,4-diazabicyclo[2.2.2]octane (DABCO).
According to one embodiment, the process is further comprising heating; preferably at a temperature ranging from 20° C. to 80° C.; more preferably at a temperature ranging from 30° C. to 60° C., even more preferably about 50° C.
According to one embodiment, the process is further a preliminary step comprising reacting a compound of formula (IIIa)
According to one embodiment, the process is further comprising two preliminary steps:
According to one embodiment, the process is further comprising four preliminary steps:
In another aspect, the present invention also relates to a compound of formula (I)
In another aspect, the process comprises a further step to manufacture a compound of formula (VII)
In another aspect, the present invention relates to a compound of formula (VII)
In another aspect, the process comprises a further step to manufacture a compound of formula (VIII);
The present invention also relates to a compound of formula (VIII)
In another aspect, the process comprises a further step to manufacture a compound of formula (IX);
In another aspect, the process comprises a further step to manufacture a compound of formula (X)
The present invention also relates to the use of compounds of formula (I) in catalysis.
In the present invention, the following terms have the following meanings:
When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise.
Where groups may be substituted, such groups may be substituted with one or more substituents, and preferably with one, two or three substituents. Substituents may be selected from but not limited to, for example, the group comprising halogen, hydroxyl, oxo, cyano, nitro, amido, carboxy, amino, haloalkoxy, and haloalkyl.
It is appreciated that in any of the mentioned reactions, any reactive group in the substrate molecules may be protected according to conventional chemical practice. Suitable protecting groups in any of the mentioned reactions are those used conventionally in the art. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
The invention relates to a process for manufacturing a compound of formula (I),
According to one embodiment, R1 and R2 are different. In this embodiment, compound of formula (I) is P-chirogenic.
According to one embodiment R1 represent each a substituted or unsubstituted group selected from alkyl, alkenyl, cycloalkyl, aryl, bisaryl, metallocenyl and alkyloxy; preferably a substituted or unsubstituted group selected from alkyl, aryl, bisaryl and metallocenyl. According to one embodiment, R1 represents a substituted or unsubstituted group selected from phenyl, anisyl, naphtyl, tolyl, adamantyl, biphenyl, methyl, ferrocenyl, preferably phenyl, o-anisyl, α-naphtyl, β-naphtyl, o-tolyl, p-tolyl, adamantyl, o-biphenyl, methyl and ferrocenyl. According to one embodiment, R1 represents phenyl, t-butyl, methyl, o-anisyl, β-naphtyl, o-tolyl, p-tolyl, o-biphenyl or ferrocenyl.
According to one embodiment R2 represent each a substituted or unsubstituted group selected from alkyl, alkenyl, cycloalkyl, aryl, bisaryl, metallocenyl and alkyloxy; preferably a substituted or unsubstituted group selected from alkyl, aryl, bisaryl and metallocenyl. According to one embodiment, R2 represents a substituted or unsubstituted group selected from phenyl, anisyl, naphtyl, tolyl, adamantyl, biphenyl, methyl, ferrocenyl, preferably phenyl, o-anisyl, α-naphtyl, β-naphtyl, o-tolyl, p-tolyl, adamantyl, o-biphenyl, methyl and ferrocenyl. According to one embodiment, R2 represents phenyl, o-anisyl, α-naphtyl, o-biphenyl, adamantyl or methyl.
According to one embodiment R3 represents a hydrogen atom or a substituted or unsubstituted group selected from alkyl, alkenyl, cycloalkyl and aryl. According to a preferred embodiment R3 represents a hydrogen atom or a substituted or unsubstituted aryl group. According to a preferred embodiment R3 represents a hydrogen atom or a phenyl group.
According to a preferred embodiment R4 represents a hydrogen atom or a substituted or unsubstituted aryl group. According to a preferred embodiment R4 represents a hydrogen atom or a phenyl group.
According to one embodiment R5 represents a hydrogen atom, a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl. According to a preferred embodiment, R5 represents an alkyl group or a hydrogen atom. According to a more preferred embodiment R5 represents a methyl group or a hydrogen atom.
According to one embodiment R6 represents a hydrogen atom, a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl group. According to a preferred embodiment, R6 represents an alkyl group or a hydrogen atom. According to a more preferred embodiment, R6 represents a methyl group or a hydrogen atom.
According to a preferred embodiment R4 and R6 represent together a substituted or unsubstituted aryl or cycloalkyl. According to a preferred embodiment R4 and R6 represent together unsubstituted or substituted group selected from group A and group B:
According to a preferred embodiment R3 and R5 represent together a substituted or unsubstituted aryl or cycloalkyl. According to a preferred embodiment R3 and R5 represent together unsubstituted or substituted group selected from group A and group B.
According to one embodiment R7 represents a hydrogen atom or a substituted or unsubstituted group selected from alkyl and aryl. According to a preferred embodiment, R7 represents a hydrogen atom or a methyl group.
According to a preferred embodiment R7 and R5 represent together a substituted or unsubstituted cycloalkyl. According to a preferred embodiment R7 and R5 represent together unsubstituted or substituted group C
According to a preferred embodiment R7 and R6 represent together a substituted or unsubstituted cycloalkyl. According to a preferred embodiment R7 and R6 represent together unsubstituted or substituted group C.
Y represents a simple bond or a (CHR8)n wherein R8 represents a substituted or unsubstituted group selected from alkyl, alkenyl, cycloalkyl and aryl; preferably a substituted or unsubstituted group selected from alkyl and cycloalkyl; and n represents a positive integer ranging from 1 to 3; preferably Y represents a simple bond or (CHR8)n with n represent 1.
According to a one embodiment R8 represents a substituted or unsubstituted group selected from alkyl and cycloalkyl. According to one embodiment n represents a positive integer ranging from 1 to 2. According to another preferred embodiment, n is equal to 1.
According to another preferred embodiment, n is equal to 2.
According to one embodiment W represents O. According to one embodiment W represents S.
According to a specific embodiment, R1 represents Ph, R2 represents o-An, R3 represents hydrogen atom, R4 and R6 represents together a 1-phenyl-prop-2-yl group, R5 represents H, R7 represents hydrogen atom, Y represents simple bond, and W represents oxygen atom.
Step (i)—Synthesis of Compound of Formula (IIIa) from Compound of Formula (IV)
Synthesis of compound (IIIa) involves the condensation of phosphorus trichloride PCl3 with the corresponding aminoalcohol (IV), followed by reaction with a Grignard or an organolithium reagent R1M2, or the condensation of bis-aminophosphines R1P(N(R9)2)2 (Scheme 4). This condensation is followed by a complexation of oxazaphosphacycloalcane of formula (Va) with borane.
According to one embodiment, compound of formula (IV) is an amino alcohol. According to a preferred embodiment, compound of formula (IV) is a 1,2 aminoalcohol or a 1,3 aminoalcohol. According to one embodiment, R3 is different from R4. According to this embodiment, compound of formula (IV) is chiral. According to one embodiment, R5 is different from R6. According to this embodiment, compound of formula (IV) is chiral.
Particularly preferred amino alcohol (IV) of the invention are those listed in Table 1 hereafter:
aL = simple bond
According to one embodiment, more preferred compound of formula (IV) are ephedrine, pseudoephedrine and (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol. According to one embodiment, compound of formula (IV) is (−)-ephedrine. According to one embodiment, compound of formula (IV) is (+)-ephedrine. According to one embodiment, compound of formula (IV) is (S)-prolinol. According to one embodiment, compound of formula (IV) is (1s, 2R)-1-amino-2,3-dihydro-1H-inden-2-ol.
According to one embodiment, compound of formula (IV) reacts with a bis-aminophosphine R1P(N(R9)2)2, in which R1, is as defined above, and R9 represents a hydrogen or a substituted or unsubstituted group selected from alkyl, alkenyl, cycloalkyl and aryl. According to a preferred embodiment, R9 represents a substituted or unsubstituted alkyl. According to a more preferred embodiment, R9 represents methyl or ethyl. According to a more preferred embodiment, R9 represents methyl. According to another more preferred embodiment, R9 represents ethyl.
According to one embodiment, bis-aminophosphine R1P(N(R9)2)2 is selected from bis(dimethylamino)phenylphosphine, bis(diethylamino)phenylphosphine and bis(dimethylamino)methylphosphine.
According to one embodiment, the condensation step with a bis-aminophosphine R1P(N(R9)2)2 is carried under heating conditions, at a temperature ranging from 40° C. to 160° C., preferably from 80° C. to 120° C., more preferably around 100° C.
According to one embodiment, the condensation step with a bis-aminophosphine is carried in presence of 1 to 1.5 equivalent, preferably of 1 to 1.1 equivalent of bis-aminophosphine.
According to one embodiment, the solvent used in this step is selected from the group comprising tetrahydrofuran, ether, diethylether, dioxane, benzene, toluene, xylenes, chlorobenzene, chloroform, dimethylsulfoxide and a mixture thereof. According to a preferred embodiment, the solvent used in this step is toluene.
According to another embodiment, compound of formula (IV) reacts with phosphorus trichloride PCl3 for obtaining a compound of formula (VI):
According to one embodiment, the condensation step with PCl3 is carried out under cooling/heating conditions, at a temperature ranging from −80° C. to 40° C., preferably −78° C. then 25° C. after stirring overnight.
The compound of formula (VI) further reacts with a reagent R1M2; in which M2 is a magnesium halide or an alkali metal; resulting in a compound of formula (Va):
According to one embodiment, M2 represents MgBr or Li. According to one embodiment, M2 represents MgBr. According to another embodiment, M2 represents Li.
According to one embodiment, the reaction with the R1M2 reagent is carried in presence of 0.70 equivalent of R1M2 reagent.
According to one embodiment, the reaction with R1M2 reagent is carried under cooling conditions, at temperature ranging from −90° C. to −50° C., preferably from −78° C. to −60° C.
According to one embodiment, the solvent used in this step is selected from the group comprising tetrahydrofuran, ether, diethylether, dioxane, benzene, toluene, xylenes and a mixture thereof. According to a preferred embodiment, the solvent used in this step is tetrahydrofuran.
Compound of formula (Va) reacts with borane BH3, preferably with BH3.THF or BH3.DMS, resulting in the borane complex of formula (IIIa);
According to one embodiment, the borane agent is BH3.THF. According to another embodiment, the borane agent is BH3.DMS.
According to one embodiment, complexation step is carried in presence of 1 to 2 equivalents, preferably of 1.5 equivalent of borane agent.
According to one embodiment, the complexation step is carried at room temperature, at a temperature ranging from 10° C. to 30° C., preferably from 15° C. to 28° C., more preferably about 25° C.
According to one embodiment, the solvent used in complexation step is selected from the group comprising tetrahydrofuran, ether, dioxane, benzene, toluene, xylenes, and a mixture thereof. According to a preferred embodiment, the solvent used in complexation step is mixture of tetrahydrofuran and toluene. According to another preferred embodiment, the solvent used in complexation step is mixture of toluene and ether.
According to one embodiment, borane complex of formula (IIIa) is purified by using chromatographic techniques or by recrystallisation.
According to one embodiment, borane complex of formula (IIIa) is obtained with an enantiomeric excess ranging from 0 to 100%, preferably from 85 to 100%. According to one embodiment, borane complex of formula (IIIa) is obtained without racemization, preferably with an enantiomeric excess of more than 85%, preferably of more than 95%, more preferably of 100%.
Step (i)—Alternative Route of Synthesis of Compound of Formula (IIIa)
According to another embodiment, compound (IIIa) may be obtained from compound (IV) via compound of formula (IIIb) and compound of formula (IIb).
Indeed, the reaction of organolithium reagent with the oxazaphospholidine-borane of formula (IIIb) led to the aminophosphine borane of formula (IIb) by ring opening of the P—O bond (Scheme 5). Interestingly, by reaction with SiO2 or by heating, the aminophosphine-borane of formula (IIb) led quantitatively to the oxazaphospholidine of formula (IIIa) by elimination of the leaving group. This new reaction offers an efficient route for a general synthesis of oxazaphospholidine variously substituted at the P-center.
Firstly, compound of formula (IV) reacts with a bis-aminophosphine ZP(N(R9)2)2; wherein Z is leaving group and R9 is as defined above; resulting in a compound of formula (Vb).
According to one embodiment, Z represent a substituted or unsubstituted group selected from dialkylamino, diarylamino, dicycloalkylamino and alkoxy group. According to a preferred embodiment, Z represents a dialkylamino group. According to another preferred embodiment, Z represents an alkoxy group. According to a more preferred embodiment, Z represents a dimethylamino group. According to another more preferred embodiment, Z represents a methoxy group.
According to one embodiment, ZP(N(R9)2)2 represents hexamethylphosphorous triamide (P(NMe2)3).
According to one embodiment, the condensation step with a bis-aminophosphine ZP(N(R9)2)2 is carried under heating conditions, at a temperature ranging from 40° C. to 130° C., preferably from 80° C. to 120° C., more preferably around 105° C.
According to one embodiment, the condensation step with a bis-aminophosphine is carried in presence of 1 to 1.5 equivalent, preferably of 1 to 1.1 equivalent of bis-aminophosphine.
According to one embodiment, the solvent used in this step is selected from the group comprising tetrahydrofuran, ether, diethylether, chloroform, dioxane, benzene, toluene, xylenes, chlorobenzene, dimethylsulfoxide and a mixture thereof. According to a preferred embodiment, the solvent used in this step is toluene.
Secondly, the compound of formula (Vb) reacts with borane BH3, preferably with BH3.THF or BH3.DMS, resulting in the borane complex of formula (IIIb).
In a specific embodiment, compound of formula (IIIb) is such that W is a O; Y is a simple bond; Z is a dimethylamino; R3 is a phenyl; R4 is a hydrogen atom; R5 is a methyl; R6 is a hydrogen atom; R7 is a methyl.
According to one embodiment, borane complex of formula (IIIb) is purified by using chromatographic techniques or by recrystallisation.
According to one embodiment, compound of formula (IIIb) is obtained with an enantiomeric excess ranging from 0 to 100%, preferably from 85 to 100%. According to one embodiment, compound of formula (IIIb) is obtained without racemization, preferably with an enantiomeric excess of more than 85%, preferably of more than 95%.
The compound of formula (IIIb) further reacts with a reagent R1M2; in which R1 is as defined above and M2 is an alkali metal; resulting in a compound of formula (IIb);
According to one embodiment, M2 represents Li.
According to one embodiment, the reaction with the R1M2 reagent is carried in presence of 2 to 3, preferably 2 equivalents of R1M2 reagent.
According to one embodiment, the reaction with R1M2 reagent is carried under cooling/heating conditions, at temperature ranging from −90° C. to 50° C., preferably from −78° C. then 25° C.
According to one embodiment, the solvent used in this step is selected from the group comprising tetrahydrofuran, ether, diethylether, dioxane, benzene, chloroform, chlorobenzene, toluene, xylenes, and a mixture thereof. According to a preferred embodiment, the solvent used in this step is tetrahydrofuran.
Compound of formula (IIb) then further reacts with silica gel or is heated to result in compound of formula (IIIa)
According to one embodiment compound of formula (IIb) reacts with silica gel.
According to this embodiment, the solvent used is selected from the group comprising tetrahydrofuran, ether, diethylether, dioxane, benzene, toluene, xylenes, chloroform, dichloromethane and a mixture of these ones. According to a preferred embodiment, the solvent used in this step is a mixture of toluene and dichloromethane.
According to one embodiment, the cyclisation step is carried at room temperature, at a temperature ranging from 10° C. to 30° C., preferably from 15° C. to 28° C., more preferably about 25° C.
According to one embodiment, this step is carried in presence of 2 to 20 equivalents, preferably of 10 equivalents of silica gel.
According to another embodiment compound of formula (IIb) is heated, preferably at a temperature ranging from 25° C. to 100° C., more preferably at a temperature ranging from 30° C. to 60° C., even more preferably at a temperature about 40° C.
According to this embodiment, the solvent used is selected from the group comprising tetrahydrofuran, ether, diethylether, dioxane, benzene, chlorobenzene, toluene, xylenes, chloroform, dichloromethane and a mixture thereof. According to a preferred embodiment, the solvent used in this step is a mixture of toluene and dichloromethane.
According to another embodiment, compound of formula (IIb) further reacts with silica gel at a temperature ranging from 25° C. to 60° C.
According to one embodiment, borane complex of formula (IIIa) is purified by using chromatographic techniques or by recrystallisation.
According to one embodiment, borane complex of formula (IIIa) is obtained with an enantiomeric excess ranging from 0 to 100%, preferably from 85 to 100%. According to one embodiment, borane complexe of formula (IIIa) is obtained without racemization, preferably with an enantiomeric excess of more than 85%, preferably of more than 95%.
Step (ii)—Synthesis of Compound of Formula (IIa) from Compound of Formula (IIIa)
According to one embodiment, the process further comprises the reaction between compound of formula (IIIa)
According to one embodiment, the reaction with the R2M1 reagent is carried in presence of 1 to 3 equivalents, preferably 2 equivalents of R2M1 reagent.
According to one embodiment, the reaction between compound of formula (IIIa) and R2M1 is carried under cooling/heating conditions, at temperature ranging from −90° C. to 50° C., preferably from −78° C. to 25° C.
According to one embodiment, the solvent used in this step is selected from the group comprising tetrahydrofuran, diethylether, dioxane, benzene, toluene, xylenes, and a mixture thereof. According to a preferred embodiment, the solvent used in this step is tetrahydrofuran.
According to one embodiment, compound of formula (IIa) is purified by using chromatographic techniques or by recrystallisation.
According to one embodiment, compound of formula (IIa) is obtained without racemization, preferably with an enantiomeric excess of more than 85%, preferably of more than 95%.
Step (iii)—Synthesis of Compound of Formula (I) from Compound of Formula (IIa)
Synthesis of compound (I) from intermediate compound (IIa), involves the deprotection of the phosphorus atom by removing of the borane protective group, followed by a P*N, P*O rearrangement.
According to one embodiment, removing of the borane group is carried out by classical methods of removal of the borane group known of a skilled artisan. According to a preferred embodiment, removing of the borane group is achieved using an amine According to a more preferred embodiment, removing of the borane group is achieved using a mono or a diamine According to a more preferred embodiment, removing of the borane group is achieved using 1,4-diazabicyclo[2.2.2]octane (DABCO), diethylamine, triethylamine or morpholine. According to an even more preferred embodiment, removing of the borane group is achieved using 1,4-diazabicyclo[2.2.2]octane (DABCO) as reactive agent according to a similar procedure described in Brisset H., Gourdel Y., Pellon P. and Le Corre M., Tetrahedron Lett., 1993, 34, 4523-4526.
According to another embodiment, removing of the borane group is carried out by warming compound (IIa) in ethanol, amines or olefines. According to a preferred embodiment the temperature is ranging from 20° C. to 80° C. According to a more preferred embodiment the temperature is ranging from 30° C. to 60° C. According to an even more preferred embodiment, the process is performed at a temperature about 50° C.
According to one embodiment, removing of the borane group and the P*N, P*0 rearrangement occur without racemization.
The present invention also relates to a compound of formula (I)
According to one embodiment, R1 and R2 are not a phenyl group. According to one embodiment, R1 and R2 are differents. According to one embodiment, when R1 is phenyl group, then R2 is not phenyl group. According to one embodiment, when R1 is methoxy group, then R2 is not phenyl group. According to one embodiment, when R2 is methoxy group, then R1 is not phenyl group. According to one embodiment, when R2 is alkyloxy group, then R1 is not phenyl group. According to one embodiment, when R1 is alkyloxy group, then R2 is not phenyl group.
According to a specific embodiment, R1 represents Ph, R2 represents o-An, R3 represents a phenyl, R4 and R6 represents together a hydrogen, R5 represents a methyl, R7 represents a methyl, Y represents simple bond, and W represents oxygen atom.
Particularly preferred compounds of formula (I) of the invention are those listed in Table 2 hereafter:
aL = simple bond;
The present invention also relates to a compound of formula (IIa)
aL = simple bond
The present invention also relates to a compound of formula (IIb)
According to a specific embodiment, R1 represents Me, Z represent NMe2, R3 represents a phenyl, R4 and R6 represents together a hydrogen, R5 represents a methyl, R7 represents a methyl, Y represents simple bond, and W represents oxygen atom.
Particularly preferred compounds of formula (IIb) of the invention are those listed in Table 4 hereafter:
aL = simple bond;
The present invention also relates to a compound of formula (IIIa)
According to a specific embodiment, R1 represents Ph, R3 represents hydrogen atom, R4 and R6 represents together a 1-phenyl-prop-2-yl group, R5 represents H, R7 represents hydrogen atom, Y represents simple bond, and W represents oxygen atom.
Particularly preferred compounds of formula (IIIa) of the invention are those listed in Table 5 hereafter:
aL = single bond
The present invention also relates to a compound of formula (IIIb)
Particularly preferred compounds of formula (IIIb) of the invention are those listed in Table 6 hereafter:
aL= single bond
In another aspect, the invention provides a process to manufacture compounds of formula (VII) by reacting phosphinites of formula (I) with sulfur (Scheme 6).
According to one embodiment, sulfuration of phosphinites is carried in presence of an excess of sulfur, preferably in presence of 2 equivalents of sulfur S8.
According to one embodiment, the complexation step is carried at room temperature, at a temperature ranging from 10° C. to 30° C., preferably from 15° C. to 28° C., more preferably about 25° C.
According to one embodiment, the solvent used in sulfuration is selected from the group comprising tetrahydrofuran, ether, dioxane, benzene, toluene, xylenes, chlorobenzene and a mixture thereof. According to a preferred embodiment, the solvent used in sulfuration is toluene.
According to one embodiment, thiophosphinites of formula (VII) are purified by using chromatographic techniques or by recrystallisation.
According to one embodiment, the process to manufacture a compound of formula (VII) is carried out without racemization. According to one embodiment, the process to manufacture a compound of formula (VII) is carried out with retention of configuration.
The present invention also relates to a compound of formula (VII)
wherein R3, R4, R5, R6 R7, Y and W are as defined above; R1 and R2 may be the same or different and represent each a substituted or unsubstituted group selected from alkyl, alkenyl, cycloalkyl, aryl, bisaryl, and metallocenyl; preferably a substituted or unsubstituted group selected from alkyl, aryl, bisaryl and metallocenyl.
According to one embodiment, R1 and R2 are not a phenyl group. According to one embodiment, R1 and R2 are differents.
Particularly preferred compounds of formula (VII) of the invention are those listed in Table 7 hereafter:
aL: simple bond
In another aspect, the invention provides a process to manufacture compounds of formula (VIII) by reacting phosphinites of formula (I) with a chlorophosphine in presence of amine (Scheme 7). The aminophosphine phosphinites AMPP* (VIII) may be isolated as diborane complexes of formula (VIIIb). The decomplexation of borane complexes of formula (VIIIb) into free AMPP* of formula (VIII) is carried out by classical methods of removal of the borane group (Scheme 7).
According to one embodiment, the amine is a trialkylamine, preferably triethylamine
According to one embodiment, this step is carried in presence of 1 to 5 equivalents, preferably of 2 equivalents of chlorophosphine R10R11PCl.
According to one embodiment, this step is carried in presence of 1 to 10 equivalents, preferably of 5 equivalents of amine
According to one embodiment, this step is carried at room temperature, preferably at a temperature around 25° C.
According to one embodiment, the solvent used in this step is selected from the group comprising tetrahydrofuran, ether, dioxane, benzene, toluene, xylenes, chlorobenzene and a mixture thereof. According to a preferred embodiment, the solvent used in this step is toluene.
According to one embodiment, aminophosphine phosphinites of formula (VIII) are purified as borane complexes of formula (VIIIb) by using chromatographic techniques or by recrystallisation.
According to one embodiment, aminophosphine phosphinites of formula (VIIIb) are obtained with an enantiomeric excess ranging from 0 to 100%, preferably from 85 to 100%. According to one embodiment, compound of formula (VIIIb) is obtained without racemization, preferably with an enantiomeric excess of more than 85%, preferably of more than 95%.
The present invention also relates to a compound of formula (VIII)
According to one embodiment, when R1, R10 and R11 are phenyl groups and {R3, R4} is {H, Ph} or {Ph, H} and {R5, R6} is {H, Me} or {Me, H} and R7 is methyl group, and W is O and Y is a simple bond, then R2 is not phenyl, o-anisyl or methyl group. According to one embodiment, when R1, R10 and R11 are phenyl groups and {R3, R4} is {H, Ph} or {Ph, H} and {R5, R6} is {H, Ph} or {Ph, H} and R7 is methyl group, and W is O and Y is a simple bond, then R2 is not phenyl, o-anisyl or methyl group. According to one embodiment, when R1, R10 and R11 are phenyl groups and {R3, R4} is {H, H} and {R5, R6} is {H, Ph} or {Ph, H} and R7 is methyl group, and W is O and Y is a simple bond, then R2 is not phenyl, o-anisyl or methyl group.
According to one embodiment, when R1, R10 and R11 are phenyl groups, R2 is not phenyl. According to one embodiment, when R1, R10 and R11 are phenyl groups, R2 is not phenyl, o-anisyl or methyl group. According to one embodiment, R1 and R10 are not phenyl group. According to one embodiment, R1 and R10 are not methyl group.
Particularly preferred compounds of formula (VIII) and formula (VIIIb) of the invention are those listed in Table 8 hereafter:
aL single bond
In still another aspect, the invention provides a process to manufacture a compound of formula (IX) from phosphinites of formula (I) and organolithium reagent (Scheme 8). The phosphine may be isolated as borane complexes of formula (IXb). The decomplexation of borane complexes of formula (IXb) into compounds of formula (IX) is carried out by classical methods of removal of the borane group.
According to one embodiment, R1 is selected from a group comprising a phenyl, a Fc, a o-Tol, a β-Np and a α-Np. According to one embodiment, R2 is selected from a group comprising a t-Bu, a phenyl, an o-An and a α-Np. According to one embodiment, R12 is selected from a group comprising a t-Bu, a methyl and a m-Xyl.
According to one embodiment, the reaction is carried in presence of 2 equivalents of R12M3 organometallic reagent. According to one embodiment, R12M3 is organolithium.
According to one embodiment, the reaction is carried under cooling/heating conditions, at temperature ranging from −90° C. to 50° C., preferably from −78° C. to 25° C.
According to one embodiment, the solvent used is selected from the group comprising tetrahydrofuran, ether, cyclohexane, dioxane, benzene, toluene, xylenes and a mixture thereof. According to a preferred embodiment, the solvent used in this step is toluene.
According to one embodiment, compound of formula (IX) is purified as borane complex (IXb) by using chromatographic techniques or by recrystallisation.
According to one embodiment, compound of formula (IX) is obtained without racemization, preferably with an enantiomeric excess of more than 85%, preferably of more than 95%
Particularly preferred compounds of formula (IX) and (IXb) of the invention are those listed in Table 9 hereafter:
In still another aspect, the invention provides a process to manufacture a compound of formula formula (X) from phosphinites of formula (I) and alkyl halide R13X by Michaelis-Arbuzov like rearrangement (Scheme 9).
According to one embodiment, R1 is selected from a group comprising t-Bu, o-An, Fc, o-Tol, β-Np, α-Np, and Ph.
According to one embodiment, R2 is selected from a group comprising phenyl and o-An;
According to one embodiment, R13 is selected from a group comprising hydrogen atom and methyl.
According to one embodiment, X is a halogen. According to one embodiment, X is Br or I.
According to one embodiment, the reaction is carried in presence of 2 to 10 equivalents of R13X reagent. According to one embodiment, when R13 represents hydrogen atom, the reaction is carried in presence of 4 equivalents of R13X reagent.
According to one embodiment, when R13 represent an alkyl, the reaction is carried in presence of 2 equivalents of R13X reagent.
According to one embodiment, the reaction is carried out at room temperature.
According to one embodiment, the solvent used is selected from the group comprising tetrahydrofuran, ether, dioxane, benzene, toluene, xylenes, chlorobenzene and a mixture thereof. According to a preferred embodiment, the solvent used in this step is toluene.
According to one embodiment, compound of formula (X) is purified by using chromatographic techniques or by recrystallisation.
According to one embodiment, compound of formula (X) is obtained with an enantiomeric excess ranging from 0 to 100%, preferably from 85 to 100%.
Particularly preferred compounds of formula (X) of the invention are those listed in Table 10 hereafter:
Compounds of formula (I), (VII), (VIII), (IX), (X) of the present invention are useful in asymmetric catalysis by transition metal complexes or organocatalysis.
Especially, compounds of formula (VII) may be used to prepare new classes of chiral Brönsted acids useful in asymmetric organocatalyzed reactions.
Especially, compounds of formula (IX) may be used in catalyzed asymmetric reactions such as palladium-catalyzed allylic reactions, nickel-catalyzed reductive coupling and or alkyne-imine coupling. Compounds of formula (IX) may also be used as chiral auxiliary in catalyzed asymmetric reactions such as alkylation, silylation, CP- and CC-coupling, hydroxyalkylation, hydrophosphination, aminoalkylation, oxidation, carbonatation, formylation.
Compounds of formula (X) may also be used as chiral auxiliary in catalyzed asymmetric reactions in alkylation, PP-coupling, Michael-addition, hydroxyalkylation, aminoalkylation, hydrophosphination, sulfuration, halogenation, O-silylation, amination, aryne addition.
According to one embodiment, compound of formula (VIII) is used as ligand of a transition metal such as rhodium, palladium, ruthenium or iridium. According to a preferred embodiment, compound of formula (VIII) is used as ligand of a transition metal such as rhodium and palladium. Complexes of transition metal according to this embodiment may be suitable for asymmetric catalyzed reactions, preferably in allylation or hydrogenation reactions.
The present invention is further illustrated by the following examples which are provided by way of illustration only and should not be considered to limit the scope of the invention.
All reactions were carried out under an Ar atmosphere in dried glassware. Solvents were dried and freshly distilled under an Ar atmosphere over sodium/benzophenone for THF, diethyl ether, toluene, CaH2 for CH2Cl2. Hexane and isopropanol for HPLC were of chromatographic grade and used without further purification. Reagents and starting materials were purchased and used as received from commercial vendors unless otherwise specified. Flash chromatography was performed with the indicated solvents using silica gel 60 A, (35-70 μm; Acros) or aluminium oxide 90 standardized (Merck).
Chiral HPLC analysis were performed on SHIMADZU 10-series apparatus, using chiral columns (Chiralcel OD-H, Chiralcel OJ, Chiralpak AD, Chiralpak IA, Chiralpak IB, Lux 5μm cellulose-2, Lux 5 μm cellulose-1), and with hexane/propan-2-ol mixtures as the mobile phase (Flow rate 1 mL·min−1; UV detection λ=254 nm).
All NMR spectra data were recorded on BRUKER AVANCE 300, 500 and 600 spectrometers at ambient temperature. Data are reported as s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, brs=broad singlet, brd=broad doublet, dhept=doublet of heptuplet, coupling constant(s) in Hertz. Optical rotations values were recorded at 20° C. on a Perkin-Elmer 341 polarimeter, using a 10 cm quartz vessel. Infrared spectra were recorded on a Bruker Vector 22 apparatus. Mass and HRMS spectra were recorded under electrospray ionization conditions (ESI) with a Thermo LTQ orbitrap XP.
A.1.1.1 Method A: From Bis(Dialkylamino)Phosphine R1P(N(R9)2)2:
The oxazaphosphacycloalcane borane complex (IIIa) are prepared by heating in toluene a bis(dimethylamino)phosphine R1P(N(R9)2)2 with the corresponding α-amino alcohols (IV). In these conditions, the condensation occurs under thermodynamic control and the P(III)-oxazaphosphacycloalcane are obtained with diastereomeric ratios up to 95:5. The addition of BH3.DMS or BH3.THF lead to the corresponding borane complex (IIIa). The oxazaphosphacycloalcane borane complexes (IIIa) are air stable and moisture resistant compounds and can be stored without any precaution.
Method A is illustrated by the synthesis of oxazaphospholidine derivative (Sp)-IIIa1 wherein the amino alcohol is the (+)-ephedrine (IV2) and R9 is methyl.
A three-necked round-bottomed flask was equipped with a magnetic stirrer, a nitrogen inlet and a short path distillation head fitted with a dropping condenser was charged with 500 mL of toluene, (+)-ephedrine (IV2) (16.5 g, 0.1 mol) and freshly distilled bis(dimethylamino)phenylphosphine (19.6 g, 0.1 mol). The solution was stirred at 105° C. for 5 h under a gentle flow of nitrogen in order to remove the dimethylamine formed, which is collected by bubbling in water (100 mL). The formation of the oxazaphospholidine was monitored by titration of the dimethylamine solution with HCl, and/or by 31P NMR (δ=+142 ppm). After cooling, BH3.DMS (or BH3.THF) was added and the mixture was stirred overnight at room temperature. The solvent was then completely distilled off under reduced pressure, to afford a viscous colorless residue which was crystallized in isopropanol or methanol to afford the diastereomerically pure borane complexes (Sp)-IIIa1 in isolated yields up to 84%.
Yield=84%. White crystals (i-PrOH). 31P NMR (CDCl3, 121.5 MHz): δ=+133.5 (m).
Yield=82%. Solid. 1H NMR (CDCl3, 300 MHz): δ=0.80 (q, J=107 Hz, 3H, BH3), 3.27 (d, J=11.9 Hz, 1H, CHN), 3.30-3.48 (m, 2H), 4.92-5.00 (m, 1H), 5.18 (m, 1H), 7.24-7.42 (m, 4H, Harom), 7.47-7.62 (m, 3H, Harom), 7.79-7.89 (m, 2H, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+138.1 (q).
Yield=62%. Uncrystallized sticky compound. 1H NMR (CDCl3, 500 MHz): δ=0.78 (q, J=90 Hz, 3H, BH3), 1.70-1.78 (m, 1H), 1.89-2.02 (m, 2H), 2.06-2.14 (m, 1H), 2.67-2.77 (m, 1H), 3.76-3.86 (m, 2H), 3.87-3.94 (m, 1H), 4.22-4.29 (m, 1H), 7.43-7.54 (m, 3H, Harom), 7.73-7.79 (m, 2H, Harom); 31P NMR (CDCl3, 202.4 MHz): δ=+141.3 (q).
A.1.1.2 Method B: Via 2-Chloro-1,3,2-Oxazaphosphacycloalcane
The 2-chloro-1,3,2-oxazaphosphacycloalcane (VI) (5.9 mmol) was prepared by addition of PCl3 (9.1 mmol) to a solution of N-methyl morpholine (18.2 mmol) in toluene (50 mL). After cooling at −78° C., a solution of amino alcohol (IV) (9.1 mmol) in 10 mL toluene was added dropwise under stirring and the reaction was allowed to reach room temperature overnight and the N-methylmorpholine hydrochloride was filtered under argon. To the resulting crude solution of 2-chloro-1,3,2-oxazaphosphacycloalcane (VI), was added at −60° C. a solution of R′MgBr Grignard or organolithium reagent in tetrahydrofuran, previously prepared by reaction from R1Br (4.1 mmol) with Mg (10 mmol) in tetrahydrofuran (10 mL) or metal halide exchange with s-BuLi (1.3 M in cyclohexane; 3.5 mL, 4.5 mmol). After stirring overnight, BH3.DMS (8.8 mmol) was added and the solution is stirred at room temperature during 6 hours. Water was added and after extraction with ethyl acetate (3×20 mL), the organic phases were dried over MgSO4, filtered and evaporated to give a residue which was purified by chromatographic column on silica gel using a mixture petroleum ether/dichloromethane (1:1) as eluent to afford the compound of formula III, which was recrystallized in methanol/dichloromethane.
Method B is illustrated by the synthesis of intermediate (S)-IIIa2 wherein amino alcohol is (+)-ephedrine (IV2) and IV is o-biphenyl.
To a solution of 2-chloro-1,3,2-oxazaphospholidine, prepared from (+)-ephedrine (1.48 g, 9.1 mmol) and PCl3 (0.79 mL, 9.1 mmol) in presence of N-methylmorpholine (2 mL, 18.2 mmol) in THF (19 mL), was added at −78° C. a solution of o-biphenyl lithium in diethyl ether, previously prepared by reaction of 2-bromobiphenyl (0.96 g, 4.1 mmol) and s-BuLi (1.3 M in cyclohexane) (3.5 mL, 4.5 mmol) in diethyl ether (19 mL) at −78° C. during 30 minutes and one hour at 0° C. After stirring overnight, BH3.DMS (0.82 mL, 8.8 mmol) was added and the solution is stirred at room temperature during 6 hours. Water was added and after extraction with ethyl acetate (3×20 mL), the organic phases were dried over MgSO4, filtered and evaporated to give a residue which was purified by chromatographic column on silica gel using a mixture petroleum ether/dichloromethane (1:1) as eluent to afford the compound (S)-IIIa2, which was recrystallized in methanol/dichloromethane.
Yield=43% (m=1.13 g); White solid; [α]D=−12.8 (c 0.3, CHCl3); 1H NMR (CD2Cl2, 300 MHz): δ=0.50 (d, J=6.5 Hz, 3H, CH3), 2.32 (d, J=10.2 Hz, 3H, CH3N), 3.21-3.33 (m, 1H, CHN), 4.56 (dd, J=2.3, 6.0 Hz, 1H, CHO), 7.02-7.06 (m, 2H, Harom), 7.14-7.22 (m, 4H, Harom), 7.26 (br.s, 5H, Harom), 7.30-7.43 (m, 2H, Harom), 7.77 (ddd, J=1.2, 7.4, 11.8 Hz, 1H, Harom); 31P NMR (CD2Cl2, 121.5 MHz): δ=+132.5-132.6 (m). Anal calcd for C22H25BNOP (361.2): C, 73.15, H, 6.98; found C, 73.02, H, 7.03.
A.1.1.3. Method C: From Tris(Dialkylamino)Phosphine P(N(R9)2)3:
A.1.1.3.1: Synthesis of the Oxazaphospholidine (IIIb)
The 2-dialkylamino-1,3,2-oxazaphosphacycloalcane (IIIb) was prepared by heating overnight P(N(R9)2)3 (1.7 mmol) and amino alcohol (IV) (1.7 mmol) in toluene (5 mL). After addition of BH3.DMS (2.6 mmol), the reaction mixture was stirred at room temperature for 2 hours, the solvent is removed under vacuum and the residue was purified by chromatography on silica gel using a mixture petroleum ether/dichloromethane (2:1) as eluent.
The first step of method C is illustrated by the synthesis of the oxazaphospholidine (R)-IIIb1 wherein amino alcohol is (−)-ephedrine (IV1) and R9 is methyl.
The 2-dimethylamino-1,3,2-oxazaphospholidine (R)-IIIb1 was prepared by heating overnight P(NMe2)3 (0.28 g, 1.7 mmol) and (−)-ephedrine (0.28 g, 1.7 mmol) in toluene (5 mL). After addition of BH3.DMS (0.24 mL, 2.6 mmol), the reaction mixture was stirred at room temperature for 2 hours, the solvent is removed under vacuum and the residue was purified by chromatography on silica gel using a mixture petroleum ether/dichloromethane (2:1) as eluent.
Yield=67% (m=0.29 g); Crystallized white solid; 1H NMR (CDCl3, 300 MHz): δ=0.76 (d, J=6.6 Hz, 3H, CH3), 2.67 (d, J=9.5 Hz, 3H, CH3N), 2.79 (d, J=9.9 Hz, 6H, CH3N), 3.73-4.01 (m, 1H, CHN), 5.56 (d, J=5.7 Hz, 1H, CHO), 7.26-7.40 (m, 5H, Harom); 13C NMR (CDCl3, 75.0 MHz): δ=12.9, 28.8 (d, J=9.5 Hz, CH3N), 36.1 (d, J=4.6 Hz, (CH3)2N), 60.3 (d, J=6.9 Hz, CHN), 81.9 (d, J=6.8 Hz, CHO), 125.9 (Carom), 127.9 (Carom), 128.3 (Carom), 136.8 (d, J=7.2 Hz, Carom). 31P NMR (CDCl3, 121.5 MHz): δ=+114.1-116.6 (m). HRMS (ESI-Q-TOF): calcd for C12H22BN2OPNa [M+Na]+: 275.1455; found: 275.1451.
A.1.1.3.1: Synthesis of the Oxazaphospholidine (IIIa) from Compound (IIIb) Via Compound of Formula (IIb)
To a solution of oxazaphosphacycloalcane (IIIb) (1.92 mmol) in THF (4 mL) was added R′Li (3.85 mmol) at −78° C. under argon. The solution was stirred for 5 h until room temperature and was then hydrolyzed with 10 mL H2O. After extraction with dichloromethane, the organic phases were dried over MgSO4, filtrated and the solvent was removed under vacuum. The residue of compound (IIb) was dissolved in a mixture toluene/CH2Cl2 (1:1) (4 mL) and then SiO2 (0.9 g) was added. After stirring for 24 h at room temperature, the solvent was removed under vacuum and the residue was purified by column chromatography on silica gel using a mixture petroleum ether/ethyl acetate (4:1) as eluent to afford the oxazaphosphacycloalcane (IIIa) which was recrystallized in hot hexane.
The second step of method C is illustrated by the synthesis of compound (R)-IIIa3 from compound (R)-IIIb1 via compound (R)-IIb1.
To a solution of (R)-IIIb1 (0.49 g, 1.92 mmol) in THF (4 mL) was added MeLi (1.6 M in Et2O; 2.4 mL, 3.85 mmol) at −78° C. under argon. The solution was stirred for 5 h until room temperature and was then hydrolyzed with 10 mL H2O. After extraction with dichloromethane, the organic phases were dried over MgSO4, filtrated and the solvent was removed under vacuum. The residue ((R)-IIb1) was dissolved in a mixture toluene/CH2Cl2 (1:1) (4 mL) and then SiO2 (0.9 g) was added. After stirring for 24 h at room temperature, the solvent was removed under vacuum and the residue was purified by column chromatography on silica gel using a mixture petroleum ether/ethyl acetate (4:1) as eluent to afford the compound (R)-IIIa3 which was recrystallized in hot hexane.
Yield=61%; Colorless crystals; [α]D=−2.3 (c 0.7, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=0.78 (d, J=6.6 Hz, 3H, CH3), 1.49 (dd, J=0.9, 7.5 Hz, 3H, CH3), 2.68 (d, J=11.0 Hz, 3H, CH3), 3.54-3.65 (m, 1H, CHN), 5.48 (dd, J=3.5, 6.0 Hz, 1H, CHO), 7.33-7.41 (m, 5H, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+146.5 (q, J=78.5 Hz). HRMS (ESI-Q-TOF): calcd for C11H19BONPNa [M+Na]+: 246.1192; found: 246.1185.
Yield=84%. Colorless oil. 31P NMR (CDCl3, 121.5 MHz): δ=+91.9 (m).
Yield=58%. Colorless oil. 1H NMR (CDCl3, 300 MHz): δ=1.05 (d, J=6.8 Hz, 3H, CH3), 1.62 (br. s, 1H, OH), 2.23 (d, J=9.7 Hz, 6H, CH3—N), 2.36 (d, J=7.3 Hz, 3H, CH3—N), 3.88-4.01 (m, 1H, CH—N), 4.63 (dd, J=3.4, 6.0 Hz, 1H, CH—O), 7.05-7.35 (m, 10H, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+93.3 (m).
A.1.1 Step 2: Synthesis of the Aminophosphine-Borane Complexes IIa
The results in synthesis of the preferred ring opening compounds IIa from oxazaphosphacycloalcane Ma, are presented in the following Table 11.
aL: simple bond
To a solution of oxazaphosphacycloalcane Ma (1.92 mmol) in THF (5 mL) was added R2Li (3.85 mmol) at −78° C. and the mixture was then stirred at room temperature for 5 h. After addition of H2O (10 mL) and extraction with CH2Cl2 (3×10 mL), the organic phases were dried over MgSO4 and the solvent was removed after filtration. The residue was purified by chromatography on silica gel using CH2Cl2 as eluent.
The general procedure is illustrated by the synthesis of intermediate (Re)-IIa10 wherein oxazaphospholidine is (RIO-IIIa1 and R2 is adamantyl.
To a solution of oxazaphospholidine (Rp)-IIIa1 (547 mg, 1.92 mmol) in THF (5 mL) was added AdLi (547 mg, 3.85 mmol) at −78° C. and the mixture was then stirred at room temperature for 5 h. After addition of H2O (10 mL) and extraction with CH2Cl2 (3×10 mL), the organic phases were dried over MgSO4 and the solvent was removed after filtration. The residue was purified by chromatography on silica gel using CH2Cl2 as eluent.
1H NMR (CDCl3, 300 MHz): δ=1.1 (d, J=7.0 Hz, 3H, CCH3), 1.6 (m, 6H, PCCH2 adamantane), 1.96 (m, 9H, adamantane), 2.87 (d, J=6.2 Hz, 3H, NCH3), 4.04 (m, 1H, NCH), 5.11 (d, J=3.0 Hz, 1H, OCH), 7.15 (m, 1H, Harom), 7.22 (m, 3H, Harom), 7.36 (m, 5H, Harom), 7.63 (m, 2H, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+83.
Yield=81%. White solid; [α]D=+9.9 (c 0.6, CHCl3); 1H NMR (CD2Cl2, 300 MHz): δ=0.85 (d, J=6.9 Hz, 3H, CH3), 1.75 (d, J=4.4 Hz, 1H, OH), 2.42 (d, J=8.4 Hz, 3H, CH3—N), 4.08-4.29 (m, 1H, CH—N), 4.51 (t, J=4.5 Hz, 1H, CH—O), 6.85-7.55 (m, 19H, Harom); 31P NMR (CD2Cl2, 121.5 MHz): δ=+70.2-70.9 (m).
Yield=87%. White solid; [α]D=−44.3 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.26 (d, J=6.7 Hz, 3H, CH3), 1.89 (s1, 1H, OH), 2.41 (s1, 3H, PhCH3), 2.49 (d, J=7.8 Hz, 3H, CH3N), 4.25-4.39 (m, 1H, CHN), 4.83 (d, J=6.6 Hz, 1H, CHO), 7.14-7.20 (m, 2H, Harom), 7.25-7.44 (m, 8H, Harom), 7.47-7.53 (m, 4H, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+69.8-70.2 (m). HRMS calcd for C23H29BNOPNa [M+Na]+: 400.19720; found: 400.19738.
Yield=80%; Yellowish oil; 1H NMR (CDCl3, 300 MHz): δ=0.1-1.1 (m, 3H, BH3), 1.67 (d, J=3.5 Hz, 1H, OH), 2.79 (d, J=16.6 Hz, 1H), 2.99 (dd, J=16.7, 4.8 Hz, 1H), 3.53 (s, 3H, CH3O), 3.60 (dd, J=10.8, 5.3 Hz, 1H), 4.22-4.30 (m, 1H), 4.96 (td, J=10.5, 4.6 Hz, 1H), 6.85 (dd, J=8.4, 3.2 Hz, 1H), 7.03-7.10 (m, 1H), 7.14-7.25 (m, 3H), 7.30-7.51 (m, 5H), 7.57-7.66 (m, 2H), 7.95 (ddd, J=13.5, 7.5, 1.7 Hz, 1H); 31P NMR (CDCl3, 121.5 MHz): δ=+54.5 (q, J=69 Hz).
Yield=65%; Colorless oil; 1H NMR (CDCl3, 500 MHz): δ=1.1 (m, J=125 Hz, 3H, BH3), 1.63-1.73 (m, 1H), 1.83-2.01 (m, 5H), 2.93-3.05 (m, 1H), 3.49-3.58 (m, 2H), 3.64-3.70 (s, 3H, OCH3), 4.06-4.17 (m, 1H), 6.95-6.99 (m, 1H), 7.05-7.12 (m, 1H), 7.37-7.59 (m, 6H), 7.70-7.77 (m, 1H); 31P NMR (CDCl3, 202.4 MHz): δ=+58.2 (m, J=84 Hz).
To sodium (96.9 mg, 4.2 mmol) was slowly added methanol (1.7 mL) at room temperature and the mixture was then stirred for 30 min. After cooling at −78° C., a solution of oxazaphospholidine (Sp)-IIIa1 (1.14 g, 4 mmol) in THF (10 mL) was slowly added. After 1 hour, the mixture was hydrolyzed at 0° C. and was then extracted with CH2Cl2 (3×10 mL). The organic phases were dried over MgSO4 and the solvent was removed after filtration to afford a residue which was purified by chromatography on silica gel using toluene as eluent.
Yield=94% (1.2 g); White solid; [α]D=+12.8 (c 3, CHCl3). 1H NMR (CDCl3, 250 MHz): δ=0.1-1.1 (m, 3H, BH3), 1.24 (d, J=6.8 Hz, 3H, CH3), 1.94 (s, 1H, OH), 2.52 (d, J=8.3 Hz, 3H, NCH3), 3.32 (d, J=11.9 Hz, 3H, OCH3), 3.98-4.10 (m, 1H, CHN), 4.75 (d, J=5.6 Hz, OCH), 7.24-7.61 (m, 10H, Harom); 31P NMR (CDCl3, 101 MHz): δ=+115.7 (q, J=67 Hz).
To a solution of aminophosphine borane IIb (1 mmol) in toluene (3 mL), was added DABCO (1.5 mmol). The mixture was added at 50° C. under argon for 1 night and the solvent was removed under vacuum. The residue was purified by chromatography on column of neutral alumine oxide using a mixture EtOAc/CH2Cl2 (9:1) as eluent.
The general procedure is illustrated by the synthesis of intermediate 13 wherein aminophosphine borane is compound IIa4.
To a solution of aminophosphine borane IIa4 (471.2 mg, 1 mmol) in toluene (3 mL), was added DABCO (168.2 mg, 1.5 mmol). The mixture was added at 50° C. under argon for 1 night and the solvent was removed under vacuum. The residue was purified by chromatography on column of neutral alumine oxide using a mixture EtOAc/CH2Cl2 (9:1) as eluent.
Yield=71%; Orange solid; [α]D=+198.8 (c 0.3, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=0.99 (d, J=6.4 Hz, 3H, CCH3), 1.41 (bs, 1H, NH), 2.33 (s, 3H, NCH3), 2.75-2.88 (m, 1H, CHN), 3.76-3.83 (m, 1H, HFc), 4.06 (s, 5H, HFc), 4.27-4.32 (m, 1H, HFc), 4.36-4.43 (m, 1H, HFc), 4.46-4.51 (m, 1H, HFc, CHN), 4.83 (dd, J=10.1, 4.8 Hz, 1H, CHO), 7.15-7.23 (m, 5H, Harom), 7.33-7.41 (m, 3H, Harom), 7.61-7.72 (m, 2H, Harom); 31P NMR (CDCl3 121.5 MHz): δ=+106.7 (s). HRMS (ESI-Q-TOF): calcd for C26H29NO2PFe [M+H]+: 458.1331; found: 458.1315.
31P NMR (CDCl3, 124.5 MHz): δ=+128.3 (s).
Yield=59%; Colorless oil; [α]D=−33.2 (c 0.4, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.01 (d, J=6.5 Hz, 3H, CCH3), 1.21 (bs, 1H, NH), 2.29 (3H, s, NCH3), 2.82 (qd, J=6.4, 4.8 Hz, 1H, CHN), 3.63 (s, 3H, OCH3), 4.84 (dd, J=9.2, 4.7 Hz, 1H, CHO), 6.74 (ddd, J=8.3, 4.5, 0.7 Hz, 1H, Harom), 6.97 (td, J=7.4, 0.7 Hz, 1H, Harom), 7.08-7.16 (m, 8H, Harom), 7.22-7.31 (m, 3H, Harom), 7.56 (ddd, J=7.4, 4.4, 1.7 Hz, 1H, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+103.4 (s). HRMS (ESI-Q-TOF): calcd for C23H27NO2P [M+H]+: 380.1774; found: 380.1764. The d.e. was checked by HPLC on chiral column: 99%, Lux 5 μm cellulose-2, 0.50 mL/min, hexane/isopropanol (95:5), t(s)=11.7 min, t(R)=14.7 min.
31P NMR (CDCl3, 121.5 MHz): δ=+116.3.
Yield=54%; Colorless oil; [α]D=+64.4 (c 0.3, CHCl3). 1H NMR (CD2Cl2, 300 MHz): δ=1.03 (d, J=6.0 Hz, 3H, CCH3), 2.35-2.36 (2s, 6H, PhCH3, NCH3), 2.89-2.92 (m, 1H, CHN), 4.95 (dd, J=9.4, 4.1 Hz, 1H, CHO), 7.18-7.20 (m, 1H, Harom), 7.26-7.37 (12H, m, Harom), 7.86-7.89 (1H, m, Harom); 31P NMR (CD2Cl2, 121.5 MHz): δ=+105.2 (s). HRMS (ESI-Q-TOF): calcd for C23H27NOP [M+H]+: 364.1825; found: 364.1813.
Yield=55%; Colorless oil; [α]D=−136.7 (c 0.4, CHCl3). 1H NMR (CD2Cl2, 300 MHz): δ=1.0 (d, J=6.5 Hz, 3H, CCH3), 2.22 (s, 3H, NCH3), 2.87-2.92 (m, 1H, NCH), 5.02 (dd, J=9.5, 4.2 Hz, 1H, OCH), 7.25-7.27 (m, 3H, Harom), 7.31-7.41 (m, 7H, Harom), 7.42-7.52 (m, 2H, Harom), 7.63 (t, J=7.9 Hz, 1H, Harom), 7.92 (d, J=8.0 Hz, 1H, Harom), 7.96 (d, J=8.3 Hz, 1H, Harom), 8.13 (td, J=7.4, 0.9 Hz, 1H, Harom), 8.37 (dd, J=8.3, 2.8 Hz, 1H, Harom); 31P NMR (CD2Cl2, 121.5 MHz): δ=+109.0 (s). HRMS (ESI-Q-TOF): calcd for C26H26NOPNa [M+Na]+: 422.1644; found: 422.1635.
Yield=62%; visquous colorless oil; [α]D=+134 (c 0.4, CHCl3). 1H NMR (CD2Cl2, 300 MHz): δ=1.0 (d, J=6.5 Hz, 3H, CCH3), 2.22 (s, 3H, NCH3), 2.84-2.88 (m, 1H, NCH), 4.84 (dd, J=9.1, 4.1 Hz, 1H, OCH), 7.20-7.35 (m, 16H, Harom), 7.49 (td, J=7.2, 1.1 Hz, 1H, Harom), 7.54 (td, J=7.5, 1.3 Hz, 1H, Harom), 8.04 (ddd, J=7.6, 3.4, 1.3 Hz, 1H, Harom); 31P NMR (CD2Cl2, 121.5 MHz): δ=+104.2 (s). HRMS (ESI-Q-TOF): calcd for C28H29NOP [M+H]+: 426.1981; found: 426.1961.
31P NMR (CDCl3, 121.5 MHz): δ=+105.3 ppm
31P NMR (CDCl3, 121.5 MHz): δ=+106 ppm
31P NMR (CDCl3, 202.4 MHz): δ=+113.6 (s).
31P NMR (CDCl3, 121.5 MHz): δ=+112.9 (s).
Yield=73%; 31P NMR (CDCl3, 121.5 MHz): δ=+103.0 (s).
Yield=47%; 31P NMR (CDCl3, 121.5 MHz): δ=+104.9 (s).
General Procedure
The phosphinite I (1 mmol) was stirred at room temperature with BH3.DMS (8 mmol) and the mixture was stirred for a night to lead to the corresponding diborane complex derivative I.2BH3. After hydrolysis (H2O 10 mL), the aqueous phase was extracted with dichloromethane. The organic phase was dried and then the solvent was removed under vacuum to afford a residue which was purified by chromatography on silica gel to afford diborane complex I.2BH3.
Chemical Characterization
Yield 71%; Colorless crystal; 1H NMR (CDCl3, 300 MHz): δ=2.96 (dd, J=16.4, 7.1 Hz, 1H), 3.22 (dd, J=16.4, 7.0 Hz, 2H), 3.69 (s, 3H, OCH3), 4.10-4.20 (m, 1H), 4.72-4.90 (m, 1H), 4.96-5.08 (m, 1H), 6.86 (dd, J=8.2, 5.7 Hz, 1H), 6.99-7.10 (m, 2H), 7.13-7.26 (m, 2H), 7.36-7.52 (m, 4H), 7.57-7.63 (m, 1H), 7.69-7.87 (m, 3H); 31P NMR (CDCl3, 121.5 MHz): δ=+110.5 (q, J=70 Hz).
Yield 43%; Colorless uncrystallized compound; 1H NMR (CDCl3, 500 MHz): δ=1.59-1.76 (m, 3H), 1.87-1.97 (m, 1H), 1.99-2.09 (m, 1H), 2.78-2.90 (m, 1H), 3.09-3.29 (m, 1H), 3.66-3.69 (s, 3H, OCH3), 3.85-4.03 (m, 1H), 4.10-4.21 (m, 1H), 4.29-4.49 (m, 1H), 6.83-6.88 (m, 1H, Harom), 6.96-7.03 (m, 1H, Harom) 7.33-7.51 (m, 4H, Harom), 7.58-7.74) (m, 3H, Harom); 31P NMR (CDCl3, 202.4 MHz): δ=+109.2 (q, J=79 Hz).
B.1.1.1 P-Chirogenic Secondary Phosphine-Oxides
To a solution of phosphinite I (1 mmol) in toluene (3 mL) was added a solution of HBr in acetic acid (10 mmol). The mixture was stirred for 4 h at room temperature and then hydrolyzed with 10 mL H2O. After extraction with dichloromethane, the organic phases were dried over MgSO4 and the solvent was removed under vacuum to afford a residue which was purified by chromatography on silica gel.
The general procedure is illustrated by the synthesis of secondary phosphine-oxide X1 wherein phosphinite I is (S)-I1.
To a solution of phosphinite (S)-I1 (329.4 mg, 1 mmol) in toluene (3 mL) was added a solution of HBr in acetic acid (10 mmol). The mixture was stirred for 4 h at room temperature and then hydrolyzed with 10 mL H2O. After extraction with dichloromethane, the organic phases were dried over MgSO4 and the solvent was removed under vacuum to afford a residue which is purified by chromatography on silica gel.
Yield=76%; Uncrystallized compound; [α]D=−26.1 (c 0.4, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.08 (9H, d, J=16.6 Hz, C(CH3)3), 6.97 (1H, d, J=452.9 Hz, PH), 7.39-7.46 (2H, m, 7.47-7.55 (1H, m, Harom), 7.57-7.66 (2H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+47.4 (s). HRMS (ESI-Q-TOF): calcd for C10H16OP [M+H]+: 183.09333; found: 183.09345. e.e.: 96%, determined by HPLC on Chiralpak IA, 1.0 mL/min, using a mixture hexane/isopropanol (9:1) as eluent; t(S)=13.8 min, t(R)=20.2 min.
Yield=80%; white powder; 1H NMR (CDCl3, 300 MHz): δ=3.71 (3H, s, OCH3), 6.84 (1H, dd, J=8.3, 5.7 Hz, Harom), 7.00-7.08 (1H, m, Harom), 7.35-7.50 (4H, m, Harom), 7.62-7.79 (3H, m, Harom), 8.10 (1H, d, J=498.9 Hz, PH); 31P NMR (CDCl3, 12.5 MHz): δ=+20.5 (s). e.e. 22% determined by HPLC on Chiralpak IB, 0.70 mL/min, using a mixture hexane/isopropanol (8:2) as eluent: t(S)=37.4 min, t(R)=45.7 min.
Yield=47%; Orange solid; 1H NMR (CDCl3, 300 MHz): δ=4.26 (5H, s, HFc), 4.35-4.446 (4H, m, HFc), 7.35-7.53 (3H, m, Harom), 7.60-7.73 (2H, m, Harom), 7.98 (1H, d, J=483.0 Hz, P—H); 31P NMR (CDCl3, 121.5 MHz): δ=+14.1 (s). e.e. 7% determined by HPLC on Chiralpak IB, 0.5 mL/min, using a mixture hexane/isopropanol (8:2) as eluent; t(R)=19.0 min, t(S)=20.1 min.
Yield=57%; White solid; 1H NMR (CDCl3, 300 MHz): δ=2.28 (3H, s, PhCH3), 7.10-7.18 (1H, m, H arom), 7.19-7.27 (1H, m, Harom), 7.32-7.48 (4H, m, Harom), 7.50-7.68 (3H, m, Harom), 8.03 (1H, d, J=480.1 Hz, P—H); 31P NMR (CDCl3, 121.5 MHz): δ=+21.7 (s). e.e. 8% determined by HPLC on Chiralpak IA, 0.70 mL/min, using a mixture hexane/isopropanol (95:5) as eluent; t(R)=92.6 min, t(S)=95.9 min.
Yield=63%; White solid; 1H NMR (CDCl3, 300 MHz): δ=7.31-7.52 (6H, m, Harom), 7.58-7.7.70 (2H, m, Harom), 7.78-8.02 (3H, m, Harom), 8.16-8.24 (1H, m, Harom), 8.34 (1H, d, J=483.4 Hz, P—H); 31P NMR (CDCl3, 121.5 MHz): δ=+21.7 (s). e.e. 33% determined by HPLC on Chiralpak IB, 0.70 mL/min, using a mixture hexane/isopropanol (8:2) as eluent; t(S)=20.8 min, t(R)=24.0 min.
Yield=53%; White solid; 1H NMR (CDCl3 300 MHz): δ=7.33-7.55 (6H, m, Harom), 7.58-7.69 (2H, m, Harom), 7.73-7.86 (3H, m, Harom), 8.25 (1H, d, J=15.7 Hz, Harom), 8.34 (1H, d, J=480.6 Hz, P—H); 31P NMR (CDCl3, 121.5 MHz): δ=+21.4 (s). e.e. 33% determined by HPLC on Chiralpak IB, 1.0 mL/min, using a mixture hexane/isopropanol (9:1) as eluent; t(S)=29.0 min, t(R)=31.4 min.
B.1.1.2 P-Chirogenic Tertiary Phosphine-Oxides
To a solution of phosphinite I (1 mmol) in toluene (3 mL) was added R13X (3 mmol). The mixture was added for 4 h at temperature between 25° C. and reflux, then hydrolyzed by 10 mL of water. After extraction with dichloromethane the organic phases were dried over MgSO4 and the solvent was removed under vacuum to afford a residue which was purified by chromatography on silica gel to afford the tertiary phosphine oxide X.
The general procedure is illustrated by the synthesis of phosphine oxide X7 wherein phosphinite is (S)-I2 and R13 is methyl.
To a solution of phosphinite (S)-I2 (379.4 mg, 1 mmol) in toluene (3 mL) was added MeI (0.19 mL; 3 mmol). The mixture was added for 4 h at room temperature, then hydrolyzed with 10 mL of water. After extraction with dichloromethane the organic phases were dried over MgSO4 and the solvent was removed under vacuum to afford a residue which was purified by chromatography on silica gel to afford the phosphine oxide X7.
Yield=67%; White solid; lull)=−18.1 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.99 (3H, d, J=14.1 Hz, PCH3), 3.63 (3H, s, OCH3), 6.80 (1H, dd, J=8.2, 5.4 Hz, Harom), 6.97-7.05 (1H, m, Harom), 7.27-7.46 (4H, m, Harom), 7.60-7.71 (2H, m, Harom), 7.88 (1H, ddd, J=13.1, 7.5, 1.7 Hz, Harom31P NMR (CDCl3, 121.5 MHz): δ=+28.4 (s1). HRMS (ESI-Q-TOF): calcd for C14H16O2P [M+H]+: 247.08824; found: 247.08843; e.e. =84% determined by chromatography on Lux 5 μm cellulose-1, 1.0 mL/min, using a mixture hexane/isopropanol (9:1) as eluent; t(R)=21.8 min, t(S)=25.0 min.
Yield=21%; White solid; [α]D=−17.3 (c 0.9, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.03 (d, J=14.8 Hz, 9H, C(CH3)3), 1.61 (d, J=12.1 Hz, 3H, PCH3), 7.29-7.45 (m, 3H, Harom), 7.55-7.69 (m, 2H, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+47.4 (bs).
Yield=67%; Orange solid; [α]D=−88.7 (c 0.6, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.82 (d, J=13.2 Hz, 3H, PCH3), 4.23 (s, 5H, HFc), 4.33-4.40 (m, 4H, HFc), 7.34-7.43 (m, 3H, Harom), 7.60-7.67 (2H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+30.5 (s1). HRMS (ESI-Q-TOF): calcd for C17H18FeOP [M+H]+: 325.04393; found: 325.04368; Calcd for C17H17FeOPNa [M+Na]+: 347.02588; found: 347.02389. e.e. 98% determined by HPLC on Lux 5 μm cellulose-1, 1.0 mL/min, using a mixture hexane/isopropanol (9:1) as eluent; t(S)=12.7 min, t(R)=16.3 min.
Yield=59%; White solid; 1H NMR (CDCl3, 500 MHz): δ=2.12 (3H, d, J=13.1 Hz, PCH3), 7.45-7.68 (6H, m, Harom), 7.75-7.81 (2H, m, Harom), 7.86-7.90 (1H, m, Harom), 7.90-7.97 (2H, m, Harom), 8.49 (1H, d, J=13.6 Hz, Harom); 31P NMR (CDCl3, 202.4 MHz): δ=+29.9 (1); HRMS (ESI-Q-TOF): calcd for C17H16OP [M+H]+: 267.09333; found: 267.09339; e.e. 87% determined by HPLC on Lux 5 μm cellulose-2, 1.0 mL/min, hexane/isopropanol (8:2), t(R)=34.3 min, t(S)=43.3 min.
Yield=63%; White solid; 1H NMR (CDCl3, 500 MHz): δ=3.69 (1H, dd, J=16.0, 14.5 Hz, PCH2), 3.77 (3H, s, OCH3), 3.79 (1H, dd, J=14.4, 13.3 Hz, PCH2), 6.81-6.85 (1H, m, Harom), 6.92-6.96 (1H, m, Harom), 7.03-7.10 (5H, m, Harom), 7.29-7.34 (2H, m, Harom), 7.35-7.41 (2H, m, Harom), 7.64-7.71 (2H, m, Harom), 7.79 (1H, ddd, J=12.8, 7.5, 1.8 Hz, Harom); 31P NMR (CDCl3, 202.4 MHz): δ (ppm)+29.3 (s); HRMS (ESI-Q-TOF): calcd for C20H20O2P [M+H]+: 323.11954; found: 323.11900; e.e. 98% determined by HPLC on Lux 5 μm cellulose-1, 1.0 mL/min, hexane/isopropanol (8:2), t(S)=11.5 min, t(R)=12.9 min.
Yield=59%; 1H NMR (CDCl3, 500 MHz): δ=3.14-3.29 (2H, m, PCH2), 3.73 (3H, s, OCH3), 5.01-5.11 (2H, m, CH2CH), 6.84 (1H, dd, J=8.2, 5.4 Hz, Harom), 7.01-7.06 (1H, m, Harom), 7.31-7.37 (2H, m, Harom), 7.38-7.46 (2H, m, Harom), 7.67-7.74 (2H, m, Harom), 7.90 (1H, ddd, J=12.8, 7.5, 1.7 Hz, Harom); 31P NMR (CDCl3, 202.4 MHz): δ (ppm) 29.1 (s); e.e. 97% determined by HPLC on Lux 5 mm cellulose-2, 1.0 mL/min, hexane/isopropanol (8:2), t(R)=24.1 min, t(S)=25.8 min.
B.1.2 Preparation of P-Chirogenic Phosphines (IX) and their Borane Complexes (IXb)
B.1.2.1 Preparation of P-Chirogenic Monophosphines and their Borane Complexes
To a solution of phosphinite I (1 mmol) in toluene (5 mL) was added 2 mmol of organolithium reagent at −78° C. The reaction mixture was stirred for 4 h to room temperature. The course of the reaction was checked by 31P NMR to follow the formation of free phosphine (IX).
Then, 2 mmol of BH3.DMS were added at 0° C. and the solution was stirred for 4 h then hydrolyzed with 10 mL H2O. The mixture was extracted by dichloromethane and the organic phases were dried over MgSO4. After removing the solvent under vacuum the residue was purified by column chromatography on silica gel to afford phosphine borane (IXb).
The general procedure is illustrated by the synthesis of phosphine IX1 and borane complex IXb1 wherein phosphinite is (Sp)—I2 and organolithium reagent is t-butyllithium.
To a solution of phosphinite (S)-I2 (379.4 mg, 1 mmol) in toluene (5 mL) was added 2 mmol of t-butyllithium at −78° C. The reaction mixture was stirred for 4 h to room temperature. The course of the reaction was checked by 31P NMR to follow the formation of free phosphine IX1 (31P NMR (CDCl3): δ=+5.6 (s)). Then, 2 mmol of BH3.DMS were added at 0° C. and the solution was stirred for 4 h then hydrolyzed with 10 mL H2O. The mixture was extracted by dichloromethane and the organic phases were dried over MgSO4. After removing the solvent under vacuum the residue was purified by column chromatography on silica gel to afford the corresponding borane complex IXb1.
Yield=73%; White crystals (CH2Cl2/Hexane); Mp=82° C.; [α]D=−8.5 (c 0.4, MeOH). 1H NMR (CDCl3, 300 MHz): δ=1.26 (9H, d, J=14.4 Hz, C(CH3)3), 3.49 (3H, s, OCH3), 6.82 (1H, ddd, J=8.3, 3.4, 0.8 Hz, Harom), 6.95-7.01 (1H, m, Harom), 7.23-7.33 (3H, m, Harom), 7.37-7.45 (1H, m, Harom), 7.55-7.65 (2H, m, Harom), 7.90 (1H, ddd, J=12.6, 7.7, 1.6 Hz, H arom); 31P NMR (CDCl3, 121.5 MHz): δ=+36.2 (q, J=67.5 Hz) HRMS (ESI-Q-TOF): calcd for C17H23BOP [M−H]+: 285.15741; found: 285.15685; Calcd for C17H24BOPNa [M+Na]+: 309.15500; found: 309.15390.
31P NMR (CDCl3, 121.5 MHz): δ=+5.6 (s).
Yield=71%; White crystals (CH2Cl2/Hexane); Mp=82° C.; lab)=+11.9 (c 0.5, MeOH). 1H NMR (CDCl3, 300 MHz): δ=1.26 (9H, d, J=14.4 Hz, C(CH3)3), 3.49 (3H, s, OCH3), 6.82 (1H, ddd, J=8.3, 3.4, 0.8 Hz, Harom), 6.95-7.01 (1H, m, Harom), 7.23-7.33 (3H, m, Harom), 7.37-7.45 (1H, m, Harom), 7.55-7.65 (2H, m, Harom), 7.90 (1H, ddd, J=12.6, 7.7, 1.6 Hz, Harom); 31P NMR (CDCl3, 12.5 MHz): δ=+36.2 (q, J=67.5 Hz) HRMS (ESI-Q-TOF): calcd for C17H23BOP [M−H]+: 285.1574; found: 285.15685; calcd for C17H24BOPNa [M+Na]+: 309.15500; found: 309.15390.
31P NMR (CDCl3, 121.5 MHz): δ=−35.9 (s)
Yield=61%; White solid; [α]D=+11.8 (c 0.6, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.86 (3H, d, J=10.6 Hz, C(CH3)3), 3.60 (3H, s, OCH3), 6.80 (1H, dd, J=8.3, 3.4, Hz, Harom), 6.93-7.01 (1H, m, Harom), 7.25-7.35 (3H, m, Harom), 7.37-7.45 (1H, m, Harom), 7.50-7.59 (2H, m, Harom), 7.80 (1H, ddd, J=13.8, 7.6, 1.7 Hz, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+8.5 (q, J=55.0 Hz). HRMS (ESI-Q-TOF): calcd for C14H17BOP [M−H]+: 243.11046; found: 243.11014; calcd pour C14H18BOPNa [M+Na]+: 267.10805; found: 267.10738.
31P NMR (CDCl3, 121.5 MHz): δ=−15.9 (s)
Yield=74%; White solid; [α]D=−8.9 (c 0.6, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=2.20 (6H, s, ArCH3), 3.45 (3H, s, O—CH3), 6.82 (1H, ddd, J=8.3, 3.8, 0.7 Hz, Harom), 6.93 (1H, tq, J=7.5, 1.0 Hz, Harom), 6.98-7.01 (1H, m, Harom), 7.09-7.13 (1H, m, Harom), 7.14-7.17 (1H, m, Harom), 7.25-7.57 (7H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+18.1 (bs). HRMS (ESI-Q-TOF): calcd for C21H23BOP [M−H]+: 333.15741; found: 333.15744; calcd pour C21H24 BOPNa [M+Na]+: 357.15500; found: 357.15411.
31P NMR (CDCl3, 121.5 MHz): δ=+8.0 (s).
Yield=71%; Orange crystals (CH2Cl2/Hexane); [α]D=−178.4 (c 0.3, MeOH). 1H NMR (CDCl3): δ=1.00 (9H, d, J=14.1 Hz, C(CH3)3), 3.87 (5H, s, HFc), 4.38-4.43 (2H, m, HFc), 4.45 (1H, m, HFc), 4.79 (1H, m, HFc), 7.40-7.50 (3H, m, Harom), 7.96-8.03 (2H, m, Carom); 31P NMR (CDCl3, 121.5 MHz): δ=+30.4 (q, J=77.9 Hz). HRMS (ESI-Q-TOF): calcd for C20H26BFePNa [M+Na]+: 387.11068; found: 387.10976.
31P NMR (CDCl3, 121.5 MHz): δ=−38.4 (s).
Yield=74%; Orange crystals (CH2Cl2/Hexane); [α]D=−31.1 (c 0.4, CH2Cl2). 1H NMR (CDCl3, 300 MHz): δ=1.71 (3H, d, J=10.2 Hz, PCH3), 4.19 (5H, s, HFc), 4.34-4.37 (1H, m, HFc), 4.38-4.44 (3H, m, HFc), 7.27-7.38 (3H, m, Harom), 7.52-7.62 (2H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+5.8 (q, J=55.1 Hz). HRMS (ESI-Q-TOF): calcd for C17H20BFePNa [M+Na]+: 345.06373; found: 345.06403.
31P NMR (CDCl3, 121.5 MHz): δ=−16.8 (s).
Yield=78%; Orange crystals; [α]D=−6.6 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=2.22 (6H, s, ArCH3), 4.03 (5H, s, HFc), 4.30-4.37 (2H, m, HFc), 4.40-4.54 (2H, m, HFc), 6.99-7.03 (1H, m, Harom), 7.06-7.09 (1H, m, Harom), 7.10-7.13 (1H, m, Harom), 7.29-7.43 (3H, m, Harom), 7.48-7.57 (2H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+15.5 (bs).
31P NMR (CDCl3, 121.5 MHz): δ=−11.2 (s).
Yield=74%; Colorless crystals; [α]D=+14.9 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.03 (9H, d, J=13.9 Hz, C(CH3)3), 1.49 (3H, d, J=9.7 Hz, PCH3), 7.32-7.43 (3H, m, Harom), 7.59-7.67 (2H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+25.1 (q, J=59.5 Hz). HRMS (ESI-Q-TOF): calcd for C11H20BPNa [M+Na]+: 217.12879; found: 217.12811.
31P NMR (CDCl3, 121.5 MHz): δ=+4.0 (s).
Yield=79%; Colorless crystals; [α]D=+44.1 (c 0.8, MeOH). 1H NMR (CDCl3, 300 MHz): δ=1.32 (9H, d, J=13.7 Hz, C(CH3)3), 1.97 (3H, s, PhCH3), 7.08-7.14 (1H, m, Harom), 7.15-7.22 (1H, m, Harom), 7.25-7.42 (4H, m, Harom), 7.52-7.60 (2H, m, 7.73-7.81 (1H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+34.5 (q, J=62.0 Hz). HRMS (ESI-Q-TOF): calcd for C17H24BPNa [M+Na]+: 293.16009; found: 293.15969.
31P NMR (CDCl3, 121.5 MHz): δ=−38.6 (s).
Yield=64%; Colorless uncrystallized compound; 1H NMR (CDCl3, 300 MHz): δ=1.80 (3H, d, J=9.9 Hz, PCH3), 2.12 (3H, s, PhCH3), 7.10-7.16 (1H, m, Harom), 7.21-7.29 (1H, m, Harom), 7.30-7.43 (4H, m, Harom), 7.48-7.56 (2H, m, Harom), 7.57-7.66 (1H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+10.3 (q, J=52.2 Hz).
31P NMR (CDCl3, 300 MHz): δ=−13.3 (s).
Yield=72%; Colorless uncrystallized compound; 1H NMR (CDCl3, 300 MHz): δ=2.20 (3H, s, PhCH3), 2.23 (6H, s, PhCH3), 6.87-6.97 (1H, m, Harom), 7.02-7.20 (5H, m, Harom), 7.26-7.46 (4H, m, Harom), 7.50-7.60 (2H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+19.8 (bs).
31P NMR (CDCl3, 121.5 MHz): δ=+0.7 (s).
Yield=77%; Colorless crystals; [α]D=+33.2 (c 0.7, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.49 (9H, d, J=14.0 Hz, C(CH3)3), 7.12-7.17 (1H, m, Harom), 7.24-7.37 (4H, m, Harom), 7.42-7.47 (1H, m, Harom), 7.53-7.59 (2H, m, Harom), 7.74 (1H, d, J=8.2 Hz, Harom), 7.81 (1H, d, J=8.8 Hz, Harom), 7.90 (1H, d, J=8.1 Hz, Harom), 8.10 (1H, ddd, J=12.3, 7.3, 1.1 Hz, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+34.7 (m). HRMS (ESI-Q-TOF): calcd for C20H24BPNa [M+Na]+: 329.16009; found: 329.15902.
Yield=67%; White solid; [α]D=+34.2 (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz): δ=1.94 (3H, d, J=9.9 Hz, PCH3), 7.25-7.43 (5H, m, Harom), 7.64-7.57 (3H, m, Harom), 7.79-7.91 (2H, m, Harom), 7.92-8.02 (2H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+10.0 (m). HRMS (ESI-Q-TOF): calcd for C17H18BPNa [M+Na]+: 287.11314; found: 287.11294.
31P NMR (CDCl3, 121.5 MHz): δ=−13.9 (s)
Yield=76%; Sticky oil; [α]D=+2.1 (c 1, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=2.20 (6H, s, PhCH3), 7.02-7.08 (2H, m, Harom), 7.12-7.45 (8H, m, Harom), 7.50-7.63 (2H, m, Harom), 7.76-7.82 (1H, m, Harom), 7.87-7.93 (1H, m, Harom), 8.03-8.11 (1H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+19.9 (m). HRMS (ESI-Q-TOF): calcd for C24H24BPNa [M+Na]+: 377.16009; found: 377.15992.
31P NMR (CDCl3, 121.5 MHz): δ=−26.5 ppm
Yield=57%; Sticky oil; [α]D=−13.5 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.87 (3H, d, J=10.1 Hz, PCH3), 7.31-7.66 (8H, m, 7.74-7.85 (3H, m, Harom), 8.19 (1H, d, J=13.1 Hz, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+10.4 (m). HRMS (ESI-Q-TOF): calcd for C17H18BPNa [M+Na]+: 287.11314; found: 287.11304.
31P NMR (CDCl3, 121.5 MHz): δ=+18.2(s).
Yield=78%; Colorless solid; Mp=94° C.; [α]D=−2.7 (c 0.7, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.26 (9H, d, J=14.1 Hz, C(CH3)3), 7.32-7.54 (5H, m, Harom), 7.68-7.86 (6H, m, Harom), 8.40 (1H, d, J=12.1 Hz, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+34.2 (m). HRMS (ESI-Q-TOF): calcd for C20H24BPNa [M+Na]+: 329.16009; found: 329.15971.
31P NMR (CDCl3, 121.5 MHz): δ=−4.7 ppm
Yield=71%; Sticky oil; [α]D=−7.7 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=2.22 (6H, s, ArCH3), 7.05-7.08 (1H, m, Harom), 7.11-7.13 (1H, m, Harom), 7.15-7.17 (1H, m, Harom), 7.32-7.59 (8H, m, Harom), 7.73-7.83 (3H, m, Harom), 8.06 (1H, d, J=12.7 Hz, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+20.5 (m). HRMS (ESI-Q-TOF): calcd for C24H24BPNa [M+Na]+: 377.16009; found: 377.16004.
B.1.2.2 Preparation of P-Chirogenic Ferrocenyldiphosphines and their Borane Complexes
To a solution of phosphinite (Rp,Rp)-I8 (1 mmol) in toluene (5 mL) was added 4 mmol of organolithium reagent at −78° C. The reaction mixture was stirred for 4 h to room temperature. The course of the reaction was checked by 31P NMR to follow the formation of free ferrocenyl bridged diphosphine (IX).
Then, 4 mmol of BH3.DMS were added at 0° C. and the solution was added for 4 h then hydrolyzed with 10 mL H2O. The mixture was extracted by dichloromethane and the organic phases were dried over MgSO4. After removing the solvent under vacuum the residue was purified by column chromatography on silica gel to afford the corresponding diphosphine diborane complex (IXb).
31P NMR (CDCl3): δ=−38.9 (s)
Yield=28%; Orange crystals; [α]D=−196.9 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.70 (d, J=10.2 Hz, 6H, PCH3), 4.23 (m, 2H, C—HFc), 4.37 (m, 2H, HFc), 4.51 (m, 4H, HFc), 7.27-7.46 (m, 6H, Harom), 7.54-7.69 (m, 4H, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+5.4 (m). HRMS (ESI-Q-TOF): calcd for C24H30B2FeP2Na [M+Na]+: 481.12505; found: 481.12420.
31P NMR (CDCl3, 121.5 MHz): δ=+8.3 (s).
Yield=38%; Orange crystals; [α]D=−25.5 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=0.95 (d, J=14.3 Hz, 18H, C(CH3)3), 3.95 (m, 2H, HFc), 3.98 m, (2H, HFc), 4.39 (m, 2H, HFc), 4.76 (m, 2H, HFc), 7.39-7.53 (m, 6H, Harom), 7.82-7.91 (m, 4H, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+30.1 (m). HRMS (ESI-Q-TOF: calcd for C30H42B2FeP2Na [M+Na]+: 565.21895; found: 565.21829. e.e. =99% determined by HPLC on Lux 5 μm cellulose-2, 1.0 mL/min, using a mixture hexane/isopropanol (98:2) as eluent; t(S)=13.0 min, t(R)=16.1 min.
31P NMR (CDCl3): δ=−17.4 (s)
Yield=47%; Orange crystals; [α]D=−18.4 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=2.20 (s, 6H, ArCH3), 4.12 (m, 2H, HFc), 4.25 (m, 2H, HFc), 4.41 (m, 4H, HFc), 6.96-7.04 (m, 6H, Harom), 7.26-7.49 (m, 10H, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+14.8 (m). HRMS (ESI-Q-TOF): calcd for C38H42B2FeP2Na [M+Na]+: 661.21895; found: 661.21923.
To a solution of phosphinite I (1 mmol) in toluene (3 mL), 2 mmol of sulfur were added. The mixture was stirred at room temperature for 2 hours. After filtration, the reaction mixture was successively hydrolyzed with 10 mL H2O, then extracted with 3×10 mL dichloromethane. The organic phase was dried on MgSO4, and the solvent removed under vacuum, to give a residue which was purified by chromatography on silica to afford the thiophosphinite VII.
The general procedure is illustrated by the synthesis of compound of formula VIII wherein phosphinite I is compound 12.
To a solution of phosphinite 12 (1 mmol) in toluene (3 mL), 2 mmol of sulfur were added. The mixture was stirred at room temperature for 2 hours. After filtration, the reaction mixture was successively hydrolyzed with 10 mL H2O, then extracted with 3×10 mL dichloromethane. The organic phase was dried on MgSO4, and the solvent removed under vacuum, to give a residue which was purified by chromatography on silica to afford the thophosphinite VII1.
Yield=67%; Yellowish uncrystallized product; Rf=0.40 (AcOEt/MeOH 10:1); [α]D=+14.5 (c=0.7, CHCl3); 1H NMR (CDCl3, 300 MHz): δ=0.96 (3H, d, J=6.6 Hz, CCH3), 1.60 (1H, brs, NH), 2.18 (3H, s, NCH3), 2.79 (1H, qd, J=6.4, 4.0 Hz, CHN), 3.50 (3H, s, OCH3), 5.61 (1H, dd, J=13.6, 3.8 Hz, CHO), 6.78 (1H, dd, J=7.9, 6.2 Hz, Harom), 6.96-7.04 (1H, m, Harom), 7.05-7.27 (8H, m, Harom), 7.35-7.44 (1H, m, Harom), 7.52-7.64 (2H, m, Harom), 8.12 (1H, ddd, J=15.7, 7.7 Hz, 1.71, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+80.9 (s). HRMS (ESI-Q-TOF): calcd for C23H27NO2PS [M+H]+: 412.14946; found: 412.14860.
Yield=79%; Yellowish uncrystallized product; 1H NMR (CDCl3, 300 MHz): δ=1.04 (3H, d, J=6.5 Hz, CH3), 1.14 (9H, d, J=17.4 Hz, C(CH3)3), 1.66 (1H, brs, NH), 2.37 (3H, s, NCH3), 3.02 (1H, qd, J=6.5, 4.4 Hz, CHN), 5.28 (1H, dd, J=13.1, 4.3 Hz, CHO), 7.01-7.10 (2H, m, Harom), 7.13-7.28 (6H, m, 7.38-7.50 (2H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+108.3 (s).
Yield=57%; Orange uncrystallized compound; 1H NMR (CDCl3, 300 MHz): δ=1.13 (3H, d, J=6.5 Hz, CCH3), 1.62 (1H, brs, NH), 2.44 (3H, s, NCH3), 2.96 (1H, qd, J=6.5, 4.3 Hz, CHN), 4.27 (5H, s, HFc), 4.40 (1H, m, HFc), 4.48 (1H, m, HFc), 4.50 (1H, m, HFc), 4.85 (1H, m, HFc, CHN), 5.41 (1H, dd, J=13.8, 4.3 Hz, CHO), 7.10-7.27 (7H, m, 7.29-7.39 (1H, m, Harom), 7.71-7.82 (2H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+86.8 (s).
To a solution of phosphinite I (1 mmol) in toluene (3 mL) were added chlorophosphine R10R11PCl (2 mmol) and triethylamine (5 mmol) to afford the free aminophosphine-phosphinite (AMPP*) VIII. The mixture was stirred at room temperature for 5 h. Then BH3.DMS (8 mmol) was added to the P-chirogenic aminophosphine-phosphinite VIII and the mixture was stirred for a night to lead to the corresponding diborane complex VIIIb. After hydrolysis with H2O (10 mL), the aqueous phase was extracted with dichloromethane. The organic phase was dried and the solvent was removed under vacuum to afford a residue which was purified by chromatography on silica gel to afford diborane complex VIIIb. A solution of AMPP diborane VIIIb (0.2 mmol) and DABCO (1.2 mmol) in toluene (3 mL) was stirred under argon at 50° C. for a night. After removing the solvent under vacuum, the residue was purified by chromatography on neutral alumine oxide using a mixture petroleum ether/AcOEt (4:1) as eluent to afford the free AMPP* VIII.
The general procedure is illustrated by the synthesis of AMPP* VIII1 and its diborane complex VIIIb1 wherein phosphinite I is (S)-I1 and chlorophosphine is chlorodiphenylphosphine.
To a solution of phosphinite (S)-I1 (329.4 mg, 1 mmol) in toluene (3 mL) were added chlorodiphenylphosphine Ph2PCl (441.3 mg or 0.36 mL, 2 mmol) and triethylamine (5 mmol). The mixture was stirred at room temperature for 5 h. Then BH3.DMS (8 mmol) was added to the P-chirogenic aminophosphine-phosphinite VIII1 and the mixture was stirred for a night. After hydrolysis with H2O (10 mL), the aqueous phase was extracted with dichloromethane. The organic phase was dried and the solvent was removed under vacuum to afford a residue which was purified by chromatography on silica gel to afford diborane complexes VIIIb1. A solution of AMPP diborane VIIIb1 (108.2 mg, 0.2 mmol) and DABCO (135 mg, 1.2 mmol) in toluene (3 mL) was stirred under argon at 50° C. for a night. After removing the solvent under vacuum, the residue was purified by chromatography on neutral alumine oxide using a mixture petroleum ether/AcOEt (4:1) as eluent to afford the free AMPP* VIII1.
31P NMR (CDCl3, 121.5 MHz): δ=+66.4 (s, P—N), +129.4 (s, P—O).
Yield=59%; Colorless crystals; [α]D=−93.6 (c 1, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.13 (9H, d, J=14.6 Hz, C(CH3)3), 1.51 (3H, d, J=6.5 Hz, CH3), 2.23 (3H, d, J=7.5 Hz, NCH3), 4.63-4.76 (1H, m, CHN), 5.26 (1H, t, J=9.5 Hz, CHO), 6.53-6.63 (2H, m, Harom), 6.96-7.62 (18H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+71.1 (m, P—N), +125.4 (m, P—O). HRMS (ESI-Q-TOF): calcd for C32H43B2NOP2Na [M+Na]+: 564.28944; found: 584.28944. Anal. calcd for C32H43B2NOP2 (541.27): C, 71.01, H, 8.01, N 2.59; found C, 70.92, H, 8.39, N 2.65.
31P NMR (CDCl3, 121.5 MHz): δ=+66.1 (s, P—N), +104.3 (s, P—O).
Yield=65%; White needle crystals (CH2Cl2/Hexane); Mp=155° C.; [α]D=+68.8 (c 0.6, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.26 (3H, d, J=6.6 Hz, CH3), 2.21 (3H, d, J=7.6 Hz, NCH3), 3.47 (3H, s, OCH3), 4.47-4.57 (1H, m, CHN), 5.33 (1H, t, J=9.4 Hz, CHO), 6.51-6.58 (2H, m, Harom), 6.77 (1H, dd, J=8.2, 4.6 Hz, Harom), 6.95-7.09 (8H, m, Harom), 7.10-7.15 (1H, m, Harom), 7.16-7.34 (7H, m, Harom), 7.35-7.50 (4H, m, Harom), 7.80 (1H, ddd, J=11.9, 7.0, 1.7 Hz, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+71.1 (m, P—N), +105.3 (m, P—O). HRMS (ESI-Q-TOF): calcd for C35H41B2NO2P2Na [M+Na]+: 614.27026; found: 614.26804.
31P NMR (CDCl3, 121.5 MHz): δ=+65.0 (s, P—N), +107.0 (s, P—O).
Yield=68%; Orange crystals; [α]D=+9.8 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.28 (3H, d, J=6.6 Hz, CH3), 2.19 (3H, d, J=7.6 Hz, NCH3), 4.02 (5H, s, HFc), 4.09 (1H, m, HFc), 4.33 (1H, m, HFc), 4.40 (2H, m, HFc, CHN), 4.58 (1H, m, HFc), 5.14 (1H, t, J=9.4 Hz, CHO), 6.52-6.58 (2H, m, Harom), 6.95-7.05 (5H, m, Harom), 7.07-7.18 (3H, m, Harom), 7.15-7.17 (1H, m, Harom), 7.19-7.24 (2H, m, Harom), 7.29-7.33 (2H, m, Harom), 7.36-7.40 (1H, m, Harom), 7.42-7.49 (4H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+71.7 (m, P—N), +106.9 (m, P—O). HRMS (ESI-Q-TOF): calcd for C38H43B2FeNOP2 [M]+: 669.23633; found: 669.23672; calcd for C38H43B2FeNOP2Na [M+Na]+: 692.22610; found: 692.22470.
31P NMR (CDCl3, 121.5 MHz): δ=+65.8 (s, P—N), +107.1 (s, P—O).
Yield=64%; Colorless crystals; [α]D=−59.3 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.17 (3H, d, J=6.5 Hz, CH3), 2.07 (3H, s, PhCH3), 2.23 (3H, d, J=7.6 Hz, NCH3), 4.42-4.62 (1H, m, CHN), 5.43 (1H, t, J=9.6 Hz, CHO), 6.50-6.60 (2H, m, Harom), 6.95-7.24 (12H, m, Harom), 7.27-7.51 (9H, m, Harom), 8.04 (1H, ddd, J=12.5, 7.4, 1.4 Hz, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+70.9 (m, P—N), +109.3 (m, P—O). HRMS (ESI-Q-TOF): calcd for C35H41B2NOP2Na [M+Na]+[: 598.27417; found: 598.27261.
31P NMR (CDCl3, 121.5 MHz): δ=+64.4 (s, P—N), +108.4 (s, P—O).
Yield=61%; Colorless crystals; [α]D=+48.9 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.02 (3H, d, J=6.6 Hz, CH3), 2.19 (3H, d, J=7.6 Hz, NCH3), 4.42-4.54 (1H, m, NCH), 5.51 (t, J=9.7 Hz, OCH), 6.56 (2H, dd, J=11.3, 7.8 Hz, Harom), 6.93-7.02 (4H, m, Harom), 7.03-7.21 (8H, m, Harom), 7.22-7.45 (8H, m, Harom), 7.49-7.54 (1H, Harom)97.77 (1H, d, J=8.2 Hz, Harom), 7.94 (2H, d, J=8.5 Hz, Harom), 8.31 (1H, ddd, J=14.8, 7.1, 0.7 Hz, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+71.3 (m, P—N), +110.0 (m, P—O); HRMS (ESI-Q-TOF): calcd for C38H42 B2NOP2 [M+H]+: 612.29348; found: 612.29213; calcd for C38H4,B2NOP2Na [M+Na]+: 634.27543; found: 634.27398.
Yield=94%; Colorless amorphous solid; 1H NMR (CD2Cl2, 300 MHz): δ=1.35 (3H, d, J=6.3 Hz, CH3), 2.19 (3H, d, J=3.2 Hz, CH3), 3.90-4.00 (1H, m, CH), 4.68 (1H, t, J=8.7 Hz, CH), 6.65-6.71 (2H, m, Harom), 6.98-7.34 (24H, m, Harom), 7.42-7.52 (2H, m, Harom), 7.93-7.97 (1H, m, Harom), 7.11-7.17 (5H, m, Harom), 7.22-7.35 (8H, m, Harom), 7.44-7.63 (7H, m, Harom), 8.33 (1H, dd, J=13.1, 7.2 Hz, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+64.9 (s, P—N), +101.9 (s, P—O).
Yield=67%; White solid; Mp=216-218° C.; [α]D=−5.9 (c 0.4, CHCl3). 1H NMR (CD2Cl2, 300 MHz): δ=1.29 (3H, d, J=5.7 Hz, CH3), 2.29 (3H, d, J=7.6 Hz, NCH3), 4.51-4.54 (1H, m, NCH), 5.54 (1H, t, J=9.9 Hz, OCH), 6.60-6.64 (2H, m, Harom), 6.69-7.73 (2H, m, Harom), 6.84-6.86 (2H, m, Harom), 6.90-6.94 (2H, m, Harom), 7.11-7.17 (5H, m, Harom), 7.22-7.35 (8H, m, Harom), 7.44-7.63 (7H, Harom), 8.33 (1H, dd, J=13.1, 7.2 Hz, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+71.1 (m, P—N), +110.6 (m, P—O). HRMS (ESI-Q-TOF): calcd for C40H43B2NOP2Na [M+Na]+: 660.2898; found: 660.2884.
Yield=88%; colorless amorphous solid; 1H NMR (CD2Cl2, 300 MHz): δ=1.15 (3H, d, J=6.8 Hz, CH3), 2.05 (3H, d, J=4.0 Hz, CH3), 3.81-3.90 (1H, m, CH), 4.63 (1H, t, J=8.1 Hz, CH), 6.52-6.57 (2H, m, Harom), 6.81-6.85 (2H, m, Harom), 6.96-7.21 (24H, m, Harom), 7.58-7.62 (1H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+65.1 (s, P—N), +104.8 (s, P—O).
Yield=58%; White solid; [α]D=−67.7 (c 0.4, CHCl3). 1H NMR (CD2Cl2, 300 MHz): δ=1.25 (3H, d, J=6.6 Hz, CH3), 2.32 (3H, d, J=7.7 Hz, NCH3), 4.57-4.65 (1H, m, NCH), 5.52 (1H, t, J=8.9 Hz, OCH), 6.69-6.73 (2H, m, Harom), 6.77-6.79 (2H, m, Harom), 7.05-7.08 (3H, m, Harom), 7.15-7.38 (21H, m, Harom), 7.84 (1H, ddd, J=13.5, 7.8, 1.0 Hz, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+71.1-71.4 (m, P—N), +107.5-107.9 (m, P—O). HRMS (ESI-Q-TOF): calcd for C40H44B2NOP2Na [M+H]+: 638.3092; found: 638.3091.
31P NMR (CDCl3, 121.5 MHz): δ=+42.3 (s, P—N), +101.2 (s, P—O).
Yield=57%; Colorless uncrystallized compound; [α]D=+3.5 (c 0.3, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=2.80-2.94 (2H, m, CH2), 3.03 (1H, d, J=17.2 Hz, NH), 3.26 (3H, s, OCH3), 4.70 (1H, dd, J=10.8, 2.8 Hz, CH), 5.03 (1H, m, CH), 6.67 (1H, dd, J=8.0, 4.3 Hz, Harom), 6.82-6.95 (2H, m, Harom), 7.05-7.14 (3H, m, Harom), 7.22-7.65 (17H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+56.1 (m, P—N), +103.8 (m, P—O). HRMS (ESI-Q-TOF): calcd for C34H37B2NO2P2Na [M+Na]+: 598.23778; found: 598.23635.
Yield=89%; Colorless amorphous solid; 1H NMR (CD2Cl2, 300 MHz): δ=1.28 (3H, d, J=6.6 Hz, CH3), 2.12 (3H, d, J=3.1 Hz, CH3), 3.85-4.05 (1H, m, CH), 4.76 (1H, t, J=8.9 Hz, CH), 6.54-6.64 (2H, m, Harom), 6.94-7.01 (2H, m, Harom), 7.03-7.23 (17H, m, Harom), 7.27-7.35 (2H, m, Harom), 7.39-7.48 (3H, m, Harom), 7.68-7.87 (3H, m, Harom), 8.02-8.11 (1H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+64.5 (s, P—N), +112.1 (s, P—O).
Yield=81%; Colorless crystals; [α]D=−66.3 (c 0.6, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.35 (3H, d, J=6.5 Hz, CH3), 2.33 (3H, d, J=7.5 Hz, NCH3), 4.58-4.74 (1H, m, NCH), 5.46 (1H, t, J=9.4 Hz, OCH), 6.59-6.71 (2H, m, Harom), 7.05-7.23 (8H, m, Harom), 7.26-7.66 (15H, m, Harom), 7.68-7.77 (1H, m, Harom), 7.86-8.00 (3H, m, Harom), 8.33 (1H, d, J=12.7 Hz, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+71.1 (m, P—N), +107.2 (m, P—O). HRMS (ESI-Q-TOF): calcd for C38H41B2NOP2Na [M+Na]+: 634.27417; found: 634.27319. Anal. calcd for C38H4,B2NOP2 (611.32):
31P NMR (CDCl3, 300 MHz): δ=+64.5 (s, P—N), +112.5 (s, P—O)
Yield=67%; Colorless crystals (CH2Cl2/Hexane); [α]D=−71.6 (c 0.5, CHCl3). 1H NMR (CDCl3, 500 MHz): δ=1.25 (3H, d, J=6.5 Hz, CH3), 2.22 (3H, d, J=7.6 Hz, NCH3), 2.32 (3H, s, PhCH3), 4.46-4.55 (1H, m, CHN), 5.30 (1H, t, J=9.4 Hz, CHO), 6.52-6.58 (2H, m, Harom), 6.97-7.11 (7H, m, Harom), 7.15-7.24 (6H, m, Harom), 7.28-7.35 (4H, m, Harom), 7.37-7.42 (1H, m, Harom), 7.43-7.49 (2H, m, Harom), 7.51-7.56 (2H, m, Harom); 31P NMR (CDCl3, 202.4 MHz): δ=+71.0 (m, P—N), +107.0 (m, P—O).
31P NMR (CDCl3, 300 MHz): δ=+64.2 (s, P—N), +105.2 (s, P—O)
Yield=77%; Orange solid; [α]D=−18.1 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ=1.26 (6H, d, J=6.4 Hz, CH3), 2.17 (6H, d, J=7.6 Hz, NCH3), 3.73 (2H, m, HFc), 4.18 (2H, m, HFc), 4.31-4.42 (2H, m, CHN), 4.52 (2H, m, HFc), 4.62 (2H, m, HFc) 5.08 (2H, t, J=9.2 Hz, CHO), 6.50-6.57 (4H, m, Harom), 6.93-7.09 (14H, m, Harom), 7.12-7.16 (4H, m, Harom), 7.17-7.25 (4H, m, Harom), 7.29-7.41 (10H, m, Harom), 7.42-7.48 (4H, m, Harom); 31P NMR (CDCl3, 121.5 MHz): δ=+71.1 (m, P—N), +106.4 (m, P—O). HRMS (ESI-Q-TOF): calcd for C66H76B4FeN2O2P4Na [M+Na]+: 1175.44711; found: 1175.44564.
The P-chirogenic AMPP* VIII were used as ligands in the palladium-catalyzed allylic reactions of malonate or benzylamine (Scheme 10).
The allylation of dimethyl malonate was performed with the allylic substrate in dichloromethane or toluene, using 2 mol % of [Pd(C3H5)Cl]2 and 4 mol % of AMPP* VIII, N,O-bis(trimethylsilyl)acetamide (BSA) and a catalytic amount of potassium acetate as base. The reactions were completed at room temperature to selectively afford the mono allylated malonates (Scheme 10a). The results are reported in Table 12.
The allylic substitution of (E)-1,3-diphenylprop-2-en-1-yl acetate catalyzed by the palladium complexes with the AMPP* VIII, was also investigated using benzylamine as nucleophiles (Scheme 10b). The reactions were performed at room temperature in dichloromethane using TBAF as additive, to afford the corresponding allylated amine products. The results are summarized in Table 13.
The AMPP* ligands VIII were used in rhodium-catalyzed asymmetric hydrogenation of the methyl α-acetamido cinnamate (Scheme 11). The results are reported in Table 14.
| Number | Date | Country | Kind |
|---|---|---|---|
| 18305304.0 | Mar 2018 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2019/056965 | 3/20/2019 | WO | 00 |
