P-Stereogenic trifluoromethyl derivatives of josiphos: Synthesis, coordination properties, and applications in asymmetric catalysis

DOI: 10.1002/chem.201102390

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Chemistry - A European Journal p. 632 - 640 (2012)

Update date:2022-08-04

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Authors:

Buergler, Jonas F.

Niedermann, Katrin

Togni, Antonio

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Article abstract of DOI:10.1002/chem.201102390

Intermolecular nucleophilic substitution of a CF₃ group of bis(trifluoromethyl)phosphanes by a lithiated Ugi's amine (4) affords both diastereoisomers of the corresponding P-stereogenic trifluoromethylphosphanes 6 and 7. Separation of the isomers by column chromatography on silica gel followed by substitution of the dimethylamino group with phosphanes or pyrazoles yields the bidentate P^P (9 and 10) or P^N ligands (12 and 13) without epimerization at the stereogenic phosphorus center. The coordination properties of these bidentate ligands were investigated on the basis of crystal structures of the corresponding palladium and rhodium complexes. IR spectroscopic measurements of rhodium-carbonyl complexes 16-23 indicated the strongly electronic-withdrawing character of these phosphanes. The catalytic potential of these ligands was demonstrated in the rhodium-catalyzed hydrogenation of olefins as well as in the palladium-catalyzed allylic alkylation reaction, where high activities and enantioselectivities were observed. CF₃, more than just a simple substituent: Intra- and intermolecular nucleophilic substitutions of a CF ₃ group in bis(trifluoromethyl)phosphanes were used in the preparation of bidentate ferrocenyl ligands bearing a P-stereogenic trifluoromethylphosphanyl group. High activities and enantioselectivities were achieved in rhodium-catalyzed olefin hydrogenation reactions and in palladium-catalyzed allylic alkylation reactions using these ligands. Copyright

Full text of DOI:10.1002/chem.201102390

DOI: 10.1002/chem.201102390

P-Stereogenic Trifluoromethyl Derivatives of Josiphos: Synthesis,

Coordination Properties, and Applications in Asymmetric Catalysis

Jonas F. Buergler, Katrin Niedermann, and Antonio Togni*^[a]

Abstract: Intermolecular nucleophilic

substitution of a CF₃group of bis(tri-

fluoromethyl)phosphanes by a lithiated

Ugiꢀs amine (4) affords both diastereo-

isomers of the corresponding P-stereo-

genic trifluoromethylphosphanes 6 and

7. Separation of the isomers by column

chromatography on silica gel followed

by substitution of the dimethylamino

group with phosphanes or pyrazoles

yields the bidentate P^P (9 and 10) or

P^N ligands (12 and 13) without epi-

merization at the stereogenic phospho-

rus center. The coordination properties

of these bidentate ligands were investi-

gated on the basis of crystal structures

of the corresponding palladium and

rhodium complexes. IR spectroscopic

measurements of rhodium–carbonyl

complexes 16–23 indicated the strongly

electronic-withdrawing character of

these phosphanes. The catalytic poten-

tial of these ligands was demonstrated

in the rhodium-catalyzed hydrogena-

tion of olefins as well as in the palladi-

um-catalyzed allylic alkylation reac-

tion, where high activities and enantio-

selectivities were observed.

Keywords: alkylation · asymmetric

catalysis · ferrocene · hydrogena-

tion · phosphanes

Introduction

phanes in the literature. Caffyn and co-workers used

TMSCF₃for the nucleophilic introduction of a trifluoro-

methyl group and also applied this methodology to the syn-

Over the last few decades, chiral bidentate ferrocenyl phos-

phanes have become one of the most successful classes of li-

gands in asymmetric catalysis and several of them are even

used in large-scale industrial processes.^[1]The high thermal

stability and conformational rigidity provided by the ferro-

cene core together with the modular introduction of the two

phosphanyl groups account for their success. Although Josi-

phos,^[2]the most-prominent representative of this family, al-

ready provides high activities and enantioselectivities in a

large variety of catalytic applications, fine-tuning of the

steric and electronic properties of the phosphanyl groups is

often needed to achieve high catalytic performance for spe-

cific reactions and/or substrates. A plethora of ligands bear-

ing different aryl and alkyl substituents on the phosphane

moieties have been reported, but the use of a trifluorometh-

yl group as a small and strongly electron-withdrawing func-

tionality is rare in the literature.^[3]Such electron-deficient

phosphanes may be used to stabilize low-valence metal spe-

cies in Lewis acid catalysis or in combination with an elec-

tron-rich phosphanyl group as a bidentate ligand consisting

of two electronically distinct donor groups. To date, mild

thesis of

a ferrocenyl ligand containing two PACHTUNGTRENNUNG(CF₃)₂

groups.^[3e,4]

On the other hand, we recently reported the use of a hy-

pervalent organoiodine reagent for the mild and efficient

synthesis of mono- and bis(trifluoromethyl)phosphanes and

applied this methodology in the synthesis of CF₃-substituted

2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (binap) and fer-

rocenyl ligands.^[5]During the course of those studies, we dis-

covered the intramolecular substitution of one of the CF₃

groups in bis(trifluoromethyl)phosphanes by phosphide

anions and we were able to apply this method to the selec-

tive synthesis of P-stereogenic trifluoromethylphosphanes.^[6]

Initial studies demonstrated the utility of such ligands in the

rhodium-catalyzed asymmetric hydrogenation of olefins.

Herein, we present a more general synthesis of P-stereogen-

ic ferrocenyl trifluoromethylphosphanes using intra- or in-

termolecular substitution of CF₃anions as well as the spec-

troscopic and crystallographic analysis of their palladium

and rhodium complexes. Moreover, we reiterate the high

catalytic potential of these diphosphanes by their use in se-

lected benchmark hydrogenations of olefins as well as asym-

metric allylic alkylations.

and general methods for the efficient formation of the P

CF₃bond are rare, thus explaining the paucity of such phos-

[a] Dr. J. F. Buergler, K. Niedermann,⁺Prof. Dr. A. Togni

Department of Chemistry and Applied Biosciences

Swiss Federal Institute of Technology,

ETH Zꢁrich, 8093 Zꢁrich (Switzerland)

Fax : (+41) 44 632 13 10

E-mail: atogni@ethz.ch

[⁺] X-ray crystallographic studies.

Results and Discussion

Intramolecular CF₃substitution: As mentioned above, we

recently discovered the ability of the trifluoromethyl anion

to act as a leaving group from corresponding phosphanes.

This observation lead to the development of a new method

for the preparation of bidentate P-stereogenic trifluoro-

Supporting information for this article is available on the WWW

under http://dx.doi.org/10.1002/chem.201102390.

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Chem. Eur. J. 2012, 18, 632 – 640

FULL PAPER

by using a carbon instead of a phosphorus nucleophile,

though this is not necessarily a very obvious reaction. In

fact, there are only few reactions that feature a trifluoro-

methyl anion as a leaving group, the most-prominent ones

being the haloform reaction of a trifluoromethyl ketone or

the transformations of TMSCF₃, the so-called Ruppert–Pra-

kash reagent.^[8]However, as shown by sporadic reports,

when exposed to nucleophiles a trifluoromethyl group may

undergo fluoride substitution reactions, in particular when

attached to an aromatic ring.^[9]

The required bis(trifluoromethyl)phosphanes 4 were ob-

tained by electrophilic trifluoromethylation of, for example,

phenylphosphane using our own reagent (8). Alternatively,

the nucleophilic route starting from a dichlorophosphane as

reported by Caffyn and co-workers was also applied

(Scheme 2).^[4]Both methods afforded the desired products

in only moderate yields, most likely owing to a loss of mate-

rial because of the high volatility of these compounds.

Scheme 1. Synthesis of bidentate P-stereogenic trifluoromethylphosphane

ligands.

methyl-substituted phosphanes, as shown in Scheme 1.^[6]The

secondary phosphanes 1 were prepared in four steps and

good overall yield from commercially available Ugiꢀs

amine.^[7]Treatment of 1 with a base such as potassium tert-

butoxide generates a phosphido group, which subsequently

undergoes an intramolecular nucleophilic attack on the bis-

(trifluoromethyl)phosphanyl moiety. This addition leads to

the removal of one of the diastereotopic CF₃groups, thereby

generating 1,2-diphospholes of type 2. This process occurs

with complete control of the absolute configuration at the

two newly formed P-stereogenic centers such that only one

of the four possible stereoisomers is formed. For compounds

2a and 2b, the absolute configuration was determined by X-

ray crystallography. Diphospholes (2) are well-suited inter-

mediates for the preparation of Josiphos-type diphosphane

ligands. Thus, the simple reaction sequence involving an

electrophilic methylation followed by the addition of a nu-

cleophile leads to their ring opening. The corresponding di-

phosphanes (3) were isolated in moderate to good yields

and as single diastereoisomers, thus indicating that the ring-

opening process is highly regio- and diastereoselective.

Again, the absolute configuration of both P-stereogenic cen-

ters in compounds 3 was assigned based on an X-ray crystal

structure of a palladium complex containing compound 3b.

Currently, the electrophilic alkylation step is limited to the

use of methyltriflate, but a variety of different nucleophiles,

such as MeLi, PhMgCl, and iPrMgCl were successfully ap-

plied to the reaction. Diphosphanes 3 are quite sensitive to-

wards oxidation in solution but are highly stable as crystal-

line solids and can therefore be handled in air.

Scheme 2. Synthesis of bis(trifluoromethyl)phosphanes 4a and 4b. Re-

agents and conditions: a) 8, DBU, CH₂Cl₂, À788C to RT; b) p-CN-

AHCTNUERTGGNN(UN C₆H₄)OH, Et₃N, THF, 08C to RT; c) TMSCF₃, CsF (cat.), Et₂O, 0 8C to

RT. DBU=1,8-diazabicycloACTHNUGTRNEUNG[5.4.0]undec-7-ene.

Subsequently, we were pleased to find that lithiated Ugiꢀs

amine (5) reacted in the desired fashion with bis(trifluoro-

methyl)phenylphosphane (4a; Scheme 2). However, the use

of an excess of nucleophile turned out to be crucial to

obtain acceptable yields. Using two equivalents of 5 enabled

the isolation of diastereoisomers (S_P)-6 and (R_P)-6 in 41%

and 51% yield, respectively, thereby indicating a poor dia-

stereoselectivity in the substitution process (Scheme 3). The

Intermolecular CF₃substitution: Although the above-men-

tioned method provides new P-stereogenic trifluoromethyl-

phosphane ligands, it suffers from some drawbacks. The

rather long reaction sequence and the relatively low yields

in certain steps together with the limitation of using methyl

triflate as the electrophilic alkylating agent prompted us to

develop another synthetic route for the preparation of this

class of ligands. We reasoned that the nucleophilic substitu-

tion of a CF₃group in a tertiary bis(trifluoromethyl)phos-

phane should also be possible in an intermolecular fashion

Scheme 3. Intermolecular substitution of a CF₃group.

two isomers were readily separated by column chromatogra-

phy on silica gel and their absolute configuration at the

phosphorus center was established by X-ray crystallography

of the corresponding diphosphane palladium complexes (see

below). When the sterically more-demanding adamantyl

phosphane 4b was subjected to the same reaction condi-

tions, the yield of the substitution product dropped signifi-

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633

A. Togni et al.

cantly. However, only one diastereoisomer was obtained in

this case, namely the one with S configuration at the phos-

phorus atom ((S_P)-7), again as confirmed by X-ray analysis.

The monophosphanes 6 and 7 were converted into diphos-

phanes 9 and 10 by standard nucleophilic substitution of the

dimethylamino group in acetic acid at elevated temperatures

(Scheme 4). In the case of the phenyl-substituted phos-

Figure 1. ORTEP representations of (R_P,R_C)-13 and (R_P,S_C)-13. Hydrogen

atoms are omitted for clarity and thermal ellipsoids are set to 50% prob-

ability.

Scheme 4. Preparation of the trifluoromethylphosphane ligands 9 and 10.

phanes, no epimerization of the stereogenic phosphorus

atom was observed and (S_P)-9 and (R_P)-9 were isolated as

enantiopure single diastereomers in good yields from (S_P)-6

and (R_P)-6, respectively. In the case of the adamantyl phos-

phane 10, partial epimerization was observed and the diaste-

reomers were isolated in low to moderate yields after sepa-

ration by column chromatography on silica gel. This specific

behavior offered access to both diastereoisomers of ligand

10 although only (S_P)-7 was obtained in the preceding sub-

stitution step.

sis (Figure 1). The S_N1-type substitution of the dimethylami-

no group in structures of type 6 with phosphorus- or nitro-

gen nucleophiles is well-known to proceed with retention of

configuration at the stereogenic carbon atom.^[10]We are not

aware of any other case where such a reaction occurs, at

least partially, with inversion of configuration at the pseudo

benzylic center. Mechanistically, such an inversion implies

the involvement of an S_N2-type reaction pathway. However,

because this appears to be an isolated case, it was not inves-

tigated further.

The dimethylamino group in 6 was also successfully sub-

stituted with pyrazoles 11a and 11b and the corresponding

P^N ligands 12 and 13 were isolated in low to moderate

yields (Scheme 5). To our surprise, partial epimerization at

the stereogenic carbon center was observed in the reaction

of (R_P)-6 with the adamantyl-substituted pyrazole 11b. Thus,

two stereoisomers that have the same absolute configuration

at the phosphorus center but differing configurations at the

carbon center were isolated after column chromatography

on silica gel and characterized by single-crystal X-ray analy-

Transition-metal complexes: To assess the coordination be-

havior of these new diphosphanes, a series of transition-

metal complexes were prepared and spectroscopically and

crystallographically characterized. The dichloropalladium

complexes 14 and 15 were accessed by the reaction of

[Pd₂Cl₂ACHTNUTRGNE(NUG cod)] with the diastereoisomeric phosphane ligands

(S_P)-9 and (R_P)-9 in dichloromethane (Scheme 6). ORTEP

Scheme 6. Synthesis of palladium complexes 14 and 15.

representations and selected bond-lengths and angles of

these two compounds are displayed in Figure 2. Derivatives

14 and 15 are structurally very similar, with only insignifi-

cant differences in Pd P and Pd Cl bond lengths. Also,

from a conformational point of view, the opposite absolute

configuration at phosphorus does not influence the overall

geometry to any notable extent. In both cases, the endo-

Scheme 5. Synthesis of the pyrazole substituted P-stereogenic phosphane

ligands 12 and 13. Reagents and conditions: 1.3–1.5 equiv 11, 1 equiv

TFA, AcOH, 908C, 16 h. TFA=trifluoroacetic acid.

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Chem. Eur. J. 2012, 18, 632 – 640

P-Stereogenic Trifluoromethyl Derivatives of Josiphos

FULL PAPER

Table 1. CO stretching frequencies of rhodium carbonyl complexes 16–

20.

Entry

Complex

R’

n₁(CO) [cm^À1

]

n₂(CO) [cm^À1

]

CF₃

2015

2019

1985

2029

2096

2103

2080

2107

–

2050

2054

2025

2064

CF₃

Figure 2. ORTEP representation of palladium complexes 14 and 15. Hy-

drogen atoms and co-crystallizing solvent molecules are omitted for clari-

ty and thermal ellipsoids are set to 50% probability. Only one of the two

independent molecules in the asymmetric unit of 15 is shown. Selected

bond lengths [ꢃ] and angles [8] for 14: Pd1–P1 2.231(1), Pd1–P2 2.291(1),

Pd1–Cl1 2.341(1), Pd1–Cl2 2.351(1); P1-Pd1-P2 95.5(5). 15: Pd1–P1

2.245(1), Pd1–P2 2.273(1), Pd1–Cl1 2.341(1), Pd1–Cl2 2.343(1); P1-Pd1-

P2 94.47(4).

(2029 cm^À1) for complex 19 which contains the most-elec-

tron-withdrawing phosphanyl group, P(CF₃)₂. The P-stereo-

AHCTUNGTRENNUNG

genic trifluoromethylphosphanyl complexes (16 and 17)

show an intermediate situation with very similar stretching

frequencies (2015 and 2019 cm^À1, respectively). A similar

trend is observed for n₁(CO) and n₂(CO) for both CO

groups in the dicarbonyl complexes 20–23 (Table 1, en-

tries 5–8). However, owing to their cationic character and

the presence of two carbonyl ligands, the stretching frequen-

cies of compounds 20–23 are in general higher than for the

neutral monocarbonyl complexes.

positioned substituent at P1 (CF₃in 14 and Ph in 15) is in an

almost-perfect axial orientation. The consequential steric re-

pulsion between this substituent and the ferrocene core

pushes the phosphorus atom out of the Cp plane by 0.52 ꢃ

and 0.46 ꢃ, respectively.

To ascertain and estimate the electron-withdrawing effect

of the P-trifluoromethylphosphanes, we prepared a series of

rhodium–carbonyl complexes (Scheme 7) and compared

Single crystals of carbonyl complexes 16 and 21 suitable

for X-ray analysis were obtained and corresponding ORTEP

representations are shown in Figure 3.

Figure 3. ORTEP representation of rhodium carbonyl complexes 16 and

21. Hydrogen atoms and PF₆counterions are omitted for clarity and ther-

mal ellipsoids are set to 50% probability. Selected bond lengths [ꢃ] and

angles [8] for 16: Rh1–P1 2.1899(6), Rh1–P2 2.3710(6), Rh1–Cl1

2.3878(7), Rh1–C32 1.884(3), C32–O1 1.127(3); P1-Rh1-P2 94.36(7). 21:

Rh1–P1 2.344(2), Rh1–P2 2.2341(1), Rh1–C32 1.893(7), Rh1–C33

1.907(4), C32–O1 1.142(8), C33–O2 1.143(5); P1-Rh1-P2 91.95(5).

Scheme 7. Synthesis of rhodium carbonyl complexes 16–20.

their carbonyl stretching frequencies (n(CO), Table 1). In

general, strong p-accepting ligands decrease the metal CO

p-backbonding, thus shortening the CO bond, this being re-

flected by an increase in the frequency n(CO) in the IR

spectrum. In the case of 16, 17, and 19, the complexes were

obtained as single isomers with the carbonyl group trans to

the more-electron-rich dicyclohexylphosphanyl group,

whereas a 2:1 isomeric mixture was observed for the Josi-

phos complex (18), thereby clearly indicating the influence

of the CF₃group on the electronic properties of the corre-

sponding phosphanyl group. The CO stretching frequencies,

n₁(CO), for these complexes show a clear trend with the

lowest value (1985 cm^À1) for complex 18 and the highest

In the neutral complex (16), a much shorter Rh1 P1 bond

compared to Rh P2 is observed (2.1899(6) ꢃ vs.

2.3710(6) ꢃ). However, in the dicarbonyl complex (21), the

opposite is the case, thus reflecting the different electronic

natures of the ligands trans to P1 (Cl in 16 vs. CO in 21).

The C O bond length in 16 is slightly longer than that ob-

served in similar complexes but a meaningful comparison is

hampered by the relatively large standard deviations usually

observed for CO distances.^[11]Both complexes display simi-

lar ligand distortions to the PdCl₂derivatives described

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A. Togni et al.

Table 3. Rhodium-catalyzed hydrogenation of methyl a-acetamido acry-

late with the P-stereogenic trifluoromethylphosphane ligands.

above, the distortion being more pronounced for 16, which

contains the endo-axial CF₃group (deviation of the P atom

from the Cp plane by 0.48 ꢃ vs. 0.34 ꢃ for 21).

Catalysis: The trifluoromethylphosphanes were tested in the

rhodium-catalyzed hydrogenation of dimethyl itaconate

(DMI) and methyl a-acetamidoacrylate (MAA) as model

substrates. For DMI, trifluoroethanol was superior to the

more-commonly used solvents for hydrogenation reactions

such as methanol or dichloromethane. With the exception of

the bulky adamantyl-substituted ligands 10, all trifluorome-

thylphosphanes tested were found to be highly active ligands

and gave turnover frequencies (TOF) of up to 6000 h^À1

(Table 2). Five ligands achieved more than 95% enantio-

[b]

Entry

Conv. [%]^[a]

TOF [h^À1

]

ee [%]^[c]

>99

4000

6000

3000

6000

88 (R)

91 (R)

97 (R)

>99 (R)

88 (R)

98 (R)

(S_P)-9

(R_P)-9

[a] Determined by GC analysis. [b] Determined by plotting the H₂-con-

sumption vs. time. [c] Determined by chiral GC analysis.

The palladium-catalyzed asymmetric allylic alkylation

(AAA) is one of the most-popular reactions for the enantio-

Table 2. Rhodium-catalyzed hydrogenation of dimethyl itaconate with

the P-stereogenic trifluoromethylphosphane ligands.

[12]

selective formation of C C bonds and is very often used

in the profiling of new ligands. Ferrocenyl ligands have been

shown to lead to high activities and selectivities in allylic

substitution reactions.^[2,13]Therefore, it was an obvious step

to test our ligands in the palladium-catalyzed reaction of

1,3-diphenylallyl compounds with dimethyl malonate, a re-

[b]

Entry

Conv. [%]^[a]

TOF [h^À1

]

ee [%]^[c]

1^[d]

>99

n.d.^[e]

5450

6000

5450

6000

3000

4000

n.d.^[e]

77 (S)

81 (S)

99 (S)

98 (S)

>99 (S)

95 (S)

97 (S)

49 (S)

15 (R)

action that is very commonly used as

(Table 4).

a benchmark

(S_P)-9

(R_P)-9

(S_P)-10

Table 4. Palladium-catalyzed asymmetric allylic alkylation of 1,3-diphe-

nylallyl acetate using P-stereogenic trifluoromethylphosphane ligands.

8^[d]

9^[d]

[a] Determined by HPLC or ¹H NMR spectroscopic analysis. [b] Deter-

mined by plotting the H₂-consumption vs. time. [c] Determined by chiral

HPLC analysis. [d] 1 mol% [RhACHTNUTRGNE(UNG cod)₂]PF₆and 1.1 mol% of L were used.

[e] n.d.=not determined. nbd=2,5-norbornadiene, cod=1,8-cycloocta-

diene.

Entry

Yield [%]^[a]

ee [%]^[b]

1^[c]

OAc

>99

80 (S)

92 (S)

77 (S)

90 (S)

82 (S)

88 (S)

59 (R)

13 (S)

95 (R)

92 (R)

94 (S)

2^[c]

3^[c]

4^[c]

meric excess, with the isopropyl-substituted ligand 3e being

the best, providing more than 99% ee. The influence of the

absolute configuration at the phosphane center turned out

to be rather modest and very similar enantioselectivities

were obtained with (S_P)-9 and (R_P)-9 (Table 2, entries 6 and

7). With the bulkier ligands 10, this influence becomes more

important, resulting in a switch in absolute configuration of

the major enantiomer, though in both cases the enantiose-

lectivities were rather low (Table 2, entries 8 and 9).

5^[c]

(S_P)-9

(R_P)-9

(S_P)-12

(R_P)-12

(S_P)-13

6^[c]

OAc

7^[d]

8^[d]

9^[d]

10^[d]

11^[d]

OCO₂Et

AHCTUNGTRENNUNG

[a] Yield of isolated product after column chromatography on silica gel.

[b] Determined by chiral HPLC analysis. [c] Standard conditions for the

reaction with 1,3-diphenylallyl acetate: 0.5 mol% [Pd₂ACHTUNGTREN(GNU h₃-C₃H₅)₂Cl₂],

The ligands also afforded high activities in the hydrogena-

tion of MAA as shown in Table 3. All of the ligands tested

provided equal or better enantioselectivities than the parent

Josiphos (88% ee),^[2]thus emphasizing the potential for this

class of phosphanes in olefin hydrogenation. The twofold P-

stereogenic ligand 3e was again the best in terms of selectiv-

ity, providing more than 99% ee, which ranks this ligand

among the best for this type of asymmetric catalysis

(Table 3, entry 4). With MAA, a more-pronounced effect of

the absolute configuration of the phosphorus atom on selec-

tivity is apparent. Thus, (R_P)-9 outperformed its S_Pisomer

by 10% ee and achieved the second-highest result in our

screening (98% ee; Table 3, entries 5 and 6).

1 mol% L, 2 equiv malonate, 2 equiv BSA, 5 mol% KOAc, 2 h. [d] Stan-

dard conditions for the reaction with ethyl 1,3-diphenylallyl carbonate:

1.5 mol% [Pd₂ACHTNUGTRENUNG(dba)₃], 4.5 mol% L, 2 equiv malonate, 16 h. BSA=N,O-

Bis(trimethylsilyl)-acetamide, dba=trans,trans-dibenzylideneacetone.

The high selectivities obtained in the hydrogenation pro-

cesses were not matched by the results achieved in the

AAA reaction, though high activities were obtained with all

of the ligands tested. Of the diphosphanes, only the two iso-

propyl-substituted ligands 3c and 3e provided ee values

above 90% (Table 4, entries 2 and 4). Therefore, the pyra-

zolyl ligands 9, 12, and 13 were tested under our slightly

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Chem. Eur. J. 2012, 18, 632 – 640

P-Stereogenic Trifluoromethyl Derivatives of Josiphos

FULL PAPER

modified, previously reported conditions.^[14](S_P)-12 and

(R_P)-12, which contain small substituents in the 3- and 5-po-

sitions of the pyrazolyl unit, provided only low selectivities

and showed a large influence of the absolute configuration

of the phosphane (Table 4, entries 7 and 8). Ferrocenyl li-

gands 13, which contained an adamantyl-substituted pyra-

zole group, afforded high enantioselectivities of up to 95%,

thus indicating the importance of a large substituent at the

3-position of the pyrazole. Whereas the absolute configura-

tion of the stereogenic phosphanyl group in 13 had nearly

no impact on the selectivity of the AAA, the stereogenic

carbon center bearing the pyrazolyl unit affected the stereo-

chemical outcome of the reaction very significantly (Table 4,

entries 9–11). Indeed, the use of (R_P,S_C)-13 yielded the (R)-

configured product in 92% ee, but the epimer (R_P,R_C)-13 af-

forded the (S)-product in 94% ee. That the absolute config-

uration of the pseudo benzylic center in ferrocenyl ligands

derived from Ugiꢀs amine may significantly influence the

enantioselectivity of corresponding catalytic reactions is not

unprecedented.^[15]However, the extent of this effect as ob-

served here is surprisingly high.

Experimental Section

General considerations: Starting materials and methods are described in

the Supporting Information. The indices Fc and P1/P2 associated with

CIP absolute configuration descriptors stand for ferrocene planar chirali-

ty and central phosphorus chirality, respectively. P1 is the phosphorus

atom directly attached to the ferrocene, P2 the one on the side chain.

When assigning the absolute configuration of P1, note that the cyclopen-

tadiene carbon has a higher CIP priority than the CF₃group because it is

attached to the Fe atom.

Compound 6: At À788C 1.3m sBuLi (6.8 mL, 8.881 mmol, 1.1 equiv) was

added dropwise to a solution of (R)-[1-(dimethylamino)ethyl]ferrocene

(2076 mg, 8.073 mmol, 1 equiv) in Et₂O (50 mL). The orange solution

was slowly warmed to room temperature and stirred at ambient tempera-

ture for 1 h. The red mixture obtained was cooled to 08C and added to a

solution of phenyltrifluoromethylphosphane (4a; 1195 mg, 4.037 mmol,

0.5 equiv) in Et₂O (5 mL) over a period of 60 min. The resulting dark-

brown mixture was allowed to warm to room temperature overnight. The

mixture was then diluted with Et₂O and H₂O, the organic layer separat-

ed, and the aqueous phase extracted with Et₂O. The combined organic

phases were dried over MgSO₄and the solvent evaporated in vacuo. The

obtained crude dark oil was purified by flash chromatography on silica

gel (n-pentane/EtOAc/Et₃N 100:2:3) to yield the two isomers in the first

two colored fractions.

(S_P)-6: Yield: 717 mg (41%), brown crystalline solid. ¹H NMR

(300 MHz, CDCl₃): d=1.15 (d, ³J

ACHTUNGTRENNUNG

6H; NMe₂), 4.17 (q, ³J

ACHTUNGTRENNUNG

4.42 (bs, 2H; Cp), 4.65 (s, 1H; Cp), 7.24–7.34 (m, 3H; Ph), 7.44 ppm (t,

Conclusions

J=7.8 Hz, 2H; Ph); ¹³C{¹H} NMR (75 MHz, CDCl₃): d=7.32 (s; CHMe),

37.70 (s; NMe₂), 57.81 (d, ³J

ACHTUNGTRENNUNG

We have shown that the CF₃group of bis(trifluoromethyl)-

phosphanes can act as a leaving group and thus may be sub-

stituted in intra- and intermolecular fashions. Based on this

type of reactivity we have developed a facile synthesis of

ferrocenyl P^P and P^N ligands containing a P-stereogenic

trifluoromethylphosphanyl group. In general, both stereoiso-

mers of the ligands may be obtained in moderate to good

overall yields and are easily separated by column chroma-

tography on silica gel. The coordination behavior of the di-

phosphane ligands to palladium and rhodium was studied by

means of X-ray analysis and the electronic properties of the

trifluoromethylphosphanes were investigated by means of

rhodium–carbonyl complexes. The relatively high CO

stretching frequencies observed for such complexes demon-

strate the strongly electron-withdrawing character of a

single CF₃group.

(d, J

ACHTUNGTRENNUNG

AHCTUNGTRENNUNG

132.22 ppm (qd, ¹J(C,F)=323.6 Hz, ¹J

ACTHNUGTRENNUGN ACHTUNGTRENNNUG

(282 MHz, CDCl₃): d=À54.48 ppm (d, ²J

ACHTUNGTRENNUNG

(121 MHz, CDCl₃): d=À16.74 ppm (q, ²J

ACHTUNGTRENNUNG

mental analysis calcd (%) for C₂₁H₂₃F₃FeNP: C 58.22, H 5.35, F 13.16,

N 3.23, P 7.15; found: C 58.19, H 5.53, F 13.28, N 3.21, P 7.07; HRMS

(MALDI): m/z calcd for C₂₁H₂₃F₃FeNP: 433.0865 [M⁺+H]; found:

433.0864, 388.0285 [M⁺ÀNMe₂], 319.0332 [M⁺ÀNMe₂ÀCF₃].

(R_P)-6: Yield: 885 mg (51%), brown crystalline solid. ¹H NMR

(300 MHz, CDCl₃): d=1.31 (d, ³J

ACHTUNGTRENNUNG

AHCTUNGTRENNUNG

CHMe), 4.38–4.43 (m, 2H; Cp), 4.45 (s, 1H; Cp), 7.48–7.56 (m, 3H; Ph),

7.96–8.04 ppm (m, 2H; Ph); ¹³C NMR (75 MHz, CDCl₃): d=9.64 (s;

CHMe), 39.38 (s; NMe₂), 56.57 (d, ³J

ACHTUNGTRENNUNG

The potential of the diphosphane ligands was demonstrat-

ed in the rhodium-catalyzed asymmetric hydrogenation of

DMI and MAA, where high activities and enantioselectivi-

ties of up to >99% ee were obtained. These experiments

clearly indicate that the formal replacement of a phenyl

group by CF₃in the parent Josiphos structure may lead to

new ligands with enhanced performance in catalytic reac-

tions. Further investigations addressing the use of these new

ligands in a variety of other catalytic reactions, as well as

mechanistic and structural studies highlighting the subtle

role of the trifluoromethyl group are part of ongoing re-

search in our group.

ACHTUNGTRENNUNG

AHCTUNGTRENNUNG

ACHTUNGTRENNUNG

ACHUTNGRENNUG CAHTUNGTRENNUNG

(C,F)=324.1 Hz, ¹J

d=À55.17 ppm (d, ²J

ACHTUNGTRENNUNG

d=À13.53 ppm (q, ²J

ACHTUNGTRENNUNG

(%) for C₂₁H₂₃F₃FeNP: C 58.22, H 5.35, F 13.16, N 3.23, P 7.15; found:

C 58.05, H 5.52, F 13.34, N 3.23, P 7.12; HRMS (MALDI): m/z calcd for

C₂₁H₂₃F₃FeNP: 433.0865 [M⁺+H]; found: 433.0875, 418.0633 [M⁺ÀMe],

389.0363 [M⁺ÀNMe₂]; 364.0912 [M⁺ÀCF₃]; 319.0337 [M⁺ÀNMe₂ÀCF₃].

Compound (S_P)-7: At À788C 1.3m sBuLi (6.6 mL, 8.678 mmol, 1.1 equiv)

was added dropwise to a solution of (R)-[1-(dimethylamino)ethyl]ferro-

cene (2029 mg, 7.889 mmol, 1 equiv) in Et₂O (15 mL). The orange solu-

tion was slowly warmed to RT and stirred for 1 h. The red mixture thus

obtained was cooled to À788C and was then added over a period of

30 min to

a solution of 1-adamantyltrifluoromethylphosphane (4b;

680 mg, 2.296 mmol, 0.5 equiv) in Et₂O (3 mL) at À788C. The resulting

dark-brown mixture was allowed to warm to room temperature over-

night. The mixture was then diluted with Et₂O and H₂O, the organic

Chem. Eur. J. 2012, 18, 632 – 640

ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

637

A. Togni et al.

layer separated, and the aqueous phase extracted with Et₂O. The com-

bined organic phases were dried over MgSO₄and the solvent evaporated

under vacuum. The crude dark oil was purified by column chromatogra-

phy on silica gel (n-pentane/EtOAc/Et₃N 100:2:3) to yield the product in

the first colored fraction. The S configuration was confirmed by X-ray

crystallography. Yield: 671 mg (35%), brown crystalline solid. ¹H NMR

(S_P)-10: Yield: 113 mg (43%), orange crystalline solid. ¹H NMR

(300 MHz, C₆D₆): d=1.19–2.04 (m, 34H; PCy₂, Ad), 1.66 (dd, ³J

7.2 Hz, J

³J(H,H)=7.0 Hz, ²J

ACTHNUGTRENNUGN ACHTUNGTRENNNUG

(s, 5H; Cp’), 4.38 (bs, 1H; Cp), 4.47 ppm (bs, 1H; Cp); ¹⁹F NMR

(282 MHz, C₆D₆): d=À46.28 ppm (d, ²J

ACHTUNGTRENNUNG

(121 MHz, C₆D₆): d=5.46 (qd, ²J

ACTHNUTRGENN(GU P,F)=64.0 Hz, JACHTNUGTRENNUNG

(300 MHz, C₆D₆): d=1.08 (d, ³J

ACTHNUTRGNEU(GN H,H)=6.7 Hz, 3H, CHMe), 1.58 (bs,

PAdCF₃), 12.60 ppm (d, JACHTNUGRTENUNG(P,P’)=32.8 Hz; PCy₂); elemental analysis calcd

6H; Ad), 1.69–1.85 (m, 6H; Ad), 2.01 (s, 6H; NMe₂), 2.04–2.08 (m, 3H;

(%) for C₃₅H₄₉F₃FeP₂(491.36): C 65.22, H 7.66, F 8.84, P 9.61; found:

C 65.24, H 7.71, F 8.91, P 9.57; HRMS (MALDI): m/z calcd for

C₃₅H₅₀F₃FeP₂: 645.2684 [M⁺+H]; found: 645.2692, 447.1150 [M⁺ÀPCy₂].

Ad), 3.89 (qd, J

Cp’), 4.13 (t, J

(62.9 MHz, C₆D₆): d=8.18 (s; CHMe), 29.26 (d, J

36.15 (dq, ¹J(C,P)=17.0 Hz, ³J

(C,F)=2.0 Hz; Ad), 37.03 (d, J

1.0 Hz; Ad), 39.19 (s; NMe₂), 39.99 (dq, ²J(C,P)=11.0 Hz, ⁴J

1.3 Hz; Ad), 56.47 (d, ³J

(C,P)=8.5 Hz; CHMe), 69.10 (dd, J(C,P)=21.7,

3.4 Hz; Cp), 69.13 (d, J(C,P)=5.5 Hz; Cp), 69.61 (s; Cp), 70.51 (s; Cp’),

72.42 (d, (C,P)=28.9 Hz; Cp),

(C,P)=7.0 Hz; Cp), 99.01 (d, ²J

(C,P)=44.8 Hz; CF₃); ¹⁹F NMR

(F,P)=61.1 Hz; CF₃); ³¹P NMR

ACHTUNGTRENNUNG

AHCTUNGTRENNUNG

(R_P)-10: Yield: 38 mg (15%), orange crystalline solid. ¹H NMR

ACHTUNGTRENNUNG

(300 MHz, C₆D₆): d=1.22–2.05 (m, 31H; PCy₂, Ad), 1.70 (dd, ³J

ACHTUNGTRENNUNG(H,H)=

ACHTUNGTRENNUNG

7.0, JACTHNUGTRENNUG(H,P)=5.7 Hz, 3H; CHMe), 2.41 (bs, 6H; Ad), 3.26 (qd, JACHTUNGTRENNUNG(H,H)=

7.3 Hz, JACTHNGUTERN(UNG H,P)=3.0 Hz, 1H; CHMe), 4.23 (s, 6H; Cp, Cp’), 4.37 (bs, 1H;

Cp), 4.57 ppm (bs, 1H; Cp); ¹⁹F NMR (282 MHz, C₆D₆): d=À47.59 ppm

(dd, ²J (F,P’)=15.5 Hz; CF₃); ³¹P NMR (121 MHz,

ACTHNUTRGENN(GU F,P)=54.8 Hz, JACHTNUGTRENNUNG

134.05 ppm (qd, ¹J(C,F)=323.4 Hz, ¹J

ACHTUNGTRENNUNG ACHTUNGTRENNUNG

C₆D₆): d=10.27 (qd, ²J

13.71 ppm (dq, (P,P’)=40.2 Hz,

ACHUTGTNREN(UNG P,F)=55.0 Hz, JACHTNUGTRENNUNG

(282 MHz, C₆D₆): d=À45.60 ppm (d, ²J

ACHTUNGTRENNUNG

JACHTUNGTRENNUNG

(121 MHz, C₆D₆): d=8.49 ppm (q, J

(MALDI): m/z calcd for C₃₅H₅₀F₃FeP₂: 645.2684 [M⁺+H]; found:

645.2692, 661.2620 [M⁺+OH].

analysis calcd (%) for C₂₅H₃₃F₃FeNP: C 61.11, H 6.77, F 11.60, N 2.85,

P 6.30; found: C 61.15, H 6.83, F 11.54, N 2.84, P 6.38; HRMS (EI): m/z

calcd for C₂₅H₃₃F₃FeNP: 491.1647 [M⁺]; found: 491.1641, 446.1070

[M⁺ÀNMe₂], 422.1696 [M⁺ÀCF₃].

Compound (S_P)-12: Compound (S_P)-6 (200 mg, 464 mmol, 1 equiv) and

3,5-dimethylpyrazole (67 mg, 696 mmol, 1.5 equiv) were dissolved in 1 mL

degassed AcOH and TFA (36 mL, 464 mmol, 1 equiv) was added. The

mixture was heated to 908C and stirred at this temperature for 20 h. The

solvent was then removed under reduced pressure and the residue dilut-

ed with Et₂O and saturated aqueous NaHCO₃solution. The organic layer

was separated and the aqueous phase extracted with Et₂O. The combined

organic phases were dried over MgSO₄and the solvent evaporated in

vacuo. The residue was purified by column chromatography on silica gel

(n-pentane/EtOAc/Et₃N 100:2:3 to 100:5:3) to yield the product as a

Compound (S_P)-9: Compound (S_P)-6 (378 mg, 873 mmol, 1 equiv) and di-

cyclohexylphosphane (211 mL, 1047 mmol, 1.2 equiv) were dissolved in

1 mL degassed acetic acid (AcOH), heated to 908C, and stirred at this

temperature for 13 h. The solvent was then removed under reduced pres-

sure and the residue diluted with Et₂O and saturated aqueous NaHCO₃

solution. The organic layer was separated and the aqueous phase extract-

ed with Et₂O. The combined organic phases were then dried over MgSO₄

and the solvent evaporated in vacuo. The residue was purified by column

chromatography on silica gel (n-pentane/EtOAc 100:1) to yield the oxi-

dation-sensitive product as a single isomer. Yield: 389 mg (76%), orange

crystalline solid. ¹H NMR (300 MHz, CD₂Cl₂): d=0.61–1.78 (m, 22H;

single isomer. Yield: 155 mg (70%), orange powder. H NMR (300 MHz,

CDCl₃): d=1.75 (d, ³J

ACHTUNGTRENNUNG

PCy₂), 1.51 (dd, J=7.1, 4.1 Hz, 3H; CHMe), 3.17 (q, ³J

ACTHNUGRTENUNG(H,H)=6.9 Hz,

(m, 1H; Cp), 4.96 (s, 1H; Pz), 5.57 (qd, JACTHNUTRGNEU(GN H,H)=6.9 Hz, J=2.2 Hz, 1H;

CHMe), 7.01 (t, J=7.6 Hz, 1H; Ph), 7.09 (td, J=7.6, 1.5 Hz, 2H; Ph),

7.21 ppm (t, J=7.3 Hz, 1H; Ph); ¹³C NMR (75 MHz, CDCl₃): d=11.30

1H; CHMe), 4.24 (s, 5H; Cp’), 4.41–4.48 (m, 2H; Cp), 4.56 (bs, 1H; Cp),

7.17–7.34 (m, 3H; Ph), 7.44 ppm (t, J=7.3 Hz, 1H; Ph); ¹⁹F NMR

(d, J

³J

(C,P)=8.5 Hz; CHMe), 67.38–67.56 (m; Cp), 70.10 (s; Cp), 70.44 (s;

Cp’), 70.84 (d, J

(C,P)=5.1 Hz; Cp), 71.60–71.91 (m; Cp), 93.86 (d, ²J-

(C,P)=26.0 Hz; Cp), 104.84 (s; Pz), 127.42 (d, J(C,P)=7.7 Hz; Ph),

129.13–129.40 (m; Ph), 129.43 (s; Ph), 131.12 (qd, ¹J(C,F)=320.5 Hz, ¹J-

ACHTUNGTREN(NUNG C,P)=5.7 Hz; CHMe), 13.33 (s; MePz), 19.87 (s; MePz), 53.10 (d,

(282 MHz, CD₂Cl₂): d=À53.36 ppm (dd, ²J

ACHUTGTNREN(UNG F,P)=65.3 Hz, JACHTNUGTRENNUNG

AHCTUNGTRENNUNG

4.3 Hz; CF₃), ³¹P NMR (121 MHz, CD₂Cl₂): d=À17.37 (dq, J

ACHTUNGTRENNUNG

AHCTUNGTRENNUNG

78.4 Hz, ²J

ACHTUNGTRENNUNG(P,F)=65.5 Hz; PPhCF₃), 16.53 ppm (d, JACHTUNGTNER(NUNG P,P’)=78.2 Hz;

ACHTUNGTRENNUNG

PCy₂); elemental analysis calcd (%) for C₃₁H₃₉F₃FeP₂: C 63.49, H 6.70, F

9.72, P 10.56; found: C 63.03, H 6.68, F 9.87, P 10.49; HRMS (MALDI):

m/z calcd for C₃₁H₄₀F₃FeP₂: 587.1901 [M⁺+H]; found: 587.1903, 389.0354

[M⁺ÀPCy₂].

AHCTUNGTRENNUNG

ACHUTNGERNNU(G C,P)=25.8 Hz; CF₃), 133.16 (d, JAHCTUNGTRENN(UGN C,P)=20.2 Hz, Ph), 136.71 (s; MePz),

146.78 ppm (s; MePz); ¹⁹F NMR (282 MHz, CDCl₃): d=À54.17 ppm (d,

²J

ACHTUNGTRENNUNG

Compound (R_P)-9: Compound (R_P)-6 (304 mg, 702 mmol, 1 equiv) and

dicyclohexylphosphane (170 mL, 842 mmol, 1.2 equiv) were dissolved in

1 mL degassed AcOH, heated to 908C, and stirred at this temperature

for 13 h. The solvent was then removed under reduced pressure and the

residue dissolved in 3 mL of hot EtOH. Cooling to À188C gave the oxi-

dation-sensitive product as orange crystals. Yield: 340 mg (83%), orange

crystalline solid. ¹H NMR (300 MHz, CD₂Cl₂): d=1.06–1.83 (m, 22H;

PCy₂), 1.55 (dd, J=6.9, 4.9 Hz, 3H; CHMe), 3.11–3.21 (m, 1H; CHMe),

3.71 (s, 5H; Cp’), 4.39 (bs, 1H; Cp), 4.44 (bs, 1H; Cp), 4.57 (bs, 1H; Cp),

7.46–7.56 (m, 3H; Ph), 7.99 ppm (t, J=8.3 Hz, 1H; Ph); ¹⁹F NMR

AHCTUNGTREGN(NUN P,F)=69.3 Hz; PPhCF₃); elemental analysis calcd (%) for

C₂₄H₂₄F₃FeN₂P: C 59.52, H 4.99, F 11.77, N 5.78, P 6.40; found: C 59.69,

H 5.10, F 11.88, N 5.76, P 6.43; HRMS (MALDI): m/z calcd for

C₂₄H₂₅F₃FeN₂P: 485.1051 [M⁺+H]; found: 485.1056, 501.1004 [M⁺+OH],

389.0365 [M⁺ÀPz].

Compound (R_P)-12: Compound (R_P)-6 (200 mg, 464 mmol, 1 equiv) and