Development of P- And N-Chirogenic Ligands Based on Chiral Induction from a Phosphorus Donor to a Nitrogen Donor in Palladium Complexes

Takahiro Iwamoto,* Yoshiyuki Mizuhata, Norihiro Tokitoh, and Masaharu Nakamura

Communication

Development of P- and N‑Chirogenic Ligands Based on Chiral

Induction from a Phosphorus Donor to a Nitrogen Donor in

Palladium Complexes

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sı Supporting Information

ABSTRACT: We herein designed and synthesized amino-phosphine ligands 1a−

c, which bear a P-chirogenic group, (R)-PtBuMe, and an N-group (NHR) on the

pyridylene backbone, as a novel class of chiral ligands possessing chirogenic

donors. Ligand 1a (R = Me) stereoselectively coordinated with PdCl₂to

predominantly aﬀord the P- and N-chirogenic metal complex 4a having an R ,S

conﬁguration. In contrast, ligands 1b (R = iPr) and 1c (R = tBu) produced a

mixture of diastereomers derived from two possible N-centered conﬁgurations. In

complex 4a, the N-centered conﬁguration was eﬃciently controlled by the P-

chirogenic center via through-space attractive interactions between P-tBu and N-

Me. Buried volume analysis indicated that this novel ligand creates a unique C₁-

symmetric chiral environment derived from both steric and electronic asymmetry.

n the ﬁeld of transition-metal-catalyzed asymmetric

reactions, the development of eﬃcient chiral ligands is a

central subject; thus, numerous types of chiral ligands have

been reported to date. Chiral ligands possessing chirogenic

donors represent a unique class of compounds that can create a

proximal chiral environment around the metal center. As

representative examples, P-chirogenic ligands have been widely

studied due to their eﬀectiveness in a variety of asymmetric

reactions.

In analogy with phosphines, amines can also serve as

chirogenic donors, and tremendous studies on N-chirogenic

compounds have been performed so far. Although the

nitrogen center usually undergoes fast inversion and thus, is

Figure 1. Metal complexes coordinated with a chiral ligand bearing

N-chirogenic donors.

conﬁgurationally labile (with the exception of amines bearing a

rigid structure), metal coordination increases the inversion

barrier to allow the formation of a stable chirogenic nitrogen

center. Consequently, control of the N-centered conﬁguration

upon metal coordination is crucial for the catalytic perform-

on the hypothesis that the N-centered conﬁguration would be

controlled by the P-chirogenic center with the help of through-

space interactions between the P- and N-substituents (Figure

ance of this type of metal complex. Previous reports have

b). To date, several chiral amino-phosphine ligands

mainly focused on systems bearing a stereogenic carbon center

possessing P-chirogenic centers have been reported, although

to the best of our knowledge, the present ligand design, namely

chiral induction from one chirogenic donor to a nitrogen

donor without the presence of any other chiral source, has yet

4a−d,5

adjacent to a nitrogen atom (Figure 1a).

, Such carbon

centers eﬃciently transfer their stereochemical information to

the nitrogen center upon metal coordination thanks to the

proximity between the groups. This strategy has been validated

with various levels of success, although it remains a challenge

to control such N-centered conﬁgurations, particularly in the

absence of a N-adjacent stereogenic carbon center in the ligand

scaﬀold.

Received: March 3, 2020

In this context, we designed a novel chiral amino-phosphine

ligand, which bears a P-chirogenic group and an N-group on a

,2-arylene backbone (Figure 1b). Our ligand design is based

XXXX American Chemical Society

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Organometallics

Communication

to be explored. However, we expect that such a system would

have several advantages. For example, two kinds of chirogenic

donors can be generated from a single chiral source.

Furthermore, the aromatic backbone would enable construc-

tion of a rigid chiral environment, wherein the rigidity of the

ligand backbone has already proven to be an important factor

Scheme 2. Coordination Study with Pd(cod)Cl₂

to attaining high selectivities in asymmetric reactions. We

herein report the synthesis of such chiral amino-phosphine

ligands, and their coordination studies with palladium metal as

a model case to elucidate the N-centered conﬁguration

generated upon metal coordination.

Imamoto et al. previously reported the development of

various bisphosphine ligands possessing the chirogenic

PtBuMe unit wherein they employed a phosphine−borane,

Estimated by H- H NOESY.

(

S)-PtBuMeH·BH , as a key precursor. This phosphine−

borane can also be readily introduced into an electron-deﬁcient

N-containing aromatic core to produce air-stable chiral

phosphine ligands. Inspired by these reports, we selected

group is oriented syn relative to the tBu group on the

phosphorus atom. Because of the S_Pconﬁguration of the

phosphine, the conﬁguration of the nitrogen center would be

the PtBuMe group as a chirogenic phosphorus group and

pyridine as a ligand backbone. Importantly, we anticipated that

the P-tBu group would be suﬃciently large to take part in

through-space interactions with the N-substituent. On the

basis of such a ligand design, N-substituents such as Me, iPr,

and tBu were examined for their ability to control the

conﬁguration of the nitrogen center.

Thus, the target amino-phosphines were readily prepared

from the commercially available 3-amino-2-chloropyridine

Scheme 1). Alkylation of the amine group provided alkyl-

R .

In contrast, ligands 1b and c formed a mixture of two

isomeric complexes in molar ratios of 68:32 and 80:20,

respectively. In complex 4b, the major and minor species were

assigned as the R ,S and S ,S isomers, respectively, on the

basis of the H− H NOESY spectrum. Variable-temperature

NMR studies revealed that coalescence of the signals derived

from each isomer was observed at ca. 135 °C. After the

solution was recooled, the obtained spectrum was comparable

to that of the crude complex (for details, see the Supporting

Information ). These results indicated that the nitrogen center

rapidly underwent inversion on the NMR time scale at ca. 135

(

Scheme 1. Syntheses of the P-Chirogenic Amino-Phosphine

Ligands

C, and the diastereomeric ratio observed in solution was

thermodynamically determined.

Unfortunately, the structure of complex 4c could not be fully

elucidated by NMR spectroscopy due to the similar chemical

shifts of the signals derived from the P-Me and P-tBu groups.

It should also be noted here that, when an excess of ligand

c was employed, the formation of a new species was observed.

On the basis of an X-ray crystallographic analysis, the structure

of this new species was determined to be the complex

PdCl (1c) , in which two phosphorus atoms are coordinated

to Pd without coordination of the nitrogen atom (see the

Supporting Information ). A similar κ -P coordination mode

substituted compounds 2. Lithium phosphide, prepared by the

has been well documented in various amino-phosphine

deprotonation of (S)-PtBuMeH·BH with BuLi, was smoothly

ligands.

reacted with compounds 2 to aﬀord borane-protected

The structures of the complexes in the solid state were

unambiguously determined by X-ray crystallographic analysis

compounds 3. After deprotection, the desired (R )-amino-

phosphines were obtained in good yields.

(Figure 2). In complex 4a, the phosphorus and nitrogen

With these ligands in hand, we then examined the syntheses

of palladium complexes by ligand exchange with Pd(cod)Cl₂

atoms coordinated toward palladium to form a slightly

distorted square planar palladium complex (∑° = 360°).

(

Scheme 2). Thus, ligands 1a−c were treated with 1 equiv of

In good agreement with the NMR results, the N-Me group was

located syn relative to the P-tBu group; the complex exhibited

an R_Nconﬁguration at the nitrogen center and an S_P

conﬁguration at the phosphorus atom. Another characteristic

point is that the Pd−Cl bond trans to the phosphine (2.402(3)

Å) is longer than that of the Pd−Cl bond trans to the nitrogen

atom (2.286(3) Å). This diﬀerence in bond lengths results

from the large trans inﬂuence of the phosphorus atom in

comparison to that of nitrogen.

Pd(cod)Cl in CH Cl . Subsequently, diethyl ether or hexane

was added, and the resulting pale yellow solid was collected to

provide the desired complexes in yields of 93−96%.

Characterization of the complex structures was ﬁrst

attempted by NMR spectroscopy using CDCl as a solvent.

In the case of complex 4a, the obtained H and P NMR

spectra showed two sets of signals in a ratio of 98:2, implying

that a single diastereomer was formed with high selectivity.

Furthermore, in the H− H NOESY spectrum, a cross peak

was observed between the proton signals of the N-Me and P-

tBu moieties, and so we tentatively concluded that the N-Me

Similar structural features were also observed in complexes

4b and c. Each crystal contained only one isomer, which

exhibited the R conﬁguration at the nitrogen center. Again, a

Organometallics XXXX, XXX, XXX−XXX

Organometallics

addition, moderate steric constraint is observed in the lower

Communication

Figure 3. Complex structures, space-ﬁlling models, and NCI plots of

the (a) R ,S and (b) S ,S isomers of 4a optimized by DFT

calculations at B3LYP/GD3BJ using the 6-31G* functional for C, H,

N, P, and Cl and using LanL2DZ for Pd. Color code: H, light gray; C,

gray; N, purple; P, orange; Pd, red; Cl, green.

Similar interactions between P-tBu and the N-substituent are

observed in the NCI plots of complexes 4b and c , which

exhibit the R ,S conﬁguration (for details, see the Supporting

Information ). However, in the opposite diastereomer of each

complex, namely the S ,S isomer, dispersion interactions

between P-Me and the N-substituent are suggested. Thus,

interactions between the P- and N-substituents occur in both

diastereomers in the cases of complexes 4b and c. This may

account for the low selectivity of the N-centered conﬁgurations

in complexes 4b and c in comparison with that of complex 4a.

Moreover, signiﬁcant structural deformation around the

phosphorus and/or palladium atoms is suggested in R ,S

isomers 4b and c, probably due to the steric repulsion

associated with the bulkiness of the N-iPr and -tBu groups (for

details, see Figure S3 in the Supporting Information). It

therefore appears that this structural deformation also causes

Figure 2. X-ray structures of complexes (a) 4a, (b) 4b, and (c) 4c

with thermal ellipsoids at 50% probability. Hydrogen atoms are

omitted for clarity. Bond lengths are given in Å. Color code: C, gray;

P, orange; Pd, blue; Cl, green; N, purple.

longer Pd−Cl bond length was also observed trans to the

phosphine.

To obtain insight regarding the highly selective generation of

a single diastereomer in the case of complex 4a, DFT

destabilization of the R conﬁguration in complexes 4b and c.

Thus, the N-Me group appears to have an appropriate size for

interaction with the P-tBu group in the R ,S isomer without

calculations were performed (Figure 3). The R ,S isomer is

any signiﬁcant structural deformation.

Finally, the chiral environment in complex 4a was evaluated

found to be more stable than the S ,S isomer with a ΔG value

of 1.8 kcal/mol, in good agreement with the NMR results. In

using the SambVca 2.0 tool, which describes the topological

the R ,S isomer, the N-Me moiety is fairly close to the P-tBu

steric map (Figure 4). The upper left quadrant, which is

group, as shown by a space-ﬁlling model. The distance of the

closest hydrogen atoms of the N-Me and P-tBu moieties is

occupied by N−H, is obviously sterically unencumbered. In

.395 Å, suggesting a dispersion interaction between the two

groups. In contrast, no signiﬁcant interaction was observed

between the P- and N-substituents in the S ,S isomer (Figure

b).

Further evaluation of the dispersion interaction between the

N- and P-substituents was performed using an NCI plot, which

is able to visualize noncovalent interactions. More speciﬁ-

cally, weak yet distinct interactions are observed between the

P-tBu and N-Me groups in the R ,S isomers, as shown by the

green isosurface. Other multiple interactions are also observed:

for example, P-tBu/P-Me, P-Me/Cl, and P-tBu/Cl. However,

these interaction patterns resemble those observed in the S ,S

isomer, except for that between the N-Me and P-tBu groups.

Hence, the dispersion interactions between the N-Me and P-

Figure 4. Buried volume analysis of complex 4a carried out using

SambVca 2.0. Values in parentheses are the buried volume

percentages of the various quadrants.

tBu moieties likely contribute to the preferred R conﬁguration

of the nitrogen center.

Organometallics XXXX, XXX, XXX−XXX

Organometallics

https://pubs.acs.org/10.1021/acs.organomet.0c00154

Communication

left quadrant, where the N-Me group is located. The value of

the buried volume on the lower left quadrant falls between that

of the upper right (P-Me) and the lower right (P-tBu)

quadrants. Thus, the steric constraint increases in the order

NM (N-H) < NE (P-Me) < SW (N-Me) < SE (P-tBu). We

Notes

The authors declare no competing ﬁnancial interest.

anticipate that the present unique C -symmetric system

ACKNOWLEDGMENTS

■

associated with both steric and electronic asymmetry could

lead to characteristic reactivity and selectivity in asymmetric

reactions.

This work was supported by a Grant-in-Aid for Young

Scientists B (15K17854) and Early-Career Scientists

18K14215) from the JSPS. This work was also supported in

(

In conclusion, we successfully synthesized a novel class of

chiral amino-phosphine ligands 1a−c, which bear a P-

chirogenic center and an N-group on the pyridylene backbone.

Upon coordination to palladium metal, these ligands bear two

stereogenic centers on the nitrogen and phosphorus atoms. In

particular, ligand 1a, containing an N-Me group, coordinated

to palladium with a high selectivity to predominantly aﬀord the

R ,S complex. Theoretical calculations suggested that the N-

part by the Asahi Glass Foundation and by the Grant for Basic

Science Research Project from The Sumitomo Foundation.

Elemental analyses and mass spectrometry were provided by

the JURC at ICR, Kyoto University. The authors also thank

Dr. Tsuneo Imamoto (Prof. Emeritus, Chiba University, and

Nippon Chemical Industries) for kindly gifting the phos-

phine−borane (S)-PtBuMeH·BH₃.

centered conﬁguration was controlled by dispersion inter-

actions between the P- and N-substituents. Considering that

chiral P,N-ligands have been proven to be applicable in various

transition-metal-catalyzed asymmetric reactions, we expect

that the present ligand may exhibit great potential for

application as a chiral ligand. Further studies, including an

investigation into the ability of this ligand in asymmetric

reactions, coordination studies with other transition metals,

and an examination of solvent eﬀects, are underway.

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ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.organomet.0c00154.

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■

Details of experimental and computational studies

(PDF)

Cartesian coordinates of calculated structures (XYZ)

Accession Codes

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AUTHOR INFORMATION

Corresponding Author

Takahiro Iwamoto − Institute for Chemical Research and

Department of Energy and Hydrocarbon Chemistry, Graduate

School of Engineering, Kyoto University, Uji, Kyoto 611-0011,

Japan; orcid.org/0000-0002-2349-0714;

Email: iwamoto@scl.kyoto-u.ac.jp

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Yoshiyuki Mizuhata − Institute for Chemical Research, Kyoto

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Norihiro Tokitoh − Institute for Chemical Research, Kyoto

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Masaharu Nakamura − Institute for Chemical Research and

Department of Energy and Hydrocarbon Chemistry, Graduate

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