A new modular phosphite-pyridine ligand library for asymmetric Pd-catalyzed allylic substitution reactions: A study of the key Pd-π-allyl intermediates

DOI: 10.1002/chem.201203365

A New Modular Phosphite-Pyridine Ligand Library for Asymmetric Pd-

Catalyzed Allylic Substitution Reactions: A Study of the Key Pd-p-Allyl

Intermediates

Javier Mazuela, Oscar Pꢀmies,* and Montserrat Diꢁguez*^[a]

Abstract: A library of phosphite-pyri-

dine ligands L1–L12a–g has been suc-

cessfully applied for the first time in

the Pd-catalyzed allylic substitution re-

actions of several di- and trisubstituted

substrates by using a wide range of C,

N and O nucleophiles, among which

are the little studied a-substituted mal-

onates, b-diketones, and alkyl alcohols.

The highly modular nature of this

ligand library enables the substituents/

configuration at the ligand backbone,

and the substituents/configurations at

the biaryl phosphite moiety to be easily

and systematically varied. We found

that the introduction of an enantiopure

biaryl phosphite moiety played an es-

sential role in increasing the versatility

of the Pd-catalytic systems. Enantiose-

lectivities were therefore high for sev-

eral hindered and unhindered di- and

Of particular note were the high enan-

tioselectivities (up to>99% ee) and

high activities obtained for the trisub-

stituted substrates S6 and S7, which

compare favorably with the best that

have been reported in the literature.

We have also extended the use of these

new catalytic systems in alternative en-

vironmentally friendly solvents such as

propylene carbonate and ionic liquids.

Studies on the Pd-p-allyl intermediates

provide a deeper understanding of the

effect of ligand parameters on the

origin of enantioselectivity.

trisubstituted substrates by using

a

wide range of C, N and O nucleophiles.

Keywords: allylic substitution

·

asymmetric catalysis · ligand design ·

P,N ligands · palladium

Introduction

embedded.^[2,4]This idea made it possible for ligands with

large bite angles to be successfully applied to the allylic sub-

stitution of sterically undemanding substrates. The third

strategy, developed by groups led by Helmchen, Pfaltz, and

Williams, uses heterodonor ligands to electronically discrimi-

nate between the two allylic terminal carbon atoms because

of the different trans influences of the donor groups.^[2,5]This

made it possible to successfully use a wide range of hetero-

donor ligands (mainly P,N ligands) in allylic substitution re-

actions. More recently, we have shown that the introduction

of biaryl-phosphite moieties into the ligand design is highly

advantageous by overcoming the most common limitations

of this process, such as low reaction rates and high substrate

specificity.^[6]These benefits have been attributed, on one

hand, to the larger p-acceptor ability of the phosphite

groups that increases reaction rates and, on the other hand,

to the flexibility of the phosphite moieties that allows the

catalyst chiral pocket (the chiral cavity in which the allyl is

embedded) to adapt to both hindered and unhindered sub-

strates.^[7]Despite this success, the potential of phosphite-

containing ligands is limited to the use of dimethyl malonate

as a nucleophile.^[6a]More effort has therefore to be made to

enlarge the scope of nucleophiles, increasing the possibilities

for their use in the synthesis of more complex chiral organic

molecules. Although the substrate versatility has recently in-

creased, there are still important substrate classes that give

unsatisfactory results with known catalysts. For example, for

trisubstituted substrates, which allow enantiomerically-en-

riched acid derivatives and lactones to be formed, the Pd

catalysts need to be more active and enantioselective.^[2]

Fine chemicals and natural product chemistry rely on enan-

tiomerically pure compounds. The discovery of synthetic

routes for preparing these compounds is one of the most

persistently pursued goals in chemistry. Asymmetric cataly-

sis is one of the most attractive approaches because it can

provide very high reactivity and selectivity, and is environ-

mentally friendly.^[1]In this respect, the asymmetric Pd-cata-

À

lyzed allylic substitution reaction, which forms C C and C–

heteroatom bonds, is a powerful and highly versatile proce-

dure because it tolerates several functional groups.^[2]Most

of the successful ligands reported to date for this process

have been designed using three main strategies. The first,

developed by Hayashi and co-workers, involves a secondary

interaction of the nucleophile with a side chain of the ligand

to direct the approach of the nucleophile to one of the allyl-

ic terminal carbon atoms.^[2,3]The second strategy, developed

by Trost and co-workers, increases the bite angle of the

ligand to create a chiral cavity in which the allyl system is

[a] Dr. J. Mazuela, Dr. O. Pꢀmies, Prof. M. Diꢁguez

Departament de Quꢂmica Fꢂsica i Inorgꢀnica

Universitat Rovira i Virgili. C/Marcel·li Domingo

s/n. 43007 Tarragona (Spain)

Fax: (+34)977559563

E-mail: oscar.pamies@urv.cat

montserrat.dieguez@urv.cat

Supporting information for this article is available on the WWW

under http://dx.doi.org/10.1002/chem.201203365.

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Chem. Eur. J. 2013, 19, 2416 – 2432

FULL PAPER

Mixed phosphorus-oxazoline ligands have played a domi-

nant role among heterodonor ligands in this process.^[2]In

recent years the range of heterodonor-phosphorous–nitro-

gen ligands has been extended to include more robust N-

donor groups (such as, amine,^[8]imine,^[9]thiazole,^[10]etc.)

than oxazolines with moderate success. In this context, the

phosphine- and phosphinite-pyridine compounds are an im-

portant class of ligands.^[11]However, only a few of them

have been successfully applied and these are limited in sub-

strate scope (enantioselectivities are only high in the allylic

substitution of hindered standard substrate rac-1,3-diphenyl-

3-acetoxyprop-1-ene).^[11]Because we are interested in discov-

ering more robust and more versatile Pd-catalytic systems,

we decided to take one further step in the design of a new

ligand library for this process and incorporate the advantag-

es of the heterodonor, the robustness of the pyridine moiety

and the extra control provided by the flexibility of the chiral

pocket through the presence of a biaryl phosphite group. To

this end, we synthesized and screened a library of 84 poten-

tial new phosphite-pyridine ligands (Figure 1). Their highly

modular construction enabled us to make a systematic study

of the effect of the substituents at the ligand backbone (R¹

and R², ligands L1–L8), the configuration of the carbon next

to the phosphite moiety (ligands L1–L8 vs. L9–L12), and the

substituents and configurations in the biaryl phosphite

moiety (a–g). By carefully selecting these elements, we ach-

ieved high enantioselectivities and activities in several di-

and trisubstituted substrates by using a wide range of C, N

and O nucleophiles, including the less studied a-substituted

malonates, b-diketones, and alkyl alcohols. The potential ap-

plication of the allylic substitution by using functionalized

malonates has been demonstrated by the practical synthesis

of chiral carbocyclic compounds using a simple sequential

allylic alkylation and ring-clos-

Figure 1. Phosphite-pyridine ligand library L1–L12a–g.

pounds ((rac)-1–8, Scheme 1). Racemic compounds 1–8 are

easily made from the corresponding 6-bromopyridines or

pyridyl-aldehydes.^[12,13]Racemic hydroxyl-pyridine com-

pounds 1–4 and 8, bearing a methyl substituents at R², were

resolved by using Candida antarctica lipase B CALB enzy-

matic kinetic resolution to yield the (S)-hydroxyl-pyridine

compounds 1–4 and (S)-hydroxyl-quinoline compound 8 in

excellent enantioselectivities (>99% ee; Scheme 1, step (a))

ing metathesis reaction. We

have also extended the use of

these new catalytic systems in

alternative

friendly solvents such as pro

ene carbonate and ionic liquids.

environmentally

AHCTUNGTRENNUNG

ACHTUNGTRENNUNG

In this paper, we also discuss

the synthesis and characteriza-

tion of the Pd-p-allyl intermedi-

ates to provide greater insight

into the origin of enantioselec-

tivity in these catalytic systems.

Results and Discussion

Synthesis of the ligand library:

Scheme 1 illustrates the se-

quence of ligand synthesis. Lig-

ACHTUNGTRENNUNGands L1–L12a–g were synthe-

sized very efficiently from the

corresponding easily accessible

Scheme 1. Synthesis of a new phosphite-pyridine ligand library L1–L12a–g. a) CALB/vinyl acetate/toluene;^[12]

racemic hydroxyl-pyridine com- b) semipreparative HPLC;^[15]c) LiOH/MeOH;^[14]and d) ClP(OR)₂; (OR)₂=a–g/Py/toluene (Yields: 41–90%).

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2417

O. Pꢀmies, M. Diꢁguez and J. Mazuela

and the corresponding enantiopure (R)-acetates.^[12]The (R)-

hydroxyl-pyridine compounds 1–2 were prepared in high

yields by a base hydrolysis of the enantiopure acetates ob-

tained from enzymatic kinetic resolution (Scheme 1, step

(c)).^[14]Resolution of racemic hydroxyl-pyridine compounds

5–7, bearing bulky substituents at R², was achieved using

preparative chiral HPLC (Scheme 1, step (b)).^[15]

Allylic substitution of rac-1,3-diphenyl-3-acetoxyprop-1-ene

S1 using several nucleophiles: In the first set of experiments,

we used the palladium-catalyzed asymmetric substitution re-

actions of S1 ([Eq. (1a)], R=Ph), with dimethyl malonate

as nucleophile, to study the potential of the phosphite-pyri-

dine ligand library L1–L12a–g. Substrate S1 was chosen be-

cause the reaction was performed with a wide range of lig-

The last step in the ligand synthesis is common to them

all (Scheme 1, step (d)). Therefore, treating the correspond-

ing enantiopure hydroxyl-pyridines with 1 equiv of the cor-

responding in situ-formed biaryl phosphorochloridite

(ClP(OR)₂; (OR)₂=a–g) in the presence of pyridine, in a

parallel manner, provided easy access to the desired ligands

L1–L12a–g.^[16]All of the ligands were stable during purifica-

tion on neutral alumina under an atmosphere of argon and

isolated in moderate-to-good yields as white solids. They

were stable at room temperature and very stable to hydroly-

sis. The elemental analyses were in agreement with the as-

ACHTUNGTRENaNUNG nds, which enabled the efficiency of the various ligand sys-

tems to be compared directly.^[2]

We first determined the optimal reaction conditions by

conducting a series of experiments with two ligands (L1a

and L2a) by using different solvents (tetrahydrofuran, tol-

uene and dichloromethane) and ligand-to-palladium ratios

(L/Pd=0.75, 1 and 2; see Table SI.1 in the Supporting Infor-

mation). We found that the activities and enantioselectivities

were optimal when using dichloromethane as the solvent.

We also found that an excess of ligand was not needed.

Under the optimized conditions (i.e., dichloromethane as

solvent and an L/Pd ratio of 1) we tested the remaining lig-

1

signed structure. The H, ¹³C and ³¹P NMR spectra were as

expected for these C₁ligands. One singlet for each com-

pound was observed in the ³¹P NMR spectrum. Rapid ring-

inversions (tropoisomerization) in the biphenyl-phosphorus

moieties (a–c) occurred on the NMR timescale because the

expected diastereoisomers were not detected by low-temper-

ature phosphorus NMR.^[17]

ACHTUNGTRENaNUGN nds. The results, which are summarized in Table 1, indicate

that the enantioselectivity is mainly affected by the substitu-

ents at the ligand backbone (R¹and R²) and by the substitu-

ents/configuration at the biaryl phosphite moiety (a–g). In-

terestingly, the sense of the enantioselectivity is controlled

by the configuration of the stereogenic carbon next to the

phosphite moiety. High activities (turnover frequencies

(TOFꢄs) of up to 500 mol S1ꢅ(mol Pdꢅh)^À1)^[18]and enantio-

meric excesses (eeꢄs up to 94%) were obtained for both

enantiomers of the substitution product 9 using ligands L1g

and L9 f.

Allylic substitution of symmetrical 1,3-disubstituted allylic

substrates: In this section, we report the use of the chiral

phosphite-pyridine ligand library (L1–L12a–g) in the Pd-cat-

alyzed allylic substitution of linear disubstituted substrates

with different steric properties [Eq. (1a)]: rac-1,3-diphenyl-

3-acetoxyprop-1-ene (S1) (widely used as a model substrate)

and rac-1,3-dimethyl-3-acetoxyprop-1-ene (S2); and cyclic

substrates [Eq. (1b)]: rac-3-acetoxycyclohexene (S3) (widely

used as a model substrate), rac-3-acetoxycyclopentene (S4)

and rac-3-acetoxycycloheptene (S5). Several nucleophiles

were tested. In all cases, the catalysts were generated in situ

The effect of the substituents at the ligand backbone (R¹

and R²) was studied by using ligands L1–L8a. We found

that the enantioselectivity decreases when the steric hin-

drance is increased at both positions (Table 1, entries 1 vs. 8,

12, 13, and 19 for substituent R¹; and entries 1 vs. 14 and 15

for substituent R²). Enantioselectivities were therefore best

when using ligands L1 with a hydrogen and a methyl sub-

stituent at R¹and R²positions, respectively.

We then moved on to investigate the effect of the configu-

ration of the stereogenic carbon next to the phosphite

moiety by using ligands L9–L12a–g. Interestingly, we found

that this stereogenic carbon atom controls the sense of the

enantioselectivity, which opens up the possibility of attaining

both enantiomers of the alkylated product. Thus, ligands

L1–L8 with an S configuration predominantly provided the

product (S)-9, whereas R-configured ligands L9–L12 afford-

ed the product (R)-9 (Table 1, entries 1–19 vs. 20–26).

The effect of the phosphite moieties was studied using lig-

from p-allyl-palladium chloride dimer [PdClACTHNUTRGNEUNG

(h³-C₃H₅)]₂and

the corresponding ligand.^[2]

AHCTUNGTREGaNNNU nds L1a–g (Table 1, entries 1–7). Results indicate that the

presence of trimethylsilyl groups at the ortho positions of

the biaryl phosphite moiety has a positive effect on enantio-

selectivity (Table 1, entries 1 vs. 3 and 5 vs. 7). Moreover,

when we compared ligands L1 f–g and L9 f–g, which have

different configurations of the stereogenic carbon next to

the phosphite moiety, we found a cooperative effect be-

tween the configuration of the biaryl phosphite moiety and

the configuration of the stereogenic carbon next to the phos-

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Chem. Eur. J. 2013, 19, 2416 – 2432

A New Modular Phosphite-Pyridine Ligand Library

FULL PAPER

Table 1. Selected results for the Pd-catalyzed allylic alkylation of S1 with dimethyl

malonate using the ligand library L1–L12a–g.^[a]

lectivity depends on the nature of the substituent.

Thus, whereas the presence of a methyl substituent

had an extremely positive effect on the enantiose-

lectivity (eeꢄs of up to 99%, compound 13), the

presence of an allyl substituent slightly decreased

enantioselectivity (eeꢄs of up to 80%, compound

14).

Finally, encouraged by these excellent results we

decided to study the scope of ligands L1–L12a–g in

the allylic substitution of more challenging nucleo-

philes: alkyl alcohols. The stereroselective construc-

tion of an ether linkage adjacent to a stererogenic

Entry

Ligand

Conv. [%]

(t

[min])^[b]

ee

Entry

Ligand

Conv. [%]

(t

[min])^[b]

ee

G

[%]^[c]

N

[%]^[c]

1

2

3

4

5

6

7

8

L1a

L1b

L1c

L1d

L1e

L1 f

L1g

L2a

L2d

L2e

L²g

100 (30)^[d]

100 (30)

32 (S)

40 (S)

45 (S)

19 (S)

59 (S)

17 (S)

90 (S)

26 (S)

8 (S)

15

16

17

18

19

20

21

22

L6a

L6d

L6e

L7a

L8a

L9a

L9d

L9e

L9 f

L9g

L10a

L12g

L1g

L9 f

100 (30)^[d]

100 (30)

100 (30)^[d]

100 (30)

100 (30)^[d]

100 (30)

96 (360)

94 (360)

21 (S)

3 (S)

72 (S)

12 (S)

28 (S)

35 (R)

20 (R)

55 (R)

89 (R)

10 (R)

100 (30)^[d]

100 (30)

9

100 (30)

23

24

25

10

11

12

13

14

3 (R)

100 (30)

50 (S)

13 (S)

29 (S)

8 (S)

26 (R) carbon center is important for the synthesis of

33 (R)

94 (S)

94 (R)

100 (30)^[d]

100 (30)

26

many biologically active targets.^[20]Despite this, few

L3a

L4a

L5a

27^[e]

28^[e]

examples on the Pd-catalyzed etherification of allyl-

100 (30)^[d]

ic substrates have been reported.^[21,22]Most of the

[a] All reactions were run at 238C with [PdClACTHNUTRGNEUNG

(h³-C₃H₅)]₂(0.5 mol%), dichloromethane

examples use phenols as nucleophiles,^[21a–g]with the

as solvent, ligand (1 mol%). [b] Conversion measured by ¹H NMR spectroscopy. Re-

action time shown in parentheses. [c] Enantiomeric excesses measured by HPLC. Ab-

solute configuration shown in parentheses. [d] Isolated 9 yields were >93%.^[e]Reac-

tions carried out at 08C.

[21e,h,i]

aliphatic ethers being much less studied.

Initially, we evaluated ligands L1–L12a–g in the

allylic substitution of S1 by using benzyl alcohol.

phite moiety. This leads to a matched combination for lig-

ACHTUNGTRENNUNG

entries 1–3) with those obtained using the related enantio-

pure biaryl ligands L1d–g (entries 4–7), we found that the

tropoisomerism in the biphenyl phosphite moieties (a–c) is

not controlled once the ligand has coordinated to the palla-

dium.^[19]Enantiopure phosphite moieties are therefore

needed if enantioselectivities are to be high.

To sum up, the results were best with ligands L1g and

L9 f, which contain the optimal combination of ligand pa-

rameters (Table 1, entries 7 and 23). These findings clearly

show the efficiency of highly modular scaffolds in ligand

design. Enantioselectivities can be improved by controlling

not only the structural but also the reaction parameters. In

this case, enantioselectivities were further improved (eeꢄs of

up to 94%) with ligands L1g and L9 f by lowering the reac-

tion temperature to 08C (Table 1, entries 27 and 28).

Figure 2. Selected results for the Pd-allylic substitution of S1 with other

several C and N nucleophiles using the ligand library L1–L12a–g. Reac-

tion conditions: Pd-catalyst precursor (1 mol%), CH₂Cl₂as solvent, RT,

4 h.

We then went on to study the allylic substitution of S1

using other nucleophiles. Figure 2 shows the most notable

results of using several carbon nucleophiles and benzyl-

We were able to fine tune the ligands to obtain high enan-

tioselectivities (eeꢄs of up to 87%) in the etherification of

substrate S1. Although, as expected, the activities were

lower than in the alkylation reaction of S1, they were similar

to those obtained used other successful ligands under similar

reaction conditions (Table 2, entry 21).^[21i]The results, which

are summarized in Table 2, indicated that the enantioselec-

tivity was again mainly affected by the substituents at the

ligand backbone (R¹and R²) and by the substituents/config-

uration at the biaryl phosphite moiety (a–g). However, the

effect of these parameters was different from their effect on

the substitution of S1 when using C and N nucleophiles.

Therefore, in contrast to the allylic substitution that used C

and N nucleophiles and led to higher eeꢄs with ligands con-

ACHTUNGTRENNUNGamine as the nitrogen nucleophile (for a full set of results,

see Table SI.2 in the Supporting Information). In general,

Pd/L1–L12a–g catalysts followed the same trends as the al-

lylic substitution of S1 using dimethyl malonate. Again, the

catalyst precursors containing ligands L1g and L9 f provided

the best enantioselectivities in both enantiomers of the sub-

stitution products (eeꢄs of up to 99%). It should be noted

that enantioselectivity was relatively insensitive to the steric

nature of the ester groups of the malonate nucleophiles and

also to the replacement of the malonate by an acetylacetone

and benzylamine. Thus, compounds 10–12 and 15 were ob-

tained with high enantioselectivities (eeꢄs ranging from 89 to

93%). However, for a-substituted malonates, the enantiose-

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O. Pꢀmies, M. Diꢁguez and J. Mazuela

Table 2. Selected results for the Pd-catalyzed allylic etherification of S1 with benzyl

alcohol using the ligand library L1–L12a–g.^[a]

to see that the reaction proceeded smoothly to

afford the desired products in excellent yields and

enantioselectivities for each nucleophile. The results

show that the catalytic performance (activity and

enantioselectivity) is not affected by the steric prop-

erties of the aryl group. However, the enantioselec-

tivity increased when an electron-withdrawing

group at the para position of the benzylic alcohol

was present (eeꢄs up to 92% for compound 18).

This behavior contrasts with the relationship be-

tween the enantioselectivity of the reaction and the

electronic nature of the substituted benzylic alcohol

previously observed for a successful Pd-catalytic

system,^[21i]which showed an important decrease of

enantioselectivity when electron-withdrawing sub-

stituents were present. Therefore, several para-sub-

stituted benzylic alcohols can be efficiently added

using Pd-6e and Pd-12d catalytic systems.

Entry

Ligand

Conv. [%]

ee

Entry

Ligand

Conv. [%]

ee

(t [h])^[b]

[%]^[c]

(t [h])^[b]

[%]^[c]

1

2

3

4

5

6

7

8

L1a

L1d

L1e

L1g

L2a

L2d

L2g

L3a

L4a

L4d

L5a

100 (18)^[d]

90 (18)

13 (S)

20 (R)

51 (S)

53 (S)

66 (S)

25 (R)

72 (S)

21 (S)

64 (S)

46 (R)

9 (S)

12

13

14

15

16

17

18

19

20

21

L5d

L5e

L6a

L6d

L6e

L7e

L9 f

L12d

L12e

L6e

100 (18)

92 (18)

68 (R)

74 (S)

1 (S)

71 (R)

87 (S)

29 (S)

52 (R)

85 (R)

70 (S)

87 (S)

100 (18)^[d]

100 (18)

94 (18)

100 (18)^[d]

100 (18)

100 (18)^[d]

98 (18)^[d]

89 (6)

100 (18)

84 (18)

85 (18)

82 (18)

100 (18)

9

10

11

[a] All reactions were run at 238C, [PdClACTHNUTRGNEUNG

(h³-C₃H₅)]₂(2 mol%), dichloromethane as

solvent, ligand (4 mol%). [b] Conversion measured by ¹H NMR spectroscopy. Reac-

tion time shown in parentheses. [c] Enantiomeric excesses measured by HPLC. Abso-

lute configuration shown in parentheses. [d] Isolated 16 yields were >91%.

taining small substituents at R¹and R²of the ligand back-

bone, in the etherification of S1 the presence of bulky sub-

stituents at either R¹or R²had a positive effect on enantio-

selectivity (Table 2, entries 2 vs. 6 and 10 for substituent R¹;

and entries 2 vs. 12 and 15 for substituent R²). However, the

simultaneous introduction of bulky substituents at both posi-

tions led to lower enantioselectivities (Table 2, entry 17).

It should be noted that both enantiomers of the product

can be obtained with high eeꢄs simply by changing either the

absolute configuration of the biaryl moieties (Table 2, en-

tries 15 and 16) or the absolute configuration of the stereo-

genic carbon next to the phosphite moiety (Table 2, en-

tries 15 and 16 vs. 19 and 20). Enantioselectivities were

therefore best with ligands L6d–e and L12d–e (Table 2, en-

tries 15 and 16, and 19 and 20). These results, which again

clearly show the efficiency of using modular scaffolds in

ligand design, are among the best reported for this type of

more challenging nucleophile.^[21i]

Allylic substitution of rac-1,3-dimethyl-3-acetoxyprop-1-ene

S2 using several nucleophiles: We also tested ligands L1–

L12a–g in the allylic substitution of the linear substrate S2

([Eq. (1a)]; R=Me). Substrate S2 is less sterically demand-

ing than the substrate S1 used previously. There are there-

fore fewer successful catalyst systems for the Pd-catalyzed

allylic substitution of this substrate than for the allylic sub-

stitution of hindered substrates such as S1.^[2]If the enantio-

meric excesses are to be high, then the ligand must create a

small chiral pocket around the metal center, mainly because

of the presence of less sterically demanding methyl syn sub-

stituents. Due to the flexibility conferred by the biaryl phos-

phite moiety in combination with the high modularity of this

ligand library, we expected to be able to tune the chiral

pocket to obtain good enantioselectivities for this substrate

as well.

Table 3 summarizes the results of using the phosphite-pyr-

idine ligand library L1–L12a–g with dimethyl malonate as a

nucleophile. In general, activities (TOFꢄs up to>250 mol

S2ꢅ(mol Pdꢅh)^À1)^[18]and enantioselectivities were also high

(eeꢄs of up to 89%) in the alkylation of S2.

To further test the effectiveness of ligands L1–L12a–g, we

examined a series of substituted benzylic alcohols. The most

notable results are summarized in Figure 3. We were pleased

Again, the enantioselectivities were mainly affected by

the substituents at the ligand backbone (R¹and R²) and by

the substituents/configurations at the biaryl phosphite

moiety (a–g). However, whereas the effect of the substitu-

ents/configurations of the biaryl moieties on the enantiose-

lectivity is similar to the effect in the alkylation of S1, the

effect of the substituents at the ligand backbone (R¹and R²)

is different: the presence of a methyl substituent at R¹has a

positive effect on enantioselectivity, yet the substituents at

R²have little effect. Again, both enantiomers of alkylation

product 21 can be accessed in high enantioselectivities

simply by changing the absolute configuration of the stereo-

genic carbon next to the phosphite moiety. Enantioselectivi-

ties (eeꢄs of up to 89%) were therefore best for ligands L2g

and L10 f (Table 3, entries 18 and 19).

Figure 3. Selected results for the Pd-allylic substitution of S1 with other

alkyl O nucleophiles using the ligand library L1–L12a–g. Reaction condi-

tions: Pd-catalyst precursor (4 mol%), CH₂Cl₂as solvent, RT, 18 h.

Subsequently we studied the allylic substitution of S2 by

using several carbon nucleophiles and benzylamine. The

2420

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Chem. Eur. J. 2013, 19, 2416 – 2432

A New Modular Phosphite-Pyridine Ligand Library

FULL PAPER

Table 3. Selected results for the Pd-catalyzed allylic alkylation of S2 with

dimethyl malonate using the ligand library L1–L12a–g.^[a]

Allylic alkylation of cyclic substrates S3–S5: With the unhin-

dered cyclic substrates S3–S5 the enantioselectivity is diffi-

cult to control, mainly because of the presence of less steri-

cally demanding anti substituents. These anti substituents

are thought to play a crucial role in the enantioselection ob-

served with cyclic substrates in the corresponding Pd-allyl

intermediates.^[2]

In this section, we show that the chiral ligand library L1–

L12a–g applied previously to the Pd-catalyzed allylic substi-

tution of 1,3-disubstituted linear substrates (S1–S2) can also

be successfully used for cyclic substrates (eeꢄs up to 96%)

by using several nucleophiles. We tested three cyclic sub-

strates [Eq. (1b)]: rac-3-acetoxycyclohexene (S3, which is

widely used as a model substrate), rac-3-acetoxycyclopen-

tene (S4), and rac-3-acetoxycycloheptene (S5).

Table 4 shows the results of using the ligand library L1–

L12a–g with dimethyl malonate as nucleophile. Enantiose-

lectivities of up to 96% were obtained in the allylic substitu-

tion of the cyclic substrates S3–S5 by using ligands L1g and

L9 f. The results indicate that the effect of the ligand param-

eters on the catalytic performance is different from the

effect of the linear substrates S1–S2. However, although the

substituents of the biaryl moieties have an effect on the

enantioselectivity that is similar to the effect in the alkyla-

tion of S1 and S2, the effect of the substituents at the ligand

backbone (R¹and R²) is different.

Entry

Ligand

Conv. [%]

ee

(t [h])^[b]

[%]^[c]

1^[d]

2

L1a

L1b

L1c

L1d

L1e

L1 f

L1g

L2a

L2g

L3a

L4a

L5a

L6a

L9a

L9 f

L9g

L10 f

L2g

L10 f

100 (2)

100 (18)

37 (S)

38 (S)

40 (S)

19 (S)

46 (S)

3 (S)

72 (S)

48 (S)

79 (S)

19 (S)

30 (S)

36 (S)

32 (R)

31 (R)

74 (R)

4 (R)

3

4^[d]

5^[d]

6

7

8^[d]

9^[d]

10

11^[d]

12^[d]

13

14

15^[d]

16

17^[d]

18^[e]

19^[e]

83 (R)

87 (S)

89 (R)

[a] All reactions were run at 238C, [PdClACTHNUTRGNEUNG

(h³-C₃H₅)]₂(0.5 mol%), di-

chloromethane as solvent, ligand (1 mol%). [b] Conversion measured by

GC. Reaction time shown in parentheses. [c] Enantiomeric excesses

measured by GC. Absolute configuration shown in parentheses. [d] Iso-

lated 21 yields were> 91%. [e] Reaction carried out at 08C.

most notable results are shown in Figure 4. In general, they

follow the same trends as for the allylic alkylation of S2

using dimethyl malonate as nucleophile. Again, the catalyst

precursors containing ligands L2g and L10 f provided the

best enantioselectivities for both enantiomers of the substi-

tution products 22–26 (eeꢄs up to 82%). In all cases, enantio-

selectivities (eeꢄs up to 82%, compounds 22 and 24–26)

were similar to those obtained when using dimethyl malo-

nate, except when acetylacetone was used as nucleophile,

which led to lower enantioselectivities (eeꢄs up to 62%,

compound 23).

Unlike S1 and S2 the methyl substituent at R²has a posi-

tive effect on enantioselectivity (Table 4, entries 1 vs. 12 and

13), while the substituents at R¹have little effect (Table 4,

entries 1 vs. 8, 11 and 14). In addition, the cooperative effect

between the configuration of the biaryl phosphite moiety

and the configuration of the carbon atom next to the phos-

phite moiety is less pronounced for these cyclic substrates

than for linear substrates. Thus, in the allylic alkylation of

cyclic substrates, ligands containing enantiopure bulky R-

and S-biaryl moieties (f and g) acted as pseudo-enantiomers

(Table 4, entries 6 and 7). Therefore, both enantiomers of

the alkylated products can be obtained with high ee values

simply by changing either the absolute configuration of the

biaryl moieties (Table 4, entries 6 and 7) or the absolute

configuration of the stereogenic carbon next to the phos-

phite moiety (Table 4, entries 6 and 7 vs. 18 and 19).

We then moved on to study the allylic substitution of

cyclic substrate S3 by using other carbon nucleophiles. The

most notable results are shown in Figure 5. In general, they

follow the same trends as for the allylic alkylation using di-

methyl malonate. Again, the catalyst precursors containing

ligands L1g and L9 f provided the best enantioselectivities

for both enantiomers of the alkylated products (eeꢄs of up to

94%). As observed for unhindered linear substrate S2, the

enantioselectivities were similar to those obtained using di-

methyl malonate in all cases, except when acetylacetone was

used as nucleophile, which led to lower enantioselectivities.

In summary, by carefully selecting the ligand components

of this new phosphite-pyridine ligand library, we have been

able to identify one of the few catalytic systems that can

Figure 4. Selected results for the Pd-allylic substitution of S2 with several

other C and N nucleophiles using the ligand library L1–L12a–g. Reaction

conditions: Pd-catalyst precursor (1 mol%), CH₂Cl₂as solvent, RT, 6 h.

Chem. Eur. J. 2013, 19, 2416 – 2432

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www.chemeurj.org

2421

O. Pꢀmies, M. Diꢁguez and J. Mazuela

Table 4. Selected results for the Pd-catalyzed allylic substitution of S3–S5 using the

ligand library L1–L12a–g.^[a]

A wide range of synthetic applications of the al-

lylic substitution using other nucleophiles than di-

methyl malonate can be envisaged. One example is

the practical synthesis of the chiral carbocycles di-

methyl (R)-2-phenylcyclopent-3-ene-1,1-dicarboxy-

late (R)-35 and dimethyl (À)-2-methylcyclopent-3-

ene-1,1-dicarboxylate (À)-36 by a simple sequential

allylic alkylation of the corresponding substrate (S1

and S2), with dimethyl allylmalonate, and ring-clos-

ing metathesis reactions (Scheme 2). Alkylated in-

termediates 14 and 25, bearing a terminal alkene,

can undergo clean ring-closing metathesis with no

loss in enantiomeric excess, affording the desired

(R)-35^[23]and (À)-36.

Entry Substrate Ligand Conv. ee

[%]

(t

[%]^[c]

[%]

(t

[%]^[c]

[h])^[b]

1

S3

L1a

L1b

L1c

L1d

L1e

L1 f

L1g

L2a

L2g

L3a

L4a

L5a

L6a

L8a

100 (6) 18

(S)

100 (6) 18

(S)

100 (6) 20

(S)

100 (6) 42

(S)

100 (6) 64

(R)

100 (6) 73

(S)

100 (6) 87

(R)

100 (6) 24

(S)

15

S3

S4

S5

L9a

L9d

L9e

L9 f

L9g

L1g

L9 f

L¹g

L9 f

L¹g

L9 f

L¹g

L9 f

100 (6) 11

(S)

100 (6) 35

(R)

100 (6) 73

(S)

100 (6) 91

(S)

100 (6) 75

(R)

87 (24) 92

(R)

84 (24) 94

(S)

100 (6) 65

(R)

100 (6) 67

(S)

100 (6) 87

(R)

100 (6) 93

(S)

84 (24) 91

(R)

2

16

3

17

4^[d]

5^[d]

6

18^[d]

19^[d]

20^[e]

21^[e]

22^[d]

23^[d]

24^[d]

25^[d]

Allylic substitution of unsymmetrical 1,3,3-trisubsti-

tuted allylic substrates: We also screened the lig-

AHCTUNGTREGUNaNN nds L1–L12a–g in the allylic substitution of rac-

7

8^[d]

9^[d]

10

11

12

13

14

1,3,3-triphenylprop-2-enyl acetate (S6) and rac-1,1,-

diphenyl-1-buten-3-yl acetate (S7) by using dimeth-

yl malonate as nucleophile ([Eq. (2)], R=Ph for S6

and R=Me for S7). These substrates are of synthet-

ic interest because the so-formed substitution prod-

ucts can easily be transformed into enantiomerically

enriched acid derivatives and lactones.^[24]They are

more sterically demanding than the previously used

substrate S1, and it is therefore more difficult to

achieve excellent enantioselectivities with them.^[25]

Interestingly, with this phosphite-pyridine ligand li-

brary, we obtained excellent enantiomeric excesses

(eeꢄs up to>99%) under standard reaction condi-

tions. Although, as expected, the activities were

lower than in the alkylation reaction of S1, they

were similar than those obtained with few other

successful ligands under similar reaction condi-

tions.^[25]

100 (6) 80

(R)

100 (6) 13

(S)

100 (6) 17

(S)

100 (6) 2 (S) 26^[e]

100 (6) 3 (R) 27^[e]

86 (24) 96

(S)

100 (6) 17

(S)

[a] All reactions were run at 238C, [PdClACTHNUTRGNEUNG

(h³-C₃H₅)]₂(0.5 mol%), dichloromethane as

solvent, ligand (1 mol%). [b] Conversion measured by GC. Reaction time shown in

parentheses. [c] Enantiomeric excesses measured by GC (substrates S3 and S5) and by

¹H NMR spectroscopy using [Eu

ACHTNUTRGNE(UNG hfc)₃] (substrate S4). Absolute configuration shown

in parentheses. [d] Isolated 27, 33, and 34 yields were> 89%. [e] Reaction carried out

at 08C.

À

create new C C, C N, and C O bonds, in several substrate

types by using a wide range of nucleophiles, in high activi-

ties and enantioselectivities.^[2i]

The results, summarized in Table 5, indicated that it is cru-

cial to have a methyl substituent at the R¹position if levels

of enantioselectivity are to be excellent (the eeꢄs increased

from 61 to 97% when the hydrogen (ligand L1a) was re-

placed by a methyl (ligand L2a) substituent at the R¹posi-

tion). Finally, by correctly tuning the substituents at both

the biaryl phosphite and the R²position, enantioselectivities

of >99% can be achieved (Table 5, entry 9). In addition,

both enantiomers of the alkylation products 37 and 38 can

be obtained with excellent ee values simply by changing the

absolute configuration of the stereogenic carbon next to the

phosphite moiety (see, for example, Table 5, entry 8 vs. 17).

These results compare favorably with the best that have

been reported for this class of substrate.^[25]

Figure 5. Selected results for the Pd-allylic substitution of S3 with several

other C nucleophiles using the ligand library L1–L12a–g. Reaction condi-

tions: Pd-catalyst precursor (1 mol%), CH₂Cl₂as solvent, RT, 12 h.

2422

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Chem. Eur. J. 2013, 19, 2416 – 2432

A New Modular Phosphite-Pyridine Ligand Library

FULL PAPER

In practice, catalyst recycling

is of fundamental importance

because of the high price of the

metal source. Recently, ionic

liquids (ILs) have emerged as

an alternative to standard or-

ganic solvents.^[28]They enable

catalysts to be repeatedly recy-

cled by a simple two-phase ex-

Scheme 2. Sequential allylic alkylation/ring-closing metathesis reactions for the preparation of carbocycles (R)-

35 and (À)-36

Table 5. Selected results for the Pd-catalyzed allylic substitution of S6

and S7 using the ligand library L1–L12a–g.^[a]

Table 6. Selected results for the Pd-catalyzed allylic substitution of S1–S7

with the ligand library L1–L12a–g in PC as a solvent.^[a]

S6

S7

Entry Substrate Ligand H-Nu

Conv. [%] ee

Entry

Ligand

Conv. [%]

ee[%]^[c]

Conv. [%]

ee[%]^[c]

(t[h])^[b]

[%]^[c]

(t[h])^[b]

1^[d]

2

3

S1

S2

S3

S4

S5

S6

S7

L1g

L9 f

L1g

L2g

L10 f

L2g

L1g

L9 f

L2a

L2d

L2a

H-CH

H-CHACHTGNUTRENNUNG

H-CMe

H-NHCH₂Ph

H-CH

H-CHACHTGNUTRENNUNG

H-CMe

H-NHCH₂Ph

H-CH

G

100 (6)

89 (S)

88 (R)

97 (R)

87 (R)

78 (S)

80 (R)

72 (À)

81 (R)

86 (R)

89 (S)

66 (S)

92 (S)

95 (R)

99 (R)

93 (R)

1

2

3

4

5

6

7

8

L1a

L1b

L1c

L1d

L1e

L1 f

L1g

L2a

L2d

L3a

L4a

L5a

L6a

L8a

L9 f

L9g

L10a

100 (24)^[d]

100 (24)

100 (24)^[d]

100 (24)

100 (24)^[d]

61 (R)

60 (R)

63 (R)

78 (S)

66 (R)

68 (S)

97 (R)

>99 (R)

40 (R)

63 (R)

42 (R)

34 (R)

77 (R)

53 (R)

64 (S)

95 (S)

100 (24)

100 (24)^[d]

100 (24)

100 (24)^[d]

58 (R)

60 (R)

62 (R)

67 (R)

77 (S)

64 (R)

62 (S)

96 (R)

99 (R)

47 (R)

65 (R)

49 (R)

31 (R)

79 (R)

52 (R)

59 (S)

94 (S)

ACHTUNGTERN(NUNG COOMe)₂100 (12)

4

96 (12)

5^[d]

6

E

100 (10)

7

8

ACHTUNGTERN(NUNG COOMe)₂100 (12)

100 (24)

100 (12)

53 (24)

9^[d]

10

11

12

13^[e]

14^[d,e]

15^[e]

ACHTUNGTRENNUNG

9

ACHTUNGTRENNUNG

10

11

12

13

14

15

16

17

ACHTUNGTRENNUNG

AHCTUNGTRENNUNG

N

67 (24)

72 (24)

A

[a] All reactions were run at 238C, [PdClACTHNUTRGNEUNG

(h³-C₃H₅)]₂(0.5 mol%), ligand

(1 mol%). [b] Conversion measured by GC or ¹H NMR spectroscopy.

Reaction time shown in parentheses. [c] Enantiomeric excesses. Absolute

configuration shown in parentheses. [d] Isolated product yields were

[a] All reactions were run at 238C, [PdClACTHNUTRGNEUNG

(h³-C₃H₅)]₂(1 mol%), dichloro-

methane as solvent, ligand (2 mol%). [b] Conversion measured by

¹H NMR spectroscopy. Reaction time shown in parentheses. [c] Enantio-

meric excesses measured by HPLC. Absolute configuration shown in pa-

rentheses. [d] Isolated 37 and 38 yields were >88%.

>91% based on recovered starting material. [e] [PdClACHTUNGTRENNUNG

(h³-C₃H₅)]₂

(1 mol%), ligand (2 mol%).

traction with an apolar solvent. However, they are little

used in asymmetric Pd-allylic substitution and limited to the

standard S1 substrate.^[29]To study whether our new phos-

phite-pyridine ligand library can be used efficiently with ILs,

we studied the Pd-allylic substitution of substrates S1–S7 by

using the ionic liquids 1-butyl-3-methyl imidazolium hexa-

fluorophosphate (IL1) and N-butyl-N-methyl pyrrolidinium

bis(trifluoromethylsulfonylamide (IL2) (Table 7). Again, we

used the ligands that provided the best enantioselectivities

for each substrate type. Two types of nucleophiles, dimethyl

malonate and benzylamine, were tested. The results show

that the nature of the IL has an important effect on catalytic

performance. Thus, the imidazolium-based IL1 led to signifi-

cantly lower enantioselectivities in the allylic substitution of

unhindered substrates S2 and S3 than dichloromethane

(Table 7 entries 5, 7 and 9). IL1 also decreases the catalytic

activity in the amination reactions probably due to the for-

mation of hydrogen bonds between the imidazolium cation

and benzylamine, which decrease its nucleophilic behav-

ior.^[30]

Allylic substitution using non-classical media: Encouraged

by the excellent results obtained, we decided to go one step

further and to study the Pd-catalyzed allylic substitution

using environmentally friendly alternative solvents such as

propylene carbonate (PC) and ionic liquids.

Recently, propylene carbonate (PC) has emerged as a sus-

tainable “green” alternative to standard organic solvents be-

cause of its high boiling point, low toxicity and environmen-

tally friendly synthesis.^[26]To study whether the new Pd-

phosphite-pyridine catalytic systems developed in this study

can be used efficiently with PC, we performed the allylic

substitution of substrates S1–S7 by using the ligands that

provided the best enantioselectivities for each substrate

type. Several C and N nucleophiles were also used. The re-

sults can be found in Table 6. We were pleased to see that

when the new catalyst library was used in PC, the enantiose-

lectivities remained as high as those observed when di-

chloromethane was used for a wide range of nucleophiles.

Unfortunately, the catalysts could not be efficiently recycled

because of the high polarity of the alkylation and amination

products considered.^[27]

Fortunately, when the reaction was carried out in the pyr-

rolidinium-based ionic liquid IL2, the activities and enantio-

selectivities were high and comparable to those obtained in

dichloromethane (Table 7, entries 2, 4, 6, 8, and 10–14).

Chem. Eur. J. 2013, 19, 2416 – 2432

ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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2423

O. Pꢀmies, M. Diꢁguez and J. Mazuela

Table 7. Pd-catalyzed allylic substitution of S1–S7 with the ligand library L1–L12a–g

using ionic liquids (IL1 and IL2) as solvents.^[a]

we were unable to obtain crystal of sufficient quali-

ty to perform X-ray diffraction measurements.

Entry

Solvent

Substrate

Ligand

H-Nu

Conv. [%]

ee

(t [h])^[b]

[%]^[c]

Palladium 1,3-diphenyl-allyl complexes: When the

phosphite-pyridine ligand library L1–L12a–g was

used in the allylic substitution of substrate S1, the

catalytic results showed that enantioselectivity is

highly affected by substituents at the ligand back-

bone (R¹and R²) and by the substituents/configura-

tions at the biaryl phosphite moiety. A small hydro-

gen group at R¹and a methyl substituent at R²in

combination with an (R)-trimethylsilyl-substituted

1^[d]

2

3

IL1

IL2

IL1

IL2

IL1

IL2

IL1

IL2

IL1

IL2

S1

S2

S3

S4

S5

S6

S7

L1g

L2g

L1g

L2a

H-CH

H-CHAHCTNUGTRENNNUG

H-NHCH₂Ph

H-CH

H-CHAHCTNUGTRENNNUG

H-NHCH₂Ph

H-CH

N

100 (0.5)

41 (4)

85 (S)

85 (R)

86 (R)

44 (S)

71 (S)

32 (S)

78 (S)

62 (R)

84 (R)

4

76 (4)

5^[d]

6

100 (2)

21 (6)

51 (6)

39 (6)

98 (6)

100 (6)

97 (6)

100 (24)

96 (24)

7

8

9^[d]

10

11

12^[d]

13^[e]

14^[e]

63 (R) binaphtyl phosphite moiety are therefore required

88 (R)

96 (R)

if enantioselectivity is to be high. To understand

this catalytic behavior, we studied the Pd-p-allyl

complexes 39–42, which contain ligands L1g, L1a,

L2a, and L5a, respectively. With complexes Pd/L1g

and Pd/L1a, we studied the effect of the substitu-

ents/configuration of the biaryl phosphite moiety.

These complexes have the same substituents at R¹

and R²and only differ in the phosphite moiety.

Therefore, whereas ligand L1g, which contains an

[a] All reactions were run at 238C, [PdClACTHNUTRGNEUNG

(h³-C₃H₅)]₂(0.5 mol%), ligand (1 mol%).

[b] Conversion measured by GC or ¹H NMR spectroscopy. Reaction time shown in

parentheses. [c] Enantiomeric excesses measured by GC or HPLC. Absolute configu-

ration shown in parentheses. [d] Isolated product yields were >87%. [e] [PdClACHTUNGTRNEUNG

(h³-

C₃H₅)]₂(1 mol%), ligand (2 mol%).

It is interesting to note that for the allylic amination of

substrates S1 and S2 using IL2, catalysts can be used up to

five times with no significant loss in activity and the high

enantioselectivities are preserved. Nevertheless, for the allyl-

ic alkylation with dimethyl malonate as nucleophile, the cat-

alytic performance of the IL solutions was not fully recov-

ered. In all cases, both the catalytic activity and the enantio-

selectivity decreased considerably after the first run.^[31]

(R)-trimethylsilyl-substituted binaphthyl phosphite, provided

the highest enantioselectivity, ligand L1a, which has a tert-

butyl-substituted biphenyl phosphite moiety, was less enan-

tioselective (eeꢄs of up to 32% (S)). By comparing the Pd-

studies of complexes 40–42, we studied how the substituents

at R¹and R²affect catalytic performance.

The VT-NMR study (308C to À808C) of the Pd-allyl in-

termediate 39, which contains ligand L1g, had a mixture of

two isomers in equilibrium at a ratio of 1.5:1.^[33]Both iso-

mers were unambiguously assigned by NMR spectroscopy

(¹H, ³¹P, ¹³C, ¹H-¹H, ¹H-¹³C and ¹H-³¹P correlation and

NOESY experiments) to the two syn/syn endo A and exo B

isomers (Scheme 4). In both isomers, the NOE indicated in-

Origin of enantioselectivity: study of the Pd-p-allyl inter-

mediates: To provide further insight into how ligand param-

eters affect catalytic performance, we studied the Pd-p-allyl

compounds 39–46 [PdACTHNUTRGNEUNG

(h³-allyl)(L)]BF₄(L=L1–L12a–g), be-

cause they are key intermediates in the allylic substitution

reactions studied.^[2]These ionic palladium complexes, which

contain 1,3-diphenyl, 1,3-dimethyl or cyclohexenyl allyl

groups, were prepared by using the previously reported

method from the corresponding Pd-allyl dimer and the ap-

propriate ligand in the presence of silver tetrafluoroborate

(Scheme 3).^[32]The complexes were characterized by ele-

1

mental analysis and by H, ¹³C and ³¹P NMR spectroscopy.

The spectral assignments were based on information from

¹H-¹H, ³¹P-¹H and ¹³C-¹H correlation measurements in com-

bination with ¹H-¹H NOESY experiments. Unfortunately,

Scheme 4. Diastereoisomer Pd-allyl intermediates for S1 with ligand L1g.

The relative amounts of each isomer are shown in parentheses. The

chemical shifts (in ppm) of the allylic terminal carbons are also shown.

Scheme 3. Preparation of [Pd

ACHTUNGTRENNUNG

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Chem. Eur. J. 2013, 19, 2416 – 2432

A New Modular Phosphite-Pyridine Ligand Library

FULL PAPER

ACTHNUTRGNEUNG

Figure 7. ³¹P{¹H} NMR spectra of [Pd(h³-1,3-diphenylallyl)(L¹g)]BF₄(39)

in CD₂Cl₂at À808C a) before the addition of sodium malonate and

b) after the addition of sodium malonate.

terminus trans to the phosphite moiety of the major A Pd-

intermediate. This is also consistent with the fact that, for

both isomers, the most electrophilic allylic terminal carbon

atom is the one trans to the phosphite in the major A

isomer.

Figure 6. Main NOE contacts from the NOESY experiment of [Pd(h³-1,3-

diphenylallyl)ACHTUNGTRENNUNG(L1g)]BF₄(39) isomers.

The VT-NMR study of Pd-allyl intermediate 40 contain-

ing ligand L1a, which has the same substituents at the

ligand backbone and differs in the presence of a tert-butyl-

substituted biphenyl phosphite moiety, also had a mixture of

two syn/syn endo (A) and exo (B) isomers, but at a ratio of

1.2:1. Also, the most electrophilic allyl carbon terminus was

trans to the phosphite moiety in isomer A (Scheme 5). How-

ever, an important difference between complexes 39 and 40

is the lower electronic differentiation between the more

electrophilic allylic terminus carbon atoms of both isomers

teractions between the two terminal protons of the allyl

group, which clearly indicates syn/syn disposition

a

(Figure 6). Moreover, the hydrogen atoms of the methyl

substituent at the R²position of the ligand backbone

showed a NOE interaction with the central allyl proton of

the minor isomer B, whereas in isomer A this interaction ap-

peared with both terminal allyl protons. These interactions

can be explained by assuming a syn/syn endo disposition for

isomer A and a syn/syn exo disposition for isomer B

(Figure 6). For both isomers, the carbon NMR chemical

shifts indicate that the most electrophilic allyl carbon termi-

nus is trans to the phosphite moiety (Scheme 4). Assuming

that the nucleophilic attack takes place at the more electro-

philic allyl carbon terminus,^[2,34]and on the basis of the ob-

served stereochemical outcome of the reaction (90% (S) in

product 9), and as the enantiomeric excess of alkylation

product 9 differs from the diastereoisomeric excess (de 20%

(S)) of the Pd-intermediates, the A isomer must react faster

than the B isomer. To prove this we studied the reactivity of

the Pd-intermediates with sodium malonate at low tempera-

ture by in situ NMR spectroscopy (Figure 7). Our results

showed that the major isomer A reacts around nine times

faster than isomer B. If we take into account the relative re-

action rates and the abundance of both isomers, the calculat-

ed ee values should be 86% (S), which matches the ee ob-

tained experimentally. We can therefore conclude that the

nucleophilic attack takes place predominantly at the allyl

(A and B) in complex 40 (D

plex 39 (D

ACHTUNGTRENNUNG

G

tion may explain the lower enantioselectivity obtained with

Pd/L1a than with Pd/L1g. Accordingly, the reactivity of the

Pd-intermediates with sodium malonate at low temperature

by in situ NMR indicates that isomer A in complex 40

reacts only around 2.5 times faster than isomer B.

The VT-NMR study of Pd-allyl intermediates 41 and 42

containing ligands L2a and L5a, respectively, also had a

mixture of two syn/syn endo (A) and exo (B) isomers, but at

a ratio of 1:1 and 1.2:1, respectively (Scheme 5). By compar-

ing complexes 40–42, we found that the ratio of isomers A

and B is affected by the substituent at R¹position of the

ligand backbone. The introduction of a bigger substituent at

R¹increases the relative amount of isomer B. The preferen-

tial formation of isomer 41B can be attributed to the fact

that the steric interaction between the methyl R¹group and

the phenyl groups of the substrate in isomer 41A is greater

than in complexes 40 and 42, which contain a smaller hydro-

Chem. Eur. J. 2013, 19, 2416 – 2432

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2425

O. Pꢀmies, M. Diꢁguez and J. Mazuela

Scheme 6. Diastereoisomer Pd-allyl intermediates for S2 with ligand L2g.

The relative amounts of each isomer are shown in parentheses. The

chemical shifts (in ppm) of the allylic terminal carbons are also shown.

Scheme 5. Diastereoisomer Pd-allyl intermediates for S1 with ligands

L1a, L2a, and L5a. The relative amounts of each isomer, the difference

in chemical shifts of the most electrophilic allyl carbon atoms and the rel-

ative reaction rates are shown.

gen R¹group. Again in complexes 41 and 42, the most elec-

trophilic allyl carbon terminus was trans to the phosphite

moiety in isomer A (Scheme 5). Like complex 40, the elec-

tronic differentiation between the more electrophilic allylic

terminus carbon atoms of both isomers (A and B) is lower

in these complexes than in complex 39 (DACTHUNGTRENNUNG

which again explains the lower enantioselectivities obtained

with respect to Pd/L1g. This behavior is more pronounced

for complex 42, which contains a tert-butyl group at the R²

position, and thus agrees with its lower enantioselectivity.

Finally, the trend of enantioselectivity observed between

complexes Pd/L1a and Pd/L2a (32% (S) and 26% (S), re-

spectively) can therefore be mainly attributed to the in-

crease in the amount of the less reactive isomer B caused by

introducing bulkier substituent at the R¹position.

Palladium 1,3-dimethyl-allyl complexes: When the phos-

phite-pyridine ligand library L1–L12a–g was used in the al-

lylic substitution of substrate S2, the catalytic results showed

that there is an important effect of the substituents/configu-

rations of the biaryl phosphite moiety. To understand this

catalytic behavior, we studied Pd-p-allyl complexes 43 and

44, which contain ligands L2g and L2a with different sub-

stituents/configuration at the biaryl phosphite moiety.

Figure 8. Main NOE contacts from the NOESY experiment of the

[Pd(h³-1,3-dimethylallyl)

ACTHNUTRGNENUG(L2g)]BF₄(43) isomers.

The VT-NMR (30 to À808C) study of Pd-allyl intermedi-

ate 43, which contains ligand L2g, showed a mixture of two

isomers in equilibrium at a ratio of 1:1.7. Isomers A and B

were assigned by NOE to the two syn/syn endo A and exo B

isomers (Scheme 6). In both isomers, the NOE indicated in-

teractions between the two terminal protons of the allyl

group, which clearly shows a syn/syn disposition (Figure 8).

Moreover, the terminal allyl proton trans to the phosphite

moiety showed a NOE interaction with the hydrogen atoms

of the methyl substituent at the R²position of the ligand

backbone of the minor isomer A, whereas in isomer B this

interaction appeared with the hydrogen atoms of the methyl

substituent at the R¹position. These interactions can be ex-

plained by assuming a syn/syn endo disposition for isomer A

2426

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Chem. Eur. J. 2013, 19, 2416 – 2432

A New Modular Phosphite-Pyridine Ligand Library

FULL PAPER

and a syn/syn exo disposition

for isomer B (Figure 8). The

NMR data also indicated that

the most electrophilic allyl

carbon terminus is trans to the

phosphite moiety in syn/syn

isomer A. Assuming that the

nucleophilic attack takes place

at the most electrophilic allyl

carbon terminus, on the basis of

the observed stereochemical

outcome of the reaction (79%

(S) in product 21), and because

the ee value of alkylation prod-

uct 21 differs from the diaster-

eoisomeric excess (de=25%

(R)), we conclude that isomer

Scheme 7. Diastereoisomer Pd-allyl intermediates for S2 with ligand L2a. The relative amounts of each isomer

are shown in parentheses. The chemical shifts (in ppm) of the allylic terminal carbons are also shown.

A reacts faster than isomer B.

This was confirmed by an in

situ NMR study of the reactivi-

ty of the Pd intermediates with

sodium malonate at low tem-

perature. This study indicated

that isomer 43A reacts approxi-

mately 10 times faster than

isomer 43B. This is also consis-

tent with the fact that, for both

isomers, the most electrophilic

allylic terminal carbon atom is

the one trans to the phosphite

in the minor A isomer.

The VT-NMR study of Pd-

allyl intermediate 44, which

contains ligand L2a with a tert-

butyl substituted biphenyl phos-

phite group and provides lower

enantioselectivity than Pd-L2g,

had a mixture of three isomers

at a ratio of 2.5:10:1. Isomers A

and B were assigned by NOE

to the two syn/syn endo A and

exo B isomers, whereas isomer

C was assigned to the syn/anti

isomer (Scheme 7). For isomers

A and B, the NOE indicated in-

teractions between the two ter-

minal protons of the allyl

group, whereas for isomer C

the central allyl proton showed

a NOE interaction with the ter-

minal allyl proton located trans

Figure 9. Main NOE contacts from the NOESY experiment of the [Pd(h³-1,3-dimethylallyl)

mers.

ACHTUNGTRENNUNG

to the pyridine group (Figure 9). Moreover, for isomers B

and C, the terminal allyl proton trans to the phosphite

moiety showed a NOE interaction with the hydrogen atoms

of the methyl substituent at the R¹position of the ligand

backbone, whereas in isomer A this interaction appeared

with the hydrogen atoms of the methyl substituent at the R²

position. The NOESY also indicated an exchange between

the allylic terminal protons located trans to the pyridine

moiety of isomers A and C (Figure 9). This confirms the h³-

h¹-h³movement for the exchange between isomers A and

C.^[35]In addition, the fact that no other H_anti-H_synexchange

was observed indicates that the exchange took place by

Chem. Eur. J. 2013, 19, 2416 – 2432

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2427

O. Pꢀmies, M. Diꢁguez and J. Mazuela

À

means of the selective opening of one of the terminal Pd C

bonds. Isomer C formed because, in complex A, the steric

interaction increased between the pyridine methyl group

and one of the methyl substituents of S2. The formation of

isomer C minimized this steric interaction (Scheme 7).

À

Therefore, the open Pd C bond belongs to the most electro-

philic carbon atom containing the substituent that undergoes

the biggest steric hindrance with the methyl pyridine frag-

ment. The NMR spectroscopic data also indicated that the

most electrophilic allyl carbon terminus is trans to the phos-

phite moiety in syn/syn isomer A and in syn/syn isomer B,

and that the allylic terminus carbon in isomer C is less elec-

trophilic. Assuming that the nucleophilic attack takes place

at the most electrophilic allyl carbon terminus, on the basis

of the observed stereochemical outcome of the reaction

(49% (S) in product 21), and since the ee value of alkylation

product 21 differs from the diastereoisomeric excess (de=

60% (R)) of the reacting Pd intermediates A and B, we con-

clude that isomer A reacts faster than isomer B.^[36]The

lower enantioselectivity with this system than with the Pd/

L2g catalytic system (43) discussed above can be attributed

to the decrease in the relative amount of isomer A with re-

spect to isomer B compared with the population of the iso-

mers (A and B) for complex 43.

Scheme 8. Diastereoisomer Pd-allyl intermediates for S3 with ligand L2g.

The relative amounts of each isomer are shown in parentheses. The

chemical shifts (in ppm) of the allylic terminal carbons are also shown.

Palladium 1,3-cyclohexenyl-allyl complexes: When the phos-

phite-pyridine ligand library L1–L12a–g was used in the al-

lylic substitution of cyclic substrates S3–S5, the catalytic re-

sults showed that the substituents/configurations of the

biaryl phosphite moiety have an important effect. To under-

stand this catalytic behavior, we studied Pd-p-allyl com-

plexes 45 and 46. These complexes contain ligands L2g and

L2a, which have different substituents/configuration at the

biaryl phosphite moiety.

The VT-NMR (358C to À808C) of Pd intermediate 45,

which contains the ligand L2g, showed a mixture of the two

possible isomers at a ratio of 9.2:1 (Scheme 8). All isomers

were unambiguously assigned by NOE to isomers A and B

(Figure 10). For isomer A, the NOE indicated interactions

between the terminal allyl proton trans to the phosphite

moiety and the hydrogen atoms of the methyl substituent at

the R¹position of the ligand backbone. For isomer B, how-

ever, this interaction appeared with the hydrogen atoms of

the methyl substituent at the R²position of the ligand back-

bone (Figure 10). The carbon NMR chemical shifts indicat-

ed that the most electrophilic allylic terminus carbon is trans

to the phosphite moiety. The matching between enantiomer-

ic excess values (80% (R) in product 27) and the diastereo-

Figure 10. Main NOE contacts from the NOESY experiment of the

ACHTUNGTRENNUNGisomeric Pd ratio (de=82% (R)) indicate that the two iso-

[Pd(h³-1,3-cyclohexenyl-allyl)

ACTHNUTRGNENUG(L2g)]BF₄(45) isomers.

mers react at a similar rate. This is in agreement with the

fact that the electrophilicities of the allylic terminal carbon

atom trans to the phosphite are rather similar in both com-

The VT-NMR (358C to À808C) of Pd intermediate 46,

which contains ligand L2a, also showed a mixture of the

two possible isomers (A and B), but at a ratio of 1:2.3, re-

spectively (Scheme 9). The carbon NMR chemical shifts

also indicated that the most electrophilic allylic terminus

carbon is trans to the phosphite moiety. In contrast to the

plexes (DdACHTUNGTRENNUNG

really are similar, we studied the reactivity of the Pd inter-

mediates with sodium malonate at low temperature by in

situ NMR spectroscopy. Our results showed that the two iso-

mers react at a similar rate.

2428

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Chem. Eur. J. 2013, 19, 2416 – 2432

A New Modular Phosphite-Pyridine Ligand Library

FULL PAPER

ture. The potential application of allylic substitution by

using functionalized malonates has been demonstrated by

the practical synthesis of the chiral carbocyclic compounds

35 and 36 using a simple sequential allylic alkylation and

ring-closing metathesis reactions. The new phosphite-pyri-

dine ligand library not only performs well in traditional or-

ganic solvents but also in alternative environmentally friend-

ly solvents such as propylene carbonate and ionic liquids.

Ionic liquids allowed the palladium catalyst to be reused

while maintaining the excellent enantioselectivities. In addi-

tion, for all substrates and nucleophiles, both enantiomers of

the substitution products were obtained with high enantiose-

lectivities. These results open up the asymmetric Pd-cata-

lyzed allylic substitution of several substrates types with a

wide range of nucleophiles to the potential effective use of

readily available and highly modular phosphite-pyridine lig-

AHCTUNGTRENNUNG

Scheme 9. Diastereoisomer Pd-allyl intermediates for S3 with ligand L2a.

The relative amounts of each isomer are shown in parentheses. The

chemical shifts (in ppm) of the allylic terminal carbons are also shown.

clohexenyl allyl intermediates with NMR spectroscopy, we

were able to better understand the observed catalytic behav-

ior. Therefore, for enantioselectivities to be high in the sub-

stitution of hindered substrate S1, the ligand parameters

need to be correctly combined so that the electronic differ-

entiation increases between the most electrophilic allylic ter-

minus carbon atoms of the isomers formed and/or the

isomer that reacts faster with the nucleophile is predomi-

nantly formed. Likewise, for unhindered substrates S2 and

S3, the ligand parameters need to be correctly combined so

that the Pd intermediate that has the fastest reaction with

the nucleophile is predominantly formed, which leads to

high enantioselectivities. We also found that the nucleophilic

attack takes place predominantly at the allylic terminal

carbon atom located trans to the phosphite moiety.

Pd-intermediate 43, the fact that the observed enantiomeric

excess (24% (S) in product 27) is lower than the diastereo-

meric excess (de=40% (S)) indicates that isomer A should

react slightly faster than isomer B. However, this catalytic

system provides lower enantioselectivities than Pd/L2g (45)

because of the lower population of isomer A in complex 46

than in complex 45.

Conclusion

A library of phosphite-pyridine ligands L1–L12a–g has been

successfully applied for the first time in the Pd-catalyzed al-

lylic substitution reactions of several di- and trisubstituted

substrates using a wide range of C, N, and O nucleophiles,

among which are the little studied a-substituted malonates

and alkyl alcohols. This ligand library combines the advan-

tages of the pyridine moiety with those of the phosphite

group. The ligands are more stable than their oxazoline

counterparts, less sensitive to air and other oxidizing agents

than phosphines and phosphinites, and easy to synthesize

from readily available feedstocks. Moreover, the highly

modular nature of the ligand library enables the substitu-

ents/configuration at the ligand backbone, and the substitu-

ents/configurations at the biaryl phosphite moiety to be

easily and systematically varied. We found that the extent to

which the chiral information was transferred to the product

can be tuned by correctly choosing the ligand components.

The introduction of an enantiopure biaryl phosphite moiety

played an essential role in increasing the versatility of the

Pd-catalytic systems. Enantioselectivities were therefore

high in a wide range of substrates using several C, N, and O

nucleophiles. Of particular note were the high enantioselec-

tivities (up to>99% ee) and high activities obtained for the

trisubstituted substrates S6 and S7, which compare favorably

with the best values that have been reported in the litera-

Experimental Section

General considerations: All reactions were carried out using standard

Schlenk techniques under an atmosphere of argon. Solvents were purified

and dried by standard procedures. Phosphorochloridites were easily pre-

pared in one step from the corresponding biaryls.^[37]Enantiopure hydrox-

yl-pyridine compounds 1–6 and 8 were prepared as previously de

ACHTUNGTRENNUNGscrib-

AHCTUNGTRENNUNG

[34a]

ed.^[38][Pd(h³-1,3-Ph₂-C₃H₃)

(m-Cl)]₂,^[39][Pd(h³-1,3-Me₂-C₃H₃)

ACHUTGTNERNNUG ACHTUNGTRENNUNG(m-Cl)]₂

[40]

and [Pd(h³-cyclohexenyl)

A

AHCTUNGTRENNUNG

ed. ¹H, ¹³C{¹H}, and ³¹P{¹H} NMR spectra were recorded using

400 MHz spectrometer. Chemical shifts are relative to that of SiMe₄(¹H

and ¹³C) as internal standard or H₃PO₄(³¹P) as external standard. H, ¹³C

1

and ³¹P assignments were made on the basis of ¹H-¹H gCOSY, ¹H-¹H

NOESY, ¹H-¹³C gHSQC and H-³¹P gHMBC experiments.

1

Preparation of hydroxyl-pyridine (S)-7: Compound 7 was synthesized by

a modified previously reported methodology.^[15]2-bromo-6-methylpyri-

dine (4.27 mL, 37.5 mmol) was dissolved in ether (150 mL) and the mix-

ture cooled to À788C. To this clear, colorless solution was added n-BuLi

(1.55m in hexanes, 27 mL, 41.2 mmol). This caused the solution to turn

yellow initially and then deep red. The solution was stirred at low tem-

perature for 1 h and pivalaldehyde (4.89 mL, 45 mmol) was added, which

immediately turned the solution a light shade of orange and deposited a

solid mass. The mixture was allowed to stir and warm up slowly over-

night. Next, the reaction was quenched with sat. NH₄Cl (aq., 100 mL)

and the biphasic mixture was stirred until all the solids had dissolved.

Chem. Eur. J. 2013, 19, 2416 – 2432

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2429

O. Pꢀmies, M. Diꢁguez and J. Mazuela

The layers were separated and the organic phase further extracted with

diethyl ether (3ꢅ50 mL). The organic extracts were combined, washed

with brine, dried (MgSO₄) and concentrated to a crude oil. The resulting

oil was purified by chromatography on silica (petroleum ether/ethyl ace-

tate 70:30, R_f=0.3) to afford the (rac)-7 as a white solid. The racemate

was separated into its enantiomers by chiral semi-preparative HPLC

using a (250ꢅ20 mm) Chiracel OD column (1% isopropanol in hexanes,

4 mLmin^À1, 31 min (S), 33 min (R)) to yield (S)-7 in>99% ee. ¹H NMR

(400 MHz, CDCl₃): d=0.9 (s, 9H, tBu), 2.55 (s, 3H, CH₃), 4.32 (b, 1H,

extracted with Et₂O (3ꢅ10 mL) and the extract dried over MgSO₄. The

solvent was removed and the conversion and regioselectivity were meas-

ured by ¹H NMR spectroscopy. The enantiomeric excess was determined

by HPLC (Chiralcel OJ, 13% 2-propanol/hexane, flow 0.5 mLmin^À1). A

sample was filtered over basic alumina using dichloromethane as the

eluent.^[25c,43]

Typical procedure for the allylic amination of disubstituted linear sub-

strates S1 and S2: A degassed solution of [PdClACTHNUTRGNEUNG

(h³-C₃H₅)]₂(0.9 mg,

0.0025 mmol) and the corresponding phosphite-pyridine (0.0055 mmol) in

dichloromethane (0.5 mL) was stirred for 30 min. Subsequently, a solu-

tion of the corresponding substrate (0.5 mmol) in dichloromethane

(1.5 mL) and benzylamine (131 mL, 1.5 mmol) were added. The reaction

mixture was stirred at room temperature. After the desired reaction time,

the reaction mixture was diluted with Et₂O (5 mL) and saturated NH₄Cl

(aq, 25 mL) was added. The mixture was extracted with Et₂O (3ꢅ10 mL)

and the extract dried over MgSO₄. For substrate S1, solvent was removed

and conversion was measured by ¹H NMR spectroscopy. To determine

the ee value by HPLC (Chiralcel OJ, 13% 2-propanol/hexane, flow

0.5 mLmin^À1), a sample was filtered over silica using 10% Et₂O/hexane

mixture as the eluent.^[42]For substrate S2, conversion and enantiomeric

excess was determined by GC.^[25b]

À

OH), 4.35 (s, 1H, CH O), 7.0–7.6 ppm (m, 3H, CH=).

General procedure for the preparation of phosphite-pyridine ligands L1–

L12a–g: Phosphorochloridite (1.1 mmol) produced in situ was dissolved

in toluene (5 mL) and pyridine (0.18 mL, 2.3 mmol) was added. Hydrox-

yl-pyridine (1 mmol) was azeotropically dried with toluene (3ꢅ1 mL)

and then dissolved in toluene (5 mL), to which pyridine (0.18 mL,

2.3 mmol) was added. The alcohol solution was transferred slowly at 08C

to the solution of phosphorochloridite. The reaction mixture was warmed

to 808C and stirred for 2 h, and the pyridine salts were removed by filtra-

tion. Evaporation of the solvent gave a white foam, which was purified

by flash chromatography (toluene/hexane/NEt₃) to produce the corre-

sponding ligand as white solid (for characterization details see the Sup-

porting Information).

Typical procedure for the allylic etherification of disubstituted linear sub-

strate S1: A degassed solution of [PdClACTHNUTRGNEUNG

(h³-C₃H₅)]₂(0.9 mg, 0.0025 mmol)

General procedure for the preparation of [Pd

39–46: The corresponding ligand (0.05 mmol) and the complex [PdAHCTUNTGRENNUNG

(h³-allyl)(L)]BF₄complexes

and the corresponding phosphite-pyridine (0.0055 mmol) in dichlorome-

thane (0.5 mL) was stirred for 30 min. Subsequently, a solution of the cor-

responding substrate (31.5 mg, 0.125 mmol) in dichloromethane (1.5 mL)

was added. After 10 min, Cs₂CO₃(122 mg, 0.375 mmol) and alkyl alcohol

(0.375 mmol) were added. The reaction mixture was stirred at room tem-

perature. After the desired reaction time, the reaction mixture was dilut-

ed with Et₂O (5 mL) and saturated NH₄Cl (aq., 25 mL) was added. The

mixture was extracted with Et₂O (3ꢅ10 mL) and the extract dried over

(m-

Cl)(h³-1,3-allyl)]₂(0.025 mmol) were dissolved in CD₂Cl₂(1.5 mL) at

room temperature under argon. AgBF₄(9.8 mg, 0.05 mmol) was added

after 30 min and the mixture was stirred for 30 min. The mixture was

then filtered over celite under argon and the resulting solutions were an-

alyzed by NMR spectroscopy. After the NMR analysis, the complexes

were precipitated as pale yellow solids by adding hexane (for characteri-

zation details see the Supporting Information).

1

MgSO₄. Conversion was measured by H NMR. HPLC was used to deter-

Study of the reactivity of the [Pd

ACHTUNGTRENNUNG

mine the ee value. A sample was filtered over silica using 10% Et₂O/

by in situ NMR spectroscopy:^[42]A solution of in situ prepared [Pd

AHCTUNGTRENNUNG

hexane mixture as the eluent.^[21i]

lyl)(L)]BF₄(L=phosphite-pyridine, 0.05 mmol) in CD₂Cl₂(1 mL) was

cooled in the NMR machine at À808C. At this temperature, a solution of

cooled sodium malonate (0.1 mmol) was added. The reaction was then

followed by ³¹P NMR spectroscopy. The relative reaction rates were cal-

culated using a capillary containing a solution of triphenylphosphine in

CD₂Cl₂as external standard.

Typical procedure for the preparation of carbocyclic compounds 35 and

36: A solution of Grubbs II catalyst (5 mg, 0.006 mmol) and the corre-

sponding alkylated product (0.12 mmol) in CH₂Cl₂(3 mL) was stirred for

16 h. The solution was directly purified by flash chromatography (95:5;

Hex/EtOAc) to obtained the desired carbocycle compounds.

(R)-35. Yield: 27 mg (86%). For characterization details and details for

ee determination see Refs. [23] and [44]

Typical procedure for the allylic alkylation of disubstituted linear (S1 and

S2) and cyclic (S3–S5) substrates: A degassed solution of [PdClACHTNUTGRNEUNG

(h³-

(À)-36. Yield: 21 mg (88%). Enantiomeric excess determined by HPLC

using Chiralcel OJ-H column (98% hexane/2-propanol, flow

0.5 mLmin^À1, l=220 nm). R_t=15.6 min (À); R_t=16.7 min (+).¹H NMR

(400 MHz, CDCl₃): d=0.93 (d, 3H, CH_3,J=7.6 Hz), 2.72 (d, 1H, H-5,

²J_5À5’=16.8 Hz), 3.28 (dd, 1H, H-5’, ²J_5’À5=16.8 Hz, ³J_5’À4=2.8 Hz), 3.61

(m, 1H, H-2), 3.72 (s, 6H, CO₂Me), 5.57 ppm (m, 2H, H-3 and H-4);

¹³C NMR (100 MHz, CDCl₃), d: 15.8 (CH₃), 39.7 (C-5), 45.3 (C-2), 52.2

(CO₂Me), 52.6 (CO₂Me), 63.1 (C-1), 126.2 (C-3 or C-4), 134.4 (C-4 or C-

3), 172.7 ppm (CO₂Me).

C₃H₅)]₂(0.9 mg, 0.0025 mmol) and the corresponding phosphite-pyridine

(0.0055 mmol) in dichloromethane (0.5 mL) was stirred for 30 min. Sub-

sequently, a solution of the corresponding substrate (0.5 mmol) in di-

chloromethane (1.5 mL), nucleophile (1.5 mmol), N,O-bis(trimethylsilyl)-

acetamide (370 mL, 1.5 mmol) and a pinch of the corresponding base

were added. The reaction mixture was stirred at room temperature. After

the desired reaction time the reaction mixture was diluted with Et₂O

(5 mL) and saturated NH₄Cl (aq., 25 mL) was added. The mixture was

extracted with Et₂O (3ꢅ10 mL) and the extract dried over MgSO₄. For

compound 9, solvent was removed and conversion was measured by

¹H NMR spectroscopy. To determine the ee value by HPLC (Chiralcel

OD, 0.5% 2-propanol/hexane, flow 0.5 mLmin^À1), a sample was filtered

over basic alumina using dichloromethane as the eluent.^[42]For com-

pounds 21, 27, and 34, the conversion and enantiomeric excess were de-

termined by GC.^[35]For compound 33, the conversion was measured by

¹H NMR spectroscopy. To determine the ee value by ¹H NMR spectro-

Acknowledgements

We would like to thank the Spanish Government for providing grant

CTQ2010-15835, the Catalan Government for grant 2009SGR116, and

the ICREA Foundation for providing M. Diꢁguez and O. Pꢀmies with fi-

nancial support through the ICREA Academia awards.

scopy [EuACHTUNGTRENNUNG

(hfc)₃] was used.^[25b]For characterization and ee determination

of the rest of products see the Supporting Information.

Typical procedure for the allylic alkylation of 1,3,3-trisubstituted sub-

strates (S6 and S7): A degassed solution of [PdClACTHNUTRGNEUNG

(h³-C₃H₅)]₂(1.8 mg,

0.005 mmol) and the corresponding phosphite-pyridine (0.011 mmol) in

dichloromethane (0.5 mL) was stirred for 30 min at room temperature.

Subsequently, a solution of substrate (0.5 mmol) in dichloromethane

(1.5 mL), dimethyl malonate (171 mL, 1.5 mmol), N,O-bis(trimethylsilyl)-

acetamide (370 mL, 1.5 mmol) and a pinch of KOAc were added. After

2 h at room temperature, the reaction mixture was diluted with Et₂O

(5 mL) and saturated NH₄Cl (aq., 25 mL) was added. The mixture was

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Received: September 20, 2012

Revised: December 3, 2012

Published online: January 7, 2013

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Chem. Eur. J. 2013, 19, 2416 – 2432

Article Doi

A new modular phosphite-pyridine ligand library for asymmetric Pd-catalyzed allylic substitution reactions: A study of the key Pd-π-allyl intermediates

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