Preparation and resolution of a modular class of axially chiral quinazoline-containing ligands and their application in asymmetric rhodium-catalyzed olefin hydroboration

P r ep a r a tion a n d Resolu tion of a Mod u la r Cla ss of Axia lly Ch ir a l

Qu in a zolin e-Con ta in in g Liga n d s a n d Th eir Ap p lica tion in

Asym m etr ic Rh od iu m -Ca ta lyzed Olefin Hyd r obor a tion

David J . Connolly,^†Patrick M. Lacey,^†Mary McCarthy,^†Cormac P. Saunders,^†

Anne-Marie Carroll,^†Richard Goddard,^‡and Patrick J . Guiry*^,†

Centre for Synthesis and Chemical Biology, Conway Institute of Biomolecular and Biomedical Research,

Department of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland, and Max-Planck-Institut

fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mu¨lheim a. d. Ruhr, Germany

p.guiry@ucd.ie

Received May 13, 2004

The preparation and resolution of a series of axially chiral quinazoline-containing ligands is

described in which the key steps are the metal-catalyzed naphthyl-phosphorus bond formation,

the naphthalene-quinazoline Suzuki coupling, and the preparation of the Suzuki electrophilic

components from the corresponding imidate and anthranilic acid. Diastereomeric palladacycles

derived from the racemic phosphinamines and (+)-di-µ-chlorobis[(R)-dimethyl(1-(1-naphthyl)ethyl)-

aminato-C₂,N]dipalladium(II) were separated by fractional crystallization. The configuration of the

resulting diastereomers was determined by X-ray crystallographic analysis. Displacement of the

resolving agent by reaction with 1,2-bis(diphenylphosphino)ethane afforded enantiopure ligand in

each case. Their rhodium complexes were prepared and applied in the enantioselective hydroboration

of a range of vinylarenes. The quinazolinap catalysts were found to be extremely active, giving

excellent conversions, good to complete regioselectivities, and the highest enantioselectivities

obtained to date for several members of the vinylarene class, including cis-â-methylstyrene (97%),

cis-stilbene (99%), and indene (99.5%).

In tr od u ction

phinamine ligand class has received the most interest

due to the combination of steric and electronic effects

exerted on substrates at the coordination sphere of the

transition metal to which they are bound.⁶The first

successful axially chiral phosphinamine ligand, Quinap

2, was developed by Brown and incorporated a naphtha-

lene-isoquinoline backbone that possessed the necessary

steric requirements to raise the energy barrier to rotation

around the carbon-carbon bond of the biaryl linkage.

Much of the success in enantioselective homogeneous

catalysis is dependent upon the application of specifically

designed chiral ligands to important synthetic transfor-

mations. In particular, the development of atropisomeric

diphosphine ligands such as Binap 1 have found wide-

spread applicability in asymmetric hydrogenation, olefin

isomerization, allylic alkylation, the Heck reaction, and

enantioselective hydroboration.^1-5This axially chiral

diphosphine is conformationally flexible about the bi-

naphthyl linkage and can therefore accommodate a

variety of transition metals, making it the most versatile

ligand ever developed. Subsequently, the development of

axially chiral heterobidentate systems has become an

active area of research as a result of their ability to

induce asymmetry in a variety of reactions. The phos-

Quinap 2 was subsequently employed in palladium-

catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl

acetate with dimethyl malonate to afford enantiomeric

excesses of up to 98%.⁷The ligand also proved to be an

extremely active catalyst for the rhodium-catalyzed hy-

droboration of vinylarenes, with enantioselectivities of

up to 97% being achieved.^8,9

^†University College Dublin.

^‡Max-Planck-Institut fu¨r Kohlenforschung.

(1) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.

(2) (a) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; VCH:

Weinheim, 2000. (b) Noyori, R. Asymmetric Catalysis in Organic

Synthesis; Wiley: New York, 1994. (c) Brunner, H.; Zettlmeier, W.

Handbook for Enantioselective Catalysis; VCH: Weinheim, 1993. (d)

Beller, M.; Bolm, C. Transition Metals for Organic Synthesis; Wiley/

VCH: Weinheim, 1998. (e) J acobsen, E. N.; Pfaltz, A.; Yamamoto, H.

Comprehensive Asymmetric Catalysis; Springer: Berlin, 1999.

(3) Rosini, C.; Franzini, L.; Raffaelii, A.; Salvadori, P. Synthesis

1992, 503.

(6) Guiry, P. J .; McCarthy, M.; Lacey, P. M.; Saunders: C. P.; Kelly,

S.; Connolly, D. J . Curr. Org. Chem. 2000, 4, 821.

(7) Brown, J . M.; Hulmes, D. I.; Guiry, P. J . Tetrahedron 1994, 50,

4493.

(4) McCarthy, M.; Guiry, P. J . Tetrahedron 2001, 57, 3809.

(5) Kilroy, T. G.; Hennessy, A. J .; Connolly, D. J .; Malone, Y. M.;

Farrell, A.; Guiry, P. J . J . Mol. Catal. 2003, 196, 65.

(8) Doucet, H.; Brown, J . M. Tetrahedron: Asymmetry 1997, 8, 3775.

Published on Web 09/08/2004

6572

J . Org. Chem. 2004, 69, 6572-6589

Axially Chiral Quinazoline-Containing Ligands

SCHEME 1

A detailed mechanistic investigation of the alkylation

process involving both solid-state studies and NMR

experiments revealed that the 3-H of the isoquinoline

unit was involved in critical ligand-reactant interactions

believed to be significant for asymmetric induction. This

led to the development of the vaulted analogue Phenap

(3), which was also screened in Pd-catalyzed allylic

alkylation and Rh-catalyzed hydroboration, although the

enantioselectivities obtained were slightly lower than

those achieved with Quinap.^10,11

The development and resolution of the atropisomeric

ligand Pyphos 4 is also a noteworthy contribution to this

area, and its successful application in enantioselective

hydroboration has been recently reported.^12-14Our study

into the preparation and application of 2-substituted

quinazoline-containing axially chiral phoshinamines in

asymmetric catalysis was initiated with 2-phenyl-Quinazo-

linap (5) as the desired target since the naphthalene-

quinazoline pivot would be essentially inert to racemi-

sation.¹⁵In light of the mechanistic observations on

related ligand systems, the 2-position of the quinazoline

fragment (equivalent to the 3-position of Quinap) is

believed to be important for asymmetric induction.

Therefore, it was of interest to expand this 2-substituted

series in an effort to investigate the effect of steric

demand on the degree of enantioselection observed.

Additionally, the reduced basicity of the Quinazolinap

donor nitrogen (pK_aof ∼3.3 vs pK_aof ∼5.1) relative to

that of Quinap 2 could also be investigated, and the

variation of this electronic desymmetrization, combined

with steric properties, may further aid our understanding

of the enantioselection process. We subsequently com-

municated the preparation of enantiopure 2-methyl-

Quinazolinap 6, and in this article we wish to report the

synthesis and resolution of a class of 2-substituted

Quinazolinap ligands for asymmetric catalysis and their

application in asymmetric rhodium-catalyzed olefin hy-

droboration.¹⁶

i-Pr, t-Bu) with different substituents at the 2-position.

As these are not commercially available, a convenient

synthetic route to the key electrophilic components of the

Suzuki coupling was required. We have developed a facile

and versatile route to 2-substituted-4-chloroquinazolines

8a -e, the key electrophilic component of the biaryl

coupling in the ligand synthesis, Scheme 1.¹⁷

This extremely convenient route afforded the required

quinazolinone system 9a -e from the reaction of anthra-

nilic acid with a variety of preformed imidates. Subse-

quently, the corresponding 4-chloroquinazolines 8a -e

could be readily prepared by reaction with phosphorus

oxychloride. A significant feature of both reactions was

that product isolation could be facilitated by the develop-

ment of workup procedures that did not include purifica-

tion by chromatography.

The subsequent synthesis of the Quinazolinap ligands

involved two metal-catalyzed couplings, the biaryl cross-

coupling and the formation of the naphthyl-phosphorus

bond, as the key steps, Scheme 2. The electrophilic

component of the Pd-catalyzed Suzuki coupling was the

4-chloro-2-substituted-quinazolines 8a -e, and the nu-

cleophilic component for the reaction was 2-methoxy-1-

naphthylboronic acid 10. This produced the correspond-

ing 2-methoxy-1-(2-substituted-quinazolin-4-yl) naph-

thalenes 11a -f in moderate to excellent yields. The

products were subsequently demethylated using boron

tribromide in dichloromethane to afford the appropriate

naphthols 12a -f in yields ranging from 71% to 93%.

However, a low yield of 30% was obtained in the case of

the 2-benzyl variant 12d , and an alternative method for

cleavage of the methyl ether was investigated. Under the

optimized conditions of refluxing hydrogen bromide in

acetic acid, the demethylation proceeded smoothly to

furnish the desired product in an improved yield of 67%.¹⁸

The next step involved treatment of the naphthols with

Liga n d Syn th esis

To develop this modular ligand series, it was necessary

to access a range of 4-chloroquinazolines (R) Me, Ph, Bn,

(9) Doucet, H.; Fernandez, E.; Layzell, T. P.; Brown, J . M. Chem.

Eur. J . 1999, 5, 1320.

(10) Valk, J .-M.; Whitlock, G. A.; Layzell, T. P.; Brown, J . M.

Tetrahedron: Asymmetry 1995, 6, 2593.

(11) Valk, J .-M.; Claridge, T. D. W.; Brown, J . M.; Hibbs, D.;

Hursthouse, M. B. Tetrahedron: Asymmetry 1995, 6, 2597.

(12) Kwong, F. Y.; Chan, K. S. Organometallics 2000, 19, 2058.

(13) Kwong, F. Y.; Chan, K. S. Organometallics 2001, 20, 2570.

(14) Kwong, F. Y.; Yang, Q.; Mak, T. C. W.; Chan, A. S. C.; Chan,

K. S. J . Org. Chem. 2002, 67, 2769.

(15) McCarthy, M.; Goddard, R.; Guiry, P. J . Tetrahedron: Asym-

metry 1999, 10, 2797.

(16) Lacey, P. M., McDonnell, C. M.; Guiry, P. J . Tetrahedron Lett.

2000, 41, 2475.

(17) Connolly, D. J .; Guiry, P. J . Synlett 2001, 11, 1707.

(18) Binch, G.; Huisgen, R.; Ko¨nig, H. Chem. Ber. 1964, 97, 2893.

J . Org. Chem, Vol. 69, No. 20, 2004 6573

Connolly et al.

SCHEME 2

trifluoromethane sulfonic anhydride in the presence of

4-(dimethylamino)pyridine to yield the corresponding

triflates 13a -f (75-97%). The final step in the sequence

employed the procedure developed by Cai, which utilized

[1,2-bis(diphenylphosphino)ethane]dichloronickel(II) as

the catalyst and diphenylphosphine as the phosphorus

source to give the desired phosphinamines 14a -f as

racemates (62-80%).

SCHEME 3

The resolution of atropisomeric P,N ligands typically

involves diastereomeric complexation using chiral pal-

ladium amine complexes, followed by fractional crystal-

lization to facilitate the isolation of diastereomerically

pure material. In particular, the ortho-palladated deriva-

tives of (R)-dimethyl(1-phenylethyl) amine 15 and (R)-

dimethyl(1-(1-naphthyl)ethyl)amine 16 have received

significant attention.^19-23The latter system was applied

in the successful resolution of both Quinap 2, Phenap 3,

2-phenyl-Quinazolinap 5, and more recently, Pyphos

4.^11,24Because the Quinazolinap ligands are structurally

related to the isoquinoline-based systems, the initial

resolution attempts focused on the use of naphthylamine

palladium dimer 16.

In each case, the palladium dimer, (+)-di-µ-chloro-

bis[(R)-dimethyl(1-(1-naphthyl)ethyl)aminato-C₂,N]-

dipalladium(II) 16 and the relevant 2-substituted-

Quinazolinap 14a -f were dissolved in dry, degassed

methanol under a nitrogen atmosphere and stirred for

18 h at room temperature, Scheme 3. The use of dichlo-

romethane was employed in some cases as solubility

problems were encountered with methanol. The diaster-

eomeric complexes 17c-f thus formed as their chloride

salts were fractionally crystallized, and in some cases, it

was possible to access both hands of the corresponding

2-substituted-Quinazolinap. In those cases where this

was not possible, it was necessary to prepare diastereo-

meric palladacycles in which the ligands were coordi-

nated in a bidentate fashion with hexafluorophosphate

as the counterion. For each ligand system, the optimized

resolution procedure will be summarized and the ³¹P

NMR signals of the isolated diastereomers will be tabu-

lated for clarity.

(19) Otsuka, S.; Nakamura, A.; Kano, T.; Tani, K. J . Am. Chem.

Soc. 1971, 93, 4301.

(20) Tani, K.; Brown, L. D.; Ahmed, J .; Ibers, J . A.; Yokota, M.;

Nakamura, A.; Otsuka, S. J . Am. Chem. Soc. 1977, 99, 7876.

(21) Leung, P. H.; Loh, S.; Mok, K. F.; White, A. J . P.; Williams, D.

J . Tetrahedron: Asymmetry 1996, 7, 45.

(22) Leung, P. H.; Loh, S.; Mok, K. F.; White, A. J . P.; Williams, D.

J . J . Chem. Soc., Chem. Commun. 1996, 591.

(23) Kerr, P. G.; Leung, P. H.; Wild, S. B. J . Am. Chem. Soc. 1987,

109, 4321.

When the resolution of 2-phenyl-Quinazolinap 14c was

attempted, a precipitate of one diastereomer was isolated

after the initial mixing period, Scheme 3. This material

was recrystallized from chloroform/pentane by isothermal

(24) Alcock, N. W.; Brown, J . M.; Hulmes, D. I. Tetrahedron:

Asymmetry 1993, 4, 743.

6574 J . Org. Chem., Vol. 69, No. 20, 2004

Axially Chiral Quinazoline-Containing Ligands

TABLE 1. ³¹P NMR Sign a ls of Isola ted

Dia ster eom er ica lly P u r e Com p lexes

entry

R in ligand

compound

X^-

(R,R)

(S,R)

1

H

Me

Ph

18a

18b

17c

18c

17d

17e

18e

17f

18f

PF₆

Cl

PF₆

Cl

PF₆

Cl

41.2

39.9

37.5

2

3¹⁵

40.0

45.1

45.5

35.2

4

5

Bn

i-Pr

42.4

42.7

6

t-Bu

43.8

43.7

PF₆

42.2

SCHEME 4

F IGURE 1. Structure of the cation in (S,R)-18b‚0.2H₂O.

Selected distances (Å) and angles (deg): Pd-P1 2.2423(5), Pd-

N1 2.187(2), Pd-N3 2.147(2), Pd-C32 1.978(3), Pd‚‚‚C9 3.146-

(3), P1-Pd-N1 82.34(6), N3-Pd-C32 80.2(1), P1-Pd-N3

155.3(1), N1-Pd-C32 171.0(1), plane(Pd, P1, N1)/plane(Pd,

N3, C32) 28(2).

diffusion to afford crystals suitable for X-ray crystal-

lographic analysis. The diastereomer was found to have

the (R,R)-configuration 17c. In this instance, the ligand

was bound to palladium in a monodentate fashion and

only a single peak at 40.0 ppm was evident by ³¹P NMR

spectroscopy, Table 1, entry 3.¹⁵Furthermore, it later

proved possible to precipitate (S,R)-18c from the residual

solution by the addition of KPF₆, which suggests a

bidentate coordination of the ligand to palladium, Scheme

4.

F IGURE 2. Structure of the cation in (S,R)-18a ‚2CHCl₃.

Selected distances (Å) and angles (deg): Pd-P1 2.256(2), Pd-

N1 2.189(5), Pd-N3 2.132(5), Pd-C31 2.002(6), P1-Pd-N1

84.7(1), N3-Pd-C31 80.4(2), P1-Pd-N3 165.9(2), N1-Pd-

C31 171.2(2), plane(Pd, P1, N1)/plane(Pd, N3, C31) 17(2).

In the case of the palladacycle derived from 2-methyl-

Quinazolinap, the addition of KPF₆to the reaction mix-

ture precipitated both diastereomers 18b in a 1:1 ratio,

Scheme 4, and a range of solvent systems were tested to

effect their separation. The use of a chloroform/diethyl

ether/trace water combination afforded diastereomeri-

cally pure material that resonated at 37.5 ppm in the

³¹P NMR spectrum, Table 1, entry 2, and was shown to

have the (S,R)-configuration by X-ray analysis, Figure

1. Unfortunately all attempts to isolate (R,R)-18b were

unsuccessful.

bond. A key resonance at 125 ppm in the ³¹P NMR

spectrum, characteristic for bound phosphinites, further

supported the structure of this impurity as (R)-[dimethyl-

(1-(1-naphthyl)ethyl)aminato-C₂,N]-[methyl(diphenyl)-

phosphite] palladium(II)chloride 19. It is significant that

there have been no previously reported examples of such

behavior with palladium, although Pregosin has reported

an analogous P-C bond cleavage in a ruthenium com-

plex.²⁵

Similarly, the Quinazolinap diastereomers 18a were

formed as their hexafluorophosphate salts, Scheme 4, and

fractional crystallization of the mixture from butanone/

diethyl ether afforded a palladacycle with a ³¹P NMR

resonance at 39.9 ppm, Table 1, entry 1, which was later

assigned as (S,R)-18a by X-ray crystallography (recrys-

tallized from chloroform/diethyl ether), Figure 2.

Palladacycle (R,R)-18a was subsequently isolated from

the filtrate with an optimal diastereomeric ratio of 96:4

by recrystallization from chloroform. Interestingly, spec-

troscopic evidence indicated that an unusual methanoly-

sis had occurred during the initial binding process,

resulting from the cleavage of the naphthyl-phosphorus

On the other hand, the 2-benzyl-Quinazolinap diastereo-

mers were formed as their chloride salts 17d , Scheme 3,

and were separated as a result of solubility differences.

An insoluble precipitate, which corresponded to a single

peak at 45.5 ppm by ³¹P NMR spectroscopy, Table 1,

(25) Geldbach, T. J .; Pregosin, P. S. Eur. J . Inorg. Chem. 2002, 1907.

J . Org. Chem, Vol. 69, No. 20, 2004 6575

Connolly et al.

F IGURE 5. Structure of (R,R)-17f. Selected distances (Å) and

angles (deg): Pd-P 2.250(1), Pd-Cl 2.390(1), Pd-N3 2.145-

(2), Pd-C35 2.007(2), P-Pd-C35 94.8(1), N3-Pd-C35 80.8-

(1), P-Pd-N3 174.1(1), Cl-Pd-C35 167.5(1), mean plane-

(naphthyl)/mean plane(quinazolinyl) 86(2).

F IGURE 3. Structure of (S,R)-17d . Selected distances (Å) and

angles (deg): Pd-P 2.264(1), Pd-Cl 2.374(1), Pd-N3 2.151-

(4), Pd-C38 2.023(4), P-Pd-C38 95.7(1), N3-Pd-C38 80.9-

(1), P-Pd-N3 173.2(1), Cl-Pd-C38 168.9(1), mean plane-

(naphthyl)/mean plane(quinazolinyl) 72(3).

linap ligand is almost identical in both (S,R)-18e (R )

i-Pr) and (S,R)-18b (R ) Me) despite different crystal

environments but different from that in (S,R)-18a (R )

H). The most likely reason is repulsive steric interaction

between the 2-substituent and one of the methyl groups

on N3 of the neighboring dimethyl(1-(1-naphthyl)ethyl)-

amine ligand, though a weakly attractive C-H‚‚‚Pd

interaction between the H atom on the R-C atom of the

2-substituent and the cationic metal atom center cannot

be ruled out. Subsequent recrystallizations to isolate the

(R,R)-palladacycle 18e were unsuccessful and resulted

in the formation of oils rather than crystals. In an

attempt to access (R)-2-isopropyl-Quinazolinap 14e, pal-

ladacycles 17e were reformed as their chloride salts,

Scheme 3, and were fractionally crystallized using dif-

ferent solvent systems. The chloroform/diethyl ether

combination enabled the isolation of diastereomerically

pure material as indicated by the existence of one peak

at 42.7 ppm in the ³¹P NMR spectrum. The remaining

diastereomer in the filtrate was found to be insoluble in

diethyl ether, and a single peak at 45.5 ppm was observed

in the ³¹P NMR spectrum. Subsequent decomplexation

of (S,R)-18e and diastereomerically pure 17e coupled

with a comparison of the optical rotation of the isolated

ligands would allow for the correct assignments of the

parent diastereomers 17e.

F IGURE 4. Structure of the cation in (S,R)-18e. Selected

distances (Å) and angles (deg): Pd-P1 2.238(2), Pd-N1 2.192-

(5), Pd-N3 2.164(6), Pd-C34 1.993(6), Pd‚‚‚C9 3.205(6), P1-

Pd-N1 84.6(2), N3-Pd-C34 80.9(2), P1-Pd-N3 152.9(2),

N1-Pd-C34 166.7(2), plane (Pd, P1, N1)/plane (Pd, N3, C34)

32(2).

entry 4, was isolated after stirring the diastereomeric

mixture in diethyl ether. A chloroform/diethyl ether

mixture was then employed to form X-ray quality crystals

of this complex, which was assigned the (S,R)-configu-

ration, Figure 3.

The filtrate was subsequently reduced in vacuo to

furnish (R,R)-17d , and a singlet at 42.4 ppm was evident

in its ³¹P NMR spectrum.

A 1:1 mixture of the (R,R)- and (S,R)-2-isopropyl-

Quinazolinap complex 18e was formed as their hexafluo-

rophosphate salts, Scheme 4. Analogous to the resolution

of 2-methyl-Quinazolinap 18b, a chloroform/diethyl ether

mixture was successful for fractional crystallization of

the diastereomeric mixture, Table 1, entry 5.

The isolated diastereomer 18e (crystallized from chlo-

roform/pentane) was shown to have (S,R)-configuration

by X-ray crystallography with bidentate coordination of

the ligand to palladium, Figure 4. Interestingly, the

introduction of a substituent into the 2-position on the

Quinazolinap ligand in the dimethyl(1-(1-naphthyl)eth-

yl)amine diastereomers results in a change in both the

conformation of the ligand and the coordination geometry

of the Pd atom. Thus, the conformation of the Quinazo-

The 2-tert-butyl-substituted quinazoline complex 17f

was formed as a 1:1 mixture of diastereomers when

dichloromethane was employed as solvent, Scheme 3.

Fractional crystallization of the mixture from hot bu-

tanone/diethyl ether afforded a yellow solid that was

subsequently stirred in methanol. The ³¹P NMR spectrum

had a peak at 43.8 ppm corresponding to a single

diastereomer, Table 1, entry 6. Additionally, a sample

suitable for X-ray crystallographic analysis was prepared

from a dichloromethane/diethyl ether combination and

was assigned as (R,R)-17f, Figure 5.

All attempts to isolate the (S,R)-palladacycle 17f failed.

Therefore, the diastereomers were reformed as their

chloride salts, and potassium hexafluorophosphate was

added to facilitate counterion exchange, Scheme 4. The

corresponding (R,R)-18f and (S,R)-18f were later isolated

in a 1:1 ratio. The resultant solid was stirred in methanol

and filtered to yield a single diastereomer of unknown

6576 J . Org. Chem., Vol. 69, No. 20, 2004

Axially Chiral Quinazoline-Containing Ligands

SCHEME 5

Rh od iu m -Ca ta lyzed Asym m etr ic Hyd r obor a tion

The development of transition-metal-catalyzed hy-

droboration has been extensively investigated since the

initial report by Ma¨nning and No¨th, in which catecholbo-

rane was found to add to a range of alkenes in the

presence of Wilkinson’s catalyst.²⁶Burgess later demon-

strated an enantioselective process based upon the use

of chiral transition metal catalysts, which included the

application of Binap- and Diop-derived rhodium species

with norbornene as the substrate.²⁷Hayashi later im-

proved the enantiomeric excesses for the hydroboration

of styrenes (up to 96% ee at -78 °C) employing rhodium-

Binap complexes.²⁸The catalytic variant of hydroboration

offered potential advantages in terms of chemo-, regio-,

and enantioselectivity. Subsequently, the search for

successful catalysts was expanded to include phosphin-

amines; for example, the ferrocenyl pyrazole ligands (98%

ee), the axially chiral Quinap (97% ee), and Phenap (84%

ee) ligands were reported by Togni and Brown, respec-

tively.^29,30As previously mentioned, our research labo-

ratories and the group of Chan have also applied novel

axially chiral phosphinamine systems in asymmetric

hydroboration with considerable success.^13,14,31Brown has

also extended the standard hydroboration-oxidation se-

quence to include the synthetically important hydrobo-

ration-amination protocol.³²This methodology has been

directed toward a formal synthesis of the antidepressant

Sertraline where an efficient kinetic resolution was

demonstrated in the Quinap-mediated hydroboration.³³

The construction of carbon-carbon bonds from boronate

esters, allowing the preparation of optically active 2-aryl-

propionic acids, has also received attention since the

nonsteroidal antiinflammatory agents such as ibuprofen

and naproxen are among this class of compounds.^34-36

In an important contribution, the Ferna´ndez group has

focused their efforts on the development of a recyclable

hydroboration process.^40,41Attempts to increase the range

of substrates to include cyclopropenes have recently been

investigated, as well as developments toward the estab-

lishment of an iridium-catalyzed asymmetric variant.^39,40

We now wish to report in full our investigations into the

configuration (single peak at 43.7 ppm by ³¹P NMR).

Subsequently, the filtrate was recrystallized from hot

methanol, and analysis of the ³¹P NMR spectrum re-

vealed a diastereomeric ratio of 96:4 with the major

resonance at 42.2 ppm. Further attempts to isolate

diastereomerically pure material proved unsuccessful. To

assign the configuration of the 2-tert-butyl palladium

complexes 18f, a strategy similar to that employed above

for the 2-isopropyl diastereomers 17e was used, as we

had previously isolated (R,R)-17f.

(26) Ma¨nnig, D.; No¨th, H. Angew. Chem., Int. Ed. Engl. 1985, 24,

878.

(27) Burgess, K.; Ohlmeyer, M. J . J . Org. Chem. 1988, 53, 5178.

(28) Hayashi, T.; Matsumoto, Y.; Ito, K. J . Am. Chem. Soc. 1989,

111, 3426.

(29) Schnyder, A.; Hintermann, L.; Togni, A. Angew. Chem., Int. Ed.

Engl. 1995, 34, 931.

(30) Brown, J . M.; Hulmes, D. I.; Layzell, T. P. J . Chem. Soc., Chem.

Commun. 1993, 1673.

Decom p lexa tion of Resolved P a lla d a cycles

(31) Guiry, P. J .; Hooper, M. W.; McCarthy, M. Chem. Commun.

2000, 1333.

Enantiopure 2-substituted-Quinazolinap ligands 14a -f

were obtained by decomplexation of the corresponding

diastereomeric palladium complexes using 1,2-bis(di-

phenylphosphino)ethane in dichloromethane, Scheme 5.

In each case, the enantiopure ligand was isolated in

excellent yield and was also found to be configurationally

stable even after refluxing in toluene for 7 days. This was

confirmed by optical rotation and by rebinding the ligand

with palladium dimer 16 followed by subsequent analysis

(32) Ferna`ndez, E.; Maeda, K.; Hooper, M. W.; Brown, J . M. Chem.

Eur. J . 2000, 6, 1840.

(33) Maeda, K.; Brown, J . M. Chem. Commun. 2002, 310.

(34) Ren, L.; Crudden, C. M. Chem. Commun. 2000, 721.

(35) Chen, A. C.; Ren, L.; Crudden, C. M. Chem. Commun. 1999,

611.

(36) Chen, A.; Ren, L.; Crudden, C. M. J . Org. Chem. 1999, 64, 9704.

(37) Segarra, A. M.; Guerrero, R.; Claver, C.; Ferna`ndez, E. Chem.

Commun. 2001, 1808.

(38) Segarra, A. M.; Guerrero, R.; Claver, C.; Ferna`ndez, E. Chem.

Eur. J . 2003, 9, 191.

(39) Rubina, M.; Rubin, M.; Gevorgyan, V. J . Am. Chem. Soc. 2003,

125, 7198.

(40) Pe´rez Luna, A.; Bonin, M.; Micouin, L.; Husson, H.-P. J . Am.

Chem. Soc. 2002, 124, 12098.

(41) Freshly distilled substrate and catecholborane were used for

optimum catalytic performance.

1

of the H/³¹P NMR spectra obtained. Ligands (R)-14c-f

were isolated from (R,R)-17c-f and (R,R)-18f, Scheme

5a, whereas (S)-14a -e were isolated from (S,R)-17c-e

and (S,R)-18a -c and e, Scheme 5b.

J . Org. Chem, Vol. 69, No. 20, 2004 6577

Connolly et al.

TABLE 2. Hyd r obor a tion of Styr en e

SCHEME 6

entry R group temp (°C) conversion (%)

R:â

ee (%)

1

2

3

4

5

6

7

8

H

Me

Ph

Bn

i-Pr

t-Bu

20

0

20

0

20

0

20

0

20

0

20

0

100

95

84:16 86 (S)

81:19 71 (S)

88:12 90 (S)

76:24 83 (S)

68:32 63 (S)

80:20 79 (S)

85:15 87 (S)

86:14 87 (S)

77:33 87 (S)

73:27 70 (S)

80:20 84 (R)

66:34 68 (R)

SCHEME 7

100

9

10

11

12

application of the Quinazolinap ligands 14a -f in the

rhodium-catalyzed hydroboration of vinylarenes.

In Situ F or m a tion of 2-Su bstitu ted -Qu in a zolin a p

Ca ta lysts

ture.⁴²The highest enantioselectivity of 90% and regio-

selectivity of 88:12 were obtained in the same reaction

with complex 20b (R ) Me, entry 3). It is interesting to

note that the degree of enantioselection observed with

the 2-unsubstituted, 2-benzyl, and 2-isopropyl-Quinazo-

linap ligands was relatively constant at room tempera-

ture (86-87% ee) (entries 1, 7, and 9). However, decreas-

ing the reaction temperature proved detrimental to the

regioselectivity and enantioselectivity of hydroboration

of styrene as a general trend. In contrast, low tempera-

tures were necessary to obtain high enantioselectivies

with Binap 1 (96% ee), although complete regioselectivi-

ties were also observed at this temperature. The regio-

selectivities obtained for the hydroboration of styrene

with rhodium complexes of Quinap 2 and Pyphos 4 were

superior, and the enantiomeric excesses of 88% and 90%,

respectively, mirrored closely those achieved with our

quinazoline-containing ligands.⁴³Additionally, an attenu-

ated enantiomeric excess of 67% was obtained with the

vaulted analogue Phenap 3, although a respectable R:â

ratio of 94:6 was produced.

Almost quantitative conversions were obtained in all

cases at room temperature with 4-methoxystyrene 22 as

the substrate. As observed with styrene, a maximum

enantioselectivity of 95% and regioselectivity of 88:12 was

obtained with the 2-methyl catalyst system 20b, Table

3, entry 3. An enantiomeric excess of 92% was produced

on increasing the size of the 2-substituent to an isopropyl

group, although this was coupled with a less favorable

regiochemistry of 76:24, entry 9. Both Quinazolinap 14a

and 2-tert-butyl-Quinazolinap 14f gave excellent enan-

tioselection (91%) at room temperature, but the effect of

the bulky tert-butyl group led to a slight decrease in the

ratio of R-alcohol formed, entries 1 and 11. Additionally,

lowering the reaction temperature had a deleterious

effect on the enantio- and regioselectivity of the hydrobo-

ration. Clearly, these results demonstrate that an electron-

releasing substituent on styrene has a favorable effect

The cationic Rh-catalysts (S)-20a -e were prepared

from cycloocta-1,5-diene-(pentane-2,4-dionato)rhodium-

(I), enantiopure (S)-phosphinamines 14a -e, and tri-

methyl-silyltrifluoromethanesulfonate, Scheme 6. As only

enantiopure (R)-2-tert-butyl-Quinazolinap was available,

the corresponding rhodium complex (R)-20f was prepared

in an identical procedure. Because of the susceptibility

of these complexes to oxidation, the catalyst was prepared

in situ immediately prior to each reaction. A comprehen-

sive study of vinylarenes was undertaken in an attempt

to understand the effect of reactivity and enantioselec-

tivity with differing aryl substituents and â-substitution

on styrene.⁴¹Furthermore, the cyclic olefins, indene and

1,2-dihydronaphthalene, which are two of the most

challenging substrates in the Rh-catalyzed hydrobora-

tion, were also screened in the present study.

The procedure involved the addition of 0.5 mmol of

catecholborane to a 1 mol % solution of the rhodium-

catalyst dissolved in dry THF. The olefin (0.5 mmol) was

added, and the reaction was stirred for the required time

at either room temperature or 0 °C, Scheme 7. The

reaction mixture was cooled in ice, and the product

borane was oxidized directly with a H₂O₂/NaOH combi-

nation over a 1 h period. After this time, the reaction

mixture was extracted into diethyl ether, and the catechol

side product was removed by washing with sodium

hydroxide and saturated brine. The percent conversion

and regioselectivity were calculated by ¹H NMR spec-

troscopy, and the enantiomeric excess was determined

by the use of either chiral GC or HPLC. Optical rotation

values from the literature were used to assign the

absolute configuration of the alcohol products. In all cases

the (S)-enantiomer was the favored product when rhod-

ium complexes (S)-20a -e were employed. [As expected

rhodium complex (R)-20f furnished the (R)-product.]

The 2-substituted-Quinazolinap-derived rhodium com-

plexes proved extremely efficient catalysts for the hy-

droboration of styrene 21 at room temperature and at 0

°C, Table 2. In all but one case, quantitative conversions

were obtained after just 2 h at the relevant tempera-

(42) The hydroboration of styrene with both Quinazolinap- and

Quinap-derived rhodium complexes was complete after 2 h at ambient

temperature, whereas an extended reaction time of 12 h was necessary

for complete reaction with Pyphos at this temperature.

(43) Regioselectivities of 97:3 and 99:1 were obtained with Quinap

and Pyphos, respectively.

6578 J . Org. Chem., Vol. 69, No. 20, 2004

Axially Chiral Quinazoline-Containing Ligands

TABLE 3. Hyd r obor a tion of 4-Meth oxystyr en e

TABLE 5. Hyd r obor a tion of Tr a n s-â-m eth ylstyr en e

entry ligand time temp (°C) conversion (%) R:â

ee (%)

1

2

3

4

5

6

7

8

H

Me

Ph

Bn

i-Pr

t-Bu

2

24

2

4

2

20

0

20

0

20

0

20

0

20

0

20

0

54

50

93

92:8

93:7

94:6

91:9

96:4

93:7

92:8

91:9

89 (S)

82 (S)

94 (S)

95 (S)

94 (S)

85 (S)

80 (S)

92 (S)

88 (S)

96

entry R group temp (°C) conversion (%)

R:â

ee (%)

100

64

1

2

3

4

5

6

7

8

H

Me

Ph

Bn

i-Pr

t-Bu

20

0

20

0

20

0

20

0

20

0

20

0

100

93

99

81:19 91 (S)

77:23 90 (S)

88:12 95 (S)

70:30 91 (S)

75:25 77 (S)

77:23 81 (S)

78:22 89 (S)

75:25 86 (S)

76:24 92 (S)

76:24 84 (S)

78:22 91 (R)

55:45 65 (R)

67

9

100

97

10

11

12

4

2

4

87:13 91 (S)

94:6

92:8

100

91

100

67

86 (R)

91 (R)

100

9

11. It appears that the presence of an electron-withdraw-

ing substituent on styrene has a significant impact on

the enantioselection but not on the regioselectivity of the

hydroboration.

10

11

12

99

100

The effect of varying the electronics on enantioselec-

tivity was less pronounced with Binap, although chang-

ing from a 4-methoxy (89% ee) to a 4-chloro (91% ee)

substituent did result in a slight increase in enantiose-

lection.²⁸4-Methoxystyrene was hydroborated in 94% ee

with Quinap- and Pyphos-derived rhodium complexes,

yet a slightly higher regioselectivity was produced in the

latter case (98:2 vs 96:4). With 4-chlorostyrene as sub-

strate, lowered enantiomeric excesses of 78% and 79%

were obtained with Quinap and Pyphos, accompanied by

high regioselectivities of 96:4 and 99:1, respectively.

Whereas the enantioselection observed with our modular

Quinazolinap series is comparable, if not superior, to

other axially chiral systems applied, they are limited in

terms of regiochemical control.

However, substitution of the vinylarene double bond

results in a marked reduction in the enantioselectivity

with Binap and other diphosphines. In contrast, the

application of P,N-ligand systems to more sterically

demanding substrates leads to an overall increase in

enantioselection. Therefore, it is of interest to apply our

quinazoline-containing phosphinamines to the hydrobo-

ration of â-substituted substrates, as well as those with

differing aromatic substitution patterns.

TABLE 4. Hyd r obor a tion of 4-Ch lor ostyr en e

entry R group temp (°C) conversion (%)

R:â

ee (%)

1

2

3

4

5

6

7

8

H

Me

Ph

Bn

i-Pr

t-Bu

20

0

20

0

20

0

20

0

20

0

20

0

100

99

83:17 81 (S)

75:25 64 (S)

88:12 77 (S)

79:21 70 (S)

78:22 46 (S)

83:17 49 (S)

81:19 71 (S)

79:21 64 (S)

81:19 73 (S)

77:23 61 (S)

84:16 70 (R)

81:19 70 (R)

98

100

92

9

10

11

12

100

99

The most obvious benefit of â-substitution, for instance

with (E)-â-methyl-styrene 24, was the marked increase

in regioselectivity compared to that of the unsubstituted

styrene derivatives, Table 5. An optimum enantioselec-

tivity of 95% was obtained with the 2-methyl rhodium

complex 20b, entry 4, while the ee range was 80-94%

irrespective of the ligand 2-substitution pattern. A fur-

ther observation was the reduced conversion obtained

with Quinazolinap 14a at room temperature, which was

further exacerbated at low temperature, where an ex-

tended reaction period of 24 h was required for a 50%

conversion, entries 1 and 2. The effect of the trans-alkene

stereochemistry on the reaction progress was less pro-

nounced with 2-phenyl, 2-isopropyl, and 2-tert-butyl-

Quinazolinap, as quantitative conversions were obtained

after 4 h at 0 °C, entries 6, 10, and 12. Overall, the

on the enantioselection, while the regiochemistry can be

adversely affected by these electronic differences.

On changing from an electron-releasing to an electron-

withdrawing substituent, a marked reduction in the

enantioselectivity was observed. The best enantioselec-

tion in the hydroboration of 4-chlorostyrene 23 of 81%

was achieved with Quinazolinap 14a coupled with an R:â

ratio of 87:13, Table 4, entry 1. Surprisingly, the influence

of a 2-phenyl group in the quinazoline ring had a

detrimental effect on the enantioselection of the reaction,

entries 5 and 6, whereas a comparable effect was not

observed with a 2-benzyl substituent, entries 7 and 8.

The more sterically encumbered 2-isopropyl and 2-tert-

butyl substituents produced enantiomeric excesses of 73%

and 70% at room temperature, respectively, entries 9 and

J . Org. Chem, Vol. 69, No. 20, 2004 6579

Connolly et al.

TABLE 7. Hyd r obor a tion of tr a n s-An eth ole

TABLE 6. Hyd r obor a tion of cis-â-Meth ylstyr en e

entry ligand time temp (°C) conversion (%) R:â

ee (%)

1

2

3

4

5

6

7

8

H

Me

Ph

Bn

i-Pr

t-Bu

2

20

0

20

0

20

0

20

0

20

0

20

0

96

85

97

99:1

92:8

94:6

99:1

98:2

96:4

93:7

91:9

94 (S)

92 (S)

95 (S)

97 (S)

91 (S)

88 (S)

90 (S)

96 (S)

90 (S)

93 (R)

100

95

100

entry ligand time temp (°C) conversion (%) R:â

ee (%)

1

2

3

4

5

6

7

8

H

Me

Ph

Bn

i-Pr

t-Bu

2

20

0

20

0

20

0

20

0

20

0

20

0

51

29

78

89

87

72

77

31

51

97

88

100

78:22 88 (S)

80:20 78 (S)

86:14 92 (S)

88:12 97 (S)

88:12 88 (S)

89:11 92 (S)

85:15 88 (S)

68:32 90 (S)

77:23 93 (S)

68:32 87 (S)

89:11 90 (R)

83:17 91 (R)

9

10

11

12

90:10 71 (R)

9

2-substituted-Quinazolinap series was found to be more

effective than Binap (42% ee) for the hydroboration of

trans-â-methyl styrene and gave results comparable to

those of Quinap (95% ee), although complexes of the

latter were more regioselective (99:1).

10

11

12

24

2

24

trans-â-methyl styrene, lower regioselectivities were

observed as a consequence of the additional 4-methoxy

aromatic substituent. Our highest enantioselectivity of

97% for trans-anethole (2-methyl-complex 20b) equals

that reported for Quinap,³⁰although a more favorable

regiochemistry of 99:1 was achieved with the isoquino-

line-derived rhodium complex.

A distinct improvement in regioselectivity was evident

on hydroboration of cis-â-methylstyrene 25 compared to

its trans-isomer 24. The smaller quinazoline 2-substit-

uents proved to be more regioselective catalysts (99:1)

compared to the bulkier ligand substituents, Table 6,

entries 1-4 vs entries 5-12. In addition, lowering the

reaction temperature slightly decreased the R:â ratio

when rhodium complexes of 2-benzyl, 2-isopropyl, and

2-tert-butyl-Quinazolinap were employed, entries 7-12.

An optimum enantiomeric excess of 97% was obtained

at 0 °C with the 2-methyl variant 20b, entry 4, whereas

the highest enantioselection (96%) at room temperature

was produced with the 2-isopropyl-derived rhodium

complex 20e, entry 9. These are the best results reported

to date for the hydroboration of cis-â-methylstyrene.

Furthermore, a significantly enhanced conversion was

observed on changing from a trans- to cis-alkene stereo-

chemistry with Quinazolinap rhodium complexes 20a ,

which highlights the difference in reactivity between the

two substrates, Table 5, entries 1 and 2 vs Table 6,

entries 1 and 2. In general, our 2-substituted-Quinazo-

linap series compares most favorably with Binap (18%),

whereas the 2-methyl and 2-isopropyl variants 20b and

20e, respectively, perform better than Quinap (93%) with

this sterically demanding substrate.

Similarly, the alkene stereochemistry of trans-anethole

26 had a detrimental effect on the conversion when

Quinazolinap-derived rhodium complexes 20a were em-

ployed, although a sluggish rate of reaction was also

observed with the 2-benzyl variant at 0 °C, Table 7,

entries 2 and 8. However, excellent conversions of 97%

and 100% were obtained using the 2-isopropyl and 2-tert-

butyl rhodium complexes 20e and 20f, respectively, after

24 h at low temperature, entries 10 and 12. An optimum

enantioselectivity of 97% was obtained with the 2-methyl

complex 20b, accompanied by a regioselectivity of 88:12,

entry 4. Unexpectedly, increased enantioselectivities

were produced at 0 °C with the 2-methyl, 2-phenyl,

2-benzyl, and 2-tert-butyl complexes. In comparison to

Surprisingly, a more favorable regiochemistry was

obtained with trans-3,4-dimethoxy-â-methyl styrene 27

relative to that of trans-anethole 26. However, as ex-

pected the hydroboration progress was attenuated with

the Quinazolinap catalyst 20a even at room temperature,

Table 8, entry 1. The enantiomeric excess and conversion

were improved at low temperature, although a 24-h

reaction period was required, entry 2. The best enantio-

selectivity of 98% was obtained using 2-methyl-Quinazo-

linap at 0 °C, entry 4. In addition, a higher degree of

enantioselection and regiocontrol was obtained with the

2-phenyl rhodium complex 20c compared to that of the

2-benzyl, 2-isopropyl, and 2-tert-butyl analogues 20d -f,

entries 5-8.

A significantly attenuated conversion was apparent in

all cases on application of the more sterically demanding

(E)-stilbene 28 substrate. This was exemplified by the

Quinazolinap-derived rhodium complex 20a , as there was

no reaction even after 24 h at room temperature, Table

9, entry 1. Similarly, there was no evidence of product

formation when 2-phenyl-Quinazolinap 14c was em-

ployed, entry 5. Again, the steric influence of 2-methyl

variant 20b proved optimal, and the highest enantiose-

lectivity and conversion of 87% and 50%, respectively,

were obtained after 21 h, entry 2. Moderate to good

enantiomeric excesses were observed with the 2-benzyl,

2-isopropyl, and 2-tert-butyl analogues, although the

reactions were also characterized by poor yields, entries

7-12. Additionally, although the hydroboration of trans-

stilbene 28 was slow with Quinap 2 as ligand (45

turnovers in 20 h), a respectable enantioselectivity of 85%

was obtained.

6580 J . Org. Chem., Vol. 69, No. 20, 2004

Axially Chiral Quinazoline-Containing Ligands

TABLE 8. Hyd r obor a tion of

tr a n s-3,4-Dim eth oxy-â-m eth yl Styr en e

TABLE 10. Hyd r obor a tion of Cis-stilben e

entry

ligand

time

temp (°C)

conversion (%)

ee (%)

1

2

3

4

5

6

7

8

H

Me

Ph

Bn

i-Pr

t-Bu

2

24

2

20

0

20

0

20

0

20

0

20

0

20

0

73

97

96

92 (S)

95 (S)

97 (S)

59 (S)

62 (S)

89 (S)

99 (S)

95 (S)

96 (R)

97 (R)

82

100

83

81

84

60

71

80

entry ligand time temp (°C) conversion (%) R:â

ee (%)

9

1

2

3

4

5

6

7

8

H

Me

Ph

Bn

i-Pr

t-Bu

2

24

2

24

2

24

2

20

0

20

0

20

0

20

0

20

0

20

0

35

68

86

75

62

65

77

74

72

55

76

88:12 76 (S)

86:14 93 (S)

10

11

12

2

93:7

92:8

93:7

91:9

95 (S)

98 (S)

94 (S)

93 (S)

TABLE 11. Hyd r obor a tion of In d en e

90:10 90 (S)

85:15 84 (S)

82:18 91 (S)

87:13 85 (S)

90:10 86 (R)

70:30 59 (R)

9

10

11

12

24

TABLE 9. Hyd r obor a tion of tr a n s-Stilben e

entry ligand time temp (°C) conversion (%) R:â

ee (%)

1

2

3

4

5

6

7

8

H

Me

Ph

Bn

i-Pr

t-Bu

2

20

0

20

0

20

0

20

0

20

0

20

0

83

39

100

95

98

99

88

100

98:2

97:3

>99:1 99.5 (S)

90 (S)

98 (S)

99:1

98:2

99:1

97:3

98:2

97:3

94:6

97:3

99 (S)

84 (S)

81 (S)

82 (S)

86 (S)

84 (S)

81 (S)

72 (R)

80 (R)

entry

ligand

time

temp (°C)

conversion (%)

ee (%)

9

1

2

4

5

7

8

9

10

11

12

H

24

21

24

2

24

2

24

2

20

0

20

0

20

0

20

0

10

11

12

Me

Ph

Bn

i-Pr

t-Bu

50

16

87 (S)

80 (S)

7

17

7

18

15

6

77 (S)

69 (S)

64 (S)

59 (S)

65 (R)

53 (R)

work was striking, as a quantitative conversion, an

enantiomeric excess of 99.5%, and complete regioselec-

tivity was observed, entry 3. This represents the highest

result reported for the hydroboration of indene. The

catalyst system was also highly efficient at 0 °C, affording

a 99% enantioselectivity and R:â ratio of 99:1, entry 4.

Interestingly, the degree of enantioselection (ca. 81-86%

ee) was comparable with that of the 2-phenyl, 2-benzyl,

2-isopropyl, and 2-tert-butyl catalyst systems, entries

5-12. The decrease in enantiomeric excess with larger

2-substituents indicates that a less sterically demanding

ligand can more easily accommodate the cyclic substrate,

and this has a profound effect on the catalytic chemistry

observed. On the whole, the Quinazolinap series are

superior to all other ligand systems reported for the

hydroboration of indene, as an enantiomeric excess of just

19% was obtained with Binap, whereas Quinap and

Phenap afforded ee’s of 76% and 64%, respectively.

Excellent regioselectivities were obtained in all cases

with 1,2-dihydronaphthalene 31 as the substrate. The

2-methyl complex 20b produced the highest enantiomeric

excess of 93% at 0 °C, entry 4, followed by the 2-tert-

butyl catalyst system 20f, which afforded an enantiose-

lectivity of 90%, Table 12, entries 4 and 12. In general,

lowering the reaction temperature led to a reduction in

24

The hydroboration of cis-stilbene 29 occurred rapidly

at room temperature and at 0 °C compared to its trans-

isomer 28. Excellent enantioselectivities were obtained

with the 2-alkyl-substituted rhodium complexes, whereas

a sharp decrease in enantiomeric excess was observed

with the 2-phenyl complex 20c, Table 10, entries 5 and

6. An optimal enantioselectivity of 99% was produced on

application of the 2-isopropyl complex 20e and is the best

result reported to date for the hydroboration of cis-

stilbene, entry 9. Furthermore, an enantiomeric excess

of 97% was obtained with the 2-methyl and 2-tert-butyl

rhodium complexes, entries 3, 4, and 12. Quinap 2 was

also an effective catalyst with this substrate and afforded

(R)-1,2-diphenyl ethanol in 91% ee and 86% yield.

An excellent enantioselectivity of 98% was achieved in

the hydroboration of indene 30 with the Quinazolinap-

derived ligand system 20a , although the conversion was

moderate at low temperature, Table 11, entry 2. The

introduction of a 2-methyl group into the ligand frame-

J . Org. Chem, Vol. 69, No. 20, 2004 6581

Connolly et al.

TABLE 12. Hyd r obor a tion of 1,2-Dih yd r on a p h th a len e

excesses for several members of the vinylarene class.

Further studies into electronic effects in enantioselective

hydroboration are currently underway and will form the

basis of future publications from these laboratories.

Exp er im en ta l Section

Gen er a l Meth od s. Melting points were determined using

a standard melting point apparatus and are uncorrected.

Infrared spectra were recorded on an infrared FT spectrom-

eter. The Microanalytical Laboratory, University College Dub-

lin, performed elemental analyses. Electron impact mass

spectra were determined on a mass spectrometer in the EI

mode unless otherwise stated. Exact mass ESI mass spectra

(HRMS) were measured on a micromass LCT orthogonal time-

of-flight mass spectrometer with leucine enkephalin (Tyr-Gly-

Phe-Leu) as an internal lock mass. ¹H NMR spectra were

obtained on a 300 and a 500 MHz spectrometer. ¹H-¹H COSY

spectra were recorded on a 300 and a 500 MHz spectrometer.

Chemical shifts are quoted in ppm relative to tetramethylsi-

lane, and coupling constants (J ) are quoted in Hz. CDCl₃was

used as the solvent for all NMR spectra unless otherwise

stated. 75.4 MHz ¹³C spectra were recorded on a 300 MHz

spectrometer and 125.7 MHz ¹³C spectra on a 500 MHz

spectrometer. Tetramethylsilane was used as the internal

standard in all ¹³C spectra recorded. 121.4 MHz ³¹P spectra

were recorded on a 300 MHz spectrometer, and ³¹P chemical

shifts are reported relative to 85% aqueous phosphoric acid

(0.0 ppm). Flash chromatography was performed using Merck

Kieselgel 60 (art. 9385) and aluminum oxide 90, standardized

(activity II-III). Merck precoated Kieselgel 60F₂₅₄and alumina

(neutral, type E) were used for thin-layer chromatography. GC

and HPLC analysis were carried out using a Supelco 2-4304

beta-Dex 120 (30 mm × 0.25 mm, 0.25 mm film) and a

Chiralcel OD column (0.46 cm i.d. × 25 cm), respectively.

Optical rotation values were measured on a standard pola-

rimeter. All commercially available solvents were purified and

dried before use. Diethyl ether and tetrahydrofuran were

distilled from sodium/benzophenone, and dichloromethane was

distilled from calcium hydride. Where necessary other solvents

and reagents used were purified according to the procedures

in Purification of Laboratory Chemicals.⁴⁴Solvents were

degassed using three freeze-thaw cycles. Note: The experi-

mental details for the preparation and resolution of 2-phenyl-

Quinazolinap have previously been published.¹⁵

entry ligand time temp (°C) conversion (%)

R:â

ee (%)

1

2

3

4

5

6

7

8

H

Me

Ph

Bn

i-Pr

t-Bu

2

20

0

20

0

20

0

20

0

20

0

20

0

78

64

98

>99:1 87 (S)

>99:1 77 (S)

>99:1 89 (S)

>99:1 93 (S)

>99:1 89 (S)

>99:1 88 (S)

>99:1 87 (S)

>99:1 78 (S)

>99:1 86 (S)

>99:1 64 (S)

>99:1 83 (R)

>99:1 90 (R)

90

100

>99

81

42

91

50

97

96

9

10

11

12

conversion, and a corresponding drop in enantiomeric

excess was observed with the 2-unsubstituted, 2-benzyl,

and 2-isopropyl variants, entries 1 and 2 and 7-10. The

highest reported enantioselection of 96% was obtained

with Quinap 2, although our modular Quinazolinap

series compares more favorably with Phenap (84%) for

the hydroboration of 1,2-dihydronaphthalene 31.¹¹

In conclusion, rhodium complexes of our 2-substituted-

Quinazolinap series were highly efficient catalysts for the

hydroboration of vinylarenes. For styrene derivatives,

higher enantioselectivities were obtained with a 4-meth-

oxy substituent (up to 95% ee) compared to those of the

4-chloro or 4-unsubstituted analogues. This signifies that

the electronic nature of the substrate combined with the

inherent steric properties of the catalyst are important

for high asymmetric induction. A marked increase in

regioselectivity and enantioselectivity was observed when

â-substituted substrates were employed, which was

particularly evident in the hydroboration of cis-â-meth-

ylstyrene (97% ee). Generally, the smaller quinazoline

2-substituents afforded a superior regiochemistry than

the bulkier ligands, whereas a trans-alkene stereochem-

istry typically lowered the regiocontrol and hampered the

reaction progress. This trend was further highlighted

with trans-anethole, although the degree of enantiocon-

trol was comparable to that obtained with trans-â-

methylstyrene. The effect of two methoxy substituents

in (E)-3,4-dimethoxy-â-methylstyrene led to an aug-

mented regio- and enantioselectivity in several cases (up

to 98% ee), demonstrating that our 2-substituted-

Quinazolinap systems also form highly stereoselective

catalysts for the hydroboration of â-substituted electron

rich vinylarenes. The increased steric demand at the

â-position in trans-stilbene had a detrimental effect on

both the enantioselection and chemical yield, although

its cis-isomer was hydroborated with an optimal enan-

tiomeric excess of 99%. Of the cyclic olefins applied,

indene was hydroborated with exceptional enantioselec-

tivity (99.5%) and regioselectivity (>99:1), while the less

sterically demanding ligands afforded higher levels of

stereocontrol. Overall, the present study has highlighted

the potential benefits of ligand-substrate matching in

this asymmetric transformation and as a consequence

has afforded some of the highest reported enantiomeric

Gen er a l Meth od for th e P r ep a r a tion of Im id a te Hy-

d r och lor id e Sa lts. Acetim id ic Acid Meth yl Ester 7a .

Hydrogen chloride was bubbled through a solution of aceto-

nitrile (28.57 mL, 0.547 mmol) in dry methanol (26.55 mL,

0.656 mmol) and hexane (160 mL) in a two-necked flask for 4

h at 0-5 °C. The mixture was allowed to stir for 30 min until

a white precipitate formed. Further precipitation occurred

after storage at -10 °C for 3 days. The product was filtered

and dried to give acetimidic acid methyl (44.94 g, 75%) as a

white solid: mp 97-100 °C (lit.⁴⁵mp 95-95.5 °C); ν_max(KBr)

3687, 3337, 2546, 2365, 2304, 2170, 1517, 1362 1143, 1048,

1

872 cm^-1; H NMR (300 MHz; CDCl₃) δ 12.5 (1H, br. s), 11.5

(1H, br. s), 4.3 (3H, s), 2.52 (3H, s); ¹³C NMR (75 MHz; CDCl₃)

δ 176.78, 59.7, 18.4.

Gen er a l Meth od for th e P r ep a r a tion of 2-Su bstitu ted -

4(3H)qu in a zolin on es. 2-Meth yl-4(3H)qu in a zolin on e 9a .

Anthranilic acid (5.00 g, 36.46 mmol) was dissolved in dry

methanol (40 mL) under nitrogen on a vacuum line. Acetimidic

acid methyl ester (3.54 g, 37.82 mmol) in dry methanol (40

mL) was placed under nitrogen in a separate Schlenk tube to

give a cloudy white suspension. Sodium metal (1.04 g, 45.38

mmol) was added carefully in several portions to this suspen-

sion, which was precooled over an ice bath. The anthranilic

(44) Perrin, D.; Armarego, W. Purification of Laboratory Chemicals,

3rd ed.; Pergamon.

(45) Bristol-Myers Co. Patent DE 1806169; Chem. Abstr. 1970, 72.

6582 J . Org. Chem., Vol. 69, No. 20, 2004

Axially Chiral Quinazoline-Containing Ligands

acid solution was transferred via cannula to the free based

imidate in methanol and stirred for 30 min. The reaction

mixture was heated at 80 °C for 6 h, the reaction mixture was

then cooled to room temperature, and the Schlenk tube was

placed in an ice bath to facilitate crystal formation. The

solution was filtered, and the white paperlike solid was dried

under vacuum. The mother liquor was reduced in volume and

allowed to crystallize overnight. The solid was filtered, dried,

and combined with the initial crop to furnish 2-methyl-4(3H)-

quinazolinone (2.52 g, 43%): mp 229-230 °C (lit.⁴⁹mp 230-

solution. Sodium carbonate solution (35 mL, 2M) was added,

and the solution was refluxed under nitrogen for 4 d. The

solution was cooled to room temperature and filtered to remove

any solid, which was washed with dichloromethane. The

solvent was removed in vacuo to give a brown oil, which was

redissolved in dichloromethane (50 mL), washed with brine

(3 × 30 mL), dried over magnesium sulfate, and reduced in

vacuo to give a brown solid.

2-H yd r ogen -4-(2-m et h oxy-n a p h t h a len -1-yl)-q u in a zo-

lin e 11a . Purified by stirring in pentane to give 2-hydrogen-

4-(2-methoxy-naphthalen-1-yl)-quinazoline (79%). The pentane

filtrate was concentrated to an oi,l which was then purified

by column chromatography (2:1 petroleum ether/ethyl acetate)

to give further product (4%): mp 180-182 °C; ν_max(KBr) 3007,

232 °C); ν_max(KBr) 3710, 3192, 3003, 2908, 1826, 1446 cm^-1

;

¹H NMR (300 MHz; CDCl₃) δ 11.5 (1H, br. s), 8.29 (1H, ddd, J

) 7.61, 1.47, 0.59 Hz), 7.77 (1H, dt, J ) 8.49, 7.03, 1.47), 7.68

(1H, ddd, J ) 8.79, 1.17, 0.59 Hz), 7.48 (1H, dt, J ) 8.2, 7.03,

1.47), 2.59 (3H, s); ¹³C NMR (75 MHz; CDCl₃) δ 164.2, 154,

149.8, 134.5, 127.3, 126.5, 126.2, 121, 22; EIMS m/z 160 (M⁺,

100), 145 (17), 132 (10), 118 (25).

1590, 1489, 1280, 1249, 1069 and 769 cm^-^{1 1}H NMR (500

;

MHz, CDCl₃) δ 9.52 (1H, s), 8.16 (1H, d, J ) 8.4 Hz), 8.05 (1H,

d, J ) 9.1 Hz), 7.90 (2H, m), 7.52 (1H, d, J ) 8.4 Hz), 7.45

(1H, dt, J ₁) 7.1 Hz, J ₂) 1.3 Hz), 7.44 (1H, d, J ) 9.1 Hz),

7.35 (1H, dt, J ₁) 6.8 Hz, J ₂) 1.3 Hz), 7.29 (1H, dt, J ₁) 7.1

Gen er a l Meth od for th e P r ep a r a tion of 2-Su bstitu ted -

4-ch lor oqu in a zolin es. 4-Ch lor o-2-m eth yl-qu in a zolin e 8a .

A solution of 2-methyl-4(3H)quinazolinone (6.0 g, 37.5 mmol),

N,N-diethylaniline (8.9 mL, 56.1 mmol), and dry benzene (100

mL) was refluxed for 5 min. Phosphorus oxychloride (2.9 mL,

31.2 mmol) was added by syringe, and the resultant mixture

was refluxed for 3 h [a clear orange color developed after 1 h

at reflux and turned deep red after 1.5 h] maintaining

anhydrous conditions by use of a CaCl₂drying tube attached

to the condenser. The solution was cooled to room temperature

and filtered. The insoluble precipitate was washed with dry

benzene (40 mL). The combined filtrate was rapidly washed

sequentially with ice water (100 mL), ice-cooled 20% sodium

hydroxide (2 × 100 mL), ice water (100 mL), and saturated

sodium chloride (100 mL). The organic layer was immediately

washed with a HCl solution (1 M, 100 mL) and water (100

mL) and dried over sodium sulfate. The solvent was removed

in vacuo at 30 °C to give 4-chloro-2-methyl-quinazoline (4.0 g,

59%) as a light yellow solid: mp 85-86 °C (lit.⁵⁴mp 81.5-83

Hz, J ₂) 1.3 Hz), 7.07 (1H, d, J ) 8.4 Hz) and 3.78 (3H, s); ¹³

C

NMR (125.7 MHz, CDCl₃) δ 167.7, 155.4, 154.8, 150.7, 134.2,

133.1, 131.6, 129.2, 128.9, 128.3, 127.9, 127.6, 127.3, 125.9,

124.5, 124.2, 119.6, 113.4 and 56.53; EIMS (70 eV) m/z 286

(M⁺, 34%), 285 (47), 271 (11), 270 (22), 269 (11), 242 (15), 114

(10) and 76 (12); Found C, 79.54; H, 5.04; N, 9.51. C₁₉H₁₄N₂O

requires C, 79.69; H, 4.93; N, 9.78.

Gen er a l Meth od for th e P r ep a r a tion of 1-(2-su bsti-

tu ted -qu in a zolin -4-yl)-n a p h th a len -2-ols 12a -f. 2-Substi-

tuted-4-(2-methoxy-naphthalen-1-yl)-quinazoline (26.81 mmol)

was dissolved in dry dichloromethane (130 mL) in a 250 mL

Schlenk tube. Boron tribromide (53.6 mmol, 1 M solution in

dichloromethane) was added slowly via syringe, and the

reaction was stirred overnight (16 h) under an atmosphere of

nitrogen. Because of the light-sensitive nature of boron tri-

bromide the reaction vessel was covered with aluminum foil

for the duration of the reaction. Distilled water (80 mL) was

added slowly to the solution, and some vigorous fizzing was

observed. An orange precipitate formed after 15 min and was

allowed to stir for an additional 1 h. This precipitate was

isolated by filtration giving pure 1-(2-substituted-quinazolin-

4-yl)-naphthalen-2-ol. The filtrate was neutralized with 1 M

NaOH and extracted with dichloromethane, and the organic

layer was then stirred with 10% HCl for 30 min. Dichlo-

romethane was added to dissolve any additional solid that

precipitated from solution, and the organic layer was isolated

once again and reduced in vacuo. All solid was combined and

dissolved in dichloromethane (orange color), and 2 M Na₂CO₃

solution was added and allowed stir for 1 h. The organic layer

was isolated from the black solution, the aqueous layer was

extracted twice with dichloromethane, and the combined

solutions were dried over MgSO₄and reduced in vacuo. 1-(2-

Substituted-quinazolin-4-yl)-naphthalen-2-ol was isolated as

a light orange powder.

°C); ν_max(KBr) 3158, 3010, 1870, 1662, 1477, 1143, 744 cm^-1

;

¹H NMR (300 MHz,CDCl₃) δ 8.22 (1H, ddd, J ) 8.2, 1.46, 0.59

Hz), 8.0-7.88 (2H, m) 7.65 (1H, dt, J ) 8.2, 6.44, 1.46 Hz),

2.86 (3H, s); ¹³C NMR (75 MHz; CDCl₃) δ 163.6, 162.2, 151.5,

134.9, 128.1, 128, 125.7, 121.8, 26.1; EIMS m/z 178 (M⁺, 21),

143 (100), 116 (7). Anal. Calcd for C₉H₇N₂Cl: C, 60.52; H, 3.95;

N, 15.68. Found: C, 60.43; H, 3.98; N, 15.40.

Note: 4-Chloroquinazoline was prepared from the com-

mercially available 4-hydroxyquinazoline employing an identi-

cal procedure: white powder (76%), mp 94-96 °C; ν_max(KBr)

3078, 1582, 1489, 1325, 761 cm^-^{1 1}H NMR (300 MHz):

; δ

(CDCl₃) 9.06 (1H, s), 8.29 (1H, d, J ) 8.4 Hz), 8.09 (1H, d, J )

8.5 Hz), 7.99 (1H, t, J ) 7.0 Hz), 7.76 (1H, t, J ) 7.0 Hz); EIMS

(70 eV) m/z 166 (M⁺, 18%), 164 (55), 130 (12), 129 (100), 102

(47), 76 (20), 75 (37), 74 (15).

Gen er a l Meth od for th e P r ep a r a tion of 2-Su bstitu ted -

4-(2-m eth oxy-n aph th alen -1-yl)-qu in azolin es 11a -f. 2-Sub-

stituted-4-chloroquinazoline (31.40 mmol) was added as a solid

to a solution of tetrakis(triphenylphosphine)palladium(0) (0.94

mmol) in DME (40 mL) and stirred for 10 min under a nitrogen

atmosphere. 2-Methyloxy-1-naphthylboronic acid (31.40 mmol),

dissolved in the minimum amount of degassed ethanol (∼50

mL), was then added to the 2-substituted-chloroquinazoline

1-(Qu in a zolin -4-yl)n a p h th a len -2-ol 12a : 83%, mp 195-

197 °C; ν_max(KBr) 3629, 3043, 1585, 1347, 1276, 814 and 772

1

cm^-1; H NMR (500 MHz, CDCl₃) δ 9.36 (1H, br s), 9.24 (1H,

s), 8.04 (1H, d, J ) 8.4 Hz), 7.85 (2H, m), 7.84 (1H, d, J ) 9.7

Hz), 7.63 (1H, d, J ) 8.4 Hz), 7.45 (1H, dt, J ₁) 6.8 Hz, J ₂

)

1.3 Hz), 7.34 (1H, dt, J ₁) 6.8 Hz, J ₂) 1.0 Hz), 7.26 (1H, dt,

J ₁) 8.1 Hz, J ₂) 1.3 Hz), 7.25 (1H, d, J ) 9.1 Hz) and 7.13

(1H, d, J ) 8.7 Hz); ¹³C NMR (125.7 MHz, CDCl₃) δ 166.8,

154.1, 153.9, 150.8, 134.6, 132.7, 132.3, 128.7, 128.6, 128.3,

127.9, 127.9, 127.0, 124.7, 124.6, 123.7, 119.2 and 115.1; EIMS

(70 eV) m/z 272 (M⁺, 32%), 271 (53), 243 (7), 122 (7) and 76

(8). Found: C, 78.97; H, 4.38; N, 10.08. C₁₈H₁₂N₂O requires

C, 79.38; H, 4.44; N, 10.29.

(46) Hunter, M. J .; Ludwig, M. L. J . Am. Chem. Soc. 1962, 84, 3491.

(47) Ganapathiplackal M.; Shafi, P. M. Indian J . Chem. 1986, 25,

204.

(48) Pattenden, G.; Thom, S. M. J . Chem. Soc., Perkin Trans. 1 1993,

1629.

(49) Mori, M.; Uozumi, Y.; Shibasaki, M. J . Organomet. Chem, 1990,

3, 225.

(50) Scheiner, P.; Frank, L.; Giusti, I.; Arwin, S.; Pearson, S. A. J .

Heterocycl. Chem. 1984, 21, 1817.

(51) Xu, X.; Lu, P.; Zhang, Y. Synth. Commun. 2001, 31, 323.

(52) Bogert, M. T.; Hand, W. F. J . Am. Chem. Soc. 1902, 24, 1042.

(53) Goerdeler, J .; Richter, R. Synthesis 1978, 760.

(54) Scarborough, H. C., Lawes, B. C., Minielli, J . L., Compton, J .

L. J . Org. Chem. 1962, 27, 957.

Gen er a l Meth od for th e P r ep a r a tion of 1-(2-Su bsti-

tu ted -qu in a zolin -4-yl)-2-n a p h th yl (tr iflu or om eth yl)su l-

fon a tes 13a -f. To a solution of 1-(2-substituted-quinazolin-

4-yl)-naphthalen-2-ol (14.0 mmol) and 4-(dimethylamino)pyri-

dine (42.0 mmol) in dry dichloromethane (130 mL) was added

trifluoromethanesulfonic anhydride (15.4 mmol), dropwise

J . Org. Chem, Vol. 69, No. 20, 2004 6583

Connolly et al.

with stirring, to give an orange solution. The reaction was

stirred overnight (16 h). The dark orange solution was then

washed with 1 M HCl (3 × 50 mL), water (2 × 60 mL), and

brine (1 × 60 mL) and dried over magnesium sulfate. The

solvent was reduced in vacuo to give an orange solid, which

was purified by column chromatography (silica gel, 2:1 petro-

leum ether/ethyl acetate) to give 1-(2-substituted-quinazolin-

4-yl)-2-naphthyl(trifluoromethyl) sulfonate.

and 214 (4). Found: C, 59.01; H, 3.76; N, 6.11. C₂₃H₁₉F₃N₂O₃S

requires C, 59.19; H, 3.84; N, 6.27.

1-(2-ter t-Bu tyl-qu in a zolin -4-yl)-2-n a p h th yl (tr iflu or o-

m eth yl)su lfon a te 13f. Purified by column chromatography

(silica gel, 2:1 petroleum ether/ethyl acetate) to give 1-(2-tert-

butyl-quinazolin-4-yl)-2-naphthyl(trifluoromethyl)sulfonate as

a yellow solid (86%): mp 115-117 °C; ν_max(KBr) 3070, 2963,

2921, 2885, 1612, 1559, 1420, 1280, 1140 and 875 cm^-^{1 1}H

;

NMR (300 MHz, CDCl₃) δ 8.15 (1H, d, J ) 8.49 Hz), 8.11 (1H,

d, J ) 9.1 Hz), 8.0 (1H, d, J ) 8.5 Hz), 7.85 (1H, dt, J ) 6.74,

1.78 Hz), 7.6 (1H, d, J ) 9.08 Hz), 7.58 (1H, dt, J ) 8.2, 1.78

Hz), 7.42 (1H, dt, J ₎9.37, 1.17 Hz), 7.38-7.31 (2H, m), 7.28

(1H, d, J ) 8.79 Hz) and 1.56 (9H, s); ¹³C (75 MHz, CDCl₃) δ

172.3, 161.5, 149.8, 143.5, 132.7, 131.6, 131.5, 130.6, 128,

127.3, 127, 126.7, 126.3, 126, 125.2, 124.9, 121.6, 118.5, 38.8,

28.5; EIMS (70 eV) m/z 460.2 (M⁺, 15%), 327.3 (100), 311.2

(46), 285.3 (11), 272.1 (14), 242.2 (14), 214.2 (8) and 189.2 (7).

Found: C, 59.66; H, 4.00; N, 5.98. C₂₄H₂₁F₃N₂O₃S requires C,

59.99; H, 4.16; N, 6.08.

Gen er a l Meth od for th e P r ep a r a tion of (R,S)-Dip h en -

yl(1-(2-su b st it u t e d -q u in a zolin -4-yl)(2-n a p h t h yl)p h os-

p h in es 14a -f. To a solution of [1,2 bis(diphenylphosphino)-

ethane]dichloronickel(II) (0.53 g, 1.0 mmol) in anhydrous DMF

(30 mL) was added diphenyl phosphine (5.75 mmol) at room

temperature. The dark orange solution was heated at 100 °C

for 30 min under nitrogen. 1-(2-Substituted-quinazolin-4-yl)-

2-naphthyl(trifluoromethyl) sulfonate (10 mmol) and 1,4-

diazabicyclo[2.2.2.]octane (DABCO) (40.0 mmol) in DMF (40

mL) were subsequently added. The dark green solution was

maintained at 100 °C, and a further portion of diphenyl

phosphine (5.75 mmol) was added after 1 h. The reaction was

then heated at 100 °C, under an atmosphere of nitrogen for 6

days. The reaction was cooled, and the solvent was removed

in vacuo. The residue was purified by chromatography (silica

gel, 2:1 petrol ether/ethyl acetate) to give (R,S)-diphenyl(1-(2-

substituted-quinazolin-4-yl)(2-naphthyl)phosphine.

(R,S)-Dip h en yl[1-(qu in a zolin -4-yl)(2-n a p h th yl)]p h os-

p h in e 14a . Purified by chromatography (silica gel, 2:1 petro-

leum ether/ethyl acetate) to give (R,S)-diphenyl[1-(quinazolin-

4-yl)(2-naphthyl)]phosphine as a white solid (62%): mp 212-

214 °C; ν_max(KBr) 3058, 1611, 1545, 1433, 744 and 698; ¹H

NMR (300 MHz, CDCl₃) δ 9.40 (1H, s), 8.13 (1H, d, J ) 8.4

Hz), 7.92 (1H, d, J ) 8.7 Hz), 7.89 (1H, d, J ) 8.4 Hz), 7.82

(1H, app septet, J ) 8.4, 5.5, 2.9 Hz), 7.49 (1H, dt, J 1 ) 6.8

Hz, J 2 ) 1.3 Hz), 7.43 (1H, dd, J 1 ) 8.4 Hz, J _P-H) 2.9 Hz),

7.31-7.18 (12H, m), 7.15 (2H, dt, J 1 ) 7.8 Hz, J 2 ) 1.6 Hz)

and 7.06 (d, J ) 8.4 Hz); ¹³C NMR (125.7 MHz, CDCl₃) δ 169.6,

154.9, 150.3, 141.7, 136.9, 134.8, 134.0, 133.9, 133.8, 133.6,

133.5, 133.3, 132.0, 131.0, 130.0, 129.5, 128.9-128.5, 128.3,

127.7, 127.3, 127.2, 126.1 and 125.2; ³¹P NMR (121 MHz,

CDCl₃) δ -12.9 ppm; EIMS (70 eV) m/z 440 (M⁺, 39%), 363

(100), 284 (18), 258 (8), 220 (13), 157 (8) and 77 (20). Found:

C, 81.55; H, 4.88; N, 6.28; P, 6.95. C₃₀H₂₁N₂P requires C, 81.80;

H, 4.81; N, 6.36; P, 7.03.

(R,S)-Dip h en yl[1-(2-m et h ylq u in a zolin -4-yl)(2-n a p h -

th yl)]p h osp h in e 14b. Purified by silica gel column chroma-

tography (petroleum ether/ethyl acetate) to give (R,S)-diphen-

yl[1-(2-methylquinazolin-4-yl)(2-naphthyl)] phosphine as a

white solid (63%): mp 195-197 °C; ν_max(KBr) 3058, 1637, 1556,

1429, 743 and 696 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 8.06 (d,

1H, J ) 8.5 Hz), 7.93 (1H, d, J ) 8.5 Hz), 7.91 (1H, d, J ) 8.5

Hz), 7.81 (1H, t, J ) 7.5 Hz), 7.51 (1H, t, J ) 7.6 Hz), 7.43

(1H, dd, J _H,H) 8.6 Hz, J _P,H) 3.2 Hz), 7.34-7.17 (13H, m),

7.13 (1H, d, J ) 8.5 Hz) and 2.82 (3H, s); ¹³C NMR (125.7 MHz,

CDCl₃) δ 169.5, 164.1, 150.8, 141.8, 137.1, 137.0, 135.0, 134.1-

133.7, 132.1, 130.1, 129.4, 128.8-128.6, 128.3, 128.3, 127.3,

127.2, 127.2, 126.9, 126.3, 123.6 and 26.6; ³¹P NMR (101.3

MHz, CDCl₃) δ -12.6; EIMS (70 eV) m/z 454 (M⁺, 29%), 377

(100), 300 (19) and 77 (16). Found: C, 81.5; H, 5.1; N, 6.1.

1-(Qu in a zolin -4-yl)-2-n a p h t h yl(t r iflu or om et h yl)su l-

fon a te 13a . Purified by chromatography (silica gel, 2:1 petrol

ether/ethyl acetate) to give 1-(quinazolin-4-yl)-2-naphthyl (tri-

fluoromethyl)sulfonate (88%): mp 110-112 °C; ν_max(KBr)

3064, 1492, 1423, 1219, 1140 and 830 cm^-^{1 1}H NMR (300

;

MHz, CDCl₃) δ 9.56 (1H, s), 8.21 (1H, d, J ) 8.4 Hz), 8.15 (1H,

d, J ) 9.1 Hz), 8.02 (1H, d, J ) 8.4 Hz), 7.96 (1H, dt, J 1 ) 6.8

Hz, J 2 ) 1.6 Hz), 7.62 (1H, d, J ) 9.1 Hz), 7.60 (1H, t, J ) 7.1

Hz), 7.52 (1H, dt, J 1 ) 7.1 Hz, J 2 ) 1.0 Hz), 7.45 (2H, m) and

7.27 (1H, dd, J ) 9.1 Hz); ¹³C NMR (125.7 MHz, CDCl₃) δ

163.3, 154.9, 150.7, 144.6, 134.5, 132.4, 132.3, 132.1, 129.1,

128.4, 128.3, 128.3, 127.5, 126.9, 126.4, 126.0, 125.0, 119.4 and

121.9-119.4-116.9-114.4 (q, J _C-F) 320 Hz); EIMS (70 eV)

m/z 404 (M⁺, 13%), 272 (23), 271 (100), 243 (53), 242 (37), 214

(14) and 69 (24). Found: C, 56.16; H, 2.72; N, 6.74; S, 8.2; F,

14.1. C₁₉H₁₁N₂O₃SF₃requires C, 56.43; H, 2.74; N, 6.93; S 7.91;

F 14.11.

1-(2-Meth ylqu in azolin -4-yl)-2-n aph th yl (tr iflu or om eth -

yl)su lfon a te 13b. Purified by silica gel column chromatog-

raphy (petroleum ether/ethyl acetate 2:1) to give 1-(2-meth-

ylquinazolin-4-yl)-2-naphthyl(trifluoromethyl)sulfonate as a

white solid (78%): mp 124-126 °C. ν_max(KBr) 3065, 1612,

1

1558, 1512, 1428, 1214 (s), 1140 (s) and 831 cm^-1; H NMR

(500 MHz, CDCl₃) δ 8.12 (1H, d, J ) 10.1 Hz), 8.10 (1H, d, J

) 9.2 Hz), 8.00 (1H, d, J ) 8.3 Hz), 7.89 (1H, dt, J ₁) 7.7 Hz,

J ₂) 1.6 Hz), 7.61 (1H, d, J ) 9.2 Hz), 7.59 (1H, t, J ) 7.6 Hz),

7.44-7.39 (3H, m), 7.27 (1H, d, J ) 8.6 Hz) and 3.01 (3H, s);

¹³C NMR (125.7 MHz, CDCl₃) δ 164.6, 163.5, 151.3, 144.9,

134.6, 132.6, 132.5, 132.2, 128.6, 128.6, 128.5, 127.6, 127.5,

127.4, 126.6, 126.3, 122.9, 119.7, 118.4 (q, J ) 320.3 Hz) and

26.6; EIMS (70 eV) m/z 418 (M⁺, 9%), 285 (100), 257 (53), 243

(12) and 69 (13). Found: C, 57.1; H, 3.2; N, 6.5; S, 8.1; F, 13.8.

C

₂₀H₁₃N₂O₃SF₃requires C, 57.4; H, 3.1; N, 6.7; S, 7.7; F, 13.6.

1-(2-P h en ylm eth yl-qu in azolin -4-yl)-2-n aph th yl (tr iflu o-

r om eth yl)su lfon a te 13d : 77% as beige solid; mp 136-138

°C; ν_max(KBr) 3065, 2935, 1615, 1552, 1425, 1214, 1136, 950

1

and 834 cm^-1; H NMR (300 MHz, CDCl₃) δ 8.13 (1H, d, J )

8.55 Hz), 8.10 (1H, d, J ) 8.95 Hz), 7.98 (1H, d, J ) 8.15 Hz),

7.88 (1H, dt, J ) 8.55, 6.56, 1.99 Hz), 7.60 (1H, d, J ) 8.95

Hz), 7.57 (1H, dt, J ) 8.15, 6.96, 1.19 Hz), 7.45 (1H, dt, J )

7.36, 1.39 Hz), 7.47-7.36 (4H, m), 7.31-7.19 (3H, m), 7.19 (1H,

d, J ) 8.35 Hz), 4.57 (1H, d, J ) 13.91 Hz) and 4.56 (1H, d, J

) 13.91 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 166.1, 163.7, 151.5,

144.8, 138.7, 134.5, 132.7, 132.2, 129.5, 129.0, 128.6, 128.5,

128.4, 127.7, 127.6, 127.3, 126.6, 126.5, 126.4, 123.2, 119.7,

119.6 and 46.5; EIMS (70 eV) m/z 494 (M⁺, 10%), 361 (100),

180 (41), 165 (25), 114 (10), 91 (84) and 65 (17). Anal. Calcd

for C₂₆H₁₇N₂O₃SF₃: C, 63.15; H, 3.47; N, 5.67; S, 6.48; F, 11.53.

Found: C, 62.83; H, 3.51; N, 5.53; S, 6.66; F, 11.14.

1-(2-Isop r op yl-qu in a zolin -4-yl)-2-n a p h th yl (tr iflu or o-

m eth yl)su lfon a te 13e. Purified by silica gel column chroma-

tography (petroleum ether/ethyl acetate 2:1) to give 1-(2-iso-

propyl-quinazolin-4-yl)-2-naphthyl(trifluoromethyl)sulfonate as

a yellow solid (97%): mp 117-118 °C; ν_max(KBr) 3059, 2978,

2929, 1616, 1491, 1434, 1229, 1135 and 847 cm^-^{1 1}H NMR

;

(300 MHz, CDCl₃) δ 8.14 (1H, d, J ) 8.49 Hz), 8.11 (1H, d, J

) 8.78 Hz), 8.0 (1H, d, J ) 8.2 Hz), 7.88 (1H, dt, J ) 8.5, 6.74,

1.78 Hz), 7.6 (1H, d, J ) 9.08 Hz), 7.58 (1H, dt, J ) 8.2,

7.03,1.47 Hz), 7.44 (1H, dt, J ₎8.49, 7.03, 1.17 Hz), 7.41-7.33

(2H, m) and 7.28 (1H, d, J ) 8.5 Hz), 3.52 (1H, sept, J ) 7.03)

and 1.50 (6H, d, J ) 6.74 Hz); ¹³C (75 MHz, CDCl₃) δ 170.6,

162.1, 150, 143.6, 133, 131.5, 130.8, 127.7, 127.3, 127.2, 126.4,

126.3, 126.1, 125.2, 125.1, 122, 119.2, 118.5, 37.1, 20.6; EIMS

(70 eV) m/z 446 (M⁺, 6%), 313 (39), 297 (14), 285 (9), 243 (5)

C

₃₁H₂₃N₂P requires C, 81.9; H, 5.1; N, 6.2.

(R,S)-Dip h en yl(1-(2-p h en ylm eth yl-qu in a zolin -4-yl)(2-

n a p h th yl)p h osp h in e 14d . Purified by silica gel column

6584 J . Org. Chem., Vol. 69, No. 20, 2004

Axially Chiral Quinazoline-Containing Ligands

chromatography (4:1 petrol ether/ethyl acetate) to give (R,S)-

diphenyl[1-(2-phenylmethylquinazolin-4-yl)(2-naphthyl)]phos-

phine (0.76 g, 80%) as a white solid: mp 218-220 °C; ν_max

(KBr) 3054, 2939, 1612, 1583, 1546, 1485, 1433, 746 and 693

cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 8.10 (1H, d, J ) 8.64 Hz),

7.94 (1H, d, J ) 8.35 Hz), 7.92 (1H, d, J ) 7.91 Hz), 7.82 (1H,

dt, J ) 8.49, 6.44, 1.90 Hz), 7.53 (1H, dt, J ) 8.05, 6.88, 1.03

Hz), 7.45 (1H, dd, J ) 8.49 Hz, J _P-H) 1.03 Hz), 7.35-7.20

(16H, m), 7.15 (2H, dt J ) 7.18, 6.30, 1.90 Hz), 7.10 (1H, d, J

) 8.49 Hz), 4.44 (1H, d, J ) 13.76 Hz) and 4.41 (1H, d, J )

13.62 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 168.7, 164.4, 149.7,

140.9, 137.6, 135.9, 133.5, 132.7, 132.7, 132.5, 132.4, 132.4,

132.1, 130.8 (d, J _P-C) 8.63 Hz), 129.0, 128.2, 128.1, 127.5-

127.0, 126.1, 125.9, 125.9, 125.8, 125.2, 125.2, 125.1, 122.7,

122.7 and 45.1; ³¹P NMR (121 MHz, CDCl₃) δ -12.9 ppm;

EIMS (70 eV) m/z 494 (M⁺, 10%), 361 (100), 180 (41), 165 (25),

114 (10), 91 (84) and 65 (17). Found: C, 83.55; H, 5.24; N,

5.26; P, 5.64. C₃₇H₂₇PN₂requires C, 83.75; H, 5.13; N, 5.28; P,

5.84.

(R,S)-Dip h en yl(1-(2-isop r op yl-qu in a zolin -4-yl)(2-n a p h -

th yl)p h osp h in e 14e. Purified by chromatography (silica gel,

2:1 petrol ether/ethyl acetate) to give (R,S)-diphenyl(1-(2-

isopropyl-quinazolin-4-yl)(2-naphthyl)phosphine as a white

solid (67%): mp 220-221 °C; ν_max(KBr) 3064, 2970, 2963,

1772, 1614, 1566 and 1470; ¹H NMR (300 MHz, CDCl₃) δ 8.07

(1H, d, J ) 8.49 Hz), 7.91 (1H, d, J ) 8.5 Hz), 7.89, (1H, d, J

) 7.32 Hz), 7.8 (1H, dt, J ) 8.2, 6.44, 1.46 Hz), 7.5 (1H, dt, J

) 7.91, 6.73, 1.17 Hz), 7.39 (1H, ddd, J ) 8.2, 1.17 Hz), 7.36-

7.19 (11H, m), 7.18 (2H, dt, 7.33, 5.57, 1.47 Hz), 7.10 (1H, d,

J ) 8.79 Hz), 3.28 (1H, sept, J ) 7.03), 1.25 (6H, d, J ) 6.74

Hz); ¹³C (75 MHz, CDCl₃) δ 172, 169, 150.8, 141.7, 138, 136.3,

133.9, 133.7, 133.5, 130.3, 129.3, 128.8, 128.6, 128.5, 128.3,

127.3-127, 126.9, 126.8, 126.5, 126.4-125.2, 125.1, 38.2, 22;

³¹P NMR (121 MHz, CDCl₃) δ -12.5 ppm; EIMS (70 eV) m/z

483 (M⁺, 8%), 482 (27), 405 (88), 334 (6), 258 (9) and 233 (25);

HRMS 483.2000, C₃₃H₂₈N₂P requires 483.1990.

C₂,N]dipalladium(II) 16 as a bright yellow solid (3.2 g, 94%).

Alternatively, the crude solution was reduced in vacuo, dis-

solved in dichloromethane, and filtered through a column of

silica gel to give an identical bright yellow solid (3.29 g, 96%):

mp 182-184 °C (lit.⁵⁹mp 183 °C); ¹H NMR 300 MHz δ (CDCl₃)

7.8-7.32 (12H, m), 4.2 (2H, q, J ) 6.15 Hz), 2.98 (6H, d, J )

9.96 Hz), 2.76 (6H, d, J ) 14.35 Hz) and 1.91 (6H, d, J ) 6.3

Hz).

Resolu tion of (R,S)-Diph en yl(1-(2-su bstitu ted-qu in azo-

lin -4-yl)(2-n a p h th yl) p h osp h in e 14a -f. (R,S)-Dip h en yl-

[1-(qu in azolin -4-yl)(2-n aph th yl)]ph osph in e 14a. Diphenyl-

[1-(quinazolin-4-yl)(2-naphthyl)]phosphine 14a (1.23 g, 2.38

mmol) and (+)-di-µ-chlorobis[(R)-dimethyl(1-(1-naphthyl)eth-

yl)aminato-C2,N]dipalladium(II) 16 (0.81 g, 1.19 mmol) were

placed under an atmosphere of nitrogen in a Schlenk tube.

Dry degassed MeOH (70 mL) was added, and the mixture was

stirred for 2 h. As all the solid had not dissolved, more

methanol (70 mL) was added. The mixture was stirred

overnight. The white precipitate was isolated by filtration.

However upon analysis this proved to be unbound diphenyl-

[1-(quinazolin-4-yl)(2-naphthyl)] phosphine contaminated with

a small amount of an unusual impurity, (R)-[dimethyl(1-(1-

naphthyl)ethyl)aminato-C₂,N]-[methyl(diphenyl)phosphite]pal-

ladium(II)chloride 19, which was isolated by column chroma-

tography and characterized: mp 116-119 °C; [R]²¹) -155

D

(c 0.11, CHCl₃); ν_max(KBr) 2933, 1583, 1436, 1107, 1030 and

1

748; H NMR (500 MHz, CDCl₃) δ 8.24-8.19 (2H, m), 7.84-

7.80 (2H, m), 7.72 (2H, d, J ) 9.6 Hz), 7.53-7.51 (3H, m),

7.43-7.34 (5H, m), 7.32-7.28 (2H, m), 4.36 (1H, quin, J ) 6.4

Hz), 3.30 (3H, d, J ) 13.4 Hz), 2.97 (3H, s), 2.61 (3H, s) and

2.09 (3H, d J ) 6.4 Hz); ¹³C NMR (125.7 MHz, CDCl₃) δ 149.9,

149.6, 135.2, 134.8, 134.5 (d, J _P-C) 11 Hz), 133.4, 133.3, 133.0,

132.9, 132.4, 132.3, 131.6, 131.4, 131.3, 129.0, 128.8, 128.6,

128.0 (d, J _P-C) 11 Hz), 125.7, 125.4 (d, J _P-C) 5.8 Hz), 124.3,

123.2, 72.7, 55.0, 50.7, 47.9 and 23.8; ³¹P NMR (121 MHz,

CDCl₃) δ 125.1 ppm; ESI/pos (CH₃OH) cation m/z 520 ) M -

Cl; HRMS (ES) m/z 520.1019 C₂₇H₂₉NOPPd, cation requires

520.1022.

(R,S)-Dip h en yl(1-(2-ter t-bu tyl-qu in a zolin -4-yl)(2-n a p h -

th yl)p h osp h in e 14f. Purified by chromatography (silica gel,

2:1 petrol ether/ethyl acetate) to give (R,S)-diphenyl(1-(2-tert-

butyl-quinazolin-4-yl)(2-naphthyl)phosphine as a white solid

(64%): mp 217-219 °C; ν_max(KBr) 3059, 2954, 2918, 1613,

1549, 1480 and 685; ¹H NMR (300 MHz, CDCl₃) δ 8.08 (1H, d,

J ) 8.2 Hz), 7.89 (2H, app d, J ) 7.91 Hz), 7.78 (1H, dt, J )

8.49, 6.15, 1.78 Hz), 7.49 (1H, dt, J ) 8.2, 5.86, 1.17 Hz), 7.37

(1H, d, J ) 8.25 Hz), 7.34-7.21 (11H, m), 7.18 (2H, dt, 8.79,

6.15, 1.47 Hz), 7.08 (1H, d, J ) 8.49), 1.31 (9H, s); ¹³C (75 MHz,

CDCl₃) δ 169, 160.3, 150.1, 150, 138, 137.7, 133.9, 133.6, 133.5,

133.4, 132.0, 131.0, 129.5, 129.3, 129.2, 129, 128.7-128.3,

127.5-127.1, 126.9, 126.8, 122, 120.1, 40, 29.6; ³¹P NMR (121

MHz, CDCl₃) δ -12.6 ppm; HRMS (ES) m/z 497.2162,

To the filtrate was added potassium hexafluorophosphate

(0.736 g, 4.0 mmol) in water (70 mL). Further addition of water

(100 mL) precipitated a yellow solid, which was collected by

filtration and dried. NMR analysis showed a 1:1 mixture of

(R,R)- and (S,R)-cis-[dimethyl(1-(1-naphthyl)ethyl)aminato-

C₂,N]-[1-(quinazolin-4-yl(2-naphthyl)diphenylphosphine]pal-

ladium(II)hexafluorophosphate 18a . Recrystallation of the

mixture from butanone/diethyl ether gave (S,R)-18a (0.56 g,

85%): mp 238-241 °C; [R]²¹) -245 (c 0.204, CHCl₃); ν_max

D

(KBr) 3045, 1613, 1569, 1438 and 842; ¹H NMR (300 MHz,

CDCl₃) δ 9.43 (1H, s), 8.18 (1H, d, J ) 8.6 Hz), 8.09 (1H, d, J

) 8.3 Hz), 7.97-7.91 (2H, m), 7.72 (1H, d, J ) 6.7 Hz), 7.70

(1H, d, J ) 6.7 Hz), 7.67 (1H, d, J ) 8.3 Hz), 7.54 (1H, t, J )

7.7 Hz), 7.49-7.42 (3H, m), 7.38 (1H, t, J ) 7.0 Hz), 7.32-

7.24 (5H, m), 7.21 (1H, d, J ) 8.6 Hz), 7.10-7.04 (4H, m), 7.01

(1H, d, J ) 8.6 Hz), 6.98 (2H, d, J ) 8.3 Hz), 6.51 (1H, dd, J 1

) 8.3 Hz, J 2 ) 6.1 Hz), 4.46 (1H, quin, J ) 6.1 Hz), 2.92 (3H,

s), 2.80 (3H, s) and 1.79 (3H, d, J ) 6.4 Hz); ¹³C NMR (125.7

MHz, CDCl₃) δ 164.8 (d, J _P-C) 6.7 Hz), 151.5, 150.5, 149.7,

149.3, 137.1, 136.7 (d, J _P-C) 12.2 Hz), 136.4 (d, J _P-C) 11.4

Hz), 135.4 (d, J _P-C) 11.4 Hz), 134.2, 133.0, 132.9, 132.8, 132.2,

132.1 (d, J ) 11.0 Hz), 131.7, 130.3, 129.3-128.7, 128.2, 127.9,

127.6, 126.6, 126.1 (d, J ) 6.7 Hz), 126.0 (d, J ) 5.9 Hz), 125.4,

125.1, 124.4, 124.0, 123.7, 123.3, 122.3, 121.9, 73.6, 52.4, 48.4,

C

₃₄H₃₀N₂P requires 497.2147.

(+)-Di-µ-ch lor obis[(R)-d im eth yl(1-(1-n a p h th yl)eth yl)-

a m in a to-C₂,N]d ip a lla d iu m (II). Palladium(II)chloride (1.78

g, 10.03 mmol) and lithium chloride (0.85 g, 20.06 mmol) were

placed in a 250 mL Schlenk tube under an atmosphere of

nitrogen.^57,58Dry degassed methanol (40 mL) was added, and

the mixture was refluxed until the palladium dissolved (∼30

min) to give a brown solution. This was allowed to cool, and

(R)-N,N dimethyl-1-(1-naphthyl)ethylamine (2.00 g, 10.03

mmol) was added dropwise over a 15 min period to give

a yellow precipitate. Triethylamine (1.4 mL, 10.03 mmol)

was then added slowly, and the solution was stirred over-

night (18 h) to give a yellow suspension. The mixture was

filtered, and the solid was washed with methanol followed by

ether. The yellow solid was dried on a vacuum line to give-

(+)-di-µ-chlorobis[(R)-dimethyl(1-(1-naphthyl)ethyl)aminato-

24.5; ³¹P NMR (121 MHz, CDCl₃) δ 39.9, -143 (septet, J _P-F

)

712.6 Hz) ppm; ESI/pos (CH₃OH) m/z cation 744 ) M - PF₆,

m/z (HRMS, ES) found 744.1758, C₄₄H₃₇N₃PPd cation requires

744.1760.

Cr ystal data for (S,R)-18a: [C₄₄H₃₇N₃PPd]⁺[PF₆]^-‚2CHCl₃,

from chloroform/diethyl ether, M_r) 1128.84, crystal size: 0.09

× 0.16 × 0.26 mm³; a ) 13.2070(7), b ) 13.9716(8), c ) 25.669-

(55) Trepanier, D. L.; Sunder, S. J . Heterocycl. Chem. 1975, 12, 321.

(56) Bowie, R. A.; Thomason, D. A. J . Chem. Soc., Perkin Trans. 1

1972, 1842.

(57) Martin, J . W. L.; Palmer, J . A. L.; Wild, S. B. Inorg. Chem. 1984,

23, 2664.

(58) Martin, J . W. L. J . Am. Chem. Soc. 1988, 110, 4346.

(59) Allen, D. G.; McLaughlin, G. M.; Robertson, G. B.; Steffen, W.

L.; Salem, G.; Wild, S. B. Inorg. Chem. 1982, 21, 1007.

J . Org. Chem, Vol. 69, No. 20, 2004 6585

Connolly et al.

(1) Å, V ) 4736.4(5) Å³, T ) 100 K, orthorhombic, space group

P2₁2₁2₁(No. 19), Z ) 4, F_calcd) 1.583 g cm^-3, F(000) ) 2272,

Siemens SMART diffractometer, λ (Mo KR) ) 0.71073 Å, µ )

0.86 mm^-1, 42281 measured and 10666 independent reflections

(R_int) 0.148), 6413 with I > 2σ(I), θ_max) 27.48°, T_min) 0.874,

T_max) 0.920, direct methods (SHELXS-97) and least-squares

refinement (SHELXL-97) on F_o², both programs from G.

Sheldrick, University of Go¨ttingen, 1997; 577 parameters, H

atoms riding, absolute configuration established (Flack pa-

rameter -0.05(3)) and confirmed by chiral reference, Cheby-

shev weights, R₁) 0.060 (I > 2σ(I)), wR₂) 0.1149 (all data),

θ_max) 33.15°, T_min) 0.886, T_max) 0.966, direct methods

(SHELXS-97) and least-squares refinement (SHELXL-97) on

F_o², both programs from G. Sheldrick, University of Go¨ttingen,

-

1997; 536 parameters, PF₆anion rotationally disordered,

residual electron density in a void in the crystal suggested

additional solvent, the size of the void indicates trace water,

which was modeled by an O atom (0.2 refined occupancy),

otherwise H atoms riding, absolute configuration established

(Flack parameter -0.05(2)) and confirmed by chiral reference,

Chebyshev weights, R₁) 0.0428 (I > 2σ(I)), wR₂) 0.0943 (all

data), ∆F_max/min) 0.955/-0.619 e Å^-3

.

∆F_max/min) 0.906/-0.546 e Å^-3

.

(R,S)-Dip h en yl(1-(2-b en zyl-q u in a zolin -4-yl)(2-n a p h -

th yl)p h osp h in e 14d . A solution of (R,S)-diphenyl[1-(2-phe-

nylmethylquinazolin-4-yl)(2-naphthyl)] phosphine 14d (0.58 g,

1.09 mmol) and (+)-di-µ-chlorobis[(R)-dimethyl(1-(1-naphthyl)-

ethyl)aminato-C₂,N]dipalladium(II) 16 (0.37 g, 0.55 mmol) in

dry, degassed dichloromethane (60 mL) was stirred overnight

(22 h) at room temperature under an atmosphere of nitrogen.

The bright yellow solution was reduced in vacuo and vacuum-

dried to give (R,R)- and (S,R)-cis-[dimethyl(1-(1-naphthyl)-

ethyl) aminato-C₂,N]-[1-(2-phenylmethylquinazolin-4-yl)(2-

naphthyl)diphenylphosphine]palladium (II)chloride 17d (0.94

g, 99%) as a pale yellow solid, which was a 1:1 mixture of

diastereomers by NMR.

The filtrate from the recrystallation was reduced in vacuo.

The solid obtained was recrystallized from dichloromethane/

2-propanol to afford 97% diastereomerically pure (R,R)-cis-

[dimethyl(1-(1-naphthyl)ethyl)aminato-C₂,N]-[1-(quinazolin-4-

yl)(2-naphthyl)diphenylphosphine]palladium(II) hexafluoro-

phosphate 18a in the filtrate: ¹H NMR (300 MHz, CDCl₃) δ

9.61 (s, 1H), 8.21 (1H, d, J ) 8.3 Hz), 8.09 (1H, d, J ) 8.3 Hz),

7.92 (2H, m), 7.76 (1H, d, J ) 8.3 Hz), 7.73-7.68 (2H, m), 7.65

(1H, d, J ) 8.3 Hz), 7.57 (1H, dt, J 1 ) 7.5 Hz, J 2 ) 2.4 Hz),

7.50-7.40 (6H, m), 7.37 (1H, d, J ) 8.0 Hz), 7.35-7.22 (3H,

m), 7.13-6.92 (5H, m), 6.41 (1H, dd, J 1 ) 8.6 Hz, J 2 ) 7.0

Hz), 4.67 (1H, quin, J ) 6.3 Hz), 3.01 (3H, s), 2.94 (3H, s) and

1.92 (3H, d, J ) 6.3 Hz); ³¹P NMR (121 MHz, CDCl₃) δ 42.1,

-143 (septet, J _P-F) 712.6 Hz) ppm.

Diph en yl[1-(2-m eth ylqu in azolin -4-yl)(2-n aph th yl)]ph os-

p h in e 14b. (+)-Di-µ-chlorobis[(R)-dimethyl(1-(1-naphthyl)-

ethyl)aminato-C₂,N]dipalladium(II)16 (0.56 g, 0.82 mmol) and

(R,S)-diphenyl[1-(2-methylquinazolin-4-yl)(2-naphthyl)] phos-

phine 14b (0.75 g, 1.65 mmol) were placed in a Schlenk tube

under nitrogen. Dry, degassed methanol (56 mL) was added

via syringe, and the solution was stirred for 12 h. Potassium

hexafluorophosphate (0.334 g, 1.83 mmol) was added in water

(52 mL) with vigorous stirring, and a cream precipitate formed.

A further 40 mL of water was added. The precipitated solid

was collected by filtration to give a 50:50 mixture of diaster-

eomers, (S,R)- and (R,R)-cis-[dimethyl(1-(1-naphthyl)ethyl)-

aminato-C₂,N]-[diphenyl[1-(2-methylquinazolin-4-yl)(2-naph-

thyl)]phosphine]palladium(II) hexafluorophosphate 18b (1.21

g, 81%). Fractional crystallization of the mixture from chlo-

roform/diethyl ether gave (S,R)-18b (0.248 g, 41%): mp 216-

218 °C; [R]_D) 247.4 (c 0.365,CH₂Cl₂); ν_max(CHCl₃) 3019, 1571,

1521, 1479, 1438 and 760 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ

8.17 (1H, d, J ) 8.5 Hz), 8.09 (1H, d, J ) 8.5 Hz), 7.88 (1H, dt,

J ₁) 7.6 Hz, J ₂) 1.3 Hz), 7.80-7.77 (2H, m), 7.72 (1H, t, J )

6.9 Hz), 7.69 (1H, d, J ) 7.2 Hz), 7.64 (1H, d, J ) 7.9 Hz),

7.53 (1H, t, J ) 7.8 Hz), 7.51 (1H, t, J ) 7.0 Hz), 7.46-7.19

(8H, m), 7.13 (1H, t, J ) 7.6 Hz), 7.10 (1H, d, J ) 8.2 Hz),

6.93 (1H, d, J ) 8.5 Hz), 6.89-6.78 (3H, m), 6.64 (1H, d, J )

8.5 Hz), 6.62 (1H, d, J ) 8.2 Hz), 4.28 (1H, quin, J ) 5.9 Hz),

3.55 (3H, s), 2.76 (3H, d, J ) 2.6 Hz), 2.49 (3H, d, J ) 3.5 Hz)

and 1.28 (3H, d, J ) 6.4 Hz); ¹³C NMR (125.7 MHz, CDCl₃) δ

165.6 (d, J _P,C) 6.2 Hz), 161.4, 150.9, 150.0 (d, 1H, J _P,C) 1.6

Hz), 149.6 (d, J _P,C) 2.3 Hz) 136.9 (d, J _P,C) 12.1 Hz), 136.9,

136.6 (d, J _P,C) 11.7 Hz), 135.9 (d, J _P,C) 10.9 Hz), 134.2 (d,

J _P,C) 26.9 Hz), 134.3 (d, J _P,C) 1.6 Hz), 129.8, 129.6, 129.5-

128.9, 128.6, 128.4 (d, J _P,C) 6.6 Hz), 125.5 (d, J _P,C) 7.0 Hz),

Diethyl ether was added to the mixture at room tempera-

ture. An insoluble solid remained, while the mother liquor was

yellow in color. The solid was removed by filtration and dried

on a vacuum line to give (S,R)-17d as a pale yellow solid: mp

200-202 °C; [R]_D) -121.6 (c 0.25, CHCl₃); ν_max(KBr) 3057,

2976, 2889, 1614, 1552, 1501, 1434, 1094 and 809 cm^-^{1 1}H

;

NMR (300 MHz, CDCl₃) δ 8.23 (1H, d, J ) 9.08 Hz), 8.04 (1H,

d, J ) 8.64 Hz), 7.94 (1H, d, J ) 8.20 Hz), 7.93-7.85 (2H, m),

7.84 (1H, d, J ) 8.05 Hz), 7.72 (1H, app d, J ) 7.03 Hz), 7.65

(1H, d, J ) 8.64 Hz), 7.57 (1H, t, J ) 7.76 Hz), 7.54-7.49 (2H,

m), 7.37 (1H, t, J ) 6.15 Hz), 7.36-7.28 (9H, m), 7.30 (1H, d,

J ) 8.20 Hz), 7.17-7.06 (3H, m), 6.95 (1H, app s), 6.82 (1H, d,

J ) 8.49 Hz), 6.62 (1H, d, J ) 9.67 Hz), 6.59 (2H, d, J ) 8.35

Hz), 6.43 (1H, app s), 4.17 (1H, d, J ) 13.62 Hz), 4.15 (1H,

quin, J ) 9.67 Hz), 4.07 (1H, d, J ) 13.18 Hz), 2.89 (3H, s),

2.51 (3H, s) and 1.76 (3H, d, J ) 4.25 Hz); ¹³C NMR (75 MHz,

CDCl₃) δ 166.7, 163.7, 149.4, 149.3 (d, J _P-C) 22.23 Hz), 147.9,

137.5, 136.1 (d, J _P-C) 12.08 Hz), 135.2, 135.0, 133.0, 132.6,

131.9, 131.7, 131.4 (d, J _P-C) 8.70 Hz), 129.9, 129.9, 129.8,

129.3, 128.8, 128.2, 128.2-127.2, 127.5, 127.2, 127.2, 127.1,

127.0, 126.8, 126.6 (d, J ) 10.15 Hz), 125.9, 125.7, 125.6, 125.2,

125.1, 124.5, 123.0, 122.9, 122.6, 122.2, 72.1 (CHMe), 49.7,

47.5, 45.3 and 22.3; ³¹P NMR (121 MHz, CDCl₃) δ 45.5 ppm;

ESI/pos (CH₃OH) m/z cation 834 ) M - Cl; HRMS (ES) m/z

found 834.2227, C₄₇H₄₃N₃PPd cation requires 834.2229.

Cr ysta l d a ta for (S,R)-17d : [C₅₁H₄₃ClN₃PPd], from chlo-

roform/diethyl ether, M_r) 870.70, crystal size: 0.10 × 0.11 ×

0.11 mm³; a ) 10.6243(1), b ) 16.1488(2), c ) 23.9876(4) Å, V

) 4115.6(1) Å³, T ) 100 K, orthorhombic, space group P2₁2₁2₁

(No. 19), Z ) 4, F_calcd) 1.405 g cm^-3, F(000) ) 1792, Nonius

KappaCCD diffractometer, λ (Mo KR) ) 0.71073 Å, µ ) 0.60

mm^-1, 37966 measured and 15577 independent reflections (R_int

) 0.086), 11181 with I > 2σ(I), θ_max) 33.19°, T_min) 0.937,

T_max) 0.947, direct methods (SHELXS-97) and least-squares

refinement (SHELXL-97) on F_o², both programs from G.

Sheldrick, University of Go¨ttingen, 1997; 514 parameters, H

atoms riding, absolute configuration established (Flack pa-

rameter -0.01(3)) and confirmed by chiral reference, Cheby-

shev weights, R₁) 0.0605 (I > 2σ(I)), wR₂) 0.1503 (all data),

125.3 (d, J _P,C) 12.5 Hz), 124.3, 124.0, 123.3, 122.6 (d, J _P,C

1.2 Hz), 121.8, 121.4, 73.8 (d, J _P,C) 3.1 Hz), 52.6 (d, J _P,C

)

2.3 Hz), 48.4 (d, J _P,C) 2.3 Hz), 27.2 and 22.8; ³¹P NMR (121.4

MHz, CDCl₃) δ 37.7 ppm; ESI/pos (CH₃OH) m/z cation 759 M

- PF₆^-. Found C, 59.5; H, 4.2; N, 4.5, C₄₅H₃₉N₃F₆P₂Pd requires

C, 59.8; H, 4.4; N, 4.7.

∆F_max/min) 0.827/-1.249 e Å^-3

.

Cr ysta l d a ta for (S,R)-18b: [C₄₅H₃₉N₃PPd]⁺[PF₆]^-‚0.2H₂O,

from chloroform/diethyl ether/trace water, M_r) 907.74, crystal

size: 0.07 × 0.10 × 0.25 mm³; a ) 11.4972(1), b ) 15.6101(1),

c ) 21.7615(2) Å, V ) 3905.59(6) Å³, T ) 100 K, orthorhombic,

space group P2₁2₁2₁(No. 19), Z ) 4, F_calcd) 1.544 g cm^-3, F(000)

) 1848, Nonius KappaCCD diffractometer, λ (Mo KR) )

0.71073 Å, µ ) 0.62 mm^-1, 31043 measured and 14658

independent reflections (R_int) 0.062), 12379 with I > 2σ(I),

The mother liquor was reduced in vacuo to give (R,R)-17d

as a pale yellow solid which was dried on the vacuum line:

mp 196-198 °C; [R]_D) +168.8 (c 0.25, CHCl₃); ν_max(KBr) 3054,

2974, 2916, 1614, 1560, 1501, 1435, 1100 and 812 cm^-^{1 1}H

;

NMR (300 MHz, CDCl₃) δ 8.09 (1H, d, J ) 7.40 Hz), 8.05 (1H,

d, J ) 7.16 Hz), 7.92 (1H, d, J ) 8.35 Hz), 7.89-7.85 (2H, m),

7.83 (1H, d, J ) 7.87 Hz), 7.74 (1H, app d, J ) 7.88 Hz), 7.68

(1H, d, J ) 6.68 Hz), 7.62 (2H, d, J ) 8.35 Hz), 7.56-7.47

6586 J . Org. Chem., Vol. 69, No. 20, 2004

Axially Chiral Quinazoline-Containing Ligands

(4H, m), 7.42 (1H, d, J ) 8.35 Hz), 7.38-7.19 (9H, m), 7.14

(1H, t, J ) 8.35 Hz), 7.05 (1H, t, J ) 7.16 Hz), 6.74 (1H, d, J

) 8.83 Hz), 6.69 (2H, t, J ) 7.16 Hz), 6.56 (1H, d, J ) 8.35

Hz), 5.90 (1H, dd, J ) 8.35, 6.20 Hz), 4.35 (1H, d, J ) 13.60

Hz, CH₂Ph), 4.30 (1H, d, J ) 14.08 Hz), 4.18 (1H, quin, J )

6.20 Hz), 2.88 (3H, s), 2.19 (3H, s) and 2.02 (3H, d, J ) 6.44

Hz); ¹³C NMR (75 MHz, CDCl₃) δ 167.2 (d, J _P-C) 4.83 Hz),

163.7, 149.6, 147.6 (d, J _P-C) 22.23 Hz), 137.5, 136.9 (d, J _P-C

) 12.56 Hz), 134.6 (d, J _P-C) 12.57 Hz), 134.2 (d, J _P-C) 10.63

Hz), 132.7, 132.3, 131.3 (d, J _P-C) 8.70 Hz), 130.2, 130.0, 129.4,

129.0, 128.7, 128.5, 128.5-127.4, 128.1, 127.6, 127.5, 127.4,

127.1, 127.0, 127.0, 126.9, 126.5, 126.0 (d, J ) 11.12 Hz), 125.8,

125.6 (d, J ) 11.12 Hz), 125.5, 125.1, 124.4, 123.0, 123.0, 122.9,

122.1, 71.8, 49.6, 47.5, 45.5 and 22.5; ³¹P NMR (121 MHz,

CDCl₃) δ 42.4 ppm; ESI/pos (CH₃OH) m/z cation 834 ) M -

Cl. Alternatively, this diastereomerically pure material, (R,R)-

17d , was also isolable as a pale yellow solid by recrystallization

of the mixture from hot methanol.

(R,S)-Dip h en yl(1-(2-isop r op yl-qu in a zolin -4-yl)(2-n a p h -

th yl)p h osp h in e 14e. A solution of (R,S)-diphenyl(1-(2-iso-

propyl-quinazolin-4-yl)(2-naphthyl)phosphine 14e (1.0 g, 2.07

mmol) and (+)-di-µ-chlorobis[(R)-dimethyl(1-(1-naphthyl)ethyl)

aminato-C₂,N]dipalladium(II) 16 (0.71 g, 1.04 mmol) in dry,

degassed dichloromethane (80 mL) was stirred for 18 h under

an atmosphere of nitrogen. The bright yellow solution was

reduced in vacuo and vacuum-dried to give (R,R)- and (S,R)-

cis-[dimethyl(1-(1-naphthyl)ethyl)aminato-C₂,N]-[1-(2-isopro-

pyl-quinazolin-4-yl)(2-naphthyl)diphenyl phosphine]palladium-

(II)chloride 17e as a light yellow solid.

solution was filtered to remove a small amount of white

precipitate that had formed overnight. Potassium hexafluo-

rophosphate (0.42 g, 2.28 mmol) in 80 mL of distilled water

was added, a yellow suspension was seen to form in the

solution, and the mixture was stirred for a further 1 h. The

solution was filtered, and the resulting cream precipitate was

dried on the vacuum line to give (R,R)- and (S,R)-cis-[dimethyl-

(1-(1-naphthyl)ethyl)aminato-C₂,N]-[1-(2-isopropyl-quinazolin-

4-yl)(2-naphthyl)diphenyl phosphine]palladium(II) hexafluo-

rophosphate 18e as a 1:1 mixture of diastereomers (1.364 g,

71%).

Recrystallization of the mixture from hot chloroform/diethyl

ether gave (S,R)-18e: mp 244-246 °C; [R]_D) -205 (c 1,

1

CHCl₃); H NMR (300 MHz, CDCl₃) δ 8.17 (1H, d, J ) 8.49

Hz), 8.10 (1H, d, J ) 7.9 Hz), 7.88 (1H, dt, J ) 8.47, 6.44, 1.17

Hz), 7.85 (2H, app dt, J ) 9.96, 8.49, 1.46 Hz), 7.74 (1 H, app

t, J ) 7.90 Hz), 7.68 (3H, app t, J ) 8.2 Hz), 7.53 (1H, dt, J )

9.67, 8.49, 1.17 Hz), 7.48-7.22 (8H, m), 7.19-7.12 (3H, m),

7.07 (1H, d, J ) 8.49 Hz), 6.92 (1H, d, J ) 8.79 Hz), 6.75 (1H,

d, J ) 7.62 Hz), 6.70 (1H, t, J ) 6.74 Hz), 6.65 (1H, d, J )

6.74 Hz), 4.25 (1H, quin, J ) 6.0 Hz), 2.7 (1H, sept, J ) 7.0

Hz), 2.46 (3H, s), 1.92 (3H, s), 1.59 (3H, d, J ) 6.20 Hz), 1.26

(6H, d, J ) 6.74 Hz); ³¹P (121 MHz, CDCl₃) δ 35.2 ppm, -143.3

(sept., J ) 712.2 Hz); HRMS (ES) m/z 786.2230, C₄₇H₄₃N₃PPd

cation requires 786.2229.

Cr ysta l d a ta for (S,R)-18e: [C₄₇H₄₃N₃PPd]⁺[PF₆]^-, from

chloroform/pentane, M_r) 932.18, crystal size: 0.08 × 0.13 ×

0.17 mm³; a ) 11.250(1), b ) 16.167(2), c ) 11.379(1) Å, â )

92.273(2), V ) 2068.0(4) Å³, T ) 100 K, monoclinic, space group

P2₁(No. 4), Z ) 2, F_calcd) 1.497 g cm^-3, F(000) ) 952, Siemens

Recrystallization of the mixture from hot chloroform/diethyl

ether gave (R,R)-17e: mp 239-241 °C; [R]_D) 269.2 (c 0.25,

SMART diffractometer, λ (Mo KR) ) 0.71073 Å, µ ) 0.59 mm^-1

,

1

CHCl₃); H NMR (300 MHz, CDCl₃) δ 8.14 (1H, d, J ) 7.03

8039 measured and 4573 independent reflections (R_int) 0.054),

3976 with I > 2σ(I), θ_max) 23.26°, T_min) 0.907, T_max) 0.956,

direct methods (SHELXS-97) and least-squares refinement

(SHELXL-97) on F_o², both programs from G. Sheldrick,

University of Go¨ttingen, 1997; 532 parameters, absolute

configuration established (Flack parameter -0.05(3)) and

confirmed by chiral reference, Chebyshev weights, H atoms

Hz), 8.09 (1H, d, J ) 7.03 Hz), 7.94 (1H, d, J ) 7.62 Hz), 7.9-

7.85 (2H, m), 7.83 (1H, d, J ) 7.76 Hz), 7.73 (1H, app d, J )

8.93 Hz), 7.7-7.59 (4H, m), 7.58 (1H, app d, J ) 7.91 Hz),

7.47-7.13 (9H, m), 7.04 (1H, t, J ) 8.2 Hz), 6.8 (1H, t, J )

6.44 Hz), 6.76 (1H, d, J ) 8.64 Hz), 5.7 (1H, d, J ) 6.44 Hz),

4.22 (1H, quin, J ) 6.15 Hz), 3.32 (1H, sept, J ) 6.88 Hz),

2.94 (3H, s), 2.33 (3H, s), 2.08 (3H, d, J ) 6.3 Hz), 1.42 (6H, d,

J ) 6.88 Hz); ¹³C NMR (75 MHz) δ (CDCl₃) 168, 150.7, 149.1,

148.9, 138.2, 138, 135.5, 133.8, 133.6, 132.8, 132.3, 132, 131.4,

130.7, 130.3, 129.6, 128.9, 128.4, 128.3, 128.2, 128, 127.9,

127.4, 128.2, 126.9, 125.7, 124.5, 124.3, 124.2, 123.4, 73.2, 51.1,

48.8, 38.2, 23.8, 22; ³¹P NMR (121 MHz, CDCl₃) δ 42.7 ppm.

riding, Chebychev weights, R₁) 0.0416 (I > 2σ(I)), wR₂

0.0868 (all data), ∆F_max/min) 0.434/-0.467 e Å^-3

All attempts to isolate (R,R)-18e were unsuccessful.

)

.

(R,S)-Dip h en yl(1-(2-ter t-bu tyl-qu in a zolin -4-yl)(2-n a p h -

th yl)p h osp h in e 14f. A solution of (R,S)-diphenyl(1-(2-tert-

butyl-quinazolin-4-yl)(2-naphthyl)phosphine 14f (1.54 g, 3.10

mmol) and (+)-di-µ-chlorobis[(R)-dimethyl(1-(1-naphthyl)ethyl)

aminato-C₂,N]dipalladium(II) 16 (1.05 g, 1.55 mmol) in dry,

degassed dichloromethane (100 mL) was stirred for 18 h under

an atmosphere of nitrogen. The clear yellow solution was

filtered, reduced in vacuo, and dried on a vacuum line to yield

(R,R)- and (S,R)-cis-[dimethyl(1-(1-naphthyl)ethyl)aminato-

C₂,N]-[1-(2-tert-butyl-quinazolin-4-yl)(2-naphthyl)diphenylphos-

phine]palladium(II)chloride 17f as a light yellow solid (2.55

g, 98%).

The filtrate from the hot chloroform/diethyl ether recrys-

tallization was stirred in cold diethyl ether for 15 min. The

solid was filtered and dried under vacuum to give (S,R)-17e

as a light yellow powder: [R]_D) -169.6 (c 0.25, CHCl₃); mp

244-246 °C; ν_max(KBr) 3058 (Ar-H), 2967 (C-H), 2915 (C-

H), 2867 (C-H), 1614 (CdN), 1551 (CdC), 1434 (P-Ph) and

1092 (Ar-H); ¹H NMR (300 MHz, CDCl₃) δ 8.3 (1H, t, J )

8.93 Hz), 8.0 (1H, d, J ) 8.64 Hz), 7.91 (1H, d, J ) 8.2 Hz),

7.86-7.73 (m, 4H), 7.71-7.61 (3H, app t, J ) 8.35 Hz), 7.55

(1H, d, J ) 7.9 Hz), 7.48 (1H, t, J ) 7.47 Hz), 7.44-7.37 (1H,

m), 7.35 (7H, app dt, J ) 6.59 Hz), 7.19 (1H, t, J ) 7.32 Hz),

6.91 (1H, t, J ) 6.59 Hz), 6.8 (1H, d, J ) 7.32 Hz), 6.67 (1H,

t, J ) 8.93 Hz), 6.62 (1H, d, J ) 8.64 Hz), 6.44 (1H, t, J ) 6.15

Hz), 4.22 (1H, quin, J ) 6.0 Hz), 3.04 (1H, sept, J ) 7.03 Hz),

2.99 (3H, s), 2.55 (3H, s), 1.77 (3H, d, J ) 6.15 Hz), 1.26 (6H,

d, J ) 6.74 Hz); ¹³C NMR (125.7 MHz, CDCl₃) δ 167.5, 150.8,

150.5, 149.1, 137.4, 137.3, 136.4, 136.1, 135.9, 134.4, 133.6,

132.8, 131.2, 130.9, 129.9, 129.1, 128.8, 128.8, 128.5, 128.3,

128.2, 128, 127.7, 127.2, 127.0, 126.9, 126.3, 125.8, 124.2,

123.5, 73.4, 51.1, 48.7, 37.8, 23.6, 22.2; ³¹P NMR (121 MHz,

CDCl₃) δ 45.5 ppm; HRMS (ES) m/z 786.2231, C₄₇H₄₃N₃PPd

cation requires 786.2229.

Recrystallization of the mixture from hot butanone/diethyl

ether afforded a yellow solid, which was stirred in cold

methanol for 10 min and filtered, producing (R,R)-17f: mp

237-239 °C; [R]_D) 254.4 (c 0.25, CHCl₃); ν_max(KBr) 3056 (Ar-

H), 2959 (C-H), 2905 (C-H), 2863 (C-H), 1614 (CdN), 1565

(CdC), 1480 (P-Ph) and 1163 (Ar-H); ¹H NMR (300 MHz,

CDCl₃) δ 8.11 (1H, d, J ) 8.05 Hz), 8.06 (1H, d, J ) 7.91 Hz),

7.98-7.83 (3H, m), 7.82 (1H, d, J ) 8.79 Hz), 7.80 (1H, d, J )

8.2 Hz), 7.74 (1H, app d, J ) 8.2 Hz), 7.7-7.59 (4H, m), 7.54

(1H, d, J ) 7.76 Hz), 7.46-7.22 (6H, m), 7.15 (2H, app t, J )

7.18 Hz), 7.69 (1H, t, J ) 7.12 Hz), 6.79-6.67 (2H, app d, J )

8.49 Hz), 6.52 (1H, d, J ) 8.64 Hz), 6.01 (1H, t, J ) 7.76 Hz),

4.26 (1H, quin, J ) 6.0 Hz), 2.98 (3H, s), 2.44 (3H, s), 2.10

(3H, d, J ) 6.15 Hz), 1.53 (9H, s); ¹³C NMR (75 MHz, CDCl₃)

δ 172.2, 167.5, 150.6, 149.2, 148.9, 143.1, 138, 137.9, 135.5,

135.3, 133.6, 132.9, 132.8, 131.4, 130.6, 130.3, 129.2, 128.9,

128.4, 128.3, 128.1, 127.3, 127.1, 126.9, 126.3, 125.8, 124.4,

124.2, 123.4, 123.7, 123.3, 122.3, 121.9, 73.2, 51.2, 48.8, 39.9,

F or m a tion of (R,R)- a n d (S,R)-18e. A solution of (R,S)-

diphenyl(1-(2-isopropyl-quinazolin-4-yl)(2-naphthyl)phos-

phine 14e (1.0 g, 2.07 mmol) and (+)-di-µ-chlorobis[(R)-

dimethyl(1-(1-naphthyl) ethyl)aminato-C₂,N]dipalladium(II) 16

(0.71 g, 1.04 mmol) in dry, degassed methanol (80 mL) was

stirred for 18 h under an atmosphere of nitrogen. The yellow

J . Org. Chem, Vol. 69, No. 20, 2004 6587

Connolly et al.

30.1, 23.8; ³¹P NMR (121 MHz, CDCl₃) δ 43.8 ppm; HRMS (ES)

m/z 800.2390, C₄₈H₄₅N₃PPd cation requires 800.2386.

the decomplexation of the (R,R)-2-tert-butyl palladium com-

plexes 17f and 18f to give enantiopure (R)-14f. (S)-Quinazo-

linap [R]²¹) -119.3 (c 0.17, CHCl₃). (S)-2-methyl-Quinazo-

Cr ysta l d a ta for (R,R)-17f: [C₄₈H₄₅ClN₃PPd], from dichlo-

romethane/diethyl ether, M_r) 836.69, crystal size: 0.19 × 0.24

× 0.26 mm³; a ) 13.2921(1), b ) 14.3043(2), c ) 21.8897(2) Å,

V ) 4162.0(1) Å³, T ) 293 K, orthorhombic, space group

P2₁2₁2₁(No. 19), Z ) 4, F_calcd) 1.335 g cm^-3, F(000) ) 1728,

Nonius KappaCCD diffractometer, λ (Mo KR) ) 0.71073 Å,

µ ) 0.59 mm^-1, 27470 measured and 10281 independent

reflections (R_int) 0.037), 9106 with I > 2σ(I), θ_max) 28.28°,

T_min) 0.877, T_max) 0.909, direct methods (SHELXS-97) and

least-squares refinement (SHELXL-97) on F_o², both programs

from G. Sheldrick, University of Go¨ttingen, 1997; 487 param-

eters, H atoms riding, absolute configuration established

(Flack parameter -0.04(2)) and confirmed by chiral reference,

Chebyshev weights, R₁) 0.0312 (I > 2σ(I)), wR₂) 0.0750 (all

D

linap [R]²³_D) -94.1 (c 1.06, CH₂Cl₂); (S)-2-phenyl-Quinazolinap

[R]¹⁸) -93.6 (c 0.25, CHCl₃); (R)-2-phenyl-Quinazolinap

D

[R]¹⁸_D) +91.2 (c 0.25, CHCl₃); (S)-2-benzyl-Quinazolinap [R]²¹

D

) -147.0 (c 0.24, CHCl₃); (R)-2-benzyl-Quinazolinap [R]²¹

+155.6 (c 0.25, CHCl₃); (S)-2-isopropyl-Quinazolinap [R]²¹

-112.0 (c 0.25, CHCl₃); (R)-2-isopropyl-Quinazolinap [R]²¹

+118.2 (c 0.25, CHCl₃); (R)-2-tert-butyl-Quinazolinap [R]²¹

+86.4 (c 0.25, CHCl₃).

)

D

Ca ta lyst F or m a tion for Rh od iu m -Ca ta lyzed Asym -

m etr ic Hyd r obor a tion . (S)-Dip h en yl[1-(2-su bstitu ted -

q u in a zolin -4-yl)(2-n a p h t h yl)]p h osp h in e R h od iu m (1,5-

cyclooct a d ien e)t r iflu or om et h a n esu lfon a t e. (1,5-Cyclo-

octadiene)(2,4-pentanedionato)rhodium (3.1 mg, 0.01 mmol)

and(S)-diphenyl[1-(2-substituted-quinazolin-4-yl)(2-naphthyl)]-

phosphine (0.01 mmol) were dissolved in dry THF (2 mL)

under an atmosphere of nitrogen to give a clear yellow solution.

Trimethylsilyltrifluoromethanesulfonate (2 µL, 1.11 equiv) was

added via syringe, and an orange color developed. The reaction

mixture was stirred for 20 min, and the volume was then

reduced in vacuo to 0.5 mL. Pentane (10 mL) was added via

syringe to produce a light orange precipitate. This was stirred

for 5 min before the pentane was removed. The precipitate

was washed with fresh pentane (2 × 10 mL), which was

syringed from the Schlenk tube to leave (S)-20a -e as light

orange powders. The catalyst was dried under vacuum for 40

min prior to use in rhodium-catalyzed hydroboration. Dry THF

(4 mL) was added to the Schlenk tube, and 2 mL portions of

the catalyst precursor (1 mol %) were transferred to two oven-

dried Schlenk tubes under nitrogen. Note: An identical

procedure was followed to form the corresponding 2-tert-butyl

complex (R)-20f.

data), ∆F_max/min) 0.443/-0.300 e Å^-3

.

F or m a tion of (R,R)- a n d (S,R)-18f. An identical procedure

was followed to form (R,R)- and (S,R)-cis-[dimethyl(1-(1-

naphthyl)ethyl)aminato-C₂,N]-[1-(2-tert-butyl-quinazolin-4-yl)-

(2-naphthyl)diphenyl phosphine]palladium(II)chloride 17f. Po-

tassium hexafluorophosphate (0.62 g, 3.39 mmol) in distilled

water (40 mL) was added to a solution of (R,R)- and (S,R)-17f

(2.5 g) in dichloromethane (40 mL) and was allowed stir

overnight (18 h). The organic layer was isolated, filtered, and

reduced in vacuo to give (R,R)- and (S,R)-cis-[dimethyl (1-(1-

naphthyl)ethyl)aminato-C₂,N]-[1-(2-tert-butyl-quinazolin-4-yl)-

(2-naphthyl) diphenylphosphine]palladium(II) hexafluorophos-

phate 18f. The yellow solid was stirred in cold methanol for

15 min and filtered to give (R,R)-18f: ¹H NMR (300 MHz,

CDCl₃) δ 8.11 (1H, app d, J ) 7.61 Hz), 8.06 (1H, app d, J )

7.61 Hz), 8.0-7.81 (4H, m), 7.74 (3H, app d, J ) 8.23 Hz),

7.58 (1H, d, J ) 8.02 Hz), 7.46-7.09 (10H, m), 7.01 (1H, t, J

) 6.99 Hz), 6.76 (3H, app d, J ) 8.64 Hz), 6.52 (1H, d, J )

8.64 Hz), 6.02 (1H, t, J ) 6.79 Hz), 4.27 (1H, quin., J ) 6.17

Hz), 2.98 (3H, s), 2.44 (3H, s), 2.10 (3H, d, J ) 6.17 Hz), 1.53

(9H, s); ³¹P NMR (121 MHz, CDCl₃) δ 43.7 ppm; HRMS (ES)

m/z 800.2387, C₄₈H₄₅N₃PPd cation requires 800.2386.

The filtrate was recrystallized from methanol to give 96%

diastereomerically pure (S,R)-18f: ¹H NMR (300 MHz, CDCl₃)

δ 8.16 (1H, d, J ) 8.93 Hz), 7.98 (3H, app d, J ) 8.07 Hz),

7.82 (1H, app d, J ) 5.74 Hz), 7.74 (1H, m), 7.68 (1H, d, J )

7.86 Hz), 7.62 (2H, app t, J ) 9.98 Hz), 7.52 (3H, d, J ) 8.5

Hz), 7.41 (1H, t, J ) 7.01 Hz), 7.37-7.19 (7H, m), 7.0 (1H, d,

J ) 8.3 Hz), 6.93 (2H, t, J ) 6.8 Hz), 6.71 (1H, d, J ) 8.5 Hz),

6.56 (1H, d, J ) 8.5 Hz), 6.23 (1H, t, J ) 7.65 Hz), 4.42 (1H,

quin, J ) 5.95 Hz), 2.86 (6H, app d, J ) 9.77 Hz), 2.11 (3H,

br. s), 1.68 (9H, s); ³¹P NMR (121 MHz, CDCl₃) δ 42.2 ppm.

Decom plexation of En an tiopu r e 2-Su bstitu ted-qu in azo-

lin a p Liga n d s. (S,R)-17c-e and (S,R)-18a ,b,e (0.32 mmol)

and 1,2-bis(diphenylphosphino)ethane (0.32 mmol) were dis-

solved in dry, degassed dichloromethane (5 mL). The light

yellow solution was stirred for 3 h at room temperature under

an atmosphere of nitrogen. The CH₂Cl₂was removed in vacuo

and the resulting solid was purified by silica gel chromatog-

raphy (CH₂Cl₂or petroleum ether/ethyl acetate) to give (S)-

2-substituted-Quinazolinap 14a -e as a white solid (>90%),

identical in allother respects to the previously prepared

racemic samples. An analogous procedure was employed for

Gen er a l P r oced u r e F or Asym m etr ic Hyd r obor a tion .

(R)- or (S)-Diphenyl[1-(2-substituted-quinazolin-4-yl)(2-naph-

thyl)]phosphine rhodium (1,5-cyclooctadiene) trifluoromethane-

sulfonate (5 µmol) in THF (2 mL) was placed under nitrogen

in a Schlenk tube. Freshly distilled catecholborane (53 µL, 0.5

mmol) was added via microliter syringe, and the light brown

solution was stirred for 5 min at the required temperature.

The substrate olefin (0.5 mmol) was injected, and the reaction

mixture was stirred for 2 h at room temperature or at 0 °C (in

some cases extended reaction times were necessary). The

reaction was then cooled to 0 °C, and ethanol (1 mL) was added

followed by 1 M NaOH (3 mL) and H₂O₂(3 mL). The ice bath

was removed, and the solution was stirred for 1 h at room

temperature. The reaction mixture was transferred to a

separatory funnel and diethyl ether (10 mL) was added. The

organic layer was washed with 1 M NaOH (10 mL), brine (10

mL) and dried with MgSO₄. The solution was filtered, and the

solvent was removed in vacuo to give the hydroborated product

as an oil. Percent conversion and regioselectivity were deter-

mined by ¹H NMR. The percent ee was calculated by chiral

GC or HPLC analysis.

Exp er im en ta l Deta ils for Ch r om a togr a p h ic Deter m in a tion of Op tica l P u r ities

substrate

conditions

(R)

(S)

styrene

120 °C, â-Dex 120 column, 16 psi

10.98 min

36.93 min

24.1 min

11.24 min

37.85 min

25.35 min

17.38 min

47.15 min

118.15 min

89.53 min

33.9 min

p-methoxystyrene

p-chlorostyrene

â-methylstyrenes

trans-anethole

3,4-dimethoxy-1-propenylbenzene

stilbenes

125 °C, â-Dex 120 column, 16 psi

130 °C, â-Dex 120 column, 16 psi

120 °C, â-Dex 120 column, 16 psi

17.1 min

130 °C, â-Dex 120 column, 16 psi

45.69 min

115.09 min

70.5 min

40.9 min

57.89 min

135 °C, â-Dex 120 column, 16 psi

HPLC, Daicel OD, 99:1 hexane/ⁱPrOH, 1 mL/min

120 °C, â-Dex 120 column, 16 psi

indene

dihydronaphthalene

59.67 min

6588 J . Org. Chem., Vol. 69, No. 20, 2004

Axially Chiral Quinazoline-Containing Ligands

Ack n ow led gm en t. We thank Enterprise Ireland for

a Basic Research Award (SC/94/565) to support our

initial work in this area and for awarding Research

Scholarships to the following students: M.McC. (BR/

94/158), P.M.L. (BR/96/108), C.P.S. (BR/97/047), and

D.J .C. (BR/99/238). A.M.C. is thankful for an IRCSET

scholarship (RS/2002/907-1). The award of the 1997

BOC Gases Postgraduate Bursary and 1999 UCD Open

Postgraduate Scholarship to M.McC. and P.M.L., re-

spectively, are gratefully acknowledged. D.J .C. thanks

Schering-Plough Corporation for their support and

Enterprise Ireland for a postdoctoral award (Sc/2002/

349).

Su p p or t in g In for m a t ion Ava ila b le: Physical data for

1

7b-e, 9b-e, 8b-e, 11b-f, 12b-f, 13b-f, 14b-f; H NMR

spectra for 11a -f, 12a -f, 13a -f, 14a -f, 17d -f, 18a -b, 18e-

f, and 19; ¹³C NMR spectra for 11a -f, 12a -f, 13a -f, 14a -f,

and 19; and ³¹P NMR spectra for 14a -f, 17d -f, 18a -b, 18e-

f, and 19. X-ray crystallographic files for (S,R)-17d , (R,R)-17f,

(S,R)-18a , (S,R)-18b, and (S,R)-18e. This material is available

free of charge via the Internet at http://pubs.acs.org.

J O049195+

J . Org. Chem, Vol. 69, No. 20, 2004 6589

Article Doi

Preparation and resolution of a modular class of axially chiral quinazoline-containing ligands and their application in asymmetric rhodium-catalyzed olefin hydroboration

DOI: 10.1021/jo049195+

Source and publish data:

Authors:

Article abstract of DOI:10.1021/jo049195+

Full text of DOI:10.1021/jo049195+

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