Rhodium-catalysed hydroboration employing new Quinazolinap ligands; An investigation into electronic effects

Tetrahedron: Asymmetry 21 (2010) 1458–1473

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Tetrahedron: Asymmetry

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Rhodium-catalysed hydroboration employing new Quinazolinap ligands;

an investigation into electronic effects

Aoife C. Maxwell ^a, Susan P. Flanagan ^a, Richard Goddard ^b, Patrick J. Guiry ^a,

*

^aCentre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Belﬁeld, Dublin 4, Ireland

^bMax-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim a. d. Ruhr, Germany

a r t i c l e i n f o

a b s t r a c t

Article history:

As part of an ongoing effort to improve the efﬁciency and substrate scope of our Quinazolinap ligand ser-

ies in the rhodium-catalysed asymmetric hydroboration of vinyl arenes, 2-(p-triﬂuoromethylphenyl)-

Quinazolinap and 2-(p-methoxyphenyl)-Quinazolinap have been synthesised and resolved in good yield.

These, along with the previously reported 2-(2-pyridyl)-Quinazolinap and 2-(2-pyrazinyl)-Quinazolinap,

form part of an electronic series of Quinazolinap ligands synthesised in order to explore electronic effects

in this ligand class. The application of this series of ligands to the rhodium-catalysed asymmetric hydrob-

oration of a range of vinylarenes is described. Good conversions and regioselectivities as well as excellent

enantioselectivities up to 97% were obtained. 2-(p-Methoxyphenyl)-Quinazolinap demonstrated consis-

tently high enantioselectivities in the hydroboration of sterically demanding vinylarenes.

Received 2 March 2010

Accepted 8 June 2010

Available online 13 July 2010

Dedicated with respect and admiration to

Professor Henri Kagan on the occasion of

his 80th birthday

1. Introduction

withdrawing group to the backbone of the ligand.¹⁴We aimed to

expand this group of electronically varied Quinazolinap ligands

The use of atropisomeric ligands in transition metal-catalysed

asymmetric transformations has been well documented.^1–3We

have developed a class of axially chiral ligands, which we term

‘Quinazolinap’, as they incorporate a quinazoline unit to the biaryl

framework (Fig. 1).

through the synthesis of a further subset. It was postulated that

by varying the electronic nature of the substituent in the 2-posi-

tion, we could alter the basicity of the donor nitrogen. We wished

to investigate whether this variation of electronics at the nitrogen

could improve the results possible with more sterically demanding

and traditionally challenging substrates for hydroboration.

Ligands 1a–f, which constitute a steric series, have been applied

in the rhodium-catalysed asymmetric hydroboration of vinylarenes

where they achieved excellent conversions, regioselectivities and

enantioselectivities as high as 99.5%.⁴We have focused on the rho-

dium-catalysed asymmetric hydroboration of vinylarenes due to

the versatility of the organoboranes produced. They are important

intermediates in many natural product and drug syntheses⁵and

are often subjected to functionalisation of the carbon–boron bond,⁶

which, importantly, occurs with the retention of stereochemistry.

While the majority of reports of ligand modiﬁcation have been

followed from systematic variation of the spatial demands of the

catalyst, manipulation of ligand electronics is another important

method of varying catalyst properties.⁷Examples include varia-

tions in the Salen-type ligands for asymmetric epoxidation,⁸an

electronic series of H-MOP ligands⁹and BINAP-derived ligands.¹⁰

Within the P,N ligand class, Brown has conducted a study of elec-

tronic effects in the QUINAP series by variation at the phosphorus

donor atom.^11,12We began our research into electronic effects in

the Quinazolinap series with a small set of ligands varied at the

phosphorus atom¹³and also through the addition of an electron-

The ﬁrst members of this new series to be prepared were the

2-(2-pyridyl)- and 2-(2-pyrazinyl)-variants 2a–b. The synthesis

and resolution of these ligands and their application in palla-

dium-catalysed allylic alkylation have already been reported.¹⁵

Herein we report the extension of this new series to include the

2-(p-triﬂuoromethylphenyl)- and 2-(p-methoxyphenyl)-Quinazol-

inap 3a–b. These were designed to preclude the possibility of an

extra donor nitrogen and so be more directly comparable to the re-

sults obtained previously with ligands 1a–f, and ligand 1c in par-

ticular. We report in detail on the synthesis and resolution of

ligands 3a–b and the application of ligands 2–3 in the rhodium-

catalysed asymmetric hydroboration of a range of vinylarenes.

2. Results and discussion

2.1. Ligand synthesis

The synthesis of 2-(p-triﬂuoromethylphenyl)- and 2-(p-meth-

oxyphenyl)-Quinazolinap, ligands 3a–b, has been achieved using

methodology based on that developed for other members of the

Quinazolinap family.^4,16This synthesis involved two metal-cata-

lysed couplings, the biaryl coupling and the formation of the

* Corresponding author. Tel.: +353 1 716 2309; fax: +353 1 716 2127.

E-mail address: p.guiry@ucd.ie (P.J. Guiry).

doi:10.1016/j.tetasy.2010.06.012

A. C. Maxwell et al. / Tetrahedron: Asymmetry 21 (2010) 1458–1473

1459

R

N

R

N

PPh₂

1a R = H; 1b R = Me

1c R = Ph; 1d R = Bn

1e R = i-Pr; 1f R = t-Bu

3a R = CF₃

3b R = OMe

2a R = C

2b R = N

Figure 1. The Quinazolinap ligand series.

naphthyl-phosphorus bond, as the key steps. The weakness of this

synthesis was a deprotection step involving BBr₃. This reagent was

undesirable due to its toxicity and the step was characterised by

relatively poor yields for a deprotection. The synthesis reported

here for ligands 3a–b avoids the use of this reagent through a

change in the protecting group strategy.

The synthesis of substituted quinazolines has been the subject

of considerable investigation¹⁷due to the diverse range of biolog-

ical properties associated with this heterocycle.^18,192-p-Triﬂuoro-

methylphenyl-4(3H)-quinazolinone 6a was synthesised by the

reaction of p-triﬂuorotolunitirile 4 with sodium methoxide and

nic acid was synthesised in three steps from 2-naphthol by the

method of Spivey.²²The Suzuki coupling was catalysed by

3 mol % tetrakis(triphenylphosphine)palladium and aqueous so-

dium carbonate was found to be the optimal base to afford the cou-

pled biaryl in good yield (Scheme 2). Removal of the benzyl ether

was achieved cleanly to form naphthols 10a–b in excellent yields.

The ease of removal of the benzyl group represents a signiﬁcant

improvement relative to the original Quinazolinap synthesis.

Naphthols 10a–b were then converted to triﬂuoromethanesulfo-

nates 11a–b by using the standard procedure of stirring with triﬂic

anhydride and 4-dimethylaminopyridine in anhydrous dichloro-

methane.²³The Ni-catalysed process developed by Cai was used

to introduce the diphenylphosphino group in good yields (60–

65%).²⁴Hence, racemic 2-(p-triﬂuoromethylphenyl)-Quinazolinap

3a and 2-(p-methoxyphenyl)-Quinazolinap 3b were synthesised

in good yield, from readily available starting materials, over six

steps.

anthranilic acid to form the quinazolinone in

a 47% yield

(Scheme 1).²⁰This approach was not suitable for the 2-p-methoxy-

phenyl analogue 6b which was formed in a 65% yield by the reac-

tion of p-anisaldehyde

5 with anthranilamide and sodium

hydrogen sulﬁte.²¹Both of these ring-forming reactions could be

easily performed on a medium to large scale (20–50 g). Phosphorus

oxychloride was then used to convert the quinazolinones to 4-

chloroquinazolines 7a–b in good yield.

2.2. Ligand resolution

2-Benzyloxy-1-naphthylboronic acid 8 was chosen as the nucle-

ophilic component of the Suzuki coupling as the benzyl ether can

be removed cleanly in the presence of the methyl ether. This boro-

The formation of diastereomeric complexes with enantiopure

palladium amine complexes is an important strategy in the resolu-

NH₂

R

OMe

CF₃

OH

N

O

NH

NaHSO₃, DMA

Na, MeOH

Δ, 12h

CHO

CN

Δ, 3h

6a R = CF₃47%

6b R = OMe 65%

4

5

POCl₃

N, N-diethylaniline

Benzene, Δ, 5h

R

N

Cl

7a R = CF₃86%

7b R = OMe 89%

Scheme 1. Synthesis of 4-chloroquinazolines.

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A. C. Maxwell et al. / Tetrahedron: Asymmetry 21 (2010) 1458–1473

R

B(OH)₂

N

OBn

Pd(PPh₃)₄

+

N

Na₂CO₃

Δ, 24h

Cl

7a R = CF₃

7b R = OMe

8

R

N

DMAP, CH₂Cl₂

10% Pd/C

OBn

OH

(CF₃SO₂)₂O

RT, 12h

H₂1 bar

EtOH, RT, 16h

9a R = CF₃57%

9b R = OMe 62%

10a R = CF₃92%

10b R = OMe 96%

R

N

NiCl₂dppe, PPh₂H

DABCO, DMF

OTf

PPh₂

Δ, 24h

11a R = CF₃92%

11b R = OMe 58%

3a R = CF₃65%

3b R = OMe 60%

Scheme 2. Synthesis of racemic Quinazolinap ligands.

tion of phosphorus-containing ligands. The ortho-palladated deriv-

ative of (R)-dimethyl[1-(1-naphthyl)ethyl]amine has been used as

the resolving agent for the resolution of QUINAP, PHENAP and

previously synthesised members of the Quinazolinap ligand

class.^23,25,4,15

Therefore, racemic 2-(p-triﬂuoromethylphenyl)-Quinazolinap

3a and (+)-di-l-chlorobis((R)-dimethyl[1-(1-naphthyl)ethyl]ami-

(p-triﬂuoromethylphenyl) substituent on the quinazolinap ligand

and the cationic metal centre, though steric effects cannot be ru-

led out.¹⁵

The cream-coloured precipitate which was formed when race-

mic ligand 3b was employed was a 3:1 mixture of diastereomers.

Fractional crystallisation using hot butanone/pentane afforded dia-

stereomerically pure (S,R)-13b. The ¹H NMR spectrum shows the

benzylic methine as a multiplet at 4.21 ppm while in ³¹P NMR

spectrum the phosphorus atom resonated at 44 ppm. To date no

X-ray crystallographic analysis of this complex has been obtained;

the conﬁguration quoted has been deduced based on speciﬁc rota-

tion values of decomplexed ligand and results obtained in catalysis

and comparison with previously studied members of the Quinazol-

inap ligand class whose conﬁgurations have been unambiguously

determined.⁴

It was also possible to isolate diastereomically pure (R,R)-13b, by

recrystallisation of the ﬁltrate using methanol. In this case, the ¹H

NMR spectrum shows the benzylic methine as multiplet at 4.09

ppm while in ³¹P NMR spectrum the phosphorus atom appears at

39 ppm.

nato-C₂,N)dipalladium(II) 12 were stirred in a 2:1 ratio in metha-

nol overnight (Scheme 3). The cream-coloured precipitate that

formed was ﬁltered and found by ¹H and ³¹P NMR spectroscopy

to be a single diastereomer. The benzylic methine of the isolated

diastereomeric complex appeared as a multiplet at 4.18 ppm in

the ¹H NMR spectrum and the phosphorus atom resonated at

42 ppm in the ³¹P NMR spectrum. It was not possible to obtain

crystals of this material suitable for X-ray crystallographic analysis.

By redissolving the complex in methanol, however, and precipitat-

ing the cationic palladium complex 14 (Scheme 4) suitable crystals

were obtained. By this method the diastereomerically pure mate-

rial obtained was shown to be (S,R)-13a.

Crystals of (S,R)-14 suitable for single-crystal X-ray structure

determination were grown from CDCl₃/pentane (Fig. 2). In the

crystal (S,R)-14 adopts a conformation in which the 2-position

of the 2-(p-triﬂuoromethylphenyl) substituent of the Quinazolin-

ap ligand (C-10) closely approaches the Pd atom [Pdꢀ ꢀ ꢀC10

3.048(2) Å]. The Pd atom is not planar coordinated and the P1–

Pd–N3 angle at 157.3(1)° is signiﬁcantly smaller than the almost

linear N-1–Pd–C-39 angle [173.6(1)°] indicating a weak C–Hꢀ ꢀ ꢀPd

intramolecular interaction between the H atom on C-10 of the 2-

Enantiomerically pure 2-(p-triﬂuoromethylphenyl)-Quinazolin-

ap and 2-(p-methoxyphenyl)-Quinazolinap were readily obtained

by decomplexation of the resolved diastereomers with 1,2-

bis(diphenylphosphino)ethane in dichloromethane (Scheme 5).

The speciﬁc rotation [a] was found to be +40.9 in CHCl₃for (S)-

D

2-(p-triﬂuoromethylphenyl)-Quinazolinap and +38.0 in CHCl₃for

(S)-2-(p-methoxyphenyl)-Quinazolinap, lending further weight to

the assignment of diastereomer (S,R)-13b.

A. C. Maxwell et al. / Tetrahedron: Asymmetry 21 (2010) 1458–1473

1461

R

N

R

Me₂

N

Cl

N

Pd

P

N

Ph₂

PPh₂

(R,R)

13a R = CF₃

13b R = OMe

3a R = CF₃

3b R = OMe

MeOH

18 h

+

R

Me₂

N

Me₂

N

Cl

Pd

N

Cl

Pd

2

P

Ph₂

12

(S,R)

13a R = CF₃

13b R = OMe

Scheme 3. Formation of diastereomeric monodentate ligand-palladium complexes.

CF₃

-

PF₆

N

Me₂

N

Me₂

N

MeOH

KPF₆

N

Cl

+

Pd

P

Ph₂

(S,R)-13a

(S,R)-14

Scheme 4. Formation of bidentate ligand-palladium complex.

2.3. Rhodium-catalysed hydroboration

The cationic rhodium catalysts were prepared in situ

(Scheme 6). A range of vinylarenes and the cyclic oleﬁns indene

and 1,2-dihydronapathelene (Fig. 3) were screened as substrates

in hydroborations using rhodium-Quinazolinap complexes 15a–d

as the active catalysts. Results obtained previously with 2-phe-

nyl-Quinazolinap are included for comparative purposes as this

has the same steric requirements as the 2-pyridyl and 2-(2-pyraz-

inyl)-Quinazolinap ligands. In addition, selected optimal results

from our previous hydroboration work with 2-alkyl-substituted

Quinazolinaps will be given to aid in determining whether the ef-

fects noted with ligands 2a–b and 3a–b can be attributed to size or

electronics.

Catalysts 15a–d were ﬁrst applied in the rhodium-catalysed

hydroboration of styrene 16 (Table 1). In this, and all subsequent

catalytic reactions, 1 mol % of the active catalyst was used. The

reactions were carried out at both room temperature and 0 °C

and the reaction mixture was oxidised after the required reaction

time. After work up the conversion and regioselectivity were deter-

mined by ¹H NMR spectroscopy and the enantiomeric excess was

calculated using either chiral GC or HPLC.

Rhodium-catalysed enantioselective hydroboration of oleﬁns is

a valuable synthetic transformation, typically employing a chiral

catalyst and an achiral borane source.^26,27Diphosphine ligands

were the ﬁrst to be employed in this transformation; Burgess devel-

oped an enantioselective hydroboration process using BINAP- and

DIOP-derived rhodium species with norbornene as the substrate.²⁸

Phosphinamine ligands have also been successfully employed in

rhodium-catalysed asymmetric hydroboration. Brown has used

the QUINAP and PHENAP ligands,^29,30while Togni has applied

ferrocenyl pyrazole ligands,³¹both with great success. Within our

research group the Quinazolinap series of ligands (1a–f) have pre-

viously been applied in asymmetric rhodium-catalysed hydrobora-

tion. 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-b-methylstyrene

(97%), cis-stilbene (99%) and indene (99.5%).^4,32Following the suc-

cess of the application of this steric series of the Quinazolinaps,

we now wish to report the application of the related electronic ser-

ies of ligands 3a–b to asymmetric rhodium-catalysed hydrobora-

tion, in order to study the potential electronic effects in this series.

Both the 2-(p-triﬂuoromethylphenyl)- and 2-(p-methoxyphenyl)-

Quinazolinap ligands 3a–b gave signiﬁcantly better regioselec-

tivities and enantioselectivities than 2-phenyl-Quinazolinap 1c at

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A. C. Maxwell et al. / Tetrahedron: Asymmetry 21 (2010) 1458–1473

F1

C4

C3

C5

C13

F3

N2

X

C14

C6

Y

C15

F2

C9

C35

C36

C12

C11

C2

16 X=H

19 (E) X=H, Y=H

17 X=OMe

18 X=Cl

20 (Z) X=H, Y=H

C34

C8

C7

C37

21 (E) X=OMe, Y=H

22 (E) X=OMe, Y=OMe

C10

N1

C1

C16

C24

C33

C50

C51

C23

Ph

C32

C25

N3

P1

Pd

C21

C22

n

C17

23 (E)

24 (Z)

25 n=1

26 n=2

C39

C31

C26

C48

C38

C20

C40

C18

C49

C47

Figure 3. Substrates screened in rhodium-catalysed hydroboration.

C19

C30

C46

C41

C27

C42

free reaction carried out at 0 °C gave a similar conversion of 30%

and regioselectivity of 34:66.

C29

C45

C43

C28

In the hydroboration of p-methoxystyrene 17 using rhodium-

Quinazolinap catalysts 1a–f, it was observed that an electron-

donating substituent on styrene had a favourable effect on the

enantioselectivity, often accompanied by a negative effect on the

regioselectivity.⁴The application of electronically varied Quinazol-

inap ligands 3a–b in the hydroboration of this substrate showed a

similar trend (Table 2).

C44

Figure 2. X-ray structure of (S,R)-14 (H atoms and CDCl₃solute have been removed

for clarity). Selected distances (Å) and angles (°): Pd–P1 2.2608(5), Pd–N1 2.178(2),

Pd–N3 2.140(2), Pd–C39 1.995(2), Pdꢀ ꢀ ꢀC10 3.048(2), P1–Pd–N1 84.0(1), P1–Pd–N3

157.3(1), N1–Pd–C39 173.6(1).

Catalysts derived from 2-(2-pyridyl)- and 2-(2-pyrazinyl)-Quin-

azolinap 2a–b produced enantiomeric excesses of 77% and 80%,

respectively (Table 2, entries 1 and 3). Although the regiochemistry

observed was lower than the excellent results obtained for styrene,

the use of these catalysts gave the highest regioselectivities (88:12)

for the Quinazolinap series in the hydroboration of substrate 17.

Both 2-(p-triﬂuoromethylphenyl)- and 2-(p-methoxyphenyl)-

Quinazolinap 3a–b achieved excellent results at room temperature

(entries 5 and 7). Enantioselectivities of 92% and 94%, respectively,

room temperature (entries 1, 3 and 6). In particular the 2-(p-

methoxyphenyl) analogue gave an excellent 90% ee, identical to

the previously optimised ee using the 2-methyl-Quinazolinap li-

gand (entry 7).⁴At 0 °C the reactivity (and selectivity) of the 2-

(p-triﬂuoromethylphenyl) ligand 3a dropped dramatically (entry

2). The conversion was low (35%) and the regioselectivity showed

that more of the b- than the

a-product had been formed. A ligand-

R

N

Me₂

N

Cl

DPPE

Pd

PPh₂

CH₂Cl₂

RT, 3h

P

Ph₂

13a R = CF₃

13b R = OMe

(S)-3a R = CF₃

(S)-3b R = OMe

Scheme 5. Decomplexation of enantiopure ligands 3a–b.

N

R

N

R

OTf

+

O

N

TMS triflate

THF

+

Rh

P

PPh₂

Ph₂

2a R = 2-(2-pyridyl)

2b R = 2-(2-pyrazinyl)

3a R = p-CF₃C₆H₄

3b R = p-MeOC₆H₄

15a R = 2-(2-pyridyl)

15b R = 2-(2-pyrazinyl)

15c R = p-CF₃C₆H₄

15d R = p-MeOC₆H₄

Scheme 6. Formation of Quinazolinap rhodium-catalysts.

A. C. Maxwell et al. / Tetrahedron: Asymmetry 21 (2010) 1458–1473

1463

Table 1

Hydroboration of styrene

O

OH

B

H

OH

O

+

Rh-Cat 15a-d

(1 mol%)

THF, 2h, [O]

16

Entry

2-Substituent

Temp (°C)

Conv. (%)

a:b

ee (%)

1

2

3

4

p-Triﬂuoromethylphenyl

p-Methoxyphenyl

Phenyl

20

0

20

0

20

0

20

93

35

97

85:15

45:55

89:11

85:15

68:32

80:20

88:12

82 (S)

14 (S)

90 (S)

84 (S)

63 (S)

89 (S)

90 (S)

80

5³²

6³²

7⁴

100

Phenyl

Methyl

Table 2

Hydroboration of p-methoxystyrene

O

OH

B

H

OH

+

MeO

Rh-Cat 15a-d

(1 mol%)

THF, [O]

MeO

17

Entry

2-Substituent

Temp (°C)

Conv. (%)

a:b

ee (%)

1

2

3

4

5

6

7

2-Pyridyl

2-Pyrazinyl

p-Triﬂuoromethylphenyl

p-Methoxyphenyl

Phenyl

20

0

20

0

20

0

20

0

83

33

99

81

92

15

91

48

87:13

74:26

88:12

86:14

79:21

52:48

82:18

65:35

75:25

77:23

88:12

77 (S)

66 (S)

80 (R)

52 (R)

92 (S)

20 (S)

94 (S)

74 (S)

77 (S)

81 (S)

95 (S)

8

9³²

20

0

20

100

99

10³²

Phenyl

Methyl

11⁴

were signiﬁcantly higher than the comparable result for the

22-phenyl ligand 1c (entry 9), but slightly lower than the previ-

ously optimised ee of 95% using the 2-methyl-Quinazolinap ligand

(entry 11).⁴The regioselectivity was also higher for both these li-

gands in comparison with that of the 2-phenyl ligand. As with

the results obtained for styrene, 2-(p-triﬂuoromethylphenyl)-

Quinazolinap 3a showed a dramatic drop in activity at 0 °C.

The hydroboration of p-chlorostyrene 18 using catalysts 15a,b,c

gave relatively low conversions, regioselectivities and enantiose-

lectivities at room temperature. The use of 2-(2-pyridyl)- and 2-

(2-pyrazinyl)-Quinazolinap 2a–b as ligands was found to decrease

the enantioselectivity of styrene from 74% and 83% to 28% and 59%

(Table 3, entries 1 and 3), respectively. The other electron-deﬁcient

ligand system 2-(p-triﬂuoromethylphenyl)-Quinazolinap 3a also

showed a drop in the enantioselectivity to 54% (entry 5). In com-

parison, the 2-(p-methoxyphenyl) analogue 3b gave one of the best

results obtained for the Quinazolinap ligand series in the hydrobo-

ration of this substrate. An enantioselectivity of 80% was accompa-

nied by an excellent regiochemistry of 92:8 with a moderate

conversion of 75% (entry 7). This compares to the previous 81%

ee value obtained using the unsubstituted Quinazolinap ligand

(entry 11).⁴As 2-phenyl-Quinazolinap 1c itself achieved poor

enantioselectivity in this reaction (entries 9 and 10), the addition

of the p-methoxy group to the ligand has an important effect on

the ee. As seen previously, 2-(p-triﬂuoromethylphenyl)-Quinazol-

inap 3a showed a drop in the activity at 0 °C, mainly manifested

as a large drop in enantioselectivity.

Substitution of the vinylarene double bond resulted in a marked

reduction in the enantioselectivity obtained with BINAP and other

diphosphines.^26,27In contrast, the application of P,N-ligand sys-

tems to more sterically demanding substrates leads to an overall

increase in enantioselection. The Quinazolinap ligands have been

successful in the hydroboration of this type of substrate, giving

ees up to 95% in the hydroboration of trans-b-methylstyrene 19.

The 2-phenyl analogue gave one of the best results at room tem-

perature; enantioselectivity of 94% combined with full conversion

and a regioselectivity of 91:9 (Table 4, entry 9). In comparison with

this result, our electronic series of catalysts 15a–d show signiﬁ-

cantly reduced activity. Catalyst 15a, derived from 2-(2-pyridyl)-

Quinazolinap 2a, showed no activity at all in this reaction (entries

1 and 2). Although the regioselectivity using catalyst 15b, based on

2-(2-pyrazinyl)-Quinazolinap 2b, was the highest obtained with

any of the Quinazolinap ligands, it was combined with low conver-

sion and a maximum ee of 90% at 0 °C (entries 2 and 3). Catalyst

15c, based on 2-(p-triﬂuoromethylphenyl)-Quinazolinap 3a, gave

a comparable ee and regioselectivity to those obtained using 2-

phenyl-Quinazolinap 1c but with a conversion of 71% (entry 5).

Catalyst 15d, based on 2-(p-methoxyphenyl)-Quinazolinap 3b, also

gave an enantioselectivity of 94% at both room temperature and

0 °C (entries 7 and 8), though with lower conversion and regiose-

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A. C. Maxwell et al. / Tetrahedron: Asymmetry 21 (2010) 1458–1473

lectivity than the parent 2-phenyl-Quinazolinap and slightly lower

than our optimised ee value of 95% using the 2-methyl-Quinazolin-

ap ligand (entry 11).⁴

be inferred that the reductive elimination route followed during

the reaction of simpler styrenes proceeds at a much slower rate

when bulkier substrates are employed.

Quinazolinap catalysts have previously given excellent results

in the hydroboration of cis-b-methylstyrene 20, for example 2-phe-

nyl-Quinazolinap 1c gave full conversion and excellent regio- and

enantioselectivity after 2 h at both room temperature and 0 °C (Ta-

ble 5, entries 8 and 9) and the 2-methyl-Quinazolinap ligand gave

an ee value of 97% (entry 10).⁴In contrast the results obtained for

our series of electronically modiﬁed ligands are characterised by

low conversion to the hydroborated products accompanied by a

relatively high degree of isomerisation to trans-b-methylstyrene.

Catalyst 15a showed only a trace amount of the product alcohol

and a high level of isomeristation (entry 1). In all catalyst systems

15a–d, the degree of isomerisation was higher than the conversion

to alcohol product. A potential explanation for these results may be

that, following oleﬁn association and migratory insertion, instead

of reductive elimination to generate the organoborane product,

the reaction proceeds via rotation about the carbon–carbon bond

(likely as a response to steric demand); subsequent b-hydride

elimination and dissociation would produce trans-b-methylsty-

rene. As minimal hydroboration product was obtained, it could

The stereochemistry of the alkene in trans-anethole 21 seems to

have a signiﬁcant effect on the conversion, similar to that observed

for the hydroboration of trans-b-methylstyrene 19, when rhodium-

Quinazolinap complexes are used as catalysts. Even the usually

very active 2-phenyl-Quinazolinap catalyst showed decreased

conversion. Despite the poor conversion, complex 15b, based on

2-(2-pyrazinyl)-Quinazolinap, gave the best regioselectivity ob-

served with any of the Quinazolinap catalysts and also an excellent

ee of 93% (Table 6, entry 1). 2-(p-Triﬂuoromethylphenyl)- and

2-(p-methoxyphenyl)-Quinazolinap 3a–b gave consistently high

enantioselectivity though the regioselectivity was modest (entries

3–5) and still below the optimal ee value of 975 obtained with the

2-methyl-Quinazolinap ligand (entry 8).⁴All conversions for these

electronically modiﬁed ligands are lower than that obtained for the

comparable 2-phenyl-Quinazolinap 1c, though the ee has been

improved in all cases at room temperature.

As expected, the stereochemistry of the alkene in trans-3,4-

dimethoxy-b-methylstyrene 22 also had a detrimental effect on

the conversion. 2-(2-Pyrazinyl)-Quinazolinap 3b was the exception

Table 3

Hydroboration of p-chlorostyrene

O

OH

+

B

H

O

Rh-Cat 15a-d

(1 mol%)

THF, [O]

Cl

18

Entry

2-Substituent

Temp (°C)

Conv. (%)

a

:b

ee (%)

1

2

3

4

5

6

7

8

2-Pyridyl

2-Pyrazinyl

p-Triﬂuoromethylphenyl

p-Methoxyphenyl

Phenyl

20

0

20

0

20

0

20

0

73

62

99

81

97

46

75

76

71:29

70:30

85:15

87:13

74:26

75:25

92:8

67:33

78:22

83:17

28 (S)

18 (S)

59 (S)

52 (S)

54 (S)

4 (S)

80 (S)

50 (S)

46 (S)

49 (S)

81 (S)

9³²

10³²

11⁴

20

0

20

100

Phenyl

H

Table 4

Hydroboration of trans-b-methylstyrene

O

OH

B

H

+

Rh-Cat 15a-d

(1 mol%)

THF, [O]

OH

19

Entry

2-Substituent

Temp (°C)

Conv. (%)

a

:b

ee (%)

1

2

2-Pyridyl

20

0

—

3

4

5

6

7

8

2-Pyrazinyl

20

0

20

0

20

0

20

0

23

50

71

22

89

49

100

96

99:1

89:12

22:78

84:16

44:56

91:9

96:4

94:6

77 (S)

90 (S)

94 (S)

48 (S)

94 (S)

85 (S)

95 (S)

p-Triﬂuoromethylphenyl

p-Methoxyphenyl

Phenyl

9³²

10³²

11⁴

Phenyl

Methyl

0

A. C. Maxwell et al. / Tetrahedron: Asymmetry 21 (2010) 1458–1473

1465

to this observation; it gave excellent conversion after 2 h at both

room temperature and 0 °C (Table 7, entries 1 and 2). In compari-

son with the results obtained for trans-anethole 21, regioselectivity

also improved generally; perhaps has a result of the substitution

pattern on the phenyl ring of the substrate. The enantioselectivities

obtained with 2-(p-triﬂuoromethylphenyl)- and 2-(p-methoxy-

Table 5

Hydroboration of cis-b-methylstyrene

O

OH

B

H

OH

O

+

Rh-Cat 15a-d

(1 mol%)

THF, [O]

20

Entry

2-Substituent

Temp (°C)

Conv. (%)

cis:trans^a

a

:b

ee (%)

1

2

3

4

5

2-Pyridyl

2-Pyrazinyl

p-Triﬂuoromethylphenyl

p-Methoxyphenyl

Phenyl

20

0

20

0

20

0

20

0

<1

18

5

11

3

12

6

100

34:66

46:54

79:21

53:47

92:8

75:25

81:19

—

68:32

86:14

85:15

55:45

62:38

92:8

64 (S)

40 (S)

60 (S)

0

94 (S)

48 (S)

91 (S)

88 (S)

97 (S)

6

7

8³²

9³²

10⁴

Phenyl

Methyl

—

94:6

99:1

0

a

Ratio of cis:trans b-methylstyrene after 2 h reaction.

Table 6

Hydroboration of trans-anethole

O

B

O

OH

H

+

MeO

Rh-Cat 15a-d

(1 mol%)

OH

MeO

21

THF, [O]

Entry

2-Substituent

Temp (°C)

Conv. (%)

a:b

ee (%)

1

2

3

4

2-Pyrazinyl

p-Triﬂuoromethylphenyl

p-Methoxyphenyl

Phenyl

20

0

20

0

20

0

52

68

66

63

52

87

72

100

96:4

97:3

93 (S)

86 (S)

94 (S)

93 (S)

94 (S)

88 (S)

92 (S)

97 (S)

79:21

80:20

79:21

88:12

89:11

99:1

5

6³²

7³²

8⁴

Phenyl

Methyl

Table 7

Hydroboration of trans-3,4-dimethoxy-b-methylstyrene

O

OH

B

H

O

+

MeO

Rh-Cat 15a-d

(1 mol%)

THF, [O]

OH

MeO

OMe

MeO

OMe

22

Entry

2-Substituent

Time

Temp (°C)

Conv. (%)

a:b

ee (%)

1

2

3

4

2-Pyrazinyl

p-Triﬂuoromethylphenyl

p-Methoxyphenyl

Phenyl

2

24

2

20

0

20

0

20

0

94

88

58

64

37

62

65

75

97:3

98:2

74:26

83:17

43:57

93:7

85 (S)

94 (S)

96 (S)

94 (S)

93 (S)

98 (S)

5

6³²

7³²

8⁴

Phenyl

Methyl

92:8

1466

A. C. Maxwell et al. / Tetrahedron: Asymmetry 21 (2010) 1458–1473

Table 9

Hydroboration of cis-stilbene

phenyl)-Quinazolinap 3a–b (entries 3–5) were consistently very

high (94–96%) and comparable with 2-phenyl-Quinazolinap 1c

and slightly lower than the 98% ee obtained with the 2-methyl-

Quinazolinap ligand (entry 8).⁴

O

OH

B

H

Ph

The hydroboration of trans-stilbene 23 is signiﬁcantly hindered

by its steric bulk. In previous studies with Quinazolinap ligands

reaction times of 24 h were needed to obtain conversions over

10%. In the present study, the 2-(p-methoxyphenyl)-Quinazolin-

ap-based catalyst 15d gave an excellent ee of 92% and a conversion

of 34% after 24 h at room temperature (Table 8, entry 5). Using 2-

(p-triﬂuoromethylphenyl)-Quinazolinap 3a as the ligand also gave

a similar conversion and a slightly lower ee of 88% after 24 h (entry

3). In comparison the 2-phenyl-Quinazolinap ligand system 1c

showed no conversion after 24 h at room temperature (entry 6)

and the less sterically encumbered 2-methyl-Quinazolinap affor-

ded 87% ee (entry 7).⁴2-(2-Pyrazinyl)-Quinazolinap 2b was also

not active in this reaction.

In comparison with the trans isomer, the hydroboration of cis-

stilbene 24 usually occurs rapidly at room temperature in the pres-

ence of rhodium-Quinazolinap catalysts. In the present study it

was found that the electronically modiﬁed ligands 2b and 3a–b

gave signiﬁcantly lower conversions than those obtained with

the steric series 1a–f, although the ees ranged from very good to

excellent. In particular, the use of the 2-(p-methoxyphenyl)-Quin-

Ph

24

Rh-Cat 15a-d

(1 mol%)

THF, [O]

Entry 2-Substituent

Time Temp Conv. cis:trans^aee (%)

(°C)

(%)

1

2

3

4

5

6

2-Pyrazinyl

p-Triﬂuoromethylphenyl

p-Triﬂuoromethylphenyl 24

p-Methoxyphenyl

Phenyl

i-Propyl

2

20

0

20

0

20

0

20

40

35

12

61

23

44:56

63:37

59:41

0:100

32:68

84:16

—

87 (S)

92 (S)

83 (S)

97 (S)

59 (S)

62 (S)

99 (S)

2

6

7³²

8³²

9⁴

100

84

—

a

Ratio of cis:trans b-methylstyrene after reaction time.

azolinap-based rhodium-catalyst 15d resulted in 97% ee after 2 h

at room temperature (Table 9, entry 5), still lower than the optimal

value of 99% ee obtained using the 2-isopropyl-Quinazolinap li-

gand (entry 9).⁴The conversion obtained was low (23%), however,

and a large proportion of the unreacted starting material had been

isomerised to the trans-isomer. The enantioselectivities obtained

with all electronically varied ligands 2–3 (entries 1–6) were signif-

icantly higher than that obtained with 2-phenyl-Quinazolinap 1c

(57% ee), although in that case full conversion was obtained (entry

7). The rhodium-Quinazolinap catalysts 15a,c,d applied in this

reaction showed a degree of isomerisation to the trans-isomer of

the starting material. The same mechanism as that postulated for

the isomerisation of cis-b-methylstyrene is proposed.

The ﬁnal part of this study looked at the hydroboration of the

cyclic oleﬁns indene 25 and 1,2-dihydronaphthalene 26. It is with

this type of substrate that Quinazolinap ligands have previously

proved very successful. From previous investigations it has been

shown that the size of the group in the 2-position of the ligand is

particularly important when indene 25 is tested. The size of 2-phe-

nyl-Quinazolinap means that it gave an enantioselectivity of 84% at

room temperature in this reaction (Table 10, entry 9); this is a sig-

niﬁcant decrease from the 2-methyl analogue 1b which gave an ee

Table 8

Hydroboration of trans-stilbene

O

OH

B

H

Ph

O

Rh-Cat 15a-d

(1 mol%)

THF, [O]

23

Entry

2-Substituent

Time

Temp (°C)

Conv (%)

ee (%)

1

2

3

4

2-Pyrazinyl

24

2

24

2

24

21

20

0

7

33

<5

34

0

—

p-Triﬂuoromethylphenyl

p-Methoxyphenyl

Phenyl

81 (S)

88 (S)

—

92 (S)

—

5

6³²

7⁴

Methyl

50

87 (S)

Table 10

Hydroboration of indene

O

OH

B

H

OH

+

Rh-Cat 15a-d

(1 mol%)

THF, [O]

25

Entry

2-Substituent

Time

Temp (°C)

Conv. (%)

a:b

ee (%)

1

2

3

4

5

6

7

8

2-Pyridyl

2-Pyrazinyl

p-Triﬂuoromethylphenyl

p-Methoxyphenyl

Phenyl

20

2

24

2

24

2

20

0

20

0

20

0

20

0

81

38

81

25

83

9

60

81

98

99

100

96:4

95:5

>99:1

99:1

100:0

99:1

59:41

98:2

84 (S)

80 (S)

70 (S)

73 (S)

87 (S)

—

82 (S)

54 (S)

84 (S)

81 (S)

99.5 (S)

9³²

10³²

11⁴

20

0

20

Phenyl

Methyl

98:2

>99:1

A. C. Maxwell et al. / Tetrahedron: Asymmetry 21 (2010) 1458–1473

1467

Table 11

Hydroboration of 1, 2-dihydronaphthalene

O

OH

B

H

OH

O

+

Rh-Cat 15a-d

(1 mol%)

THF, [O]

26

Entry

2-Substituent

Time

Temp (°C)

Conv. (%)

a:b

ee (%)

1

2

3

4

5

6

2-Pyrazinyl

2

24

2

20

0

20

0

20

0

20

0

77

76

56

<5

76

8

100

>99

90

>99:1

90 (S)

91 (S)

87 (S)

—

91 (S)

78 (S)

89 (S)

88 (S)

93 (S)

p-Triﬂuoromethylphenyl

p-Methoxyphenyl

Phenyl

7³²

8³²

9⁴

Phenyl

Methyl

20

of 99.5% (entry 11).⁴The enantioselectivities and regioselectivities

obtained for electronically varied catalysts 15a–d at room temper-

ature are quite similar to those obtained for the 2-phenyl-ligand 1c

and show the importance of the size of the ligand rather than

electronic effects for the hydroboration of this substrate. The major

differences are the activity of the catalyst systems. The 2-(2-pyri-

dyl)-Quinazolinap rhodium-catalyst 15a showed no reaction after

2 h and only after 20 h were comparable results obtained (entries

1 and 2). A signiﬁcant decrease in the conversion was seen for

catalysts 15a–c at 0 °C (entries 2, 4 and 6) though the enantioselec-

tivities were not affected. Like all members of the Quinazolinap

ligand class these new ligands gave excellent regioselectivities in

the hydroboration of this substrate at room temperature.

In the hydroboration of 1,2-dihydronaphthalene 26, excellent

regioselectivities have been generated by all members of the Quin-

azolinap family. The highest enantioselectivity (93%) was obtained

previously using 2-methyl analogue 1b (entry 9).⁴In the present

study this was closely followed by 2-(2-pyrazinyl)-Quinazolinap

and 2-(p-methoxyphenyl)-Quinazolinap at 91% (Table 11, entries

2 and 5). Lowering the reaction temperature led to an unexpected

reduction in conversion when using the 2-(p-methoxyphenyl)-

Quinazolinap rhodium-catalyst 15b (entry 6), though this was

not seen for 2-(2-pyrazinyl)-Quinazolinap 2b or 2-phenyl-Quin-

azolinap 1c (entries 2 and 8).

no ligand is used in the reaction seems to suggest that the elec-

tron-poor nitrogen donor atom is not binding properly to the metal

at 0 °C. The use of 2-(p-methoxyphenyl)-Quinazolinap as the

ligand gave one of the best results obtained for the Quinazolinap

ligand series in the hydroboration of p-chlorostyrene (80% ee),

which was also accompanied by excellent regioselectivity (92:8).

In comparison the other ligands tested in this study produced a

maximum of 59% ee. The relatively electron-rich nitrogen donor

atom of ligand 3b seems to have a positive effect on the reaction

of what is often seen as a challenging substrate for hydroboration.

2-(p-Methoxyphenyl)-Quinazolinap also gave consistently high

enantioselectivities, mainly between 90% and 97% ee.

From this study of the electronically varied Quinazolinap li-

gands it does seem that the introduction of an electron-withdraw-

ing substituent can result in an improvement in regioselection. The

size of the substituent in the 2-position of the Quinazolinap ligand

seems to have more of an impact on certain types of substrate, par-

ticularly cyclic oleﬁns. The introduction of an electron-donating

group in the 2-position resulted in a Quinazolinap ligand that gave

some of the most consistently high enantioselectivities seen in this

series, although still consistently lower than those obtained with

the 2-methyl-Quinazolinap ligand. Further investigation into the

Quinazolinap ligand series continues and the results of this re-

search will be reported in due course.

3. Conclusion

4. Experimental

In conclusion, new Quinazolinap ligands have been synthesised

as part of an electronic series of ligands. These ligands have been

applied in the enantioselective hydroboration of substituted sty-

renes with the aim of studying electronic effects in this reaction.

Conversions with the electronically varied ligands tended to be

lower than that achieved with the comparable 2-phenyl ligand.

2-(2-Pyridyl)-Quinazolinap proved capable of hydroborating sim-

ple styrene derivatives only. In contrast 2-(2-pyrazinyl)-Quinazol-

inap was successful in hydroborating all but one of the substrates

tested, with regioselectivities which were almost always superior

to those obtained using the earlier members of the Quinazolinap

series. The optimum enantioselectivity obtained for this ligand

was 93%, in the hydroboration of trans-anethole. The strong elec-

tron-withdrawing effect of the 2-(p-triﬂuoromethylphenyl) ligand

seemed to affect the activity of the catalyst system at 0 °C, with de-

creases observed in conversion, regioselectivity and enantioselec-

tivity. The similarity of these results with those obtained when

4.1. General remarks

Melting points were determined using a Gallenkamp melting

point apparatus and are uncorrected. Infrared spectra were re-

corded on a Perkin–Elmer Paragon 1000 Infrared FT spectrometer.

The Microanalytical Laboratory, University College Dublin, per-

formed elemental analyses. ¹H NMR spectra and ¹H–¹H COSY spec-

tra were recorded on a 300 MHz Varian-Unity spectrometer, a

400 MHz Varian-Unity spectrometer. Chemical shifts are quoted

in parts per million (ppm) relative to tetramethylsilane and cou-

pling constants (J) are quoted in hertz and are uncorrected.

75.4 MHz ¹³C spectra were recorded on a 300 MHz Varian-Unity

spectrometer and 100 MHz ¹³C spectra on a 400 MHz Varian-Unity

spectrometer. Tetramethylsilane was used as the internal standard

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

on a 300 MHz Varian-Unity spectrometer and 162 MHz ³¹P spectra

on a 400 MHz Varian-Unity spectrometer. ³¹P Chemical shifts are

1468

A. C. Maxwell et al. / Tetrahedron: Asymmetry 21 (2010) 1458–1473

reported relative to 85% aqueous phosphoric acid (0.0 ppm). Flash

chromatography was performed using Merck Kieselgel 60 (Art.

9385). Merck precoated Kieselgel 60F₂₅₄was used for thin layer

chromatography. GC and HPLC analysis was carried out using a

Supelco 2-4304 beta-Dex^Ò120 (30 ꢁ 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 Perkin Elmer 241

Polarimeter. All commercially available solvents were puriﬁed

and dried before use. Diethyl ether and tetrahydrofuran were dis-

tilled from sodium/benzophenone and dichloromethane was dis-

tilled from calcium hydride. Where necessary, other solvents and

reagents used were puriﬁed according to the procedures in ‘Puriﬁ-

cation of Laboratory Chemicals’.³³Pd salts were obtained on loan

from Johnson Matthey. Solvents were degassed using three

freeze–thaw cycles. Oxygen-free nitrogen was obtained from BOC

gases.

sion, which was reﬂuxed for 2 h. Phosphorus oxychloride (1.5 mL,

16.20 mmol) was added and the suspension was reﬂuxed over-

night or until a pale yellow solution was formed. The solvent

was removed in vacuo to yield a dark orange solid. After column

chromatography (silica, dichloromethane/pentane 1:1), 2-p-tri-

ﬂuoromethylphenyl-4-chloroquinazoline (18.16 g, 86%) was ob-

tained as a white solid, R_f0.64; mp 102–104 °C; m_max(KBr) 1562

(C@C), 1483 (Ar-H), 1320 (CF₃) and 767 (C–Cl) cm^ꢂ^{1 1}H NMR

;

(300 MHz): d (CDCl₃) 8.65 (2H, d, J = 8.5 Hz, o-H), 8.22 (1H, dd,

J = 8.3, 0.44 Hz, H₅), 8.07 (1H, d, J = 8.3 Hz, H₈), 7.93 (1H, dt,

J = 8.3, 1.3 Hz, H₇), 7.74 (2H, d, J = 8.5 Hz, m-H), 7.67 (1H, dt,

J = 7.0, 1.1 Hz, H₆); ¹³C NMR (75 MHz): d (CDCl₃) 162.7 (C4),

158.5 (C2), 151.6 (C9), 139.8 (i-C), 135.0 (C7), 132.8 (p-C), 132.3

(C10), 129.0 (2o-C), 128.8 (2m-C), 125.8 (C5), 125.5 (C6), 125.4

(C8), 122.7 (CF₃); Anal. Calcd for C₁₅H₈F₃ClN₂: C, 58.36; H, 2.61;

F, 18.46; Cl, 11.49; N, 9.08. Found: C, 58.30; H, 2.61; F, 18.25; Cl,

11.57; N, 8.88.

4.1.1. 2-p-Triﬂuoromethylphenyl-4(3H)quinazolinone 6a

a,a

,a-Triﬂuoro-p-tolunitrile (50.00 g, 292 mmol) was dissolved

4.1.4. 2-p-Methoxyphenyl-4-chloroquinazoline 7b

in dry methanol (285 mL) under nitrogen. To this solution sodium

metal (1.22 g, 53 mmol) was added carefully in several portions.

Once addition was complete, the solution was stirred for 1 h.

Anthranilic acid (36.43 g, 265 mmol) in dry methanol (285 mL)

was added via cannula. The solution was then reﬂuxed overnight.

The cream-coloured precipitate that formed was ﬁltered, washed

with cold methanol and dried under vacuum to afford 2-p-triﬂuo-

romethylphenyl-4(3H)quinazolinone (40.96 g, 45%) as a cream so-

lid. For analysis, a sample was recrystallised from ethanol to yield

white needles, mp 310–312 °C (lit. mp 306–308 °C); m_max(KBr)

3311 (N–H), 1687 (C@O), 1608 (C@C), 1452 (Ar-H), 1303 (CF₃)

2-p-Methoxyphenyl-4(3H)quinazolinone (10.84 g, 42.98 mmol)

and N,N-diethylanaline (9.74 mL, 64.47 mmol) were reﬂuxed in

benzene (200 mL) for 15 min. Phosphorus oxychloride (4.0 mL,

42.98 mmol) was added carefully to this white suspension, which

was then reﬂuxed overnight or until all the solid was in solution.

The solvent was removed in vacuo to yield a pale yellow solid.

After column chromatography (silica, dichloromethane/pentane

3:1) 2-p-methoxyphenyl-4-chloroquinazoline (10.35 g, 89%) was

obtained as a white solid, R_f0.29; mp 123–125 °C (lit. mp 123–

124 °C); m_max(KBr) 1534 (C@C), 1509 (Ar-H), 1337 (C–N), 1176

(C–O) and 769 (C–Cl) cm^ꢂ^{1 1}H NMR (300 MHz): d (CDCl₃) 8.54

;

and 758 (Ar-H) cm^ꢂ1

;

¹H NMR (400 MHz): d (DMSO) 12.79 (1H,

(2H, d, J = 8.8, o-H), 8.20 (1H, app. d, J = 8.3 Hz, H₅), 8.02 (1H, app.

d, J = 8.5 Hz, H₈), 7.88 (1H, app. t, J = 7.7 Hz, H₇), 7.60 (1H, app. t,

J = 7.6 Hz, H₆), 7.02 (2H, d, J = 8.8, m-H), 3.89 (3H, s, OCH₃); ¹³C

NMR (75 MHz): d (CDCl₃) 162.3 (p-C), 162.2 (C4), 159.9 (C2),

152.0 (C9), 134.7 (C7), 130.4 (2o-C), 129.3 (i-C), 128.6 (C5), 127.7

(C6), 125.8 (C8), 122.1 (C10), 114.0 (2m-C), 55.4 (OMe); Anal. Calcd

for C₁₅H₁₁ClN₂O: C, 66.55; H, 4.10; Cl, 13.10; N, 10.35. Found: C,

66.52; H, 4.11; Cl, 13.36; N, 10.30.

br s, NH), 8.36 (2H, d, J = 8.2 Hz, o-H), 8.16 (1H, dd, J = 7.9,

1.02 Hz, H₅), 7.91 (2H, d, J = 8.2 Hz, m-H), 7.85 (1H, dt, J = 7.6,

1.02 Hz, H₇), 7.76 (1H, app. d, J = 7.6, H₈), 7.55 (1H, dt, J = 7.9, 1.3,

H₆); ¹³C NMR (100 MHz): d (DMSO) 162.4 (C4), 152.0 (C2), 148.8

(C9), 136.8 (i-C), 135.4 (C7), 131.9 (p-C), 129.4 (2o-C), 127.8 (C5),

126.6 (2m-C), 126.2 (C6), 126.1 (C8), 122.5 (C10), 121.9 (CF₃); Anal.

Calcd for C₁₅H₉F₃N₂O: C, 62.07; H, 3.13; F, 19.64; N, 9.65. Found: C,

62.05; H, 3.16; F, 19.90; N, 9.61.

4.1.5. 2-p-Triﬂuoromethylphenyl-4-(2-benzyloxy-naphthalen-

1-yl)-quinazoline 9a

4.1.2. 2-p-Methoxyphenyl-4(3H)quinazolinone 6b

Sodium hydrogen sulﬁte (11.20 g, 107.63 mmol) was added to a

solution of anthranilamide (14.00 g, 102.82 mmol) and p-anisalde-

hyde (14.00 g, 102.82 mmol) in N,N-dimethylacetamide (280 mL).

The mixture was reﬂuxed overnight and then poured onto ice

water (500 mL). The white solid that precipitated was collected

by ﬁltration and stirred in diethyl ether for 1 h to yield 2-p-

methoxyphenyl-4(3H)quinazolinone (11.55 g, 65%) as a cream so-

lid. For analysis, a sample was recrystallised from ethanol to give

cream needles, mp 250–252 °C (lit. mp 252 °C); m_max(KBr) 3158

(N–H), 1678 (C@O), 1600 (C@C), 1458 (Ar-H), 1322 (C@N), 1249

2-p-Triﬂuoromethylphenyl-4-chloroquinazoline (0.506 g, 1.64

mmol) and tetrakis(triphenylphosphine)palladium(0) (0.057 g,

0.049 mmol) were stirred in DME (15 mL) at ambient tempera-

ture for 20 min. 2-Benzyloxy-1-naphthylboronic acid (0.500 g, 1.80

mmol) and Na₂CO₃(7 mL, 2 M) were added and the reaction was

heated to reﬂux overnight. After cooling, the reaction mixture

was ﬁltered and the ﬁltrate was washed three times with brine

(30 mL) and once with deionised water (30 mL). The organic layer

was dried over magnesium sulfate and the solvent removed in va-

cuo. The brown oil obtained was stirred in pentane to yield a white

precipitate of 2-p-triﬂuoromethylphenyl-4-(2-benzyloxy-naphtha-

len-1-yl)-quinazoline (0.470 g, 57%), mp 128–130 °C; m_max(KBr)

3062 (Ar-H), 1617 (C–C), 1538 (Ar-H), 1300 (CF₃), 1267 (C–O) and

(C–O) and 767 (Ar-H) cm^ꢂ^{1 1}H NMR (400 MHz): d (DMSO) 12.41

;

(1H, br s, NH), 8.18 (2H, d, J = 8.9, o-H) 8.12, (1H, dd, J = 7.9,

1.0 Hz, H₅), 7.80 (1H, dt, J = 7.6, 1.0 Hz, H₇), 7.69 (1H, app. d,

J = 7.6 Hz, H₈), 7.47 (1H, dt, J = 7.6, 1.0 Hz, H₆), 7.07 (2H, d, J = 8.9,

m-H), 3.83 (3H, s, OCH₃); ¹³C NMR (100 MHz): d (DMSO) 163.0

(p-C), 162.6 (C4), 152.6 (C2), 149.7 (C9), 135.2 (C7), 130.1 (2o-C),

127.8 (C5), 126.8 (C6), 126.5 (C8), 125.5 (C10), 121.4 (i-C), 114.7

(2m-C), 56.1 (OMe); Anal. Calcd for C₁₅H₁₂N₂O₂: C, 71.42; H,

4.79; N, 11.10. Found: C, 71.19; H, 4.78; N, 10.93.

755 (Ar-H) cm^ꢂ1

;

¹H NMR (300 MHz): d (CDCl₃) 8.81 (2H, d,

0

J = 8.2 Hz, o-H), 8.22 (1H, d, J = 8.5 Hz, H₈), 8.04 (1H, d, J = 9.1 Hz,

0

H₄), 7.91 (2H, m, H₇, H₆), 7.76 (2H, d, J = 8.2 Hz, m-H), 7.57 (1H,

d, J = 7.6 Hz, H₅), 7.48 (1H, app. d, J = 9.1, H₃), 7.43 (1H, app. d,

0

J = 6.6, H₅), 7.36 (1H, dd, J = 6.8, 1.4 H₆), 7.31 (1H, dd, J = 6.7, 1.2,

H₇), 7.25 (1H, d, J = 8.2, H₈), 7.13 (3H, m, Ph), 7.01 (2H, m, Ph),

5.14 (2H, s, CH₂); ¹³C NMR (100 MHz): d (CDCl₃) 168.4 (4 °C),

154.4 (4 °C), 151.4 (4 °C), 141.9 (4 °C), 137.1 (4 °C), 134.7 (CH),

134.6 (4 °C), 133.5 (4 °C), 131.8 (CH), 131.7 (4 °C), 129.7 (CH),

129.6 (4 °C), 129.4 (CH), 128.8 (CH), 128.7 (4 °C), 128.6 (CH),

128.2 (CH), 128.1 (CH), 127.8 (4 °C), 127.3 (CH), 127.2 (4 °C),

126.0 (CH), 125.1 (CH), 125.0 (CH), 124.8 (CH), 115.6 (CH), 71.8

4.1.3. 2-p-Triﬂuoromethylphenyl-4-chloroquinazoline 7a

2-p-Triﬂuoromethylphenyl-4(3H)quinazolinone (20.00 g, 64.78

mmol) and N,N-diethylanaline (15.5 mL, 97.18 mmol) were re-

ﬂuxed in benzene (300 mL) for 15 min. Phosphorus oxychloride

(4.5 mL, 48.58 mmol) was added carefully to this white suspen-

A. C. Maxwell et al. / Tetrahedron: Asymmetry 21 (2010) 1458–1473

1469

(CH₂); Anal. Calcd for C₃₂H₂₁F₃N₂O: C, 75.88; H, 4.18; F, 11.25; N,

5.53. Found: C, 75.76; H, 4.47; F, 11.34; N, 5.28.

mp 112–114 °C; m_max(KBr) 3306 (OH), 1614 (Ar-H), 1536 (Ar-H),

1485 (OH), 1290 (C–O) and 1027 (C–O) cm^ꢂ^{1 1}H NMR

;

(400 MHz): d (CDCl₃) 8.63 (2H, d, J = 8.4 Hz, o-H), 8.17 (1H, d,

0

J = 8.5 Hz, H₈), 8.13 (1H, d, J = 9.1 Hz, H₄), 8.00 (1H, d, J = 8.3 Hz,

4.1.6. 2-p-Methoxyphenyl-4-(2-benzyloxy-naphthalen-1-yl)-

quinazoline 9b

0

H₅), 7.87 (1H, dt, J = 7.5, 2.0 Hz, H₇), 7.63 (1H, d, J = 9.2 Hz, H₃),

0

7.57 (1H, dt, J = 7.5, 1.3 Hz, H₆), 7.41 (1H, dt, J = 7.8, 1.2 Hz, H₆),

2-p-Methoxyphenyl-4-chloroquinazoline (5.70 g, 21.00 mmol)

and tetrakis(triphenylphosphine)palladium(0) (0.73 g, 0.63 mmol)

were dissolved in degassed toluene (85 mL). 2-Benzyloxy-1-naph-

thylboronic acid (7.57 g, 27.30 mmol), sodium carbonate (85 mL,

2 M) and ethanol (5 mL) were added and the reaction was heated

to reﬂux overnight. After cooling, the layers were separated and

the aqueous layer was extracted twice with dichloromethane

(200 mL). The organic layers were combined, dried over magne-

sium sulphate and the solvent was removed in vacuo. The brown

oil obtained was stirred in diethyl ether to yield a white precipitate

of 2-p-methoxyphenyl-4-(2-benzyloxy-naphthalen-1-yl)-quinazo-

line (6.09 g, 62%), mp 168–169 °C; m_max(KBr) 1523 (C@C), 1513

(Ar-H), 1334 (C–N), 1244 (C–O), 1214 (C–O), 1025 (C–O) and

0

7.36 (3H, m, H₅, H₇, H₈), 7.02 (2H, d, J = 8.2 Hz, m-H), 7.36 (3H, s,

OCH₃); ¹³C NMR (100 MHz): d (CDCl₃) 163.4 (4 °C), 162.2 (4 °C),

160.8 (4 °C), 151.7 (4 °C), 144.9 (4 °C), 134.9 (CH), 132.7 (4 °C),

132.6 (4 °C), 132.1 (CH), 130.8 (CH), 130.7 (4 °C), 129.3 (CH),

128.6 (CH), 128.4 (CH), 127.8 (4 °C), 127.6 (CH), 127.3 (CH),

126.6 (CH), 126.5 (CH), 123.3 (4 °C), 119.8 (CH), 114.2 (CH),

55.61 (CH₃); Anal. Calcd for C₂₅H₁₈N₂O₂: C, 79.35; H, 4.79; N,

7.40. Found: C, 79.09; H, 4.93; N, 7.29.

4.1.9. 1-(2-p-Triﬂuoromethylphenyl-quinazolin-4-yl)-2-

naphthyl(triﬂuoromethyl)sulfonate 11a

Triﬂuoromethylsulfonic anhydride (2.24 g, 7.92 mmol) was

added dropwise to a yellow solution of 1-(2-p-triﬂuoromethyl-

phenyl-quinazolin-4-yl)-naphthalen-2-ol (3.00 g, 7.20 mmol) and

4-dimethylaminopyridine (2.63 g, 21.60 mmol) in dry dichloro-

methane (150 mL). The colour of the solution gradually faded dur-

ing the addition. The pale yellow solution was allowed to stir

overnight under nitrogen. The solution was then washed with 1 M

HCl (3 ꢁ 50 mL), water (2 ꢁ 60 mL), brine (1 ꢁ 60 mL) and dried

over magnesium sulfate. The solvent was reduced in vacuo and the

concentrated solution was passed through a short column of silica

to give 1-(2-p-triﬂuoromethylphenyl-quinazolin-4-yl)-2-naphthyl-

(triﬂuoromethyl)sulfonate as a white solid (3.51 g, 92%), mp 144–

146 °C; m_max(KBr) 3068 (Ar-H), 1619 (Ar-H), 1542 (Ar-H), 1423

(–SO₃–), 1340 (CF₃), 1211 (–SO₃–), 1124 (C–O), 1064 (C–O) and

1005 (C–O) cm^ꢂ1

;

¹H NMR (300 MHz): d (CDCl₃) 8.63 (2H, d,

0

J = 7.3, o-H) 8.15 (1H, d, J = 8.5 Hz, H₈), 8.00 (1H, d, J = 8.5 Hz, H₆),

0

7.86 (2H, app. t, J = 9.2 Hz, H₇, H₅), 7.47 (2H, app. t, J = 8.9 Hz, H₅,

H₄), 7.36–7.25 (4H, m, H₃, H₈, H₇, H₆), 7.12 (3H, s Ph), 7.01 (4H, m,

o-H, Ph), 5.12 (2H, s, CH₂), 3.87 (3H, s, OCH₃); ¹³C NMR (100 MHz):

d (CDCl₃) 167.7 (4 °C), 162.1 (4 °C), 161.3 (4 °C), 160.9 (4 °C), 154.2

(4 °C), 151.5 (4 °C), 144.2 (4 °C), 137.1 (4 °C), 134.1 (CH), 133.5

(4 °C), 131.4 (CH), 130.9 (CH), 129.6 (4 °C), 129.0 (CH), 128.7 (CH),

128.4 (CH), 128.0 (CH), 127.5 (CH), 127.3 (CH), 126.9 (CH), 125.1

(CH), 124.5 (CH), 124.2 (4 °C), 121.7 (4 °C), 115.6 (CH), 114.2 (CH),

71.7 (CH₂), 55.4 (OMe); Anal. Calcd for C₃₂H₂₄N₂O₂: C, 82.03; H,

5.16; N, 5.98. Found: C, 81.73; H, 5.18; N, 5.91.

819 (Ar-H) cm^ꢂ1

;

¹H NMR (300 MHz): d (CDCl₃) 8.82 (2H, d,

4.1.7. 1-(2-p-Triﬂuoromethylphenyl-quinazolin-4-yl)-

naphthalen-2-ol 10a

0

J = 8.2 Hz, o-H), 8.27 (1H, d, J = 8.5 Hz, H₈), 8.19 (1H, d, J = 9.1 Hz,

0

H₄), 8.05 (1H, d, J = 8.2 Hz, H₅), 7.96 (1H, dt, J = 7.6, 1.6 Hz, H₇),

2-p-Triﬂuoromethylphenyl-4-(2-benzyloxy-naphthalen-1-yl)-

quinazoline (0.257 g, 0.507 mmol) was dissolved in ethanol

(40 mL) in a 500 mL ﬂask and 10% Pd/C (0.960 g) was added.

The reaction vessel was ﬁlled with hydrogen gas (1 atm) and

the mixture was stirred extremely vigorously overnight. The

black mixture was ﬁltered over Celite and the yellow ﬁltrate

was evaporated to obtain 1-(2-p-triﬂuoromethylphenyl-quinazo-

lin-4-yl)-naphthalen-2-ol (0.195 g, 92%) as a yellow solid, mp

164–166 °C; m_max(KBr) 3200 (OH), 3060 (Ar-H), 1619 (Ar-H),

7.85 (2H, d, J = 8.2 Hz, m-H), 7.66 (1H, d, J = 9.1, H₃), 7.60 (1H, d,

J = 7.7, H₆), 7.47 (3H, m, H_{6 ,}H₅, H₇), 7.34 (1H, d, J = 8.5, H₈); ¹³C

NMR (100 MHz): d (CDCl₃) 163.8 (4 °C), 159.9 (4 °C), 151.5 (4 °C),

145.0 (4 °C), 141.6 (4 °C), 134.9 (CH), 132.6 (4 °C), 132.3 (CH),

129.6 (CH), 129.3 (CH), 128.7 (CH), 128.6 (CH), 128.4 (CH), 127.7

(CH), 127.4 (4 °C), 126.7 (CH), 126.6 (CH), 125.7 (CH), 125.6 (4 °C),

123.9 (4 °C), 122.8 (4 °C), 119.8 (CH), 119.6 (4 °C), 117.6 (4 °C); Anal.

Calcd for C₂₆H₁₄F₆N₂O₃S: C, 56.94; H, 2.57; F, 20.78; N, 5.11; S, 5.85.

Found: C, 56.68; H, 2.61; F, 20.48; N, 5.30; S, 6.20.

0

1536 (Ar-H), 1300 (CF₃), 1280 (C–O) and 1014 (C–O) cm^ꢂ^{1 1}H

;

NMR (400 MHz): d (CDCl₃) 8.97 (1H, br s, OH), 8.65 (2H, d,

4.1.10. 1-(2-p-Methoxyphenyl-quinazolin-4-yl)-2-naphthyl

(triﬂuoromethyl)sulfonate 11b

0

J = 8.2 Hz, o-H), 8.09 (1H, d, J = 8.3 Hz, H₈), 7.94 (1H, d,

J = 9.0 Hz, H₄), 7.87 (1H, d, J = 8.0 Hz, H₅), 7.82 (1H, dt, J = 8.3,

Triﬂuoromethylsulfonic anhydride (2.25 g, 7.97 mmol) was

added dropwise to a yellow solution of 1-(2-p-methoxyphenyl-qui-

nazolin-4-yl)-naphthalen-2-ol (2.74 g, 7.24 mmol) and 4-dimethyl-

aminopyridine (2.65 g, 21.73 mmol) in dry dichloromethane

(100 mL). The pale yellow solution was allowed to stir overnight.

The solvent was removed in vacuo and the reaction mixture puriﬁed

by column chromatography (silica, dichloromethane) to yield 1-(2-

p-methoxyphenyl-quinazolin-4-yl)-2-naphthyl(triﬂuoromethyl)-

sulfonate (1.92 g, 52%) as a white solid, R_f0.40, mp 151–153 °C; m_max

(KBr) 3077 (Ar-H), 1604 (Ar-H), 1540 (Ar-H), 1434 (–SO3–), 1229

0

1.4 Hz, H₇), 7.71 (2H, d, J = 8.3 Hz, m-H), 7.54 (1H, dt, J = 9.3,

0

0.8 Hz, H₅), 7.38–7.28 (3H, m, H₆, H₃, H₆), 7.27–7.21 (2H, m,

H₇, H₈); ¹³C NMR (100 MHz):

d

(CDCl₃) 166.8 (4 °C), 158.6

(4 °C), 154.1 (4 °C), 152.0 (4 °C), 140.7 (4 °C), 140.6 (4 °C), 135.0

(CH), 132.8 (CH), 132.7 (4 °C), 132.6 (4 °C), 129.4 (CH), 129.1

(4 °C), 129.0 (CH), 128.7 (CH), 128.1 (CH), 127.9 (CH), 127.2

(CH), 125.8 (CH), 124.9 (CH), 124.1 (CH), 123.3 (4 °C), 119.4

(CH), 115.3 (4 °C); Anal. Calcd for C₂₅H₁₅F₃N₂O: C, 72.11; H,

3.63; F, 13.69; N, 6.73. Found: C, 71.85; H, 3.72; F, 13.38; N, 6.43.

(–SO3–), 1137 (C–O), 1047 (C–O) and 819 (Ar-H) cm^ꢂ1

;

¹H NMR

4.1.8. 1-(2-p-Methoxyphenyl-quinazolin-4-yl)-naphthalen-2-ol

10b

0

(300 MHz): d (CDCl₃) 8.64 (2H, d, J = 8.9, o-H), 8.17 (2H, m, H₄, H₈),

0

8.03 (1H, d, J = 8.2 Hz, H₅), 7.89 (1H, dt, J = 7.4, 1.9, H₇), 7.65 (1H, d,

2-p-Methoxyphenyl-4-(2-benzyloxy-naphthalen-1-yl)-quinaz-

oline (4.00 g, 9.45 mmol) was dissolved in EtOH (300 mL) in a 1 L

ﬂask and 10% Pd/C (1.79 g) was added. The reaction vessel was

ﬁlled with hydrogen gas (1 atm) and the mixture was stirred vigor-

ously overnight. The black mixture was ﬁltered over Celite and the

yellow ﬁltrate removed in vacuo to obtain 1-(2-p-methoxyphenyl-

quinazolin-4-yl)-naphthalen-2-ol (3.43 g, 96%) as a yellow solid,

0

J = 9.2 Hz, H₃), 7.59 (1H, d, J = 7.0, H₆), 7.36 (4H, m, H₈, H₇, H_{5 ,}H₆),

7.03 (2H, d, J = 8.9, m-H), 3.88 (3H, s, OCH₃); ¹³C NMR (75 MHz): d

(CDCl₃) 163.1 (4 °C), 162.0 (4 °C), 160.5 (4 °C), 151.5 (4 °C), 144.7

(4 °C), 134.3 (CH), 132.5 (4 °C), 132.4 (4 °C), 131.8 (CH), 130.6 (2o-

C), 130.5 (4 °C), 129.1 (CH), 128.4 (CH), 128.2 (CH), 128.1 (CH),

127.5 (4 °C), 127.4 (CH), 127.1 (CH), 126.3 (CH), 123.1 (4 °C), 119.5

(CH), 114.0 (2m-C), 55.4 (CH₃); Anal. Calcd for: C₂₆H₁₇F₃N₂O₄S: C,

1470

A. C. Maxwell et al. / Tetrahedron: Asymmetry 21 (2010) 1458–1473

61.17; H, 3.56; F, 11.16; N, 5.49; S, 6.28. Found: C, 60.96; H, 3.42; F,

11.27; N, 5.26; S, 6.57.

4.1.13. (S,R)-cis-[Dimethyl(1-(1-naphthyl)ethyl)aminato-C²,N]-

[1-(2-p-triﬂuoromethylphenyl-quinazolin-4-yl)(2-naphthyl)

diphenylphosphine]palladium(II) chloride (S,R)-13a

4.1.11. (R,S)-Diphenyl(1-(2-p-triﬂuoromethylphenyl-

quinazolin-4-yl)(2-naphthyl)phosphine 3a

A solution of (R,S)-diphenyl(1-(2-p-triﬂuoromethylphenyl-qui-

nazolin-4-yl)(2-naphthyl)phosphine (1.0 g, 1.71 mmol) and (+)-di-

Diphenylphosphine (0.53 g, 2.83 mmol) was added to a solution

of nickel dichloride diphenylphosphinoethane (0.28 g, 0.53 mmol)

in anhydrous DMF (4 mL) and the reaction mixture was heated

to 100 °C under nitrogen. After 30 min a solution of 1-(2-p-triﬂuo-

romethylphenyl-quinazolin-4-yl)-2-naphthyl(triﬂuoromethyl)sul-

fonate (2.50 g, 4.72 mmol) and diazobicyclooctane (1.27 g, 11.32

mmol) in anhydrous DMF (7 mL) was added to the reaction mixture

and heating was continued at 100 °C for a further hour. After

this time an additional portion of diphenylphosphine (0.53 g,

2.83 mmol) was added. The reaction mixture was stirred at 100 °C

under nitrogen for three days. The solvent was removed in vacuo

and the reaction mixture puriﬁed by column chromatography (sil-

ica, pentane/dichloromethane, 3:1) to yield (R,S)-diphenyl(1-(2-p-

triﬂuoromethylphenyl-quinazolin-4-yl)(2-naphthyl)phosphine as

a white solid (1.79 g, 65%), R_f0.11, mp 209–211 °C; m_max(KBr)

3066 (Ar-H), 1540 (Ar-H), 1490 (P-Ph), 1300 (CF₃), 1118 (Ph) and

l-chlorobis[(R)-dimethyl(1-(1-naphthyl)ethyl)aminato-C₂,N]dipal-

ladium(II) (0.58 g, 0.86 mmol) in dry, degassed methanol (70 mL)

was stirred for 18 h under an atmosphere of nitrogen. After 4 h a

cream-coloured precipitate was observed. The precipitate was

ﬁltered to yield (S,R)-cis-[dimethyl(1-(1-naphthyl)ethyl)aminato-

C²,N]-[1-(2-p-triﬂuoromethylphenyl-quinazolin-4-yl)(2-naphthyl)-

diphenylphosphine]palladium(II) chloride as a cream solid (0.592 g,

75%), mp 190–192 °C; ½a _D²⁰

¼ ꢂ48:7 (c 1.18, CHCl₃); m_max(KBr)

ꢃ

3054 (Ar-H), 2867 (Ar-H), 1569 (C@C), 1435 (P-Ph), 1320 (CF₃)

and 1124 (Ar-H) cm^ꢂ^{1 1}H NMR (300 MHz): d (CDCl₃) 8.22 (3H,

;

app. d, J = 8.4 Hz), 8.08 (1H, d, J = 8.5 Hz), 7.96 (2H, d, J = 9.2 Hz),

7.75 (4H, m), 7.65–7.40 (6H, m), 7.40–7.27 (7H, m), 7.19 (1H, t,

J = 7.3 Hz), 6.82 (2H, d, J = 8.5 Hz), 6.70 (3H, m), 6.50 (1H, app t,

J = 7.6 Hz), 4.18 (1H, m, CH(Me)), 2.82 (3H, s, NMe), 2.39 (3H, s,

NMe), 1.74 (3H, d, J = 6.2 Hz, CHMe); ¹³C NMR (100 MHz): d (CDCl₃)

167.9 (4 °C), 159.2 (4 °C), 150.8 (4 °C), 150.2 (4 °C), 149.3 (4 °C),

141.7 (4 °C), 139.4 (4 °C), 137.5 (CH), 137.3 (CH), 136.1 (CH),

136.0 (CH), 134.3 (4 °C), 134.1 (CH), 134.0 (CH), 132.8 (4 °C),

132.7 (4 °C), 131.9 (4 °C), 131.5 (4 °C), 131.3 (4 °C), 131.0 (CH),

130.6 (4 °C), 130.2 (CH), 130.0 (CH), 129.4 (CH), 129.2 (CH), 128.8

(CH), 128.7 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 127.9 (CH),

127.7 (CH), 127.3 (CH), 127.2 (CH), 127.0 (CH), 126.5 (CH), 125.8

(CH), 125.2 (CH), 125.1 (CH), 124.6 (4 °C), 124.3 (CH), 73.3 (CHMe),

50.9 (NMe), 48.7 (NMe), 23.5 (CHMe); ³¹P NMR (121 MHz): d

(CDCl₃) 42.8. The ﬁltrate was reduced in vacuo to yield a 4:1

mixture of diastereomers (R,R)- and (S,R)-cis-[dimethyl(1-(1-naph-

thyl)ethyl)aminato-C²,N]-[1-(2-p-triﬂuoromethylphenyl-quinazo-

lin-4-yl)(2-naphthyl)diphenyl phosphine]palladium(II)chloride

(0.988 g) as a light yellow solid. The major diastereomer was the

(R,R) diastereomer. Further crystallisation from methanol yielded

additional (S,R)-cis-[dimethyl(1-(1-naphthyl)ethyl)aminato-C²,N]-

[1-(2-p-triﬂuoromethylphenyl-quinazolin-4-yl)(2-naphthyl)diphen-

ylphosphine]palladium(II)chloride (0.091 g) from this mixture of

diastereomers.

694 (Ar-H) cm^ꢂ^{1 1}H NMR (400 MHz): d (CDCl₃) 8.25 (2H, d,

;

0

J = 8.2 Hz, o-H), 8.21 (1H, d, J = 8.6 Hz, H₈), 7.94 (2H, m, H₇, H₅),

7.87 (1H, d, J = 7.6 Hz, H₄), 7.55 (2H, d, J = 8.2 Hz, m-H), 7.49 (1H, d,

0

J = 7.6 Hz, H₃), 7.41 (3H, m, H₆, H₆, H₇), 7.35–7.21 (9H, m, H₅, Ar-

H), 7.18–7.11 (3H, m, H₈, Ar-H); ¹³C NMR (100 MHz): d (CDCl₃)

169.8 (4 °C), 159.3 (4 °C), 151.4 (4 °C), 142.1 (4 °C), 141.8 (4 °C),

137.6 (4 °C), 137.0 (4 °C), 135.1 (4 °C), 134.5 (CH), 134.2 (CH),

134.1 (CH), 134.0 (CH), 133.8 (CH), 132.6 (4 °C), 132.2 (4 °C), 131.8

(4 °C), 130.5 (CH), 129.7 (CH), 129.6 (CH), 129.4 (CH), 129.0 (CH),

128.8 (CH), 128.1 (CH), 127.4 (CH), 126.6 (CH), 125.5 (CH), 124.5

(CH), 124.5 (4 °C); ³¹P NMR (162 MHz): d (CDCl₃) ꢂ13.2 ppm; Anal.

Calcd for C₃₇H₂₄F₃N₂P: C, 76.02; H, 4.14; F, 9.75; N, 4.79; P, 5.30.

Found: C, 75.58; H, 4.09; F, 9.87; N, 4.63; P, 5.51.

4.1.12. (R,S)-Diphenyl(1-(2-p-methoxyphenyl-quinazolin-4-

yl)(2-naphthyl)phosphine 3b

Diphenylphosphine (0.397 g, 2.13 mmol) was added to a solu-

tion of nickel dichloride diphenylphosphinoethane (0.247 g,

0.46 mmol) in anhydrous DMF (4 mL) and the reaction mixture

was heated to 100 °C under nitrogen. After 30 min, a solution of

1-(2-p-methoxyphenyl-quinazolin-4-yl)-2-naphthyl(triﬂuorometh

yl)sulfonate (2.170 g, 4.26 mmol) and diazobicyclooctane (1.194 g,

10.65 mmol) in anhydrous DMF (7 mL) was added to the reaction

mixture and heating was continued at 100 °C for a further hour.

After this time an additional portion of diphenylphosphine

(0.397 g, 2.13 mmol) was added. The reaction mixture was stirred

at 100 °C under nitrogen for three days. The solvent was removed

in vacuo and the reaction mixture puriﬁed by column chromato-

graphy (silica, pentane/ethyl acetate, 6:1) to yield (R,S)-diphe-

nyl(1-(2-p-methoxyphenyl-quinazolin-4-yl)(2-naphthyl)phosphine

as a white solid, R_f0.17, mp 109–111 °C; m_max(KBr) 3066 (Ar-H),

1530 (Ar-H), 1486 (P-Ph), 1255 (C–O), 1027 (Ph) and 696 (Ar-H)

4.1.14. (S,R)-cis-[Dimethyl(1-(1-naphthyl) ethyl)aminato-C²,N]-

[1-(2-p-triﬂuoromethylphenyl-quinazolin-4-yl)(2-naphthyl)

diphenylphosphine]palladium (II)hexaﬂuorophosphate (S,R)-14

(S,R)-cis-[Dimethyl(1-(1-naphthyl)ethyl)aminato-C²,N]-[1-(2-p-

triﬂuoromethylphenyl-quinazolin-4-yl)(2-naphthyl)diphenylphos-

phine]palladium(II)chloride (0.689 g, 0.746 mmol) was dissolved

in methanol (100 mL). Potassium hexaﬂuorophosphate (0.137 g,

0.746 mmol) in distilled water (60 mL) was added to this solution.

A creamy precipitate was seen and this was stirred overnight. The

cationic palladium complex that precipitated was ﬁltered and

recrystallised from deuterated chloroform and pentane to give

yellow crystals of (S,R)-cis-[dimethyl(1-(1-naphthyl)ethyl)amina-

to-C²,N]-[1-(2-p-triﬂuoromethylphenyl-quinazolin-4-yl)(2-naphthyl)-

diphenylphosphine]palladium(II)hexaﬂuorophosphate (0.703 g,

89%); ¹H NVR (300 MHz): d (CDCl₃) 9.12 (2H, d, J = 7.5 Hz), 8.16

(1H, d, J = 9.4 Hz), 8.07–7.95 (3H, m), 7.84 (2H, d, J = 8.2 Hz), 7.72

(2H, 7, J = 7.02 Hz), 7.61–7.09 (15H, m), 6.85 (3H, app. d,

J = 9.7 Hz), 6.76 (2H, br s), 3.96 (1H, m, CH(Me)), 2.12 (3H, s,

NMe), 1.29 (3H, s, NMe), 1.14 (3H, d, J = J = 4.99 Hz, CHMe); ³¹P

NMR (121 MHz): d (CDCl₃) 31.0, -144.7 (sept., J = 712.2 Hz) ppm.

1

cm^ꢂ1

;

H NMR (400 MHz): d (CDCl₃) 8.13 (3H, d, J = 8.6, o-H, H₈),

0

7.91 (2H, app. t, J = 7.9 Hz, H₄, H₅), 7.81 (1H, t, J = 6.9 Hz, H₇), 7.49

(1H, t, J = 7.4 Hz, H₆), 7.40 (1H, dd, J = 8.5, 3.1 Hz, H₃), 7.35–7.17

0

(14H, m, H₆, H₅, H₇, H₈, Ar-H), 6.83 (2H, d, J = 8.8 Hz, m-H), 3.83

(3H, s, OCH₃); ¹³C NMR (100 MHz): d (CDCl₃) 169.3 (4 °C), 161.8

(4 °C), 160.4 (4 °C), 151.3 (4 °C), 142.5 (4 °C), 137.8 (4 °C), 137.1

(4 °C), 134.0 (4 °C), 134.8 (4 °C), 134.0 (CH), 133.9 (CH), 133.7

(CH), 132.1 (4 °C), 131.1 (4 °C), 130.7 (2o-C), 130.3 (CH), 129.4

(CH), 129.0 (CH), 128.8 (CH), 128.7 (CH), 128.6 (CH), 128.5 (CH),

128.4 (CH), 128.3 (CH), 127.2 (CH), 127.1 (CH), 126.9 (CH), 126.7

(CH), 123.9 (4 °C), 113.8 (2m-C), 55.6 (CH₃); ³¹P NMR (162 MHz):

d (CDCl₃) ꢂ12.3 ppm; Anal. Calcd for C₃₇H₂₇N₂OP: C, 81.30; H,

4.98; N, 5.13; P, 5.67. Found: C, 81.12; H, 4.99; N, 5.00; P, 5.51.

4.1.15. Crystal data for (S,R)-14

[C₅₁H₄₀F₃N₃PPd]⁺[PF₆]^ꢂꢀ2[CCl₃D], from deuterochloroform/

pentane, M_r= 1274.94, yellow plate, crystal size: 0.30 ꢁ 0.14 ꢁ

0.08 mm³; a = 10.7119(1), b = 21.3500(2), c = 12.5470(1) Å, b =

113.353(1)°, V = 2634.42(4) Å³, T = 100 K, monoclinic, space group

A. C. Maxwell et al. / Tetrahedron: Asymmetry 21 (2010) 1458–1473

1471

P2₁(No. 4), Z = 2,

paCCD diffractometer, k(Mo

72841 measured and 19998 independent reﬂections (R_int= 0.043),

19049 with I > 2 (I), h_max= 33.1°, T_min= 0.878, T_max= 0.967, direct

q

_calcd= 1.61 g cm^ꢂ3, F(0 0 0) = 1280, Nonius Kap-

) = 0.71073 Å,

= 0.79 mm^ꢂ1

(3H, s, CHMe); ¹³C NMR (100 MHz): d (CDCl₃) 168.2 (4 °C), 162.0

(4 °C), 160.1 (4 °C), 152.8 (4 °C), 148.6 (4 °C), 138.5 (CH), 138.4

(CH), 136.3 (4 °C), 135.9 (4 °C), 133.9 (CH), 131.8 (4°°C), 131.7

(4 °C), 130.8 (CH), 130.7 (CH), 130.6 (CH), 130.2 (CH), 130.1

(4 °C), 128.9 (CH), 128.7 (4 °C), 128.6 (4 °C), 128.5 (CH), 128.4

(CH), 128.2 (CH), 128.1 (CH), 128.0 (CH), 127.4 (CH), 127.3 (CH),

127.2 (CH), 127.1 (CH), 126.7 (CH), 126.6 (CH), 125.4 (CH), 124.3

(4 °C), 124.1 (4 °C), 124.0 (CH), 123.9 (4 °C), 123.3 (4 °C), 123.0

(CH), 123.3 (CH), 113.8 (CH), 73.0 (CHMe), 55.7 (OMe), 50.6

(NMe), 48.8 (NMe), 23.7 (CHMe); ³¹P NMR (121 MHz): d (CDCl₃)

39.9 ppm.

Ka

l

,

r

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

F²_o, both programs from G. Sheldrick, University of Göttingen,

1997; 667 parameters, H atoms riding, absolute conﬁguration

established (Flack parameter ꢂ0.01(1)), Chebyshev type weights,

R₁= 0.0346 (I > 2r(I)), wR₂= 0.0866 (all data), Dq_max/min= 1.313

(0.85 Å from Pd)/ꢂ1.286 (0.68 Å from Cl6) e Å^ꢂ3, CCDC 630664.³⁴

4.1.16. (S,R)-cis-[dimethyl(1-(1-naphthyl)ethyl)aminato-C²,N]-

[1-(2-p-methoxyphenyl-quinazolin-4-yl)(2-naphthyl)diphenyl-

phosphine]palladium(II)chloride (S,R)-13b

4.1.17. (S)-Diphenyl(1-(2-p-triﬂuoromethylphenyl-quinazolin-

4-yl)(2-naphthyl)phosphine (S)-3a

A solution of (RS)-diphenyl(1-(2-p-methoxyphenyl-quinazolin-

4-yl)(2-naphthyl)phosphine (0.33 g, 0.59 mmol) and (+)-di-l-

(S,R)-cis-[Dimethyl(1-(1-naphthyl)ethyl)aminato-C²,N]-[1-(2-p-

triﬂuoromethylphenyl-quinazolin-4-yl)(2-naphthyl)diphenylphos-

phine]palladium(II)chloride (0.20 g, 0.22 mmol) and 1,2-bis

(diphenylphosphino)ethane (0.09 g, 0.22 mmol) were dissolved in

dry, degassed dichloromethane (15 mL). The pale yellow solution

was stirred for 3 h at room temperature under an atmosphere of

nitrogen. The dichloromethane was removed in vacuo and puriﬁed

by column chromatography (silica, dichloromethane) to give (S)-

diphenyl(1-(2-p-triﬂuoromethylphenyl-quinazolin-4-yl)(2-naph-

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

dium(II) (0.20 g, 0.29 mmol) in dry, degassed methanol (40 mL)

was stirred for 18 h under an atmosphere of nitrogen. After 2 h a

cream-coloured precipitate was observed. The precipitate was

ﬁltered to yield (R,R) and (S,R)-cis-[dimethyl(1-(1-naphthyl) ethyl)-

aminato-C²,N]-[1-(2-p-methoxy-quinazolin-4-yl)(2-naphthyl)di-

phenylphosphine]palladium(II)chloride as a cream solid. This mix-

ture was dissolved in hot butanone and pentane was added slowly

until a cream precipitate was just seen. Further hot butanone was

added and the solution was allowed to stand overnight. By this

time a cream-coloured precipitate had formed. Filtration of this

precipitate gave diastereomerically pure (S,R)-cis-[dimethyl(1-(1-

naphthyl)ethyl)aminato-C²,N]-[1-(2-p-methoxyphenyl-quinazolin-

4-yl)(2-naphthyl)diphenylphosphine]palladium(II)chloride (0.148 g,

thyl)phosphine as a white solid (0.12 g, 97%), R_f0.66, ½a _D²⁰

¼ þ40:9

ꢃ

(c 0.70, CHCl₃), identical in all other respects to the previously

prepared racemic sample.

4.1.18. (S)-Diphenyl(1-(2-p-methoxyphenyl-quinazolin-4-yl)(2-

naphthyl)phosphine (S)-3b

(S,R)-cis-[Dimethyl(1-(1-naphthyl)ethyl)aminato-C²,N]-[1-(2-p-

methoxyphenyl-quinazolin-4-yl)(2-naphthyl)diphenylphosphine]-

palladium(II)chloride (0.45 g, 0.50 mmol) and 1,2-bis (diphenyl-

phosphino)ethane (0.20 g, 0.50 mmol) were dissolved in dry, de-

gassed dichloromethane (30 mL). The pale yellow solution was

stirred for 3 h at room temperature under an atmosphere of nitro-

gen. The dichloromethane was removed in vacuo and puriﬁed by

column chromatography (silica, pentane/ethyl acetate, 6:1) to give

(S)-diphenyl(1-(2-p-methoxyphenyl-quinazolin-4-yl)(2-naphthyl)-

56%), mp 203–205 °C; ½a _D²⁰

¼ ꢂ44:2 (c 0.65, CHCl₃); m_max(KBr)

ꢃ

3052 (Ar-H), 2913 (Ar-H), 1540 (C@C), 1435 (P-Ph), 1250 (C–O)

and 1168 (Ar-H) cm^ꢂ^{1 1}H NMR (400 MHz): d (CDCl₃) 8.33 (1H, t,

;

J = 3.9 Hz), 8.14 (2H, d, J = 9.0 Hz, o-H), 8.03 (1H, d, J = 8.7 Hz),

7.92 (1H, d, J = 8.0 Hz), 7.84 (3H, m), 7.76 (1H, d, J = 8.1 Hz), 7.73

(1H, m), 7.63 (1H, d, J = 8.4 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.46 (2H,

m), 7.37–7.26 (7H, m), 7.17 (1H, m), 6.86 (2H, d, J = 9.0 Hz, m-H),

6.81 (1H, d, J = 8.6 Hz), 6.74 (2H, m), 6.59 (2H, t, J = 6.5 Hz), 6.48

(1H, t, J = 6.0 Hz), 4.21 (1H, m, CH(Me)), 3.85 (3H, s, OMe), 2.88

(3H, d, J = 3.4 Hz, NMe), 2.56 (3H, s, NMe), 1.76 (3H, d, J = 6.3 Hz,

CHMe); ¹³C NMR (100 MHz): d (CDCl₃) 167.5 (4 °C), 161.7 (4 °C),

160.0 (4 °C), 150.9 (4 °C), 150.7 (4 °C), 149.2 (4 °C), 139.7 (4 °C),

137.3 (CH), 137.2 (CH), 136.5 (CH), 136.4 (CH), 136.1 (CH), 136.0

(CH), 134.2 (4 °C), 133.8 (CH), 133.3 (CH), 132.7 (4 °C), 131.1

(4 °C), 130.9 (CH), 130.8 (4 °C), 130.7 (CH), 130.6 (CH), 130.1

(4 °C), 130.0 (CH), 129.1 (CH), 128.8 (CH), 128.7 (4 °C), 128.5

(CH), 128.4 (CH), 128.3 (CH), 128.2 (CH), 128.1 (CH), 127.9 (CH),

127.7 (CH), 127.1 (CH), 127.0 (CH), 126.8 (CH), 126.6 (CH), 125.7

(CH), 124.3 (CH), 124.2 (4 °C), 124.12 (CH), 124.10 (4 °C), 123.4

(CH), 113.7 (CH), 73.3 (CHMe), 55.6 (OMe), 51.1 (NMe), 48.7

(NMe), 23.6 (CHMe); ³¹P NMR (121 MHz): d (CDCl₃) 45.2 ppm.

The ﬁltrate contained a mixture of diastereomers; two subsequent

recrystallisations with hot butanone/pentane realised further

quantities of the (S,R) diastereomer (0.053 g and 0.024 g). By

recrystallisation of the remaining ﬁltrate from methanol the

isolation of a small quantity of (R,R)-cis-[dimethyl(1-(1-naphthyl)-

ethyl)aminato-C²,N] -[1-(2-p-methoxy-quinazolin-4-yl)(2-naph-

thyl)diphenylphosphine]palladium(II)chloride (0.048 g, 18%) was

phosphine as a white solid (0.21 g, 77%), R_f0.17, ½a _D²⁰

¼ þ38:0 (c

ꢃ

0.65, CHCl₃), identical in all other respects to the previously pre-

pared racemic sample.

4.1.19. (S)-Diphenyl[1-(2-(2-pyridyl)-quinazolin-4-yl)(2-naph-

thyl)]phosphine rhodium(1,5-cyclooctadiene) methanesulfo-

nate 15a

(1,5-Cyclooctadiene)(2,4-pentanedionato)rhodium (3.1 mg, 0.01

mmol) and (S)-2-(2-pyridyl)-Quinazolinap (5.1 mg, 0.01 mmol)

were dissolved in dry THF (2 mL) under an atmosphere of nitrogen

to give a clear yellow solution. Trimethylsilyltriﬂuoromethanesulf-

onate (2 lL, 1.11 equiv) was added via syringe producing a light

brown solution. The solution was stirred for 20 min and the vol-

ume reduced in vacuo to approx. 0.5 mL. Pentane (15 mL) was

added via syringe, resulting in the formation of a pale brown pre-

cipitate. This was stirred for 10 min and the pentane was removed

via syringe. The precipitate was washed once more with pentane

(15 mL), which was again removed using a syringe to leave (S)-di-

phenyl{1-[2-(2-pyridyl)-quinazolin-4-yl][2-naphthyl]}phosphine

rhodium(1,5-cyclooctadiene)methanesulfonate as a light yellow

powder. ¹H NMR (300 MHz): d (CDCl₃) 9.87 (d, 1H, J = 5.1 Hz),

8.78 (d, 1H, J = 8.0 Hz), 8.24 (d, 1H, J = 7.6 Hz), 8.23–6.35 (m,

21H), 5.59 (br s, 1H CH@CH), 4.09 (br s, 1H CH@CH), 3.47 (br s,

1H CH@CH), 2.37 (br s, 1H CH@CH), 1.85 (m, 2H, CH₂), 1.74–1.60

(m, 4H, CH₂, CH₂), 1.26 (m, 2H, CH₂); ³¹P NMR (121 MHz): d (CDCl₃)

25.84 ppm (d, J = 123 Hz). The product was dried under vacuum for

45 min before use in Rh-catalysed hydroboration. Dry THF (4 mL)

was added to the Schlenk tube and 2 mL portions of the catalyst

possible, mp 200–202 °C; ½a _D²⁰

¼ þ43:3 (c 0.91, CHCl₃); m_max(KBr)

ꢃ

3050 (Ar-H), 2892 (Ar-H), 1538 (C@C), 1435 (P-Ph), 1250 (C–O)

and 1166 (Ar-H) cm^ꢂ^{1 1}H NMR (300 MHz): d (CDCl₃) 8.41 (2H, d,

;

J = 8.8 Hz), 8.18 (2H, t, J = 8.9 Hz), 7.99–7.80 (5H, m), 7.71 (1H, t,

J = 7.7 Hz), 7.59 (1H, d, J = 8.2 Hz), 7.52–7.38 (5H, m), 7.32–7.19

(7H, m), 6.99 (4H, d, J = 8.8 Hz), 6.80 (1H, d, J = 8.6 Hz), 6.21 (1H,

d, J = 8.5 Hz), 6.03 (1H, t, J = 6.2 Hz), 4.12 (1H, m, CH(Me)), 3.95

(3H, s, OMe), 2.85 (3H, d, J = 2.4 Hz, NMe), 2.00 (3H, s, NMe), 1.97

1472

A. C. Maxwell et al. / Tetrahedron: Asymmetry 21 (2010) 1458–1473

precursor (1 mol %) were transferred to two oven-dried Schlenk

tubes under nitrogen.

(10 mL) was added via syringe and to produce a bright yellow pre-

cipitate. This was allowed stir for 5 min before the pentane was re-

moved via syringe. The precipitate was washed twice more with

pentane (2 ꢁ 10 mL), which was syringed from the Schlenk tube

to leave (S)-diphenyl[1-(2-p-methoxyphenyl-quinazolin-4-yl)(2-

naphthyl)]phosphine rhodium(1,5-cyclooctadiene)triﬂuorometh-

anesulfonate as a light yellow powder. ¹H NMR (400 MHz): d

(CDCl₃) = 8.99 (2H, d, J = 8.4 Hz), 8.33 (1H, d, J = 8.7 Hz), 8.10 (1H,

d, J = 8.2 Hz), 7.88–7.81 (2H, m), 7.74 (1H, t, J = 8.1 Hz), 7.63–7.57

(3H, m), 7.50 (3H, m), 7.47–7.39 (5H, m), 7.25 (3H, m), 7.09 (1H,

d, J = 8.8 Hz), 6.71 (1H, t, J = 7.0 Hz), 6.59 (1H, t, J = 6.9 Hz), 5.60

(1H, br s, CH@CH), 4.22 (1H, br s, CH@CH), 3.99 (3H, s, OMe),

3.79 (1H, br s, CH@CH), 3.28 (1H, br s, CH@CH), 1.55 (2H, m,

CH₂), 1.28 (2H, m, CH₂), 1.15 (2H, m, CH₂), 0.81 (2H, m, CH₂); ¹³P

NMR (162 MHz): d (CDCl₃) 19.25 (d, J = J = 133.5 Hz) ppm. The

product was dried under vacuum for 45 min before use in Rh-cat-

alysed 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.

4.1.20. (S)-Diphenyl[1-(2-(2-pyrazinyl)-quinazolin-4-yl)(2-

naphthyl)]phosphine rhodium(1,5-cyclooctadiene)

methanesulfonate 15b

(1,5-Cyclooctadiene)(2,4-pentanedionato)rhodium 32 (3.1 mg,

0.01 mmol) and (S)-2-(2-pyrazinyl)-Quinazolinap (5.1 mg, 0.01

mmol) were dissolved in dry THF (2 mL) under an atmosphere of

nitrogen to give a clear yellow solution. Trimethylsilyltriﬂuorome-

thanesulfonate (2 lL, 1.11 equiv) was added via syringe, producing

a light brown solution. The solution was stirred for 20 min and the

volume reduced in vacuo to approx. 0.5 mL. Pentane (15 mL) was

added via syringe, resulting in the formation of a pale brown pre-

cipitate. This was stirred for 10 min and the pentane was removed

via syringe. The precipitate was washed once more with pentane

(15 mL), which was again removed using a syringe to leave (S)-di-

phenyl[1-(2-(2-pyrazinyl)-quinazolin-4-yl)(2-naphthyl)]phosphine

rhodium(1,5-cyclooctadiene)methanesulfonate as a light brown

powder. The product was dried under vacuum for 45 min before

use in Rh-catalysed 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.

4.2. Asymmetric hydroboration general procedure

The required Quinazolinap-rhodium(1,5-cyclooctadiene)triﬂuo-

romethanesulfonate catalyst (5

under nitrogen in a Schlenk tube. Freshly distilled catecholborane

(53 L, 0.5 mmol) was added via microlitre syringe and the light

lmol) in THF (2 mL) was placed

4.1.21. (S)-Diphenyl[1-(2-p-triﬂuoromethylphenyl-quinazolin-

4-yl)(2-naphthyl)]phosphine rhodium(1,5-cyclooctadiene)

methanesulfonate 15c

(1,5-Cyclooctadiene)(2,4-pentanedionato)rhodium (3.2 mg,

0.01 mmol) and (S)-diphenyl[1-(2-p-triﬂuoromethylphenyl-qui-

nazolin-4-yl)(2-naphthyl)]phosphine (5.8 mg, 0.01 mmol) were

dissolved in dry THF (2 mL) under an atmosphere of nitrogen to

l

brown solution was allowed to stir for 5 min at the required tem-

perature. The substrate oleﬁn (0.5 mmol) was injected and the

reaction mixture was stirred for either 2 h or 24 h at room temper-

ature or at 0 °C. The reaction was then cooled to 0 °C; 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. Conversion and regioselectivity were determined by ¹H NMR.

The ee was calculated by chiral GC or HPLC analysis. Conditions

for chiral GC and HPLC analysis as previously reported.⁴

give

a clear yellow solution. Trimethylsilylmethanesulfonate

(2 L, 1.11 equiv) was added via syringe and a dark orange/red col-

l

our 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

allowed to stir for 5 min before the pentane was removed. The pre-

cipitate was washed with fresh pentane (2 ꢁ 10 mL), which was

syringed from the Schlenk tube to leave (S)-diphenyl[1-(2-ptriﬂuo-

romethylphenyl-quinazolin-4-yl)(2-naphthyl)]phosphinerhodium-

(1,5-cyclooctadiene)triﬂuoromethanesulfonate as a light orange

powder. ¹H NMR (400 MHz): d (CDCl₃) = 9.10 (2H, s), 8.34 (1H, d,

J = 8.6 Hz), 8.09 (3H, d, J = 8.3 Hz), 7.90 (2H, m), 7.77 (1H, s), 7.63

(1H, t, J = 7.2 Hz), 7.48 (7H, m), 7.26 (3H, t, J = 8.3 Hz), 7.16 (1H,

s), 6.76 (1H, s), 6.64 (2H, s), 4.18 (1H, br s, CH@CH), 3.95 (1H, br

s, CH@CH), 2.65 (1H, br s, CH@CH), 2.20 (1H, br s, CH@CH), 1.78

(2H, m, CH₂), 1.39 (2H, m, CH₂), 1.33 (2H, m, CH₂), 0.80 (2H, m,

CH₂); ¹³P NMR (162 MHz): d (CDCl₃) 19.42 (d, J = 126.0 Hz) ppm.

The product was dried under vacuum for 45 min before use in

Rh-catalysed 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.

Acknowledgements

We wish to thank IRCSET for a Research Scholarship (RS/2002/

64-1) awarded to A.M. and also Enterprise Ireland for a Research

Scholarship (BRS/2000/168) awarded to S.F. We also acknowledge

the facilities provided by the Centre for Synthesis and Chemical

Biology (CSCB), funded by the Higher Education Authority’s Pro-

gramme for Research in Third-Level Institutions (PRTLI). We are

grateful to Dr. Jimmy Muldoon, Dr Dilip Rai of the CSCB for NMR

and mass spectra, respectively.

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methanesulfonate 15d

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Article Doi

Rhodium-catalysed hydroboration employing new Quinazolinap ligands; An investigation into electronic effects

DOI: 10.1016/j.tetasy.2010.06.012

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