The preparation and resolution of 2-(2-pyridyl)- and 2-(2-pyrazinyl)- Quinazolinap and their application in palladium-catalysed allylic substitution

Article abstract of DOI:10.1016/j.tet.2005.06.071

The preparation and resolution of two new axially chiral quinazoline-containing phosphinamine ligands, 2-(2-pyridyl)-Quinazolinap and 2-(2-pyrazinyl)-Quinazolinap, is described. The ligands were synthesised in good yield over eight steps and included two

Full text of DOI:10.1016/j.tet.2005.06.071

Tetrahedron 61 (2005) 9808–9821
The preparation and resolution of 2-(2-pyridyl)- and
2-(2-pyrazinyl)-Quinazolinap and their application in
palladium-catalysed allylic substitution
Susan P. Flanagan,a Richard Goddardb and Patrick J. Guirya,
*
aDepartment of Chemistry, Centre for Synthesis and Chemical Biology, Conway Institute of Biomolecular and Biomedical Research,
University College Dublin, Belfield, Dublin 4, Ireland
b
¨
¨
¨
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mulheim an der Ruhr, Germany
Received 21 March 2005; revised 19 May 2005; accepted 17 June 2005
Available online 18 July 2005
Abstract—The preparation and resolution of two new axially chiral quinazoline-containing phosphinamine ligands, 2-(2-pyridyl)-
Quinazolinap and 2-(2-pyrazinyl)-Quinazolinap, is described. The ligands were synthesised in good yield over eight steps and included two
Pd-catalysed reactions, a Suzuki coupling to form the biaryl linkage and the introduction of the diphenylphosphino group, as the key
transformations. The racemic ligands were resolved via the fractional crystallisation of diastereomeric palladacycles derived from (C)-di-m-
chlorobis{(R)-dimethyl[1-(1-naphthyl)ethyl]aminato-C2,N}dipalladium (II) X-ray crystal structures of the (S,R)-2-pyridyl- and (S,R)-2-
pyrazinyl-palladacycles are included. Displacement of the resolving agent by reaction with 1,2-bis(diphenylphosphino)ethane gave
enantiopure 2-(2-pyridyl)-Quinazolinap and 2-(2-pyrazinyl)-Quinazolinap, new atropisomeric phosphinamine ligands for asymmetric
catalysis. These ligands were applied in the palladium-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate resulting in moderate
conversions and enantioselectivities of up to 81%.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Within our research group, attention has focused on the
development of a new class of atropisomeric ligands with a
quinazoline unit incorporated into the biaryl framework. We
call this ligand series ‘Quinazolinaps’ and their preparation
involves a synthetic route similar to that of Quinap and
Phenap. The first of these synthesised and resolved was
2-phenyl-Quinazolinap (2a), which was successfully
applied in Pd-catalysed allylic substitution providing good
conversions but moderate enantioselectivities.7,8 Following
on from the aforementioned mechanistic insight into allylic
substitution provided by Brown’s study, we were prompted
to vary the size of the substituent at the corresponding
2-position of the quinazoline moiety and hence the series of
ligands 2b–f were prepared and resolved.9 Improved
conversions and enantioselectivities up to 91% were
obtained in the Pd-catalysed allylic alkylation of 1,3-
diphenyl-propenyl acetate10 and dimethyl malonate and up
to 99% in the Rh-catalysed hydroboration of vinylarenes.9
To date, atropisomeric ligands have been applied in a wide
range of transition metal catalysed asymmetric transforma-
tions.1 One of the most successful and widely applicable of
these ligands is Noyori’s diphosphine BINAP.2 The
principle of inducing enantioselectivity through the influ-
ence of electronic as well as steric factors led to the design
of axially chiral heterobidentate ligands such as Brown’s
Quinap (1), the first example of this class successfully
applied in asymmetric catalysis.3 During solid state and
solution 1H NMR investigations into the mechanism of
allylic substitution catalysed by Pd–Quinap complexes, it
had been determined that the 3H of the isoquinoline unit
occupies a position of crucial steric influence over ligand–
reactant interactions and hence over the stereochemical
outcome of the reaction.4 This led to the preparation of the
vaulted analogue Phenap, also developed by Brown, which
was applied in the rhodium-catalysed hydroboration of
olefins and palladium-catalysed allylic alkylation resulting
in enantioselectivities of up to 84 and 95%, respectively.5,6
Due to the success of this ligand series we wished to
examine the effect of altering the electronic nature of the
2-substituent. Herein we report the extension of the
Quinazolinap ligand class to include the 2-(2-pyridyl)- and
2-(2-pyrazinyl)-variants (3a–b). It was intended that the
presence of the nitrogen atom(s) of the pyridyl and
Keywords: Catalysis; Atropisomeric P.N. ligand; Allylic substitution.
*
Corresponding author. Tel.: C353 1 716 2309; fax: C353 1 716 2127;
e-mail: p.guiry@ucd.ie
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.071

S. P. Flanagan et al. / Tetrahedron 61 (2005) 9808–9821
9809
pyrazinyl rings would alter the basicity of the donor
nitrogen of the quinazoline unit. There is also the added
possibility of hemi-labile coordination of the extra nitrogen
atom (3 vs 2) with potentially beneficial effects in transition
metal catalysed asymmetric transformations.
sulfonates were formed in good yield (71–78%) although
a longer reaction time of 48 h was necessary in the case
of the 2-pyrazinyl variant. The Ni-catalysed process
developed by Cai et al. had been successfully employed
for the incorporation of the diphenylphosphino group into
2. Ligand preparation
Quinazolinaps (2a–f) but it proved unsuitable for the
transformation of the 2-pyridyl and 2-pyrazinyl triflates
with a substantial amount of unreacted triflate remaining
after 6 days at reflux.14 Conversion of 10a to the aryl-
diphenylphosphine oxide followed by subsequent reduction
using trichlorosilane and triethylamine also resulted in low
yields.15 Direct formation of the desired products was
achieved through the use of palladium acetate as catalyst
and triphenylphosphine as the phosphinylating agent in
dimethyl formamide, as reported by Chan and co-workers.16
Thus 2-(2-pyridyl)-Quinazolinap (3a) and 2-(2-pyrazinyl)-
Quinazolinap (3b) were obtained in racemic form over eight
steps in good yields.
The synthetic approach chosen to prepare ligands 3a–b is
analogous to that used to obtain Quinazolinaps 2a–f. The
two key steps in the synthesis are the Pd-catalysed reactions
to effect the biaryl coupling, and the formation of the
naphthyl–phosphorus bond. The introduction of the phos-
phine in the final step is preferred as it allows facile handling
of the intermediate compounds. The coupling partners of the
palladium catalysed Suzuki reaction were the appropriate
4-chloroquinazoline (6a–b) and 2-methoxy-1-naphthyl-
boronic acid (7), Scheme 1. The boronic acid was easily
prepared from 1-bromo-2-methoxynaphthalene via a
Grignard reaction, while the 4-chloroquinazolines were
derived from the corresponding 2-substituted 4(3H)-
quinazolinones (5a–b). These quinazolinones were readily
obtained in yields of 83 and 97%, respectively, using a
highly versatile methodology developed within our research
group involving a sodium methoxide-mediated cyclisation
between anthranilic acid and the appropriately substituted
nitrile (4a–b).11 The Suzuki coupling was catalysed by
3 mol% of tetrakis(triphenylphosphine)palladium (0) in
dimethoxyethane at reflux in the presence of 2 M aqueous
sodium carbonate and gave the methyl ethers (8a–b) as
white solids in good yield (77 and 78%) after column
chromatography. In order to introduce the diphenylphos-
phino group, it is first necessary to convert the methoxy
group to a trifluoromethanesulfonate. For the earlier ligands
of the Quinazolinap series, treatment with boron tribromide
in dichloromethane provided the desired naphthol in all
cases in high yields. However, the presence of the extra
nitrogen atom(s) of the 2-pyridyl and 2-pyrazinyl analogues
altered the process sufficiently that none of the required
naphthol was obtained when boron tribromide was
employed. The problem was solved through the use of
aluminium chloride for the demethylation of 2-(2-pyridyl)-
4-(2-methoxynaphthalen-1-yl)-quinazoline,12 whereas heat-
ing at 120 8C with sodium ethanethiolate in dimethyl
formamide removed the methyl group of the pyrazinyl
analogue.13 Both naphthols (9a–b) were then converted to
their trifluoromethanesulfonate analogues (10a–b) by
reaction with trifluoromethanesulfonic anhydride in the
presence of 4-dimethylaminopyridine. The trifluoromethane-
3. Ligand resolution
The resolution of many racemic phosphorus-containing
ligand systems has been accomplished by the formation of
diastereomeric complexes with enantiopure palladium
amine complexes, followed by fractional crystallisation to
obtain diastereomerically pure material.17 As the ortho-
palladated derivative of (R)-dimethyl[1-(1-naphthyl)ethyl]
amine (11) had been successfully employed as the resolving
agent for the resolution of Quinap and the earlier members
of the Quinazolinap series, it was also applied in the
attempts to resolve 2-(2-pyridyl)- and 2-(2-pyrazinyl)-
Quinazolinap. Therefore, 2-(2-pyridyl)-Quinazolinap (3a)
and (C)-di-m-chlorobis{(R)-dimethyl[1-(1-naphthyl)ethyl]
aminato-C2,N}dipalladium (II) (11) were stirred in a 2:1
ratio in methanol for 18 h at room temperature, Scheme 2.
An aqueous solution of KPF6 was added to precipitate a
yellow solid, which was shown by 1H NMR to consist of a
2:1 mixture of diastereomers. The benzylic methines
appeared as quintets, at 4.10 ppm for the major diastereomer
and at 4.46 ppm for the minor. In the 31P NMR spectrum the
resonances associated with the two species appear at 27.61
and 22.16 ppm, respectively. A range of solvent systems
was investigated to separate the diastereomeric pair before a
mixture of hot butanone and diethyl ether proved successful.
The precipitate that had formed was found to be a mixture of
the two diastereomers but the mother liquor was proven to
contain only the major one with a single peak in the 31P

9810
S. P. Flanagan et al. / Tetrahedron 61 (2005) 9808–9821
Scheme 1.
NMR at 27.61 ppm. A sample of this diastereomer was
recrystallised from a dichloromethane–diethyl ether mixture
to obtain crystals suitable for X-ray analysis. The crystal
structure indicated that the (S,R)-diastereomer had been
isolated, Figure 1. It also shows that, interestingly, the Pd
atom adopts an almost ideal trigonal-bipyramidal coordin-
ation geometry in which the equatorial ligand and the metal
similar approach, Scheme 3, although the mixture contain-
ing the ligand and resolving agent had to be stirred at 60 8C
for 18 h to ensure complete complexation. By this time a
pale yellow precipitate had formed and was removed by
filtration. 1H NMR spectroscopy confirmed the presence of
a single diastereomer with the benzylic methine quintet at
4.11 ppm and only one peak appeared in the 31P NMR at
39.50 ppm. The filtrate was found to contain both dia-
stereomers but attempts to separate the two failed and so the
residue was re-dissolved in methanol and the counter-ion
˚
are almost coplanar (rms deviation 0.04 A).
Resolution of 2-(2-pyrazinyl)-Quinazolinap (3b) followed a

S. P. Flanagan et al. / Tetrahedron 61 (2005) 9808–9821
9811
Scheme 2.
changed to PFK6 . Both diastereomers were apparent in the
1H NMR spectrum, this time in a 1:1 ratio with the benzylic
methine quintets appearing at 4.37 and 4.12 ppm and the
phosphorus resonances at 28.97 and 24.50 ppm. Again,
isolation of diastereomerically pure material was effected by
fractional crystallisation from hot butanone–diethyl ether
and crystals for X-ray analysis were obtained through
recystallisation from chloroform–diethyl ether. The X-ray
structure showed this to be the (S,R)-2-(2-pyrazinyl)
diastereomer, which adopts a similar trigonal–bipyramidal
geometry as had been found for the (S,R)-2-(2-pyridyl)
diastereomer, Figure 2. The geometries of the two palladium
cations in both crystal structures are markedly similar in
spite of their different crystal environments. The most
significant difference between the two structures is a
˚
shortening of the Pd–N3 bond by 0.062(4) A and an
Figure 1. Structure of the cation in (S,R)-12$1.5(CH2Cl2), showing the
approximate trigonal–bipyramidal coordination geometry of the Pd atom.
˚
Selected distances (A) and angles (8): Pd–P1 2.223(1), Pd–N1 2.182(3), Pd–
Figure 2. Structure of the cation in (S,R)-14$C4H10O, with the (R)-
dimethyl(1-(1-naphthyl)ethyl)aminato ligand in the same orientation as for
˚
Figure 1. Selected distances (A) angles (8): Pd–P1 2.2211(4), Pd–N1 2.
N3 2.408(3), Pd–N4 2.216(3), Pd–C36 1.982(3), P1–Pd–N1 83.7(1), P1–
Pd–N3 120.7(1), P1–Pd–N4 145.8(1), P1–Pd–C36 96.2(1), N1–Pd–N3
72.9(1), N1–Pd–N4 102.5(1), N1–Pd–C36 176.2(1), N3–Pd–N4 93.0(1),
N3–Pd–C36 104.1(1), N4–Pd–C36 79.8(1).
185(1), Pd–N3 2.346(2), Pd–N4 2.245(2), Pd–C35 1.981(2), P1–Pd–N1 85.
06(4), P1–Pd–N3 124.49(4), P1–Pd–N4 139.66(4), P1–Pd–C35 97.5(1),
N1–Pd–N3 74.3(1), N1–Pd–N4 102.7(1), N1–Pd–C35 173.3(1), N3–Pd–
N4 95.5(1), N3–Pd–C35 99.2(1), N4–Pd–C35 79.4(1).

9812
S. P. Flanagan et al. / Tetrahedron 61 (2005) 9808–9821
Scheme 3.
Figure 3. Structures of the palladium cations of variously substituted 2-Quinazolinaps (HZgreen; isopropylZred; pyridylZyellow; pyrazinylZwhite) with
the (R)-dimethyl[1-(1-naphthyl)ethyl]aminato ligand in the same orientation as for Figures 1 and 2.

S. P. Flanagan et al. / Tetrahedron 61 (2005) 9808–9821
9813
Table 1. A comparison of the geometries of cationic substituted (S,R)-Quinazolinap Pd complexes
Quinazolinap ligand
Ligand
R
P1–Pd–N1
angle (deg)
N1–Pd–N3
angle (deg)
Plane (naphthyl)/
plane (quinazolinyl)
dihedral angle (deg)
Plane (quinazolinyl)/
plane (pyr/pyraz)
dihedral angle (deg)
Pd–P1
distance
˚
(A)
Pd–N1
distance
˚
(A)
Pd–N3
distance
˚
(A)
2aa
2ba
2ea
3ab
3bb
H
Me
iPr
Pyr
Pyraz
84.7(1)
82.34(6)
84.6(2)
83.7(1)
85.06(4)
—
—
—
72.9(1)
74.3(1)
112(2)
119(1)
113(2)
115(1)
118(1)
—
—
—
159(1)
154(1)
2.256(2)
2.2423(5)
2.238(2)
2.223(1)
2.2211(4)
2.189(5)
2.187(2)
2.192(5)
2.182(3)
2.185(1)
—
—
—
2.408(3)
2.346(2)
Aminato ligand
Pd–Cc
Inter-ligand geometry
Cc–Pd–N4
angle (deg)
Pd–N3a/N4b
Trans-N1-Pd-Cc
angle (deg)
N3b–Pd–N4b
angle (deg)
P1–Pd–N3a/N4b
angle (deg)
Plane(P1,Pd,N1)/plane
(N3a/N4b,Pd,Cc) dihedral
angle (deg)
˚
distance (A)
˚
distance (A)
80.4(2)
80.2(1)
80.9(2)
79.8(1)
79.4(1)
2.132(5)
2.147(2)
2.164(6)
2.216(3)
2.245(2)
2.002(6)
1.978(3)
1.993(6)
1.982(3)
1.981(2)
171.2(2)
171.0(1)
166.7(2)
176.2(1)
173.3(1)
—
—
—
93.0(1)
95.5(1)
165.9(2)
155.3(1)
152.9(2)
145.8(1)
139.7(1)
17(2)
28(1)
32(2)
35(1)
42(1)
a Ref. 9.
b This publication.
c Carbon atom attached to Pd.
associated increase in the N3–Pd–N4 angle of 2.5(2)8 on
substitution of the 2-pyridyl group by the 2-pyrazinyl group
on the Quinazolinap ligand. Since both the pyridyl and
pyrazinyl groups are sterically similar, the difference is
presumably due to the increased electron donor ability of the
pyrazinyl substituent compared with the pyridyl group.
useful way of assessing the ability of the ligand to induce
enantioselectivity.18 One of the most typically used systems
involves nucleophilic attack of the dimethyl malonate anion
on 1,3-diphenylprop-2-enyl acetate. Palladium complexes
of homobidentate ligands have proven to be successful in
this transformation by creating a chiral environment, which
influences the orientation of the reactants sufficiently to
cause one enantiomer of product to predominate.19
Heterobidentate ligands such as the phosphinamines
developed by Pfaltz,20 Williams,21 Helmchen22 and
Brown3 affect the stereochemical outcome of the bond-
forming process by the desymmetrisation of the substrate
allyl through electronic effects. The incoming nucleophile
then reacts preferentially at the more electrophilic end of the
substrate, giving rise to the enantioselectivity observed.
This is referred to as the trans effect as nucleophilic attack
tends to occur trans to the phosphorus atom of the ligand–Pd
complex.23 The two standard methods employed for the
reaction between dimethyl malonate and 1,3-diphenylprop-
2-enyl acetate are the malonate procedure (method A), in
which the nucleophile is preformed as its sodium salt, and
the BSA procedure (method B), in which it is generated
in situ upon addition of a base (typically a bis(trimethyl-
silyl)acetamide–KOAc mixture). Both methods were
applied in the alkylation of 1,3-diphenylprop-2-enyl acetate
catalysed by palladium complexes of Quinazolinaps 3a and
3b. In some cases, 15-crown-5 was added to aid the
dissolution of the preformed sodium malonate.
If one compares the structures of various 2-substituted
Quinazolinap Pd cations containing the same (R)-
dimethyl(1-(1-naphthyl)ethyl)aminato ligand, there is a
clear rearrangement of the ligands with respect to one
another depending on the nature of the 2-substituent,
Figure 3. Thus, in going from H/Me/isopropyl/2-
pyridyl/2-pyrazinyl, the P1–Pd–N angle between the P
atom of the Quinazolinap ligand and the N atom of the
amidato ligand decreases steadily from 166 to 1408 whereas
the dihedral angle between the planes defined by P1, Pd and
N1 of the Quinazolinap ligand and N, Pd and C of the
amidato ligand increases by 258 (Table 1). Although the
most significant change takes place in the equatorial plane
of the metal, increase in steric bulk of the ligand along the
series is likely to be the most dominant cause, though donor
ability of the substituent must be a contributing factor since
steric bulk alone does not explain the difference resulting
from substitution of the 2-pyridyl substituent by the more
electron-donating 2-pyrazinyl group.
Enantiomerically pure 2-(2-pyridyl)- and 2-(2-pyrazinyl)-
Quinazolinap derived from the resolved diastereomers were
readily obtained following decomplexation by stirring in
dichloromethane in the presence of 1,2-bis(diphenylphos-
phino)ethane and purification by column chromatography,
Scheme 4.
The application of the palladium complex derived from (S)-
(2-pyridyl)-Quinazolinap resulted in good conversions to
product 15 when dichloromethane was used as solvent,
reaching an optimum of 92% when the BSA method was
employed (Table 2, entry 3). However, the enantioselec-
tivities were low in all cases (13–19% (S)). When
acetonitrile was used, conversions were poor for both the
malonate and BSA procedures but showed a substantial
improvement when 15-crown-5 was added (entry 5 vs entry
4). Again, the enantioselectivities were quite poor with the
4. Pd-catalysed allylic alkylation
The formation of asymmetric carbon–carbon linkages
catalysed by palladium complexes of chiral ligands is a

9814
S. P. Flanagan et al. / Tetrahedron 61 (2005) 9808–9821
Scheme 4.
(R)-product predominating when the conversions were low
(entries 4 and 6). When the reactions were carried out in
THF, the malonate procedure resulted in a yield of 59% and
an ee of 12% (entry 7). The conversion showed an increase
to 84% when 15-crown-5 was added but the opposite
enantiomer of product was obtained (entry 8). When the
BSA method was applied the reaction proceeded much more
slowly, with only an 11% conversion being recorded (entry
9). Poor, if any, enantio-differentiation was also achieved in
DMF (entries 10–12). Again, the conversion was lowest for
the BSA method (11%) but contrary to the results obtained
when dichloromethane, acetonitrile and THF were used, the
addition of 15-crown-5 actually lead to a decrease in the
conversion from 63 to 20% (entries 10 vs 11).
Improved enantioselectivities were obtained when (R)-2-(2-
pyrazinyl)-Quinazolinap was applied, Table 3. When
dichloromethane was employed an increase in conversion
from 15 to 38% was apparent with the addition of 15-crown-
5 (entry 1 vs 2). The conversion was further improved to
72% with the BSA method (entry 3). When acetonitrile or
dimethylformamide were used as solvent, the inclusion of
the additive to increase the solubility of the malonate
nucleophile had a slightly detrimental effect on the yield and
Table 2. Palladium-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate with 2-(2-pyridyl)-Quinazolinap 3a
Entry
Methoda
Solvent
Conv. (%)b
Ee (%)c
1
2
3
4
5
6
7
8
A
Ad
B
A
Ad
B
A
Ad
B
A
Ad
B
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeCN
MeCN
THF
THF
THF
DMF
DMF
DMF
79
89
92
27
82
25
59
84
11
63
20
11
16 (S)
19 (S)
13 (S)
6 (R)
12 (S)
8 (R)
12 (S)
23 (R)
3 (R)
10 (S)
5 (S)
Racemic
9
10
11
12
a Reactions performed at room temperature for 3 days.
1
b Conversions detemined by H NMR.
c Enantiomeric excesses of 15 determined by chiral HPLC.
d 15-crown-5 added.

S. P. Flanagan et al. / Tetrahedron 61 (2005) 9808–9821
9815
Table 3. Palladium-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate with 2-(2-pyrazinyl)-Quinazolinap 3b
Entry
Methoda
Solvent
Conv. (%)b
Ee (%)c
1
2
3
4
5
6
7
8
A
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeCN
MeCN
THF
15
38
72
25
13
52
20
22
8
14 (S)
24 (S)
26 (S)
60 (S)
19 (S)
45 (S)
22 (S)
20 (S)
6 (S)
Ad
B
A
Ad
B
A
Ad
B
THF
THF
9
10
11
12
A
DMF
DMF
DMF
18
15
79
68 (S)
6 (S)
38 (S)
Ad
B
a Reactions performed at room temperature for 3 days.
b Conversions determined by 1H NMR.
c Enantiomeric excesses of 15 determined by chiral HPLC.
d 15-crown-5 added.
also led to a dramatic decrease in the enantioselectivity from
60 to 19% in the case of acetonitrile (entries 4 and 5), and
from 68 to 6% for DMF (entries 10 and 11). On changing to
the BSA method, the conversions obtained in both these
solvents increased, however, the enantioselectivities were
lower with respect to those seen for the malonate procedure
(entries 6 vs 4 and 12 vs 10). The reaction was also carried
out in THF but in all instances the conversions and
enantioselectivities were poor (entries 7–9).
the higher reaction temperature but a slight decrease in
enantioselectivity was apparent (entry 6).
The fact that low enantioselectivities were obtained
using palladium complexes derived from Quinazolinaps
3a and 3b is consistent with the presence of a bulky
substituent in the 2-position of the quinazoline ring.
Low to moderate enantio-differentiation had been
observed in the case of the similarly sized 2-(phenyl)-
Quinazolinap 2e, although the rate of reaction was not
as slow for 2e, with some reactions reaching completion
after a couple of hours.8 Similar reaction times were
recorded for the other members of the Quinazolinap
ligand series, 2a–f, all of which possess alkyl groups as
the 2-substituent.10 Hence, the retardation of reaction
rate seen when ligands 3a and 3b were employed could
possibly be attributed to electronic alterations to the
catalytic complex due to the presence of the electron-
withdrawing 2-pyridyl and 2-pyrazinyl substituents. The
possible hemi-labile nature of these substituents, evident
in the crystal structures obtained in the present study,
Figures 1 and 2, may also be a factor in hindering the
progress and stereochemical outcome of the reaction.
When the reaction temperature was lowered to 0 8C the
yields decreased sharply, although enhanced ees were
achieved with an optimum result for (R)-2-(2-pyrazinyl)-
Quinazolinap of 81% being obtained in acetonitrile
(Table 4, entry 2). Improvements were also seen for the
reaction in DMF, wherein the enantioselectivity rose from
38 to 61% (Table 3, entry 12 vs Table 4, entry 5). In an effort
to increase the conversion, reactions were then carried out at
40 8C (entries 6–8). When acetonitrile was used as solvent
the conversion was greatly enhanced, reaching completion
when the BSA-promoted procedure was employed although
the enantioselectivity remained unchanged. On changing
solvent to DMF, an improved conversion was again seen at
Table 4. Palladium-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate with 2-(2-pyrazinyl)-Quinazolinap 3b
Entry
Method
Solvent
Time (d)
Temperature (8C)
Conv. (%)a
Ee (%)b
1
2
3
4
5
6
7
8
Ac
A
B
A
B
A
A
B
CH2Cl2
MeCN
MeCN
DMF
DMF
DMF
5
5
5
5
5
3
3
3
0
0
0
0
29
25
36
0
18
60
85
100
37 (S)
81 (S)
42 (S)
n/a
61 (S)
61 (S)
75 (S)
45 (S)
0
40
40
40
MeCN
MeCN
a Conversions determined by 1H NMR.
b Enantiomeric excesses of 15 determined by chiral HPLC.
c 15-crown-5 added.

9816
S. P. Flanagan et al. / Tetrahedron 61 (2005) 9808–9821
Also noteworthy in the reactions catalysed by (S)-2-(2-
pyridyl)-Quinazolinap (Table 3), is that, in some
instances the (S)-enantiomer was formed preferentially.
This is the opposite sense of asymmetry to that obtained
by Pd-complexes of the less sterically demanding
members of the Quinazolinap ligand series (2a–c) but
was observed in reactions involving the bulky 2-phenyl
and 2-tert-butyl analogues (2d–e).
purified and dried before use. Diethyl ether and tetrahydro-
furan were distilled from sodium/benzophenone and
dichloromethane was distilled from calcium hydride.
Where necessary other solvents and reagents (purchased
from Aldrich Chemical Co.) used were purified according to
the procedures in ‘Purification of Laboratory Chemicals’.
Pd salts were obtained on loan from Johnson Matthey.
Solvents were degassed using three freeze–thaw cycles.
Oxygen-free nitrogen was obtained from BOC gases. The
following compounds, 2-methoxy-1-naphthylboronic acid,3
(C)-di-m-chlorobis{(R)-dimethyl[1-(1-naphthyl)ethyl]
aminato-C2,N}dipalladium (II),24 1,3-diphenylprop-2-enyl
acetate25 and di-m-chloro-bis(p-allyl)dipalladium26 were
prepared according to literature procedures. For ease of
interpretation of NMR data the following numbering
schemes were used for compounds 5 and 3 and related
compounds are numbered similarly.
In conclusion, two new atropisomeric phosphinamine ligands,
2-(2-pyridyl)-Quinazolinap and 2-(2-pyrazinyl)-Quinazoli-
nap were synthesised and resolved via fractional crystal-
lisation of their diastereomeric palladacycles. These ligands
were applied in the palladium-catalysed asymmetric allylic
alkylation of 1,3-diphenylprop-2-enyl acetate by dimethyl
malonate. Low conversions and enantioselectivities were
obtained with both ligands, possibly due to the hemi-labile
nature of the nitrogen atom of the 2-substituent as revealed in
the X-ray crystal structures of the Pd-bound diastereomers.
Mechanistic studies are currently underway to further investi-
gate both the steric and electronic influences of 2-(2-pyridyl)-
and 2-(2-pyrazinyl)-Quinazolinap on the outcome of the
allylic alkylation reaction.
5. Experimental
5.1. General
Melting points were determined using a Gallenkamp
melting point apparatus and are uncorrected. Infrared
spectra were recorded on a Perkin–Elmer Paragon 1000
Infrared FT spectrometer. The Microanalytical Laboratory,
University College Dublin, performed elemental analyses.
Electron impact mass spectra were determined on a VG
Analytical 770 mass spectrometer with attached INCOS
2400 data system in the EI mode unless otherwise stated.
Electrospray mass spectra were recorded on a Micromass
Quattro with electrospray probe. 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 MHz Varian-Unity
spectrometer and a 500 MHz Varian-Unity spectrometer.
1H–1H COSY spectra were recorded on a 300 MHz Varian-
Unity spectrometer and a 500 MHz Varian-Unity spectro-
meter. Chemical shifts are quoted in ppm relative to
tetramethylsilane and coupling constants (J) are quoted in
Hz. CDCl3 was used as the solvent for all NMR spectra
unless otherwise stated. 75.4 MHz 13C spectra were
recorded on a 300 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 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 aluminium oxide 90,
standardized (activity II–III). Merck precoated Kieselgel
60F254 and alumina (neutral, type E) were used for thin layer
chromatography. HPLC analysis was carried out using a
Chiralcel OD column (0.46 cm 1.d.!25 cm). Optical
rotation values were measured on a Perkin Elmer 241
Polarimeter. All commercially available solvents were
5.1.1. 2-(2-Pyridyl)-4(3H)quinazolinone 5a. 2-Cyanopyri-
dine (7.18 g, 6.64 mL, 68.97 mmol) was added to anhydrous
methanol (20 mL) under an atmosphere of nitrogen. A
solution of sodium metal (0.40 g, 17.40 mmol) in anhydrous
methanol (100 mL) was added via cannula. This was stirred
at room temperature for 1 h. A solution of anthranilic acid
(12.00 g, 87.51 mmol) in dry methanol (125 mL) was added
via cannula and the resulting yellow solution stirred at room
temperature for a further 45 min. The reaction mixture was
then refluxed for 18 h at 85 8C. After cooling to room
temperature and then in an ice bath for 1 h a yellow
precipitate of 2-(2-pyridyl)-4(3H)quinazolinone (11.14 g,
72%) was removed by filtration. On standing overnight, the
mother liquor yielded a yellow needle-like precipitate
(1.73 g, 11%), which was also collected by filtration, mp
169–171 8C (lit.27, mp 168.3–168.4 8C); nmax (KBr) 3339
(N–H), 1682 (C]O), 1616 (C]C), 1471 (Ar-H), 1329
(C]N) and 737 (Ar-H) cmK1
;
1H NMR (300 MHz): d
0
(CDCl3) 10.94 (br s, 1H, NH), 8.67 (d, 1H, JZ4.8 Hz, H6 ),
0
8.59 (d, 1H, JZ8.1 Hz, H3 ), 8.36 (dd, 1H, J1Z7.2 Hz, J2Z
1.6 Hz, H5), 7.92 (dt, J1Z8.1 Hz, J2Z1.6 Hz, H7), 7.80 (m,
0
0
2H, H4 , H8) and 7.50 (m, 2H, H7, H5 ); Found: C, 69.64; H,
3.96; N, 19.05. C13H9N3O requires C, 69.94; H, 4.06; N,
18.82%.
2-(2-Pyrazinyl)-4(3H)quinazolinone 5b was prepared from
pyrazinecarbonitrile on a similar scale and in a similar
manner and was obtained in 97% yield as a yellow solid, mp
218–220 8C; nmax (KBr) 3040 (N–H), 1697 (C]O), 1603
(C]C), 1472 (Ar-H) and 766 (Ar-H) cmK1 1H NMR
;
(300 MHz): d (CDCl3) 10.63 (br s, 1H, NH), 9.82 (d, 1H,
0
0
JZ1.3 Hz, H3 ), 8.79 (d, 1H, JZ2.5 Hz, H5 ), 8.65 (d, 1H,
0
JZ1.9 Hz, H6 ), 8.36 (d, 1H, JZ7.9 Hz, H5), 7.85 (m, 2H,

S. P. Flanagan et al. / Tetrahedron 61 (2005) 9808–9821
9817
H7, H8) and 7.56 (dt, 1H, J1Z8.1 Hz, J2Z1.8 Hz, H6); 13
C
turn green followed by the formation of a white precipitate.
The mixture was refluxed at 95 8C for 4 days. The solution
was cooled to room temperature and filtered. The solid was
washed with dichloromethane and the filtrate reduced in
vacuo to give a purple residue, which was redissolved in
dichloromethane (100 mL), washed with brine (3!50 mL),
dried over magnesium sulfate and the solvent removed in
vacuo yielding a dark orange solid. 2-(2-Pyridyl)-4-(2-
methoxynaphthalen-1-yl)-quinazoline (7.81 g, 77%) was
isolated via column chromatography (aluminium oxide,
2:1 petrol ether–ethyl acetate), mp 204–206 8C; nmax (KBr)
3056 (Ar-H), 1622 (C]N), 1582 (C]C), 1511 (Ar-H),
NMR (75 MHz): d (CDCl3) 161.1, 148.7, 147.3, 146.9,
144.3, 143.8, 142.9, 134.9, 128.3, 128.0, 126.8, 122.6;
Found: C, 63.95; H, 3.44; N, 24.85. C12H8N4O requires C,
64.28; H, 3.60; N, 24.99%.
5.1.2. 2-(2-Pyridyl)-4-chloroquinazolinone 6a. N,N-
Diethylaniline (4.09 g, 4.39 mL, 27.61 mmol) was added
via syringe to 2-(2-pyridyl)-4(3H)quinazolinone (4.11 g,
18.41 mmol) in anhydrous benzene (85 mL). This was
heated for 5 min at 100 8C to remove water. Phosphorus
oxychloride (2.22 g, 1.33 mL, 14.53 mmol) was added via
syringe and the resulting deep red solution was refluxed for
4 h at 90 8C after, which time additional phosphorus
oxychloride (0.44 g, 0.27 mL, 3.20 mmol) was added. The
solution was refluxed for a further 2 h, allowed to cool then
washed with iced water (40 mL). The organic layer was then
washed sequentially with 20% NaOH (2!30 mL), iced
water (30 mL) and brine (30 mL) and dried over anhydrous
sodium sulfate. The organic solvent was removed in vacuo
and the residue was purified by column chromatography
(aluminium oxide, cyclohexane until the N,N-diethylaniline
eluted, then 2:1 cyclohexane–ethyl acetate) to give 2-(2-
pyridyl)-4-chloroquinazoline (4.45 g, 68%) as a pale yellow
powder. The aqueous layers were combined and extracted
with dichloromethane. The organic layer was reduced in
vacuo to yield a yellow oil, which was purified by column
chromatography as above, providing further product to give
a total yield of 3.33 g (77%). Mp 120–121 8C (lit.28, mp
119.7–122.4 8C); nmax (KBr) 3068 (Ar-H), 2922 (Ar-H),
1546 (C]C), 1483 (Ar-H), 1342 (C–N) and 779 (C–Cl)
1
1341 (C–O), 1249 (C–O) and 789 (Ar-H) cmK1; H NMR
00
(500 MHz): d (CDCl3) 8.92 (d, 1H, JZ4.5 Hz, H6 ), 8.68 (d,
00
0
1H, JZ8.1 Hz, H3 ), 8.40 (d, 1H, JZ8.4 Hz, H5 ), 8.05 (d,
0
1H, JZ9.1 Hz, H4), 7.89 (m, 2H, H7 , H5), 7.81 (dt, 1H, J1Z
7.4 Hz, J2Z1.6 Hz, H4 ), 7.52 (d, 1H, JZ8.4 Hz, H7), 7.44
00
0
00
0
(m, 2H, H3, H8 ), 7.36 (m, 2H, H5 , H6 ), 7.28 (dt, 1H, J1Z
8.7 Hz, J2Z1.6 Hz, H6), 7.18 (d, 1H, JZ8.4 Hz, H8) and
3.77 (s, 3H, OCH3); 13C NMR (75 MHz): d (CDCl3) 168.1,
160.1, 155.9, 155.0, 151.5, 150.5, 137.0, 134.1, 133.4,
131.5, 129.9, 129.3, 128.3, 128.0, 127.4, 127.2, 124.9,
124.9, 124.7, 124.7, 124.2, 120.2, 113.6, 56.8; Found: C,
79.06; H, 4.77; N, 11.49. C24H17N3O requires C, 79.32; H,
4.72; N, 11.56%.
Similarly, 2-(2-pyrazinyl)-4-(2-methoxynaphthalen-1-yl)-
quinazoline 8b was prepared by the coupling of 2-(2-
pyrazinyl)-4-chloroquinazoline with 2-methoxy-1-naphthyl-
boronic acid in a 78% yield, mp 202–204 8C; nmax (KBr)
3080 (Ar-H), 2936 (Ar-H), 1620 (C]N), 1541 (C]C),
1512 (Ar-H), 1272 (C–O) and 758 (Ar-H) cmK1; 1H NMR
1
cmK1; H NMR (300 MHz): d (CDCl3) 8.92 (d, 1H, JZ
00
(300 MHz): d (CDCl3) 9.90 (s, 1H, H3 ), 8.85 (deform. T.,
0
0
4.7 Hz, H6 ), 8.68 (d, 1H, JZ7.8 Hz, H3 ), 8.31 (m, 2H, H8,
H5), 7.99 (dt, 1H, J1Z8.5 Hz, J2Z1.5 Hz, H7), 7.91 (dt, 1H,
00
00
1H, JZ1.5 Hz, H5 ), 8.69 (d, 1H, JZ2.3 Hz, H6 ), 8.39 (d,
0
0
1H, JZ8.5 Hz, H8 ), 8.08 (d, 1H, JZ9.1 Hz, H4), 7.93 (m,
J1Z7.9 Hz, J2Z1.8 Hz, H4 ), 7.75 (t, 1H, JZ8.1 Hz, H6)
and 7.45 (m, 1H, H5 ); 13C NMR (75 MHz): d (CDCl3)
0
0
0
2H, H7 , H6), 7.57 (d, 1H, JZ7.6 Hz, H5 ), 7.51 (d, 1H, JZ
6.6 Hz, H6 ), 7.46 (d, 1H, JZ8.9 Hz, H3), 7.33 (m, 2H, H5,
0
163.1, 158.8, 153.9, 151.8, 150.4, 137.1, 135.1, 129.6,
129.1, 125.8, 125.2, 124.4 and 123.0.
H7), 7.16 (d, 1H, JZ8.3 Hz, H8) and 3.80 (s, 3H, OCH3);
13C NMR (75 MHz): d (CDCl3) 186.4, 158.7, 154.8, 151.2,
151.0, 146.3, 145.2, 144.6, 134.4, 133.1, 131.5, 129.6,
129.0, 128.4, 128.2, 127.4, 127.2, 125.0, 124.3, 124.0,
119.5, 113.3, 56.6; Found: C, 75.51; H, 4.49; N, 15.19.
C23H16N4O requires C, 75.81; H, 4.43; N, 15.38%.
2-(2-Pyrazinyl)-4-chloroquinazoline 6b was similarly pre-
pared in 56% yield as a yellow solid, mp 178–180 8C; nmax
(KBr) 2928 (Ar-H), 1549 (C]C), 1486 (Ar-H), 1342
1
(C]N) and 758 (C–Cl) cmK1; H NMR (300 MHz): d
0
(CDCl3) 9.87 (s, 1H, H3 ), 8.86 (dd, J1Z2.5 Hz, J2Z1.5 Hz,
0
0
1H, H5 ), 8.74 (d, JZ2.5 Hz, 1H, H6 ), 8.35 (d, 1H, JZ
7.6 Hz, H5), 8.29 (d, 1H, JZ8.1 Hz, H8), 8.03 (dt, 1H,
J1Z6.9 Hz, J2Z1.5 Hz, H7) and 7.80 (dt, 1H, J1Z8.3 Hz,
J2Z1.2 Hz, H6); 13C NMR (75 MHz): d (CDCl3) 163.5,
157.8, 151.6, 149.3, 145.9, 145.8, 144.7, 135.5, 129.7,
129.6, 126.0 and 122.7; Found: C, 59.71; H, 2.72; N, 14.66,
Cl, 22.89. C12H7N4Cl requires C, 59.39; H, 2.91; N, 14.61, Cl,
23.09%.
5.1.4. 1-[2-(2-Pyridyl)-quinazolin-4-yl]-2-hydroxy-
naphthalene 9a. 2-(2-Pyridyl)-4-(2-methoxynaphthalen-1-
yl)-quinazoline (1.02 g, 2.81 mmol) and aluminium chlor-
ide (2.24 g, 16.80 mmol) were refluxed in anhydrous
benzene (110 mL) under a nitrogen atmosphere for 3 h.
The dark purple mixture was allowed to cool and the pH was
adjusted to 4 using 10% HCl. The resulting fine orange
precipitate formed was filtered through sintered glass to
yield 1-[2-(2-pyridyl)-quinazolin-4-yl]-2-hydroxynaphtha-
1
lene (0.48 g, 48%). Tdec 226 8C; H NMR (300 MHz): d
00
5.1.3. 2-(2-Pyridyl)-4-(2-methoxynaphthalen-1-yl)-quina-
zoline 8a. 2-(2-Pyridyl)-4-chloroquinazoline (6.68 g,
27.64 mmol) and tetrakis(triphenylphosphine)palladium
(0) (1.10 g, 0.96 mmol) were dissolved in anhydrous,
degassed DME (65 mL) in a Schlenk tube under nitrogen
and stirred for 1 h to give a yellow solution. 2-Methoxy-1-
naphthylboronic acid (5.75 g, 28.46 mmol), in the minimum
amount of degassed ethanol (18 mL) was added via syringe
resulting in a dark purple solution. Sodium carbonate
solution (28.4 mL, 2 M) was added causing the solution to
(CDCl3) 8.92 (d, 1H, JZ4.7 Hz, H6 ), 8.72 (d, 1H, JZ
00
00
8.2 Hz, H5 ), 8.33 (d, 1H, JZ8.2 Hz, H4 ), 8.00–7.91 (m,
3H), 7.86 (d, 1H, JZ7.8 Hz), 7.66 (d, 1H, JZ7.8 Hz), 7.51–
7.43 (m, 2H), 7.41 (d, 1H, JZ8.9 Hz and 7.38–7.32) (m,
3H); m/z (HRMS, ES) found: 350.1306; C23H16N3O
requires 350.1293.
5.1.5. 1-[2-(2-Pyrazinyl)-quinazolin-4-yl]-2-hydroxy-
naphthalene 9b. Sodium ethanethiolate (2.41 g, 28.6 mmol)

9818
S. P. Flanagan et al. / Tetrahedron 61 (2005) 9808–9821
was added to a solution of 2-(2-pyrazinyl)-4-(2-methoxy-
naphthalen-1-yl)-quinazoline (4.70 g, 12.90 mmol) in
degassed DMF (80 mL) and the red solution refluxed at
120 8C for 3.5 h. After cooling to room temperature, the pH
was adjusted to 5 using 10% HCl (3 mL), which caused the
solution to turn orange in colour. The solution was allowed
to stir for 10 min and a yellow precipitate formed. This was
filtered through sintered glass to yield 1-[2-(2-pyrazinyl)-
quinazolin-4-yl]-2-hydroxynaphthalene (3.01 g, 66%) as a
bright yellow powder. The filtrate was extracted into
dichloromethane (100 mL). The organic layer was washed
with water (4!100 mL), dried over sodium sulfate and the
solvent removed in vacuo giving a dull yellow solid.
Recrystallisation of this solid from hot dichloromethane
furnished a further 0.80 g of the desired naphthol resulting
in a combined yield of 84%. Tdec 250 8C; nmax (KBr), 3732
(OH), 3060 (Ar-H), 1563 (Ar-H), 1494 (OH), 1341 (C]N),
dissolved in dry dichloromethane (40 mL) to give a bright
yellow solution. Trifluoromethanesulfonic anhydride
(1.53 g, 0.91 mL, 7.28 mmol) was added and the orange
solution stirred at room temperature for 48 h under nitrogen.
A white precipitate formed, which was removed by
filtration. The solid was washed with dichloromethane and
the combined filtrates were reduced in vacuo to give a
yellow solid. This was purified by column chromatography
(aluminium oxide, 2:1 pentane–ethyl acetate) to yield 1-[2-
(2-pyrazinyl)-quinazolin-4-yl]-2-naphthyltrifluoromethyl-
sulfonate (1.24 g, 71%) as a white solid, mp 160–162 8C;
nmax (KBr) 3070 (Ar-H), 1512 (C]C), 1427 (–SO3–), 1343
(C]N), 1218 (–SO3–), 1142 (C–O) and 831 (Ar-H) cmK1
;
H NMR (300 MHz): d (CDCl3) 9.91 (s, 1H, H3 ), 8.87 (app
1
00
00
00
t, 1H, JZ1.6 Hz, H5 ), 8.72 (d, 1H, JZ2.3 Hz, H6 ), 8.45 (d,
0
1H, JZ8.5 Hz, H8 ), 8.19 (d, 1H, JZ9.1 Hz, H4), 8.05 (d,
1H, JZ7.6 Hz, H5), 8.00 (dt, 1H, J1Z7.0 Hz, J2Z1.5 Hz,
1
1210 (C–O), 763 (Ar-H) cmK1; H NMR (300 MHz): d
H7 ), 7.65 (d, 1H, JZ9.1 Hz, H3), 7.54 (m, 4H, H5 , H6 , H6,
H7) and 7.31 (d, 1H, JZ8.3 Hz, H8); 13C NMR (75 MHz): d
(CDCl3) 164.2, 158.1, 151.4, 150.3, 146.3, 145.6, 144.8,
144.7, 135.1, 132.4, 132.3, 123.0, 129.1, 128.5, 128.5,
127.6, 126.6, 126.1, 124.3 and 119.6; Found: C, 57.05; H,
2.91; N, 11.32; S, 6.95; F, 11.72. C23H13N4SF3O3 requires
C, 57.26; H, 2.72; N, 11.61; S 6.65; F, 11.81%.
0
0
0
00
(CDCl3) 9.84 (s, 1H, H3 ), 9.31 (br s, 1H, OH), 8.66 (m, 2H,
00
00
0
H5 , H6 ), 8.26 (d, 1H, JZ8.5 Hz, H8 ), 7.93 (dt, 1H, J1Z
0
6.8 Hz, J2Z1.5 Hz, H7 ), 7.85 (d, 2H, JZ9.0 Hz, H4, H5),
7.68 (d, 1H, JZ8.2 Hz, H5 ), 7.48 (dt, 1H, J1Z6.8 Hz, J2Z
0
0
1.2 Hz, H6 ), 7.36 (dt, 1H, J1Z6.6 Hz, J2Z1.5 Hz, H6) and
7.25 (m, 3H, H3, H7, H8); 13C NMR (75 MHz): d (CDCl3)
167.7, 157.2, 154.1, 151.6, 150.0, 145.6, 145.5, 144.2,
134.8, 132.8, 132.1, 129.6, 128.7, 128.4, 128.3, 128.0,
127.4, 126.9, 124.4, 124.2, 123.6, 119.4 and 115.3; Found:
C, 74.93; H, 4.13; N, 15.51. C22H14N4O requires C, 75.41;
H, 4.03; N, 15.99%.
5.1.8. (R,S)-2-Diphenylphosphino-1-[2-(2-pyridylquina-
zolin-4)-yl]naphthalene 3a. 1-[2-(2-Pyridyl)quinazolin-4-
yl]-2-naphthyltrifluoromethylsulfonate (2.66 g, 5.54 mmol),
palladium acetate (0.12 g, 0.55 mmol) and triphenylphos-
phine (3.34 g, 12.74 mmol) were dissolved under a nitrogen
atmosphere in degassed DMF (24 mL). The yellow solution
was heated at 115 8C causing it to turn red in colour. The
solution was maintained at this temperature, under an
atmosphere of nitrogen, for 6 days. The solvent was
removed in vacuo. The residue was purified by column
chromatography (aluminium oxide, 2:1 petroleum ether–
ethyl acetate) to furnish (R,S)-2-diphenylphosphino-1-[2-(2-
pyridylquinazolin-4)-yl]naphthalene (1.68 g, 59%) as a
white solid, mp 216–218 8C; nmax (KBr) 3053 (Ar-H),
2921 (Ar-H), 1613 (Ar-H), 1542 (Ph), 1491 (Ph), 1340
5.1.6. 1-[2-(2-Pyridyl)quinazolin-4-yl]-2-naphthyltri-
fluoromethylsulfonate 10a. 1-[2-(2-Pyridyl)-quinazolin-4-
yl]-2-hydroxynaphthalene (0.38 g, 1.10 mmol) and
4-dimethylaminopyridine (0.34 g, 2.75 mmol) were dis-
solved in dry dichloromethane (20 mL). Trifluoromethane-
sulfonic anhydride (0.66 g, 0.4 mL, 2.37 mmol) was added
and the solution stirred for 20 h under nitrogen. A white
precipitate formed, which was removed by filtration. The
solid was washed with dichloromethane and the combined
filtrates were reduced in vacuo to give a yellow solid. This
was purified by column chromatography (aluminium oxide,
2:1 petrol ether–ethyl acetate) to yield 1-[2-(2-pridyl)-
quinazolin-4-yl]-2-naphthyltrifluoromethylsulfonate (0.47 g,
78%) as a white solid, mp 176–177 8C; nmax (KBr) 2929
(Ar-H), 1544 (Ar-H), 1405 (–SO3–), 1219 (–SO3–), 1135
(C]N) and 744 (Ar-H) cmK1
;
1H NMR (300 MHz): d
00
(CDCl3) 8.86 (d, 1H, JZ4.6 Hz, H6 ), 8.44 (d, 1H, JZ
00
8.6 Hz, H3 ), 7.97–7.87 (m, 3H), 7.75 (d, 1H, JZ7.7 Hz),
7.56–7.48 (m, 2H), 7.43–7.37 (m, 3H) and 7.34–7.10 (m,
14H); 13C NMR (75 MHz): d (CDCl3) 169.4, 161.2, 155.2,
151.3, 150.1, 141.8, 141.5, 136.7, 134.6, 134.0, 133.9,
133.7, 133.6, 133.4, 131.8, 129.9, 129.3, 128.5, 128.4,
128.3, 128.1, 127.9, 127.0, 126.8, 126.2, 124.7 and 124.4;
31P NMR (121 MHz): d (CDCl3) K12.23 ppm. m/z (HRMS,
ES) 518.1808 C35H25N3P cation.
(C–O) and 828 (Ar-H) cmK1
;
1H NMR (300 MHz): d
00
(CDCl3) 8.94 (d, 1H, JZ3.8 Hz, H6 ), 8.70 (d, 1H, JZ
00
0
7.9 Hz, H3 ), 8.46 (d, 1H, JZ8.6 Hz, H8 ), 8.17 (d, 1H,
JZ9.1 Hz, H4), 8.03 (d, 1H, JZ8.3 Hz, H5), 7.97 (dt, 1H,
0
J1Z6.7 Hz, J2Z1.6 Hz, H7 ), 7.86 (dt, 1H, J1Z7.5 Hz, J2Z
1.8 Hz, H4 ), 7.64 (d, 1H, JZ9.1 Hz, H3), 7.60 (dt, 1H, J1Z
00
0
0
00
6.8 Hz, J2Z1.3 Hz, H6), 7.47 (m, 4H, H6 , H5 , H7, H5 ) and
7.31 (d, 1H, JZ7.5 Hz, H8); 13C NMR (75 MHz): d (CDCl3)
163.8, 159.7, 155.0, 151.6, 150.4, 144.8, 137.1, 134.7,
132.5, 132.4, 132.1, 130.1, 128.5, 128.5, 128.4, 127.5,
127.3, 126.3, 126.2, 124.9, 124.8, 124.0, 119.6; Found: C,
59.58; H, 2.83; N, 8.54; S, 6.76; F, 11.39. C24H14N3SF3O3
requires C, 59.87; H, 2.93; N, 8.73; S, 6.66; F, 11.84%.
(R,S)-2-Diphenylphosphino-1-[2-(2-pyrazinylquinazolin-
4)-yl]naphthalene 3b was prepared in an analogous fashion
via phosphinylation of 1-[2-(2-pyrazinyl)quinazolin-4-yl]-
2-naphthyltrifluoromethylsulfonate in a 53% yield after
column chromatography on aluminium oxide. Mp 220–
222 8C; nmax (KBr) 3050 (Ar-H), 2904 (Ar-H), 1612 (Ar-H),
1564 (Ph), 1546 (Ph), 1340 (C]N) and 744 (Ar-H) cmK1
;
1H NMR (300 MHz): d (CDCl3) 9.02 (d, JZ1.4 Hz, 1H,
00
00
5.1.7. 1-[2-(2-Pyrazinyl)quinazolin-4-yl]-2-naphthyltri-
fluoromethylsulfonate 10b. 1-[2-(2-Pyrazinyl)-quinazolin-
4-yl]-2-hydroxynaphthalene (1.28 g, 3.64 mmol) and
4-dimethylaminopyridine (1.30 g, 10.81 mmol) were
H3 ), 8.79 (d, JZ2.3 Hz, 1H, H5 ), 8.61 (d, JZ2.5 Hz, 1H,
00
0
H6 ), 8.42 (d, JZ8.1 Hz, 1H, H8 ), 7.99–7.91 (m, 3H, Ar-H)
and 7.55–7.10 (m, 16H, Ar-H); 13C NMR (75 MHz): d
(CDCl3) 170.0, 157.7, 151.2, 150.5, 146.2, 145.2, 144.4,

S. P. Flanagan et al. / Tetrahedron 61 (2005) 9808–9821
9819
141.4, 141.0, 136.9, 136.3, 134.8, 134.4, 133.8, 133.5,
132.2–131.9, 130.0, 129.4, 128.7–128.2, 127.1, 127.0,
126.0, 125.5, and 124.7; 31P NMR (121 MHz): d (CDCl3)
K13.20 ppm; m/z (HRMS, ES) 519.1754 C34H24N4P
cation.
123.9, 123.5, 123.0, 72.8 (CH(Me)), 50.6 (NMe), 48.6
(NMe) and 23.5 (CH(Me)); 31P NMR (121 MHz): d
(CDCl3) 27.61 ppm; C89 (c 0.69, CHCl3), m/z (HRMS,
ES) found: 823.2048; C48H40N5PPd requires 823.2056.
To the orange filtrate, was added aqueous potassium
hexafluorophosphate and the yellow suspension was stirred
at room temperature for 18 h. Water (50 mL) was added and
stirring continued for 1 h. The orange solid was filtered off,
dissolved in hot butanone and diethyl ether was added until
a light suspension formed. The suspension was left to stand
overnight, then filtered. The mother liquor was reduced in
vacuo to yield (S,R)-14 as a bright orange solid, (0.97 g,
56%), mp 230–232 8C; nmax (KBr) 3056 (Ar-H), 2868 (Ar-
H), 1562 (C]C), 1437 (P-Ph), 1098 (Ar-H) and 842 (P–F)
5.1.9. Resolution of (R,S)-2-diphenylphosphino-1-[2-(2-
pyridylquinazolin-4)-yl]naphthalene. (R,S)-2-Diphenyl-
phosphino-1-[2-(2-pyridylquinazolin-4)-yl]naphthalene
(1.67 g, 3.2 mmol) and (C)-di-m-chlorobis{(R)-dimethyl[1-
(1-naphthyl)ethyl]aminato-C2,N}dipalladium (II) (1.10 g,
1.62 mmol) were dissolved in dry, degassed methanol
(110 mL) under an atmosphere of nitrogen and stirred for
18 h. Aqueous potassium hexafluorophosphate (0.65 g,
110 mL water) was added causing a yellow suspension to
form. This was stirred for 1 h and water was added (100 mL)
and stirring continued for a further 3 h. The mixture was
filtered to give an orange solid (2.61 g, 84%). The solid was
dissolved in hot butanone and diethyl ethyl until a light
suspension had formed. After standing overnight the
mixture was filtered and the mother liquor was concentrated
in vacuo to yield (S,R)-12 as a bright orange solid, (1.86 g,
60%). Tdec 200 8C; nmax (KBr) 3060 (Ar-H), 1569 (C]C),
1
cmK1; H NMR (300 MHz): d (CDCl3) 10.06 (d, 1H, JZ
00
00
00
2.0 Hz, H3 ), 8.87 (s, 1H, H6 ), 8.45 (s, 1H, H5 ), 8.17 (d,
1H, JZ8.4 Hz), 8.09–7.97 (m, 3H), 7.75–7.63 (m, 3H),
7.52–6.83 (m, 19H), 4.12 (q, 1H, JZ6.0 Hz, CH(Me)), 2.13
(s, 3H, NMe), 1.97 (s, 3H, NMe) and 1.26 (d, 3H, JZ
3.7 Hz, CH(Me)); 13C NMR (75 MHz): d (CDCl3) 166.4,
154.9, 151.4, 150.0, 149.1, 148.2, 149.1, 148.2, 147.6,
147.0, 142.1, 137.0, 135.1, 133.2, 132.7, 132.3, 132.3,
132.0, 131.4, 130.7, 129.4, 129.1, 128.9, 128.8, 128.7,
128.1, 126.7, 126.5, 126.4, 126.0, 125.3, 124.8, 124.5,
123.2, 123.0, 122.3, 72.2 (CH(Me)), 51.3 (NMe), 47.4
(NMe) and 20.8 CH(Me)); 31P NMR (121 MHz): d (CDCl3)
28.97 ppm; K249 (c 0.74, CHCl3), m/z (HRMS, ES) found:
822.2018; C48H39N5PPd requires 822.1978.
1
1438 (P-Ph), 1098 (Ar-H) and 841 (P-F) cmK1; H NMR
00
(300 MHz): d (CDCl3) 8.89 (d, 1H, JZ8.0 Hz, H6 ), 8.44 (d,
00
1H, JZ4.3 Hz, H3 ), 8.25 (dt, 1H, J1Z8.0 Hz, J2Z1.8 Hz,
00
H5 ), 8.07–7.93 (m, 3H), 7.74 (d, 1H, JZ7.6 Hz), 7.66 (t,
1H, JZ7.3 Hz), 7.59–6.82 (m, 22H), 4.10 (q, 1H, JZ
6.0 Hz, CH(Me)), 2.06 (s, 3H, NMe), 1.90 (s, 3H, NMe) and
1.26 (d, 1H, JZ6.5 Hz, CH(Me)); 13C NMR (75 MHz): d
(CDCl3) 165.8, 156.6, 153.9, 152.0, 150.1, 148.8, 147.8,
138.9, 136.7, 135.2, 135.0, 133.1, 132.7, 132.6, 132.6,
131.7, 131.2, 130.1, 129.2, 129.1, 128.9, 128.8, 128.6,
128.4, 128.1, 126.6, 126.5, 126.3, 125.9, 125.1, 124.6,
124.3, 122.9, 71.7 (CH(Me)), 51.2 (NMe), 47.3 (NMe) and
20.5 (CH(Me)); 31P NMR (121 MHz): d (CDCl3)
27.61 ppm; K324 (c 0.58, CHCl3), m/z (HRMS, ES)
found: 822.2116; C49H40N4PPd requires 822.2104.
5.1.11. (S)-2-Diphenylphosphino-1-[2-(2-pyridylquina-
zolin-4)-yl]naphthalene. Compound (S,R)-12 (0.62 g,
0.65 mmol) and 1,2-bis(diphenylphosphino)ethane
(0.257 g, 0.65 mmol) were dissolved in dichloromethane
under an atmosphere of nitrogen and stirred at room
temperature for 2 h. The solvent was almost all reduced in
vacuo to a yellow oil, which was purified using a short
aluminium oxide column (pentane–ethyl acetate 2:1) to give
(S)-diphenylphosphino-1-[2-(2-pyridylquinazolin-4)-yl]
naphthalene as a white solid (0.29 g, 85%), C319 (c 0.3,
CHCl3), and identical in all other respects to the racemic
diphenyl phosphine.
5.1.10. Resolution of (R,S)-2-diphenylphosphino-1-[2-(2-
pyrazinylquinazolin-4)-yl]naphthalene. (R,S)-2-Diphenyl-
phosphino-1-[2-(2-pyrazinylquinazolin-4)-yl]naphthalene
(0.94 g, 1.8 mmol) and (C)-di-m-chlorobis{(R)-dimethyl[1-
(1-naphthyl)ethyl]aminato-C2,N}dipalladium (II) (0.61 g,
0.9 mmol) were dissolved in dry, degassed methanol
(42 mL) under an atmosphere of nitrogen and stirred at
60 8C for 20 h. A white precipitate had formed by this time,
which was removed by filtration and washed with a small
amount of cold methanol to give (R,R)-13 (0.49 g, 28%).
Tdec 240 8C; nmax (KBr) 3057 (Ar-H), 2919, (Ar-H), 1569
(C]C), 1545 (C]C), 1434 (P-Ph), 1098 (Ar-H) and 747
(Ar-H) cmK1; 1H NMR (300 MHz): d (CDCl3) 9.65 (s, 1H,
(R)-diphenylphosphino-1-[2-(2-pyrazinylquinazolin-4)-yl]
naphthalene was similarly isolated from (R,R)-13as a white
solid in a 95% yield, C8.0 (c 0.55, CHCl3), and identical in
all other respects to the previously prepared racemic sample.
5.1.12. Allylic alkylation procedures. Method A. (S)-2-(2-
pyridyl)- or (R)-2-(2-pyrazinyl)-Quinazolinap (0.006 mmol)
and di-m-chloro-bis(p-allyl)dipalladium (0.0025 mmol)
were placed in a Schlenk tube under an atmosphere of
nitrogen. Dry, degassed solvent was added (0.3 mL) and the
mixture stirred for 10 min. To this was added a solution of
1,3-diphenylprop-2-enyl acetate (0.063 g, 0.250 mmol) in
dry, degassed solvent (0.2 mL). The suspension was stirred
for 10 min and then sodium dimethyl malonate (0.042 g,
0.275 mmol) was added and also, if required, 15-crown-5
(55 mL, 0.275 mmol). Reaction progress was monitored by
TLC (pentane–diethyl ether 2:1). The reactions were stirred
at room temperature for 3 days, or at 0 8C for 5 days, before
being quenched by the addition of acetic acid (0.1 mL). The
solvent was reduced in vacuo and water (25 mL) was added.
00
00
H3 ), 8.82 (d, 1H, JZ2.3 Hz, H6 ), 8.71 (d, 1H, JZ2.3 Hz,
00
H5 ), 8.18–8.08 (m, 3H), 7.97–7.79 (m, 5H), 7.57–7.40 (m,
6H), 7.31–7.16 (m, 8H), 6.95 (appt, 2H), 6.70 (d, 1H, JZ
8.7 Hz), 6.19 (d, 1H, JZ8.2 Hz), 5.93 (t, 1H, JZ6.1 Hz)
4.12 (q, 1H, JZ5.6 Hz, CH(Me)), 2.83 (s, 3H, NMe), 1.93
(d, 3H, JZ6.1 Hz, CH(Me)) and 1.63 (s, 1H, NMe); 13C
NMR (75 MHz): d (CDCl3) 168.9, 164.5, 157.4, 150.9,
150.7, 148.8, 148.1, 146.0, 145.2, 144.6, 138.2, 138.1,
135.7, 135.6, 153.4, 134.4, 133.4, 132.3, 132.3, 131.1,
130.6, 130.4, 130.3, 128.9, 128.7, 128.6, 128.4, 128.3,
128.1, 128.0, 127.3, 127.2, 127.0, 126.2, 125.4, 125.2,

9820
S. P. Flanagan et al. / Tetrahedron 61 (2005) 9808–9821
The reaction mixture was extracted into diethyl ether
(25 mL), washed with water (25 mL) then brine (25 mL),
dried over MgSO4, filtered and the solvent removed in
vacuo to give a yellow oil. The % conversion was calculated
using 1H NMR of the crude product. The product was
purified on preparative silica plates (pentane–diethyl ether
2:1) to afford (R)- or (S)-methyl-2-carbomethoxy-3,5-
diphenylpent-4-enoate 15 as a colourless oil.20 1H NMR
(300 MHz): d (CDCl3) 7.34–7.20 (10H, m, Ar-H), 6.47 (1H,
d, JZ15.82 Hz, H3), 6.34 (1H, dd, JZ15.82, 8.35, H2), 4.27
(1H, dd, JZ10.84, 8.49 Hz, H1), 3.95 (1H, d, JZ10.84 Hz,
CH(CO2Me)2), 3.70 (3H, s, OMe) and 3.52 (3H, s, OMe).
The enantiomeric excess was determined by chiral HPLC
[Daicel (Chiracel OD) column, 0.46 cm I.D.!25 cm],
pentane–isopropanol 99:1, 0.3 mL/min, RtZ(R)K42 min,
(S)K45 min.
and 14940 independent reflections (RintZ0.038), 14207
with IO2s(I), qmaxZ30.998, TminZ0.956, TmaxZ0.989,
direct methods (SHELXSK97) and least-squares refinement
(SHELXL-97) on F2o, both programs from G. Sheldrick,
¨
University of Gottingen, 1997; 631 parameters, Flack para-
meter K0.03(1), the diethylether solute is disordered over
two positions, H atoms riding except for the solute where
they are absent, Chebyshev type weights, R1Z0.0259
(IO2s(I)), wR2Z0.0615 (all data), Drmax/minZ0.440/
K0.376 e AK3. CCDC 265943.1
˚
Data for the crystal structures of (S,R)-12$1.5(CH2Cl2) and
(S,R)-14$C4H10O can be obtained free of charge on
quotation of the CCDC deposition numbers 265942 and
265943 via www.ccdc.cam.ac.uk/conts/retrieving.html (or)
from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: C44 1223-
336-033; or e-mail: deposit@ccdc.cam.ax.uk.
Method B. (S)-2-(2-pyridyl)- or (R)-2-(2-pyrazinyl)-Quina-
zolinap (0.006 mmol) and di-m-chloro-bis(p-allyl)dipalla-
dium (0.0025 mmol) were placed in a Schlenk tube under
an atmosphere of nitrogen. Dry, degassed solvent was
added (0.3 mL) and the mixture stirred for 10 min. To this
was added a solution of 1,3-diphenylprop-2-enyl acetate
(0.063 g, 0.250 mmol) in dry, degassed solvent (0.2 mL).
Potassium acetate (0.005 mmol) was added and the
suspension was stirred for 10 min. Dimethyl malonate
(31.5 mL, 0.275 mmol) and N,O-bis(trimethylsilyl)aceta-
mide (BSA) (68 mL, 0.275 mmol) were added and the
reactions stirred at room temperature for 3 days, or 0 8C for
5 days. The work-up and determination of conversion and
enantioselectivity were the same as described for method A.
Acknowledgements
We wish to thank Enterprise Ireland for a Research
Scholarship (BR/2000/168) awarded to SF to support this
work.
References and notes
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[PF6]K$1.5(CH2Cl2), from dichloromethane/dietheylether,
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˚
˚
˚
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˚
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100 K, monoclinic, space group C 2 (No. 5), ZZ4,
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˚
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˚
aZ8.9132(1) A, bZ22.5067(3) A, cZ12.0303(1) A, bZ
3
˚
103.079(1)8, VZ2350.75(5) A , TZ100 K, monoclinic,
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