Synthesis, resolution, and application of cyclobutyl- and adamantyl-quinazolinap ligands

Article abstract of DOI:10.1002/ejoc.200800650

An expedient, seven-step synthesis of two new members of the Quinazolinap ligand family, 2-cyclobutyl- and 2-(1-adamantyl)-Quinazolinaps, has been developed. The racemic ligands have been efficiently resolved by fractional crystallization of their diastereomeric palladacycle complexes. The enantioenriched ligands provide good levels of enantioselection (ee's up to 89%) in a prototypical Pd^II-catalyzed allylic alkylation reaction. 2-Cyclobutyl-Quinazolinap has been further functionalized at the 2-position via metalation with a superbase followed by reaction with a range of electrophiles. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800650

FULL PAPER
DOI: 10.1002/ejoc.200800650
Synthesis, Resolution, and Application of Cyclobutyl- and
Adamantyl-Quinazolinap Ligands
Tomasz Fekner,[a][‡] Helge Müller-Bunz,[a][‡‡] and Patrick J. Guiry*[a]
Keywords: Asymmetric catalysis / P,N ligands / Palladium / Atropisomerism / Biaryl compounds
An expedient, seven-step synthesis of two new members of
tion (ee’s up to 89%) in a prototypical PdII-catalyzed allylic
the Quinazolinap ligand family, 2-cyclobutyl- and 2-(1-ada- alkylation reaction. 2-Cyclobutyl-Quinazolinap has been fur-
mantyl)-Quinazolinaps, has been developed. The racemic li-
gands have been efficiently resolved by fractional crystalli-
zation of their diastereomeric palladacycle complexes. The
enantioenriched ligands provide good levels of enantioselec-
ther functionalized at the 2-position via metalation with a su-
perbase followed by reaction with a range of electrophiles.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
less common 2-substituents, i.e., the sterically miniscule cy-
clobutyl and extremely bulky 1-adamantyl (Scheme 1, 5a
and 5b, respectively).[11]
Introduction
Axially chiral biaryls are arguably the most versatile class
of ligands developed for asymmetric catalysis mediated by
transition metals.[1] Following the pioneering work by Dang
and Kagan on rational design of their DIOP ligand[2] and,
most importantly, the spectacular success of Noyori’s BI-
NAP,[3] the notion that C2-symmetrical molecules are gen-
erally more efficient in chiral-information transfer became
deeply rooted in the field of homogeneous asymmetric ca-
talysis for over two decades.[4] A seminal report by Ach-
iwa,[5] who demonstrated that desymmetrization of C2-sym-
metric ligands can bring about higher levels of enantiocon-
trol, ushered in a period of intense interest in lower-sym-
metry ligands in general, and biaryls in particular.[6]
Figure 1. Quinap (1) and Quinazolinap ligands 2–4.
Our research in this arena, inspired by the proven versa-
tility of Brown’s Quinap (1) (Figure 1),[7] centers on the de-
velopment of a new class of atropisomeric P,N ligands[8]
based on the parent Quinazolinap (2) scaffold.[9] To date,
we have developed a series of 2-alkyl- and 2-aryl-Quinazoli-
naps (3 and 4, respectively)[10] and applied them, with some
success, to asymmetric hydroboration.[10c] Pursuant to our
long-term goals, this paper describes the synthesis, resolu-
tion, and application of a pair of Quinazolinaps bearing
Results and Discussion
In our previous studies on Quinazolinap ligands, anthra-
nilic acid and alkyl (or aryl) nitriles were used as starting
materials in the synthesis of the requisite quinazolines.[10c,12]
This method, while superior to older synthetic protocols, is
nonetheless operationally tedious and provides the desired
products in moderate yield only. Cognizant of this, in the
current studies we opted for an alternative approach involv-
ing an acylation–cyclocondensation sequence between com-
[a] Centre for Synthesis and Chemical Biology, Conway Institute
of Biomolecular and Biomedical Research, School of Chemistry mercially available and inexpensive anthranilamide (6) and
an appropriate acyl chloride.[13] W had used a similar strat-
and Chemical Biology, University College Dublin,
Belfield, Dublin 4, Ireland
egy for the synthesis of quinazoline–oxazoline-containing
(Quinazox) ligands.[10a] Therefore (Scheme 1), the synthesis
of ligand 5a commenced with acylation of 6 with cyclobu-
tanecarbonyl chloride (7a) in the presence of Et3N to give
the corresponding amide 8a that, upon treatment with
NaOH in EtOH, underwent cyclocondensation to quinazol-
inol 9a in high overall yield (94% from 6). Chlorination
Fax: +353-1-716-2127
E-mail: p.guiry@ucd.ie
[‡] Present address: Department of Chemistry, The Ohio State
University,
100 W. 18th Avenue, Columbus, OH 43210, USA
[‡‡]Correspondence concerning single-crystal X-ray analyses
should be directed to this author (helge.muellerbunz@ucd.ie).
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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T. Fekner, H. Müller-Bunz, P. J. Guiry
FULL PAPER
Scheme 1. Synthesis of racemic ligands 5a and 5b.
of 9a with POCl3/PhNEt2 in boiling benzene provided the ee) and (Ra)-(+)-5b (46%, 97.8% ee). The optical purity of
electrophilic partner 10a for the subsequent Suzuki– the enantioenriched ligands was determined by CSP HPLC
Miyaura cross-coupling. The entire synthetic sequence (ex- (see Supporting Information).
emplified herein by the conversion of 6 to 10a and 10b)
The assignment of the absolute stereochemistry for each
requires only one chromatographic purification, and can be enantiomer of the two newly prepared ligands 5a and 5b
easily scaled up even in the laboratory setting. When cou- was cogently secured by single-crystal X-ray analysis of the
pled with the arylboronic acid 11[14] in the presence of PdII complexes (Sa,R)-(–)-16a and (Ra,R)-(+)-17b (Fig-
Pd(PPh3)4 (1.5 mol-%), aryl chloride 10a furnished biaryl ure 2).[19] In the two palladacycles, biaryls (Sa)-(–)-5a and
12a in good yield. The methyl ether cleavage with BBr3, (Ra)-(+)-5b, respectively, act as monodentate ligands with
followed by treatment of the resulting naphthol 13a with their soft phosphorus atoms positioned trans relative to the
Tf2O in the presence of DMAP gave triflate 14a. Finally, hard nitrogen donors of the ortho-palladated sub-unit. Ste-
nickel-catalyzed cross-coupling between 14a and Ph2PH in ric constraints within these molecules result in a distorted
the presence of NiCl2(dppe)/DABCO according to Cai’s square-planar geometry around the palladium as evident by
protocol[15] provided the racemic triarylphosphane 5a.[16] contraction (to 80.9° and 80.5°, respectively) of the N–Pd–
All in all, 5a was obtained in seven operationally simple C angles with concomitant enlargement of the other angles
steps (four chromatographic purifications, 48% yield) from (in particular, the P–Pd–C angles to 100.0° and 95.4°,
6. The racemic adamantyl-based ligand 5b was prepared in respectively). There are also significant tetrahedral-like out-
a similar manner (Scheme 1) from 6 in 53% overall yield.
of-plane deviations of the coordinated atoms (up to 0.31 Å
The racemic phosphanes 5a and 5b were resolved via for- and 0.15 Å, respectively) from their corresponding mean
mation and separation of their diastereomeric PdII com- planes. The C-methyl substituent of the chiral auxiliary oc-
plexes.[17] Thus, when (Ϯ)-5a was treated with one equiva- cupies a pseudo-axial position to minimize unfavorable in-
lent of the chloro-bridged resolving agent (R,R)-cis-15,[18] teractions with the H(8Ј) (see Scheme 2 for numbering); the
an equimolar mixture of the diastereomeric mononuclear very feature that is deemed crucial for the creation of a con-
palladacycles (Sa,R)-(–)-16a and (Ra,R)-(+)-17a was formed formationally locked and rigid asymmetric envelope that, in
(Scheme 2). Separation of the isomers was accomplished via turn, is prerequisite for efficient resolution with the ortho-
fractional crystallization from CHCl3/Et2O. Subsequent palladate 15.[20] In (Ra,R)-(+)-17b, the naphthalene ring sys-
treatment of the resolved complexes with dppe in CH2Cl2 tem of the chiral auxiliary protrudes in between the two
brought about the ligand exchange with concomitant liber- aromatic rings of the PPh2 group. It positions the H(3Ј)
ation of the enantioenriched phosphanes (Sa)-(–)-5a (41%, within the shielding cones of the phenyl rings in accordance
Ͼ99.9% ee) and (Ra)-(+)-5a (35%, 98.6% ee). Optical reso- with Pople’s ring-current model (RCM).[21] As the H(3Ј) sig-
1
lution of phosphane (Ϯ)-5b was carried out in an analogous nal in the H NMR spectrum is found significantly upfield
fashion to provide its enantiomers (Sa)-(–)-5b (45%, 98.2% [at δ = 6.03 ppm; cf. 6.59 ppm for (Sa,R)-(–)-16b] relative to
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Synthesis and Resolution of Atropisomeric P,N Ligands
Scheme 2. Optical resolution of ligands 5a and 5b.
the remaining aromatic protons,[22] it strongly indicates that duced {entry 4 [40% ee (R)] and entry 7 [47% ee (S)]}. We
the conformations of (Ra,R)-(+)-17b in the solid state and have observed similar trends when comparing Quinap (1)
in solution are not dissimilar.
to our 2-phenyl-Quinazolinap ligand 4a.[10e] It can also be
noted that the stereochemical outcome of the reaction is
strongly dependent on the alkali metal salt used as the addi-
tive. For ligand 5a, the larger counterions (K+ and Cs+,
entries 1 and 2) provide 20 in high optical purity (89% ee
Scheme 3. Asymmetric allylic alkylation (AAA) with cyclobutyl-
and adamantyl-Quinazolinap ligands 5a and 5b.
Figure 2. Single-crystal X-ray structures of PdII complexes (Sa,R)-
(–)-16a (top left) and (Ra,R)-(+)-17b (top right), and phosphane
oxide (Sa)-5b-(O) (bottom). Hydrogen atoms and solvent molecules
(when applicable) omitted for clarity.
Table 1. AAA with ligands 5a and 5b.
Entry Ligand
Base
Solvent
Yield (%)[a] ee (%)[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
(Sa)-(–)-5a KOAc
(Sa)-(–)-5a Cs2CO3
(Sa)-(–)-5a NaOAc
(Sa)-(–)-5a LiOAc
(Sa)-(–)-5a KOAc
(Sa)-(–)-5a KOAc
(Sa)-(–)-5b LiOAc
(Sa)-(–)-5b NaOAc
(Sa)-(–)-5b KOAc
(Sa)-(–)-5b Cs2CO3
(Sa)-(–)-5b LiOAc
(Sa)-(–)-5b LiOAc
(Sa)-(–)-5b LiOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
47
89 (R)
87 (R)
82 (R)
40 (R)
41 (R)
59 (R)
47 (S)
15 (R)
44 (R)
49 (R)
66 (S)
44 (S)
21 (R)
Ligands 5a and 5b were initially tested in the asymmetric
allylic alkylation (AAA) of the racemic acetate 19 with di-
methyl malonate (18) (Scheme 3). Because of its synthetic
importance, combined with the detailed understanding of
the catalytic cycle, the AAA is frequently employed for pre-
liminary screening of new ligand candidates.[23] The results
(Table 1) clearly show that the cyclobutyl-based ligand 5a is
superior to its adamantyl analog 5b in terms of the levels
of enantioselectivity that can be reached (entry 1 vs. entry
11). Furthermore, it is apparent that the steric size of the
ligand 2-substituent plays, under certain reaction condi-
PhMe
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
PhMe
MeCN
Ͼ95
Ͼ95
88
Ͼ95
56
89
Ͼ95
[a] Isolated yield of 20. [b] Determined by CSP HPLC (see Support-
tions, an important role in the sense of the asymmetry in- ing Information). BSA: N,O-bis(trimethylsilyl)acetamide.
Eur. J. Org. Chem. 2008, 5055–5066
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T. Fekner, H. Müller-Bunz, P. J. Guiry
FULL PAPER
and 87% ee, respectively) that steadily decreases (entries 3 tionalization. This modification strategy should be suitable
and 4) when smaller counterions (80% ee for Na+ and 40% for the previously reported 2-alkyl-Quinazolinap ligands
ee for Li+) are present. For ligand 5b, both the level and 3[10] bearing benzylic-type protons at the 2-position.[26]
sense of enantioselection change as the size of the counter-
ion decreases (entries 7–10). There is also a notable solvent
effect (entries 7 and 11–13) with THF (entry 11) being opti-
Conclusions
mal for enantiopurity of 20 (66% ee).
In summary, we have developed short and operationally
Our earlier studies demonstrated that varying a substitu-
simple syntheses of homochiral bidentate Quinazolinap li-
tion pattern at the 2-position of Quinazolinap ligands is the
gands bearing cyclobutyl and 1-adamantyl substituents.
most straightforward and effective way to modulate their
The ligands (especially 5a) provide good levels of enantio-
selectivity (up to 89% ee) in the prototypical AAA reaction.
We have also demonstrated that 5a is a suitable substrate
for the preparation of new Quinazolinap ligands via the
metalation/functionalization strategy. Exploratory work is
currently underway to test these new ligands in a wide range
of asymmetric processes.
catalytic properties.[10] Because no direct way to modify the
previously prepared Quinazolinaps was developed, each
new ligand could only be accessed through a relatively
lengthy de novo synthesis and resolution along the lines
similar to those described herein for the preparation of li-
gands 5a,b. One potential strategy allowing for the synthesis
of new ligands via modification of the known Quinazolin-
aps could take advantage of an increased acidity, due to
the presence of the two activating azomethine groups, of
benzylic-type protons attached to the quinazoline core. To
test this hypothesis, deprotonation of cyclobutyl-Quinazol-
inap 5a was investigated. Gratifyingly (Scheme 4, Table 2),
when it was treated with a superbasic mixture comprising
iPr2NH, KOtBu, and BuLi (dubbed LIDAKOR)[24] in THF
at –40 °C for 1 h, a dark blue solution of a presumed met-
alated species was formed.[25] Its subsequent treatment with
D2O resulted in an almost complete (Ͼ97%) incorporation
of deuterium into the parent ligand 5a to give its deuterated
analogue 21a. As summarized in Table 2, other electro-
philes could also be used to quench the metalated species,
thus providing access to a range of modified Quinazolinaps
that themselves should also be amenable to further func-
Experimental Section
General Methods: All reactions were performed under anhydrous
conditions and an inert atmosphere of nitrogen in the oven-dried
glassware with magnetic stirring. Yields refer to chromatographi-
cally and spectroscopically (1H NMR) homogeneous materials, un-
less otherwise indicated. Reagents were used as obtained from com-
mercial sources, or purified according to the guidelines of Perrin
and Armarego.[27] Evaporation in vacuo refers to the removal of
volatiles on a Büchi rotary evaporator attached to a water respira-
tor (≈ 20 Torr). Flash chromatography was carried out using Merck
Kiesegel 60 F254 (230–400 mesh) silica gel following the method of
Still et al.[28] Only distilled solvents were used as eluents. Thin-layer
chromatography (TLC) was performed on Merck DC-Alufolien
plates pre-coated with silica gel 60 F254. They were visualized either
by quenching of ultraviolet fluorescence, or by charring with 5%
w/v phosphomolybdic acid in 95% EtOH, 10% w/v ammonium
molybdate in 1  H2SO4, or 10% KMnO4 in 1  H2SO4. Observed
retention factors (Rf) are quoted to the nearest 0.05, unless a higher
accuracy was necessary to distinguish close-eluting compounds. All
reaction solvents were distilled before use, unless otherwise indi-
cated. Anhydrous CH2Cl2 and CHCl3 were obtained by refluxing
over CaH2. Anhydrous DMF was obtained by distillation under
reduced pressure from CaH2, and stored over 4 Å molecular sieves.
Anhydrous Et2O was obtained by distillation, immediately before
use, from sodium/benzophenone ketyl under an inert atmosphere
of nitrogen. High-resolution mass spectrometry (HRMS) measure-
ments are valid to Ϯ5 ppm. Melting points (m.p.) are quoted to
the nearest 0.5 °C.
Scheme 4. Metalation of phosphane (Ϯ)-5a with LIDAKOR and
2-(Cyclobutanecarbonylamino)benzamide (8a) and 2-Cyclobutylquin-
azolin-4-ol (9a): To a suspension of anthranilamide (6) (11.5 g,
84.4 mmol) in CH2Cl2 (250 mL) was added Et3N (15 mL,
110 mmol) and the mixture was cooled in an ice bath. During vig-
orous stirring, cyclobutanecarbonyl chloride (7a) (10.0 g,
84.4 mmol) was added dropwise over 15 min. At the beginning of
the addition, a clear solution resulted but later on a lot of precipi-
tate formed. After the addition was complete, the reaction mixture
was stirred at 0 °C for 15 min, and at room temperature for an
additional 15 min. The volatiles were removed in vacuo to give an
off-white solid (31.3 g) containing amide 8a that was used in the
next step without any further purification. An analytical sample of
amide 8a was obtained by chromatography of a small amount of
the crude product (silica gel; EtOAc) followed by crystallization
subsequent functionalization.
Table 2. Synthesis of modified 2-cyclobutyl-Quinazolinaps 21a–d.[a]
Entry
Electrophile
R
Product
Yield (%)[b]
1
2
3
4
D2O
D
CHO
CO2Me
CH(OH)Ph
21a
21b
21c
21d
97[c]
92
HCO2Et
(MeO)2CO
PhCHO
63
94[d]
[a] For reaction conditions, see Scheme 4. [b] Isolated yield. [c]
1
Ͼ97% deuterium incorporation by H NMR and HRMS. [d] Ca.
1
6:4 mixture of diastereomers, analysed by H NMR and HPLC.
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Synthesis and Resolution of Atropisomeric P,N Ligands
(EtOAc/pentane). Amide 8a: a white solid; Rf = 0.70 (EtOAc); m.p.
partitioned between CH2Cl2 and water. The phases were separated,
183.0–184.5 °C (EtOAc/pentane). 1H NMR (400 MHz, [D6]- and the extraction was completed with additional portions of
DMSO): δ = 1.74–1.85 (m, 1 H), 1.88–2.01 (m, 1 H), 2.11–2.28 (m, CH2Cl2. The combined organic extracts were dried (MgSO4), and
4 H), 3.21 (dquint, J = 8.6, 1.0 Hz, 1 H), 7.10 (ddd, J = 7.9, 7.4,
1.2 Hz, 1 H), 7.48 (ddd, J = 8.4, 7.4, 1.5 Hz, 1 H), 7.71 (br. s, 1
H), 7.80 (dd, J = 7.9, 1.4 Hz, 1 H), 8.26 (br. s, 1 H), 8.52 (dd, J =
8.4, 1.0 Hz, 1 H), and 11.9 (s, 1 H) ppm. 13C{1H} NMR (101 MHz,
[D6]DMSO): δ = 17.3, 24.7, 40.6, 119.1, 119.8, 122.0, 128.5, 132.1,
the solvents evaporated in vacuo. Purification by flash chromatog-
raphy (silica gel; CH2Cl2/pentane, 1:1ǞCH2Cl2) gave a pink solid
that was triturated with pentane (100 mL), filtered, washed with
pentane (100 mL), and dried to give the title compound 12a (5.37 g,
79%) as a yellow solid: Rf = 0.55 (pentane/CH2Cl2, 15:1); m.p.
1
139.8, 170.7, and 172.8. IR (CHCl ): νmax = 1664, 1608, 1579, 1518,
143.5–144.0 °C (EtOAc/pentane). H NMR (400 MHz, CDCl3): δ
= 1.94–2.04 (m, 1 H), 2.05–2.20 (m, 1 H), 2.43–2.56 (m, 2 H), 2.62–
˜
3
1448, 1377, and 1288 cm–1. HRMS calcd. for C12H14N2NaO2
[MNa+] 241.0953, found 241.0944. C12H14N2O2 (218.25): calcd. C 2.76 (m, 2 H), 3.78 (s, 3 H), 4.10 (dquint, J = 8.5, 0.7 Hz, 1 H),
66.04, H 6.47, N 12.84; found C 66.06, H 6.47, N 12.79.
7.12 (≈ dd, J = 8.4, 1.1 Hz, 1 H), 7.29 (ddd, J = 8.4, 6.8, 1.5 Hz, 1
H), 7.32–7.38 (m, 2 H), 7.43 (d, J = 9.0 Hz, 1 H), 7.44 (ddd, J =
8.3, 1.5, 0.6 Hz, 1 H), 7.82 (ddd, J = 8.4, 6.8, 1.5 Hz, 1 H), 7.87 (≈
dd, J = 8.3, 1.2 Hz, 1 H), 8.02 (d, J = 9.0 Hz, 1 H), and 8.10 (≈ d,
J = 8.4 Hz, 1 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ =
18.3, 27.7, 27.8, 43.5, 56.6, 113.4, 120.0, 123.5, 123.8, 124.4, 126.5,
126.9, 127.0, 128.0, 128.3, 129.0, 131.0, 133.0, 133.5, 150.6, 154.6,
The foregoing solid was dissolved in EtOH (250 mL) and treated
with 10  NaOH (25 mL, 0.25 mol), and the reaction mixture was
refluxed for 1 h. The resulting clear solution was subsequently re-
cooled to 0 °C, neutralized with concd HCl and diluted with water
(≈ 2 L). The precipitate formed was filtered, washed with a copious
amount of water, and dried to give the title compound 9a (15.8 g,
94% from 6) as an off-white solid that was used in the next step
without any further purification. An analytical sample of quinazol-
inol 9a was obtained by chromatography of a small amount of the
crude product (silica gel; EtOAc) followed by crystallization
(EtOAc/pentane). Quinazolinol 9a: a white solid; Rf = 0.70
(EtOAc); m.p. 238.5–239.5 °C (EtOAc/pentane). 1H NMR
(400 MHz, [D6]DMSO): δ = 1.79–1.90 (m, 1 H), 1.93–2.06 (m, 1
H), 2.20–2.30 (m, 2 H), 2.35–2.48 (m, 2 H), 3.51 (dquint, J = 8.6,
0.9 Hz, 1 H), 7.46 (ddd, J = 8.1, 7.2, 1.2 Hz, 1 H), 7.65 (ddd, J =
8.3, 1.2, 0.5 Hz, 1 H), 7.78 (ddd, J = 8.3, 7.2, 1.6 Hz, 1 H), and
8.09 (ddd, J = 8.1, 1.6, 0.5 Hz, 1 H) ppm. 13C{1H} NMR
(101 MHz, [D6]DMSO): δ = 17.4, 25.7, 37.9, 120.7, 125.6, 125.8,
167.2, and 169.0. IR (CHCl ): νmax = 1616, 1595, 1568, 1550, 1514,
˜
3
1493, 1344, 1269, and 1252 cm–1. HRMS calcd. for C23H21N2O
[MH+] 341.1654, found 341.1669. C23H20N2O (340.42): calcd. C
81.15, H 5.92, N 8.23; found C 81.16, H 5.95, N 8.17.
1-(2-Cyclobutylquinazolin-4-yl)naphthalen-2-ol (13a) and 1-(2-
Cyclobutylquinazolin-4-yl)naphthalen-2-yl Trifluoromethanesulfon-
ate (14a): A solution of biaryl 12a (4.76 g, 14.0 mmol) in CH2Cl2
(55 mL) was cooled in an ice bath. During vigorous stirring, BBr3
(1.0  in CH2Cl2, 28 mL, 28 mmol) was added dropwise over
10 min to give a dark red solution. The reaction mixture was stirred
at room temperature for 19 h, re-cooled to 0 °C, and quenched with
1  HCl (50 mL) to give a yellow suspension. The precipitate was
filtered, and washed successively with water (2ϫ50 mL) and
CH2Cl2 (50 mL). The organic phase from the filtrate was separated,
and the extraction was completed with additional portions of
CH2Cl2. The combined organic extracts were washed with brine,
dried (MgSO4), and the solvents evaporated in vacuo to give a yel-
low residue that was combined with the previously isolated solid
(4.82 g in total). An analytical sample of naphthol 13a was ob-
tained by chromatography of a small amount of the crude product
(silica gel; CH2Cl2/EtOAc, 2:1) followed by crystallization (EtOAc/
pentane). Naphthol 13a: a yellow solid; Rf = 0.75 (CH2Cl2/EtOAc,
2:1); m.p. 197.0–198.0 °C (EtOAc/pentane). 1H NMR (400 MHz,
CDCl3): δ = 1.91–2.02 (m, 1 H), 2.04–2.17 (m, 1 H), 2.40–2.64 (m,
4 H), 3.99 (dquint, J = 8.7, 0.8 Hz, 1 H), 7.21–7.25 (m, 2 H), 7.26–
7.35 (m, 3 H), 7.55 (≈ ddd, J = 8.4, 1.2, 0.5 Hz, 1 H), 7.99 (ddd, J
= 8.3, 6.8, 1.4 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.87 (d, J =
8.9 Hz, 1 H), 8.00 (≈ d, J = 8.5 Hz, 1 H), and 9.93 (br. s, 1 H) ppm.
13C{1H} NMR (101 MHz, CDCl3): δ = 18.4, 27.6, 27.8, 42.9, 114.8,
119.2, 122.2, 123.6, 124.9, 126.5, 126.7, 127.9, 128.3, 128.4, 128.7,
132.5, 132.6, 134.2, 151.5, 154.7, 166.3, and 168.0 ppm. IR
126.8, 134.1, 148.7, 159.0, and 161.8. IR (CHCl ): ν
= 1676,
˜
3
max
1610, and 1470 cm–1. HRMS calcd. for C12H13N2O [MH+]
201.1028, found 201.1028. C12H12N2O (200.24): calcd. C 71.98, H
6.04, N 13.99; found C 71.93, H 6.04, N 14.03.
4-Chloro-2-cyclobutylquinazoline (10a): A solution of quinazolinol
9a (15.4 g, 77 mmol) in benzene (120 mL) was azeotropically dried
under a Dean–Stark trap. The solution was cooled to room tem-
perature and treated with PhNEt2 (20 mL, 0.13 mol) followed by
POCl3 (4.7 mL, 51 mmol). The reaction mixture was then refluxed
for 2 h, cooled to room temperature, and diluted with EtOAc
(250 mL). The mixture was washed successively with water
(3ϫ250 mL),
1  HCl (3ϫ250 mL), water (250 mL), satd.
NaHCO3 (250 mL), water (250 mL), and brine (250 mL). The or-
ganic layer was dried (MgSO4), and the solvents evaporated in
vacuo to give a brown oil. Purification by flash chromatography
(silica gel; CH2Cl2/pentane, 1:1) gave the title compound 10a
(15.6 g, 96%) as a clear oil that solidified upon standing.[29] Quin-
azoline 10a: a white solid; Rf = 0.40 (CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ = 1.92–2.20 (m, 2 H), 1.93–2.06 (m, 1 H), 2.38–2.67 (m,
4 H), 3.93 (quint, J = 8.6 Hz, 1 H), 7.56 (ddd, J = 8.2, 6.9, 1.1 Hz,
1 H), 7.84 (ddd, J = 8.3, 6.9, 1.3 Hz, 1 H), 7.95 (ddd, J = 8.3, 1.1,
0.6 Hz, 1 H), and 8.11 (ddd, J = 8.2, 1.3, 0.6 Hz, 1 H). 13C{1H}
NMR (75 MHz, CDCl3): δ = 18.1, 27.4, 42.7, 121.6, 125.3, 127.5,
(CHCl ): ν
= 1620, 1597, 1562, 1549, 1489, 1462, 1406, 1392,
˜
3
max
1348, 1286, 1269, 1232, and 1207 cm–1. HRMS calcd. for
C22H19N2O [MH+] 327.1497, found 327.1491. C22H18N2O
(326.39): calcd. C 80.96, H 5.56, N 8.58; found C 80.91, H 5.62, N
8.59.
128.0, 134.2, 151.1, 162.0, and 168.2. IR (CHCl ): ν
= 1618,
˜
3
max
The foregoing crude naphthol 13a was dissolved in CH2Cl2
(70 mL) and treated with DMAP (5.12 g, 42.0 mmol). After the
mixture had been cooled in an ice bath, Tf2O (2.6 mL, 15 mmol)
was added dropwise over 5 min, and the stirring was continued at
room temperature for 4 h. The reaction mixture was re-cooled to
0 °C, 1  HCl (50 mL) was added, and the mixture was stirred
vigorously for 5 min. The phases were separated and the extraction
was completed with additional portions of CH2Cl2. The combined
organic extracts were washed with brine, dried (MgSO4), and the
1568, 1555, 1480, 1461, 1335, 1310, and 1251 cm–1. HRMS calcd.
for C12H12ClN2 [MH+] 219.0689, found 219.0696.
2-Cyclobutyl-4-(2-methoxynaphthalen-1-yl)quinazoline (12a): To a
solution of aryl chloride 10a (4.36 g, 20.0 mmol) in 1,2-dimethoxy-
ethane (DME, 25 mL) was added Pd(PPh3)4 (347 mg, 0.30 mmol)
followed by 2  Na2CO3 (20 mL, 40 mmol), arylboronic acid 11[14]
(4.24 g, 16.7 mmol), and EtOH (30 mL). The resulting thick sus-
pension was refluxed for 18 h, cooled to room temperature, and
Eur. J. Org. Chem. 2008, 5055–5066
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5059

T. Fekner, H. Müller-Bunz, P. J. Guiry
FULL PAPER
solvents evaporated in vacuo to give an orange solid. Purification
by flash chromatography (silica gel; CH2Cl2) gave the title com-
pound 14a (5.59 g, 87% from 12a) as a white solid: Rf = 0.35
(CH2Cl2); m.p. 142.5–143.0 °C (EtOAc/pentane). 1H NMR
During vigorous stirring, a solution of 1-adamantoyl chloride (7b)
(5.00 g, 25.1 mmol) in CH2Cl2 (30 mL) was added dropwise over
30 min. At the beginning of the addition, a clear solution resulted
but later on a lot of precipitate formed. After the addition was
(400 MHz, CDCl3): δ = 1.93–2.05 (m, 1 H), 2.06–2.20 (m, 1 H), complete, the reaction mixture was stirred at 0 °C for 2 h, and at
2.42–2.55 (m, 2 H), 2.57–2.77 (m, 2 H), 4.10 (dquint, J = 8.7,
1.0 Hz, 1 H), 7.28 (≈ dd, J = 8.5, 0.8 Hz, 1 H), 7.35 (ddd, J = 8.3,
1.5, 0.6 Hz, 1 H), 7.41 (ddd, J = 7.9, 6.7, 1.1 Hz, 1 H), 7.43 (ddd,
J = 8.4, 6.9, 1.2 Hz, 1 H), 7.59 (ddd, J = 8.2, 6.9, 1.1 Hz, 1 H),
7.61 (d, J = 9.0 Hz, 1 H), 7.88 (ddd, J = 8.5, 6.7, 1.6 Hz, 1 H), 8.00
(≈ d, J = 8.3 Hz, 1 H), 8.13 (d, J = 9.0 Hz, 1 H), and 8.14 (≈ d, J
= 8.5 Hz, 1 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 18.3,
27.4, 27.8, 43.4, 118.1 (q, J = 320 Hz), 119.5, 122.9, 126.1, 126.2,
127.1, 127.3, 127.4, 128.2, 128.3, 128.6, 131.8, 132.4, 134.1, 144.6,
150.9, 163.2, and 169.1 ppm (one-carbon signal, obscured). IR
room temperature for an additional 1 h. The reaction mixture was
evaporated in vacuo to give an off-white solid (11.3 g) containing
amide 8b that was used in the next step without any further purifi-
cation. An analytical sample of amide 8b was obtained by
chromatography of a small amount of the crude product (silica gel;
CH2Cl2 ǞCH2Cl2/EtOAc, 10:1) followed by crystallization
(EtOAc/pentane). Amide 8b: a white solid; Rf = 0.65 (CH2Cl2/
EtOAc, 2:1); m.p. 228.0–229.0 °C (EtOAc/pentane). 1H NMR
(400 MHz, [D6]DMSO): δ = 1.63–1.76 (m, 6 H), 1.88 (d, J =
2.7 Hz, 6 H), 2.03 (dt, J = 2.7 Hz, 3 H), 7.09 (ddd, J = 7.9, 7.5,
1.2 Hz, 1 H), 7.47 (ddd, J = 8.5, 7.5, 1.5 Hz, 1 H), 7.73 (br. s, 1
H), 7.80 (dd, J = 7.9, 1.4 Hz, 1 H), 8.29 (br. s, 1 H), 8.56 (dd, J =
8.5, 1.1 Hz, 1 H), and 11.9 (s, 1 H) ppm. 13C{1H} NMR (101 MHz,
[D6]DMSO): δ = 27.5, 35.9, 38.6, 41.3, 119.0, 119.8, 121.9, 128.4,
(CHCl ): νmax = 1568, 1552, 1425, 1248, 1230, 1140, and 951 cm–1.
˜
3
HRMS calcd. for C23H18F3N2O3S [MH+] 459.0990, found
459.0970. C23H17F3N2O3S (458.45): calcd. C 60.26, H 3.74, N 6.11,
S 6.99; found C 60.24, H 3.73, N 6.05, S 7.14.
132.2, 140.1, 170.9, and 175.8 ppm. IR (CHCl ): νmax = 2914, 2854,
˜
3
(؎)-2-Cyclobutyl-4-(2-diphenylphosphanylnaphthalen-1-yl)quinaz-
oline (؎)-(5a): To a solution of NiCl2(dppe) (549 mg, 1.04 mmol)
in DMF (10 mL) was added Ph2PH (0.7 mL, 4.0 mmol), and the
mixture was stirred at 100 °C for 30 min. A solution of triflate 14a
(4.78 g, 10.4 mmol) and DABCO (4.66 g, 41.6 mmol) in DMF
(10 mL) was added via cannula and the resulting dark brown mix-
ture was stirred at 100 °C. Additional portions of Ph2PH (0.7 mL,
4.0 mmol; and 0.8 mL, 4.6 mmol) were added after 25 min and
55 min, respectively. After 46 h at 100 °C, the volatiles were re-
moved in vacuo, the residue was taken up in EtOAc, and washed
successively with water and brine. The organic layer was dried
(MgSO4), and concentrated in vacuo to give a brown oil. Purifica-
tion by flash chromatography (silica gel; CH2Cl2/pentane,
1:2ǞCH2Cl2) furnished a pale yellow foam. Re-crystallization
(EtOAc/pentane) gave the title compound (Ϯ)-5a as a white solid
(3.53 g, 69%). The mother liquor was concentrated and chromato-
graphed (silica gel; CH2Cl2/pentane, 1:1) to give an additional por-
tion of the product (Ϯ)-5a (0.43 g, 8%; 3.96 g, 77% overall). Biaryl
(Ϯ)-5a: a white solid; Rf = 0.20 (CH2Cl2), 0.35 (hexane/EtOAc,
1664, 1606, 1577, 1523, 1448, 1377, 1298, and 1291 cm–1. HRMS
calcd. for C18H23N2O2 [MH+] 299.1760, found 299.1744.
C18H22N2O2 (298.38): calcd. C 72.46, H 7.43, N 9.39; found C
72.39, H 7.45, N 9.46.
The foregoing residue was suspended in EtOH (40 mL) and treated
with 10  NaOH (7.5 mL, 75 mmol). The reaction mixture was
refluxed for 2 h, and the resulting clear solution was subsequently
re-cooled to 0 °C, neutralized with concd HCl, and diluted with
water (≈ 2 L). The precipitate formed was filtered, washed with a
copious amount of water, and dried to give the title compound 9b
(6.20 g, 88% from 6) as an off-white solid that was used in the
next step without any further purification. An analytical sample of
quinazolinol 9b was obtained by chromatography of a small
amount of the crude product (silica gel; CH2Cl2 ǞCH2Cl2/EtOAc,
10:1) followed by crystallization (EtOAc/pentane). Quinazolinol 9b:
a white solid; Rf = 0.80 (CH2Cl2/EtOAc, 2:1); m.p. 213.5–215.0 °C
(EtOAc/pentane). 1H NMR (400 MHz, [D6]DMSO): δ = 1.66–1.76
(m, 6 H), 1.99–2.09 (m, 9 H), 7.46 (ddd, J = 8.1, 7.2, 1.1 Hz, 1 H),
5:1); m.p. 164.0–164.5 °C (EtOAc/pentane). 1H NMR (400 MHz, 7.60 (ddd, J = 8.2, 1.1, 0.5 Hz, 1 H), 7.77 (ddd, J = 8.2, 7.2, 1.6 Hz,
CDCl3): δ = 1.69–1.80 (m, 1 H), 1.88–2.04 (m, 1 H), 2.16–2.39 (m, 1 H), and 8.08 (ddd, J = 8.1, 1.6, 0.5 Hz, 1 H) ppm. 13C{1H} NMR
4 H), 3.87 (dquint, J = 8.7, 0.9 Hz, 1 H), 7.09 (≈ dd, J = 8.5, 0.7 Hz,
(101 MHz, [D6]DMSO): δ = 27.6, 35.7, 38.65, 38.67, 120.7, 125.5,
1 H), 7.12–7.18 (m, 2 H), 7.19–7.33 (m, 11 H), 7.37 (dd, J = 8.5, 126.0, 127.2, 134.1, 148.4, and 162.2 ppm (one carbon signal ob-
3.2 Hz, 1 H), 7.48 (ddd, J = 8.1, 6.8, 1.1 Hz, 1 H), 7.79 (ddd, J = scured). IR (CHCl ): ν
= 2912, 1670, 1604, 1470 cm–1. HRMS
max
˜
3
8.4, 6.6, 1.7 Hz, 1 H), 7.88 (d, J = 8.2 Hz, 1 H), 7.90 (d, J = 8.4 Hz,
1 H), and 8.07 (d, J = 8.5 Hz, 1 H) ppm. 13C{1H} NMR (101 MHz,
CDCl3):[30] δ = 18.3, 27.2, 27.5, 43.3, 123.5, 123.6, 126.2, 126.3,
126.6, 126.8, 126.9, 127.0, 128.0, 128.21, 128.25, 128.27, 128.29,
128.34, 128.35, 128.5, 129.1, 130.01, 130.02, 131.8, 131.9, 133.3,
133.5, 133.6, 133.7, 134.3, 134.5, 136.5, 136.6, 137.3, 137.4, 142.0,
142.3, 150.4, 168.7, 169.2, and 169.3 ppm. 31P{1H} NMR
calcd. for C18H21N2O [MH+] 281.1654, found 281.1646.
C18H20N2O (280.36): calcd. C 77.11, H 7.19, N 9.99; found C
77.39, H 7.49, N 9.70.
2-(Adamantan-1-yl)-4-chloroquinazoline (10b): A solution of quin-
azolinol 9b (5.97 g, 21.3 mmol) in benzene (40 mL) was azeo-
tropically dried under a Dean–Stark trap. The solution was cooled
to room temperature and treated with PhNEt2 (5.1 mL, 32 mmol)
followed by POCl3 (1.2 mL, 13 mmol). The reaction mixture was
then refluxed for 3 h, cooled to room temperature, and diluted with
EtOAc (50 mL). The mixture was washed successively with water
(3ϫ50 mL), 1  HCl (3ϫ50 mL), water (50 mL), satd. NaHCO3
(50 mL), water (50 mL), and brine (50 mL). The organic layer was
dried (MgSO4), and the solvents evaporated in vacuo to give an
off-white solid.[29] Purification by flash chromatography (silica gel;
CH2Cl2) gave the title compound 10b (5.45 g, 86%) as a white solid:
(162 MHz, CDCl ): δ = –12.5. IR (CHCl ): ν = 1615, 1569,
˜
max
3
3
1550, 1491, 1434, and 1338 cm–1. HRMS calcd. for C34H28N2P
[MH+] 495.1990, found 495.1984. C34H27N2P (494.57): calcd. C
82.57, H 5.50, N 5.66; found C 82.43, H 5.50, N, 5.62. Crystals of
phosphane (Ϯ)-5a suitable for X-ray diffraction analysis were
grown by slow evaporation of a CH2Cl2/pentane solution. During
the crystallization, phosphane (Ϯ)-5a underwent partial oxidation
to the corresponding phosphane oxide (Ϯ)-5a-(O). For the crystal-
lographic data of (Ϯ)-5a/5a-(O), see Supporting Information.
1
Rf = 0.60 (pentane/CH2Cl2, 3:1). H NMR (400 MHz, CDCl3): δ
2-(Adamantane-1-carbonylamino)benzamide (8b) and 2-(Ada- = 1.76–1.87 (m, 6 H), 2.09–2.28 (m, 9 H), 7.60 (≈ dd, J = 8.3,
mantan-1-yl)quinazolin-4-ol (9b): To
nilamide (6) (3.42 g, 25.1 mmol) in CH2Cl2 (50 mL) was added
Et3N (4.5 mL, 33 mmol) and the mixture was cooled in an ice bath.
a
suspension of anthra-
7.0 Hz, 1 H), 7.86 (ddd, J = 8.3, 7.0, 1.1 Hz, 1 H), 7.99 (d, J =
8.3 Hz, 1 H), and 8.18 (≈ d, J = 8.3 Hz, 1 H) ppm. 13C{1H} NMR
(75 MHz, CDCl3): δ = 28.5, 36.7, 40.9, 41.1, 121.9, 125.5, 127.6,
5060
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5055–5066

Synthesis and Resolution of Atropisomeric P,N Ligands
128.5, 134.1, 151.4, 162.0, and 172.1 ppm. IR (CHCl ): ν
2980, 2852, 1618, 1568, 1554, 1479, 1456, 1344, 1329, 1308, 1248,
987, and 976 cm–1. HRMS calcd. for C18H20ClN2 [MH+] 299.1315,
found 299.1323.
=
max
C28H26N2O (406.52): calcd. C 82.73, H 6.45, N 6.89; found C
82.43, H 6.47, N 6.83.
˜
3
The foregoing crude naphthol 13b was dissolved in CH2Cl2
(100 mL) and treated with DMAP (5.64 g, 46.2 mmol). After the
mixture had been cooled in an ice bath, Tf2O (2.9 mL, 17 mmol)
was added dropwise over 5 min, and the stirring was continued at
2-(Adamantan-1-yl)-4-(2-methoxynaphthalen-1-yl)quinazoline (12b):
To a solution of aryl chloride 10b (4.73 g, 15.9 mmol) in DME
(40 mL) was added Pd(PPh3)4 (276 mg, 0.24 mmol) followed by 2 room temperature for 4 h. The reaction mixture was re-cooled to
 Na2CO3 (17.5 mL, 35 mmol), arylboronic acid 11[14] (3.37 g,
16.7 mmol), and EtOH (45 mL). The resulting thick suspension
was refluxed for 25 h, cooled to room temperature, and partitioned
between CHCl3 (due to poor solubility of 12b in common organic
solvent, a large amount of CHCl3 was required) and water. The
phases were separated, and the extraction was completed with ad-
ditional portions of CHCl3. The combined organic extracts were
dried (MgSO4), and the solvents evaporated in vacuo. The residue
was loaded on top of a column filled with silica gel, and the column
was eluted with CH2Cl2/pentane (1:1) and, after the fractions con-
taining the desired product 12b began to elute, with pure CH2Cl2.
Fractions containing 12b were combined and the solvents evapo-
rated in vacuo. The resulting pink solid was triturated with Et2O
(50 mL), filtered, washed with Et2O (50 mL), and dried to give the
title compound 12b (6.48 g, 97%) as a white solid: Rf = 0.75
0 °C, 1  HCl (50 mL) was added, and the mixture was stirred
vigorously for 5 min. The phases were separated and the extraction
was completed with additional portions of CH2Cl2. The combined
organic extracts were washed with brine, dried (MgSO4), and the
solvents evaporated in vacuo to give an orange solid. Purification
by flash chromatography (silica gel; pentane/CH2Cl2, 1:1) gave the
title compound 14b (8.10 g, 97% from 12b) as a white solid: Rf =
0.40 (CH2Cl2/pentane, 2:1); m.p. 217.5–218.5 °C (EtOAc/pentane).
1H NMR (400 MHz, CDCl3): δ = 1.77–1.89 (m, 6 H), 2.11–2.18
(m, 3 H), 2.27 (≈ d, J = 2.6 Hz, 6 H), 7.31 (≈ dd, J = 8.5, 0.8 Hz,
1 H), 7.34 (ddd, J = 8.3, 1.5, 0.5 Hz, 1 H), 7.40 (ddd, J = 7.9, 6.7,
1.1 Hz, 1 H), 7.44 (ddd, J = 8.4, 6.9, 1.2 Hz, 1 H), 7.59 (ddd, J =
8.1, 6.8, 1.1 Hz, 1 H), 7.61 (d, J = 9.1 Hz, 1 H), 7.86 (ddd, J = 8.4,
6.7, 1.6 Hz, 1 H), 8.01 (d, J = 8.3 Hz, 1 H), and 8.10–8.17 (m, 2
H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 28.7, 36.9, 41.0,
(CH2Cl2); m.p. 275.5–276.5 °C (EtOAc). 1H NMR (400 MHz, 41.4, 118.1 (q, J = 320 Hz), 119.5, 122.7, 125.9, 126.2, 127.0, 127.3,
CDCl3): δ = 1.76–1.87 (m, 6 H), 2.10–2.17 (m, 3 H), 2.28 (d, J = 127.7, 128.1, 128.3, 128.9, 131.6, 132.5, 132.6, 133.7, 144.5, 150.9,
2.8 Hz, 6 H), 3.77 (s, 3 H), 7.12–7.17 (m, 1 H), 7.30 (ddd, J = 8.2, 162.5, and 172.6 ppm. IR (CHCl ): νmax = 2908, 2852, 1570, 1549,
˜
3
6.8, 1.4 Hz, 1 H), 7.34 (ddd, J = 7.9, 6.8, 1.4 Hz, 1 H), 7.36 (ddd,
J = 8.2, 6.8, 1.2 Hz, 1 H), 7.41 (ddd, J = 8.2, 1.6, 0.6 Hz, 1 H),
7.44 (d, J = 9.1 Hz, 1 H), 7.80 (ddd, J = 8.5, 6.8, 1.6 Hz, 1 H), 7.88
(≈ d, J = 7.9 Hz, 1 H), 8.03 (d, J = 9.1 Hz, 1 H), and 8.09 (d, J =
8.5 Hz, 1 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 28.8,
36.9, 41.2, 41.3, 56.9, 113.9, 123.3, 123.9, 124.6, 126.3, 126.7, 127.0,
128.0, 128.6, 129.2, 130.9, 133.0, 133.2, 150.7, 154.7, 166.5, and
1425, 1306, 1248, 1230, 1213, 1140, and 949 cm–1. HRMS calcd.
for C29H26F3N2O3S [MH+] 539.1616, found 539.1594.
C29H25F3N2O3S (538.58): calcd. C 64.67, H 4.68, N 5.20, S 5.95;
found C 64.53, H 4.65, N 5.11, S 6.30.
(؎)-2-(Adamantan-1-yl)-4-(2-diphenylphosphanylnaphthalen-1-yl)-
quinazoline (؎)-(5b): To a solution of NiCl2(dppe) (686 mg,
1.30 mmol) in DMF (25 mL) was added Ph2PH (0.8 mL,
4.6 mmol), and the mixture was stirred at 100 °C for 30 min. A
solution of triflate 14b (7.00 g, 13.0 mmol) and DABCO (5.82 g,
52 mmol) in DMF (10 mL) was added via cannula and the resulting
dark brown mixture was stirred at 100 °C. Additional portions of
Ph2PH (0.9 mL, 5.2 mmol; and 1.0 mL, 5.8 mmol) were added after
172.6 ppm (one carbon signal obscured). IR (CHCl ): νmax = 2929,
˜
3
2913, 1850, 1616, 1597, 1568, 1347, 1514, 1454, 1346, 1304, 1269,
1250, and 1223 cm–1. HRMS calcd. for C29H29N2O [MH+]
421.2280, found 421.2274. C29H28N2O (420.55): calcd. C 82.82, H
6.71, N 6.66; found C 82.47, H 6.74, N 6.66.
1-(2-Adamantan-1-yl-quinazolin-4-yl)naphthalen-2-ol (13b) and 1-(2- 1 h and 3 h, respectively. After 65 h at 100 °C, the volatiles were
Adamantan-1-yl-quinazolin-4-yl)naphthalen-2-yl Trifluoroethanesul-
fonate (14b): A suspension of biaryl 12b (6.68 g, 15.9 mmol) in
CH2Cl2 (70 mL) was cooled in an ice bath. During vigorous stir-
ring, BBr3 (1.0  in CH2Cl2, 32 mL, 32 mmol) was added dropwise
over 10 min to give a red solution. The reaction mixture was stirred
at room temperature for 20 h, re-cooled to 0 °C, and quenched
with 1  HCl (50 mL) to give a yellow solution. The phases were
separated, and the extraction was completed with additional por-
tions of CH2Cl2. The combined organic extracts were washed with
brine, dried (MgSO4), and the solvents evaporated in vacuo to give
the crude naphthol 13b as a bright-yellow solid (6.28 g). An analyti-
cal sample of naphthol 13b was obtained by chromatography of a
small amount of the crude product (silica gel; CH2Cl2) followed by
crystallization (EtOAc/pentane). Naphthol 13b: a yellow solid; Rf
removed in vacuo, the residue was taken up in EtOAc, and washed
successively with water and brine. The organic layer was dried
(MgSO4), and concentrated in vacuo to give a brown oil. Purifica-
tion by flash chromatography (silica gel; CH2Cl2/pentane, 1:2) gave
a yellow foam, and its re-crystallization (EtOAc/pentane) provided
the title compound (Ϯ)-5b as a white solid (4.7 g, 63%). The
mother liquor was concentrated and chromatographed (silica gel;
pentane/CH2Cl2, 4:1Ǟ2:1) to give an additional portion of the
product (Ϯ)-5b (0.85 g, 11%; 5.55 g, 74% overall). Biaryl (Ϯ)-5b: a
white solid; Rf = 0.15 (CH2Cl2/pentane, 2:1); m.p. 235.5–236.5 °C
(EtOAc/pentane).[31] 1H NMR (400 MHz, CDCl3): δ = 1.63–1.75
(m, 6 H), 1.87–2.03 (m, 9 H), 7.09 (dd, J = 8.5, 0.7 Hz, 1 H), 7.15–
7.39 (m, 14 H), 7.51 (ddd, J = 8.1, 6.9, 1.1 Hz, 1 H), 7.81 (ddd, J
= 8.4, 6.5, 1.9 Hz, 1 H), 7.91 (≈ d, J = 8.4 Hz, 2 H), and 8.12 (d,
J = 8.5 Hz, 1 H) ppm. 13C{1H} NMR (101 MHz, CDCl3):[30] δ =
1
= 0.75 (CH2Cl2); m.p. 230.0–231.5 °C (EtOAc/pentane). H NMR
(400 MHz, CDCl3): δ = 1.80–1.90 (m, 6 H), 2.14–2.22 (m, 3 H), 28.7, 36.8, 40.7, 41.1, 123.32, 123.34, 126.3, 126.4, 126.5, 126.8,
2.24–2.30 (m, 6 H), 7.26 (≈ ddd, J = 7.9, 7.9, 1.2 Hz, 1 H), 7.30– 126.9, 128.05, 128.09, 128.2, 128.29, 128.35, 128.43, 128.7, 129.0,
7.37 (m, 3 H), 7.38 (d, J = 8.9 Hz, 1 H), 7.59 (d, J = 8.3 Hz, 1 H),
130.13, 130.14, 131.8, 131.9, 133.1, 133.3, 133.4 (two signals over-
7.80–7.89 (m, 2 H), 7.95 (d, J = 8.9 Hz, 1 H), 8.10 (d, J = 8.5 Hz, lapped), 133.5, 133.6, 134.0, 134.1, 136.6, 136.7, 137.7, 137.8, 142.6,
1 H), and 10.4 (br. s, 1 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): 142.9, 150.5, 168.35, 168.42, and 172.3 ppm. 31P{1H} NMR
δ = 28.7, 36.8, 41.1, 41.3, 114.3, 119.2, 121.7, 123.6, 125.3, 126.3,
(162 MHz, CDCl ): δ = –12.5 ppm. IR (CHCl ): νmax = 2908, 2850,
˜
3 3
126.5, 128.0, 128.4, 128.7, 129.0, 132.4, 132.7, 133.9, 152.1, 155.5,
1614, 1572, 1547, 1489, 1452, 1435, 1333, 1304, 1223, and
1213 cm–1. HRMS calcd. for C40H36N2P [MH+] 575.2616, found
575.2633. C40H35N2P (574.69): calcd. C 83.60, H 6.14, N 4.87;
165.2, and 171.2. IR (CHCl ): νmax = 2908, 2852, 1620, 1599, 1560,
˜
3
1545, 1487, 1462, 1454, 1406, 1396, 1302, and 1213 cm–1. HRMS
calcd. for C28H27N2O [MH+] 407.2123, found 407.2136. found C 83.43, H 6.09, N 4.82.
Eur. J. Org. Chem. 2008, 5055–5066
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5061

T. Fekner, H. Müller-Bunz, P. J. Guiry
FULL PAPER
126.6 (CH), 126.7 (CH), 126.9 (CH), 127.4 (CH), 127.6 (CH), 127.7
(CH), 127.9 (CH), 128.0 (CH), 128.1 (CH), 128.2 (ipso C), 128.5
(CH), 128.7 (ipso C), 128.8 (CH), 129.57 (CH), 129.59 (CH), 130.0
(ipso C), 130.4 (ipso C), 130.68 (CH), 130.71 (CH), 130.9 (ipso C),
132.4 (ipso C), 132.5 (ipso C), 133.4 (CH), 133.99 (ipso C), 134.01
(ipso C), 135.6 (CH), 135.7 (CH), 135.7 (CH), 136.0 (CH), 136.1
(CH), 137.1 (CH), 137.2 (CH), 139.5 (ipso C), 148.84 (ipso C),
148.86 (ipso C), 150.1 (ipso C), 150.3 (ipso C), 167.2 (ipso C), 168.0
(ipso C) ppm. 31P{1H} NMR (162 MHz, CDCl3): δ = 45.19 (br. s)
Optical Resolution of Racemic Phosphane (5a): To a solution of the
racemic phosphane 5a (1.00 g, 2.02 mmol) in CH2Cl2 (70 mL) was
[32]
added the resolving agent (R,R)-cis-15·CH2Cl2
(771 mg,
1.01 mmol) and the reaction mixture was stirred at room tempera-
ture for 28 h. The solvent was evaporated in vacuo to give a light
green foam that was dissolved in CHCl3 (5 mL) and brought to
reflux. Et2O (70 mL) was added dropwise over 5 min, the reflux
was continued for an additional 5 min, and the resulting yellow
solution was cooled to room temperature. The mixture was stirred
for 45 h (after ca. 30 min a precipitate began to form). The precipi-
tate was filtered, washed with Et2O (18 mL), and dried to give the
PdII complex (Sa,R)-(–)-16a (SOLID 1A, 762 mg, 45%) as a pale
yellow solid. The mother liquor was evaporated to give the PdII
complex (Ra,R)-(+)-17a as a yellow solid (SOLID 2A, 946 mg,
56%). SOLID 1A (ca. 4 mg) was suspended in CH2Cl2 (0.5 mL)
and treated with dppe (2.3 mg, 5.7 µmol). The mixture was stirred
at room temperature for 2 h and chromatographed directly (silica
gel; CH2Cl2/pentane, 1:1) to give a small sample of the enantioen-
riched phosphane (Sa)-(–)-5a. The CSP HPLC analysis [Daicel’s
Chiralcel® OD, 4.6 mmϫ25 cm; hexanes/2-propanol, 99:1;
0.7 mLmin–1; 10 °C; 254 nm; tR1 = 9.8 min for (Sa)-(–)-5a and tR2
= 11.2 min for (Ra)-(+)-5a], revealed the sample to be of 96.0%
ee. SOLID 2A was analyzed as described for SOLID 1A and the
corresponding phosphane (Ra)-(+)-5a was shown to be of 82.7%
ee. The remainder of SOLID 1A was suspended in Et2O (40 mL),
refluxed for 30 min, cooled to room temperature, and stirred for 46
h. The precipitate was filtered, washed with Et2O (18 mL), and
dried to give the re-purified PdII complex (Sa,R)-(–)-16a (SOLID
1B, 731 mg, 43%) as a pale yellow solid. The remainder of SOLID
2A was dissolved in Et2O (20 mL) and stirred at room temperature
for 49 h. The precipitate formed was filtered, washed with Et2O
(5 mL), and dried to give the re-purified PdII complex (Ra,R)-(+)-
17a as a pale yellow solid (SOLID 2B, 620 mg, 37%). SOLID 1B
and SOLID 2B were analyzed as described for SOLID 1A, and the
corresponding enantiomeric phosphanes (Sa)-(–)-5a and (Ra)-(+)-
5a were shown to be of Ͼ99.9% ee and 98.6% ee, respectively (Fig-
ure S1, Supporting Information). The remainder of SOLID 1B was
treated with dppe (383 mg, 0.96 mmol) in CH2Cl2 (5 mL) for 1 h.
Direct purification by column chromatography (silica gel; pentane/
CH2Cl2, 4:1ǞCH2Cl2) gave the free phosphane (Sa)-(–)-5a
(406 mg, 41%) as a white foam. Similarly, the remainder of SOLID
2B was treated with dppe (325 mg, 0.82 mmol) in CH2Cl2 (5 mL)
for 1 h to give, after chromatographic purification, the free phos-
phane (Ra)-(+)-5a (349 mg, 35%) as a white foam. (sp,cis)-
Chloro{1-[(1R)-1-(dimethylamino-κN)ethyl]-2-naphthalenyl-κC}-
{(Sa)-4-[2-(diphenylphosphanyl-κP)-1-naphthalenyl]-2-cyclobutyl-
quinazoline}palladium (Sa,R)-(–)-16a: a yellow solid; m.p. 214.0–
215.5 °C (dec., CHCl3/Et2O); [α]2D0 = –104 (c = 0.68, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 1.73–1.83 (m, 1 H), 1.77 (d, J =
6.3 Hz, 3 H), 1.88–2.03 (m, 1 H), 2.10–2.25 (m, 3 H), 2.36–2.54 (m,
4 H), 2.86 (d, J = 3.0 Hz, 3 H), 3.66 (quint, J = 8.6 Hz, 1 H), 4.21
(quint, J = 6.1 Hz, 1 H), 6.41–6.53 (m, 1 H), 6.66 (d, J = 8.6 Hz,
1 H), 6.71 (≈ t, J = 6.3 Hz, 2 H), 6.81 (d, J = 8.6 Hz, 1 H), 6.94 (t,
J = 7.1 Hz, 1 H), 7.19 (ddd, J = 8.4, 7.0, 1.1 Hz, 1 H), 7.23–7.41
(m, 6 H), 7.35 (ddd, J = 8.2, 6.8, 1.3 Hz, 1 H), 7.39–7.45 (m, 1 H),
7.49 (≈ dt, J = 7.9, 0.8 Hz, 1 H), 7.56 (≈ d, J = 8.2 Hz, 1 H), 7.63
(d, J = 8.4 Hz, 1 H), 7.67 (ddd, J = 8.1, 6.9, 1.0 Hz, 1 H), 7.71–
7.87 (m, 4 H), 7.92 (d, J = 8.1 Hz, 1 H), 8.00 (d, J = 8.7 Hz, 1 H),
and 8.23 (t, J = 8.6 Hz, 1 H) ppm. 13C{1H}/13C DEPT 135 NMR
(101 MHz, CDCl3):[30] δ = 18.3 (CH2), 23.3 (CH3), 27.3 (CH2), 27.7
(CH2), 43.2 (CH), 48.43 (CH), 48.44 (CH), 50.69 (CH3), 50.72
ppm. IR (CHCl ): ν
= 1614, 1572, 1550, 1502, 1491, and
˜
3
max
1473 cm–1. HRMS calcd. for C48H43N3PPd (M – Cl–) 798.2229,
found 798.2232. Crystals of (Sa,R)-(–)-16a suitable for X-ray dif-
fraction analysis were grown by slow evaporation of a CHCl3/pen-
tane solution. For the crystallographic data, see Supporting In-
formation. (sp,cis)-Chloro{1-[(1R)-1-(dimethylamino-κN)ethyl]-2-
naphthalenyl-κC}{(Ra)-4-[2-(diphenylphosphanyl-κP)-1-naphtha-
lenyl]-2-cyclobutylquinazoline}palladium (Ra,R)-(+)-17a: A yellow
solid; m.p. 227.0–228.0 °C (dec., CHCl3/Et2O); [α]2D0 = +241 (c =
0.66, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.92–1.99 (m, 1
H), 2.08 (d, J = 6.3 Hz, 3 H), 2.08–2.21 (m, 1 H), 2.26 (s, 3 H),
2.38–2.50 (m, 2 H), 2.53–2.66 (m, 2 H), 2.94 (d, J = 3.2 Hz, 3 H),
3.96 (dquint, J = 8.4, 0.8 Hz, 1 H), 4.22 (quint, J = 6.1 Hz, 1 H),
5.95 (dd, J = 8.2, 6.5 Hz, 1 H), 6.64 (d, J = 8.6 Hz, 1 H), 6.81 (d,
J = 8.6 Hz, 1 H), 6.87 (≈ t, J = 6.9 Hz, 2 H), 7.11 (t, J = 7.2 Hz,
1 H), 7.19 (ddd, J = 8.4, 6.9, 1.2 Hz, 1 H), 7.22–7.34 (m, 4 H), 7.36
(ddd, J = 8.2, 6.8, 1.3 Hz, 1 H), 7.43 (ddd, J = 8.1, 6.8, 1.1 Hz, 1
H), 7.46 (ddd, J = 7.9, 6.9, 0.9 Hz, 1 H), 7.59 (dd, J = 8.1, 0.9 Hz,
1 H), 7.60–7.65 (m, 2 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.69 (ddd, J =
8.2, 6.8, 1.3 Hz, 1 H), 7.77 (≈ d, J = 8.2 Hz, 1 H), 7.86 (d, J =
8.2 Hz, 1 H), 7.88–7.93 (m, 2 H), 7.95 (≈ d, J = 8.2 Hz, 1 H), and
8.12–8.21 (m, 1 H) ppm. 13C{1H}/13C DEPT-135 NMR (101 MHz,
CDCl3):[30] δ = 18.4 (CH2), 23.4 (CH3), 27.3 (CH2), 27.9 (CH2),
43.4 (CH), 48.41 (CH), 48.43 (CH), 50.59 (CH3), 50.61 (CH3),
72.78 (CH3), 72.81 (CH3), 123.0 (CH), 123.81 (CH), 123.89 (CH),
123.95 (CH), 124.02 (ipso C), 125.3 (CH), 126.0 (CH), 126.62 (CH),
126.69 (CH), 126.73 (CH), 127.0 (CH), 127.4 (CH), 127.8 (CH),
127.9 (CH), 128.1 (CH), 128.4 (ipso C), 128.5 (CH), 128.8 (ipso C),
129.3 (ipso C), 129.4 (CH), 129.96 (CH), 129.99 (CH), 130.2 (ipso
C), 130.3 (CH), 130.4 (CH), 130.7 (ipso C), 131.1 (ipso C), 131.4
(CH), 131.6 (CH), 132.2 (ipso C), 132.3 (ipso C), 133.2 (ipso C),
133.3 (ipso C), 133.6 (CH), 135.1 (CH), 135.2 (CH), 135.4 (CH),
137.7 (CH), 137.9 (CH), 148.6 (ipso C), 148.69 (ipso C), 148.71
(ipso C), 150.3 (ipso C), 167.78 (ipso C), 167.83 (ipso C), and 167.9
(ipso C) ppm. 31P{1H} NMR (162 MHz, CDCl3): δ = 42.12 (br. s)
ppm. IR (CHCl ): ν
= 1614, 1522, 1549, 1502, 1491, and
˜
3
max
1437 cm–1. HRMS calcd. for C48H43N3PPd (M – Cl–) 798.2229,
found 798.2216. Phosphane (Sa)-(–)-5a:[33] a white foam; [α]2D0
=
–102 (c = 0.71, CHCl3). Phosphane (Ra)-(+)-5a:[33] a white foam;
[α]2D0 +100 (c = 0.66, CHCl3).
Optical Resolution of Racemic Phosphane (5b): To a solution of the
racemic phosphane 5b (3.73 g, 6.49 mmol) in CH2Cl2 (100 mL) was
[32]
added the resolving agent (R,R)-cis-15·CH2Cl2
(2.47 g,
3.24 mmol) and the reaction mixture was stirred at room tempera-
ture for 28 h. The solvent was evaporated in vacuo to give a yellow
foam that was suspended in CHCl3 (22 mL) and brought to reflux.
After 10 min, Et2O (52 mL) was added dropwise over 5 min, and
the reflux was continued for an additional 5 min. The resulting yel-
low suspension was stirred at room temperature for 22 h, the pre-
cipitate was filtered, washed with Et2O/CHCl3 (8:1, 75 mL), and
dried to give the PdII complex (Ra,R)-(+)-17b a pale yellow solid
(SOLID 1, 3.11 g). The mother liquor was evaporated to give the
(CH3), 73.02 (CH3), 73.05 (CH3), 123.2 (CH), 123.75 (ipso C), PdII complex (Sa,R)-(–)-16b as a yellow solid (SOLID 2, 3.28 g).
123.87 (CH), 123.92 (CH), 125.5 (CH), 126.1 (CH), 126.5 (CH), SOLID 1 (ca. 8 mg) was suspended in CH2Cl2 (0.5 mL) and treated
5062
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5055–5066

Synthesis and Resolution of Atropisomeric P,N Ligands
H), 7.10–7.26 (m, 4 H), 7.28–7.57 (m, 9 H), 7.60 (ddd, J = 8.3, 6.9,
1.2 Hz, 1 H), 7.62 (d, J = 7.4 Hz, 2 H), 7.68 (d, J = 8.3 Hz, 1 H),
7.73–7.83 (m, 1 H), 7.95 (d, J = 8.1 Hz, 1 H), and 8.11 (br. s, 1 H)
ppm. 13C{1H}/13C DEPT-135 NMR (101 MHz, CDCl3):[30] δ =
23.2 (CH3), 28.6 (CH), 36.7 (CH2), 40.8 (CH2), 40.9 (ipso C), 48.4
(CH), 50.63 (CH), 50.65 (CH), 73.00 (CH3), 73.03 (CH3), 123.1
(CH), 123.4 (ipso C), 123.84 (CH), 123.87 (CH), 123.92 (CH), 125.4
(CH), 126.1 (sh, CH), 126.4 (CH), 126.5 (CH), 126.8 (CH), 127.0
(ipso C), 127.38 (CH), 127.41 (ipso C), 127.5 (CH), 127.6 (CH),
127.8 (br., CH), 127.9 (br., CH), 128.0 (CH), 128.1 (CH), 128.2
(CH), 128.37 (ipso C), 128.42 (CH), 129.19 (CH), 129.21 (CH),
130.13 (CH), 130.15 (CH), 130.8 (ipso C), 132.57 (ipso C), 132.65
(ipso C), 132.73 (CH), 134.0 (ipso C), 135.3 (br., CH), 135.4 (br.,
CH), 135.7 (CH), 135.8 (CH), 136.5 (br., CH), 148.73 (ipso C),
148.74 (ipso C), 149.9 (ipso C), 166.49 (ipso C), 166.53 (ipso C),
and 171.1 (ipso C) ppm. 31P{1H} NMR (162 MHz, [D6]Me2CO): δ
with dppe (4 mg, 10 µmol). The mixture was stirred at room tem-
perature for 2 h and chromatographed directly (silica gel; CH2Cl2/
pentane, 1:1) to give a small sample of an enantioenriched phos-
phane (Ra)-(+)-5b. The CSP HPLC analysis (Daicel’s Chiralcel®
OD-H, hexanes/2-propanol, 99.6:0.4; 1 mLmin–1; 40 °C; tR1
=
10.4 min, tR2 = 13.3 min) revealed the sample to be of 97.8% ee
(Figure S2, Supporting Information). SOLID 2 was analyzed as
described for SOLID 1 and the corresponding phosphane (Sa)-(–)-
5b was shown to be of 98.2% ee. The remainder of SOLID 1 was
treated with dppe (1.49 g, 3.74 mmol) in CH2Cl2 (20 mL) for 1 h.
The volatiles were removed in vacuo and the residue was purified
by column chromatography (silica gel; pentane/CH2Cl2, 4:1Ǟ2:1)
to give the free phosphane (Ra)-(+)-5b (1.72 g, 46%) as a white
solid. Similarly, the remainder of SOLID 2 was treated with dppe
(1.57 g, 3.94 mmol) in CH2Cl2 (20 mL) for 1 h to give, after chro-
matographic purification, the free phosphane (Sa)-(–)-5b (1.67 g,
45%) as a white solid. (sp,cis)-Chloro{1-[(1R)-1-(dimethylamino-
κN)ethyl]-2-naphthalenyl-κC}{(Ra)-4-[2-(diphenylphosphanyl-κP)-
= 44.44 (br. s) ppm. IR (CHCl ): ν
= 2981, 2905, 2851, 1547,
˜
3
max
1436, and 1305 cm–1. HRMS calcd. for C54H51N3PPd (M – Cl–)
878.2855, found 878.2816. Phosphane (Sa)-(–)-5b:[34] a white solid;
[α]2D0 = –84.0 (c = 0.87, CHCl3). Phosphane (Ra)-(+)-5b:[34] a white
solid; [α]2D0 = +83.2 (c = 0.75, CHCl3). It was attempted to grow
crystals of phosphane (Sa)-(–)-5b suitable for X-ray diffraction
analysis by slow evaporation of a CH2Cl2/pentane solution. During
the crystallization, phosphane (Sa)-(–)-5b underwent oxidation to
the corresponding phosphane oxide (Sa)-5b-(O). For the crystallo-
graphic data of (Sa)-5b-(O), see Supporting Information.
1-naphthalenyl]-2-(1-adamantyl)quinazoline}palladium
(Ra,R)-
(+)-17b (SOLID 1): a yellow solid; m.p. 224.0–225.5 °C (dec.,
CHCl3/Et2O); [α]2D0 = +215 (c = 0.54, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.85 (t, J = 3.0 Hz, 6 H), 2.13 (d, J = 6.3 Hz, 3 H),
2.12–2.20 (m, 3 H), 2.24 (≈ s, 6 H), 2.46 (s, 3 H), 3.00 (d, J =
3.1 Hz, 3 H), 4.28 (quint, J = 8.4, 0.8 Hz, 1 H), 6.03 (≈ t, J ≈ 7.0 Hz,
1 H), 6.52 (d, J = 8.6 Hz, 1 H), 6.71–6.79 (m, 2 H), 6.79 (d, J =
8.6 Hz, 1 H), 6.99 (t, J = 7.0 Hz, 1 H), 7.14–7.23 (m, 3 H), 7.26–
7.33 (m, 3 H), 7.35–7.48 (m, 3 H), 7.58 (d, J = 7.9 Hz, 1 H), 7.64–
7.74 (m, 3 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.84 (d, J = 8.1 Hz, 1 H),
7.86–7.94 (m, 2 H), 8.00 (t, J ≈ 7.0 Hz, 1 H), and 8.09–8.20 (m, 2
H) ppm. 13C{1H}/13C DEPT 135 NMR (101 MHz, CDCl3):[30] δ =
23.5 (CH3), 28.8 (CH), 36.9 (CH2), 41.24 (ipso C), 41.27 (CH2),
48.5 (CH), 50.80 (CH), 50.82 (CH), 72.92 (CH3), 72.95 (CH3),
123.1 (CH), 123.9 (CH), 124.0 (ipso C), 124.1 (CH), 124.2 (CH),
125.5 (CH), 126.0 (CH), 126.6 (CH), 126.70 (CH), 126.73 (CH),
126.8 (CH), 127.0 (CH), 127.5 (CH), 127.7 (CH), 127.8 (CH),
127.93 (CH), 127.97 (CH), 128.1 (CH), 128.6 (CH), 128.9 (CH),
129.84 (CH), 129.87 (CH), 130.30 (CH), 130.32 (CH), 131.1 (ipso
C), 132.2 (br., CH), 132.4 (br., CH), 132.5 (ipso C), 132.6 (ipso C),
133.19 (CH), 133.25 (ipso C), 133.27 (ipso C), 135.1 (CH), 135.2
(CH), 137.6 (CH), 137.8 (CH), 148.6 (ipso C), 148.86 (ipso C),
148.87 (ipso C), 150.4 (ipso C), 167.21 (ipso C), 167.25 (ipso C),
and 171.2 (ipso C) ppm. 31P{1H} NMR (162 MHz, CDCl3): δ =
Asymmetric Allylic Alkylation (AAA) Studies. General Procedure:
See Table 1, entry 1. A solution of [(η3-C3H5)PdCl]2 (1.4 mg, 3.8
µmol, 1.8 mol-%) and ligand (Sa)-(–)-5a (4.5 mg, 9.1 µmol, 4.3 mol-
%) in CH2Cl2 (0.9 mL) was stirred at room temperature for 30 min.
The resulting pale yellow solution was added to (Ϯ)-(E)-1,3-di-
phenyl-2-propenyl acetate (19)[35] (53.7 mg, 0.21 mmol) and stirred
for an additional 5 min. Dimethyl malonate (18) (51 µL,
0.45 mmol), N,O-bis(trimethylsilyl)acetamide (BSA, 111 µL,
0.45 mmol), and a pinch of KOAc (≈ 1 mg) were added. The re-
sulting yellow mixture was stirred at room temperature for 24 h,
quenched with satd. NH4Cl, and extracted with CH2Cl2. The com-
bined organic extracts were dried (MgSO4), and the solvents evapo-
rated in vacuo to give a yellow oil (91 mg). The level of conversion
of (Ϯ)-(19) and the yield of 20 were estimated by 1H NMR
(300 MHz, CDCl3) analysis. Alternatively, purification by flash
chromatography (silica gel; hexane/EtOAc, 9:1) gave the title com-
pound 20 (67 mg, 97%) as a clear oil: Rf = 0.25 (hexane/EtOAc,
42.75 (br. s) ppm. IR (CHCl ): νmax = 3020, 2906, 2851, 1547, 1436,
˜
3
1
and 1305 cm–1. IR (KBr): νmax = 2900, 1554, 1502, 1489, 1454, and
9:1). H NMR (300 MHz, CDCl3): δ = 3.49 (s, 3 H), 3.68 (s, 3 H),
˜
1435 cm–1. HRMS calcd. for C54H51N3PPd (M – Cl–) 878.2855,
found 878.2820. Crystals of (Ra,R)-(+)-17b suitable for X-ray dif-
fraction analysis were grown by slow evaporation of a CHCl3/pen-
tane solution. For the crystallographic data, see Supporting In-
formation. (sp,cis)-Chloro{1-[(1R)-1-(dimethylamino-κN)ethyl]-2-
naphthalenyl-κC}{(Sa)-4-[2-(diphenylphosphanyl-κP)-1-naphtha-
lenyl]-2-(1-adamantyl)quinazoline}palladium (Sa,R)-(–)-16b (SO-
3.93 (d, J = 10.9 Hz, 1 H), 4.24 (dd, J = 10.9, 8.3 Hz, 1 H), 6.30
(dd, J = 15.7, 8.3 Hz, 1 H), 6.45 (d, J = 15.8 Hz, 1 H), and 7.15–
7.33 (m, 10 H). Its enantiomeric composition (89.2% ee) was estab-
lished by CSP HPLC [Figure S3; Daicel’s Chiralpak® AD,
4.6 mmϫ25 cm; hexanes/2-propanol, 95:5; 1.0 mLmin–1; 10 °C;
250 nm; tR1 = 16.1 min for (R)-20 and tR2 = 24.2 min for (S)-20],
and its optical rotation was compared with the literature data[36]
to assign the absolute configuration of the major (dextrorotatory)
enantiomer as R.
LID 2): a yellow solid; [α]2D0 = –130 (c = 1.06, CHCl3). H NMR
1
(400 MHz, [D6]Me2CO): δ = 1.68–1.79 (m, 6 H), 1.88 (d, J =
6.2 Hz, 3 H), 1.88–2.03 (m, 9 H), 2.43 (br. s, 3 H), 2.87 (s, 3 H),
4.43 (quint, J = 6.2 Hz, 1 H), 6.56 (d, J = 8.5 Hz, 1 H), 6.66 (br.
s, 3 H), 6.82–6.98 (m, 2 H), 7.14–7.33 (m, 6 H), 7.37 (ddd, J = 8.2,
6.8, 1.3 Hz, 1 H), 7.41–7.54 (m, 4 H), 7.58 (ddd, J = 8.1, 7.0,
1.0 Hz, 1 H), 7.59–7.67 (m, 2 H), 7.70 (ddd, J = 8.1, 6.9, 1.2 Hz, 2
H), 7.77 (d, J = 8.4 Hz, 2 H), 8.05 (d, J = 8.2 Hz, 1 H), and 8.08–
8.16 (m, 1 H) ppm. 1H NMR (400 MHz, CDCl3): δ = 1.69–1.79
(m, 6 H), 1.85–1.96 (m, 6 H), 1.96–2.06 (m, 6 H), 2.55 (br. s, 3 H),
2.92 (s, 3 H), 4.25 (quint, J = 6.1 Hz, 1 H), 6.50–6.70 (br. s, 3 H),
General Procedure for Metalation of Phosphane (؎)-(5a): A solu-
tion of iPr2NH (63 µL, 0.45 mmol) and KOtBu (50 mg, 0.45 mmol)
in THF (5 mL) was cooled to –78 °C. BuLi (2.5  in hexanes, 180
µL, 0.45 mmol) was added dropwise, and the resulting yellow solu-
tion was warmed to –50 °C over 35 min. A solution of phosphane
(Ϯ)-(5a) (149 mg, 0.30 mmol) in THF (2 mL) was added dropwise,
and the mixture was stirred between –50 and –40 °C for 1 h to give
a dark blue solution. The reaction mixture was re-cooled to –78 °C,
treated with an appropriate electrophile (3–30 equiv.), and stirred
6.59 (d, J = 8.6 Hz, 1 H), 6.80 (br. s, 1 H), 6.91 (d, J = 8.5 Hz, 1 at a specified temperature for a specified period of time. After hy-
Eur. J. Org. Chem. 2008, 5055–5066
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5063

T. Fekner, H. Müller-Bunz, P. J. Guiry
FULL PAPER
drolysis with H2O (3 mL), the reaction mixture was warmed to
room temperature, and then extracted with CH2Cl2. The combined
organic extracts were dried (MgSO4) and the solvents evaporated in
vacuo. Purification by flash chromatography furnished the desired
product.
(400 MHz, CDCl3): δ = 1.81–1.92 (m, 1 H), 1.98–2.09 (m, 1 H),
2.55–2.71 (m, 2 H), 2.73–2.88 (m, 2 H), 3.61 (s, 3 H), 7.12 (d, J =
8.4 Hz, 1 H), 7.17–7.37 (m, 13 H), 7.40 (dd, J = 8.5, 3.1 Hz, 1 H),
7.53 (ddd, J = 8.2, 6.9, 1.0 Hz, 1 H), 7.86 (ddd, J = 8.4, 5.8, 2.5 Hz,
1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 8.5 Hz, 1 H), and 8.15
(d, J = 8.5 Hz, 1 H) ppm. 13C{1H}/13C DEPT-135 NMR
(101 MHz, CDCl3):[30] δ = 16.2 (CH2), 30.38 (CH2), 30.4 (CH2),
52.1 (CH3), 55.5 (ipso C), 123.68 (ipso C), 123.71 (ipso C), 126.21
(CH), 126.23 (CH), 126.7 (CH), 126.8 (CH), 127.0 (CH), 127.1
(CH), 128.06 (CH), 128.12 (ipso C), 128.19 (CH), 128.21 (CH),
128.28 (CH), 128.33 (CH), 128.4 (CH), 128.6 (CH), 128.8 (CH),
129.2 (CH), 129.99 (CH), 130.00 (CH), 131.9 (ipso C), 132.0 (ipso
C), 133.0 (CH), 133.2 (CH), 133.5 (CH), 133.6 (CH), 133.7 (CH),
133.8 (ipso C), 134.1 (ipso C), 134.3 (ipso C), 136.6 (ipso C), 136.7
(ipso C), 137.2 (ipso C), 137.3 (ipso C), 142.0 (ipso C), 142.3 (ipso
C), 150.2 (ipso C), 166.3 (ipso C), 169.6 (ipso C), 169.7 (ipso C),
and 175.2 (ipso C) ppm. 31P{1H} NMR (101 MHz, CDCl3): δ =
Deuterium Incorporation into Phosphane (؎)-(5a): Preparation of
(؎)-2-(1-Deuteriocyclobutyl)-4-(2-diphenylphosphanylnaphthalen-1-
yl)quinazoline (21a): Phosphane (Ϯ)-(5a) (149 mg, 0.30 mmol) was
metalated as described in the general procedure and treated with
D2O (99.9% D, 540 µL, 30 mmol). The reaction mixture was then
stirred at –78 °C for 10 min. The standard workup provided a crude
product as a pale yellow oil. Purification by chromatography (silica
gel; hexanes/EtOAc, 10:1) gave the title compound 21a (145 mg,
97%, 98% D) as a clear oil: Rf = 0.35 (hexane/EtOAc, 5:1). 1H
NMR (400 MHz, CDCl3): δ = 1.64–1.82 (m, 1 H), 1.88–2.02 (m, 1
H), 2.16–2.40 (m, 4 H), 3.88 (quint, J = 8.8 Hz, 0.02 H), 7.09 (d,
J = 8.5 Hz, 1 H), 7.12–7.18 (m, 2 H), 7.13–7.33 (m, 11 H), 7.37
(dd, J = 8.5, 3.2 Hz, 1 H), 7.47 (dd, J = 8.1, 6.8 Hz, 1 H), 7.78 (dd,
J = 8.4, 6.6 Hz, 1 H), 7.88 (d, J = 8.2 Hz, 1 H), 7.90 (d, J = 8.4 Hz,
1 H), and 8.07 (d, J = 8.5 Hz, 1 H) ppm. 13C{1H} NMR (101 MHz,
CDCl3):[30,37] δ = 18.3, 27.0, 27.2, 27.3, 27.5, 42.9 (t, J = 20.7 Hz),
43.3, 123.5, 123.6, 126.2, 126.3, 126.6, 126.7, 126.9, 127.0, 128.0,
128.19, 128.24, 128.26, 128.27, 128.34, 128.5, 129.1, 130.00, 130.01,
131.8, 131.9, 133.3, 133.4, 133.5, 133.6, 134.3, 134.5, 136.5, 136.6,
137.3, 137.4, 142.0, 142.4, 150.4, 168.7, 169.16, and 169.22 ppm.
31P{1H} NMR (101 MHz, CDCl3): δ = –13.5 ppm. IR (CHCl3):
–13.9 ppm. IR (CHCl ): ν
= 1731, 1552, 1435, 1334, and
˜
3
max
1280 cm–1. HRMS calcd. for C36H30N2O2P [MH+] 553.2045, found
553.2018.
Phenyl(1-{4-[2-(Diphenylphosphanyl)naphthalen-1-yl]quinazolin-2-yl}-
cyclobutyl)methanol (21d): Phosphane (Ϯ)-(5a) (149 mg,
0.30 mmol) was metalated as described in the general procedure
and treated with benzaldehyde (91 µL, 0.90 mmol). The reaction
mixture was stirred at –78 °C for 1 h. The standard workup pro-
vided a crude product as a yellow oil. Purification by flash
chromatography (silica gel; hexanes/EtOAc, 10:1Ǟ5:1) gave the
title compound 21d (173 mg, 96%)[38] as a white foam: Rf = 0.25
ν
max = 1615, 1569, 1548, 1491, 1435, and 1334 cm–1. HRMS calcd.
˜
for C34H27DN2P [MH+] 496.2053, found 496.2037.
1
(hexane/EtOAc, 5:1). H NMR (400 MHz, CDCl3): δ = 1.59–1.83
1-{4-[2-(Diphenylphosphanyl)naphthalen-1-yl]quinazolin-2-yl}cyclo-
butanecarbaldehyde (21b): Phosphane (Ϯ)-(5a) (149 mg, 0.30
mmol) was metalated as described in the general procedure and
treated with ethyl formate (72 µL, 0.90 mmol). The reaction mix-
ture was stirred at –78 °C for 30 min. The standard workup pro-
vided a crude product as a yellow oil. Purification by flash
chromatography (silica gel; hexanes/EtOAc, 10:1Ǟ5:1) gave the ti-
tle compound 21b (145 mg, 92%) as a white foam: Rf = 0.35 (hex-
(m, 0.9 H, minor 2 H), 1.83–1.98 (m, 1.2 H, major 2 H), 1.98–2.11
(m, 0.6 H, major 1 H), 2.15–2.26 (m, 0.4 H, minor 1 H), 2.30–2.40
(m, 0.6 H, major 1 H), 2.40–2.50 (m, 1.0 H, major 1 H and minor
1 H), 2.65–21.83 (m, 0.7 H, minor 2 H), 3.10–3.22 (m, 0.5 H, major
1 H), 5.15 (br. d, J ≈ 5.5 Hz, 0.6 H, major 1 H), 5.19 (br. s, 0.4 H,
minor 1 H), 5.79 (br. d, J ≈ 5.5 Hz, 0.6 H, major 1 H), 5.91 (br. s,
0.4 H, minor 1 H), 6.90 (≈ d, J = 8.4 Hz, 1 H), 7.10–7.45 (m, 19
H), 7.51–7.61 (m, 1 H), 7.81–7.90 (m, 1 H), 7.92–8.03 (m, 3 H), and
8.05–8.14 (m, 1 H) ppm. 13C{1H}/13C DEPT-135 NMR (101 MHz,
CDCl3):[30] δ = 15.30 (CH2), 15.34 (CH2), 27.1 (CH2), 27.6 (CH2),
31.4 (CH2), 31.9 (CH2), 53.06 (ipso C), 53.12 (ipso C), 79.3 (CH),
79.4 (CH), 126.05 (CH), 126.07 (CH), 126.07 (CH), 126.6 (CH),
126.7 (CH), 126.8 (CH), 126.91 (CH), 126.96 (CH), 127.03 (CH),
127.05 (CH), 127.11 (CH), 127.13 (CH), 127.5 (CH), 127.6 (CH),
128.0 (CH), 128.17 (CH), 128.27 (CH), 128.30 (CH), 128.31 (CH),
128.34 (CH), 128.36 (CH), 128.40 (CH), 128.41 (CH), 128.42 (CH),
128.46 (CH), 128.60 (CH), 128.64 (CH), 128.66 (CH), 129.2 (CH),
129.4 (CH), 129.86 (CH), 129.86 (CH), 129.90 (CH), 129.91 (CH),
131.56 (ipso C), 131.64 (ipso C), 131.74 (ipso C), 131.82 (ipso C),
132.94 (CH), 133.00 (CH), 133.1 (CH), 133.2 (CH), 133.38 (ipso
C), 133.42 (CH), 133.5 (CH), 133.6 (CH), 133.7 (CH), 133.89 (CH),
133.92 (CH), 133.94 (CH), 134.03 (ipso C), 134.06 (ipso C), 134.2
(ipso C), 136.1 (ipso C), 136.2 (ipso C), 136.4 (ipso C), 136.5 (ipso
C), 136.8 (ipso C), 136.9 (ipso C), 137.1 (ipso C), 137.2 (ipso C),
141.4 (ipso C), 141.67 (ipso C), 141.68 (ipso C), 142.0 (ipso C), 142.1
(ipso C), 142.5 (ipso C), 149.7 (ipso C), 149.9 (ipso C), 168.56 (ipso
C), 168.58 (ipso C), 168.62 (ipso C), 169.0 (ipso C), 169.1 (ipso C),
and 169.3 (ipso C) ppm. 31P{1H} NMR (101 MHz, CDCl3): δ =
1
ane/EtOAc, 5:1). H NMR (400 MHz, CDCl3): δ = 1.62–1.87 (m,
2 H), 2.28–2.50 (m, 4 H), 6.93–7.34 (m, 15 H), 7.41 (≈ t, J = 7.5 Hz,
1 H), 7.58–7.84 (m, 3 H), 8.01 (dd, J = 8.4, 0.4 Hz, 1 H), and 9.73
(s 1 H) ppm. 13C{1H}/13C DEPT-135 NMR (101 MHz, CDCl3)[30]
δ = 15.4 (CH2), 27.2 (CH2), 27.7 (CH2), 59.5 (ipso C), 123.61 (ipso
C), 123.63 (ipso C), 126.04 (CH), 126.06 (CH), 126.8 (CH), 127.0
(CH), 127.1 (CH), 127.4 (CH), 128.1 (CH), 128.2 (CH), 128.31
(CH), 128.34 (CH), 128.35 (CH), 128.41 (CH), 128.6 (CH), 129.3
(CH), 129.98 (CH), 129.98 (CH), 131.7 (ipso C), 131.8 (ipso C),
133.1 (CH), 133.3 (CH), 133.37 (ipso C), 133.43 (CH), 133.6 (CH),
133.9 (CH), 134.2 (ipso C), 134.3 (ipso C), 136.3 (ipso C), 136.4
(ipso C), 137.0 (ipso C), 137.2 (ipso C), 141.6 (ipso C), 141.9 (ipso
C), 150.4 (ipso C), 165.4 (ipso C), 169.7 (ipso C), 169.8 (ipso C),
200.3 (ipso C) ppm. 31P{1H} NMR (101 MHz, CDCl3): δ = –13.5
ppm. IR (CHCl ): ν
= 1717, 1615, 1548, 1490, 1435, and
˜
3
max
1335 cm–1. HRMS calcd. for C35H28N2OP [MH+] 523.1939, found
523.1919.
Methyl 1-{4-[2-(Diphenylphosphanyl)naphthalen-1-yl]quinazolin-2-
yl}cyclobutanecarboxylate (21c): Phosphane (Ϯ)-(5a) (149 mg,
0.30 mmol) was metalated as described in the general procedure
and treated with dimethyl carbonate (76 µL, 0.90 mmol). The reac-
tion mixture was stirred at –45 °C for 3 h and then warmed to
room temperature. The standard workup provided a crude product
as a yellow oil. Purification by flash chromatography (silica gel;
hexanes/EtOAc, 10:1Ǟ5:1) gave the title compound 21c (105 mg,
63 %) as a clear oil: Rf = 0.30 (hexane/EtOAc, 5:1). 1H NMR
–14.2 and –13.9 ppm. IR (CHCl ): ν = v
3352 (br), 1558, 1491,
˜
3
max
1435, (and 1335) cm–1. HRMS calcd. for C41H34N2OP [MH+]
601.2409, found 601.2394.
Supporting Information (see also the footnote on the first page of
this article): CSP HPLC profiles for 5a,b, 1H/13C/31P NMR spectra
5064
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5055–5066

Synthesis and Resolution of Atropisomeric P,N Ligands
dation, respectively, at phosphorus. For the relevant phos-
phane/phosphane oxide [(Ϯ)-5a/5a-(O)] and phosphane oxide
[(Sa)-5b-(O)] crystal structures, see Supporting Information.
For selected examples of ortho-palladated N donor ligands as
resolving agents for Lewis bases, see: a) J. Albert, R. Bosque,
J. M. Cadena, S. Delgado, J. Granell, G. Muller, J. I. Ordinas,
M. F. Bardia, X. Solans, Chem. Eur. J. 2002, 8, 2279–2287; b)
S. B. Wild, Coord. Chem. Rev. 1997, 166, 291–311.
a) J. W. L. Martin, F. S. Stephens, K. D. V. Weerasuria, S. B.
Wild, J. Am. Chem. Soc. 1988, 110, 4346–4356; b) J. W. L. Mar-
tin, J. A. L. Palmer, S. B. Wild, Inorg. Chem. 1984, 23, 2664–
2668.
for all new compounds, and additional views of X-ray single-crystal
structures of (Ϯ)-5a/5a-(O), and (Sa)-5b-(O), (Sa,R)-(–)-16a, and
(Ra,R)-(+)-17b.
[17]
Acknowledgments
This work was supported by the European Community’s Sixth
Framework Programme (FP6-505267-1). A generous donation of
equipment by Radleys Discovery Technologies, Ltd. is also grate-
fully acknowledged. We thank Dr. Dilip Rai, UCD, for recording
the MS spectra.
[18]
[19]
Crystal data for (Sa,R)-(–)-16a: C50H45N3PCl7Pd; MW =
1073.41; 0.80ϫ0.70ϫ0.50 mm; monoclinic; space group P21
(#4); T = 100(2) K; λ = 0.71073 Å; a = 9.7033(8), b =
12.3291(11),
c = 20.0872(17) Å; β = 92.397(2)°; V =
[1] M. McCarthy, P. J. Guiry, Tetrahedron 2001, 57, 3809–3844.
[2] T. P. Dang, H. B. Kagan, J. Chem. Soc., Chem. Commun. 1971,
481.
2401.0(4) Å3; Z = 2; Dcalc = 1.485 Mg m–3; F(000) = 1092;
µ(Mo-Kα) = 0.848 mm–1; 19437 reflections collected with 1.01
Ͻ Θ Ͻ 26.00°, 9289 of which were independent (Rint = 0.0338);
594 parameters; R1 = 0.0428, wR2 = 0.1009 [for reflections with
IϾ2σ(I)]; R1 = 0.0510, wR2 = 0.1253 (all data); –0.05(3)
(Flack). Crystal data for (Ra,R)-(+)-17b: C54H51N3PClPd; MW
= 914.80; 0.30ϫ0.20ϫ0.10 mm; orthorhombic; space group
P212121 (#19); T = 100(2) K; λ = 0.71073 Å; a = 13.4372(8), b
= 15.4246(9), c = 20.7925(12) Å; V = 4309.5(4) Å3; Z = 4; Dcalc
= 1.410 Mg m–3; F(000) = 1896; µ(Mo-Kα) = 0.572 mm–1;
42261 reflections collected with 1.64 Ͻ Θ Ͻ 29.08°, 10571 of
which were independent (Rint = 0.0323); 544 parameters; R1 =
[3] a) H. Kumobayashi, T. Miura, N. Sayo, T. Saito, X. Zhang,
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[6] P. Kocˇovský, S. Vyskocˇil, M. Smrcˇina, Chem. Rev. 2003, 103,
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Layzell, J. M. Brown, Chem. Eur. J. 1999, 5, 1320–1330; c) J. M.
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[9] For other notable examples of atropisomeric P,N ligands, see:
a) T. F. Knöpfel, P. Aschwanden, T. Ichikawa, T. Watanabe,
E. M. Carreira, Angew. Chem. Int. Ed. 2004, 43, 5971–5973; b)
F. Y. Kwong, Q. Yang, T. C. W. Mak, A. S. C. Chan, K. S.
Chan, J. Org. Chem. 2002; 67, 2769–2777.
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[11] An even sterically more encumbered ligand, 2-(9-triptycyl)-
Quinazolinap, has also been prepared. Unfortunately, it has so
far resisted all our attempts at optical resolution.
[12] D. J. Connolly, P. J. Guiry, Synlett 2001, 11, 1707–1710.
[13] a) S. B. Mhaske, N. P. Argade, J. Org. Chem. 2004, 69, 4563–
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0.0309, wR2 = 0.0782 [for reflections with IϾ2σ(I)]; R1
0.0326, wR2 = 0.0790 (all data); –0.005(16) (Flack). Crystal
data for (Sa)-5b-(O): C40H37N2O2P; MW 608.69;
=
=
0.80ϫ0.80ϫ0.60 mm; orthorhombic; space group P212121
(#19); T = 100(2) K; λ = 0.71073 Å; a = 11.508(4), b =
13.208(4), c = 20.400(7) Å; V = 3100.8(18) Å3; Z = 4; Dcalc
=
1.304 Mg m–3; F(000) = 1288; µ(Mo-Kα) = 0.129 mm–1; 29056
reflections collected with 1.84 Ͻ Θ Ͻ 28.00°, 7453 of which
were independent (Rint = 0.0422); 414 parameters; R1 = 0.0397,
wR2 = 0.0977 [for reflections with IϾ2σ(I)]; R1 = 0.0461, wR2
= 0.1075 (all data); –0.05(7) (Flack). CCDC-693169 for (Ϯ)-
5a/5a-(O), -693170 for (Ra,R)-(+)-17b, -693171 for (Sa)-5b-(O),
and -693172 for (Sa,R)-(–)-16a contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[20]
a) J. D. McFarlane, J. D. Swarbrick, J. I. Bookham, J. Chem.
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dron: Asymmetry 1996, 7, 285–292.
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a) J. A. N. F. Gomes, R. B. Mallion, Chem. Rev. 2001, 101,
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An analogous trend is observed for the cyclobutyl-based iso-
mers (Sa,R)-(–)-16a (δ = 6.48 ppm) and (Ra,R)-(+)-17a (δ =
5.95 ppm). The 1H NMR signals of H(3Ј) can therefore be po-
tentially used as a diagnostic tool for the determination of the
absolute configuration of Quinazolinaps. For a similar phe-
nomenon in a series of centrally-chiral bidentate quinoline-
based P,N ligands, see: D. G. Allen, G. M. McLaughlin, G. B.
Robertson, W. L. Steffen, G. Salem, S. B. Wild, Inorg. Chem.
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a) B. M. Trost, J. Org. Chem. 2004, 69, 5813–5837; b) B. M.
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Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 336–345; d)
M. Johannsen, K. A. Jørgensen, Chem. Rev. 1998, 98, 1689–
1708; e) B. M. Trost, D. L. van Vranken, Chem. Rev. 1996, 96,
395–422.
[23]
[24]
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even, P. J. Reider, J. Org. Chem. 1994, 59, 7180–7181.
[16] When it was attempted to grow single crystals of (Ϯ)-5a and
(Sa)-5b, the compounds underwent partial and complete oxi-
C. Margot, M. Schlosser, Tetrahedron Lett. 1985, 26, 1035–
1038.
Eur. J. Org. Chem. 2008, 5055–5066
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5065

T. Fekner, H. Müller-Bunz, P. J. Guiry
FULL PAPER
[25] For metalation of 2-isopropylpyridine with LIDAKOR, see: E.
Pasquinet, P. Rocca, F. Marsais, A. Godard, G. Quéguiner, Tet-
rahedron 1998, 54, 8771–8782.
tin, J. A. L. Palmer, S. B. Wild, Inorg. Chem. 1984, 23, 2664–
2668; c) D. G. Allen, G. M. McLaughlin, G. B. Robertson,
W. L. Steffen, G. Salem, S. B. Wild, Inorg. Chem. 1982, 21,
1007–1014.
[26] We have used this approach to convert iPr-Quinazolinap into
The 1H, 13C, and 31P NMR spectroscopic data as well as Rf
(TLC) were identical to those listed for racemic 5a. Because
phosphanes (Sa)-(–)-5a and (Ra)-(+)-5a (unlike the racemic 5a)
failed to provide crystalline materials from various solvent sys-
tems tested, their further enantiomeric enrichment, if desired,
should be performed prior to the removal of the chiral auxil-
iary [i.e., for PdII complexes (Sa,R)-(–)-16a and (Ra,R)-(+)-17a].
tridentate
Quinazoline–Oxazoline-containing
(Quinazox)
[33]
P,N,N ligands (manuscript in preparation) thus improving
upon the previously reported multi-step synthesis.[10a]
[27] D. D. Perrin, W. L. F. Armarego, Purification of Laboratory
Chemicals, Pergamon Press, 1988, New York.
[28] W. C. Still, M. Hahn, A. Mitra, J. Org. Chem. 1978, 43, 2923–
2925.
[29] Aryl chlorides 10a and 10b are relatively unstable. Upon stor-
age at room temperature they significantly degrade within
weeks. They should, therefore, be used shortly after their prep-
aration.
[30] Due to the spectrum complexity, the C–P and C–Pd (if appli-
cable) couplings were not assigned.
[31] When a sample of phosphane (Ϯ)-5b was heated from 210 °C
at a rate of 1 °Cmin–1, it softened at 212 °C and then melted
at 235.5–236.5 °C. Alternatively, when a sample of phosphane
(Ϯ)-5b was placed in a melting-point apparatus pre-heated to
213 °C, it melted at this temperature.
[32] a) J. W. L. Martin, F. S. Stephens, K. D. V. Weerasuria, S. B.
Wild, J. Am. Chem. Soc. 1988, 110, 4346–4356; b) J. W. L. Mar-
The 1H, 13C, and 31P NMR spectroscopic data as well as Rf
(TLC) were identical to those listed for racemic 5b.
[34]
[35]
I. D. G. Watson, S. A. Styler, A. K. Yudin, J. Am. Chem. Soc.
2004, 126, 5086–5087.
[36] a) J. Sprintz, G. Helmchen, Tetrahedron Lett. 1993, 34, 1769–
1772; b) T. Mino, A. Saito, Y. Tanaka, S. Hasegawa, Y. Sato,
M. Sakamoto, T. Fujita, J. Org. Chem. 2005, 70, 1937–1940.
[37] The signals at δ = 27.2, 27.5, and 43.3 ppm are attributed to
the non-deuterated phosphane 5a.
[38] A mixture of diastereomers (major:minor ≈ 6:4).
Received: July 1, 2008
Published Online: September 12, 2008
5066
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Eur. J. Org. Chem. 2008, 5055–5066