Synthesis and Resolution of Quinazolinone Atropisomeric Phosphine Ligands

Article abstract of DOI:10.1021/jo972105z

The syntheses of 2-methyl-3-[2′-(diphenylphosphino)phenyl]-4(3H)-quinazolinone (MPQ, 1a) and methyl-substituted analogues were achieved in good yield by coupling N-acetylanthranilic acid with the corresponding phosphinoanilines. Resolution of ligand 1b was achieved using (-)-di-μ-chlorobis-[(S)-dimethyl-(1-phenylethyl)aminato-C ²,N]dipalladium(II) (5). The resulting crystalline complex (S,R)-6 served to unambiguously assign the absolute configuration of antipode (R)-(-)-1b. A practical resolution of this series of ligands 1a-c was accomplished using the (benzenesulfonyl-)hydrazone derivative of camphorsulfonic acid (7) as a resolving agent.

Full text of DOI:10.1021/jo972105z

J . Org. Chem. 1998, 63, 2597-2600
2597
Syn th esis a n d Resolu tion of Qu in a zolin on e Atr op isom er ic
P h osp h in e Liga n d s†,‡
Xuedong Dai, Audrey Wong, and Scott C. Virgil*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue,
Cambridge, Massachusetts 02139
Received November 17, 1997
The syntheses of 2-methyl-3-[2’-(diphenylphosphino)phenyl]-4(3H)-quinazolinone (MPQ, 1a ) and
methyl-substituted analogues were achieved in good yield by coupling N-acetylanthranilic acid with
the corresponding phosphinoanilines. Resolution of ligand 1b was achieved using (-)-di-µ-chlorobis-
[(S)-dimethyl-(1-phenylethyl)aminato-C2,N]dipalladium(II) (5). The resulting crystalline complex
(S,R)-6 served to unambiguously assign the absolute configuration of antipode (R)-(-)-1b.
A
practical resolution of this series of ligands 1a -c was accomplished using the (benzenesulfonyl-
)hydrazone derivative of camphorsulfonic acid (7) as a resolving agent.
Sch em e 1. P r ep a r a tion of th e Ra cem ic Liga n d s
In tr od u ction
1a -c
Asymmetric catalysis has been advanced in many
areas by the discovery and application of the atropiso-
meric ligand BINAP.1 The chiral environment imposed
by the orthogonal naphthalene rings as well as the
chelating nature of this ligand has proven effective for
inducing high stereoselectivity in a variety of asymmetric
reactions.2 More recently, the binaphthylmonophos-
phines (MOP’s) and related ligands have also found use
in catalytic asymmetric reactions.3 As an addition to this
class of atropisomeric phosphine ligands, we have devel-
oped an efficient synthesis and resolution of the quinazoli-
none-containing atropisomeric phosphine ligands 1a -c.
substituted ligands 1b and 1c would be essentially inert
to racemization by N-Caryl bond rotation.
Resu lts a n d Discu ssion
Tw o-Sta ge Syn th esis of Liga n d 1a -c. Our syn-
thesis begins with the preparation of phosphinoanilines
4a -c from the commercially available chloroanilines by
Cooper’s method (Scheme 1).5 The anilines 2a -c were
reacted with triphenylphosphine and anhydrous nickel-
(II) chloride to afford the phosphonium salts 3a -c after
aqueous acidic workup and recrystallization from tet-
rahydrofuran. Reduction of 3a -c with sodium naphtha-
lenide at -78 °C afforded the phosphinoanilines 4a -c
in 71-84% yield after recrystallization. We found the
removal of naphthalene by sublimation allowed a more
straightforward isolation and higher yields than Cooper’s
reported two-step procedure.
The atropisomeric nature of substituted quinazolinones
has been studied in connection with their medicinal
properties. In particular, the activation barrier for
racemization of 2-methyl-3-o-tolyl-4(3H)-quinazolinone
(methaqualone) was found to be 31.5 kcal/mol at 135 °C
in diphenyl ether.4 We therefore expected that ligand
1a would possess a suitable activation barrier to race-
mization to allow resolution and that the methyl-
† Dedicated to Professor E. J . Corey with deep respect on the
occasion of his 70th birthday.
‡ Presented at the 214th National American Chemical Society
Meeting, Las Vegas, NV, Sep 1997; ORGN 224.
(1) Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi,
H.; Taketomi, T.; Akutagawa, S.; Noyori, R. J . Org. Chem. 1986, 51,
629.
(2) Noyori, R. Asymmetric Catalysis in Organic Synthesis; J ohn
Wiley & Sons: New York, 1994; Chapter 1.
Reaction of the phosphinoanilines 4a -c with N-acetyl-
anthranilic acid and benzenesulfonyl chloride6 as the
coupling agent afforded the racemic ligands 1a -c in 65-
(3) (a) Uozumi, Y.; Tanahashi, A.; Lee, S.-Y.; Hayashi, T. J . Org.
Chem. 1993, 58, 1945. (b) Hayashi, T.; Iwamura, H.; Uozumi, Y.;
Matsumoto, Y.; Ozawa, F. Synthesis 1994, 15, 526. (c) Alcock, N. W.;
Brown, J . M.; Hulmes, D. I. Tetrahedron: Asymmetry 1993, 4, 743.
(4) Mannschreck, A.; Koller, H.; Stu¨hler, G.; Davies, M. A.; Traber,
J . Eur. J . Med. Chem. Chim. Ther. 1984, 19, 381.
(5) (a) Cooper, M. K.; Downes, J . M.; Duckworth, P. A. Inorg. Synth.
1989, 25, 129. (b) Cooper, M. K.; Downes, J . M.; Duckworth, P. A.;
Tiekink, E. R. T. Aust. J . Chem. 1992, 45, 595.
(6) J ackman, G. B.; Petrow, V.; Stephenson, O. J . Pharm. Pharma-
col. 1960, 12, 529.
S0022-3263(97)02105-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/25/1998

2598 J . Org. Chem., Vol. 63, No. 8, 1998
Dai et al.
istry of the phosphine ligand chiral axis is assigned as R
according to the Cahn-Ingold-Prelog rule.10
Rota tion a l Ba r r ier of Liga n d s 1a ,b. A study on the
thermal racemization of 1a and 1b was conducted by
heating their toluene solutions to reflux under argon.
Small portions of the solutions were taken out at regular
time intervals up to 96 h and analyzed by chiral HPLC
analysis. For 1a , the t1/2 was found to be 40 h at 110 °C,
which corresponds to a rotational barrier (∆Gq) of 32 kcal/
mol. As for 1b, which has an extra o-methyl group, there
was no detectable racemization after 96 h at relux in
toluene.
Resolu tion of th e Liga n d s 1a -c Usin g a New
Resolvin g Agen t. To achieve larger scale and economi-
cal resolution of the ligands 1a -c, a suitable acid-
resolving agent was sought to ionize the nitrogen of the
quinazolinone ring. Since quinazolinone derivatives are
only weakly basic (pKa ≈ 2.2), the field of possible
resolving acids has been limited to camphorsulfonic
acid.11,12 When ligand 1a and (S)-camphorsulfonic acid
((S)-CSA) were combined in equimolar proportions in
ethyl acetate, large hexagonal-shaped crystals were
obtained. Upon neutralization of the 1:1 salt, only
racemic 1a was obtained. Similar results were obtained
for the ligand 1b using (S)-CSA, and no crystalline salt
was obtained using π-bromocamphorsulfonic acid.
X-ray diffraction analysis of the hexagonal salt above
confirmed the composition as ((S)-CSA)2‚((R)-1a )‚((S)-1a )
and further revealed the structural features of this salt
(Figure 2).13 The monoclinic P21 unit cell is divided into
adjacent domains of homotopic salt cores extending along
the crystallographic 21 screw axes. This led us to surmise
that the stronger ionic interactions in the crystal had
achieved the segregation of the two enantiomers of the
ligand 1a while the weaker interactions between the
aromatic rings and (S)-CSA had allowed the quasi-
racemate unit cell to form.14 Indeed, the hydrophobic and
roughly spherical nature of the bicyclic portion of (S)-
CSA seems to adopt analogous positions in the two salt
bridge motifs.
F igu r e 1. ORTEP plot of complex (S,R)-6.
77% yield. In particular, ligand 1c was prepared on a
25 g scale from the readily available dimethylchloro-
aniline 2c.
Con ven t ion a l R esolu t ion of 1b a n d Ab solu t e
Con figu r a tion of P a lla d iu m Com p lex 6. Ligand 1b
was resolved on a 6 g scale using (-)-di-µ-chlorobis[(S)-
dimethyl-(1-phenylethyl)aminato-C2,N]dipalladium(II) (5),
which is a conventional resolving agent for monophos-
phines.7 Reacting dimer (S)-5 with 4 equiv of racemic
1b yielded palladium complex 6 as a yellow crystalline
precipitate that was collected by filtration. The (+)-1b
was recovered from the filtrate in good yield (82%) and
high enantiomeric excess (96% ee as determined by chiral
HPLC). Treatment of the complex 6 with ethylenedi-
amine in CH2Cl2 released the ligand (-)-1b, which was
isolated in 91% yield and 99% ee (HPLC). The resulting
palladium ethylenediamine complex was converted back
to complex 5 in nearly quantitative yield using 2 N
aqueous hydrochloric acid.8
Our solution to the resolution of ligands 1a -c was to
investigate a simple derivative of camphorsulfonic acid
that would more distinctly define the chirality about the
bicyclic core without affecting the ability of the salt bridge
formation. The (benzenesulfonyl)hydrazone of (S)-cam-
phorsulfonic acid (S-CSZ, 7) is readily prepared in 99%
yield by combination of solutions of the two reagents in
The X-ray structure9 of complex 6 displays a significant
π-stacking between one phenyl ring on phosphorus and
the quinazolinone ring system with the palladium center
oriented to the side of the quinazolone methyl group
(Figure 1). On the basis of the known S-stereochemistry
of the phenethylamine ligand, the absolute stereochem-
(10) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; J ohn Wiley & Sons: New York, 1994.
(11) Perrin, D. D. Dissociation Constants of Organic Bases in
Aqueous Solution; International Union of Pure and Applied Chemis-
try: London, 1965; p 227.
(12) Kashima, C.; Katoh, A. J . Chem. Soc., Perkin Trans. 1 1980,
1599.
(13) Crystalline salt ((S)-CSA)2‚((R)-1a )‚((S)-1a ) (C74H74N4O10P2S2;
Mw ) 1305.58 crystallized in the monoclinic P21 space group with cell
dimensions a ) 11.1602(5) Å, b ) 10.8868(5) Å, c ) 27.2325(12) Å, â
) 95.132°, and Z ) 2. A total of 8796 reflections were collected at 20
°C using a Siemens SMART/CCD diffractometer. Least-squares refine-
ment of the data using 4690 reflections converged upon the structure
shown in Figure 2 with R ) 0.1176 and a goodness of fit ) 1.044.
(14) For examples of quasi-racemates, see: (a) Eliel, E. L.; Wilen,
S. H.; Mander, L. N. Stereochemistry of Organic Compounds; J ohn
Wiley & Sons: New York, 1994; Chapter 5. (b) Fredga, A. Tetrahedron
1960, 8, 126. (c) Auburn, M.; Ciriano, M.; Howard, J . A. K.; Murry,
M.; Pugh, N. J .; Spencer, J . L.; Stone, F. G. A.; Woodward, P. J . Chem.
Soc., Dalton Trans. 1980, 659. (d) Schurig, V.; Pille, W.; Winter, W.
Angew. Chem., Int. Ed. Engl. 1983, 22, 327. (e) Alcock, N. W.; Hulmes,
D. I.; Brown, J . M. J . Chem. Soc., Chem. Commun. 1995, 395. (f) Vedejs,
E.; Donde, Y. J . Am. Chem. Soc. 1997, 119, 9293.
(7) (a) Otsuka, S.; Nakamura, A.; Kano, T.; Tani, K. J . Am. Chem.
Soc. 1971, 93, 4301. (b) Tani, K.; Brown, L. D.; Ahmed, J .; Ibers, J . A.;
Yokota, M.; Nakamura, A.; Otsuka, S. J . Am. Chem. Soc. 1977, 99,
7876.
(8) (a) Dunina, V. V.; Golovan’, E. B. Tetrahedron: Asymmetry 1995,
5, 2747. (b) Martin, J . W. L.; Palmer, J . A. L.; Wild, S. B. Inorg. Chem.
1984, 23, 2664.
(9) Complex 6 (C38H37ClN3OPPd; Mw ) 724.53) crystallized in the
orthorhombic P212121 space group with cell dimensions a ) 10.4822-
(7) Å, b ) 17.3192(12) Å, c ) 18.5003(12) Å, and Z ) 4. A total of 13 752
reflections were collected at -85 °C using a Siemens SMART/CCD
diffractometer. Least-squares refinement of the data using 4839
reflections converged upon the structure shown in Figure 1 with R )
0.0308 and a goodness of fit ) 1.114.

Synthesis of Quinazolinone Atropisomeric Phosphine Ligands
J . Org. Chem., Vol. 63, No. 8, 1998 2599
F igu r e 2. X-ray structure of the salt ((S)-CSA)2‚((R)-1a )‚((S)-1a ) showing adjacent crystallographic screw axes. Antipode (R)-1a
and (S)-CSA comprise the extended salt core on the left, while (S)-1a and (S)-CSA are seen at right.
Sch em e 2. Resolu tion of Liga n d 1c Usin g th e
Exp er im en ta l Section
(S)-CSZ (7) Resolvin g Agen t
Tetrahydrofuran was distilled from sodium benzophenone
ketyl under nitrogen. TLC was carried out on silica gel 60-
F254 plates (0.25 mm, E. Merck) and visualized with UV light
and phosphomolybdic acid stain. 1H NMR and 13C NMR
spectra were obtained on a Varian XL-300, Varian Unity-300,
or a Varian VXR-500 spectrometer. 31P NMR spectra were
measured on a Varian XL-300 (121.4 MHz) spectrometer, and
chemical shifts were reported in ppm relative to 85% H3PO4
external standard. HPLC analyses were performed using a
Daicel CHIRALCEL OJ column. 2-Diphenylphosphinoaniline
(4a ) and 6-methyl-2-diphenylphosphinoaniline (4b) were pre-
pared according to Cooper’s procedure with modifications as
described below for 4c.5 (-)-Di-µ-chlorobis[(S)-dimethyl(1-
phenylethyl)aminato-C2,N]dipalladium(II) was prepared ac-
cording to the literature procedure.7
4,6-Dim et h yl-2-(d ip h en ylp h osp h in o)a n ilin e
(4c).5
ethyl acetate and filtration of the resulting precipitate
(Scheme 2). Addition of a solution of 1c to 1 equiv of
(S)-CSZ (7) in hot ethanol and slow cooling to 0 °C caused
precipitation of one antipode as the sulfonate salt that
was collected by filtration. Trituration of the crystalline
salt with ethyl acetate freed the ligand into solution,
leaving behind the recovered (S)-CSZ (7). After washing
with aqueous sodium bicarbonate and recrystallization,
the ethyl acetate solution afforded optically pure (+)-1c
in 73% yield. The concentrated ethanol filtrate treated
in the same manner afforded the antipode (-)-1c in 72%
yield. The above procedure, which can be performed on
a 25 g scale for ligand 1c and also proceeds favorably for
ligands 1a ,b, represents the first preparation of CSA
derivatives such as 7 and their use as resolving agents.
The enantiomeric excess of both resolved samples in each
case was greater than 96%.15
In conclusion, our ligand system represents the first
example of an atropisomeric biaryl phosphine ligand
about a central N-Caryl bond. The quinazolinone ring
structure facilitates a straightforward synthesis that may
be applied to related ligands. The weakly basic imine
nitrogen of this heterocycle is a unique feature allowing
the convenient resolution of 1a -c using a new class of
camphorsulfonic acid (benzenesulfonyl)hydrazone resolv-
ing agents. Furthermore, although poorly positioned for
chelation, the same nitrogen may have an effect on the
asymmetric reactions of chiral ligands based on the
quinazolinone ring system. Further work will be dis-
closed on the catalytic reactions using the ligands de-
scribed above.
2-Chloro-4,6-dimethylaniline (25.0 g, 0.16 mol), triphenylphos-
phine (42.6 g, 0.16 mol), and anhydrous nickel chloride (10.5
g, 0.08 mol) were combined and heated to 200 °C with stirring
and removal of residual water over 4 h. The blue melt was
poured into water (300 mL) and concd HCl (2 mL) and stirred
to dissolve. The aqueous phase was extracted with diethyl
ether (4 × 40 mL) and then with dichloromethane (4 × 50 mL).
The combined CH2Cl2 extracts were dried (MgSO4) and
evaporated to an oil. After addition of tetrahydrofuran (300
mL) and cooling at 4 °C overnight, the resulting white crystals
were collected by filtration, washed with ether, and vacuum-
dried to afford 47.0 g (70%) of phosphonium salt 3c (mp 131.3-
132.5 °C).
An oven-dried, three-neck, 1-L round-bottom flask equipped
with a mechanical stirrer was charged with naphthalene (34.7
g, 0.27 mol) in THF (300 mL) under argon, and sodium metal
pieces (5.7 g, 0.25 mol) were added. After the solution was
stirred for 3 h at room temperature, the solution was cooled
to -78 °C. The powdered phosphonium salt 3c (47.0 g, 0.11
mol) was added with stirring, and the mixture was left
overnight to warm to room temperature. Acetic acid (2.8 mL)
was added dropwise followed by a 20% aqueous ammonium
chloride solution (69 mL). The resulting phases were sepa-
rated, and the aqueous layer was extracted with diethyl ether
(2 × 100 mL). The combined organic phases were dried
(MgSO4) and evaporated to a brown oil. The naphthalene was
removed by sublimation at 60 °C and 0.1 mmHg using a
Kugelrohr apparatus. Recrystallization from ethyl acetate and
hexane (2:3) afforded 24.44 g (71%) of the phosphinoaniline
4c: mp 58.5-59.5 °C; Rf ) 0.47 (silica, 1:2 ethyl acetate/
hexane); FTIR (thin film, cm-1) 3455, 3354, 3050, 2913, 1616,
1585, 1473, 1434, 1236, 743, 696, 490; 1H NMR (300 MHz,
CDCl3) δ 7.21-7.46 (m, 10 H), 6.92 (br s, 1 H), 6.48 (dd, 1 H,
J ) 1.5, 5.5 Hz), 4.07 (br s, 2 H), 2.16 (s, 3 H), 2.10 (s, 3 H);
31P NMR (121.4 MHz) -19.83 (s); HRMS calcd for C20H20NP
(M+) 305.1334, found: 305.1332.
2-Meth yl-3-[6′-m eth yl-2′-(d ip h en ylp h osp h in o)p h en yl]-
4(3H)-qu in a zolin on e (1b). To a solution of N-acetylanthra-
nilic acid (16.58 g, 92.5 mmol) and 4-(dimethylamino)pyridine
(50 mg) in pyridine (27 mL) was added dropwise benzene-
(15) After the palladium resolution, determination of the ee value
of ligands 1a -c was conducted by addition of a slight excess of the
reagent 5 and 1H NMR analysis of the ratio of the palladium complex
6 and its diastereomer in the region of 3.5-7.0 ppm.

2600 J . Org. Chem., Vol. 63, No. 8, 1998
Dai et al.
sulfonyl chloride (PhSO2Cl, 9.64 mL, 75.5 mmol). The result-
ing slurry was treated with a solution of aminophosphine 4b
(10.0 g, 34.4 mmol) in benzene (100 mL), and the mixture was
heated at reflux for 36 h. After cooling, the solvent was
evaporated, and the residue was partitioned with ethyl acetate
(250 mL) and water (50 mL). The aqueous layer was extracted
with ethyl acetate (50 mL), and the combined ethyl acetate
fractions were dried (MgSO4). After removal of the solvent,
crystallization from ethyl acetate (80 mL) and hexane (80 mL)
afforded ligand 1b (11.48 g, 77%) as white needles: mp 169-
170 °C; Rf ) 0.28 (silica, 1:2 ethyl acetate/hexane); FTIR (thin
film, cm-1) 3054, 1683, 1603, 1569, 1472, 1434, 1377, 1326,
Ca m p h or su lfon ic Acid (Ben zen esu lfon yl)h yd r a zon e
(7). To a solution of (1S)-(+)-camphorsulfonic acid (10.73 g,
46.2 mmol) in ethyl acetate (170 mL) and ethanol (30 mL) was
added a solution of (benzenesulfonyl)hydrazine (7.95 g, 46.2
mmol) in ethyl acetate (130 mL). After being stirred for 2 h,
the mixture was filtered to afford 7 as a white solid (17.8 g,
99%): mp 266-268 °C dec; Rf ) 0.58 (silica, 1:2 methanol/
ethyl acetate); FTIR (thin film, cm-1) 3436, 2964, 1673, 1359,
1
1231, 1174, 1041; H NMR (300 MHz, DMF-d7) δ 8.3-9.8 (br
s, 2 H), 7.78 (d, 2 H, J ) 8.3 Hz), 7.49 (t, 1 H, J ) 7.3 Hz),
7.42 (t, 2 H, J ) 7.6 Hz), 3.22 (d, 1 H, J ) 14.7 Hz), 2.66 (d, 1
H, J ) 15.1 Hz), 2.46 (m, 1 H), 2.31 (dt, 1 H, J ) 18.1, 3.9 Hz),
1.84 (d, 1 H, J ) 17.6 Hz), 1.6-1.7 (m, 2 H), 1.21 (m, 1 H),
0.96 (m, 1 H), 0.89 (s, 3 H), 0.46 (s, 3 H); 13C NMR (75 MHz,
CF3COOH-CDCl3) δ 212.3, 137.1, 135.0, 131.1, 129.1, 60.3,
55.7, 50.7, 43.8, 40.6, 30.6, 26.4, 19.6, 18.4; [R]23D ) -9.5° (c )
1.01, DMF); HRMS 386.0972 (calcd for C16H22N2S2O5 (M+)
386.0970).
1
1267, 1116, 774, 743, 696; H NMR (300 MHz, CDCl3) δ 8.07
(dd, 1 H, J ) 1.2, 7.8 Hz), 7.74 (ddd, 1 H, J ) 1.5, 6.9, 8.4 Hz),
7.67 (d, 1 H, J ) 7.8 Hz), 7.33-7.42 (m, 8 H), 7.10-7.25 (m, 6
H), 2.13 (s, 3 H), 2.04 (s, 3 H); 31P NMR (121.4 MHz) -18.2
(s); HRMS 434.1548 (calcd for C28H23N2OP 434.1548). Anal.
C 77.33, H 5.49, N 6.30 (calcd for C28H23N2OP: C 77.41, H
5.34, N 6.45).
Resolu tion of 1c Usin g Resolvin g Agen t 7. In a 200-
mL, round-bottom flask 21.6 g (56.0 mmol, 1.00 equiv) of acid
7 was dissolved in 1200 mL of ethanol at reflux, and 25.1 g
(56.0 mmol, 1.00 equiv) of racemic 1c was added. The clear
solution was cooled slowly to 0 °C and kept at 0 °C overnight.
The crystals were filtered, washed with ethanol (3 × 20 mL),
and air-dried to afford 22.4 g (96%) of white (S)-1c‚7 salt.
Trituration of this salt in ethyl acetate (100 mL) and filtration
freed the ligand. Acid 7 was recovered as a white solid. After
washing with aqueous sodium bicarbonate (2 × 30 mL) and
recrystallization, the ethyl acetate solution afforded optically
2-Me t h yl-3-[2′-(d ip h e n ylp h osp h in o)p h e n yl]-4(3H )-
qu in a zolin on e (1a ). Ligand 1a was obtained as white
needles (65%) under the above conditions: mp 181-182 °C;
Rf ) 0.21 (silica, 1:2 ethyl acetate/hexane); FTIR (thin film,
cm-1) 3053, 1684, 1604, 1566, 1471, 1435, 1377, 1340, 1275,
771, 744, 696; 1H NMR (300 MHz, CDCl3) δ 8.12 (dd, 1 H, J )
1.3, 8.1 Hz), 7.73 (ddd, 1 H, J ) 1.3, 6.9, 8.2 Hz), 7.66 (d, 1 H,
J ) 8.1 Hz), 7.53 (ddd, 1 H, J ) 1.5, 7.6, 7.6 Hz), 7.30-7.47
(m, 8 H), 7.15-7.29 (m, 6 H), 2.05 (s, 3 H); 31P NMR (121.4
MHz) -16.87 (s); HRMS 420.1392 (calcd for C27H21N2OP:
420.1392).
pure (+)-1c (9.05 g, 73%): mp 167-169 °C; [R]23 ) +186° (c
D
) 0.90, CHCl3) (>96% ee).15
2-Me t h yl-3-[4′,6′-d im e t h yl-2′-(d ip h e n ylp h osp h in o)-
p h en yl]-4(3H)-qu in a zolin on e (1c). Ligand 1c was obtained
as white needles (79%) under the above conditions: mp 179-
180 °C; Rf ) 0.34 (silica, 1:2 ethyl acetate/hexane); FTIR (thin
film, cm-1) 3052, 1682, 1602, 1570, 1471, 1434, 1377, 1340,
The ethanolic mother liquor was concentrated to dryness.
The residue was triturated, neutralized, and crystallized as
above to give 9.05 g of white prisms (72%): mp 166-167 °C;
[R]23 ) -193° (c ) 0.90, CHCl3) (>96% ee).15
D
1
Resolu tion of 1b Usin g Resolvin g Agen t 7. Compound
1b was resolved analogously to that described for 1c, starting
from racemic 1b (2.33 g, 5.36 mmol) and acid 7 (2.08 g, 5.39
mmol) in 120 mL of ethanol. The white (S)-1b‚CSZ salt
1325, 773, 741, 698; H NMR (300 MHz, CDCl3) δ 8.07 (dd, 1
H, J ) 1.2, 7.9 Hz), 7.73 (ddd, 1 H, J ) 1.4, 6.9, 6.9 Hz), 7.66
(d, 1 H, J ) 7.3 Hz), 7.1-7.4 (m, 13 H), 6.91 (br s, 1 H), 2.28
(s, 3 H), 2.08 (s, 3 H), 2.05 (s, 3 H); 31P NMR (121.4 MHz)
provided 0.862 g of white prisms (74%): mp 143-145 °C; [R]23
D
-16.27 ppm (s); HRMS 448.1704 (calcd for
448.1705).
C29H25N2OP
) +172° (c ) 0.93, CHCl3) (>96% ee).15 The ethanolic mother
liquor affored 1.07 g of white prisms (91%): mp 142-144 °C;
Resolu tion of Liga n d 1b Usin g (-)-Di-µ-ch lor obis[(S)-
d im et h yl-(1-p h en ylet h yl)a m in a t o-C2,N]d ip a lla d iu m (II)
(5). To a solution of complex 5 (2.00 g, 3.44 mmol) in toluene
(80 mL) was added 1b (6.00 g, 13.8 mmol), and the solution
was stirred for 4 h at ambient temperature. The mixture was
treated with hexane (50 mL) and stored at 0 °C overnight.
Yellow crystals of (S, R)-6 were collected by filtration (4.79 g,
96% yield): mp 185 °C (dec); Rf ) 0.67 (silica, ethyl acetate);
FTIR (thin film, cm-1) 3448, 1676, 1601, 1474, 1437, 1340,
[R]23 ) -176° (c ) 0.97, CHCl3) (>96% ee).15
D
Resolu tion of 1a Usin g Resolvin g Agen t 7. Compound
1a was resolved analogously to that described for 1c, starting
from racemic 1a (2.44 g, 5.81 mmol) and acid 7 (2.27 g, 5.88
mmol) in 140 mL of ethanol. The white (S)-1a ‚CSZ salt
provided 0.935 g of white prisms (77%): mp 142-144 °C; [R]23
D
) +229° (c ) 1.29, CHCl3) (>96% ee).15 The ethanolic mother
liquor affored 1.06 g of white prisms (87%): mp 138-141 °C;
[R]23 ) -245° (c ) 1.31, CHCl3) (>96% ee).15
D
1
1267, 1092, 774, 731, 697; H NMR (300 MHz, CDCl3) δ 8.09
(dd, 2 H, J ) 7.2, 11.6 Hz), 7.81 (dd, 1 H, J ) 1.4, 8.0 Hz),
7.74 (dd, 2 H, J ) 7.7, 12.1 Hz), 7.54-7.67 (m, 2 H), 7.22-
7.52 (m, 7 H), 6.87 (dd, 1 H, J ) 2.0, 7.2 Hz), 6.71 (t, 1 H, J )
7.3 Hz), 6.61 (ddd, 2 H, J ) 2.0, 7.3, 7.3 Hz), 6.45 (ddd, 1 H,
J ) 1.3, 7.2, 7.2 Hz), 6.16 (ddd, 1 H, J ) 1.2, 7.5, 7.5 Hz), 5.86
(t, 1 H, J ) 6.9 Hz), 3.78 (quin, 1 H, J ) 5.5 Hz), 2.86 (d, 3 H,
J ) 1.7 Hz), 2.75 (d, 3 H, J ) 3.0 Hz), 2.67 (s, 3 H), 1.93 (s, 3
H), 1.74 (d, 3 H, J ) 6.4 Hz); 31P NMR (121.4 MHz) 45.53 (s);
Ack n ow led gm en t. We would like to thank Dr.
William Davis for solution of the crystal structures for
6 and the CSA salt of 1a . We would like to thank
Professor Edwin Vedejs for his helpful suggestions on
quasi-racemates. We would also like to thank the David
and Lucile Packard Foundation, Pfizer Inc. (research
awards to S.C.V.) and the MIT Chemistry Department
for their financial support.
[R]23 ) -10.5° (c ) 1.04, CHCl3); HRMS (FAB, 3-nitrobenzyl
D
alcohol) 723.1397 (calcd for C38H37ClN3OPPd 723.1398).
Su p p or tin g In for m a tion Ava ila ble: Tables of atomic
coordinates and thermal parameters for complex 6 and the salt
((S)-CSA)2‚((R)-1a )‚(S)-1a ). 1H NMR and 13C NMR spectra of
compounds 4c, 1a -c, 6, and 7 as well as the use of 5 for
analysis of the ee of 1c (28 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
The mother liquor was concentrated, and the residue was
recrystallized from ethyl acetate/hexanes (1:3) to afford (S)-
(+)-1b (2.45 g, 82%) (96% ee based on chiral HPLC analyses;
98:2 hexane/2-propanol, flow rate 1.5 mL/min, tR ) 13.5 min).
Treatment of the complex (S,R)-6 with ethylenediamine
(0.115 mL, 1.72 mmol) in CH2Cl2 (30 mL), followed by filtration
and crystallization from ethyl acetate-hexanes (1:3) solvent
mixture, gave 2.73 g (91%) of free ligand (R)-(-)-1b as white
needles (99% ee based on chiral HPLC analyses, 98:2 hexane/
2-propanol, flow rate 1.5 mL/min, tR ) 8.9 min).
J O972105Z