Practical preparation and resolution of 1-(2′-diphenylphosphino-1′-naphthyl)isoquinoline: A useful ligand for catalytic asymmetric synthesis

Article abstract of DOI:10.1021/op034007n

A practical synthesis of the atropisomerically chiral ligand QUINAP is described, followed by its efficient resolution into enantiomers by employing a deficiency of the chloropalladium complex derived from 1′-(R)-1′-(dimethylamino)-1-ethylnaphthalene. The X-ray structure of the ligand, which crystallises as a conglomerate, is reported.

Full text of DOI:10.1021/op034007n

Organic Process Research & Development 2003, 7, 379−384
Practical Preparation and Resolution of
1
-(2′-Diphenylphosphino-1′-naphthyl)isoquinoline: A Useful Ligand for Catalytic
Asymmetric Synthesis
†
†
†
†
,†
‡
Chung Woo Lim, Olivier Tissot, Andrew Mattison, Mark W. Hooper, John M. Brown,* Andrew R. Cowley,
David I. Hulmes, and A. John Blacker§
†,§
Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, UK, Chemical Crystallography Laboratory,
Parks Road, Oxford OX1, UK, and AVecia plc, Leeds Road, Huddersfield, UK
7
Abstract:
6
de and 99% e.e. with AgSbF as co-reactant. Examples of
A practical synthesis of the atropisomerically chiral ligand
QUINAP is described, followed by its efficient resolution into
enantiomers by employing a deficiency of the chloropalladium
complex derived from 1′-(R)-1′-(dimethylamino)-1-ethylnaph-
thalene. The X-ray structure of the ligand, which crystallises
as a conglomerate, is reported.
the application of QUINAP to diverse catalytic processses
have been reported sporadically. The main application has
8
been in asymmetric hydroboration/oxidation, catalysed by
its cationic rhodium complexes. The general tendency for
biphosphine and phosphinamine complexes that have been
applied to this reaction is to provide a successful outcome
with monosubstituted vinylarenes; further substitution at the
R- or â-position of the alkene affords low enantioselectivities,
9
however. With ligand 1 and its close relatives the reaction
Introduction
may be carried out with R,â-disubstituted arylalkenes,
including bicyclic reactants. Reaction is not limited to the
synthesis of alcohols, despite the fact that the initially formed
boronic ester is unreactive towards the range of ambiphiles
that are typically reactive towards trialkylboranes.10 The
limitation can be overcome by direct B-alkylation of the
In 1993 we reported the synthesis and resolution of the
atropisomeric ligand 1-(2′-diphenylphosphino-1′-naphthyl)-
isoquinoline 1, prepared by a multistage synthesis from
1
2-methoxynaphthyl-1-boronic acid and 2-chloroisoquinoline.
The racemic ligand was resolved by formation of the
corresponding diastereomeric complexes with enantiomeri-
cally pure dichlorobis[dimethyl(1-(1-naphthyl)ethyl)aminato-
2
boronate ester with R Zn or RMgX, followed by reacting
the resulting trialkylborane with N-electrophiles. This leads
to the corresponding primary or secondary amine with
2
C ,N]dipalladium(II), and fractional crystallisation. Since our
early reports of application of the ligand 1 to catalytic
11
complete chemo- and stereoselectivity. A further develop-
ment of the protocol lies in the kinetic resolution of chiral
2
3
asymmetric hydroboration, and allylic alkylation, a variety
of uses in catalysis have been reported. These include
application to the Ru complex-catalysed hydrogenation of
1
2
4
-substituted 1,2-dihydronaphthalenes. The ligand combi-
nation has been successfully applied to clay-supported
4
ketones and the control of sterospecificity in alkene/CO
1
3
asymmetric hydroboration.
5
copolymerisation catalysed by Pd complexes. In the Cu-
(
(
7) Faller, J. W.; Grimmond, B. J. Organometallics 2001, 20, 2454.
8) Ghosh, A. K.; Matsuda, H. Org. Lett. 1999, 1, 2157; Hii, K. K.; Claridge,
T. D. W.; Brown, J. M.; Smith, A.; Deeth, R. J. HelV. Chim. Acta 2001,
84, 3043; Lloyd-Jones, G. C.; Stephen, S. C. Chem. Eur. J. 1998, 4, 2539;
Namyslo, J. C.; Kaufmann, D. E. Synlett 1999, 804; Rabeyrin, C.; Nguefack,
C.; Sinou, D. Tetrahedron Lett. 2000, 41, 7461; Tillack, A.; Koy, C.;
Michalik, D.; Fischer, C. J. Organomet. Chem. 2000, 603, 116; Yamashita,
M.; Nagata, T. (Takeda Chemical Industries, Ltd., Japan). PCT Int. Appl.
Wo 0119777, 2001.
catalysed R-alkynylation of enamines by primary acetylenes,
ligand 1 proved to be the most effective in screening studies,
affording the addition product in typical yields of g80% and
6
up to 90% e.e. For the Diels-Alder reaction between
cyclopentadiene and methacrolein, a crystallographically
characterised Ru-QUINAP complex (one of a pair of
diastereomers) catalysed formation of the exo product in 91%
(
9) For recent examples, see: Kwong, F. Y.; Yang, Q. C.; Mak, T. C. W.; Chan,
A. S. C.; Chan, K. S. J. Org. Chem. 2002, 67, 2769; Demay, S.; Volant, F.;
Knochel, P. Angew. Chem., Int. Ed. 2001, 40, 1235; Ruiz, J. L.; Flor, T.;
Bayon, J. C. Inorg. Chem. Commun. 1999, 2, 484; Kang, J. Y.; Lee, J. H.;
Kim, J. B.; Kim, G. J. Chirality 2000, 12, 378. The quinazoline ligands
related to QUINAP prepared by Guiry and co-workers are comparably
effective for the asymmetric hydroboration of disubstituted arylalkenes:
Lacey, P. M.; McDonnell, C. M.; Guiry, P. J. Tetrahedron Lett. 2000, 41,
2475; McCarthy, M.; Hooper, M. W.; Guiry, P. J. Chem. Commun. 2000,
1333.
*
Author for correspondence. E-mail: bjm@herald.ox.ac.uk, John.Blacker@
avecia.com.
†
Dyson Perrins Laboratory.
Chemical Crystallography Laboratory.
Avecia plc.
‡
§
(
1) Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron: Asymmetry 1993,
, 743.
4
(2) Brown, J. M.; Hulmes, D. I.; Layzell, T. P. Chem. Commun. 1993, 1673;
Doucet, H.; Fernandez, E.; Layzell, T. P.; Brown, J. M. Chem. Eur. J. 1999,
(10) For C-C bond-forming procedures directly from the boronate ester, see:
Chen, A. C.; Ren, L.; Crudden, C. M. Chem. Commun. 1999, 611; Chen,
A.; Ren, L.; Crudden, C. M. J. Org. Chem. 1999, 64, 9704.
(11) Fernandez, E.; Hooper, M. W.; Knight, F. I.; Brown, J. M. Chem. Commun.
1997, 173; Fernandez, E.; Maeda, K.; Hooper, M. W.; Brown, J. M. Chem.
Eur. J. 2000, 6, 1840.
5
9
, 1320. Brown, J. M. (Isis Innovation Ltd., UK). PCT Int. Appl. Wo
513284, 1995.
(
(
3) Brown, J. M.; Hulmes, D. I.; Guiry, P. J. Tetrahedron 1994, 50, 4493.
4) Rautenstrauch, V.; Challand, R.; Churlaud, R.; Morris, R. H.; Abdur-Rashid,
K.; Brazi, E.; Mimoun, H. (Firmenich S. A., Switz.). PCT Int. Appl. Wo
0
222526, 2002.
(12) Maeda, K.; Brown, J. M. Chem. Commun. 2002, 310.
(13) Segarra, A. M.; Guerrero, R.; Claver, C.; Fernandez, E. Chem. Commun.
2001, 1808. Segara, A. M.; Guerro, R.; Claver, C.; Fernandez, E.
Chem.sEur. J. 2003, 9, 191.
(
(
5) Consiglio, G.; Gsponer, A. Polym. Mater. Sci. Eng. 2002, 87, 78.
6) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41,
2
535.
1
0.1021/op034007n CCC: $25.00 © 2003 American Chemical Society
Vol. 7, No. 3, 2003 / Organic Process Research & Development
•
379
Published on Web 05/16/2003

Scheme 1a
a
Conditions: (i) 3 mol% Pd(Ph
, DMSO, 85 °C. (v) HSiCl
3
)
4
2 equiv Na
2
CO
3
; DME reflux. (ii) BBr
3 2 2 3 2 2 2 2
, CH Cl (iii) (CF SO )O, xs DMAP, CH Cl (iv) 3 mol% Pd(OAc)2 dppp; Ph PHO,
NaHCO
3
3
, NEt , C , reflux. (vi) Ph
3
H
7 8
2
PH, Cl Ni(DPPE), DMF, 100 °C. Current route is (i)-(ii)-(iii)-(vi).
2
The ability to synthesise functional molecules with a
defined stereogenic centre at a benzylic position has potential
for considerable application, since that substitution pattern
is very common in pharmacology. This provided additional
motivation for improvement of the synthesis of compound
X-ray Structure of Racemic Ligand. In the course of
purifying the product from the phosphination reaction, it was
observed that the initial reaction product, dissolved in CHCl ,
3
deposited very large single crystals over 7 days (up to 250
mg) that were enantiomerically pure but of random handed-
ness. However, when the recrystallisation process was
repeatedly carried out, the number of microscopic crystal-
lisation nuclei increased. As a result the crystals were
obtained faster (within 2 days), but their size was greatly
decreased. From later batches a crystal suitable for X-ray
analysis was grown, and the details are reported in the
Experimental Section. The structure is shown in Figure 1,
1
4
1, so that its catalytic properties could be fully evaluated.
The original synthesis is as shown in Scheme 1. Modifica-
tions and improvements centered on two aspectssthe phos-
phination step and the resolution. In the course of this work
minor changes were made to the preceding steps, and a
complete description is therefore recorded in the Experi-
mental Section.
1
and indicates the chiral space group P2 .
Results and Discussion
The key improvements to the original literature arose from
a change in the method of forming the C-P bond and in the
details of the resolution procedure. These are recorded in
turn.
Phosphination. A particular drawback to the initially
published method was that it led initially to the racemic
phosphine oxide 2 which then required HSiCl
3
reduction to
afford the racemic phosphine. With the later advent of direct
15
nickel-catalysed protocols for the phosphination of triflates,
a superior alternative was in prospect. The reaction was
attempted under the conditions described by Cai and co-
workers and initially gave the desired phosphine 1 but was
contaminated with up to 15% of the corresponding phosphine
oxide 1. This required careful recrystallisation from CHCl
3
or from acetone to remove the impurity. After further
experimentation an improved procedure was developed that
involved sequential addition of portions of the secondary
phosphine PPh H to the mixture of triflate, base, and Ni
2
catalyst in hot DMF over several hours. In this way pure
ligand 1 was isolated in 68% yield by a simple workup.
3
Following the recommendation that PPh replace dppe in
nickel-catalysed reactions of this type, there could be scope
for further improvement.16
Figure 1. X-ray structure of (S)-1-(2′-diphenylphosphino-1′-
naphthyl)isoquinoline, 1. Important bond lengths and angles:
P(1)-C(19), 1.8397(15); P(1)-C(20), 1.8403(19); P(1)-C(26),
1
.8314(19); N(1)-C(1), 1.319(2); N(1)-C(9), 1.370(3); C(1)-
C(10), 1.502(2); C(19)-P(1)-C(20), 98.29(7); C(19)-P(1)-
C(26), 102.63(9); C(20)-P(1)-C(26), 103.89(8), P(1)-C(20)-
C(21), 115.35(15); P(1)-C(20)-C(25), 125.97(15).
17
Refinement of the Flack enantiopole parameter gave a value
(
(
14) Both enantiomers of QUINAP are commercially available via Strem.
15) Cai, D. W.; Payack, J. F.; Bender, D. R.; Hughes, D. L.; Verhoeven, T. R.;
Reider, P. J. J. Org. Chem. 1994, 59, 7180.
of -0.04(7), showing the crystal to be the S-enantiomer. The
(16) Kwong, F. Y.; Chan, A. S. C.; Chan, K. S. Tetrahedron 2000, 56, 8893.
(17) Flack H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143.
380
•
Vol. 7, No. 3, 2003 / Organic Process Research & Development

Scheme 2. Resolution of rac-QUINAP with (R)-Pd dimer (a) with 1 equiv of the resolving agent and (b) with 0.5 equiv of the
resolving agent as described in the Experimental Section
dihedral angle between the quinoline and naphthalene rings
is 85.3°.
The protocol employed is similar to the “method of half-
equivalents” occasionally used in acid-base resolution
methodologies and described in detail in standard Stereo-
chemistry texts. Because of the intrinsic dynamic properties
of metal complexes, it should find wider application in the
resolution of racemic ligands.
Resolution Procedure. In the course of the original work
it was observed that the R,S-diastereomer of the resolution
complex was more stable than the R,R-diastereomer, an
observation reinforced during ES-MS studies.18 The molec-
ular interactions observed in X-ray structures of the com-
21
19
plexes accord with this stability difference. To develop the
effect for preparative purposes, excess ligand (2 equiv) was
added to the Pd complex and the course of reaction
monitored by NMR. In acetone, the isolated product was
solely the R,S diastereomer of complex together with an
equivalent of free ligand (Scheme 2). When the solution was
Experimental Section
General Details. All reactions were carried out under
argon, and HPLC grade solvents were used without further
purification. The NMR spectra were recorded on Bruker AM
2
50 (250 MHz) or 500 (500 MHz), melting points were
determined on a Reichert-Kofler block and are uncorrected.
Optical rotations were recorded on a Perkin-Elmer 241
polarimeter, and elemental analyses were carried out in the
Dyson Perrins Laboratory using a Carlo Erba 1106 elemental
2 2
made up in CD Cl it was observed that both R,R and R,S
complexes were formed initially in comparable proportions;
on standing for 24 h the R,S isomer gradually became
predominant and then exclusive. These experiments defined
that the discrimination was due to thermodynamic factors
and did not lead to kinetic control of the product ratio. Since
the discrimination in favour of the (R,S)-diastereomer is near-
complete and the mass economy of a single-step resolution
based on this observation is far greater than one based on
complete formation of the Pd complex from both hands of
ligand, it was applied in the large-scale procedure using the
22
analyzer. 1-Chloroisoquinoline, tetrakis(triphenylphosphine)-
23
palladium(0), and dichlorobis[(R)-dimethyl(1-(1-naphthyl)-
2
24
ethyl)aminato-C ,N]dipalladium(II) were prepared accord-
ing to the literature, the last-named from (R)-1-naphthyl-1′-
ethylamine purchased from Avocado. Diphenylphosphine and
1
,2-bis(diphenylphosphino)ethane were purchased from Strem
Chemicals Inc. and used without further purification.
-Bromo-2-methoxynaphthalene. Bromine (100.7 g,
1
(
4
R)-Pd complex. The recovered phosphine was obtained in
6% yield as pure R enantiomer, and the isolated complex
0
2
.63 mol) in AcOH (125 mL) was added to a solution of
-methoxynaphthalene (100 g, 0.63 mol) in AcOH (500 mL)
20
was treated with dppe to give pure S enantiomer. In this way
0 g of each enantiomer of ligand 1 was obtained in a single
synthetic run.
at room temperature and stirred overnight. After filtering the
white precipitate, the remaining solute was diluted with water
2
(
21) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates and Resolu-
tions; John Wiley and Sons: New York, 1981; pp 307 ff; Eliel, E. L.; Wilen
S. H.; Mander L. N. Stereochemistry of Carbon Compounds; John Wiley
and Sons: New York, 1994; Chapter 7.3, p 350.
(
18) Aplin, R. T.; Doucet, H.; Hooper, M. W.; Brown, J. M. Chem. Commun.
997, 2097.
19) Alcock, N. W.; Hulmes, D. I.; Brown, J. M. Chem. Commun. 1995, 395.
20) The quoted specific rotation of ([R] ) (166 (c ) 1, CHCl ) has been
1
(
(
D
3
(22) Ikehara, M. Chem. Pharm. Bull., 1954, 2, 111.
(23) Coulson, D. R. Inorg. Synth. 1972, 13, 121.
(24) Allen, D. G.; McLaughlin, G. M.; Robertson, G. B.; Steffen, W. L.; Salem,
G.; Wild, S. B. Inorg. Chem. 1982, 21, 1007.
checked to consistency and accords with values obtained from the equipment
at the National Chiroptical Centre, KCL. It therefore replaces the value of
(153 quoted in the original paper (ref 1).
Vol. 7, No. 3, 2003 / Organic Process Research & Development
•
381

to give more precipitate which was collected by filtration.
The solids were washed with water and dried in vacuo giving
1-(2-Hydroxy-1-naphthyl)isoquinoline. Boron tribro-
mide (84.3 g, 0.34 mol) was added to a solution of 1-(2-
1
8
8
1
-bromo-2-methoxynaphthalene; yield: 138.6 g, 93%; mp
methoxy-1-naphthyl)isoquinoline (80 g, 0.28 mol) in CH Cl2
(1 L) via dropping funnel at room temperature, then refluxed
2
1
3
3-85 °C; H NMR (200 MHz, CDCl ): δ ) 8.25 (d, J )
.6 Hz, 1H), 7.83 (d, J ) 8.9 Hz, 1H), 7.80 (d, J ) 8.3 Hz,
H), 7.59 (t, J ) 7.7 Hz, 1H), 7.41 (t, J ) 7.5 Hz, 1H), 7.28
for 1 h. After the resulting dark reddish solution was stirred
overnight at room temperature, water (400 mL) was added
cautiously at 0 °C. The yellow precipitate was collected by
filtration. The filtrate was neutralized with aqueous 2 M
NaOH solution, and extracted with CH Cl (400 mL × 3).
(d, J ) 8.9 Hz, 1H), 4.04 (s, 3H) ppm.
2-Methoxy-1-naphthylboronic Acid. A solution of 1-bro-
mo-2-methoxynaphthalene (137.1 g, 0.58 mol) in THF (800
mL) was added dropwise to Mg (16.9 g, 0.69 mol, activated
by stirring overnight under argon at rt).25 After stirring for
2
2
Aqueous 10% HCl solution was added to the organic layer
with stirring and more yellow precipitate formed which was
collected by filtration. The combined yellow solids were
2
h, the reaction mixture was cooled to -78 °C, and
trimethylborate (119.2 g, 1.16 mol) was added followed by
stirring overnight at room temperature. Water (150 mL) was
added with stirring to give a homogeneous solution, and then
volatiles were removed in vacuo. The remaining aqueous
stirred in dichlomethane (600 mL) and 2 M aqueous Na
CO (200 mL) solution, and the organic layer was separated.
The aqueous phase was extracted with CH Cl
(200 mL ×
), and the organic layers were combined and concentrated
to give yellow solid. This was purified by recrystallization
with cold CH Cl to give 1-(2-hydroxy-1-naphthyl)isoquino-
line as a colorless solid; yield: 59.8 g, 79%; mp 244-245
2
-
3
2
2
3
solution was extracted with CH
organic layers were combined and dried over anhydrous
MgSO , filtered, and concentrated to give a brown solid. The
resulting material was stirred for 0.5 h in CH Cl (300 mL),
filtered, and washed with cold CH Cl
(3 × 50 mL) to give
-methoxy-1-naphthylboronic acid as a white solid; yield:
2
Cl
2
(300 mL × 3), and the
2
2
4
1
2
2
°
1
7
C; H NMR (500 MHz, CDCl
3
) δ ) 8.65 (d, J ) 5.7 Hz,
H), 7.94 (d, J ) 8.3 Hz, 1H), 7.85 (d, J ) 8.1 Hz, 1H),
.84 (d, J ) 8.9 Hz, 1H), 7.78 (d, J ) 5.7 Hz, 1H), 7.72 (t,
2
2
2
1
1
18.7 g, 73%; mp 117-119 °C; H NMR (250 MHz,
): δ ) 8.86 (d, J ) 8.0 Hz, 1H), 7.95 (d, J ) 9.0 Hz,
H), 7.79 (d, J ) 8.0 Hz, 1H), 7.52 (t, J ) 8.0 Hz, 1H),
.38 (t, J ) 8.0 Hz, 1H), 7.29 (d, J ) 9.0 Hz, 1H), 6.30 (br,
J ) 7.6 Hz, 1H), 7.61 (d, J ) 8.5 Hz, 1H), 7.41 (t, J ) 7.6
CDCl
1
7
3
Hz, 1H), 7.33 (t, J ) 7.6 Hz, 1H), 7.28 (d, J ) 8.9 Hz, 1H),
13
7
.23 (t, J ) 7.6 Hz, 1H), 7.13 (d, J ) 8.5 Hz, 1H) ppm; C
NMR (125.8 MHz, CDCl
1
1
3
) δ ) 157.8, 152.9, 141.7, 136.8,
33.6, 130.7, 130.6, 128.6, 128.0, 127.9, 127.5, 126.9, 126.5,
24.6, 123.1, 120.8, 118.7, 117.9 ppm. Anal. found: C, 84.4;
13NO, C, 84.1; H, 4.8; N,
13
s, 2H), 4.04 (s, 3H) ppm; C NMR (62.5 MHz, DMSO-d
δ ) 159.3, 136.4, 130.0, 129.2, 128.6, 128.0, 126.5, 123.7,
14.3, 56.5 ppm. Anal. Found: C, 65.2; H, 5.3. Calcd For
: C, 65.4; H, 5.5.
-(2-Methoxy-1-naphthyl)isoquinoline. To a solution of
6
):
1
H, 4.65; N, 5.1. Calcd for C19
H
11 3
C H11BO
5
.5.
1
1
-(2-Trifluoromethanesulfonyloxy-1-naphthyl)isoquin-
oline. To a mixture of 1-(2-hydroxy-1-naphthyl)isoquinoline
55 g, 0.2 mol) and 4-dimethyl aminopyridine (2.47 g, 20
mmol) in CH Cl (1 L) was added CF SO H (62.9 g, 0.22
tetrakis(triphenylphosphine)palladium (0) (13.7 g, 11.9 mmol)
in DME (600 mL) was added 1-chloroisoquinoline (64.8 g,
(
0.4 mol) as a solid and stirred for 0.5 h. 2-Methoxy-
2
2
3
3
naphthylboronic acid (100 g, 0.5 mol) in ethanol (50 mL)
and sodium carbonate (109 g, 1.03 mol) in water were
successively added at room temperature to the solution
followed by refluxing for overnight. The solution was cooled
to 0 °C and filtered to remove the solid which was washed
mol) at room temperature followed by stirring overnight. The
resulting solution was washed with 1 M HCl solution (1 L),
water (1 L), and brine (500 mL). The organic phase was
4
dried over anhydrous MgSO and filtered, and the solvent
was removed in vacuo to give a yellow solid which was
purified by stirring in diethyl ether (300 mL) and filtering.
This gave 1-(2-trifluoromethanesulfonyloxy-1-naphthyl)iso-
with CH
trated, and the residues were dissolved in CH
washed with water and brine, dried over MgSO
2
Cl
2
until it was white. The filtrates were concen-
Cl (700 mL),
, filtered,
2
2
4
quinoline as a white solid; yield: 68.4 g, 84%; mp 98-100
and concentrated to give a brown solid. The solid was stirred
in ethyl ether (150 mL), filtered and washed with ethyl ether
several times to give 1-(2-methoxy-1-naphthyl)isoquinoline
1
°
C; H NMR (500 MHz, CDCl
3
) δ ) 8.79 (d, J ) 5.7 Hz,
1
7
H), 8.11 (d, J ) 9.1 Hz, 1H), 8.00 (d, J ) 8.3 Hz, 1H),
.97 (d, J ) 8.3 Hz, 1H), 7.85 (d, J ) 5.7 Hz, 1H), 7.72
as a colorless solid; yield: 84.6 g, 75%; mp 130-133 °C;
(ddd, J ) 2.1, 6.0, 8.2 Hz, 1H), 7.62 (d, J ) 9.1 Hz, 1H),
1
H NMR (500 MHz, CDCl
3
) δ ) 8.74 (d, J ) 6.0 Hz, 1H),
7
7
.57 (t, J ) 7.6 Hz, 1H), 7.49-7.43 (m, 2H), 7.40 (t, J )
8.03 (d, J ) 9.0 Hz, 1H), 7.93 (d, J ) 8.5 Hz, 1H), 7.88 (d,
13
.7 Hz, 1H), 7.29 (d, J ) 8.5 Hz, 1H) ppm; C NMR (125.8
) δ ) 154.1, 145.1, 142.7, 136.4, 133.3, 132.6,
31.3, 130.6, 129.5, 128.6, 128.3, 127.9, 127.8, 127.2, 127.2,
26.8, 126.6, 121.3, 119.5 ppm. Anal. found: C, 59.7; H,
J ) 8.5 Hz, 1H), 7.77 (d, J ) 6.0 Hz, 1H), 7.68 (t, J ) 7.0
Hz, 1H), 7.52 (d, J ) 8.5 Hz, 1H), 7.45 (d, J ) 9.0 Hz,
MHz, CDCl
3
1
1
2
3
1H), 7.41 (t, J ) 7.0 Hz, 1H), 7.32 (t, J ) 8.0 Hz, 1H), 7.25
(
t, J ) 8.5 Hz, 1H), 7.04 (d, J ) 8.5 Hz, 1H), 3.78 (s, 3H)
.9; N, 3.6. Calcd for C20
.5.
3 3
H12NO SF , C, 59.6; H, 3.0; N,
13
ppm; C NMR (125.8 MHz, CDCl
3
) δ ) 157.9, 154.6,
1
1
5
42.2, 136.1, 133.6, 130.3, 130.3, 130.0, 128.8, 128.6, 127.7,
27.2, 127.0, 126.6, 126.5, 124.5, 123.5, 121.7, 120.0, 113.3,
6.3 ppm.
(
R,S)-(()-1-(2-Diphenylphosphino-1-naphthyl)isoquin-
oline. In a dried 1-L three-neck flask, diphenylphosphine (9
g, 48 mmol) was added to a solution of NiCl (dppe) (8.51
2
g, 16.1 mmol) in DMF (200 mL) at room temperature, and
the resulting dark brown solution was heated for 0.5 h. In
(
25) Baker, K. V.; Brown J. M.; Hughes, N.; Skarnulis A. J.; Sexton A. J. Org.
Chem, 1991, 56, 698.
382
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Vol. 7, No. 3, 2003 / Organic Process Research & Development

the other part, a solution of 1-(2-trifluoromethanesulfonyloxy-
-naphthyl)isoquinoline (65 g, 0.16 mol) in DMF (100 mL)
was added to the solution of 1,4-diazabicyclo[2,2,2]octane
72.3 g, 0.65 mol) in DMF (200 mL), and it was transferred
in one portion to the reaction flask via cannula. The resulting
solution was kept at 100 °C, and three additional portions
of diphenylphosphine (9 g × 3, 0.14 mol) were added by
syringe after 1, 3, and 7 h. After being stirred for 40 h at
Table 1. Crystal data and refinement details
1
crystal identification
empirical formula
formula weight
temperature (K)
wavelength (Å)
crystal system
space group
a (Å)
ARC107
C H22NP
31
439.50
293
0.71073
monoclinic
(
P 2
1
9.3582(3)
b (Å)
c (Å)
R (deg)
â (deg)
11.2325(3)
11.0655(4)
90
94.2238(12)
90
1
00 °C, the reaction mixture was allowed to cool to 0 °C.
The mixture was diluted with CH Cl (1 L) and then washed
with saturated Na CO , water, and brine successively. The
organic layer was dried over MgSO , filtered, and concen-
2
2
2
3
γ (deg)
4
3
cell volume (Å )
1160.0
trated. The resulting sludge was suspended with acetone (200
mL) and stirred for 1 h under argon and filtered, and the
filter cake was washed with acetone and methanol to give
Z
2
3
calculated density (Mg/m )
1.258
0.138
absorption coefficient (mm-1)
F
000
460.248
(
R,S)-(()-1-(2-diphenylphosphino-1-naphthyl)isoquinoline as
crystal size (mm)
description of crystal
absorption correction
0.30 × 0.60 × 0.60
colorless fragment
semiempirical from
equivalent reflections
0.92, 0.96
1
a colorless solid; yield: 48.3 g, 68%; mp 217-219 °C; H
NMR (500 MHz, benzene-d ) δ ) 8.58 (d, J ) 5.7 Hz, 1H),
.61 (d, J ) 8.5 Hz, 1H), 7.58 (d, J ) 8.5 Hz, 1H), 7.56
dd, J ) 8.5 Hz, JP,H ) 2.9 Hz, 1H), 7.44 (d, J ) 8.3 Hz,
6
7
(
transmission coefficients (min,max)
θ range for data collection (deg)
index ranges
5.0 e θ e 27.5
-12 e h e 12,
-14 e k e 13,
1
7
1
6
H), 7.38 (t, J ) 7.5 Hz, 1H), 7.35 (d, 1H), 7.30 (m, 2H),
.28 (d, 1H), 7.26 (d, J ) 5.7 Hz, 1H), 7.16 (t, 1H), 7.15 (t,
H), 7.05-6.98 (m, 6H), 6.95 (dd, J ) 8.5, 6.8 Hz, 1H),
0
e l e 14
reflections measured
unique reflections
Rint
observed reflections (I > 3σ(I))
refinement method
7688
4727
0.032
3870
full-matrix
least-squares on F
298
13
.86 (dd, J ) 8.5, 6.8 Hz, 1H) ppm; C NMR (125.8 MHz,
) δ ) 160.5, 144.4, 142.3, 137.4, 135.9, 134.9, 133.7,
CDCl
33.6, 133.2, 132.7, 131-126, 120.3 ppm; P NMR (101.3
MHz, CDCl ) δ ) -13.1 ppm. Anal. found: C, 84.9; H,
.0; N, 3.0. Calcd for C31 22NP, C, 84.7; H, 5.05; N, 3.2.
R)-(+)-1-(2-Diphenylphosphino-1-naphthyl)isoquino-
3
31
1
3
5
H
parameters refined
weighting scheme
(
Chebychev
3-term polynomial
line. Dichlorobis[(R)-dimethyl(1-(1-naphthyl)ethyl)aminato-
goodness of fit
R
1.0648
0.0327
2
C ,N]dipalladium(II) (17.4 g, 25.6 mmol) in acetone (600
mL) was added to a suspension of (R,S)-(()-1-(2-diphe-
nylphosphino-1-naphthyl)isoquinoline (45 g, 0.1 mol) in
acetone (1 L) via cannula at 55 °C and the resulting solution
stirred for 2 h. Potassium hexafluorophosphate (9.42 g, 51.2
mmol) in acetone (300 mL) was added via cannula, and the
resulting mixture was stirred at 55 °C for 2 h. On cooling to
room temperature, a white precipitate was obtained and
collected by filtration, saving the orange filtrate for the next
step below. The solid was dried in vacuo and dissolved in
chloroform, and the resulting solution was filtered through
Celite. The filtrate was concentrated in vacuo, and the
remaining white solid was washed with acetone (100 mL)
and dried to give enantiomerically pure (R)-(+)-1-(2-
ωR
0.0331
-0.213, 0.263
residual electron density
-
3
(min,max) (e Å )
1.8 Hz, 1H), 8.20 (d, J ) 8.3 Hz, 1H), 8.13 (d, J ) 6.2 Hz,
1H), 7.97 (d, J ) 8.2 Hz, 1H), 7.79 (d, J ) 8.3 Hz, 1H),
7.79 (t, J ) 7.6 Hz, 1H), 7.72 (t, J ) 7.5 Hz, 1H), 7.71 (d,
J ) 8.0 Hz, 1H), 7.61 (t, J ) 7.6 Hz, 2H), 7.47-7.39 (m,
H), 7.39-7.33 (m, 4H), 7.26 (d, J ) 8.5 Hz, 1H), 7.15
dd, J ) 8.2, 9.1 Hz, 2H), 7.09 (t, 2H), 7.06 (d, J ) 8.5 Hz,
4
(
1H), 7.00 (d, J ) 8.5 Hz, 1H), 6.99 (br, 1H), 6.61 (dd, J )
8.5 Hz, JP,H ) 5.8 Hz, 1H), 4.61 (quin, J ) 6.0 Hz, 1H),
2.95 (d, J ) 2.2 Hz, 3H), 2.81 (d, JP,H ) 3.5 Hz, 3H), 1.75
diphenylphosphino-1-naphthyl)isoquinoline ([R]
D
) +166
13
(
d, J ) 6.3 Hz, 3H) ppm; C NMR (125.8 MHz, acetone-
(
c ) 1, CHCl
+)-cis-[(R)-Dimethyl(1-(1-naphthyl)ethyl)aminato-C ,N]-
(S)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline]di-
3
) as a white solid; yield: 20.8 g, 46%.
d
6
) δ ) 150.6, 141.9, 137.7, 136.2, 136-123, 74.0, 51.9,
2
31
(
6
48.1, 24.2 ppm; P NMR (101.3 MHz, acetone-d ) δ ) 40.5,
[
-50.7 (heptet, J ) 713 Hz) ppm; HRMS (MALDI)
found: M ) 743.188, Calcd for C H N PPd , 743.181.
(S)-(-)-1-(2-Diphenylphosphino-1-naphthyl)isoquino-
line. A mixture of [(R)-dimethyl(1-(1-naphthyl) ethyl)-
aminato-C ,N]-[(S)-1-(2-diphenylphosphino-1-naphthyl)iso-
quinoline]dipalladium (II) hexafluorophosphate (40 g, 45
mmol) and 1,2-bis(diphenylphosphino)ethane (19.7 g, 49.4
mmol) in CH Cl (400 mL) was stirred for 3 h at room
P,F
+
+
palladium (II)Hexafluorophosphate. All of the above
solution was combined and evaporated to give an orange
solid which was washed with toluene (2 × 100 mL) and
4
5
38
2
2
CHCl
3
(2 × 100 mL). The remaining yellow solid was dried
in vacuo to give [(R)-dimethyl(1-(1-naphthyl)ethyl)aminato-
2
C ,N]-[(S)-1-(2-diphenylphosphino-1-naphthyl) isoquinoline]-
dipalladium (II) hexafluorophosphate as a pale yellow
2
2
powder; yield: 40.7 g, 45%; mp 228-230 °C; ([R]
D
)
6
)
)
temperature. The solvent was removed under reduced pres-
sure to give a pale yellow solid. The solid was stirred for 30
min in acetone (200 mL) and collected by filtration; washing
1
-
245.3 (c ) 1, acetone); H NMR (500 MHz, acetone-d
δ ) 9.01 (d, J ) 6.2 Hz, 1H), 8.32 (dd, J ) 8.5 Hz, JP,H
Vol. 7, No. 3, 2003 / Organic Process Research & Development
•
383

several times with acetone gave pure (S)-(-)-1-(2-diphe-
nylphosphino-1-naphthyl)isoquinoline ([R] ) -165 (c )
) as a white solid; yield: 19.2 g, 97%.
X-ray Structure of (S)-(-)-1-(2-Diphenylphosphino-
-naphthyl)isoquinoline, C31 22NP. A large single crystal
was cut to give a fragment with dimensions
nates and anisotropic thermal parameters of all non-hydrogen
atoms were refined. Hydrogen atoms were positioned geo-
metrically after each cycle of refinement. A three-term
Chebychev polynomial weighting scheme was applied.
Refinement converged satisfactorily to give R ) 0.327, ωR
) 0.0331. The crystal data is displayed in Table 1, and the
full CIF file is provided as Supporting Information.
D
1
, CHCl
3
1
H
from CHCl
3
approximately 0.3 mm × 0.6 mm × 0.6 mm. This was
mounted on a glass fibre using cyanoacrylate adhesive.
Diffraction data were measured at ambient temperature using
an Enraf-Nonius KappaCCD diffractometer (graphite-mono-
chromated Mo KR radiation, λ ) 0.71073 Å). Intensity data
Acknowledgment
We thank EPSRC and DTI for support under the LINK
Asymmetric Synthesis managed by Dr. Trevor Laird, the
European Commission for a Marie Curie Fellowship (to
O.T.), Johnson-Matthey for the loan of palladium salts, and
Strem UK for support of C.W.L.
2
6
were processed using the DENZO-SMN package.
Examination of the systematic absences of the intensity
data showed the space group to be either P2 or P2 /m. The
structure was solved in the space group P2 using the direct-
1
1
1
Supporting Information Available
methods program SIR92,27 which located all non-hydrogen
atoms. Examination of the structure clearly showed no mirror
plane to be present, confirming the assignment of space
group. Subsequent full-matrix least-squares refinement was
Tables of crystallographic data (PDF). X-ray crystal-
lographic data in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
2
8
carried out using the CRYSTALS program suite. Coordi-
Received for review January 10, 2003.
OP034007N
(
26) Otwinowski, Z. Minor, W. Processing of X-ray Diffraction Data Collected
in Oscillation Mode. In Methods in Enzymology; Carter, C. W., Sweet, R.
M., Eds.; Academic Press: New York, 1997; Vol. 276.
(28) Watkin, D. J.; Prout, C. K.; Carruthers, J. R.; Betteridge, P. W.; Cooper, R.
I. CRYSTALS; Chemical Crystallography Laboratory: Oxford, UK, 2001;
issue 11.
(27) Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi, A.; Burla, M.
C.; Polidori G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435.
384
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Vol. 7, No. 3, 2003 / Organic Process Research & Development