A new class of chiral P,N-ligands and their application in palladium-catalyzed asymmetric allylic substitution reactions

Article abstract of DOI:10.1021/jo0494275

An efficient and modular synthesis of a series of chiral nonracemic P,N-ligands is reported. The P,N-ligands were prepared from 2-chloro-4-methyl-6, 7-dihydro-5H-[1]pyrindine-7-one and a series of substituted chiral C ₂-symmetric 1,2-ethanediol

Full text of DOI:10.1021/jo0494275

A New Cla ss of Ch ir a l P ,N-Liga n d s a n d Th eir Ap p lica tion in
P a lla d iu m -Ca ta lyzed Asym m etr ic Allylic Su bstitu tion Rea ction s
Michael P. A. Lyle, Arun A. Narine, and Peter D. Wilson*
Department of Chemistry, Simon Fraser University, 8888 University Drive,
Burnaby, British Columbia, Canada V5A 1S6
pwilson@sfu.ca
Received April 6, 2004
An efficient and modular synthesis of a series of chiral nonracemic P,N-ligands is reported. The
P,N-ligands were prepared from 2-chloro-4-methyl-6,7-dihydro-5H-[1]pyrindine-7-one and a series
of substituted chiral C2-symmetric 1,2-ethanediols (R ) Me, i-Pr, and Ph). The ligands were
evaluated for use in catalytic asymmetric synthesis in the palladium-catalyzed allylic substitution
reactions of a racemic allylic acetate and dimethyl malonate. In the case of the P,N-ligand (R )
Ph), the reaction was found to be highly stereoselective (90% ee).
In tr od u ction
We have recently designed, synthesized, and evaluated
a series of 7-hydroxyindan-1-one-derived chiral auxilia-
ries 1 (Figure 1).1 These structurally rigid chiral auxil-
iaries were synthesized in a modular and convergent
manner from readily available 7-hydroxyindan-1-one 2
and a series of chiral nonracemic C2-symmetric 1,2-diols
3. Of note, the use of C2-symmetric diols ensured that
only a single diastereoisomer of these acetals was formed
and that one of the substituents of the orthogonally fused
acetal moiety blocked one of the diastereotopic faces of
these molecules. In the case of the acrylate derivative 4
of the 7-hydroxyindan-1-one-derived chiral auxiliary 1 (R
) i-Pr), a high degree of stereochemical induction was
observed in a diethylaluminum chloride-promoted Diels-
Alder reaction with cyclopentadiene (91:9 dr). This
demonstrated that these chiral acetals could serve as
effective chiral directors in asymmetric substrate-directed
reactions.
In this article, we describe an extension of the design
concept employed in the synthesis of these novel chiral
auxiliaries and report an efficient and modular synthesis
of a series of chiral nonracemic P,N-ligands.2 In addition,
the evaluation of these ligands in palladium(II)-catalyzed
asymmetric allylic substitution reactions is described in
which excellent levels of asymmetric stereochemical
induction were achieved.3 Of the many different types of
chiral ligands that have been studied in catalytic asym-
metric reactions, chiral P,N-ligands have received con-
F IGURE 1. 7-Hydroxyindan-1-one-derived chiral auxiliaries
1.
siderable recent attention.2 This type of unsymmetrical
chiral ligand is of interest because of the different
electronic properties of the phosphorus and nitrogen
atoms and the effect that this has on the reactivity of
transition metal complexes in catalytic asymmetric pro-
cesses. This effect is absent in the well-studied and elec-
tronically symmetrical N,N-bidentate ligands, such as the
2,2′-bipyridine and bis(oxazoline) ligands, that have been
employed in many asymmetric transformations.4,5
The retrosynthetic analysis of a series of novel chiral
nonracemic 2-(phosphinoaryl)pyridine ligands (P,N-
ligands) 5a -c (R ) Me, i-Pr, and Ph) is illustrated below
(Figure 2). Condensation of the chloroketone 6 with a
series of chiral nonracemic C2-symmetric 1,2-diols 3a -c
(R ) Me, i-Pr, and Ph) should afford the corresponding
acetals. Subsequent elaboration of the 2-chloropyridine
moiety of these acetals, to install the phosphinoaryl
substituent, would complete the synthesis of the target
P,N-ligands. For these investigations, we selected three
C2-symmetric 1,2-diols [(2R,3R)-2,3-butanediol (3a : R )
Me), (1S,2S)-1,2-diisopropyl-1,2-ethanediol (3b: R )
i-Pr), and (1S,2S)-1,2-diphenyl-1,2-ethanediol (3c: R )
(1) Narine, A. A.; Wilson, P. D. Synthesis and Evaluation of
7-Hydroxyindan-1-one-Derived Chiral Auxiliaries. Submitted for pub-
lication.
(2) For recent reviews on chiral nonracemic P,N-ligands; see: (a)
Chelucci, G.; Orru`, G.; Pinna, G. A. Tetrahedron 2003, 59, 9471. (b)
Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336.
(3) For reviews on transition metal-catalyzed asymmetric allylic
substitution reactions, see: (a) Trost, B. M.; Crawley, M. L. Chem. Rev.
2003, 103, 2921. (b) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996,
96, 395. (c) Trost, B. M.; Lee, C. In Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; Chapter 8E.
(4) For recent reviews on chiral 2,2′-bipyridyl ligands; see: (a)
Malkov, A. V.; Kocovsky, P. Curr. Org. Chem. 2003, 7, 1737. (b)
Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102, 3129. (c) Fletcher,
N. C. J . Chem. Soc., Perkin Trans. 1 2002, 1831.
(5) For a recent review on chiral bis(oxazoline) ligands; see, for
example: J ohnson, J . S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
10.1021/jo0494275 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/01/2004
5060
J . Org. Chem. 2004, 69, 5060-5064

A New Class of Chiral P,N-Ligands
SCHEME 2. Syn th esis of P ,N-Liga n d s 5a -c (R )
Me, i-P r , a n d P h )a
F IGURE 2. Retrosynthetic analysis of chiral P,N-ligands
5a -c (R ) Me, i-Pr, and Ph). For R ) Me, the compound used
in the following study was the enantiomer of that indicated
in the figure.
SCHEME 1. Syn th esis of Ch lor ok eton e 6a
a
Reagents and conditions: (a) 1,2-diols 3a -c (R ) Me, i-Pr,
and Ph), p-TsOH (cat.), benzene, reflux, 16 h, 85% (11a ), 89%
(11b), 79% (11c); (b) o-fluorophenylboronic acid, 5 mol % of
Pd2dba3, 10 mol % of P(t-Bu)3, Cs2CO3, THF, reflux, 16 h, 93%
(12a ), 81%, (12b), 88% (12c); (c) Ph2PH, KOt-Bu, 18-crown-6, THF,
b
room temperature, 24 h, 72% (5a ), 66% (5b), 63% (5c). The
compound used in this study was the enantiomer of that indicated
in the reaction scheme.
good yield on condensation of the chloroketone 6 with the
corresponding chiral nonracemic C2-symmetric 1,2-diols
3a -c (R ) Me, i-Pr, and Ph) on heating at reflux in
benzene with a catalytic amount of p-toluenesulfonic
acid.11 The acetals 11a -c were then subjected to a Suzuki
coupling reaction with o-fluorophenylboronic acid.12 It
was found that the 2-chloropyridine moiety of these
acetals reacted exceedingly slowly with this boronic acid
under standard reaction conditions.13 However, the reac-
tions proceeded smoothly on employment of the condi-
tions recently reported by Fu and co-workers and afforded
the desired reaction products, the aromatic fluorides
12a -c (R ) Me, i-Pr, and Ph), in good yield.14 These
reaction conditions involved heating a mixture of the
acetals 11a -c, the boronic acid, and anhydrous cesium
carbonate at reflux in tetrahydrofuran with catalytic
amounts of tris(dibenzylideneacetone)dipalladium(II)
and tri-tert-butylphosphine. The products of the latter
reactions were then converted efficiently to the target
compounds, the P,N-ligands 5a -c, on reaction with the
potassium salt of diphenylphosphine in the presence of
18-crown-6.15 Of note, this modular and efficient synthetic
route is amendable to the preparation of multigram
quantities of these P,N-ligands.16
a
Reagents and conditions: (a) ethyl acetoacetate, NH4OAc (ref
6); (b) PhP(O)Cl2, 160 °C, 16 h, 83%; (c) H2O2, H2O, AcOH, 80 °C,
16 h; (d) Ac2O, room temperature, 1 h then 100 °C, 4 h, 60% (over
two steps); (e) LiOH, THF, H2O, room temperature, 16 h, 94%; (f)
(COCl)2, DMSO, CH2Cl2; NEt3, -78 °C to room temperature, 90%.
Ph)] in order to vary the steric environment around the
complexation site of the chiral P,N-ligands.
Resu lts a n d Discu ssion
The chloroketone 6 was synthesized in six steps from
the 2-hydroxypyridine 7 that can be prepared on a
multigram scale from cyclopentanone and ethyl aceto-
acetate (Scheme 1).6 The latter compound was then
converted to the 2-chloropyridine 8 on heating with
phenylphosphonic dichloride.7 Subsequent oxidation with
hydrogen peroxide afforded the corresponding pyridine
N-oxide that was converted to the known acetate 9 on
heating with acetic anhydride.8,9 Hydrolysis of the acetate
9 with lithium hydroxide afforded the corresponding
alcohol 10 and subsequent Swern oxidation afforded the
desired chloroketone 6.10
The chiral P,N-ligands 5a -c (R ) Me, i-Pr, and Ph)
were synthesized in three steps from the chloroketone 6
(Scheme 2). The chiral acetals 11a -c were prepared in
With a series of structurally diverse chiral P,N-ligands
5a -c (R ) Me, i-Pr and Ph) in hand, we undertook the
(6) Sakurai, A.; Midorikawa, H. Bull. Chem. Soc. J pn. 1968, 41, 165.
(7) Robison, M. M. J . Am. Chem. Soc. 1958, 80, 6254.
(8) Detailed synthetic procedures for the preparation of the acetate
9 have been described elsewhere; see: Lyle, M. P. A.; Wilson, P. D.
Org. Lett. 2004, 6, 855 (Supporting Information). In this instance, the
acetate 9 was used to prepare a nonrelated chiral bipyridyl ligand that
was used in the asymmetric copper(I)-catalyzed cyclopropanation
reactions of a series of alkenes and diazoesters.
(9) The synthesis of the acetate 9 by similar methods has been
communicated by Fu and co-workers; see: Rios, R.; Liang, J .; Lo, M.
M.-C.; Fu, G. C. Chem. Commun. 2000, 377.
(10) Mancuso, A. J .; Huang, S. L.; Swern, D. J . Org. Chem. 1978,
43, 2480.
(11) The noncommercially available chiral nonracemic diol 3b (R )
i-Pr) was prepared from L-diethyl tartrate according to literature
procedures; see: (a) Wang, X.; Erickson, S. D.; Iimori, T.; Still, W. C.
J . Am. Chem. Soc. 1992, 114, 4128. (b) Matteson, D. S.; Beedle, E. C.;
Kandil, A. A. J . Org. Chem. 1987, 52, 5034.
(12) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(13) Tetrakis(triphenylphosphine)palladium(0) [(Pd(PPh3)4] was em-
ployed as a catalyst for this reaction in the first instance. The reactions
were performed at reflux in benzene or toluene with potassium
carbonate as the base.
(14) Littke, A. F.; Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2000, 122,
4020.
(15) Ku¨ndig, E. P.; Meier, P. Helv. Chim. Acta 1999, 82, 1360.
J . Org. Chem, Vol. 69, No. 15, 2004 5061

Lyle et al.
TABLE 1. P a lla d iu m -Ca ta lyzed Asym m etr ic Allylic
Su bstitu tion Rea ction s
methyl group. The use of the pseudo-enantiomeric P,N-
ligand 5b (R ) i-Pr), derived from (1S,2S)-1,2-diisopropyl-
1,2-ethanediol (3b: R ) i-Pr), afforded the enantiomeric
product R-14 in similar enantiomeric excess (43-60%).
It was somewhat surprising that the use of ligand 5b (R
) i-Pr) showed, in general, slightly lower enantioselec-
tivity. The superior result (60% ee) was obtained when
cesium carbonate was employed as the base. The use of
the P,N-ligand 5c (R ) Ph), derived from (1S,2S)-1,2-
diphenyl-1,2-ethanediol (3c: R ) Ph), again afforded the
product R-14 in similar enantiomeric excess (58-62%)
when BSA and a catalytic amount of potassium acetate
or potassium carbonate and 18-crown-6 were employed
as reagents. However, and to our delight, the product
R-14 was formed in high enantiomeric excess (86%) and
in excellent yield (97%) when cesium carbonate was
employed as the base in this room temperature reaction.
On decreasing the temperature to 12 °C a further
improvement in the enantioselectivity of the reaction was
observed (88% ee). The optimal reaction conditions
involved performing this catalytic asymmetric reaction
with cesium carbonate at 0 °C for 4 h. This afforded the
product R-14 in high enantiomeric excess (90%). A
further decrease in the reaction temperature to -12 °C
did not result in any further improvement of the enan-
tioselectivity and the yield of this reaction was compro-
mised.
yield ee
entry P,N-ligand
base/additives
temp (%)a (%)b confc
1
2
3
4
5
6
7
8
9
5a
5a
5a
5b
5b
5b
5c
5c
5c
5c
5c
5c
BSA, KOAc (cat.) rt
K2CO3, 18-crown-6 rt
97
97
97
92
93
97
71
97
97
97
91
65
60
60
43
54
60
58
62
86
88
90
90
S
S
S
Cs2CO3
rt
BSA, KOAc (cat.) rt
K2CO3, 18-crown-6 rt
R
R
R
R
R
R
R
R
R
Cs2CO3
rt
BSA, KOAc, (cat.) rt
K2CO3, 18-crown-6 rt
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
rt
12 °C
0 °C
10
11
12
-12 °C 83
a
Isolated yield of the reaction product R-14 and S-14 after
b
purification by flash chromatography. Determined by analytical
chiral HPLC (Daicel Chiracel OD column). c The absolute stereo-
chemistry of the reaction product was determined by comparison
of the optical rotation with literature values (ref 18).
evaluation of these ligands in the palladium(II)-catalyzed
asymmetric allylic substitution reaction of racemic 3-
acetoxy-1,3-diphenyl-1-propene RS-13 with dimethyl
malonate (Table 1). In the series of asymmetric allylic
substitution reactions that were performed, the active
asymmetric palladium(II) catalyst was generated by the
reaction of 6.25 mol % of the chiral P,N-ligand 5a -c with
2.5 mol % of allylpalladium(II) chloride dimer in dichlo-
romethane at room temperature.17 On subsequent addi-
tion of racemic 3-acetoxy-1,3-diphenyl-1-propene RS-13
(1 equiv) and dimethyl malonate (3 equiv), a range of
bases and associated reagents were then added. The
bases and associated reagents employed in these reac-
tions were the following: (1) N,O-bis(trimethylsilyl)-
acetamide (BSA, 3 equiv) and a catalytic amount of
potassium acetate;3b (2) anhydrous potassium carbonate
(3 equiv) and 18-crown-6 (3 equiv);3b and (3) anhydrous
cesium carbonate (3 equiv).3a
In all cases, these catalytic systems proved to be
reactive and afforded the expected product, (1,3-diphen-
ylallyl)-malonic acid dimethyl ester 14, in good yield (up
to 97%). However, the enantioselectivities of these reac-
tions varied substantially depending on the P,N-ligand
and reaction conditions that were employed. The use of
the P,N-ligand 5a (R ) Me), derived from (2R,3R)-2,3-
butanediol (3a : R ) Me), afforded the product S-14 in
moderate enantiomeric excess (60-65%) with the three
individual sets of reaction conditions.18 These results
were encouraging when one considers that this asym-
metric reaction is directed by the steric influence of a
To postulate a plausible mechanism for this highly
enantioselective reaction (90% ee), a 31P NMR study was
undertaken. The corresponding cationic π-allyl palladium
complex was prepared in deuterated dichloromethane by
the reaction of (1,3-diphenylpropenyl)palladium(II) chlo-
ride dimer and the P,N-ligand 5c (R ) Ph) in the
presence of silver tetrafluoroborate.19,20 Examination of
the 31P NMR spectrum of this reaction mixture indicated
the formation of two isomeric complexes in a ∼2:1 ratio.
These isomeric π-allyl intermediates were assigned as the
W- and M-isomers (W-5c and M-5c), respectively (Figure
3).21 Assuming that these intermediates are involved in
the reaction of racemic 3-acetoxy-1,3-diphenyl-1-propene
RS-13 with the P,N-ligand 5c (R ) Ph) and allylpalla-
dium(II) chloride dimer, the reaction pathway can be
described by a Curtin-Hammett scheme.22 Thus, the
interconversion of these π-allyl intermediates must be
rapid with respect to nucleophilic attack of the anion of
dimethyl malonate.
It would be expected that nucleophilic attack of the
anion of dimethyl malonate on these isomeric π-allyl
intermediates W-5c and M-5c would be regioselective and
(19) (1,3-Diphenylpropenyl)palladium(II) chloride dimer was pre-
pared from the corresponding propenyl chloride according to a litera-
ture procedure; see: Hayashi, T.; Yamamoto, A.; Ito, Y.; Nishioka, E.;
Miura, H.; Yanagi, K. J . Am. Chem. Soc. 1989, 111, 6301.
(20) Gilbertson, S. R.; Lan, P. Org. Lett. 2001, 3, 2237.
(21) This assignment was made on the basis of careful inspection
of molecular models of the M- and W-isomers of the π-allyl intermedi-
ate. It was observed that the isomer M-5c was more sterically
encumbered (and presumably less stable) than the corresponding
isomer W-5c. This is due to the close proximity of the 1,3-diphenylallyl
moiety and one of the phenyl rings on the acetal as indicated by the
double-headed arrow (see Figure 3). It was not possible to make this
assignment with 1H NMR techniques. Of note, other isomers of π-allyl
complexes are possible. However, M- and W-isomers are assumed to
be the mechanistically relevant π-allyl intermediates; for discussion,
see ref 3b.
(16) A typical catalyst loading was employed in these asymmetric
reactions; see refs 2 and 3b.
(17) Analytical chiral HPLC (Daicel Chiracel OD column) indicated
that the enantiomeric purity of the P,N-ligands 5a -c was greater than
99% ee. For a related class of chiral nonracemic P,N-ligands, see: Ito,
K.; Kashiwagi, R.; Iwasaki, K.; Katsuki, T. Synlett 1999, 1563.
(18) Evans, D. A.; Campos, K. R.; Tedrow, J . S.; Michael, F. E.;
Gagne´, M. R. J . Am. Chem. Soc. 2000, 122, 7905.
(22) Seeman, J . I. Chem. Rev. 1983, 83, 83.
5062 J . Org. Chem., Vol. 69, No. 15, 2004

A New Class of Chiral P,N-Ligands
lithium hydroxide monohydrate (1.49 g, 35.6 mmol) and the
resultant solution was stirred at room temperature for 16 h.
The reaction mixture was then diluted with water (15 mL)
and extracted with chloroform (3 × 25 mL). The combined
organic extracts were washed with brine (15 mL) and water
(15 mL), dried over anhydrous magnesium sulfate, and
concentrated in vacuo to afford the crude product. Flash
chromatography with hexanes:ether (1:1) as the eluant af-
forded the title compound 10 (1.37 g, 94%) as a white
crystalline solid. Mp 100-102 °C, hexanes/ether; 1H NMR (400
MHz, CDCl3) δ 1.99-2.16 (1H, m), 2.24 (3H, s), 2.47-2.57 (1H,
m), 2.62-2.72 (1H, m), 2.92 (1H, ddd, J ) 4.0, 8.9, 13.1 Hz),
3.82 (1H, broad s), 5.19 (1H, dd, J ) 5.8, 7.3 Hz), 6.99 (1H, s);
13C NMR (101 MHz, CDCl3) δ 18.8, 25.9, 32.5, 74.7, 124.0,
135.0, 147.6, 150.4, 164.8; IR (KBr) 3283 (broad), 1594, 1567,
1445, 1374, 1298, 1191, 1094, 1064, 1019, 965, 925, 888, 861
cm-1; MS (CI) m/z (rel intensity) 184 (M + H, 100), 166 (20).
Anal. Calcd for C9H10ClNO: C, 58.86; H, 5.49; N, 7.63.
Found: C, 58.62; H, 5.62; N, 7.46.
2-Ch lor o-4-m e t h yl-6,7-d ih yd r o-5H -[1]p yr in d in e -7-
on e (6). To a stirred solution of oxalyl chloride (57 µL, 0.65
mmol) in dichloromethane (6 mL) at -78 °C was added
dimethyl sulfoxide (150 µL, 2.18 mmol) and the resultant
solution was stirred for 10 min. A solution of the alcohol 10
(100 mg, 0.540 mmol) in dichloromethane (5 mL) was then
added via a cannula over the course of 5 min. The reaction
mixture was stirred for an additional 10 min and triethylamine
(380 µL, 2.73 mmol) was then added and the reaction mixture
was allowed to warm slowly to room temperature. The reaction
mixture was then diluted with ether (30 mL) and washed with
brine (3 × 5 mL). The organic layer was dried over anhydrous
magnesium sulfate and concentrated in vacuo to afford the
crude product. Flash chromatography with hexanes:ether (1:
1) as the eluant afforded the title compound 6 (89 mg, 90%)
as a white crystalline solid. Mp 149-152 °C, hexanes/ether;
1H NMR (400 MHz, CDCl3) δ 2.38 (3H, s), 2.69-2.78 (2H, m),
2.96-3.06 (2H, m), 7.26 (1H, s); 13C NMR (101 MHz, CDCl3) δ
17.9, 22.1, 35.1, 128.7, 148.9, 149.6, 153.3, 153.8, 204.0; IR
(KBr) 1714, 1587, 1439, 1421, 1285, 1256, 1203, 1112, 871,
570 cm-1; MS (CI) m/z (rel intensity) 182 (M + H, 100). Anal.
Calcd for C9H8ClNO: C, 59.52; H, 4.44; N, 7.71. Found: C,
59.44; H, 4.44; N, 7.67.
F IGURE 3. Isomeric π-allyl intermediates W-5c and M-5c
and stereochemical rationale [Nu ) CH(CO2Me)2].
occur trans to the phosphine moiety.23 It also would be
expected that the nucleophile would attack these π-allyl
intermediates from the top face of the complex as
indicated. This would be influenced by one of the phenyl
substituents of the acetal moieties, which is positioned
beneath the palladium π-allyl complexes. Thus, to ac-
count for the observed absolute stereochemistry of the
major reaction product, (1R)-(1,3-diphenylallyl)malonic
acid dimethyl ester R-14, we conclude that the π-allyl
intermediate M-5c reacts at a faster rate with the anion
of dimethyl malonate.24 A related stereochemical inter-
pretation has also been described recently by Helmchen
and Pfaltz for a chiral P,N-ligand.2b
Con clu sion
An efficient and modular synthesis of a series of chiral
nonracemic P,N-ligands 5a -c (R ) Me, i-Pr, and Ph) has
been achieved. These novel acetals were prepared from
2-chloro-4-methyl-6,7-dihydro-5H-[1]pyrindine-7-one 6 and
a series of chiral C2-symmetric 1,2-diols 3. The palladium-
catalyzed asymmetric allylic substitution reaction of
racemic 3-acetoxy-1,3-diphenyl-1-propene RS-13 with
dimethyl malonate was investigated. The P,N-ligand 5c
(R ) Ph), derived from (1S,2S)-1,2-diphenyl-1,2-ethanediol
(3c: R ) Ph), proved to be the most effective ligand and
afforded the product (1R)-(1,3-diphenylallyl)malonic acid
dimethyl ester 14 in high enantiomeric excess (up to 90%)
and in good yield up to (97%). The optimal reaction
conditions involved the use of 6.25 mol % of the chiral
P,N-ligand, 2.5 mol % of allylpalladium(II) chloride
dimer, and cesium carbonate (3 equiv) in dichloromethane
at 0 °C. Current investigations are focused on the use of
the P,N-ligands 5a -c in other catalytic asymmetric
processes.
2-Ch lor o-4-m e t h yl-6,7-d ih yd r o-5H -[1]p yr in d in e -7-
on e (1S,2S)-1,2-diph en yl-1,2-eth an ediol Acetal (11c): Rep-
r esen ta tive P r oced u r e for th e P r ep a r a tion of Aceta ls
(11a a n d 11b). To a stirred solution of the chloroketone 6 (100
mg, 0.550 mmol) in benzene (3 mL) was added (1S,2S)-1,2-
diphenyl-1,2-ethanediol 3c (152 mg, 0.719 mmol) and p-
toluenesulfonic acid monohydrate (16 mg, 0.083 mmol). The
resultant solution was heated at reflux in a Dean-Stark
apparatus for 16 h. The reaction mixture was then allowed to
cool to room temperature and potassium carbonate (100 mg)
was added. After an additional 10 min, the reaction mixture
was filtered and the filter-cake was washed with ether (10 mL).
The combined filtrates were concentrated in vacuo to afford
the crude product. Flash chromatography with hexanes:ether
(4:1) as the eluant afforded the title compound 11c (163 mg,
79%) as a white foam/solid. Mp 44-46 °C; [R]20 -108 (c
D
0.38, chloroform); 1H NMR (400 MHz, C6D6) δ 1.54 (3H, s),
2.26-2.32 (2H, m), 2.51-2.65 (2H, m), 4.99 (1H, d, J ) 8.9
Hz), 5.99 (1H, d, J ) 8.9 Hz), 6.68 (1H, s), 7.07-7.15 (4H, m),
7.18-7.29 (4H, m), 7.74-7.79 (2H, m); 13C NMR (101 MHz,
C6D6) δ 18.0, 24.1, 36.9, 87.1, 87.9, 115.7, 125.4, 127.8, 129.1,
129.2, 135.4, 137.5, 138.1, 147.7, 152.1, 162.9; IR (KBr) 2914,
2362, 2336, 1594, 1570, 1496, 1453, 1443, 1384, 1320, 1298,
1267, 1229, 1201, 1160, 1113, 1059, 1021, 939, 925, 879, 759,
699 cm-1; MS (CI) m/z (rel intensity) 378 (M + H, 41), 271
(27), 182 (100). Anal. Calcd for C23H20ClNO2: C, 73.11; H, 5.33;
N, 3.71. Found: C, 72.96; H, 5.39; N, 3.78.
Exp er im en ta l Section
(7RS)-2-Ch lor o-4-m eth yl-6,7-d ih yd r o-5H-[1]p yr in d in e-
7-ol (10). To a stirred solution of the acetate 98,9 (2.00 g, 8.88
mmol) in tetrahydrofuran:water (3:1, 20 mL) was added
(23) The strong trans-effect of the phosphine donor relative to the
pyridine donor is well-established in related P,N-ligands; see ref 2.
(24) This stereochemical assumption was based on inspection of
molecular models of the M- and W-isomer of the π-allyl intermediate
as discussed earlier; see also footnote 21.
2-(2-F lu or op h en yl)-4-m eth yl-6,7-d ih yd r o-5H-[1]p yr in -
d in e-7-on e (1S,2S)-1,2-Dip h en yl-1,2-et h a n ed iol Acet a l
(12c): Rep r esen ta tive P r oced u r e for th e P r ep a r a tion of
J . Org. Chem, Vol. 69, No. 15, 2004 5063

Lyle et al.
Ar om a tic F lu or id es (12a a n d 12b). To a stirred solution of
the acetal 11c (351 mg, 0.926 mmol) and o-fluorophenylboronic
acid (195 mg, 1.39 mmol) in degassed tetrahydrofuran (20 mL)
was added tris(dibenzylideneacetone)dipalladium(II) (41.1 mg,
0.0463 mmol), tri-tert-butylphosphine (925 µL of a 0.10 M
solution in tetrahydrofuran, 0.0925 mmol), and anhydrous
cesium carbonate (1.51 g, 4.63 mmol). The resultant suspen-
sion was heated at reflux for 16 h. The reaction mixture was
then allowed to cool to room temperature and was diluted with
ethyl acetate (15 mL). The resultant solution was washed with
brine (10 mL), dried over anhydrous magnesium sulfate, and
concentrated in vacuo to afford the crude product. Flash
chromatography with hexanes:ether (8:1) as the eluant af-
forded the title compound 12c (356 mg, 88%) as a white foam/
solid. Mp 46-48 °C; [R]20D +119.1 (c 0.56, chloroform); 1H NMR
(400 MHz, CDCl3) δ 2.36 (3H, s), 2.64-2.79 (2H, m), 2.94-
3.02 (2H, m), 4.87 (1H, d, J ) 8.6 Hz), 5.72 (1H, d, J ) 8.6
Hz), 7.14-7.21 (1H, m), 7.27-7.34 (9H, m), 7.35-7.42 (1H,
m), 7.62-7.69 (3H, m), 8.12-8.17 (1H, m); 13C NMR (101 MHz,
CDCl3) δ 41.8, 52.2, 55.4, 61.6, 75.8, 110.6, 120.9, 123.6, 127.9,
128.59, 128.62, 128.8, 128.9, 129.5, 129.9, 131.2, 134.3, 157.2,
157.9, 167.3; IR (KBr) 3061, 2904, 1654, 1598, 1541, 1455,
1377, 1347, 1320, 1275, 1241, 1211, 1176, 1154, 1099, 1060,
1019, 936, 884, 867, 818, 761 cm-1; MS (CI) m/z (rel intensity)
438 (M + H, 25), 331 (6), 242 (100), 197 (19), 169 (11), 146 (8),
113 (22), 81 (59). Anal. Calcd for C29H24FNO2: C, 79.61; H,
5.53; N, 3.20. Found: C, 79.90; H, 5.52; N, 3.41.
th esis of (1R)-(1,3-Dip h en yla llyl)m a lon ic Acid Dim eth yl
Ester (R-14) a n d (1S)-(1,3-Dip h en yla llyl)m a lon ic Acid
Dim eth yl Ester (S-14). A solution of allylpalladium(II)
chloride dimer (3.7 mg, 0.010 mmol) and the chiral P,N-ligand
5a -c (0.025 mmol) in dichloromethane (1.5 mL) was stirred
at room temperature for 1 h. A solution of (3RS)-3-acetoxy-
1,3-diphenyl-1-propene RS-13 (100 mg, 0.400 mmol) and
dimethyl malonate (208 mg, 1.20 mmol) in dichloromethane
(1.5 mL) was then added via a cannula followed by one of three
bases and associated reagents [(1) BSA (295 µL, 1.20 mmol)
and a catalytic amount of potassium acetate (3.0 mg); (2)
potassium carbonate (166 mg, 1.20 mmol) and 18-crown-6 (296
mg, 1.20 mmol); (3) anhydrous cesium carbonate (391 mg, 1.20
mmol)]. The reaction mixture was then stirred at the temper-
ature specified (see Table 1) and was monitored by thin-layer
chromatography until the starting material had been con-
sumed (the reaction times varied from 2 to 24 h depending on
the ligand and reagents employed). The reaction mixture was
then diluted with ether (25 mL) and washed with a saturated
aqueous solution of ammonium chloride (5 mL) and water (5
mL) before being dried over anhydrous magnesium sulfate and
concentrated in vacuo to afford the crude product. Flash
chromatography with hexanes:ether (3:1) as the eluant af-
forded the title compounds R-14 or S-14 as colorless oils. The
enantiomeric purity of the reaction products was determined
by analytical chiral HPLC, using a Daicel Chiracel OD column
[hexanes:2-propanol (97:3), flow rate at 0.5 mL/min, detection
at λ ) 245 nm; t1 ) 19.4 min, t2 ) 20.5 min]. The absolute
configuration of the reaction product was determined by
comparing the sign of the optical rotation to literature values.18
1H NMR (400 MHz, CDCl3) δ 3.53 (3H, s), 3.71 (3H, s), 3.96
(1H, d, J ) 10.7 Hz), 4.27 (1H, dd, J ) 8.6, 11.0 Hz), 6.33 (1H,
dd, J ) 8.6, 15.9 Hz), 6.48 (1H, d, J ) 15.9 Hz), 7.17-7.35
(10H, m); 13C NMR (101 MHz, CDCl3) δ 49.2, 52.4, 52.6, 57.6,
126.4, 127.2, 127.6, 127.9, 128.5, 128.7, 129.1, 131.8, 136.8,
140.2, 167.8, 168.2; IR (KBr) 1759, 1733, 1600, 1494, 1433,
1321, 1261, 1141, 1020, 968, 921, 803, 766, 745, 700 cm-1; MS
(CI) m/z (rel intensity) 324 (M + H, 3), 235 (10), 193 (100).
2-(2-Diph en ylph osph an ylph en yl)-4-m eth yl-6,7-dih ydr o-
5H-[1]pyr in din e-7-on e (1S,2S)-1,2-Diph en yl-1,2-eth an ediol
Aceta l (5c): Rep r esen ta tive P r oced u r e for th e P r ep a r a -
tion of P ,N-Liga n d s (5a a n d 5b). To a stirred solution of
potassium tert-butoxide (177 mg, 1.58 mmol) and 18-crown-6
(502 mg, 1.90 mmol) in tetrahydrofuran (12 mL) at 0 °C was
added diphenylphosphine (294 mg, 1.58 mmol) and the result-
ant red solution was stirred for 1 h. A solution of the aromatic
fluoride 12c (346 mg, 0.790 mmol) in tetrahydrofuran (5 mL)
was then added via a cannula and the resultant mixture was
stirred at room temperature for 24 h. The reaction was
quenched by the addition of methanol (5 mL) and concentrated
in vacuo to afford the crude product. Flash chromatography
with hexanes:ether (8:1) as the eluant afforded the title
compound 5c (302 mg, 63%) as a white crystalline solid. Mp
Ack n ow led gm en t. We are grateful to the Natural
Sciences and Engineering Research Council of Canada
(NSERC) and Simon Fraser University (SFU) for finan-
cial support. In addition, the authors wish to acknowl-
edge the Canadian Foundation for Innovation (CFI) for
support of our research program. M.P.A.L. thanks SFU
for graduate research fellowships and an entrance
scholarship. A.A.N. also thanks SFU for graduate
research fellowships. We are grateful to Mrs. Marcy
Tracey for assistance with the 31P NMR studies.
79-80 °C, hexanes:ether; [R]20 -129 (c 0.55, chloroform); 1H
D
NMR (400 MHz, CDCl3) δ 2.16 (3H, s), 2.55-2.75 (2H, m),
2.83-2.97 (2H, m), 4.75 (1H, d, J ) 8.7 Hz), 5.38 (1H, d, J )
8.7 Hz), 7.04-7.06 (1H, m), 7.12-7.35 (20H, m), 7.47 (1H, m),
7.56-7.62 (2H, m), 7.73 (1H, ddd, J ) 1.1, 4.4, 7.6 Hz); 13C
NMR (101 MHz, CDCl3) δ 18.4, 24.3, 36.5, 85.5, 86.5, 115.7,
126.5, 126.6, 126.9, 128.2, 128.3, 128.49, 128.53, 128.6, 128.7,
128.9, 130.6, 130.7, 134.1, 134.2, 134.3, 134.4, 134.6, 135.0,
136.2, 136.4, 137.2, 137.3, 138.5, 138.65, 138.69, 138.8, 143.6,
147.4, 147.6, 159.2, 160.7; IR (KBr) 3452, 3052, 2923, 1655,
1600, 1585, 1495, 1477, 1453, 1376, 1346, 1319, 1277, 1177,
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures and complete product characterization data
for all of the additional new compounds synthesized (5a , 5b,
11a , 11b, 12a , and 12b), as well as 1H and 13C NMR spectra
for compounds 5a -c, 6, 10, 11a -c, and 12a -c. This material
is available free of charge via the Internet at http://pubs.acs.org.
1156, 1102, 1073, 1059, 1021, 937, 923, 760, 746, 698 cm-1
;
MS (MALDI-TOF) 605 (M + H). Anal. Calcd for C41H34NO2P:
C, 81.57; H, 5.68; N, 2.32. Found: C, 81.63; H, 5.72; N, 2.33.
Gen er al P r ocedu r es for P alladiu m (II)-Catalyzed Asym -
m etr ic Allylic Su bstitu tion Rea ction s: Asym m etr ic Syn -
J O0494275
5064 J . Org. Chem., Vol. 69, No. 15, 2004