Pyridyl Phosphinites and Pyridyl Phosphites from Chiral Pyridyl Alcohols - A Modular Approach

Article abstract of DOI:10.1002/ejoc.200300368

Chiral arylated pyridyl alcohols, pyridyl phosphinites and pyridyl phosphites were prepared by Suzuki arylation and/or O-functionalization with a chlorodiarylphosphane or a chlorodiarylphosphite of chiral 2-bromo-6-(1-hydroxyalkyl)pyridines or 2-(1-hydrox

Full text of DOI:10.1002/ejoc.200300368

FULL PAPER
Pyridyl Phosphinites and Pyridyl Phosphites from Chiral Pyridyl Alcohols —
A Modular Approach
Fredrik Rahm,[a] Andreas Fischer,[b] and Christina Moberg*[a]
Keywords: Asymmetric catalysis / Chiral pool / Palladium / Pyridine ligands / Zinc
Chiral arylated pyridyl alcohols, pyridyl phosphinites and py-
ridyl phosphites were prepared by Suzuki arylation and/or
O-functionalization with a chlorodiarylphosphane or a chloro-
diarylphosphite of chiral 2-bromo-6-(1-hydroxyalkyl)pyrid-
ines or 2-(1-hydroxyalkyl)pyridines, with the chirality origin-
ating from the chiral pool. The pyridyl alcohols were as-
dium-catalysed substitutions of rac-1,3-diphenyl-2-propenyl
acetate and rac-2-cyclohexenyl acetate with dimethyl malon-
ate. Moderate enantioselectivities were observed in the cata-
lytic reactions. We observed kinetic resolution of the racemic
acetate when using one of the phosphite ligands.
sessed as catalysts for the addition of diethylzinc to benzal- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
dehyde and the P,N-ligands were employed in the palla-
Germany, 2003)
Introduction
Previously, we developed a simple methodology for the
preparation of chiral enantiopure pyridyl alcohols [1, R ϭ
H, Br; RЈ ϭ neomenthyl,[10] (S)-methoxybenzyl, (S)-1-me-
thoxyethyl][11] that employs cheap and readily available
compounds that originate from the chiral pool. Here we
describe the transformation of the pyridyl alcohols into 6-
aryl-substituted pyridyl alcohols (1, R ϭ Ar), chiral pyridyl
phosphinites (2, R ϭ H, Ar) and pyridyl phosphites (3,
R ϭ H).
Recent progress in asymmetric synthesis has provided
powerful catalytic procedures for the preparation of a wide
variety of organic compounds in enantiopure or enantio-
enriched forms.[1] This development has been based on
combinations of trial-and-error and attempted rational
catalyst design. To meet the increasing demand for enanti-
opure or enantioenriched products, more efficient methods
are required for catalyst development and screening of me-
tal complexes.[2,3] Today, high-throughput screening tech-
nologies — whereby a combination of synthetic procedures
and efficient analytical methods allow on-line determi-
nation of yield[4] and enantioselectivity[5] — are being ex-
plored, together with methods that allow downsizing.[6]
Simple variation of catalyst structure can sometimes be
achieved by the use of additives or activators,[7] but struc-
tural variations of the ligand responsible for chirality trans-
fer is usually required to achieve high selectivity. Efficient
methods are required for their preparation of chiral ligands
having the desired structural variations.[8] Modular ap-
proaches are widely employed for this purpose.[9] Such
methods are particularly important when they permit the
preparation of different types of ligands, for example, those
containing different sets of donor atoms, starting from the
same basic skeleton.
Chiral pyridyl alcohols have found extensive use in cata-
lytic applications, in particular for the addition of diethyl-
zinc to aldehydes and the conjugate addition to α,β-unsatu-
rated carbonyl compounds.[12] Achiral[13] as well as chiral[14]
pyridinophosphinites and a tridentate bisphosphinated 2,6-
bis(1-hydroxyethyl)pyridine[15] have been prepared and used
in palladium-catalysed allylations, rhodium-catalysed
hydroformylations, and Rh- and Ir-catalyzed hydrogen-
ations of prochiral imines,[16] respectively. Pyridinophos-
phites have recently also been applied to a variety of cata-
lytic processes.[17]
[a]
Department of Chemistry, Organic Chemistry, Royal Institute
of Technology,
100 44 Stockholm, Sweden
Fax: (internat.) ϩ46-(0)8-791-2333
E-mail: kimo@orgchem.kth.se
We have applied the pyridyl alcohols described here as
catalysts for the addition of diethylzinc to benzaldehyde and
we have used the P,N derivatives in palladium-catalysed al-
lylic alkylations.
[b]
Department of Chemistry, Inorganic Chemistry, Royal Institute
of Technology,
100 44 Stockholm, Sweden
Eur. J. Org. Chem. 2003, 4205Ϫ4215
DOI: 10.1002/ejoc.200300368
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4205

F. Rahm, A. Fischer, C. Moberg
FULL PAPER
Results and Discussion
Preparation of Ligands
Diastereoisomeric alcohols 1a and 1b were obtained as
described previously from reaction of (1S,2S,5R)-1-cyano-
2-isopropyl-5-methylcyclohexane (neomenthyl-1-nitrile, 4a)
with 2-lithiopyridine, followed by reduction of the ketone 5
obtained using sodium borohydride, and chromatographic
separation of the products;[10] the analogous reactions of
mandelic acid methyl ester derivative 6 afforded the ketone
7, which upon reduction yielded pyridyl alcohol 1c as a sin-
gle diastereoisomer (Scheme 1).[11]
Scheme 2
1f was obtained analogously starting from 2,6-dibromopyri-
dine and 6.[11]
To gain access to menthyl derivatives, a variety of con-
ditions were tested for the epimerization of (1S,2S,5R)-2-
isopropyl-5-methylcyclohexane-1-carbonitrile. With the cy-
ano group in the axial position, proton abstraction is highly
disfavoured and rather drastic conditions are required for
epimerization to occur. Microwave irradiation at 160 °C
over a period of 20 min in 0.1  NaOEt in ethanol afforded
a 1:1 mixture of the epimers 4a and 4b,[18] which could not
be separated by chromatography (Scheme 3).
Some epimerization occurred in the reactions of 2-
bromo-6-lithiopyridine and 4a and we isolated products
that seemingly were obtained from 4b. Use of a solvent con-
sisting of a 1:1:2 mixture of THF/hexane/diethyl ether, in
place of the 1:1:3 mixture normally employed, increased the
degree of epimerization, although at the expense of the total
yield of the reaction. To optimize the formation of menthyl
alcohols, the 1:1 mixture of epimeric nitriles was treated
with 2-bromo-6-lithiopyridine in the 1:1:2 mixture of sol-
vents. From this reaction, we isolated in a pure form only
the isomer with absolute (R) configuration at the carbinol
carbon atom (1g; 24% yield from the nitrile, Scheme 3).
6-Aryl-substituted pyridyl alcohols were conveniently ac-
cessible by Suzuki coupling of bromo derivatives 1d and 1f
Scheme 1
The derivatives 1d and 1e were prepared by reaction of using tetrakis(triphenylphosphane)palladium and sodium
2-bromo-6-lithiopyridine, obtained by lithiation of 2,6-di- carbonate. Phenylboronic acid, o-methylphenylboronic
bromopyridine in THF/hexane/diethyl ether (1:1:3), with 4a acid, p-methoxyphenylboronic acid, and p-(trifluoromethyl)-
to give the ketone 8 (58%), which was reduced with sodium phenylboronic acid were selected as reagents to allow us
borohydride to give a ca. 4:1 ratio of the (S) and (R) iso- to study the effects of electron-withdrawing and electron-
mers in a total isolated yield of 68% (Scheme 2). Compound donating substituents on the subsequent catalytic reactions.
4206
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4205Ϫ4215

Pyridyl Phosphinites and Pyridyl Phosphites from Chiral Pyridyl Alcohols
FULL PAPER
Scheme 5
Scheme 3
Scheme 4
The reactions afforded good-to-high yields (64Ϫ93%) of
products 1hϪ1n (Scheme 4).
Nickel-mediated dimerization of TBDMS-protected 1f
and the analogous lactic acid derivative afforded, after de-
Scheme 6
protection, bipyridine compounds 1o and 1p (Scheme 5).[11] we employed this method for the preparation of the aryl-
We prepared phosphinites from the appropriate pyridyl ated analogue 2bϪBH3 as well as for neomenthyl ligands
alcohols by deprotonation with nBuLi, followed by reaction 2cϪBH3 and 2dϪBH3.
with chlorodiphenylphosphane (Scheme 6). The desired
Finally, we prepared the phosphites 3a and 3b from pyri-
phosphinite was obtained from mandelic acid derivative 1c dyl alcohol 1c and (S)- and (R)-4-chloro-3,5-dioxa-4-phos-
in 43% yield. In situ protection of the labile product by phacyclohepta[2,1-a:3,4-aЈ]binaphthalenes [(S)-9 and (R)-
using BH3·SMe2 increased the yield to 77% and, therefore, 9], respectively, in the presence of triethylamine (Scheme 7).
Eur. J. Org. Chem. 2003, 4205Ϫ4215
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4207

F. Rahm, A. Fischer, C. Moberg
FULL PAPER
Scheme 7
Assignment of Absolute Configuration
mation[20] of the esters or to some other effect; compounds
containing substituents having additional chiral centres
should anyway be treated with caution.[21] Finally, the abso-
lute configuration of compound 1f was correlated to that
of 1c by debromination and, thus, it is (R).
Previously, we assigned the absolute configuration of the
pyridyl alcohols 1a and 1b from NMR spectroscopic data
of their Mosher ester derivatives.[10] Grayson and co-work-
ers,[19] however, prepared compounds 1a and 1b by an
alternative procedure and showed by X-ray crystallography
that the absolute configuration at the carbinol carbon
atoms is opposite to that assigned by us and, thus, 1a has
an (S) and 1b an (R) absolute configuration. From these
assignments, it follows that 1d should have an (S) and 1e
an (R) absolute configuration at the epimeric centres, as
judged by the similarities of their NMR spectra to those of
1a and 1b, respectively. This assumption is supported by the
expected formation of the (S) isomer as the major com-
pound upon reduction of ketone 8. For the same reasons,
compound 1g is believed to have an (R) absolute configura-
tion at the centre formed upon reduction of the ketone.
The assignment of an (S) absolute configuration at the
carbinol carbon atom in compound 1c was previously de-
duced from NOEs observed in the Mosher ester deriva-
tive.[11] To support this assignment, the compound was
crystallized and its structure determined by X-ray crystal-
lography (Figure 1). It was shown that, for this compound
also, the absolute configuration was opposite to that as-
signed from the NMR spectroscopic data. It is still unclear
whether the failure of the Mosher method in the present
cases is due to the preference of an unexpected confor-
Addition of Diethylzinc to Benzaldehyde
Chiral amino alcohols have been used extensively in the
addition of diethylzinc to aldehydes, a reaction that is
widely employed as a benchmark to compare the efficiency
of these types of ligands. Among amino alcohols, several
pyridyl alcohols have also been used previously in the cata-
lytic reaction. We assessed the pyridyl alcohols 1aϪ1p as
catalysts for the addition of diethylzinc to benzaldehyde in
toluene at 0 °C [Equation (1)]. The reaction conditions were
not optimized because the purpose of this study was to in-
vestigate the effect of structural changes in the ligand on
the enantioselectivity of the reaction. We found that the
absolute configuration of the product alcohol is determined
by the absolute configuration at the carbinol carbon atom
of the ligand. Neomenthyl ligands 1a and 1b gave products
with the same degree of enantioselectivity, but with differ-
ent absolute configurations (64% ee; Table 1, Entries 1 and
2). The mandelic acid derivative 1c provided the product
with a slightly higher enantioselectivity (67% ee, Entry 3).
For the 2-bromo derivatives 1d, 1e and 1g, we found that
the relative configuration of the stereocentres has a pro-
found influence on the enantioselectivity (69%, 56% and
28% ee, respectively; Entries 4, 5 and 7). The selectivity in
this case was more sensitive to the structure of the substitu-
ent. For 1e and for the ligand derived from mandelic acid
derivative 1f , the presence of a bromine atom in the 2-
position of the pyridine ring has a negative effect on the
enantioselectivity (54% ee for 1f, cf. 67% for 1c; Entries 6
and 3), whereas we observed the opposite effect for 1d and,
previously, for 2-(1-hydroxy-2,2-dimethylpropyl)pyridine.[22]
The introduction of a phenyl or a p-substituted aryl sub-
stituent in the 6-position of the pyridine ring in the neomen-
thyl derivatives (1hϪ1j) resulted in a somewhat increased
enantioselectivity (Entries 8Ϫ10), whereas for the mandelic
acid derivatives 1kϪ1n we observed enantioselectivities
Figure 1. Crystal structure of 1c; thermal ellipsoids are drawn at a
50% probability level
4208
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4205Ϫ4215

Pyridyl Phosphinites and Pyridyl Phosphites from Chiral Pyridyl Alcohols
FULL PAPER
Table 1. Addition of diethylzinc to benzaldehyde in the presence of
ligands 1
(1)
Entry
Ligand[a]
Yield (%)[b]
ee (%)[c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
94
96
94
84
88
77
94
80
96
84
93
74
85
83
90
88
64 (S)
64 (R)
67 (S)
69 (S)
56 (R)
54 (S)
28 (R)
79 (S)
79 (S)
82 (S)
67 (S)
61 (S)
66 (S)
70 (S)
83 (S)
47 (S)
Palladium-Catalysed Substitution of rac-1,3-Diphenyl-2-
propenyl Acetate with Malonate
We chose to study the performance of pyridinophosphin-
ite ligands 2aϪ2d in the palladium-catalysed alkylation[24]
of rac-1,3-diphenyl-2-propenyl acetate by using dimethyl
malonate as the nucleophile [Equation (2)].
9
10
11
12
13
14
15
16
(2)
[a]
The reactions were performed in toluene at 0 °C with 10 mol %
[b]
[c]
ligand and 2.0 equiv. Et2Zn (1.1  in toluene).
GC yields.
Determined by GC using a chiral column (Chrompack CP-Cyclo-
dextrin β-2,3,6-m-19).
Deprotection of the BH3-protected ligands was achieved
either with diethylamine prior to the catalytic reaction or in
similar to that of 1c, except for 1l, having a methyl group situ with palladium acetate,[25] which was employed simul-
in the ortho position, which resulted in a somewhat lower taneously as the palladium source for the catalytic reac-
selectivity (Entries 11Ϫ14). The electronic properties, how- tion.[26] Use of ligand 2a and 4 mol % of bis(π-allylpal-
ever, have a minor influence on the reactivity and selectivity ladium chloride) in a ratio of 1.5:1 resulted in full conver-
in the catalytic reaction, as is shown by comparing ligands sion within 4 h into the product in 46% ee, with the (R)
1hϪ1j and 1k, 1m and 1n having hydrogen, methoxy and enantiomer as the major isomer (Table 2, Entry 1). In situ
trifluoromethyl groups in the para position of the aromatic deprotection with palladium acetate, which required a Pd:L
ring in the 6-position of the pyridine ring. This observation ratio of 1:1, gave the same product with similar selectivity,
is in contrast to the situation with hydroxyalkylimidazol- but within a shorter period of time (48% ee; Entry 2). As
ines, where electronic effects have been shown recently to expected, a prolonged reaction time was required for full
exert a profound influence on the enantioselectivity.[23] The conversion when using a lower amount of catalyst (Entry
bipyridines 1o and 1p, derived from mandelic and lactic 3). Deprotection with diethylamine prior to reaction al-
acid, respectively, exhibit marked differences in enantiose- lowed us to study the influence of the ligand:palladium ra-
lectivity (83 and 47%, respectively; Entries 15 and 16).
tio. We found for 2a that the reactivity and selectivity were
Table 2. Palladium-catalysed substitution of rac-1,3-diphenyl-2-propenyl acetate with dimethyl malonate in the presence of ligands 2 and 3
Entry
Ligand[a]
Pd:L (% cat.)[a]
Pd source[a]
Time (h)
Conv. (%)[b]
ee (%)[c]
1
2
3
4
5
6
7
8
2a
1:1.5 (4)
1:1 (4)
1:1 (2)
1:1 (4)
1:1.5 (4)
1:1 (2)
1:1 (4)
1:1.5 (4)
1:1 (2)
1:1 (4)
1:1 (2)
1:1 (2)
1:1 (4)
1:1 (2)
1:1 (4)
[(C3H5)PdCl]2
Pd(OAc)2
Pd(OAc)2
[(C3H5)PdCl]2
[(C3H5)PdCl]2
Pd(OAc)2
[(C3H5)PdCl]2
[(C3H5)PdCl]2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[(C3H5)PdCl]2
[(C3H5)PdCl]2
[(C3H5)PdCl]2
[(C3H5)PdCl]2
4
100
100
100
100
100
36
99
100
95
100
95
99
99
100
100
46 (R)
48 (R)
48 (R)
48 (R)
47 (R)
52 (R)
56 (R)
10 (R)
44 (R)
44 (R)
50 (S)
51 (S)
51 (S)
2 (S)
2aϪBH3
2aϪBH3
2aϪBH3
2aϪBH3
2bϪBH3
2bϪBH3
2bϪBH3
2cϪBH3
2cϪBH3
2dϪBH3
3a
1.5
17
8
[d]
[d]
8
189
100
4
4
1
16
31
21
31
21
[d]
[d]
9
10
11
12
13
14
15
3a
3b
3b
5 (S)
[a] The catalysts were generated in situ from the amounts of the ligand and the palladium source indicated. The reactions were performed
[b]
[c]
[d]
in CH2Cl2 at room temp.
Determined by HPLC.
Determined by HPLC using a chiral column (Daicel Chiralcel OD-H).
The
ligand was deprotected using Et2NH.
Eur. J. Org. Chem. 2003, 4205Ϫ4215
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4209

F. Rahm, A. Fischer, C. Moberg
FULL PAPER
essentially independent of this ratio (Entries 4 and 5). Li- found to induce only moderate enantioselectivities in the
gand 2b, with a phenyl substituent in the 6-position of the product: 3a afforded the (S) isomer in 31% ee and 3b the
pyridine ring, exhibited lower reactivity than 2a, but gave opposite enantiomer in 17% ee, both in moderate yields
the product having slightly higher enantioselectivity (52% even after extended reaction times (Table 3).
ee; Entry 6). Full conversion was reached when bis(π-allyl-
Table 3. Palladium-catalysed substitution of rac-2-cyclohexenyl
acetate with dimethyl malonate in the presence of ligands 3.
palladium chloride) was employed as the palladium source,
although this process required a reaction time of 100 h
(56% ee; Entry 7). It is interesting to note that using a 1:1.5
Pd:L ratio in this case resulted in a considerably lower en-
Entry Ligand[a] Pd:L (% cat.)[a] Time (h) Yield. (%) ee (%)
antioselectivity (10%; Entry 8), probably as a result of the
formation of a 1:2 palladiumϪligand complex. Ligands 2c
and 2d, which differ only in their absolute configurations
at the benzylic position, afforded products with different
absolute configurations, but with similar enantioselectivi-
ties: 44% ee for the (R) enantiomer and 50% ee for the (S)
enantiomer, respectively (Entries 9Ϫ11). The former ligand
exhibits a higher reactivity, providing 95% conversion into
the product within 4 h, cf. 16 h for 2d.
1
2
3a
3b
1:1 (4)
1:1 (4)
112
143
61
58
31 (S)
17 (R)
[a]
The catalysts were generated in situ from the amounts of the
ligand and the palladium source indicated. The reactions were per-
formed in CH2Cl2 at room temp.
Pyridyl phosphites have been shown to serve as mono-
dentate P-ligands as well as bidentate P,N-ligands.[17] Ac-
cording to NMR spectroscopy, both donor atoms take part
in coordination to the metal in an allylϪpalladium() com-
plex,[17a] whereas a ligand obtained from (S)-4-chloro-3,5-
dioxa-4-phosphacyclohepta[2,1-a;3,4-aЈ]binaphthalene and
8-hydroxyquinoline is able of coordinate to RuII and RhIII
in both fashions.[17c]
(3)
Ligands 3a and 3b, each of which has a centre and an
axis of chirality, were next assessed in the palladium-cata-
lysed allylations. Ligand 3a turned out to be the dia-
stereoisomer that affords the highest enantioselectivity: 51%
ee, cf. 2Ϫ5% ee for 3b (Table 2, Entries 12Ϫ15).
Conclusion
Chiral 6-arylpyridyl alcohols, pyridyl phophinites and
pyridyl phosphites were prepared by employing a modular
approach starting from chiral pyridyl alcohols whose chiral-
ity originates from the chiral pool. The methodology we
have employed allows wide structural variations of the li-
gands to be made. We employed the new ligands in the ad-
dition of diethylzinc to benzaldehyde and in the palladium-
catalysed substitution of allylic acetates with malonate.
A ligand analogous to 3, but having a binaphthyl group
as the only element of chirality, has previously been em-
ployed by Arena et al. in the same palladium-catalysed pro-
cess and it was found to yield racemic product.[17a] Intro-
duction of a substituent (Me, Ph or Br) in the 6-position of
the pyridine ring resulted in 7Ϫ11% enantioselectivity in
the catalytic reaction.[17b] The authors suggest that the lack
of chiral induction is due in part to flexible conformations
of the six-membered chelate formed upon coordination to
palladium. This assumption is corroborated by the obser-
vation of higher enantioselectivity in reactions employing a
five-membered analogue, which is believed to have a more
rigid structure. The more rigid quinoline-containing ligand
has also been used in palladium-catalysed aminations and
alkylations of rac-1,3-diphenyl-2-propenyl acetate to afford
products with moderate enantioselectivities.[27]
Experimental Section
General: 1H and 13C NMR spectra were recorded with a Bruker
DMX 500 instrument or with a Bruker Avance 400 instrument at
25 °C in CDCl3, with residual CHCl3 (1H: δ ϭ 7.26 ppm; 13C: δ ϭ
77.0 ppm) used as the internal standard. 31P NMR spectra were
recorded by using a Bruker DMX 500 instrument with 85% phos-
phoric acid as an external standard. Tetrahydrofuran (THF), tolu-
ene, and diethyl ether were distilled from sodium benzophenone
ketyl. CH2Cl2 and Et3N were distilled from CaH2.
The methoxybenzyl substituent in our ligands is situated
far from the substrate in the palladiumϪallyl complex. Be-
cause of the bulkiness of the substituent, however, we be-
lieve that it prefers a pseudoequatorial position in the six-
membered chelate, which thereby increases the rigidity of
the complex and, consequently, the chiral induction in the
catalytic process. The absolute configurations of the prod-
ucts observed are those expected from the commonly used
model for product formation.[28]
Determination of the Crystal Structure of 1c: C14H15NO2, M ϭ
229.28, orthorhombic, space group P212121, a ϭ 788.98(4), b ϭ
818.73(5), c ϭ 1919.15(1) pm, V ϭ 1239.7(1) ϫ 106 pm3. Density
(calcd.) ϭ 1.228 g·cmϪ3. Crystal size 0.2 ϫ 0.4 ϫ 0.5 mm3.
2Θmax. ϭ 36.32°. Ag-Kα radiation, λ ϭ 56.085 pm, T ϭ 299 K.
Diffraction data were collected with a BrukerϪNonius KappaCCD
diffractometer. All non-hydrogen atoms were refined with aniso-
tropic temperature parameters. Hydrogen atoms were localized
from difference-Fourier syntheses and refined using a riding model.
Structure solution: SHELXS-97, structure refinement on F2 by
Ligands 3a and 3b were also employed in the substitution
of rac-2-cyclohexenyl acetate [Equation (3)], but they were using SHELXL-97. Final R values: R1 ϭ 0.0518, wR2 ϭ 0.119,
4210  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2003, 4205Ϫ4215

Pyridyl Phosphinites and Pyridyl Phosphites from Chiral Pyridyl Alcohols
FULL PAPER
GooF ϭ 1.167 for 1736 unique reflections and 154 parameters.
Residual electron density: 0.18/Ϫ0.26. CCDC-211551 contains the
supplementary crystallographic data for this paper. These data can
be obtained free of charge at www.ccdc.cam.ac.uk/conts/retriev-
1 H), 1.88Ϫ1.98 (m, 1 H), 2.18Ϫ2.22 (m, 1 H, neomenthyl-1-H),
3.56 (d, J ϭ 5.5 Hz, 1 H, OH), 5.06 (dd, J ϭ 5.5, 3.4 Hz, 1 H,
CHOH), 7.22 (dd, J ϭ 7.6, 0.8 Hz, 1 H, 3- or 5-pyridyl), 7.37 (dd,
J ϭ 7.6, 0.8 Hz, 1 H, 3- or 5-pyridyl), 7.53 (t, J ϭ 7.6 Hz, 1 H, 4-
ing.html or from the Cambridge Crystallographic Data Centre, 12 pyridyl) ppm. 13C NMR (125.8 MHz): δ ϭ 21.57, 21.70, 23.34,
Union Road, Cambridge CB2 1EZ, UK (Fax: (internat.) 26.25, 28.18, 29.36, 35.86, 40.69, 47.82, 73.21, 119.16, 126.09,
ϩ44(1223)-336033 or E-mail: deposit@ccdc.cam.ac.uk.
138.77, 140.79, 165.06 ppm.
(1S,2S,5R)-(6-Bromopyridin-2-yl)(2-isopropyl-5-methylcyclohexyl)-
methanone (8): 2,6-Dibromopyridine (1403 mg, 5.80 mmol) in
THF/hexane/diethyl ether (1:1:3, 15 mL) was added dropwise dur-
ing 10 min to a solution of butyllithium (2.43 mL, 2.5  in hexane,
(R)-[(1ЈR,2ЈS,5ЈR)-1Ј-(2Ј-Isopropyl-5Ј-methyl)cyclohexyl](6ЈЈ-
bromo-2ЈЈ-pyridyl)methanol (1g): 2,6-Dibromopyridine (804 mg,
3.33 mmol) in THF/hexane/diethyl ether (1:1:2, 9 mL) was added
dropwise during 10 min to a solution of butyllithium (1.35 mL, 2.5
6.08 mmol) at Ϫ78 °C under nitrogen. After 10 min, a solution of  in hexane, 3.38 mmol) at Ϫ78 °C under nitrogen. After 15 min,
nitrile 4a (872 mg, 5.28 mmol) in THF/hexane/diethyl ether (1:1:3, a solution of a mixture of nitriles 4a and 4b (500 mg, 3.03 mmol,
4 mL) was added and the reaction mixture was stirred at Ϫ78 °C 1:1) in THF/hexane/diethyl ether (1:1:2, 4 mL) was added and the
for 2.5 h followed by another 1.5 h at room temperature. The reac-
tion was quenched by the addition of aqueous sulfuric acid (7 mL,
2 ). After vigorous stirring for 2 h, water (15 mL) and diethyl
ether (15 mL) were added and the phases were separated. The
aqueous phase was extracted with diethyl ether (2 ϫ 15 mL), the
combined organic phases were washed with saturated aqueous
reaction mixture was stirred at Ϫ78 °C for 2 h followed by another
2 h at room temperature. The reaction was quenched by the ad-
dition of aqueous hydrochloric acid (6 mL, 2 ). After vigorous
stirring for 2 h, water (25 mL) and diethyl ether (25 mL) were ad-
ded and the phases were separated. The aqueous phase was ex-
tracted with diethyl ether (2 ϫ 25 mL) and the combined organic
Na2CO3 (20 mL) and dried (Na2SO4). Evaporation under reduced phases were dried (MgSO4). Evaporation under reduced pressure
pressure gave a brown oil that was purified by MPLC on silica gel gave a brown oil that was purified by column chromatography on
(3 8.5 cm column; hexane/EtOAc continuous gradient: silica gel (3 ϫ 6 cm column; hexane/EtOAc, 95:5) to yield a ketone
ϫ
0.375Ϫ2.5% EtOAc) to give 8 (989 mg, 58%) as a colourless oil
that slowly crystallized upon standing. [α]2D2 ϭ ϩ37.0 (c ϭ 1.63 in
together with an unidentified byproduct (670 mg) as a colourless
oil. This oil was dissolved in THF/MeOH (10:1, 33 mL) and cooled
CH2Cl2). 1H NMR (400 MHz): δ ϭ 0.789 (d, J ϭ 6.5 Hz, 3 H, to 0 °C before NaBH4 (254 mg, 0.66 mmol) was added in a few
Me), 0.792 (d, J ϭ 6.5 Hz, 3 H, Me), 0.90 (d, J ϭ 6.5 Hz, 3 H, portions. After stirring at 0 °C for 31 h, the reaction was quenched
Me), 0.93Ϫ0.98 (m, 1 H), 1.12Ϫ1.47 (m, 3 H), 1.53Ϫ1.62 (m, 1 H), by the addition of water (20 mL) and aqueous hydrochloric acid
1.73Ϫ2.00 (m, 4 H), 4.51 (br. s, 1 H, neomenthyl-1-H), 7.63 (dd,
J ϭ 7.6, 1.3 Hz, 1 H, 3- or 5-pyridyl), 7.69 (t, J ϭ 7.6 Hz, 1 H, 4-
(10 mL, 0.5 ) and the phases were separated. The aqueous phase
was extracted with diethyl ether (3 ϫ 30 mL), the combined organic
pyridyl), 7.95 (dd, J ϭ 7.6, 1.3 Hz, 1 H, 3- or 5-pyridyl) ppm. 13C phases were washed with brine (50 mL) and dried (MgSO4) and
NMR (100.6 MHz): δ ϭ 21.54, 21.62, 22.28, 26.27, 27.14, 30.14, then the solvents were evaporated under reduced pressure to give
35.45, 37.36, 40.70, 46.84, 120.87, 131.30, 139.16, 141.17, 154.55, a slightly yellow oil. Purification by column chromatography on
202.99 ppm.
silica (3 ϫ 5 cm column, hexane/EtOAc 95:5) yielded alcohol 1g
(240 mg, 24% over two steps) as a colourless oil. [α]2D2 ϭ Ϫ35.8 (c ϭ
0.83 in CH2Cl2). 1H NMR (400 MHz): δ ϭ 0.24 (app q, J ϭ
12.2 Hz, 1 H), 0.62Ϫ0.74 (m, 1 H), 0.78 (d, J ϭ 6.9 Hz, 3 H, Me),
0.81 (d, J ϭ 6.6 Hz, 3 H, Me), 0.94 (d, J ϭ 6.9 Hz, 3 H, Me),
0.97Ϫ1.11 (m, 2 H), 1.26Ϫ1.38 (m, 1 H), 1.62Ϫ1.67 (m, 2 H),
1.78Ϫ1.83 (m, 1 H), 1.86Ϫ1.93 (m, 1 H), 2.25 (dsept, J ϭ 6.9,
2.3 Hz, 1 H, CHMe2), 3.67 (d, J ϭ 5.8 Hz, 1 H, OH), 4.98 (dd,
J ϭ 5.8, 3.3 Hz, 1 H, CHOH), 7.17 (d, J ϭ 7.7 Hz, 1 H, 3- or 5-
pyridyl), 7.37 (d, J ϭ 7.7 Hz, 1 H, 3- or 5-pyridyl), 7.52 (t, J ϭ
7.7 Hz, 1 H, 4-pyridyl) ppm. 13C NMR (100.6 MHz): δ ϭ 15.24,
21.36, 22.59, 24.21, 26.75, 32.59, 34.88, 35.65, 43.56, 46.22, 72.51,
119.80, 126.23, 138.31, 140.60, 162.53 ppm.
(S)-[(1ЈS,2ЈS,5ЈR)-1Ј-(2Ј-Isopropyl-5Ј-methyl)cyclohexyl](6ЈЈ-bromo-
2ЈЈ-pyridyl)methanol (1d), and (R)-[(1ЈS,2ЈS,5ЈR)-1Ј-(2Ј-Isopropyl-
5Ј-methyl)cyclohexyl](6ЈЈ-bromo-2ЈЈ-pyridyl)methanol (1e): NaBH4
(83 mg, 2.15 mmol) was added at Ϫ78 °C to a solution of ketone
5 (116 mg, 0.36 mmol) in MeOH (6 mL). The reaction mixture was
stirred for 114 h during which time it was warmed room tempera-
ture. Water (5 mL) and CH2Cl2 (10 mL) were added and the phases
were separated. The aqueous phase was extracted with CH2Cl2 (2
ϫ 10 mL), the combined organic phases were dried (MgSO4) and
the solvent was then evaporated under reduced pressure to give an
oil. Purification by MPLC on silica gel (1 ϫ 4 cm column; hexane/
EtOAc continuous gradient: 0.375Ϫ5% EtOAc) yielded 1d (63 mg,
54%) and 1e (17 mg, 14%) as white solids. 1d: C16H24BrNO (326.3):
calcd. C, 58.90, H 7.41, N 4.29; found C 58.68, H 7.47, N 4.28.
[α]2D2 ϭ Ϫ9.1 (c ϭ 1.25 in CH2Cl2). M.p. 64Ϫ66 °C. 1H NMR
(S)-[(1ЈS,2ЈS,5ЈR)-1Ј-(2Ј-Isopropyl-5Ј-methyl)cyclohexyl](6ЈЈ-phenyl-
2ЈЈ-pyridyl)methanol (1h): Na2CO3 (39 mg, 0.37 mmol) in water
(0.7 mL) and phenylboronic acid (27 mg, 0.22 mmol) in MeOH
(400 MHz): δ ϭ 0.67 (d, J ϭ 6.5 Hz, 3 H, Me), 0.84Ϫ0.96 (m, 2 (2 mL) were added to a solution of pyridyl alcohol 1d (60 mg,
H), 0.92 (d, J ϭ 6.5 Hz, 3 H, Me), 1.04 (d, J ϭ 6.5 Hz, 3 H, Me), 0.18 mmol) and [Pd(PPh3)4] (8.5 mg, 0.007 mmol, 4 mol %) in tolu-
1.03Ϫ1.17 (m, 2 H), 1.38Ϫ1.56 (m, 2 H), 1.76Ϫ1.86 (m, 2 H),
2.00Ϫ2.09 (m, 1 H), 2.32Ϫ2.35 (m, 1 H, neomenthyl-1-H), 2.67 (d, reaction was monitored by TLC. After 20 h, saturated aqueous
J ϭ 8.5 Hz, 1 H, OH), 4.91 (t, J ϭ 8.5 Hz, 1 H, CHOH), 7.22 (dd, Na2CO3 (5 mL) and CH2Cl2 (5 mL) were added and the phases
ene (2 mL). The reaction mixture was heated under reflux and the
J ϭ 7.7, 0.8 Hz, 1 H, 3- or 5-pyridyl), 7.37 (dd, J ϭ 7.7, 0.8 Hz, 1 were separated. The aqueous phase was extracted with CH2Cl2 (3
H, 3- or 5-pyridyl), 7.51 (t, J ϭ 7.7 Hz, 1 H, 4-pyridyl) ppm. 13C ϫ 10 mL) and the combined organic phases were dried (Na2SO4).
NMR (100.6 MHz): δ ϭ 22.20, 22.53, 22.65, 24.87, 27.04, 30.02, Evaporation under reduced pressure gave yellow crystals that were
35.91, 38.93, 42.26, 49.79, 74.44, 120.32, 126.72, 138.56, 141.64, purified by recrystallization from hexane to yield 1h (38 mg, 64%)
165.06 ppm. 1e: [α]2D2 ϭ Ϫ6.4 (c ϭ 0.95 in CH2Cl2). M.p. 79Ϫ80
as a slightly yellow solid. [α]2D2 ϭ Ϫ16.1 (c ϭ 0.78 in CH2Cl2). M.p.
115Ϫ116 °C. H NMR (400 MHz): δ ϭ 0.71 (d, J ϭ 6.5 Hz, 3 H),
1
°C. 1H NMR (400 MHz): δ ϭ 0.74 (d, J ϭ 6.6 Hz, 3 H, Me),
0.76Ϫ0.86 (m, 2 H), 0.99 (d, J ϭ 6.6 Hz, 6 H, 2 ϫ Me), 1.11Ϫ1.18 0.95 (d, J ϭ 6.7 Hz, 3 H, Me), 0.87Ϫ0.98 (m, 2 H), 1.07 (d, J ϭ
(m, 1 H), 1.32Ϫ1.38 (m, 1 H), 1.64Ϫ1.76 (m, 3 H), 1.77Ϫ1.84 (m, 6.7 Hz, 3 H, Me), 1.11Ϫ1.19 (m, 1 H), 1.25Ϫ1.31 (m, 1 H),
Eur. J. Org. Chem. 2003, 4205Ϫ4215
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4211

F. Rahm, A. Fischer, C. Moberg
FULL PAPER
1.47Ϫ1.58 (m, 1 H), 1.58Ϫ1.69 (m, 1 H), 1.80Ϫ1.88 (m, 2 H), 7.7 Hz, 1 H, 3- or 5-pyridyl), 7.64 (t, J ϭ 7.7 Hz, 1 H, 4-pyridyl),
2.10Ϫ2.19 (m, 1 H), 2.38Ϫ2.43 (m, 1 H), 3.47 (d, J ϭ 8.2 Hz, 1 H, 7.90 (d, J ϭ 7.1 Hz, 2 H, Ph) ppm. 13C NMR (100.6 MHz): δ ϭ
OH), 5.02 (t, J ϭ 8.2 Hz, 1 H, CHOH), 7.19 (dd, J ϭ 7.6, 1.0 Hz,
57.09, 75.48, 87.25, 119.27, 129.73, 126.86, 127.79, 127.90, 127.99,
1 H, 3-or 5-pyridyl), 7.42 (m, 1 H, Ph), 7.49 (m, 2 H, Ph), 7.64 (dd, 128.66, 129.04, 136.85, 137.96, 138.86, 155.55, 158.44 ppm.
J ϭ 7.6, 1.0 Hz, 1 H, 3-or 5-pyridyl), 7.71 (t, J ϭ 7.6 Hz, 1 H, 4-
pyridyl), 8.03 (m, 2 H, Ph) ppm, 13C NMR (100.6 MHz): δ ϭ
(1R,2S)-2-Methoxy-1-[6Ј-(2ЈЈ-methyl-1ЈЈ-phenyl)-2Ј-pyridyl]-2-
22.29, 22.50, 22.79, 25.05, 27.16, 30.06, 36.12, 39.10, 42.55, 50.02,
phenylethan-1-ol (1l): Compound 1l was synthesized from 1f
74.42, 118.93, 120.00, 126.81, 128.70, 129.05, 136.92, 139.01,
(62 mg, 0.20 mmol) and o-methylphenylboronic acid (29 mg,
156.29, 163.04 ppm.
0.21 mmol) in a manner analogous to that of 1h. Purification by
column chromatography on silica gel (1.5 ϫ 4 cm column; hexane/
EtOAc, 4:1) yielded 1l (53 mg, 82%) as a colourless oil. [α]2D2
ϭ
(S)-[(1ЈS,2ЈS,5ЈR)-1Ј-(2Ј-Isopropyl-5Ј-methyl)cyclohexyl][6ЈЈ-(4ЈЈЈ-
methoxy-phenyl)-2ЈЈ-pyridyl]methanol (1i): Compound 1i was syn-
thesized from 1d (80 mg, 0.245 mmol) and p-methoxyphenylbo-
ronic acid (41 mg, 0.26 mmol) in an manner analogous to that of
1h. Purification by column chromatography on silica (2 ϫ 8 cm
column; hexane/EtOAc, 9:1) yielded 1i (71 mg, 82%) as a white
solid. C23H31NO2 (353.5): calcd. C 78.15, H 8.84, N 3.96; found C
77.87, H 8.90, N 3.86. [α]2D2 ϭ Ϫ32.4 (c ϭ 0.54 in CH2Cl2). M.p.
1
ϩ15.8 (c ϭ 0.52 in CH2Cl2). H NMR (400 MHz): δ ϭ 2.23 (s, 3
H, Me), 3.26 (s, 3 H, OMe), 4.40Ϫ4.42 (m, 2 H, CHOMe and OH),
5.05 (t, J ϭ 5.9 Hz, 1 H, CHOH), 7.16 (d, J ϭ 7.7 Hz, 1 H, 3- or
5-pyridyl), 7.19Ϫ7.31 (m, 10 H), 7.69 (t, J ϭ 7.7 Hz, 1 H, 4-pyridyl)
ppm. 13C NMR (100.6 MHz): δ ϭ 20.28, 57.05, 75.38, 87.18,
120.12, 122.87, 125.80, 127.79, 127.89, 127.97, 128.34, 129.60,
130.76, 135.96, 136.37, 137.54, 139.79, 157.58, 158.18 ppm.
1
122Ϫ123 °C. H NMR (400 MHz): δ ϭ 0.71 (d, J ϭ 6.6 Hz, 3 H,
Me), 0.93 (d, J ϭ 6.4 Hz, 3 H, Me), 0.85Ϫ0.98 (m, 2 H), 1.06 (d,
J ϭ 6.4 Hz, 3 H, Me), 1.10Ϫ1.17 (m, 1 H), 1.25Ϫ1.31 (m, 1 H),
1.46Ϫ1.68 (m, 2 H), 1.79Ϫ1.87 (m, 2 H), 2.09Ϫ2.18 (m, 1 H),
2.35Ϫ2.41 (m, 1 H), 3.47 (d, J ϭ 8.2 Hz, 1 H, OH), 3.87 (s, 3 H,
OMe), 4.99 (t, J ϭ 8.2 Hz, 1 H, CHOH), 7.01 (d, J ϭ 9.1 Hz, 2 H,
Ph), 7.11 (dd, J ϭ 7.6, 0.8 Hz, 1 H, 3- or 5-pyridyl), 7.57 (dd, J ϭ
7.6, 0.8 Hz, 1 H, 3- or 5-pyridyl), 7.67 (t, J ϭ 7.6 Hz, 1 H, 4-
(1R,2S)-2-Methoxy-1-[6Ј-(2ЈЈ-methoxy-1ЈЈ-phenyl)-2Ј-pyridyl]-2-
phenylethan-1-ol (1m): Compound 1m was synthesized from 1f
(90 mg, 0.29 mmol) and p-methoyphenylboronic acid (54 mg,
0.35 mmol) in a manner analogous to that of 1h. Purification by
column chromatography on silica gel (1.5 ϫ 7 cm column; hexane/
EtOAc, 4:1) yielded 1f (68 mg, 70%) as a white solid. [α]2D2 ϭ ϩ36.7
(c ϭ 0.57 in CH2Cl2). M.p. 108Ϫ109 °C. 1H NMR (400 MHz): δ ϭ
3.26 (s, 3 H, CHOMe), 3.87 (s, 3 H, Ph-OMe), 4.38 (d, J ϭ 6.1 Hz,
1 H, OH), 4.50 (d, J ϭ 6.1 Hz, 1 H, CHOMe), 4.99 (t, J ϭ 6.1 Hz,
1 H, CHOH), 6.98 (d, J ϭ 9.1 Hz, 2 H, Ph), 7.09 (d, J ϭ 7.7 Hz,
1 H, 3-or 5-pyridyl), 7.23Ϫ7.33 (m, 5 H, Ph), 7.56 (d, J ϭ 7.7 Hz,
1 H, 3-or 5-pyridyl), 7.65 (t, J ϭ 7.7 Hz, 1 H, 4-pyridyl), 7.88 (d,
J ϭ 9.1 Hz, 2 H, Ph) ppm. 13C NMR (100.6 MHz): δ ϭ 55.33,
57.06, 75.32, 87.24, 113.99, 118.48, 119.97, 127.45, 127.89, 127.95,
128.09, 131.41, 136.78, 137.95, 155.13, 158.10, 160.47 ppm.
pyridyl), 7.98 (d,
J ϭ 9.1 Hz, 2
H, Ph) ppm. 13C NMR
(100.6 MHz): δ ϭ 22.29, 22.50, 22.79, 25.05, 27.16, 30.06, 36.14,
39.09, 42.52, 50.05, 55.35, 74.36, 114.09, 118.13, 119.26, 128.05,
131.65, 136.82, 155.96, 160.54, 162.80 ppm.
(S)-[(1ЈS,2ЈS,5ЈR)-1Ј-(2Ј-Isopropyl-5Ј-methyl)cyclohexyl][6ЈЈ-(4ЈЈЈ-
trifluoromethyl-phenyl)-2ЈЈ-pyridyl]methanol (1j): Compound 1j was
synthesized from 1d (110 mg, 0.34 mmol) and p-(trifluoromethyl)-
phenylboronic acid (78 mg, 0.40 mmol) in a manner analogous to
that of 1h. The product was obtained as a white solid (123 mg,
93%) after filtration through a silica plug using CH2Cl2 as the elu-
ent. C23H28F3NO (391.5): calcd. C 70.57, H 7.21, N 3.58; found C
70.49, H 7.21, N 3.52. [α]2D2 ϭ Ϫ11.1 (c ϭ 1.23 in CH2Cl2). M.p.
(1R,2S)-2-Methoxy-2-phenyl-1-[6Ј-(2ЈЈ-trifluoromethyl-1ЈЈ-phenyl)-
2Ј-pyridyl]ethan-1-ol (1n): Compound 1n was synthesized from 1f
(179 mg, 0.58 mmol) and p-(trifluoromethyl)phenylboronic acid
(135 mg, 0.71 mmol) in a manner analogous to that of 1h. Purifi-
cation by column chromatography on silica gel (3 ϫ 5 cm column;
hexane/EtOAc, 9:1) yielded 1n (188 mg, 87%) as a white solid.
[α]2D2 ϭ ϩ11.5 (c ϭ 2.18 in CH2Cl2). M.p. 93Ϫ94 °C. 1H NMR
(500 MHz): δ ϭ 3.28 (s, 3 H, OMe), 4.29 (br. d, J ϭ 5.1 Hz, 1 H,
OH), 4.44 (d, J ϭ 5.1 Hz, 1 H, CHOMe), 5.05 (br. t, J ϭ 5.1 Hz,
1 H, CHOH), 7.19 (d, J ϭ 7.7 Hz, 1 H, 3- or 5-pyridyl), 7.23 (app
d, J ϭ 8.1 Hz, 2 H, Ph), 7.28Ϫ7.33 (m, 3 H, Ph), 7.66 (d, J ϭ
7.7 Hz, 1 H, 3- or 5-pyridyl), 7.71Ϫ7.74 (m, 3 H, Ph and 5-pyridyl),
8.02 (d, J ϭ 8.1 Hz, 2 H, Ph) ppm. 13C NMR (125.8 MHz): δ ϭ
57.09, 75.63, 87.10, 119.64, 121.59, 124.23 (q, JC,F ϭ 272.2 Hz),
125.58 (q, JC,F ϭ 3.8 Hz), 127.13, 127.86, 127.88, 128.01, 130.81
(q, JC,F ϭ 32.2 Hz), 137.07, 137.64, 142.14, 154.03, 158.88 ppm.
1
107Ϫ108 °C. H NMR (400 MHz): δ ϭ 0.70 (d, J ϭ 6.5 Hz, 3 H,
Me), 0.94 (d, J ϭ 6.4 Hz, 3 H, Me), 0.87Ϫ0.98 (m, 2 H), 1.07 (d,
J ϭ 6.4 Hz, 3 H, Me), 1.12Ϫ1.19 (m, 1 H), 1.21Ϫ1.26 (m, 1 H),
1.46Ϫ1.68 (m, 2 H), 1.80Ϫ1.87 (m, 2 H), 2.08Ϫ2.17 (m, 1 H),
2.38Ϫ2.42 (m, 1 H), 3.25 (d, J ϭ 8.1 Hz, 1 H, OH), 5.04 (t, J ϭ
8.1 Hz, 1 H, CHOH), 7.27 (dd, J ϭ 7.7, 1.0 Hz, 1 H, 3- or 5-
pyridyl), 7.67 (dd, J ϭ 7.7, 1.0 Hz, 1 H, 3- or 5-pyridyl), 7.74 (dd,
J ϭ 8.1, 0.8 Hz, 2 H, Ph), 7.76 (t, J ϭ 7.7 Hz, 1 H, 4-pyridyl), 8.13
(dd, J ϭ 8.1, 0.8 Hz, 2 H, Ph) ppm. 13C NMR (100.6 MHz): δ ϭ
22.27, 22.48, 22.76, 25.03, 27.17, 30.11, 36.07, 39.06, 42.56, 50.01,
74.56, 119.34, 120.92, 124.16 (q, JC,F ϭ 272.0 Hz), 125.68 (q,
JC,F ϭ 3.7 Hz), 127.09, 130.89 (q, JC,F ϭ 32.4 Hz), 137.24, 142.20,
154.80, 163.59 ppm.
(1R,2S)-2-Methoxy-2-phenyl-1-(6Ј-phenyl-2Ј-pyridyl)ethan-1-ol Phosphinite 2cϪBH3: nBuLi (134 µL, 2.5  in hexane, 0.34 mmol)
(1k): Compound 1k was synthesized from 1f (144 mg, 0.47 mmol)
and phenylboronic acid (64 mg, 0.51 mmol) in a manner analogous
was added to a solution of pyridyl alcohol 1a (69 mg, 0.28 mmol)
in THF (3 mL) at Ϫ78 °C under nitrogen. After stirring for 30 min,
to that of 1h. Purification by column chromatography on silica gel the temperature was increased to 0 °C. Chlorodiphenylphosphane
(1.5 ϫ 9 cm column; hexane/EtOAc, 9:1) yielded 1k (121 mg, 85%)
(58 µL, 0.30 mmol) was added and the reaction mixture was stirred
at 0 °C for 3 h. BH3·SMe2 (154 µL, 2.0  in THF, 0.31 mmol) was
as a white solid. [α]2D2 ϭ ϩ29.8 (c ϭ 1.56 in CH2Cl2). M.p. 91Ϫ92
°C. 1H NMR (400 MHz): δ ϭ 3.23 (s, 3 H, OMe), 4.38 (d, J ϭ added and the stirring was continued at 0 °C overnight (15 h).
6.0 Hz, 1 H, OH), 4.45 (d, J ϭ 6.0 Hz, 1 H, CHOMe), 4.99 (t, J ϭ
6.0 Hz, 1 H, CHOH), 7.11 (d, J ϭ 7.7 Hz, 1 H, 3- or 5-pyridyl), separated. The aqueous phase was extracted with CH2Cl2 (3 ϫ
7.20Ϫ7.30 (m, 5 H, Ph), 7.37Ϫ7.45 (m, 3 H, Ph), 7.59 (d, J ϭ 7 mL), the combined organic phases were dried (MgSO4) and then
Water (5 mL) and CH2Cl2 (5 mL) were added and the phases were
4212
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4205Ϫ4215

Pyridyl Phosphinites and Pyridyl Phosphites from Chiral Pyridyl Alcohols
FULL PAPER
the solvents were evaporated under reduced pressure to give an oil.
Purification by column chromatography on silica gel (3 ϫ 7 cm; pyridyl alcohol 1c (102 mg, 0.44 mmol) in a manner analogous to
hexane/EtOAc, 19:1) yielded 2cϪBH3 (77 mg, 62%) as a colourless that of 2cϪBH3. Purification by column chromatography on silica
Phosphinite 2aϪBH3: Compound 2aϪBH3 was synthesized from
1
oil. [α]2D2 ϭ Ϫ8.6 (c ϭ 1.1 in CH2Cl2). H NMR (400 MHz): δ ϭ gel (1.5 ϫ 8.5 cm; hexane/EtOAc, 4:1) yielded 2aϪBH3 (146 mg,
0.42 (d, J ϭ 6.2 Hz, 3 H, Me), 0.63 (d, J ϭ 6.2 Hz, 3 H, Me), 0.65
(d, J ϭ 6.5 Hz, 3 H, Me), 0.68Ϫ1.30 (m, 8 H, including broad
77%) as a colourless oil. [α]2D2 ϭ Ϫ3.0 (c ϭ 0.74 in CHCl3). 1H
NMR (400 MHz): δ ϭ 1.40Ϫ1.26 (m, 3 H, BH3), 3.09 (s, 3 H,
signal from BH3), 1.34Ϫ1.45 (m, 1 H), 1.64Ϫ1.71 (m, 1 H), OMe), 4.81 (d, J ϭ 7.1 Hz, 1 H, CHOMe), 5.60 (dd, J ϭ 9.8,
1.79Ϫ1.90 (m, 2 H), 2.08Ϫ2.14 (m, 1 H), 2.87 (dd, J ϭ 8.2, 3.8 Hz, 7.1 Hz, 1 H, CHOP), 7.11 (ddd, J ϭ 7.6, 4.8, 1.3 Hz, 1 H, 5-pyri-
1 H, neomenthyl-1-H), 5.69 (t, J ϭ 8.2 Hz, 1 H, CHOP), 6.98 (ddd,
J ϭ 7.6, 4.8, 1.3 Hz, 1 H, 5-pyridyl), 7.15 (td, J ϭ 7.1, 2.0 Hz, 2
dyl), 7.21Ϫ7.51 (m, 17 H), 8.54 (ddd, J ϭ 4.8, 1.8, 1.0 Hz, 1 H, 6-
pyridyl) ppm. 13C NMR (100.6 MHz): δ ϭ 56.90, 81.71 (d, JC,P
ϭ
H, Ph), 7.24Ϫ7.29 (m, 2 H), 7.34Ϫ7.50 (m, 6 H), 7.75 (ddt, J ϭ 1.5 Hz), 85.03 (d, JC,P ϭ 8.2 Hz), 127.98, 128.01, 128.08, 128.14 (d,
10.8, 7.1, 2.0 Hz, 2 H, Ph), 8.47 (ddd, J ϭ 4.8, 1.8, 1.0 Hz, 1 H, 6- JC,P ϭ 4.5 Hz), 128.37, 131.30, 131.31, 131.38, 131.41, 131.42,
pyridyl) ppm. 13C NMR (125.8 MHz): δ ϭ 21.01, 21.81, 22.59, 132.03 (d, JC,P ϭ 4.5 Hz), 135.95, 137.69, 149.12, 156.99 ppm.
25.11, 26.98, 28.67, 35.85, 37.57, 39.62 (d, JC,P ϭ 6.7 Hz), 49.02,
31P{1H} NMR (202 MHz): δ ϭ 109.05 (app d, JP,B ϭ 79.4 Hz)
81.07 (d, JC,P ϭ 3.0 Hz), 122.69, 124.23, 127.88 (d, JC,P ϭ 11.2 Hz), ppm.
128.36 (d, JC,P ϭ 10.5 Hz), 131.00 (d, JC,P ϭ 2.2 Hz), 131.33 (d,
Phosphinite 2bϪBH3: Compound 2bϪBH3 was synthesized from
pyridyl alcohol 1k (45 mg, 0.15 mmol) in a manner analogous to
that of 2cϪBH3. Purification by column chromatography on silica
gel (2 ϫ 4 cm; hexane/EtOAc, 19:1) yielded 2bϪBH3 (44 mg, 60%)
J
C,P ϭ 5.2 Hz), 131.45 (d, JC,P ϭ 5.2 Hz), 131.58 (d, JC,P ϭ 2.2 Hz),
132.26 (d, JC,P ϭ 6.0 Hz), 132.91 (d, JC,P ϭ 15.7 Hz), 135.65,
149.21, 159.79 ppm. 31P{1H} NMR (202 MHz): δ ϭ 106.12 (app
d, JP,B ϭ 81.0 Hz) ppm.
as a colourless oil. [α]2D2 ϭ Ϫ92.2 (c ϭ 1.60 in CH2Cl2). H NMR
1
(500 MHz): δ ϭ 0.64Ϫ1.36 (m, 3 H, BH3), 3.14 (s, 3 H, OMe), 4.96
(d, J ϭ 6.6 Hz, 1 H, CHOMe), 5.71 (dd, J ϭ 9.5, 6.6 Hz, 1 H,
CHOP), 7.15Ϫ7.19 (m, 3 H), 7.28Ϫ7.54 (m, 10 H), 7.40Ϫ7.54 (m,
8 H), 7.94 (d, J ϭ 7.0 Hz, 2 H, Ph). 13C NMR (100.6 MHz): δ ϭ
57.03, 82.15 (d, JC,P ϭ 2.2 Hz), 85.15 (d, JC,P ϭ 7.5 Hz), 119.45,
122.43, 126.93, 127.95 (d, JC,P ϭ 2.2 Hz), 128.04, 128.16, 128.45,
128.55, 128.82, 131.33 (d, JC,P ϭ 2.2 Hz), 131.42 (d, JC,P ϭ 7.5 Hz),
131.53 (d, JC,P ϭ 7.5 Hz), 131.65, 132.08, 132.29, 132.77, 136.50,
137.92, 139.25, 156.28, 156.77; 31P{1H} NMR (202 MHz): δ ϭ
108.61 (app d, JP,B ϭ 75.1 Hz).
Phosphinite 2dϪBH3: Compound 2dϪBH3 was synthesized from
pyridyl alcohol 1b (84 mg, 0.34 mmol) in a manner analogous to
that of 2cϪBH3. Purification by column chromatography on silica
gel (3 ϫ 6 cm; hexane/EtOAc, 9:1) yielded 2dϪBH3 (66 mg, 43%)
as a white solid. [α]2D2 ϭ ϩ18.9 (c ϭ 1.1 in CH2Cl2). M.p. 121Ϫ122
1
°C. H NMR (400 MHz): δ ϭ 0.56 (d, J ϭ 6.4 Hz, 3 H, Me), 0.73
(d, J ϭ 6.4 Hz, 3 H, Me), 0.88 (d, J ϭ 6.5 Hz, 3 H, Me), 0.80Ϫ0.98
(m, 3 H), 1.04Ϫ1.49 (m, 5 H, including broad signal from BH3),
1.53Ϫ1.62 (m, 1 H), 1.65Ϫ1.74 (m, 1 H), 1.78Ϫ1.82 (m, 2 H), 2.93
(dd, J ϭ 9.4, 3.4 Hz, 1 H, neomenthyl-1-H), 5.76 (dd, J ϭ 9.4,
8.4 Hz, 1 H, CHOP), 6.95 (dd, J ϭ 7.6, 4.8 Hz, 1 H, 5-pyridyl),
7.10 (td, J ϭ 7.8, 2.0 Hz, 2 H, Ph), 7.17 (d, J ϭ 7.6 Hz, 1 H, 3-
pyridyl), 7.21 (t, J ϭ 7.8 Hz, 1 H, Ph), 7.33 (td, J ϭ 7.6, 1.1 Hz, 1
H, 4-pyridyl), 7.38Ϫ7.48 (Ph, 5 H), 7.78 (dd, J ϭ 11.1, 7.8 Hz, 2
H, Ph), 8.47 (dt, J ϭ 4.8, 1.1 Hz, 1 H, 6-pyridyl) ppm. 13C NMR
(100.6 MHz): δ ϭ 22.21, 22.34, 22.64, 24.62, 26.72, 29.31, 35.92,
38.55, 39.97 (d JC,P ϭ 6.8 Hz), 49.94, 81.46 (d JC,P ϭ 3.0 Hz),
Phosphite 3b: (R)-4-Chloro-3,5-dioxa-4-phosphacyclohepta[2,1-
a:3,4-aЈ]binaphthalene, obtained according to a published pro-
cedure,[15b] but with toluene as the solvent (330 mg, 0.884 mmol)
was dissolved in toluene (7 mL) under nitrogen and cooled to Ϫ50
°C. Et3N (0.124 mL, 0.884 mmol) was added followed by a solution
of pyridyl alcohol 1c (203 mg, 0.884 mmol) in toluene (13 mL). The
reaction mixture was stirred on the thawing ice bath for 17 h. The
suspension was filtered under nitrogen, the filter cake was washed
with toluene (4 mL) and the filtrate was evaporated under reduced
pressure to yield 3b (520 mg, 84%) as a yellow solid contaminated
122.64, 123.73, 127.7 (d, JC,P ϭ 10.6 Hz), 128.20 (d, JC,P
ϭ
11.3 Hz), 130.86 (d, JC,P ϭ 2.3 Hz), 131.27 (d, JC,P ϭ 11.3 Hz),
131.46 (d, JC,P ϭ 11.3 Hz), 131.55 (d, JCϪP ϭ 2.3 Hz), 131.91,
132.42 (d, JC,P ϭ 14.4 Hz), 135.73, 149.40, 158.85 ppm. 31P{1H}
NMR (202 MHz): δ ϭ 103.44 (app d, JP,B ϭ 82.3 Hz) ppm.
1
by 1c and toluene. H NMR (500 MHz): δ ϭ 3.28 (s, 3 H, OMe),
4.65 (d, J ϭ 5.6 Hz, 1 H, CHOMe), 5.63 (dd, J ϭ 10.6, 5.6 Hz, 1
H, CHOP), 6.71 (d, J ϭ 8.8 Hz, 1 H, 1 H), 7.03 (d, J ϭ 7.7 Hz, 1
H), 7.17Ϫ7.38 (m, 9 H), 7.40Ϫ7.43 (m, 4 H), 7.57 (td, J ϭ 7.7,
1.5 Hz, 1 H, 4-pyridyl), 7.68 (d, J ϭ 8.8 Hz, 1 H), 7.86 (d, J ϭ
8.0 Hz, 1 H), 7.91 (d, J ϭ 7.7 Hz, 1 H), 7.94 (d, J ϭ 8.8 Hz, 1 H),
8.66 (d, J ϭ 4.8 Hz, 1 H, 6-pyridyl) ppm. 13C NMR (125.8 MHz):
δ ϭ 57.09, 79.59 (d, JC,P ϭ 16.6 Hz), 85.62 (d, JC,P ϭ 3.0 Hz),
121.96 (d, JC,P ϭ 2.3 Hz), 122.36, 122.81, 124.25 (d, JC,P ϭ 5.3 Hz),
124.70, 124.94, 125.94, 126.12, 126.99 (d, JC,P ϭ 4.5 Hz), 127.77,
127.83, 127.95, 128.03, 128.16, 128.54, 129.20, 130.13, 131.00,
131.49, 132.55 (d, JC,P ϭ 1.5 Hz), 132.76 (d, JC,P ϭ 1.5 Hz), 136.26,
136.55, 147.44 (d, JC,P ϭ 2.3 Hz), 147.82 (d, JC,P ϭ 3.8 Hz), 148.61,
158.26 (d, JC,P ϭ 3.0 Hz) ppm. 31P{1H} NMR (202 MHz): δ ϭ
151.64 ppm.
Phosphinite 2a: Pyridyl alcohol 1c (40 mg, 0.17 mmol) was dis-
solved in THF (2.5 mL) and then cooled to Ϫ78 °C and placed
under nitrogen. nBuLi (84 µL, 2.5  in hexane, 0.21 mmol) was
added and after stirring at Ϫ78 °C for 15 min the temperature was
raised to 0 °C. Chlorodiphenylphosphane (36 µL, 0.19 mmol) was
added and the reaction mixture was stirred at 0 °C for 8 h. Evapor-
ation of the solvent under reduced pressure gave an oil that was
purified by column chromatography on silica gel (1 ϫ 4 cm column;
hexane/EtOAc, 4:1) to yield 2a (31 mg, 43%) as a colourless oil.
[α]2D2 ϭ Ϫ8.7 (c ϭ 0.52 in CH2Cl2). 1H NMR (400 MHz): δ ϭ 3.16
(s, 3 H, OMe), 4.71 (d, J ϭ 6.5 Hz, 1 H, CHOMe), 5.17 (dd, J ϭ
9.8, 6.5 Hz, 1 H, CHOP), 7.13Ϫ7.28 (m, 17 H), 7.51 (td, J ϭ 7.7,
1.8 Hz, 1 H, 4-pyridyl), 8.59 (dd, J ϭ 5.4, 1.8 Hz, 1 H, 6-pyridyl)
Phosphite 3a: Compound 3a was synthesized from pyridyl alcohol
ppm. 13C NMR (125.8 MHz): δ ϭ 56.87, 85.08 (d, JC,P ϭ 18.9 Hz), 1c (240 mg, 1.05 mmol) and (S)-4-chloro-3,5-dioxa-4-phos-
86.16 (d, JC,P ϭ 6.0 Hz), 122.61, 123.02, 127.79, 127.81, 127.90 (d, phacyclohepta[2,1-a:3,4-aЈ]binaphthalene (370 mg, 1.05 mmol) in a
JC,P ϭ 1.5 Hz), 127.95 (d, JC,P ϭ 1.5 Hz), 128.92, 129.01, 130.43
(d, JC,P ϭ 21.9 Hz), 130.74 (d, JC,P ϭ 21.9), 131.62 (d, JC,P
manner analogous to that of 3b. Yield: 560 mg (95%), contami-
nated by 1c and toluene. H NMR (500 MHz): δ ϭ 3.31 (s, 3 H,
1
ϭ
10.6 Hz), 131.85 (d, JC,P ϭ 10.6 Hz), 135.99, 138.06, 148.93, 159.36 OMe), 4.69 (d, J ϭ 5.1 Hz, 1 H, CHOMe), 5.69 (dd, J ϭ 9.9,
ppm. 31P{1H} NMR (202 MHz): δ ϭ 116.0 ppm.
5.1 Hz, 1 H, CHOP), 6.92 (d, J ϭ 7.7 Hz, 1 H), 7.02 (d, J ϭ 8.8 Hz,
Eur. J. Org. Chem. 2003, 4205Ϫ4215
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4213

F. Rahm, A. Fischer, C. Moberg
FULL PAPER
[4b]
Soc. 1999, 121, 2123Ϫ2132.
gew. Chem. Int. Ed. 1999, 38, 3163Ϫ3165.
R. Stauffer, K. H. Shaughnessy, J. F. Hartwig, J. Am. Chem.
O. Lavastre, J. P. Morken, An-
1 H), 7.13Ϫ7.25 (m, 9 H), 7.32Ϫ7.37 (m, 2 H), 7.40Ϫ7.44 (m, 3
H), 7.73 (d, J ϭ 8.4 Hz, 1 H), 7.88Ϫ7.92 (m, 3 H), 8.57 (d, J ϭ
4.8 Hz, 1 H, 6-pyridyl) ppm. 13C NMR (125.8 MHz): δ ϭ 57.05,
79.33 (d, JC,P ϭ 11.3 Hz), 85.53 (d, JC,P ϭ 4.5 Hz), 121.84 (d,
JC,P ϭ 2.3 Hz), 122.16, 122.34, 122.61, 124.22 (d, JC,P ϭ 5.3 Hz),
124.72, 124.95, 125.92, 126.13, 127.00 (d, JC,P ϭ 7.6 Hz), 127.72,
127.77, 127.89, 128.20, 128.30, 128.51, 129.33, 130.15, 130.98,
131.47, 132.47 (d, JC,P ϭ 1.5 Hz), 132.78 (d, JC,P ϭ 1.5 Hz), 136.24,
136.79, 137.86, 147.38 (d, JC,P ϭ 2.3 Hz), 148.10 (d, JC,P ϭ 5.3 Hz),
148.56, 158.26 (d, JC,P ϭ 1.5 Hz) ppm. 31P{1H} NMR (202 MHz):
δ ϭ 147.63 ppm.
[4c]
J. P. Stambuli, S.
[4d]
Soc. 2001, 123, 2677Ϫ2678.
O. Löber, M. Kawatsura, J. F.
Hartwig, J. Am. Chem. Soc. 2001, 123, 4366Ϫ4367.
[5] [5a]
M. T. Reetz, M. H. Becker, H.-W. Klein, D. Stöckigt, An-
gew. Chem. Int. Ed. 1999, 38, 1758Ϫ1761. [5b] D. G. I. Petra, J.
N. H. Reek, P. C. J. Kamer, H. E. Schoemaker, P. W. N. M.
[5c]
van Leeuwen, Chem. Commun. 2000, 683Ϫ684.
P. A b at o,
C. T. Seto, J. Am. Chem. Soc. 2001, 123, 9206Ϫ9207. [5d] R. A.
van Delden, B. L. Feringa, Angew. Chem. Int. Ed. 2001, 40,
[5e]
3198Ϫ3200.
D. D. Diaz, S. Yao, M. G. Finn, Tetrahedron
Lett. 2001, 42, 2617Ϫ2619.
[6]
[7]
General Procedure for the Addition of Diethylzinc to Benzaldehyde:
Benzaldehyde (61 µL, 0.60 mmol) and the ligand (0.06 mmol, 10
mol %) were dissolved in toluene (1 mL) under nitrogen and the
solution was then cooled to 0 °C. After stirring for 30 min, Et2Zn
(1.09 mL, 1.1  in toluene, 1.2 mmol) was added dropwise and the
stirring was continued at 0 °C for 20 h. The reaction was quenched
by the addition of aqueous HCl (5 mL, 0.25 ). The phases were
separated and the aqueous phase was extracted with diethyl ether
(3 ϫ 5 mL). The combined organic phases were dried (MgSO4) and
the solvents evaporated under reduced pressure.
G. M. Greenway, S. J. Haswell, D. O. Morgan, V. Skelton, P.
Styring, Sensors and Actuators 2000, B63, 153Ϫ158.
[7a] K. Mikami, R. Angelaud, K. Ding, A. Ishii, A. Tanaka, N.
Sawada, K. Kudo, M. Senda, Chem. Eur. J. 2001, 7, 730Ϫ737.
K. Mikami, M. Terada, T. Korenaga, Y. Matsumoto, M.
Ueki, R. Angelaud, Angew. Chem. Int. Ed. 2000, 39,
[7b]
3532Ϫ3556.
[8] [8a]
A. J. Brouver, H. J. van der Linden, R. M. J. Liskamp, J.
Org. Chem. 2000, 65, 1750Ϫ1757. [8b] C. Gennari, S. Ceccarelli,
U. Piarulli, C. A. G. N. Montalbetti, R. F. W. Jackson, J. Org.
Chem. 1998, 63, 5312Ϫ5313.
[9] [9a]
B. M. Trost, D. L. Van Vranken, C. Bingel, J. Am. Chem.
General Procedure for the Palladium-Catalysed Allylic Alkylation of
rac-1,3-Diphenyl-2-propenyl Acetate: The appropriate amounts of
the ligand and the palladium source were dissolved in CH2Cl2
(1 mL) together with the allyl acetate (121 mg, 0.48 mmol) under
nitrogen. The solution was stirred at room temperature for 1 h and
then cooled to Ϫ78 °C. Dimethyl malonate (123 µL, 1.08 mmol),
N,O-bis(trimethylsilyl)acetamide (375 µL, 1.44 mmol), KOAc (a
few crystals) and CH2Cl2 (1 mL) were added. The reaction mixture
was stirred at room temperature and monitored by HPLC (Chiracel
OD-H column; hexane/iPrOH, 99:1; 0.5 mL·minϪ1).
[9b]
Soc. 1992, 114, 9327Ϫ9343.
B. H. Lipshutz, Y.-J. Shin,
Tetrahedron Lett. 1998, 39, 7017Ϫ7020. [9c] D. A. Evans, K. R.
Campos, J. S. Tedrow, F. E. Michael, M. R. Gagne, J. Am.
´
[9d]
Chem. Soc. 2000, 122, 7905Ϫ7920.
S. Bellemin-Laponnaz,
[9e]
L. H. Gade, Angew. Chem. Int. Ed. 2002, 41, 3473Ϫ3475.
J. F. Jensen, I. Søtofte, H. O. Sørensen, M. Johannsen, J. Org.
[9f]
Chem. 2003, 68, 1258Ϫ1265.
F. Lake, C. Moberg, Eur. J.
Org. Chem. 2002, 3179Ϫ3188.
[10]
[11]
H. Adolfsson, K. Nordström, K. Wärnmark, C. Moberg,
Tetrahedron: Asymmetry 1996, 7, 1967Ϫ1972.
F. Rahm, R. Stranne, U. Bremberg, K. Nordström, M. Cer-
nerud, E. Macedo, C. Moberg, J. Chem. Soc., Perkin Trans. 1
2000, 1983Ϫ1990.
General Procedure for the Palladium-Catalysed Allylic Alkylation of
rac-2-Cyclohexenyl Acetate: The same procedure was employed as
that used for rac-1,3-diphenyl-2-propenyl acetate. The reaction
mixture was stirred at room temperature and the conversion was
monitored by GC/MS. The reaction mixture was filtered through
a silica plug using CH2Cl2. The solvent was evaporated and the
crude oil was purified by column chromatography on silica gel (1.5
ϫ 7 cm column; hexane/EtOAc, 39:1).
[12] [12a]
[12b]
[12c]
L. Pu, H.-B. Yu, Chem. Rev. 2001, 101, 757Ϫ824.
Bolm, Tetrahedron: Asymmetry 1991, 2, 701Ϫ704.
C.
C.
Bolm, M. Ewald, M. Felder, Chem. Ber. 1992, 125, 1205Ϫ1215.
R. J. van Haaren, C. J. M. Druijven, G. P. F. van Strijdonck,
H. Oevering, J. N. H. Reek, P. C. J. Kamer, P. W. N. M. van
Leeuwen, J. Chem. Soc., Dalton Trans. 2000, 1549Ϫ1554.
[13]
[14] [14a]
`
C. G. Arena, F. Nicolo, D. Drommi, G. Bruno, F. Faraone,
J. Chem. Soc., Chem. Commun. 1994, 2251Ϫ2252. [14b] G. Chel-
ucci, M. Marchetti, B. Sechi, J. Mol. Catal. A 1997, 122,
111Ϫ114.
[15] [15a]
Acknowledgments
This work was supported by the Swedish Research Council and by
the Göran Gustafsson Foundation for Research in Sciences and
Medicine.
Q. Jiang, D. van Plew, S. Murtuza, X. Zhang, Tetrahedron
[15b]
Lett. 1996, 37, 797Ϫ800.
R. Sablong, C. Newton, P. Di-
erkes, J. A. Osborn, Tetrahedron Lett. 1996, 37, 4933Ϫ4936.
R. Sablong, J. A. Osborn, Tetrahedron Lett. 1996, 37,
4937Ϫ4940.
[16]
[17] [17a]
C. G. Arena, D. Drommi, F. Faraone, Tetrahedron: Asym-
[17b]
metry 2000, 11, 2765Ϫ2779.
C. G. Arena, D. Drommi, F.
[17c]
[1] [1a]
Faraone, Tetrahedron: Asymmetry 2000, 11, 4753Ϫ4759.
I. Ojima, Catalytic Asymmetric Synthesis, John Wiley &
[1b]
`
D. Drommi, F. Faraone, G. Francio, D. Belletti, C. Graiff, A.
Sons, New York, 2000.
R. Noyori, Asymmetric Catalysis in
Tiripicchio, Organometallics 2002, 21, 761Ϫ764. [17d] C. G. Ar-
[1c]
Organic Synthesis, John Wiley & Sons, New York, 1994.
`
`
ena, G. P. Calabro, G. Francio, F. Faraone, Tetrahedron: Asym-
J. Seyden-Penne, Chiral Auxiliaries and Ligands in Asymmetric
[1d]
metry 2000, 11, 2387Ϫ2392.
Synthesis, John Wiley & Sons, New York, 1995.
E. N. Ja-
[18]
[19]
M. Y. Lebedev, M. B. Erman, Tetrahedron Lett. 2002, 43,
1397Ϫ1399.
D. Cunningham, E. T. Gallagher, D. H. Grayson, P. J.
McArdle, C. B. Storey, D. J. Wilcock, J. Chem. Soc., Perkin
Trans. 1 2002, 2692Ϫ2698.
cobsen, A. Pfaltz, H. Yamamoto, Comprehensive Asymmetric
Catalysis, Vol. 1Ϫ3, Springer, Berlin, 1999.
[2] [2a]
K. D. Shimizu, M. L. Snapper, A. H. Hoveyda, Chem. Eur.
J. 1998, 4, 1885Ϫ1889. [2b] T. Bein, Angew. Chem. Int. Ed. 1999,
38, 323Ϫ326.
[20]
[3] [3a]
I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem.
A. M. Porte, J. Reibenspies, K. Burgess, J. Am. Chem. Soc.
[3b]
Soc. 1991, 113, 4092Ϫ4096.
1998, 120, 9180Ϫ9187.
M. T. Reetz, Angew. Chem. Int. Ed.
[21]
[22]
2001, 40, 284Ϫ310. [3c] J. F. Traverse, M. L. Snapper, Drug Dis-
covery Today 2002, 7, 1002Ϫ1012.
J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512Ϫ519.
C. Bolm, M. Ewald, M. Felder, G. Schlingloff, Chem. Ber.
1992, 125, 1169Ϫ1190.
[4] [4a]
K. H. Shaughnessy, P. Kim, J. F. Hartwig, J. Am. Chem.
4214
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4205Ϫ4215

Pyridyl Phosphinites and Pyridyl Phosphites from Chiral Pyridyl Alcohols
FULL PAPER
[23]
[26]
[27]
[28]
M. Casey, M. P. Smyth, Synlett 2003, 102Ϫ106.
P. Wimmer, M. Widhalm, Tetrahedron: Asymmetry 1995, 6,
657Ϫ660.
G. Delapierre, J. M. Brunel, T. Constantieux, G. Buono, Tetra-
hedron: Asymmetry 2001, 12, 1345Ϫ1352.
A. Saitoh, K. Achiwa, K. Tanaka, T. Morimoto, J. Org. Chem.
2000, 65, 4227Ϫ4240.
[24] [24a]
B. M. Trost, D. L. Van Vranken, Chem. Rev. 1996, 96,
[24b]
395Ϫ422.
B. M. Trost, C. Lee, Catalytic Asymmetric Syn-
thesis, 2nd Ed., (Ed.: I. Ojima), John Wiley & sons, New York,
2000, pp. 593Ϫ649.
[25]
´
´
N. Riegel, C. Darcel, O. Stephan, S. Juge, J. Organomet. Chem.
1998, 567, 219Ϫ233.
Received June 18, 2003
Eur. J. Org. Chem. 2003, 4205Ϫ4215
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4215