2-(Phosphinoaryl)pyridine ligand (2): Asymmetric allylic alkylation of 2-cycloalkenyl carboxylate

Article abstract of DOI:10.1055/s-2001-10794

Palladium complex of 2-(phosphinoaryl)pyridine 1b, which is an effective catalyst for asymmetric allylic alkylation (denoted as AAA) of acyclic alkenyl carboxylate, was also found to be a highly effective catalyst for AAA of cyclic alkenyl carboxylate: high enantioselectivities of 87% ee and 94% ee were achieved in the reactions of 2-cyclohexenyl and 2-cycloheptenyl pivalates, respectively.

Full text of DOI:10.1055/s-2001-10794

2
84
LETTER
2
-(Phosphinoaryl)pyridine Ligand (2): Asymmetric Allylic Alkylation of 2-
Cycloalkenyl Carboxylate
a
a
a
b
b
Katsuji Ito, * Risa Kashiwagi, Sakiko Hayashi, Tatsuya Uchida, Tsutomu Katsuki *
a
Department of Chemistry, Fukuoka University of Education, Akama, Munakata, Fukuoka 811-4192, Japan
b
Department of Chemistry, Faculty of Science, Graduate School, Kyushu University 33, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
Fax +81-92-642-2607; E-mail: itokat@fukuoka-edu.ac.jp
Received 4 December 2000
Ph2
P
Ph2
P
Abstract: Palladium complex of 2-(phosphinoaryl)pyridine 1b,
which is an effective catalyst for asymmetric allylic alkylation (de-
noted as AAA) of acyclic alkenyl carboxylate, was also found to be
a highly effective catalyst for AAA of cyclic alkenyl carboxylate:
high enantioselectivities of 87% ee and 94% ee were achieved in the
reactions of 2-cyclohexenyl and 2-cycloheptenyl pivalates, respec-
tively.
R'
R'
N
N
B
Ph1
Ph1
A
Ph2
P
Ph2
P
Key words: asymmetric allylic alkylation, asymmetric catalysis,
palladium, chiral P-N ligand
R'
R'
Nu
N
N
Ph1
Ph1
Nu
D
Carbon-carbon bond formation using a combination of 2-
alkenyl carboxylate, palladium catalyst and nucleophile is
of high use in organic synthesis due to its mild reaction
conditions, high chemoselectivity, and high chemical
yield and, therefore, its asymmetrization is a current topic.
As a result, remarkable advancement has been made in
this field by introduction of efficient and sophisticated
C
Scheme 1
1
chiral ligands. Of these ligands, only a few can be suc-
cessfully applied to AAA of C -cycloalkenyl carboxyl-
1
2
N
PPh2
2
a,b
ates. For example, -phosphinocarboxylic acids,
C -
2
1a: R= Ph
b: R= i-Pr
c: R= CMe2OSiMe2Bu-t
7
2
c-h
symmetric diphosphine ligands with a large bite angle,
R
2
i,j
and P-S chelate ligand showed high enantioselectivity
in this type of reaction. Recently, chiral P-N chelate
ligands were found to be efficient chiral sources for
O
R
NaCH(CO2Me)2, CH3CN
15-crown-5
MeOOC
COOMe
R
1
b
O
R'
AAA, but their scopes are also mostly limited to AAA
3
of acyclic alkenyl carboxylates. Two isomeric -allyl Pd
R
R
1
b + [Pd(C3H5)Cl]2
intermediates are formed in the reaction using a chiral P-
N ligand and they have been considered to be in rapid
racemic
R= Ph, R'= CH3; 98% ee
R= Me, R'= OPh; 93% ee
1
c,4
equilibrium.
To achieve high enantioselectivity in
Scheme 2
AAA of cyclic substrates, some devices in chiral ligand to
shift the equilibrium to one side and not to destabilize the
corresponding -complex are required.
few ligands which show high enantioselectivity in the re-
actions of both acyclic substrates bearing large or small
substituent and cyclic substrates.2
Recently, Helmchen et al. have introduced a new P-N
ligand bearing an axial 2-biphenylyl group (Ph ) which
destabilizes intermediate B and -complex D of the four
2
j
intermediary species (A, B and C, D) and achieved high We recently developed novel 2-(phosphinoaryl)pyridine
enantioselectivities in the reaction of cycloalkenyl ace- ligands 1, a new class of chiral P-N chelate ligands, in
tates, though it has not been applied to the reaction of which the substituent R at C7 directs inward upon com-
5
a
acyclic substrates. A different type of P-N ligand has plex formation, and achieved high enantioselectivity in
5b
also been applied to the reaction of cyclic substrates. On the reaction of acyclic substrates irrespective of the bulk-
the other hand, Osborn et al. have reported that a xan- iness of allylic substituents, e.g., 1,3-diphenyl-2-propenyl
thene-diphosphine ligand which chelates palladium ion acetate (98% ee) and 1-methyl-2-butenyl phenyl carbon-
with a large bite angle shows high enantioselectivity in al- ate (93% ee), with palladium complex of 1b as the catalyst
6
lylic alkylation of both 1,3-diphenyl-substituted allyl and (Scheme 2). A feature of this complex is that the substit-
cyclohexenyl acetates, though the reaction of 1-methyl-2- uents at C7 directs in- and up-ward. Therefore, it was ex-
2
e
butenyl acetate is less than satisfactory. Still, there are pected that the equilibrium of two possible isomeric
Synlett 2001, No. 2, 284–286 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
2-(Phosphinoaryl)pyridine Ligand (2)
285
intermediates (A and B) would be shifted toward A and 1). We also examined the reaction with sodium salt of
the undesirable -complex D would be destabilized by dimethyl malonate in the presence of 15-crown-5 in ace-
tuning the size of 7-substituent (Scheme 1). Thus, we ex- tonitrile with the palladium complex of 1b, which were
amined AAA of cyclic alkenyl carboxylate.
the best conditions for the reaction of acyclic substrates.
Reaction proceeded smoothly but enantioselectivity was
decreased to a considerable extent (entry 3). We next ex-
First we examined AAA of 2-cyclohexenyl acetate with
dimethyl malonate in the presence of the palladium com-
plexes of 1a-c in dichloromethane using N,O-bis(trimeth-
ylsilyl)acetamide (BSA) and potassium acetate as the base
2
f
amined the reaction of 2-cyclohexenyl pivalate. Reac-
tion rate was enhanced considerably and enantiose-
lectivity was improved up to 81% ee (entry 4). Enantiose-
lectivity was further improved to 86% ee by lowering the
reaction temperature to -20 °C but the reaction rate was
(
Table 1). The catalytic activity of these palladium com-
plexes and their asymmetric induction greatly depended
on the C7-substituent. Reaction with 1a as the chiral aux-
iliary proceeded smoothly but enantioselectivity was poor
7
decreased dramatically (entry 5). However, we were
pleased to find that the reaction using a combination of
BSTFA and AcOK as the base proceeded at an acceptable
(
entry 1). On the other hand, the reaction with 1c bearing
bulky 1-(t-butyldimethylsiloxy)-1-methylethyl group was
sluggish and enantioselectivity was poor (entry 4). In
7
rate even at -20 °C, showing good enantioselectivity of
9
8
7% ee and high chemical yield (entry 7). Further lower-
contrast, the reaction with 1b bearing isopropyl group
showed good enantioselectivity of 79% ee (entry 2). It
was further found that the reaction rate was increased
when N,O-bis(trimethylsilyl)trifluoroacetamide (BST-
ing the reaction temperature to -40 °C did not improve
enantioselectivity, though the reaction rate was decreased
considerably (entry 8). We also examined the solvent ef-
fect on enantioselectivity and reaction rate under the con-
ditions using a combination of BSTFA and AcOK. The
use of THF showed adverse effect on both selectivity and
rate (entry 9). On the other hand, the reactions in aromatic
solvents showed slightly improved enantioselectivities,
but the reaction rates were decreased substantially (entries
8
FA) was used as the base, although enantioselectivity
was diminished to some extent (entry 3).
Cl
Pd Pd
MeOOC
COOMe
(1mol%)
OAc
Cl
1
0-13).
chiral ligand (2.5 mol%)
CH2(COOMe)2
base
O
O
Cl
Pd Pd
Cl
racemic
MeOOC
COOMe
(1mol%)
R'
1
b (2.5 mol%)
Table 1 Asymmetric allylic alkylation of 2-cyclohexenyl acetate.a)
CH2(COOMe)2
base
racemic
Table 2 Asymmetric allylic alkylation of cyclic allyl substrates
using 1b as the chiral source.
a) Reactions were carried out at room temperature in dichloromethane
using BSA and potassium acetate as a base, unless otherwise mentio-
ned.
1
b) Enantiomeric excess was determined by H NMR analysis in
the presence of chiral shift reagent Eu(hfc)3.
c) Determined by chiroptical comparison with the reported value
(
reference 2c,i).
d) BSTFA was used instead of BSA.
e) Reaction was not completed after 24 h.
As described above, isomeric -allyl intermediates are
usually in rapid equilibrium but it has been reported that
the equilibrium is not very rapid in some reactions. In the
latter case, the nature of the leaving group can affect enan-
tioselectivity. In addition to this, it is well-known that the
nature of the leaving group affects the reaction rate. Thus,
we examined the effect of the leaving group on enantiose-
lectivity and reaction rate (Table 2). We first examined the
reaction of 2-cyclohexenyl phenyl carbonate with 1b,
which showed the same level of enantioselectivity as that
a) Enantiomeric excess was determined by HPLC using a chiral
stationary phase column (Daicel Chiralcel OB-H; hexane:
i-PrOH = 9:1).
b) Reaction was carried out in the presence of 15-crown-5.
of acetate, though the reaction rate was decreased (entry c) Reaction was not completed.
Synlett 2001, No. 2, 284–286 ISSN 0936-5214 © Thieme Stuttgart · New York

2
86
K. Ito et al.
LETTER
1999, 64, 6247. h) Longmire, J. M.; Wang, B.; Zhang, X.
Tetrahedron Lett. 2000, 41, 5435. i) Evans, D. A.; Campos, K.
R.; Tedrow, J. S.; Michael, F. E.; Gagnè, M. R. J. Org. Chem.
We also examined AAA of 2 and 3 under the optimized
reaction conditions. The reaction of 2 proceeded smoothly
at -20 °C with good enantioselectivity of 78% ee. Lower-
ing the reaction temperature to -40 °C did not improve
enantioselectivity, though reaction rate became slow. On
the other hand, reaction of 3 proceeded with high enantio-
selectivity of 91% ee at -20 °C and excellent enantioselec-
tivity of 94% ee was achieved at -40 °C without decaying
chemical yield.
1
999, 64, 2994. j) Evans, D. A.; Campos, K. R.; Tedrow, J. S.;
Michael, F. E.; Gagnè, M. R. J. Am. Chem. Soc. 2000, 122,
905.
7
(
3) a) 2-(Phosphinophenyl)oxazoline ligands bearing large 2-
biphenylyl group at phosphorus atom exhibited high
enantioselectivity of 85% ee in the reaction of 2-cyclooctenyl
bromide, though low enantioselectivity was obtained in the
reaction of 2-cyclohexenyl acetate (54% ee): Sennhenn, P.;
Gabler, B.; Helmchen, G. Tetrahedron Lett. 1994, 46, 8595.
b) Moderate enantioselectivity of 69% ee was obtained in the
reaction of 2-cyclohexenyl pivalate using the P-N ligand
bearing phenyl imino groups derived from L-valine; Saitoh,
A.; Misawa, M.; Morimoto, T. Synlett 1999, 483.
Cl
Pd Pd
MeOOC
COOMe
Cl
(1mol%)
OPiv
1b (2.5 mol%)
(
4) Saitoh, A.; Achiwa, K.; Tanaka, K.; Morimoto, T. J. Org.
Chem. 2000, 65, 4227.
5) a) Kudis, S.; Helmchen, G. Angew. Chem., Int. Ed. 1998, 37,
CH2(COOMe)2
n
n
(
BSTFA, cat. AcOK
dichloromethane
racemic
4: n= 1; 86% yield, 78% ee ( -20 °C, 1 h)
4% yield, 79% ee ( -40 °C, 72 h)
: n= 3; 92% yield, 91% ee ( -20 °C, 12 h)
8% yield, 94% ee ( -40 °C, 72 h)
3047. b) Gilbertson, S. R.; Xie, D. Angew. Chem. Int. Ed.
7
1999, 38, 2750.
2
3
: n= 1
: n= 3
5
(6) Ito, K.; Kashiwagi, R.; Iwasaki, K.; Katsuki, T. Synlett 1999,
563.
9
1
(
7) Side reaction product other than the desired allylic alkylation
product was not detected by TLC analysis, even if the reaction
was slow.
In conclusion, palladium-catalyzed AAA of both acyclic
and cyclic alkenyl substrates was for the first time demon-
strated to be effected by using a common chiral auxiliary,
(
(
8) Koch, G.; Pfaltz, A. Tetrahedron: Asymmetry 1996, 7, 2213.
9) Typical experimental procedure
Allylpalladium(II) chloride dimer (0.9 mg, 2.5 µmol) was
placed in a flask under nitrogen and to this flask was added
ligand 1b (2.6 mg, 6.3 µmol) in dichloromethane (0.3 ml).
After being stirred for 1h at room temperature, 2-cyclohexenyl
pivalate (45.6 mg, 0.25 mmol) in dichloromethane (0.5 ml)
was added and cooled to -20 °C. To this solution was added
dimethyl malonate (88 µl, 0.75 mmol), BSTFA (199 µl, 0.75
mmol) and catalytic amount of potassium acetate
2
-(phosphinoaryl)pyridine 1b.
References and Notes
(
1) Reviews: a) Hayashi, T. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: Weinheim, 1993, p 325. b) Trost, B. M.;
van Vranken, D. L. Chem. Rev. 1996, 96, 395. c) Pfaltz, A.;
Lautens, M. In Comprehensive Asymmetric Catalysis,
Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer:
Berlin, 1999, Vol. II, p 833.
successively. The solution was left in the refrigerator (-20 °C)
for 25 h. The solution was quenched with saturated aqueous
NH
with ethyl acetate. The extract was dried over anhydrous
MgSO and concentrated. Silica gel chromatography of the
Cl, allowed to warm to room temperature, and extracted
4
(
2) a) Okada, Y.; Minami, T.; Umezu, Y.; Nishikawa, S.; Mori,
R.; Nakayama, Y. Tetrahedron: Asymmetry 1991, 2, 667. b)
Knühl, G.; Sennhenn, P.; Helmchen, G. J. Chem. Soc., Chem.
Commun. 1995, 1845. c) Trost, B. M.; Bunt, R. C. J. Am.
Chem. Soc. 1994, 116, 4089. d) Trost, B. M.; Radinov, R. J.
Am. Chem. Soc. 1997, 119, 5962. e) Dierkes, P.; Ramdeehul,
S.; Barloy, L.; De Cian, A.; Fischer, J.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Osborn, J. A. Angew. Chem., Int. Ed.
Engl. 1998, 37, 3116. f) Saitoh, A.; Misawa, M.; Morimoto, T.
Tetrahedron: Asymmetry 1999, 10, 1025. g) Zang, W.;
Shimanuki, T.; Kida, T.; Nakatsuji, Y.; Ikeda, I. J. Org. Chem.
4
residue (hexane:ethyl acetate = 9:1) gave the desired product
(52 mg, 98%) as an oil. Enantiomeric excess of the product
was determined to be 87% by HPLC using a chiral stationary
phase column (Daicel Chiralcel OB-H; hexane:i-PrOH =
9:1).
Article Identifier:
1437-2096,E;2001,0,02,0284,0286,ftx,en;Y20000ST.pdf
Synlett 2001, No. 2, 284–286 ISSN 0936-5214 © Thieme Stuttgart · New York