New Ligands for Regio- and Enantiocontrol in Pd-Catalyzed Allylic Alkylations

Full text of DOI:10.1002/(sici)1521-3773(19980216)37:3<323::aid-anie323>3.0.co;2-t

COMMUNICATIONS
[
12] (E)-1-[3-(tert-Butyldimethylsilyl)oxy-1-propenyl]-1,3,2-benzodioxa-
linear product 5 is formed rather than the chiral, branched
isomer 4 or its enantiomer ent-4, which are the preferred
products for applications in asymmetric synthesis. Although
predominant formation of the branched isomers has been
observed with achiral catalysts derived from other metals[
borole could be used instead of the boronic acid for this reaction.
�
1
[
13] 2: Oil; R
f
ˆ 0.34 (EtOAc/hexane, 5/95); IR (KBr): nÄ ˆ 1677, 1580 cm
;
1
UV (EtOH): lmax ˆ 379, 243 nm; H NMR (300 MHz, C
6
D
6
): d ˆ 1.11
(
6H, s), 1.44 ± 1.50 (2H, m), 1.53 ± 1.63 (2H, m), 1.72 (3H, s), 1.76 (3H,
3]
d, J ˆ 1.0 Hz), 1.95 (2H, br t, J ˆ 6.5 Hz), 5.79 (1H, m), 6.01 (1H, dd,
J ˆ 15.1, 7.7 Hz), 6.27 (1H, d, J ˆ 16.1 Hz), 6.35 ± 6.47 (3H, m), 7.12
(most notably W and Ir), the development of enantioselective
1
3
(
(
1
1H, dd, J ˆ 15.1, 12.0 Hz), 9.42 (1H, d, J ˆ 7.7 Hz); C NMR
catalysts for this class of substrate remains a challenge.
In 1995 we reported on the conversion of (E)-3-aryl-2-
75 MHz, C
6
D
6
): d ˆ 12.4, 19.6, 21.9, 29.1 (2C), 33.3, 34.5, 39.8,
24.8, 126.2, 130.1, 130.4, 132.2, 133.8, 137.9, 138.0, 141.0, 144.8, 192.2;
‡
‡
propenylphosphates 1 (R ˆ aryl, X ˆ OP(O)(OEt) ) into
FAB-MS: m/z: 271 (M ‡H); HR-MS calcd for C19
71.2062; found: 271.2068.
14] K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 4467 ±
470.
15] 3: Oil; R
H
27O (M ‡H):
2
[4]
2
chiral malonic acid derivatives 4 (Nu ˆ CH(CO Me) ). High
2
2
[
[
enantiomeric excesses and moderate to good regioselectiv-
ities were achieved with a tungsten catalyst prepared from the
chiral (phosphanyloaryl)dihydrooxazole ligand 6a[ (see
Scheme 3). The corresponding (Z) isomers and racemic
substrates 2, on the other hand, afford low enantioselectiv-
ities, in contrast with analogous Pd-catalyzed reactions, which
generally proceed via rapidly equilibrating allyl intermediates
and, therefore, in most cases give identical results with these
three types of substrates.
4
f
ˆ 0.23 (EtOAc/hexane, 15/85); IR (KBr): nÄ ˆ 2160, 1659,
5]
�
1
1
1
C
(
1
(
1
3
1
584 cm ; UV (EtOH): lmax ˆ 370, 252 nm; H NMR (300 MHz,
6
D
6
): d ˆ 1.04 (6H, s), 1.35 ± 1.45 (2H, m), 1.50 ± 1.60 (2H, m), 1.61
3H, s), 1.63 (3H, s), 1.89 (2H, br t, J ˆ 6.5 Hz), 5.16 (1H, d, J ˆ
0.5 Hz), 6.20 (1H, d, J ˆ 16.0 Hz), 6.36 (1H, br d, J ˆ 16.0 Hz), 6.62
1H, dd, J ˆ 12.1, 10.5 Hz), 6.78 (1H, d, J ˆ 12.1 Hz), 8.91 (1H, d, J ˆ
.2 Hz); 1 C NMR (100 MHz, C
3
6
D
6
): d ˆ 15.6, 19.6, 21.8, 29.1 (2C),
3.2, 34.5, 39.8, 91.9, 96.5, 104.6, 127.0, 130.8, 131.4, 137.6, 137.7, 142.9,
‡
43.1, 175.4; MS (70 eV): m/z (%): 268 (M ); HR-MS calcd for
‡
C
19
H
24O (M ): 268.1826; found: 268.1814.
Here we describe a new class of palladium catalysts that
afford good enantio- and regioselectivities with both achiral
and racemic aryl-substituted substrates 1 and 2. The design of
these catalysts was based on the following considerations:
1
) Nucleophilic attack by an S 2-type process should take
N
place preferentially at the less substituted allyl terminus,
whereas the opposite regioselectivity would be expected in an
S 1-like reaction via a cationic transition state (Scheme 2a).
N
New Ligands for Regio- and Enantiocontrol in
Pd-Catalyzed Allylic Alkylations
Roger Pr e t oà t and Andreas Pfaltz*
During the last few years dramatic progress has been made
in the enantiocontrol of palladium-catalyzed allylic alkyla-
tions. New chiral ligands have been developed which can
induce impressive levels of enantioselectivity in reactions with
stabilized carbanions and various N-, O-, and S-nucleo-
L
L
L
L
Pd
Pd
a)
R
R
O
Nu
–
[
1]
philes. However, the lack of regiocontrol is often a problem.
For example, monosubstituted allylic substrates such as 1 and
Nu
2
(R ˆ aryl) generally react predominantly at the unsubsti-
O
[2]
tuted allyl terminus (Scheme 1). Consequently, the achiral,
X
X
P
N
P
N
+
+
Pd
b)
Pd
X
R'
X
R
R'
Nu
PdLn
R
–
–
Nu
R
Nu
R
R
X
A
B
4
3
a
1
Scheme 2. Nucleophilic attack in the Pd-catalyzed allylic alkylation.
a) Transition states in S 1- (left) and S 2-like (right) processes. b) Steric
Nu–
N
N
R
Nu
encumbrance introduced by bulky substituents X on the P atom of the
ligand favors attack of the substituted allyl terminus.
5
X
PdLn
Nu
R
R
In order to enhance the S 1 character, we decided to
N
rac-2
R
3b
introduce electronegative substituents at the coordinating P
atom that render the Pd center more electrophilic. 2) Steric
factors affecting the equilibrium between allyl intermediates
A and B also can play an important role (Scheme 2b). Bulky
groups at the P atom are expected to destabilize isomer B as
well as the transition states of the reaction pathways leading
from B to the corresponding substitution products. Therefore,
a pathway via A should be preferred and, assuming that
nucleophilic attack at the allyl terminus trans to the Pd ± P
ent-4
Scheme 1. Pd-catalyzed allylic alkylations generally produce the same
products, regardless of whether substrate 1 or 2 is employed.
[
*] Prof. Dr. A. Pfaltz, Dipl.-Chem. R. Pr e t oà t
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, D-45470 Mülheim an der Ruhr (Germany)
Fax: Int. code ‡ (49)208-3062992
E-mail: pfaltz@mpi-muelheim.mpg.de
Angew. Chem. Int. Ed. 1998, 37, No. 3
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3703-0323 $ 17.50+.50/0
323

COMMUNICATIONS
bond is electronically favored,[6] reaction at the substituted
allyl end should be facilitated. Although there are certainly
other factors affecting the regioselectivity, these straightfor-
ward concepts put us on the right track.
The regio- and enantioselectivities could be further improved
by introduction of a second stereogenic unit derived from
binaphthol. The best results were obtained with ligand (S,S)-
9
a; the (R,S) diastereomer 10, derived from (R)-binaphthol,
Replacement of the phenyl groups at the P atom of 6b
by electron-withdrawing pentafluorophenyl groups ( !7,
gave lower regio- and enantioselectivities. Apparently, the
enantioselectivity is determined largely by the chiral dihy-
drooxazole ring. The chiral binaphthol unit has a minor, but
still significant effect. The analogous isopropyldihydrooxazole
ligand 9b gave a somewhat lower ee value; the phenyl-
dihydrooxazole ligand 9c, on the other hand, was inferior in
terms of regioselectivity. Introduction of two ortho-methyl
groups in the binaphthol system ( !9d) improved the
enantioselectivity, but the regioselectivity decreased. The
best results were achieved with ligand 9a in benzene at 238C
[
7]
Scheme 3) shifted the regioselectivity in the desired direc-
O
O
O
O
O
O
P
N
Ph2P
N
(C6F5)2P
N
R
R
R
(
�
90% ee, 4a:5a 76:24; Table 1) and in dichloromethane at
358C (88% ee, 79:21).
Even better regio- and enantioselectivities were obtained
6
6
a
b
R =i Pr
t Bu
7 R = t Bu
8 R = t Bu
R1
with 1-naphthyl-substituted allylic acetates 1b and 2b
Table 2). The achiral substrates 1a ± 1c afforded essentially
the same regio- and enantioselectivities as the corresponding
(
O
O
O
P
O
O
P
O
O
N
N
S
R
S
S
O
R2
R
Table 2. Allylic alkylation of various substrates 1 and rac-2 using ligand 9a
R1
[
a]
(
Scheme 1; X ˆ OAc, Nu ˆ CH(CO
2 2
Me) ). .
1
2
9a
9b
9c
9d
R =H R =t Bu
10 R = t Bu
Yield[%][b]
ee of 4[%][c]
4:5[d]
R
H
H
Me
i Pr
Ph
t Bu
1
2
1
2
2
1
2
b
b
c
1-naphthyl
1-naphthyl
2-naphthyl
2-naphthyl
phenyl
87
91
72
71
82
75
72
94(S)
96(S)
88
95:5
96:4
77:23
74:26
66:34
30:70
75:25[
Scheme 3. Chiral ligands L* tested in the Pd-catalyzed allylic alkylation.
c
89
a
d
e
88(S)
[
e]
methyl
41
51
f]
(CH
3
)
2
CˆCH
tion from 4:96 to 48:57 (Table 1). A similar effect was
observed when ligand 8 was used, which has a biphenylphos-
phite group in place of the diphenylphosphane substituent.
[a] For experimental conditions see Table 1. [b] Total yield of 4 and 5 after
chromatography. [c] Determined by HPLC analysis (Chiralcel OJ and
OD-H). Configurations of 4a and 4b were assigned by comparison to
ref. [4]. [d] Determined by GC analysis of the crude reaction mixture and
H2C(CO2Me)2
Pd / L*
MeO2C
Ph
CO2Me
MeO2C
CO2Me
(1)
1
H NMR analysis after chromatography. [e] Determined by GC analysis
+
(Chiraldex G-TA). [f] Reaction in benzene.
Ph
OAc
BSA, KOAc
CH2Cl2, 23 °C
Ph
1
a
4a
5a
racemic isomers 2. Apparently, the intermediate allyl com-
plexes undergo rapid isomerization before they react with the
nucleophile in the slower selectivity-determining step. The
limitations of these catalysts become apparent with substrates
1d and 2e, which react with distinctly lower selectivities.
A comparison of 3-phenyl-2-propenyl acetate 1a with the
corresponding p-methoxyphenyl- and p-cyanophenyl-2-pro-
penyl acetates confirms that the regioselectivity is strongly
affected by electronic factors. While the electron-donating p-
methoxy substituent enhances the regioselectivity from 69:31
to 76:24 in favor of the chiral isomer (76% ee), the cyano
group has the opposite effect, resulting in a reversed product
ratio of 13:87 with the linear isomer 5 as the main product.
The synthesis of ligands 9 is straightforward (Scheme 4).
Starting from various amino alcohols, hydroxy acids, and diols,
a wide range of analogues can be readily prepared in this way.
Libraries of ligands that are accessible by this route could be
used to further optimize the selectivities obtained so far.
Our results demonstrate how the regioselectivity of allylic
alkylations can be changed by systematic modification of the
electronic and steric properties of the ligand attached to the
Table 1. Results of enantioselective allylic alkylation [Eq. (1)] using
different ligands L*.[
a]
L*
Yield[%][b]
ee of 4a[%][c]
4a:5a[d]
6
7
8
9
b
90
87
75
84
78
84
81
86
4:96
47:53
63:37
69:31
76:24[e]
a
a
9
86
90
1
9
9
9
0
b
c
80
92
84
88
79
77
91
92
46:54
68:32
39:61
55:45
d
[
a] 1 mol% [Pd(C
CH (CO Me)
KOAc, 238C, 18 h. [b] Total yield of purified (S)-4a and (E)-5a after
3
H
5
)Cl]
2
, 2.4 mol% L*, 508C, CH
2
Cl
2
, 2 h; 2 equiv of
2
2
2
and N,O-bis(trimethylsilyl)acetamide (BSA), 4 mol%
[
12]
[4]
chromatography. [c] Determined by HPLC (Chiralcel OJ). All reactions
gave the (S)-(� ) enantiomer. [d] Determined by GC analysis of the crude
1
reaction mixture and H NMR analysis after chromatography. [e] Reaction
in benzene.
3
24
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3703-0324 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 3

COMMUNICATIONS
K. Zetterberg, S. Hansson, B. Krankenberger, A. Vitagliano, J.
Organomet. Chem. 1987, 335, 133 ± 142; M. P. T. Sjögren, S. Hansson,
B. Škermark, A. Vitagliano, Organometallics 1994, 13, 1963 ± 1971.
3] a) W: B. M. Trost, M.-H. Hung, J. Am. Chem. Soc. 1983, 105, 7757 ±
O
O
OH
OH
PCl
[
7
759; b) see also: G. C. Lloyd-Jones, J. Lehmann, Tetrahedron 1995,
5
1, 8863 ± 8874; c) Ir: R. Takeuchi, M. Kashio, Angew. Chem. 1997,
1
0
109, 268 ± 270; Angew. Chem. Int. Ed. Engl. 1997, 36, 263 ± 265; d) Mo:
B. M. Trost, M. Lautens, Tetrahedron 1987, 43, 4817 ± 4840; e) Ru: T.
Kondo, H. Ono, N. Satake, T. Mitsudo, Y. Watanabe, Organometallics
1995, 14, 1945 ± 1953; S.-W. Zhang, T. Mitsudo, T. Kondo, Y.
Watanabe, J. Organomet. Chem. 1993, 450, 197 ± 207.
O
O
P
O
O
Et3N
3 °C
N
2
HO
NH2
R
[
[
4] G. C. Lloyd-Jones, A. Pfaltz, Angew. Chem. 1995, 107, 534 ± 536;
Angew. Chem. Int. Ed. Engl. 1995, 34, 462 ± 464.
9
R
5] a) P. von Matt, A. Pfaltz, Angew. Chem. 1993, 105, 614 ± 615; Angew.
Chem. Int. Ed. Engl. 1993, 32, 566 ± 568; A. Pfaltz, Acta Chem. Scand.
B 1996, 50, 189 ± 194; b) J. Sprinz, G. Helmchen, Tetrahedron Lett.
1993, 34, 1769 ± 1772; G. Helmchen, S. Kudis, P. Sennhenn, H.
Steinhagen, Pure Appl. Chem. 1997, 69, 513 ± 518; c) G. J. Dawson,
C. G. Frost, J. M. J. Williams, S. J. Coote, Tetrahedron Lett. 1993, 34,
+
O
HO
N
HO
CO2H
1
1
R
[
10]
Scheme 4. Synthesis of ligands 9. The preparation of compounds 10 and
[
11]
1
1
is described elsewhere.
3
149 ± 3150; J. M. J. Williams, Synlett 1996, 705 ± 710.
[
[
6] J. Sprinz, M. Kiefer, G. Helmchen, M. Reggelin, G. Huttner, O.
Walter, L. Zsolnai, Tetrahedron Lett. 1994, 35, 1523 ± 1526; J. M.
Brown, D. J. Hulmes, P. J. Guiry, Tetrahedron 1994, 50, 4493 ± 4506; A.
Togni, U. Burckhardt, V. Gramlich, P. S. Pregosin, R. Salzmann, J. Am.
Chem. Soc. 1996, 118, 1031 ± 1037; P. E. Blöchl, A. Togni, Organo-
metallics 1996, 15, 4125 ± 4132; T. R. Ward, ibid. 1996, 15, 2836 ± 2838.
7] Synthesis of 7: O. Loiseleur, Dissertation, University of Basel, 1996.
palladium catalyst. By using a new type of chiral P,N ligand,
practically useful enantio- and regioselectivities have been
obtained in the reaction with 1- and 3-aryl-2-propenyl
[
8]
acetates. Although at present the range of substrates that
afford good selectivities is limited to aryl-substituted deriva-
tives, the concepts used for the design of ligands 9 may serve
as guidelines for the development of new catalysts for
different classes of substrates. In addition, these ligands have
[8] After completion of this work analogous regioselective reactions of 3-
aryl-2-propenyl acetates 1 with dimethyl methylmalonate catalyzed by
a chiral monophosphane ± Pd complex were reported (4:5 ˆ 4:1, 68 ±
8
6% ee; R ˆ Ph): T. Hayashi, M. Kawatsura, Y. Uozumi, J. Chem. Soc.
Chem. Commun. 1997, 561 ± 562.
[
9]
other possible applications in asymmetric catalysis.
[9] Cu-catalyzed 1,4-addition of organozinc reagents to enones: A. K. H.
Knöbel, I. H. Escher, A. Pfaltz, Synlett 1997, 1429 ± 1431.
[
[
10] N. Green, T. P. Kee, Synth. Comm. 1993, 23, 1651 ± 1657.
11] J. V. Allen, J. M. J. Williams, Tetrahedron: Asymmetry 1994, 5, 277 ±
Experimental Section
2
82; L. N. Pridgen, G. Miller, J. Heterocycl. Chem. 1983, 20, 1223 ±
9
a: All reactions were performed under argon in degassed solvents. A
[10]
1230.
solution of 10 (1.1 g, 3.2 mmol) in toluene (10 mL) was added dropwise
to Et
[
12] P. von Matt, G. C. Lloyd-Jones, A. B. E. Minidis, A. Pfaltz, L. Macko,
M. Neuburger, M. Zehnder, H. Rüegger, P. S. Pregosin, Helv. Chim.
Acta 1995, 78, 265 ± 284.
3
N (2.6 g, 25.7 mmol) in toluene (20 mL) at � 788C. This solution was
[11]
stirred for 5 min at � 788C before a solution of 11 (0.6 g, 3.2 mmol) in
toluene (5 mL) was added quickly. The solution was allowed to gradually
warm up to room temperature and stirred for 12 h. The white precipitate
was removed by filtration. Evaporation of the solvent afforded a yellow oil,
which was purified by column chromatography (silica gel, 3.0 Â 20 cm; n-
hexane/EtOAc 4/1, R
f
ˆ 0.4) to afford (S,S)-9a (890 mg, 56%) as an
1
amorphous solid. [a]589 ˆ ‡269 (CHCl
3
, c ˆ 3.1, 238C); H NMR (200 MHz,
CDCl
3
): d ˆ 0.96 (s, 9H; tBu), 1.65 (s, 3H; Me), 1.75 (s, 3H; Me), 3.95 ± 4.00
O), 7.22 ± 7.52 (m, 8H; arom. CH),
.89 ± 7.96 (m, 4H; arom. CH); 3C NMR (75 MHz, CDCl
): d ˆ 25.8 (tBu),
O),
Synthesis of a New Class of Solvent-Sensitive
Fluorescent Labels
(
m, 1H; HCN), 4.20 ± 4.35 (m, 2H; CH
2
1
7
2
7
3
1
3
8.1 (d, J ˆ 7.9 Hz; Me), 28.2 (d, J ˆ 5.7 Hz; Me), 33.9 (tBu), 69.7 (CH
2
James J. La Clair*
5.7 (CHN), 77.2 (C), 121.9/122.4 (arom. CH), 123.2 (arom. C), 124.5 (d, J ˆ
.1 Hz; arom. C), 124.6/124.8/125.8/126.0/126.9/127.0/128.1/128.2/129.3/
30.0 (arom. CH), 131.1/131.4/132.7/132.8 (arom. C), 147.9 (d, J ˆ 2.3 Hz;
Charge transfer (CT) labels such as 5-(dimethylamino)-
naphthalene-1-sulfonyl (dansyl) chloride have been used
extensively for the detection, characterization, and localiza-
tion of carbohydrates, phospholipids, proteins, oligonucleo-
tides, and numerous other synthetic and natural substances.
These materials typically experience shifts in their UV/Vis
absorption and/or fluorescence bands depending on the
3
1
arom. C), 148.0 (d, J ˆ 3.7 Hz; arom. C), 168.3 (CˆN); P NMR (100 MHz,
CDCl
3
): d ˆ 151.5.
Catalytic reactions (Tables 1 and 2) were carried out according to the
literature procedure.[ Purification and analytical data of the products are
described elsewhere.[3b, 4].
12]
[1]
Received: July 28, 1997 [Z10745IE]
German version: Angew. Chem. 1998, 110, 337 ± 339
[2]
nature of their solvent shells. This effect together with
modifications of fluorescence lifetimes, extent of intersystem
crossing, and fluorescence quantum yield have encouraged
Keywords: allylic alkylations
dihydrooxazoles ´ N ligands ´ palladium ´ P ligands
´
asymmetric catalysis
´
[
[
1] a) B. M. Trost, D. L. Van Vranken, Chem. Rev. 1996, 96, 395 ± 422; b)
T. Hayashi in Catalytic Asymmetric Synthesis, (Ed.: I. Ojima), VCH,
New York, 1993, pp. 325 ± 365.
2] a) For a discussion of the various regioselectivity-determining factors,
see: B. M. Trost, M.-H. Hung, J. Am. Chem. Soc. 1984, 106, 6837 ±
[*] Prof. J. J. La Clair
Department of Molecular Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: Int. code ‡ (1)619784-2584
E-mail: laclair@scripps.edu
6839; b) systematic study of the influence of the ligand: B. Škermark,
Angew. Chem. Int. Ed. 1998, 37, No. 3 ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3703-0325 $ 17.50+.50/0
325