LETTER
Highly Active Thiophene and Benzothiophene Containing Diphosphine Ligands
1115
Acknowledgment
1 mol% Pd2dba3·CHCl3
OCO2Et
Generous financial support from the Deutsche Forschungsgemein-
schaft (SFB 416) and the Fonds der Chemischen Industrie is grate-
fully acknowledged. We are also indebted to the companies BASF,
Bayer, Degussa, Symrise, and Wacker-Chemie for generous gifts of
chemicals.
3 mol% ligand,
O
OH
HO
( )
n
( )
n
HO
23a: n = 1
23b: n = 2
24a: n = 1
24b: n = 2
THF/CH2Cl2, r.t.
References
eea
(%)
Entry
n
Ligand
Time
(h)
Yield
(1) Reviews: (a) Tietze, L. F.; Ila, H.; Bell, H. P. Chem. Rev.
2004, in press. (b) Overman, L. E.; Dounay, A. B. Chem.
Rev. 2003, 103, 2945. (c) Shibasaki, M.; Boden, C. D. J.;
Kojima, A. Tetrahedron 1997, 53, 7371.
(2) (a) Graening, T.; Schmalz, H.-G. Angew. Chem. Int. Ed.
2003, 42, 2580; Angew. Chem. 2003, 115, 2684. (b) Trost,
B. M. Chem. Pharm. Bull. 2003, 50, 1. (c) Trost, B. M.;
Crawley, M. L. Chem. Rev. 2003, 103, 2921.
(%)
1
2
3
2
2
2
5
6
7
6
8
4
82
87
91
79
85
90
(3) (a) Trost, B. M.; Van Vranken, D. L. Angew. Chem., Int. Ed.
Engl. 1992, 31, 228; Angew. Chem. 1992, 104, 194.
(b) Knuehl, G.; Sennhenn, P.; Helmchen, G. J. Chem. Soc.,
Chem. Commun. 1995, 18, 1845. (c) Pfaltz, A.; von Matt, P.
Angew. Chem., Int. Ed. Engl. 1993, 32, 566; Angew. Chem.
1993, 105, 614. (d) Helmchen, G.; Sprinz, J. Tetrahedron
Lett. 1993, 34, 1769.
(4) (a) Tietze, L. F.; Thede, K. Synlett 2000, 1470. (b) Tietze,
L. F.; Thede, K.; Sannicolò, F. Chem. Commun. 2000, 583.
(c) Tietze, L. F.; Thede, K. Chem. Commun. 1999, 18, 1811.
(5) Tietze, L. F.; Lohmann, J. K. Synlett 2002, 2083.
(6) (a) Shilai, M.; Kondo, Y. T. J. Chem. Soc., Perkin Trans. 1
2001, 442. (b) Kristensen, J.; Lysen, M.; Vedsø, P.; Begtrup,
M. Org. Lett. 2001, 3, 1435.
4
2
8
10
88
82
5
6
2
1
1
5
14
6
76
83
89
58
7
8
1
1
1
1
6
7
8
1
8
4
83
79
85
81
82
56
81
28
9
3
10
14
a Determined by chiral HPLC using a chiracel OD-column with
hexane:isopropanol 99:1 as eluent.
(7) Persigehl, P.; Jordan, R.; Nuyken, O. Macromolecules 2000,
33, 6977.
(8) Synthesis of Ligand 7: A mixture of 3-bromo-thiophene-2-
carboxylic acid (16, 9.44 g, 46 mmol) and Me3SiCl (92
mmol, 2.0 equiv) in MeOH was refluxed for 24 h. After
cooling, the crude product was adsorbed on silica gel (20 g)
and purified by column chromatography (n-pentane/EtOAc,
10:1). The methyl ester 17 (9.50 g, 43.0 mmol, 93%) was
obtained as a white solid. A solution of this ester (7.1 g, 32.1
mmol), dry NaOAc (5.47 g, 66.7 mmol, 2.1 equiv) and
catalyst 19 (620 mg, 2 mol%) was degassed and
Scheme 5 Enantioselective allylation of catechol with cyclopente-
nyl and cyclohexenyl carbonate 23a and 23b using ligands 1 and 5–8
ligand 78 (entry 3), which was slightly better than with
ligand 1 giving 89% ee and 76% yield within 12 hours
(entry 5). With ligands 5, 6 and 8 a slightly decreased
enantioselectivity was found compared to ligand 1, but the
yields were still higher and the reaction time reduced.
However, in the allylation of catechol with cyclopentenyl
carbonate the new ligands showed an astounding superi-
ority over ligand 1. Thus, using ligand 1 an enantioselec-
tivity of only 28% ee was obtained (entry 10), whereas
with the thiophene ligands 5 and 7 an asymmetric induc-
tion of 58% and 56% ee, respectively was observed. (en-
tries 6 and 8). A still much better selectivity of 81% and
82% ee, respectively was found for the reaction using
the benzothiophene containing ligands 6 and 8 (entries 7
and 9).
diphenylphosphine (7.5 mL, 8.03 g, 43.1 mmol, 1.3 equiv)
was added via syringe. The solution was heated under argon
to 100 °C for 5 h. After cooling, H2O (200 mL) was added.
Extraction with EtOAc (3 × 200 mL) gave the crude product,
which was purified via column chromatography (n-pentane:
EtOAc, 10:1). The ester (6.90 g, 21.1 mmol) was dissolved
in THF/MeOH/H2O (5:5:1, 100 mL) and LiOH·H2O (105
mmol, 5.0 equiv) was added. After 24 h 1 N HCl (200 mL)
was added and the solution was extracted with EtOAc
(3 × 150 mL). The product was purified by chromatography
(n-pentane:EtOAc, 10:1, 1% HOAc) and the acid 18 (6.25 g,
20.0 mmol, 95%) was obtained as a white solid. The acid
(1.12 g, 3.6 mmol) was dissolved in DMF (50 mL) and
HOBt (3.6 mmol) and EDC·HCl (3.6 mmol) were added at
r.t. After 30 min, cyclohexanediamine (1.8 mmol) was added
and the reaction mixture was stirred for 24 h. 1 N HCl (100
mL) was added add the resulting mixture was extracted
thrice with EtOAc (100 mL). After purification by column
chromatography ligand 7 was obtained as a white foam.
[a]D20 –110.8 (c 0.3, CHCl3); Rf (n-pentane:EtOAc = 4:1,
1% Et3N) = 0.41. IR (KBr): n = 3281, 3014, 2932, 2051,
1638, 1526 cm–1. 1H NMR (300 MHz, CDCl3): d = 1.26 (mc,
2 H, 3¢-H), 1.68 (mc, 1 H, 2¢-Ha), 2.04 (mc, 1 H, 2¢-Hb), 3.87
The improved selectivity and reactivity of the new ligands
5 → 8 might be due to the different bond angles and the
different electronic properties of the phosphine moiety in
the thiophene compounds as compared to 1. We are now
in the process to investigate the new ligands in the allyla-
tion using different nucleophiles and allylic substrates.
Synlett 2004, No. 6, 1113–1116 © Thieme Stuttgart · New York