Synthesis of novel chiral thiophene-, benzothiophene- and benzofuran-oxazoline ligands and their use in the enantioselective Pd-catalyzed allylation

Article abstract of DOI:10.1055/s-2002-35577

Novel thiophene, benzothiophene and benzofuran-oxazoline ligands 6-11 containing a diphenylphosphino group at different positions of the heterocyclic skeleton have been prepared and used in the enantioselective allylation. The advantage of these new ligands is their easy accessibility and their high reactivity. The best results were obtained with ligand 9 to give the product 13 in 97.0% ee with 92% yield in 2 hours at 0°C.

Full text of DOI:10.1055/s-2002-35577

LETTER
2083
Synthesis of Novel Chiral Thiophene-, Benzothiophene- and Benzofuran-
Oxazoline Ligands and their Use in the Enantioselective Pd-Catalyzed
Allylation
Synthesis of
No
u
vel Chira
l
T
h
iophen
z
e-, Benzothiophe
F
ne- and Benzo
.
furan-Oxaz
o
T
line
L
igands ietze,* J. Klaas Lohmann
Institut für Organische Chemie der Georg-August-Universität, Tammannstraße 2, 37077 Göttingen, Germany
Fax +49(55)1399476; E-mail: ltietze@gwdg.de
Received 2 August 2002
Abstract: Novel thiophene, benzothiophene and benzofuran-ox-
azoline ligands 6–11 containing a diphenylphosphino group at dif-
ferent positions of the heterocyclic skeleton have been prepared and
used in the enantioselective allylation. The advantage of these new
ligands is their easy accessibility and their high reactivity. The best
results were obtained with ligand 9 to give the product 13 in 97.0%
ee with 92% yield in 2 hours at 0 °C.
O
R
PPh2
N
PPh2
PPh2
2 R = i-Pr
3 R = t-Bu
1
Key words: allylation, asymmetric catalysis, furan, ligands, palla-
dium, thiophene
S
S
The preparation of enantiopure compounds is one of the
main objectives in organic synthesis. Here the application
of Pd-catalyzed reactions using chiral ligands is an impor-
tant field.1 In the past years several very highly potent
ligands have been developed for these reactions such as
BINAP 1, the PHOX-ligands 2 and 3, the salen derivative
4 and BITIANP 5 (Figure 1).1–5
O
O
PPh2
PPh2
NH HN
PPh2 Ph2P
5
4
Figure 1 Chiral ligands for Pd-catalyzed reactions.
However, there is still a great need for the design of new
ligands, which may be better accessible and show a higher
reaction rate. Thus, recently we have shown that the
thiophene containing ligand 5 expresses a much higher
selectivity and reactivity in the asymmetric Heck-reac-
tion than BINAP 1.5 Here we describe novel chiral
thiophene-, benzothiophene- and benzofuran-oxazoline
ligands 6–11 and their use in the asymmetric allylation
of malonate. The ligands differ in the position of their
substituents at the heterocyclic skeleton containing a di-
phenylphosphine and the oxazoline moiety either at posi-
tion 2, 3, or 4. The ligands are easily accessible in high
yields starting from commercially available inexpensive
substrates in a few steps (Figure 2).
PPh2
PPh2
O
O
S
N
S
N
t-Bu
t-Bu
7
6
i-Pr
O
PPh2
N
O
N
PPh2
O
t-Bu
A main advantage of the use of thiophene, ben-
zothiophene and benzofuran as the backbone in 6–11 is
the simple introduction of the necessary substituents ei-
ther by direct metallation or by bromination with succes-
sive halogen metal exchange followed by reaction either
with dimethylformamide to give an aldehyde or PPh2Cl to
introduce the diphenylphosphino group. For the prepara-
tion of the oxazoline moiety6 the aldehyde was oxidized
using NaClO2 and transformed into the acid chloride
which was then treated either with (S)-tert-leucinol or (S)-
S
9
8
t-Bu
t-Bu
O
O
Ph2P
N
N
PPh2
S
S
11
10
Figure 2 Novel thiophene-, benzothiophene-, and benzofuran-oxa-
zoline ligands.
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,2083,2085,ftx,en;G21602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

2084
L. F. Tietze, J. K. Lohmann
LETTER
CO2H
valinol. The final ring closure was performed by reaction
with methanesulfonyl chloride and afterwards with KOH
in methanol (Scheme 1 and Scheme 2). The new ligands
6–11 were used in the asymmetric allylation of sodium
malonic acid dimethylester with diphenylpropenyl acetate
(12) under standard conditions using 2.5 mol% of [Pd(al-
lyl)Cl]2 and 6 mol% of the ligand in THF at –10 °C to give
13. The enantioselectivity, the yield and the reaction rate
of all transformations were very high (Scheme 3,
Table 1). However, the best results with 97.0% ee in a
reaction time of 2 hours at 0 °C and a yield of 92% were
obtained using the ligand 9 with an isopropyl group at the
oxazoline moiety (Table 1, entry 4).7,8
a,b,c
94%
d,i,f,g
66%
S
S
O
O
i-Pr
i-Pr
h
N
N
73%
S
S
PPh2
9
CO2H
O
t-Bu
d,e,f,g
76%
N
S
S
Br
Br
O
a,b,c
86%
d,e,f,g
77%
t-Bu
h
N
CO2H
PPh2
S
S
89%
S
PPh2
10
Br
O
N
h
O
N
Br
CO2H
a,b,c
83%
d,e,f,g
72%
83%
S
S
t-Bu
t-Bu
S
6
S
Br
t-Bu
d,e,f,g
76%
a,b,c
92%
O
t-Bu
O
Br
CO2H
h
Ph2P
S
N
N
S
88%
S
S
Br
PPh2
11
O
O
N
h
Scheme 2 Synthesis of ligands 9, 10 and 11. Reagents and
conditions: see Scheme 3.
86%
S
N
S
t-Bu
t-Bu
7
O
N
d,e,f,g
CO2H
2.5 mol% [Pd(allyl)Cl]2
O
78%
MeO2C
CO2Me
O
6 mol% ligand,
t-Bu
OAc
Ph
Ph
Na
CO2Me
Ph
Ph
PPh2
2 eq.
h
O
N
MeO2C
12
13
THF, –10 °C
78%
O
t-Bu
Scheme 3 Enantioselective allylation using ligands 2, 3, 6–11
8
Scheme 1 Synthesis of ligands 6, 7 and 8. Reagents and conditions:
(a) Br2, CH2Cl2, NaOAc, 0 °C; (b) n-BuLi, Et2O, –78 °C, then DMF;
(c) NaH2PO4, 2-methyl-2-butene, NaClO2, acetone/water; (d)
(COCl)2, DMF, toluene; (e) (S)-tert-leucinol, NEt3, CH2Cl2; (f) MsCl,
Et3N, CH2Cl2, 0 °C; (g) KOH, MeOH; (h) n-BuLi, Et2O, –78 °C, then
PPh2Cl; (i) (S)-valinol, Et3N, CH2Cl2, 0 °C.
ing an isopropyl group at the oxazoline moiety instead of
a tert-butyl group as in 3 and 10 cannot be given so far.
However, it is of interest that the Pd-complex formed
from 9 does not react at –10 °C, whereas the Pd-complex
formed from 10 expresses already a high reactivity at
this temperature. Summing up it can be said that the new
benzothiophene-oxazoline 9 is an excellent ligand for the
Pd-catalyzed allylation, as it gives very high ee-values, is
easily accessible, and shows a high reation rate. We are
now in the process to use the new ligands for other Pd-
catalyzed processes.
It should be mentioned that the ligand 2 described by
Pfaltz and Helmchen gave an enantiomeric excess of 99%
and 98.5% respectively, with 97% and 72% yield within 1
hour at room temperature (Table 1, entry 7). In contrast,
the application of ligand 3 and 10 containing a tert-butyl
group led to 13 with an ee of 94% at –10 °C. An explana-
tion for the better results using the ligands 2 and 9 contain-
Synlett 2002, No. 12, 2083–2085 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Chiral Thiophene-, Benzothiophene- and Benzofuran-Oxazoline Ligands
2085
(5) (a) Tietze, L. F.; Thede, K. Synlett 2000, 10, 1470.
Table 1 Asymmetric Allylation with Various Ligands
(b) Tietze, L. F.; Thede, K.; Sannicolò, F. Chem. Commun.
2000, 583. (c) Tietze, L. F.; Thede, K. Chem. Commun.
1999, 18, 1811. (d) Tietze, L. F.; Thede, K.; Sannicolò, F.
Chem. Commun. 1999, 1811.
Entry
Ligand
Time (h)
Yield (%)
ee (%)a
1
2
3
4
5
6
7
8
6
7
14
14
14
83
75
(6) Peer, M.; de Jong, J. C.; Kiefer, M.; Langer, T.; Rieck, H.;
Schell, H.; Sennhenn, P.; Sprinz, J.; Steinhagen, H.; Wiese,
B.; Helmchen, G. Tetrahedron 1996, 52, 7547.
86
88
8
89
86
(7) Synthesis of Ligand 9: To a suspension of benzothiophene-
3-carboxylic acid (1.0 g, 5.6 mmol) in DMF (0.5 mL) and
toluene (10 mL), oxalyl chloride (2.13 g, 16.8 mmol) was
added dropwise at 0 °C with stirring, which was continued
for 3 h at r.t. The solvent was removed in vacuo and the
crude acid chloride dissolved in CH2Cl2 (20 mL). This
solution was added dropwise to a mixture of (S)-valinol (865
mg, 6.7 mmol) and Et3N (1.41 g, 14 mmol) in CH2Cl2 (50
mL). After stirring overnight, 1 N HCl (50 mL) was added,
the aqueous phase extracted twice with CH2Cl2 (50 mL) and
the combined organic layers dried over MgSO4. The solvent
was removed in vacuo and the residue dissolved in CH2Cl2
(50 mL). After the addition of NEt3 (1.41 g, 14 mmol) the
solution was cooled to 0 °C and MsCl (767 mg, 6.7 mmol)
added dropwise. After complete conversion (TLC, n-
pentane/EtOAc = 1:1) the solvent was removed in vacuo,
MeOH (20 mL) added followed by powdered KOH (1.56 g,
28 mmol) and the mixture stirred for 3 h. After removal of
methanol in vacuo water (60 mL) was added and the mixture
extracted with ether (2 50 mL). Drying of the organic
layers over MgSO4 gave the crude oxazoline, which was
purified by column chromatography (Et2O/pentane = 1:10)
to afford 900 mg (3.7 mmol, 66% over 3 steps) of a yellow
oil, which solidified at –20 °C. The oxazoline was dissolved
in dry Et2O (50 mL) and treated with n-BuLi (4.1 mmol of a
2.2 M solution in hexane) at –78 °C. After 5 min PPh2Cl
(977 mg, 4.4 mmol) was added and the cooling bath
removed with continuation of stirring for 1 h. Afterwards the
solvent was removed in vacuo and the residue purified by
column chromatography (n-pentane:Et2O = 10:1) to give
b
9
2
92
97.0
10
11
2
6
14
1c
91
94
89
86
97/72
79
99/98.53c,d
94
3
14
a Determined by chiral HPLC using a chiracel OD-column with
hexane/isopropanol 99:1 as eluent.
b Reaction was carried out at 0 °C.
c Reaction at r.t.
Acknowledgment
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 BASF AG, the
Bayer AG, the Degussa AG, the Dragoco Gerberding & Co. AG,
Wacker-Chemie GmbH for generous gifts of chemicals.
References
(1) Reviews: (a) Helmchen, G.; Pfaltz, A. Acc. Chem. Res.
2000, 33, 336. (b) Johannsen, M.; Jørgensen, K. A. Chem.
Rev. 1998, 98, 1689. (c) Shibasaki, M.; Boden, C. D. J.;
Kojima, A. Tetrahedron 1997, 53, 7371. (d) Trost, B. M.;
Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(2) (a) Oestreich, M.; Dennison, P. R.; Kodanko, J. J.; Overman,
L. E. Angew. Chem. Int. Ed. 2001, 40, 1439. (b) Ashimori,
A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem.
Soc. 2000, 122, 192. (c) Ashimori, A.; Overman, L. E. J.
Org. Chem. 1992, 57, 4571.
(3) (a) Bergner, E. J.; Helmchen, G. Eur. J. Org. Chem. 2000,
5072. (b) Schleicher, S.; Helmchen, G. Eur. J. Org. Chem.
1999, 5072. (c) Pfaltz, A.; von Matt, P. Angew. Chem., Int.
Ed. Engl. 1993, 32, 566. (d) Helmchen, G.; Sprinz, J.
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(4) (a) Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L.
J. Am. Chem. Soc. 2000, 122, 5968. (b) Trost, B. M.; Oslob,
J. D. J. Am. Chem. Soc. 1999, 121, 3057.
20
ligand 9, as a white foam (1.15 g, 2.7 mmol, 73%). [ ]D
–72.5 (c 1.0, CHCl3); Rf 0.26 (n-pentane/Et2O = 10:1);
1H NMR (300 MHz, CDCl3): = 0.80 (d, J = 7.0 Hz, 3 H,
CH3), 0.89 (d, J = 7.0 Hz, 3 H, CH3), 1.64 (oct, J = 7.0 Hz,
1 H, CHMe2), 3.87 (t, J = 8.0 Hz, 1 H, 4-Ha), 3.98 (ddd,
J = 9.0, 8.0, 7.0 Hz, 1 H, 3-H), 4.14 (dd, J = 9.0, 8.0 Hz, 1 H,
4-Hb), 7.27–7.48 (m, 12 H, Ph-H, 5 -H, 6 -H), 7.66 (d,
J = 8.0 Hz, 1 H, 4 -H*), 8.56 (d, J = 8.0 Hz, 1 H, 7-H*), (the
assignments of the signals with an asterisk may have to be
exchanged); 13C NMR (150 MHz, CDCl3): = 18.39 (CH3),
18.67 (CH3), 32.82 [CH(CH3)2], 69.50 (C-3 ), 72.37 (C-4 ),
123.39 (C-H), 124.58 (Ph-C4), 124.59 (Ph-C4), 124.80 (CH),
127.95 (d, J = 16.4 Hz, C-3), 128.26 (d, J = 2.7 Hz, Ph-C3),
128.31 (d, J = 2.3 Hz, Ph-C3), 129.00 (C-H), 129.20 (C-H),
133.46 (d, J = 20.9 Hz, Ph-C2), 133.87 (d, J = 21.0 Hz, Ph-
C2), 136.74 (d, J = 9.9 Hz, Ph-C1), 137.05 (d, J = 10.3 Hz,
Ph-C1), 139.39 (d, J = 2.1 Hz, C-3a), 141.69 (C-7a), 147.55
(d, J = 41.8 Hz, C-2), 159.47 (d, J = 3.3 Hz, C-1 ); 31P NMR
(80 MHz, CDCl3): = –13.19; MS (EI): m/z = 429 (M+), 358,
338; Anal. Calcd for C26H24NOPS: C, 72.70; H, 5.63%.
Synlett 2002, No. 12, 2083–2085 ISSN 0936-5214 © Thieme Stuttgart · New York