Regio- and enantio-selective Heck reactions of aryl and alkenyl triflates with the new chiral ligand (R)-BITIANP

Article abstract of DOI:10.1039/a905309c

The Heck reaction of dihydrofuran 3 with aryl triflates 4 and 6a-d and alkenyl triflate 8 in the presence of the chiral ligand (R)-BITIANP 1 provides the 2-substituted 2,3-dihydrofurans 5a, 7a-d and 9, respectively, with complete regioselectivity, high en

Full text of DOI:10.1039/a905309c

Regio- and enantio-selective Heck reactions of aryl and alkenyl triflates with
the new chiral ligand (R)-BITIANP
Lutz F. Tietze,*a Kai Thedea and Franco Sannicolo`b
a
Institut fu¨r Organische Chemie der Universita¨t Tammannstraße 2, D-37077 Go¨ttingen, Germany.
E-mail: ltietze@gwdg.de
b
Dipartimento di Chimica Inorganica, Metallorganica e Analitica, Universita` di Milano, Via Venezian 21, I-20133
Milano, Italy
Received (in Liverpool, UK) 29th June 1999, Accepted 29th July 1999
The Heck reaction of dihydrofuran 3 with aryl triflates 4 and
6a–d and alkenyl triflate 8 in the presence of the chiral
ligand (R)-BITIANP 1 provides the 2-substituted 2,3-dihy-
drofurans 5a, 7a–d and 9, respectively, with complete
regioselectivity, high enantioselectivity (86–96% ee) and
good yields (76–93%).
triflates 4, 6a–d and 8. In principle, the Heck reaction of
dihydrofuran 3 with phenyl triflate 4 leads to the two isomers 5a
and 5b (Scheme 1). Using BINAP7 the regioselectivity is rather
low, whereas with a substituted MeO-BIPHEP8 ligand a 22+1
ratio of 5a and 5b was obtained, and with chiral phosphino-
oxazolines9 only 5b is obtained.10
We have now shown that the Heck reaction of 3 and 4 in
DMF at 90 °C using Pd2dba3·dba and the new chiral ligand 1
employing a Pd ligand ratio of 1+2 and 1,8-bis(dimethylamino)-
naphthalene (proton sponge) as the base affords 5a exclusively
in 84% yield and 91% ee within 18 h (Table 1, entry 1).† Similar
results were obtained using Pri2NEt as base (entry 2); however,
with THF as solvent at 70 °C the transformation was less
selective and much slower. Even after 7 days the reaction was
not complete (entry 3). Interestingly, (R)-BINAP as chiral
ligand using the best conditions found for the transformation
with 1 gave 5a with a 3+1 regioselectivity and only 42% ee
(entry 4). The use of the second new ligand (+)-TMBTP 2 was
only marginally successful. Here the regioisomer 5b was
obtained preferentially, but with very poor ee values (entries
5–7).
In the presence of the ligand (R)-BITIANP 1, other phenyl
triflates 6a–d containing either an electron-withdrawing or an
electron-donating group also reacted with high regio- and
enantio-selectivities (Scheme 2, Table 2). In addition alkenyl
triflates could be transformed successfully; thus, the Pd
catalyzed reaction of cyclohex-1-enyl triflate 8 with dihy-
drofuran 3 provides exclusively the dihydrofuran derivative 9
within 13 h with good yield and high enantioselectivity.
The described Heck reactions with the new chiral ligand (R)-
BITIANP 1 have shown that this ligand has an excellent
potency and may serve as a useful alternative to the ligands
One of the main objectives in modern synthetic organic
chemistry is the catalytic enantioselective formation of C–C
bonds. In this respect, the Heck reaction1—the Pd0 catalyzed
coupling of an aryl or alkenyl halide or triflate with an alkene—
is a highly versatile procedure since it tolerates several
functional groups. In the years since the first enantioselective
Heck reactions in 1989, published by Shibasaki2 and Overman,3
several novel chiral ligands have been developed which give
high enantioselectivities and which have been used in natural
product syntheses.4 However, one of the problems encountered
in the use of chiral ligands, especially in intermolecular Heck
reactions, is the often low reactivity of the formed Pd
complexes.5 Therefore it is important to develop novel ligands
and show their applicability in C–C bond formation. Here we
report on the use of the new chiral ligands (R)-(+)-2,2A-
bis(diphenylphosphino)-3,3A-bi(benzo[b]thiophene) [(R)-BI-
TIANP] 1 and (+)-4,4A-bis(diphenylphosphino)-2,2A,5,5A-tetra-
methyl-3,3A-bithiophene [(+)-TMBTP] 2 in Heck reactions;
ligand 1 has been employed with great success in the
hydrogenation of C–C and C–O bonds,6 whereas ligand 2 has
not been used so far for enantioselective transformations.
To allow a comparison with other chiral ligands we
investigated the Heck reactions of dihydrofuran 3 with the
Scheme 1
Table 1 Enantioselective Heck reactions of 3 and 4 providing 5a and 5b
Yield (%)
Ee (%)b
Pd2dba3·dba/
mol%
Ligand
(mol%)
Base
(equiv.)
Conversiona
Ratioa
Solvent T/°C
t
(4+5a + 5b)
5a+5b
5a
5b
5a
5b
1
2
3
4
5
6
7
3
3
5
3
5
5
5
BITIANP 1 (12)
BITIANP 1 (12)
BITIANP 1 (10)
BINAP (12)
TMBTP 2 (10)
TMBTP 2 (10)
TMBTP 2 (10
PS (3)c
DMF
DMF
THF
DMF
DMF
THF
90
90
70
90
90
70
70
18 h
20 h
7 d
18 h
3 d
< 1+100
< 1+100
16+84
100+ < 1
100+ < 1
7+1
84
90
62
58
27
54
73
—
—
—
20
58
19
12
91
90
80
42
4
Pri2 NEt (3)
Pri2NEt (3)
PS (3)c
< 1+100
< 1+100
1+22
3+1
33
2
10
0
Pri2NEt (3).
Pri2NEt (3)
PS (3)c
1+2
4 d
4 d
3+1
14
4
C6H6
1+26
6+1
a Determined by GC. b Determined by chiral GC. c PS = Proton sponge = 1,8-bis(dimethylamino)naphthalene.
Chem. Commun., 1999, 1811–1812
1811

1,8-bis(dimethylamino)naphthalene (142.1 mg, 0.663 mmol, 3 equiv.) in
dry and degassed DMF (5 ml) was stirred for 0.5 h at 40 °C until an orange
solution was formed. Then 4 (50.0 mg, 0.221 mmol) and 3 (77.5 mg, 1.105
mmol, 5 equiv.) were added and the mixture was stirred for 18 h at 90 °C
until the reaction was complete [GC analysis; SGE BPX-5% phenyl (equiv.)
polysilphenylene-siloxane, 50 m, 60–160 °C, 5 °C min21, 50 kPa: tR = 8.8
min (4), tR = 15.1 min (5a)]. The red solution was filtered through a batch
of silica gel, eluted with Et2O (100 ml), concentrated, diluted with the same
volume of water and extracted with Et2O (3 3 30 ml). The organic layers
were combined, washed with water and brine and dried over Na2SO4.
Removal of the solvent in vacuo and purification of the residue by column
chromatography (silica gel, 2 3 25 cm, light petroleum–CH2Cl2 3+1) gave
(R)-(2)-5a (27.0 mg, 84%) as a colourless oil, [a]D 261.5 (c 2.30, CHCl3,
20 °C, 91% ee according to GC). GC [octakis(6-O-methyl-2,3-di-O-
pentyl)-g-cyclodextrin (50% in OV 1701 w/w), 25 m, 70–100 °C, 1 °C
min21, 50 kPa]: 13.1 min (S)-5a, 14.4 min (R)-5a.
1 Reviews: M. Shibasaki, C. D. J. Boden and A. Kojima, Tetrahedron,
1997, 53, 7371; E. Negishi, C. Coperet, S. Ma, S.-Y. Liou and F. Liu,
Chem. Rev., 1996, 96, 365; W. Cabri and I. Candiani, Acc. Chem. Res.,
1995, 28, 2; A. de Meijere and F. E. Meyer, Angew. Chem., Int. Ed.
Engl., 1994, 33, 2379; H.-G. Schmalz, Nachr. Chem. Tech. Lab., 1994,
42, 270; R. F. Heck, Palladium Reagents in Organic Synthesis,
Academic Press, London, 1985.
Scheme 2
2 Y. Sato, M. Sodeoka and M. Shibasaki, J. Org. Chem., 1989, 54,
4738.
Table 2 Enantioselective Heck reaction with the aryl triflates 4, 6a–d and
the alkenyl triflate 8
3 N. E. Carpenter, D. J. Kucera and L. E. Overman, J. Org. Chem., 1989,
54, 5846.
4 L. F. Tietze and T. Raschke, Liebigs Ann. Chem., 1996, 1981; L. F.
Tietze and T. Raschke, Synlett, 1995, 597; T. Ohshima, K. Kagechika,
M. Adachi, M. Sodeoka and M. Shibasaki, J. Am. Chem. Soc., 1996,
118, 7108; L. E. Overman, Pure Appl. Chem., 1994, 66, 1423.
5 S. Y. Cho and M. Shibasaki, Tetrahedron Lett., 1998, 39, 1773.
6 P. Antognazza, T. Benincori, E. Brenna, E. Cesarotti, L. Trimarco and
F. Sannicolo`, EP 0770085 to Chemi SpA (Chem. Abstr., 1996, 124,
317487w); T.Benincori, E. Brenna, F. Sannicolo`, L. Trimarco, P.
Antognazza, E. Cesarotti, F. Demartin and T. Pilati, J. Org. Chem.,
1996, 61, 6244.
Yield
(%)
Ee
Entry
R
Substrate Product t/h
(%)a
1
2
3
4
5
6
H
Cl
MeO
CN
MeCO
—
4
5a
7a
7b
7c
7d
9
18
18
18
24
24
13
84
87
84
91
93
76
91
94
90
96
95
86
6a
6b
6c
6d
8
7 F. Ozawa, A. Kubo, Y. Matsumoto and T. Hayashi, Organometallics,
1993, 12, 4188; F. Ozawa, Y. Kobatake and T. Hayashi, Tetrahedron
Lett., 1993, 34, 2505.
8 G. Trabesinger, A. Albinati, N. Feiken, R. W. Kunz, P. S. Pregosin and
M. Tschoerner, J. Am. Chem. Soc., 1997, 119, 6315.
9 O. Loiseleur, M. Hayashi, N. Schmees and A. Pfaltz, Synthesis, 1997,
1338; O. Loiseleur, P. Meier and A. Pfaltz, Angew. Chem., Int. Ed.
Engl., 1996, 35, 200.
10 For further investigations about Heck reactions with dihydrofurans, see
K. K. Hii, T. D. W. Claridge and J. M. Brown, Angew. Chem., Int. Ed.
Engl., 1997, 109, 984; S. Hillers and O. Reiser, Chem. Commun., 1996,
2197; S. Hillers, S. Sartori and O. Reiser, J. Am. Chem. Soc., 1996, 118,
2087.
a Determined by chiral GC.
described by Hayashi,7 Pfaltz,9 Pregosin8 and Shibasaki5 with
the special advantage of high reactivity.
The work was supported by the Deutsche Forschungsge-
meinschaft (SFB 416) and the Fonds der Chemischen Industrie.
We thank the Degussa AG for a generous gift of precious metals
and Dr S. Console, Chemi SpA, Italy, for a gift of the
ligands.
Notes and references
† Typical experimental procedure: A mixture of Pd2dba3·dba (7.6 mg, 6.63
mmol, 3 mol%), (R)-BITIANP 1 (16.8 mg, 26.5 mmol, 12 mol%) and
Communication 9/05309C
1812
Chem. Commun., 1999, 1811–1812