SCHEME 3. Synthesis of All Isomers 1-4a
SCHEME 4. Synthesis of a 2,2′-Bipyridine
Analoguea
a Reagents and conditions: (a) (i) n-BuLi-LiDMAE (3 equiv),
hexane, 0 °C, 1 h; (ii) C2Cl6 (3.5 equiv), THF, -78 °C, 1 h. (b) (i)
n-BuLi-LiDMAE (3 equiv), hexane, 0 °C, 1 h; (ii) CBr4 (3.5 equiv),
THF, -78 °C, 1 h. (c) (i) 5 (1 equiv), sec-BuLi; (ii) ZnCl2; (iii) 23 (1
equiv), PdCl2(PPh3)2 (5 mol %), THF, rt, 10 h; (iv) p-TSA (1 equiv),
THF, H2O, rt, 2 h. (d) t-BuOK (2 equiv), DMF, rt, 2 h. (e)
NiCl2‚6H2O (1 equiv), PPh3 (4 equiv), Zn (1 equiv), DMF, 50 °C, 3
h.
a Reagents and conditions: (a) (i) sec-BuLi; (ii) ZnCl2; (iii) 13 (1
equiv), PdCl2(PPh3)2 (5 mol %), THF, rt, 10 h; (iv) p-TSA (1 equiv),
THF, H2O, rt, 2 h. (b) (i) sec-BuLi; (ii) ZnCl2; (iii) 14 (1 equiv),
PdCl2(PPh3)2 (5 mol %), THF, rt, 10 h; (iv) p-TSA (1 equiv), THF,
H2O, rt, 2 h. (c) (i) sec-BuLi; (ii) ZnCl2; (iii) 15 (0.5 equiv), Pd2(dba)3
(5 mol %), dppf (5 mol %), THF, 65 °C, 10 h; (iv) p-TSA (1 equiv),
THF, H2O, rt, 2 h. (d) (i) sec-BuLi; (ii) ZnCl2; (iii) 16 (1 equiv),
Pd2(dba)3 (2.5 mol %), P(2-furyl)3, THF, rt, 10 h. (e) (i) Me4Sn (2
equiv), Pd(PPh3)4 (5 mol %), DMF, 100 °C, 20 h; (ii) p-TSA (1
equiv), THF, H2O, rt, 2 h. (f) t-BuOK (2 equiv, 1 equiv in the case
of 18), DMF, rt, 2 h.
SCHEME 5. Asymmetric Synthesis of 1a
One other advantage for using picolines as starting
material for this synthesis was the expertise of our
laboratory in the functionalization of such compounds
using the superbase n-BuLi-LiDMAE (lithium dimethy-
laminoethoxide).19 This method allowed us to introduce
successively a chlorine and a bromine atom in the 2- and
6-positions of 3-picoline 21 (Scheme 4). The resulting
compound 23 was then used to synthesize in three steps
one analogue of 2,2′-bipyridine. The Negishi protocol
between 23 and 5 followed by deprotection of the acetal
furnished 24, which was cyclized to yield 25. Homocou-
pling of 25 in the presence of a nickel complex20 allowed
the formation of both diastereoisomers of 26, the meso
and the dl, in a 1:1 mixture, as shown by 1H NMR
analysis.21
a Reagents and conditions: (a) (i) t-BuLi, Et2O, -78 °C to rt, 1
h; (ii) ZnCl2, THF, -78 °C to rt, 1 h; (iii) 13 (1 equiv), PdCl2(PPh3)2
(5 mol %), THF, rt, 10 h; (iv) p-TSA (1 equiv), THF, H2O, rt, 2 h.
(b) t-BuOK (2 equiv), DMF, rt, 2 h.
and coupled with 13 to furnish (R)-17, which was cyclized
in the presence of t-BuOK to give (S)-1 in moderate yield.
In conclusion, the present study reveals an easy access
to all isomers of the chiral ferroceno-(iso)quinolines. The
synthetic protocol described in this paper is simple and
convenient and has been applied to the asymmetric
synthesis of ferroceno[h]quinoline 1 and to the synthesis
of the bipyridine analogue 26. The functionalization of
these new molecules as well as the activity of the
enantiopure forms in asymmetric synthesis and catalysis
is in progress in our laboratory.
To prove the viability of this method for the asym-
metric synthesis of these new ferrocenylpyridine deriva-
tives, we performed the synthesis of (S)-1 (Scheme 5).22
Following the procedure used previously, 27 was ortholithi-
ated diastereoselectively,23 transmetalated with ZnCl2,
Experimental Section
Representative Procedure for the Negishi Cross-Cou-
pling Reaction. Preparation of 2-(3-Methylpyridin-2-yl)-
ferrocenecarbaldehyde (17). To a solution of 5 (816 mg, 3.0
(19) (a) Mathieu, J.; Gros, P.; Fort, Y. Chem. Commun. 2000, 951-
952. (b) Gros, P.; Viney, C.; Fort, Y. Synlett 2002, 628-630. (c)
Kaminski, T.; Gros, P.; Fort, Y. Eur. J. Org. Chem. 2003, 3855-3860.
For a review see: Gros, P.; Fort, Y. Eur. J. Org. Chem. 2002, 3375-
3383.
(22) The stereochemistry is given according to the Schlo¨gl rule:
Schlo¨gl, K. Top. Stereochem. 1967, 1, 39-93.
(23) (a) Riant, O.; Samuel, O.; Kagan, H. B. J. Am. Chem. Soc. 1993,
115, 6733-6745. (b) Riant, O.; Samuel, O.; Flessner, T.; Taudien, S.;
Kagan, H. B. J. Org. Chem. 1997, 62, 6733-6745.
(20) Tiecco, M.; Testaferri, L.; Tingoli, M.; Chianelli, D.; Montanucci,
M. Synthesis 1984, 736-738.
(21) One diastereoisomer has been isolated by chromatography on
silica gel and characterized.
8222 J. Org. Chem., Vol. 70, No. 20, 2005