and chemical yield, e.g., 97% ee, 53% yield for E ) PPh2
(3f), without recrystallization.15
Table 1. n-BuLi/(-)-Sparteine-Induced Mono-metalation of
1,1′-N,N,N′,N′-Tetraisopropylferrocenedicarboxamide (1)
Reduction of the amount of (n-BuLi/2) to 2.2 equiv caused
a slight decline in the chemical yield of the product but did
not lead to erosion of ee (entry 8). The heteroatom-hinged
phenyl derivatives 3f-h (entries 11-13) were found to
surrender their optical integrity on standing in solution.4,16
To demonstrate the combined potential of the DoM-cross
coupling strategy as a route to aryl-substituted ferrocenes,17
the iodo (3a) and stannane (3e) ferrocene diamides were
subjected to Suzuki18 and Stille/Gronowitz19 cross coupling
entry
E+
product
solvent
yield, %
ee, %
1
2
3
4
5
6
7
8
9
10
11
12
13
14
I2
I2
I2
MeI
MeI
Ph2CdO
Ph2CdO
Ph2CdO
Et2CdO
Bu3SnCl
Ph2PCl
(PhS)2
3a
3a
3a
3b
3b
3c
3c
3c
3d
3e
3f
Et2O
53
77
70
56
71
77
92
72a
45
58
53
71
82
68a
59
70
89
68
92
64
94
96
91
g82b
97c
89c
71c
d
t-BuOMe
PhMe
Et2O
PhMe
Et2O
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
(6) (a) Suzuki, A. In Metal-catalyzed Cross-coupling Reactions; Dieder-
ich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, p 49. (b) Mitechell, T.
N. ref 6a, p 167.
(7) Recently, Jendralla reported a synthesis of optically pure C2-
symmetric 2,2′-bis(diphenylphosphino)-1,1′-ferrocenedicarboxamide: Jen-
dralla, H.; Paulus, E. Synlett 1997, 471.
(8) (a) Hayashi. T., Togni, A. Eds. Ferrocenes: Homogeneous Catalysis,
Organic Synthesis, Material Science; VCH: Weinheim, 1995. (b) Kagan,
H. B.; Riant, O. AdV. Asymm. Synth. 1997, 2, 189. (c) Ojima, I. Catalytic
Asymmetric Synthesis; VCH Publishers: New York; 1993.
(9) An asymmetric hydrogenation in the synthesis of (+)-biotin by
Lonza: McGarrity, J.; Spindler, F.; Fuchs, R.; Eyer, M. (LONZA AG),
EP-A 624 587-A2,1995; Chem. Abstr. 1995, 122, P81369q. Togni, A.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1475. Ciba-Geigy AG (Novartis)
multiton synthesis of the herbicide (S)-Metolachlor: Spiendler, F.; Pugin,
B.; Jalett, H.-P.; Buser, H.-P.; Pittelkow, W.; Blasser, H.-U. In Catalysis
of Organic Reactions; Malz, R. E., Ed.; Marcel Dekker: New York, 1996,
p 153. Spiendler, F.; Pugin, B. (Ciba-Geigy AG), EP-A 0 256982, 1988;
Chem. Abstr. 1990, 112, 138725c.
3g
3h
3i
(PhSe)2
TMSCl
a 2.1 equiv of both n-BuLi and 2 was used. b Enantiomeric resolution
was not feasible, and ee was determined after conversion into 3c by
transmetalation with n-BuLi followed by benzophenone quench. c Undergoes
racemization; therefore, % ee determination was carried out immediately
after purification. d CSP HPLC enantiomeric resolution was not feasible,
[R]23 +67.5 (c 0.54, CHCl3).
578
metric metalation of 2-substituted 1,1′-N,N,N′,N′-tetraiso-
propylferrocenedicarboxamides 3f,g,i7 which results in dia-
stereoselective amplification of enantioselectivity. We also
report preliminary findings which show the potential of tri-
(3) and tetrasubstituted (dl-4) ferrocene ligands in benchmark
asymmetric alkylation and Pd-catalyzed allylic substitution
reactions (Scheme 3).
These results are of potential significance in areas of
asymmetric catalysis, enantioselective synthesis, and material
science,8 including spectacular industrial applications, wherein
planar chiral ferrocenes are receiving flourishing application.9
Metalation of ferrocenyldiamide 110 with n-BuLi/2 in Et2O
furnished, almost exclusively, products from electrophilic
trapping of monolithium anion, the 1,1′,2-trisubstituted
derivatives 3a-c, in good yields but with moderate enantio-
selectivities (Table 1 entries 1, 4, and 6).11,12 Use of solvents
of lower coordinating abilities allowed for the preparation
of 1,1′,2-trisubstituted derivatives13 in augmented optical and
chemical yields (entries 1-3).14 Toluene was found to give
the optimal balance between the level of enantioinduction
(10) Prepared from 1,1′-ferrocenedicarboxylic acid (Aldrich), by sequen-
tial treatment with (COCl)2/cat. DMF/PhMe and HN(i-Pr)2/Et2O in 80%
yield after recrystallization (Et2O/hexane).
(11) In initial trials, double DoM-electrophile quench (2 equiv of
s-BuLi/2 in Et2O/-78 °C/2 h and then 6 equiv of E+/-78 °C to rt, 4 h) led
to high yields of the 1,1′,2,2′-tetrasubstituted derivatives 4; however, the
reaction exhibited a prohibitively strong preference for the meso diastereomer
and low levels of optical induction (e.g., E+ ) MeI 70% yield, meso:dl )
76:24, 53% ee; E+ ) TMSCl (4b) 99% yield, meso:dl ) 96:4, 15% op (op
) optical purity); E+ ) PPh2Cl (4a) 49% yleid, meso:dl ) >95:<5) (For
other data, see Laufer, R. M.Sc. Thesis, University of Waterloo, 1998).
(12) Notably, n-BuLi‚2 is capable of effecting a double deprotonation
of 1 but only in the presence of TMSCl as the electrophilic partner (e.g. in
PhMe 71% yield of 4b, dl:meso ) 72:28, 97% op (Laufer, R. M.Sc. Thesis,
University of Waterloo, 1998).
(13) (S) absolute configuration for carbinol 3c was established by single-
crystal X-ray crystallography. Crystal data for 3c: C37H46FeN2O3, M )
624.4, orthorhombic, P212121, a ) 10.100(1) Å, b ) 17.098(1) Å, c )
19.335(2) Å, V ) 3338.9(8) Å3, Z ) 4; Dc ) 1.242 g/cm3, F(000) ) 1332,
T ) 160 K. Data were collected on a Siemens P4 diffractometer with Mo
KR radiation (λ ) 0.710 73 Å); 6416 reflections were collected giving 3208
Friedel pairs. The structure was solved using Patterson and Fourier routines
(SHELXTL IRIS) and refined by full-matrix least-squares on F resulting
in final R, Rw, and GOF (for 5445 data with F > 6.0σ(F)) of 0.0238, 0.0272,
and 2.05, respectively, for solution using the (S) model. The corresponding
values for solution of the (R) model were 0.0433, 0.0492, and 3.70.
(14) Typical procedure for lithiation of 1: A solution of (-)-sparteine
(0.91 mL, 4.2 mmol) or TMEDA (0.64 mL, 4.20 mL) in PhMe (20 mmol)
was stirred at rt (5 min), cooled to -78 °C, and treated with n-BuLi (solution
in hexane, 4.2 equiv). After 10 min of stirring at -78 °C, a solution of 1
(0.44 g, 1.0 mmol) in PhMe (4.5 mL) was added dropwise (ca. 1 drop/10
s). The stirring was continued (1-2 h) at -78 °C, and the reaction mixture
was quenched by addition of an electrophile (6 mmol) and allowed to warm
to rt (or 0 °C for 3f), treated with saturated aqueous NH4Cl, extracted with
Et2O or CH2Cl2, washed with brine, dried (MgSO4), concentrated in vacuo,
and purified by flash chromatography on silica gel (deactivated with 2%
Et3N for diphenylphosphine derivative 3f). Diphenylphosphine derivatives
3f and 4a were found to be air-sensitive but could be stored indefinitely as
solids under argon at -20 °C.
Table 2. n-BuLi/(-)-Sparteine-Induced Mono-metalation of
2-Substituted-1,1′-N,N,N′,N′-tetraisopropylferrocenedicarboxamide
(3f,g,i)
(SM) ee, %
E+
product
yield,%
dl:meso
ee, %
(3i) 0
(3i) c
(3f) 97
(3g) 89
TMSCla
TMSCld
Ph2PCle
4b
4b
4a
4c
86
75
45
60
51:49
84:16
>95:<5f
99:1
72b
91b
98b,7
97g
(15) Toluene offers greatly improved solubility of ferrocenyldiamide 1.
The opposite solvent effect was observed in (-)-sparteine-assisted DoM
of N,N-diisopropylferrocenecarboxamide (ref 4).
a
(PhS)2
a 2.1 equiv of n-BuLi/2 was used. b Determined as optical purity (op).
(16) Derivative 3g undergoes racemization at rt, t1/2 ≈ 9 h at rt (either
c [R]23 +67.5 (c 0.54, CHCl3). d 4.2 equiv of n-BuLi/2 was used. e 1.5
578
in 90:10 or 98:2 hexane:i-PrOH).
equiv of n-BuLi/2 was used. f dr determined by 31P NMR. g dr and ee
(17) Quesnelle, C. A.; Familioni, O. B.; Snieckus, V. Synlett 1994, 349
and references therein.
determined using CSP HPLC.
(18) Pd(PPh3)4/ 2M aqueous Na2CO3/DME/85 °C/5 d.
630
Org. Lett., Vol. 2, No. 5, 2000