Ferrocenyl-QUINAP: A planar chiral P,N-ligand for palladium-catalyzed allylic substitution reactions

Article abstract of DOI:10.1016/j.tetasy.2005.12.001

The new planar chiral P,N-ligands 1a and 1b were prepared via a straightforward enantioselective synthesis using a Negishi cross-coupling and a sulfoxide/lithium exchange. Ligand 1a was successfully applied to Pd-catalyzed allylic alkylation (86% ee) and

Full text of DOI:10.1016/j.tetasy.2005.12.001

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 116–123
Ferrocenyl-QUINAP: a planar chiral P,N-ligand
for palladium-catalyzed allylic substitution reactions
Ralf J. Kloetzing and Paul Knochel*
Department of Chemistry and Biochemistry, Ludwig-Maximilians-University, Butenandtstrasse 5-13, 81377 Munich, Germany
Received 2 November 2005; accepted 1 December 2005
Abstract—The new planar chiral P,N-ligands 1a and 1b were prepared via a straightforward enantioselective synthesis using a Negi-
shi cross-coupling and a sulfoxide/lithium exchange. Ligand 1a was successfully applied to Pd-catalyzed allylic alkylation (86% ee)
and amination (83% ee) reactions.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Enantioselective synthesis using metal complexes with
chiral ligands has been a growing field of interest in or-
ganic chemistry over the past decades.1 P,N-Ligands are
the most widely used heterodentate ligands,2 and they
can be classified according to their elements of chiral-
ity.2b Various ligands with central,3 axial,4 and planar5
chirality have been reported. A ferrocene scaffold allows
a unique combination of planar and central chirality.6
However, in many cases the configuration of the stereo-
genic center in the side chain directs the configuration of
the planar chirality. Thus, these elements of chirality
cannot be varied independently. Herein, we have de-
signed a new planar chiral ferrocene-based P,N-ligand
1a, which only possesses a plane of chirality. This allows
us to look at the effect of the planar chirality on the per-
formance of ferrocenyl ligands without the interference
of a stereogenic center in the side chain. The structure
of this planar chiral 1,2-disubstituted ferrocenyl ligand
1a is related to the axial chiral QUINAP ligand,7 which
is one of the most successful P,N-ligands and has found
widespread application in asymmetric catalysis (Scheme
1).8 For example, QUINAP is an excellent ligand for the
copper-catalyzed enantioselective three-component syn-
thesis of chiral propargyl amines which was recently
developed in our laboratory (Scheme 2).9
N
N
PPh2
PPh2
Fe
1a
QUINAP
Scheme 1. Design of the new ligand.
Carreira has reported a readily available diastereomeric
biaryl P,N-ligands (PINAP), which can replace QUI-
NAP for several applications including the synthesis of
propargyl amines described above.4a
Herein, we report the synthesis of a new P,N-ligand 1a
as a QUINAP analogue bearing a plane of chirality in-
stead of an axis of chirality. As an advantage, we expect
that the planar chiral ferrocene exhibits a higher stabil-
ity toward racemization and should therefore be config-
urationally stable. Furthermore, this approach allows a
stereoselective synthesis avoiding resolution processes. It
has recently been shown that a planar chiral ferrocenyl
diphosphine can serve as a BINAP analogue as it forms
axially chiral complexes upon complexation to transi-
tion metals.10
A drawback for the use of QUINAP is its difficult reso-
lution via diastereomeric Pd-complexes.7a Recently,
2. Synthesis
The new P,N-ligand 1a was readily prepared by a
straightforward enantioselective synthesis using Kaganꢀs
sulfoxide11 2. It offers a general possibility of controlling
*
Corresponding author. Tel.: +49 (0)89 2180 77681; fax: +49 (0)89
2180 77680; e-mail: paul.knochel@cup.uni-muenchen.de
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.001

R. J. Kloetzing, P. Knochel / Tetrahedron: Asymmetry 17 (2006) 116–123
117
O
NBn2
CuBr (5 mol%), toluene, r.t.
SiMe3 HNBn2
H
SiMe3
72%, 98% ee
N
PPh2
(5.5 mol%)
Scheme 2. Application of QUINAP: enantioselective three-component synthesis of propargyl amines.
the planar chirality of 1,2-disubstituted ferrocenes by
a directed ortho-lithiation with LDA, which proceeds
with 98% de.12 The resulting ferrocenyllithium was
transmetalated to zinc and a subsequent Negishi
cross-coupling13 with 1-iodoisoquinoline14 3 furnished
intermediate 5a in 78% yield (Scheme 3). Similarly,
ferrocenyl sulfoxide 5b was prepared using 8-bromo-
quinoline15 4 in 79% yield.
on the chiral sulfoxide 9 using iodine as electrophile
(Scheme 5).
Table 1 shows that the ratio of the desired product 10
and the protonated by-product 11 obtained after sulf-
oxide/lithium exchange with tert-butyllithium is highly
dependent on the temperature. While at ꢀ90 °C (entry
1) an unfavorable ratio was obtained, with the results
improving when the temperature was raised to ꢀ30 °C
leading to a ratio of 95:5 (entry 3). At a higher tempera-
ture (0 °C, entry 4), a larger amount of protonated
by-product 11 was formed. Interestingly, an acceptable
ratio of the desired product and protonated by-product
was obtained, if the reaction was performed with an
inverse addition at ꢀ78 and ꢀ50 °C (entries 5 and 6).
Further lithium reagents were tested for this reaction.
Very unfavorable results were obtained with n-butyl-
lithium (entry 7), due to the acidic protons in the resulting
sulfoxide. By using phenyllithium, the reaction pro-
ceeded unexpectedly well (entry 8). Sulfoxide 9 was con-
verted to the lithium-reagent within 10 min at ꢀ78 °C
and the desired product 10 was obtained in 87% yield
We thought to use a sulfoxide/lithium exchange for
further functionalization of the ferrocenes 5a and 5b.
Usually, tert-butyllithium is used for this exchange
reaction giving complete conversion after 10 min at
ꢀ78 °C.16 However, the reaction of sulfoxide 5a with
tert-butyllithium gave only minimal amounts of product
7a due to the formation of 1-ferrocenylisoquinoline 8 as
a by-product (Scheme 4).
To optimize the sulfoxide/lithium exchange on ortho-
substituted ferrocenyl sulfoxides, we have examined
various reaction conditions and used several lithium
reagents for performing the sulfoxide/lithium exchange
N
O
60 oC
20 h
S
N
p-Tol
Fe
I
3
Br
5a: 78%
1. LDA (1.1 equiv.)
THF, -78 oC, 30 min
O
O
Zn
Pd(dba)2 (5 mol%)
tfp (10 mol%)
S
S
p-Tol
Fe
Fe
p-Tol
N
2. ZnBr2 (1.3 equiv.),
-78 oC to r.t. 60 min
O
S
p-Tol
2
60 oC
20 h
N
Fe
Br
4
5b: 75%
Scheme 3. ortho-Lithiation of sulfoxide 2 and cross-coupling.
1. tBuLi (2.0 equiv.)
-78 oC (10 min)
THF
N
N
N
O
S
PPh2
H
BH3
2.
p-Tol
Fe
Fe
Fe
BH3
(6)
Ph2P
(3.0 equiv.)
Cl
- 78 oC - r.t. (12 h)
5a
7a : 11%
8 : 46%
Scheme 4. Sulfoxide/lithium exchange with isoquinoline derivative 5a.

118
R. J. Kloetzing, P. Knochel / Tetrahedron: Asymmetry 17 (2006) 116–123
O
1. RLi (2.0 equiv.)
10 min
S
I
H
p-Tol
Fe
Fe
Fe
2. I2 (3.0 equiv.)
0 oC; 30 min
10
9
11
Scheme 5. Optimization of the sulfoxide/lithium exchange.
Table 1. Sulfoxide/lithium exchange with t-BuLi
was used to perform the sulfoxide/lithium exchange on
chiral sulfoxide 9. The reaction mixture was warmed
up to 0 °C and the protonated product 11 isolated in
quantitative yield. The iodosulfoxide 13 was isolated
from the reaction mixture and H NMR spectroscopic
analysis confirmed the ortho-substitution (Scheme 7).
Entry RLi
Temperature Addition 10:11a Yield of
(°C)
10 (%)
1
2
3
4
5
6
7
8
t-BuLi
ꢀ90
ꢀ60
ꢀ30
0
ꢀ78
ꢀ50
ꢀ78
ꢀ78
Normal
Normal
Normal
Normal
Inverse
Inverse
Inverse
Inverse
85:15
93:7
95:5
43:57
94:6
93:7
73
83
86
—
75
79
44
87
1
t-BuLi
t-BuLi
t-BuLi
t-BuLi
t-BuLi
n-Bu
In summary, these experiments on the sulfoxide/lithium
exchange with chiral sulfoxide 9 could show that the
high reactivity of the resulting sulfoxides for ortho-lithi-
ation can cause the undesired formation of the proton-
ated by-product 11.
50:50
95:5
PhLi
a Determined by 1H NMR.
The sulfoxide/lithium exchange and the subsequent
reaction with iodine proceeds with complete retention
of configuration concerning the planar chirality. This
was proven by the iodine/lithium exchange on iodide
10 and reaction with paraformaldehyde (Scheme 8).
The enantiomers of the resulting alcohol 14 were sepa-
rated by HPLC.17 The enantiomeric excess was deter-
mined to be 99%.
along with the formation of only 5% of the protonated
by-product 11. The competitive deprotonation of the
resulting p-tolyl phenyl sulfoxide at the ortho-position
may be responsible for the formation of this by-product
(Scheme 6).
The isolation of iodosulfoxide 12 could not be accom-
plished. Instead of p-tolyl iodophenyl sulfoxide 12, a sta-
tistical mixture of iodides of diphenyl sulfoxide, p-tolyl
phenyl sulfoxide and di-p-tolyl sulfoxide was found.
These sulfoxides were formed by sulfoxide/lithium
exchange with excess phenyllithium. Thus, p-tolyllithium
Applying these findings to isoquinoline derivative 5a, it
was shown that phenyllithium is the appropriate reagent
for the sulfoxide/lithium exchange on heterocyclic sub-
strates (Scheme 9).
O
S
Li
O
S
O
S
PhLi
Li
H
Fe
p-Tol
Fe
Fe
11
9
I2
I2
I
O
S
I
Fe
12
10
Scheme 6. Formation of the protonated by-product 11.
1. p-tolLi
THF/Et2O
O
S
I
O
S
H
p-Tol
Fe
Fe
-78 to 0 oC
2h
2. I2
9
11: quant.
13
Scheme 7. Proton source for the formation of the protonated by-product 11.

R. J. Kloetzing, P. Knochel / Tetrahedron: Asymmetry 17 (2006) 116–123
119
Table 2. Pd-catalyzed allylic alkylation with ligand 1a
Entry Solvent
Ligand Yielda Enantioselectivityb
1. t-BuLi (2.0 equiv.)
THF, -78 oC, 10 min
T
(°C) (mol %) (%)
(% ee)
OH
I
Fe
Fe
2. (CH2O)n (3.0 equiv.)
-78 ˚C to 0 oC, 12 h
1
2
CH2Cl2
22
22
4.0
4.0
49
59
69
73
CH2Cl2/
toluene 1:3
Toluene
Toluene/
n-hexane 3:2
THF
14: 49%, 99% ee
10
3
4
22
22
4.0
4.0
99
91
86
56
Scheme 8. Synthesis of alcohol 12 for demonstration of enantiomeric
purity.
5
6
7
22
0
22
4.0
4.0
2.0
94
29
88
59
84
72
BH3
Toluene
Toluene
Ph2P
Ar
Fe
Ar
Fe
O
PhLi (2.0 equiv.)
(6)
Cl
a Isolated yield after purification by column chromatography.
b Determined by HPLC (Daicel Chiralcel OD-H).
Li
S
(3 equiv.),
p-Tol
THF/Et2O
-78 oC, 10 min
-78 oC to r.t., 1 h
5a: Ar = 1-isoquinolyl
5b: Ar = 8-quinolyl
Table 2 shows the important influence of the solvent on
the selectivity of the catalyst. Ligand 1a gave moderate
enantioselectivity and low conversion in CH2Cl2. Both
selectivity and reactivity were increased by using a mix-
ture of CH2Cl2 and toluene. The best results were
obtained in pure toluene (entry 3, 99%, 86% ee) showing
the adverse effect of chlorinated solvents on ligand 1a.
Reducing the solvent polarity by adding n-hexane low-
ered the catalyst solubility. In a toluene/n-hexane mix-
ture 3:2, the catalyst was still soluble but gave low
enantioselectivity (entry 4). In THF, the catalyst is less
selective than in toluene (entry 5). Low reaction temper-
ature reduced the catalyst activity substantially, but the
selectivity remained almost unchanged (entry 6). With a
ligand load of 2 mol % instead of the previously used
4 mol % and a ligand/Pd ratio of 1:1, the product was
obtained only with a moderate enantiomeric excess (en-
try 7). Pd-black precipitated during the reaction, indicat-
ing that a stable catalytic system is only formed with a
ligand/Pd ratio of 2:1. This result could indicate that
ligand 1a acts as a monodentate ligand without particip-
ation of the nitrogen donor. Monophosphine 1716c was
therefore used for the performance of the allylic alkyl-
ation under the same reaction conditions (Scheme 10,
toluene, 22 °C). However, no conversion was observed
with monophosphine 17 indicating that the nitrogen
donor is important for the formation of an active cata-
lyst. Ligand 1a was also employed for the Pd-catalyzed
allylic amination (Scheme 11).
Ar
N
N
HNEt2
PPh2
BH3
PPh2
PPh2
Fe
Fe
Fe
neat
50 oC, 30 min,
evaporation
(repeat 5 times)
7a: 69%
7b: 38%
1b
1a
Scheme 9. Synthesis of the borane complexes 7a and 7b via the
optimized sulfoxide/lithium exchange and deprotection.
The resulting lithium compound was reacted with
Ph2PClÆBH3 6. The reaction with this electrophile is faster
and more efficient compared to the unprotected chloro-
diphenylphosphine. Thus, product 7a was isolated in
69% yield. Similarly, the reaction of ferrocene 5b leads
to borane complex 7b in 38% yield. The stable borane
protected P,N-ligands 7a and 7b can be handled in air
and purified by conventional column chromatography.
The borane complexes 7a and 7b were deprotected by
treatment with diethylamine18 giving the ligands 1a
and 1b in pure form and quantitative yield. 1H
NMR experiments at various temperatures were per-
formed with ligand 1a and the borane-complex 7a.
No coalescence was observed over a broad range of tem-
perature (+100 to ꢀ80 °C) in DMSO-d6 or acetone-d6.
3. Catalysis
We herein report the results obtained with ligand 1a in
preliminary experiments on the Pd-catalyzed allylic sub-
stitution. The reaction was performed with 1,3-diphenyl-
allyl acetate 15 under standard Trost19 conditions. The
catalyst was preformed in situ from allylpalladium(II)
chloride dimer as Pd-precursor (1 mol %) and ligand
1a (4 mol %) giving a ligand/Pd ratio of 2:1 (Scheme 10).
PPh2
Fe
17
CH (CO Me) (2 equiv.)
N,O-BSA (2 equiv.)
2
2
2
OAc
Ph
CH(CO2Me)2
Ph
R
OAc
Ph
HN
R-NH2, KH (1.4 equiv.)
Ph
Ph
Ph
Ph
Ph
[(C H )PdCl] (1 mol%)
3
5
2
[(C3H5)PdCl]2 (1 mol%)
1a (4 mol%)
1a (4 mol%)
KOAc (4.7 mol%)
15
16
18
19a : R = −SO Tol
2
THF, 18 h
19b : R = −NH-CO-Ph
12-14 h
Scheme 10. Allylic alkylation with ligand 1a.
Scheme 11. Allylic amination with ligand 1a.

120
R. J. Kloetzing, P. Knochel / Tetrahedron: Asymmetry 17 (2006) 116–123
Table 3. Pd-catalyzed allylic amination
Entry –R
T (°C) Yielda (%) Enantioselectivityb
sodium/benzophenone, toluene was dried with sodium,
and dichloromethane was dried with CaH2 and distilled.
(% ee)
5.1. Diasteroselective ortho-lithiation and cross-coupling
1
2
3
4
–SO2Tol
22
15
83
77
80
71
77
57
83
40
–NH–CO–Ph 22
40
5.1.1. (SFc,S)-[2-(1-Isoquinolinyl)-ferrocen-1-yl]-p-tolyl-
sulfoxide 5a. Sulfoxide 2 (1.95 g, 6.00 mmol) in THF
(60 mL) was cooled to ꢀ78 °C. LDA (6.60 mmol) was
added and the mixture stirred for 30 min at ꢀ78 °C. A
solution of ZnBr2 in THF (1.7 M, 7.80 mmol) was
added. It was warmed up to 22 °C and stirred for
1 h. The solvent was removed under reduced pressure.
For the cross-coupling reaction, bis(dibenzylideneacet-
one)palladium(0) (173 mg, 0.30 mmol), tris-o-furylphos-
phine (139 mg, 0.60 mmol) and 1-iodoisoquinoline
(2.14 g, 8.40 mmol) in THF (10 mL) were stirred for
5 min at 22 °C. The above prepared zinc reagent was
added in THF (25 mL). The mixture was heated to
60 °C for 20 h. After the addition of satd NH4Cl soln,
the mixture was extracted with diethyl ether (150 mL).
The organic layer was washed with water and brine
and dried over MgSO4. Purification by flash chromato-
graphy (n-pentane/diethyl ether 2:1, 1% triethylamine)
afforded the sulfoxide 5a as red solid (78%, 2.11 g,
4.67 mmol). Mp: 79–81 °C. [a]D = +131.3 (c 0.34,
a Isolated yield after purification by column chromatography.
b Enantioselectivity determined by HPLC (Daicel Chiralcel OD), (+)-
enantiomer for both substrates.
Table 3 shows the results of allylic aminations yielding
amines 19a and 19b at different temperatures. As for
the allylic alkylation, the catalyst displays a higher selec-
tivity and better reactivity at elevated temperature. The
differences in reactivity are less remarkable for the more
nucleophilic reagent benzoyl hydrazine (entries 3 and 4)
giving allyl hydrazone 19b.
4. Conclusion
In conclusion, we have reported the straightforward syn-
thesis of the new planar chiral P,N-ligands 1a and 1b.
We optimized the sulfoxide/lithium exchange by using
PhLi as a more selective reagent. Ligand 1a was used in
Pd-catalyzed allylic substitution reactions. The allylic
alkylation proceeds with quantitative yield and 86% ee.
The enantioselectivity with QUINAP was higher (98%
ee)7a thus illustrating the unpredictable nature of ligand
design. The allylic amination with two different nucleo-
philes gave 77% and 83% ee. Remarkably, the Pd-catalyst
with ligand 1a is more efficient and selective at higher
temperature. Further experiments extending the scope
of the P,N-ligands to other transition metal catalyzed
reactions are currently underway in our laboratories.
~
THF). Mp: 79–81 °C IR: (KBr): m ¼ 3051 (w), 2922
1
(w), 1623 (m), 1343 (w), 1038 (m), 823 (m) cmꢀ1. H
NMR: (300 MHz, C6D6): d 8.77 (d, J = 5.6 Hz, 1H),
8.06 (d, 3J = 8.1 Hz, 1H), 7.88 (d, 3J = 8.0 Hz, 2H),
3
7.50 (d, J = 8.1 Hz, 1H), 7.36–7.25 (m, 2H), 7.22–7.13
(m, 1H), 6.94 (d, 3J = 8.0 Hz, 2H), 4.57 (dd, 3J =
4
3
2.6 Hz, J = 1.3 Hz, 1H), 4.32 (s, 5H), 4.28 (dd, J =
2.6 Hz, 4J = 1.3 Hz, 1H), 4.17 (dd, 3J = 2.6 Hz, 1H),
2.10 (s, 3H). 13C NMR: (75 MHz, CDCl3): d 156.0,
142.0 (CH), 141.3, 141.0, 136.3, 129.6 (CH), 129.2
(CH), 128.1, 127.0 (CH), 126.9 (CH), 126.8 (CH),
125.6 (CH), 119.7 (CH), 97.1, 87.7, 72.8 (CH), 71.5
(CH), 69.0 (CH), 68.4 (CH), 21.4 (CH3). EI MS:
(70 eV): m/z (%) = 451 (14) [M+], 435 (100) [M+ꢀO],
12
5. Experimental
312 (73), 279 (19). HR EI MS: for
C
26
1H2156Fe
14N32S16O: calcd: 451.0693, found: 451.0694.
All reactions were carried out under argon using stan-
dard Schlenk techniques. Melting points are uncor-
5.1.2. (SFc,S)-[2-(8-Quinolinyl)-ferrocen-1-yl]-p-tolylsulf-
oxide 5b. Prepared according to the procedure de-
scribed above (Section 5.1.1) from sulfoxide 2 (486 mg,
1.50 mmol) in THF (15 mL), LDA (1.65 mmol), and
ZnBr2 in THF (1.7 M, 1.15 mmol). For the cross-coup-
ling reaction, bis(dibenzylideneacetone)palladium(0)
(43.1 mg, 0.075 mmol), tris-o-furylphosphine (34.8 mg,
1
rected. H and 13C NMR spectra were recorded on a
Bruker AMX 300 or AMX 600 instrument. 31P NMR
spectra were recorded on a VARIAN Mercury 200
instrument. Chemical shifts (d) are given as ppm relative
to the residual solvent peak. IR spectra were recorded
on a PERKIN ELMER 1420 Infrared Spectrometer.
Mass spectra were recorded on a FINNIGAN MAT
95 Q spectrometer. Optical rotations were measured
on a PERKIN ELMER 241 polarimeter. Column chro-
matography was performed on MERCK silica gel 60
(230–400 mesh ASTM). Enantiomeric excesses were
determined by HPLC. Chiralcel OD-H and OD (Daicel
Chemical Industries) columns were used with n-heptane/
i-propanol as a mobile phase and detection by a diode
array UV–vis detector at 214 nm. BuLi was titrated
prior to use according to the method of Paquette.20
ZnBr2 was used as 1.7 M solution prepared by drying
ZnBr2 (3.78 g, 15.0 mmol) under vacuum for 6 h at
140 °C and dissolving the cold salt in dry THF
(8.8 mL). THF and diethyl ether were dried with
0.150 mmol)
and
8-bromoquinoline
(437 mg,
2.10 mmol) in THF (2.5 mL), and the above prepared
zinc reagent THF (6 mL) were used. Purification by
flash chromatography (n-pentane/diethyl ether 2:1)
afforded sulfoxide 5b as a red solid (75%, 511 mg,
1.13 mmol). [a]D = +360.9 (c 0.44, THF). Mp: 195–
197 °C (decomp.) IR: (KBr): ~m ¼ 3085 (w), 3046 (w),
1636 (m), 1611 (m), 1596 (m), 1496 (m), 1042 (s), 826
1
(s), 801 (s), 494 (s) cmꢀ1. H NMR: (600 MHz, C6D6):
d 9.15 (d, J = 7.4 Hz, 1H), 8.69–8.64 (m, 1H), 7.57 (d,
J = 9.7 Hz, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.51–7.46
(m, 1H), 7.42 (d, J = 8.1 Hz, 1H), 6.82–6.77 (m, 1H),
6.66 (d, J = 7.9 Hz, 2H), 5.33–5.28 (m, 1H), 4.53–4.49
(m, 1H), 4.34 (s, 5H), 4.33–4.30 (m, 1H), 1.86 (s, 3H).

R. J. Kloetzing, P. Knochel / Tetrahedron: Asymmetry 17 (2006) 116–123
121
12
13C NMR: (151 MHz, C6D6): d 149.0 (CH), 147.3,
142.4, 139.2, 135.7 (CH), 135.2, 134.9 (CH), 128.6
(CH), 128.3, 127.5 (CH), 126.1 (CH), 125.1 (CH),
120.4 (CH), 96.2, 86.7, 76.5 (CH), 71.5 (CH), 70.9
(CH), 68.9 (CH), 20.8 (CH3). EI MS: (70 eV): m/z
C
1H1356Fe127I16O32S: calcd: 355.9732, found:
14
355.9731.
5.2.3. (SFc)-1-Hydroxymethyl-2-phenylferrocene 14.
(SFc)-1-Iodo-2-phenylferrocene 10 (165 mg, 0.391 mmol)
in THF (4 mL) was cooled to ꢀ78 °C. t-BuLi (1.5 M
in pentane, 0.52 mL, 0.78 mmol) was added and
the mixture stirred for 10 min at ꢀ78 °C. Parafor-
maldehyde (23 mg, 0.78 mmol) was added as a suspen-
sion in THF (1 mL) via PTFE-cannula. The mixture
was stirred for 12 h while it was allowed to warm to
0 °C. Satd NH4Cl soln was added and the mixture
extracted with diethyl ether. The combined organic
phases were washed with brine and dried over MgSO4.
Purification by flash chromatography (n-pentane/diethyl
ether 2:1) afforded the alcohol 14 (49%, 56 mg,
0.19 mmol). The enantiomeric excess was determined
to be 99% by HPLC (OD, 92% n-heptane, 8% i-propa-
nol, 0.8 mL/min); retention time (min): 24.9 (RFc), 29.5
(SFc).17 [a]D = +201.0 (c 0.59, acetone). IR: (KBr):
(%) = 451 (18) [M+], 435 (100) [M+ꢀO], 370
12
(74), 312 (54), 191 (31). HR EI MS: for
C
1H2156Fe-
26
14N32S16O: calcd: 451.0693, found: 451.0675.
5.2. Sulfoxide–lithium exchange
5.2.1. (SFc)-1-Iodo-2-phenylferrocene (optimized proce-
dure) 10. A pre-cooled solution of sulfoxide 9 (120 mg,
0.300 mmol) in THF (3 mL) was added to a solution of
PhLi in diethyl ether (0.60 mmol)21 at ꢀ78 °C. After
10 min, a solution of iodine (228 mg, 0.90 mmol) in
THF (3 mL) was added and the mixture was warmed
to rt. After 10 min, a satd soln of Na2S2O3 was added.
The mixture was extracted with diethyl ether. The com-
bined organic phases were washed with brine and dried
over MgSO4. Purification by flash chromatography
(n-pentane/diethyl ether 100:3) afforded iodide 10
(101 mg, 0.26 mmol, 87%) as an inseparable mixture
with phenylferrocene 11 (3.4 mg, 0.013 mmol). The ratio
~
m ¼ 3091 (m), 2923 (m), 1601 (m), 1506 (w), 1460 (m),
1384 (m), 1106 (m), 1002 (s), 765 (s), 701 (s) cmꢀ1. H
1
NMR: (300 MHz, C6D6): d 7.70–7.64 (m, 2H), 7.23–
7.07 (m, 3H), 4.46 (dd, J = 12.0, 6.6 Hz, 1H), 4.35 (dd,
J = 2.4, 1.7 Hz, 1H), 4.31 (dd, J = 12.0, 3.2 Hz, 1H),
4.13 (dd, J = 2.4, 1.7 Hz, 1H), 4.00 (dd, J = 2.4 Hz,
1H), 3.85 (s, 5H), 1.19 (dd, J = 12.0, 3.2 Hz, 1H).
1
was determined by H NMR. [a]D = ꢀ6.9 (c 0.64, acet-
~
one). IR: (KBr): m ¼ 3090 (m), 3056 (m), 2921 (m),
1602 (m), 1107 (m), 904 (s), 822 (s), 762 (s), 698 (s),
546 (m), 499 (m) cmꢀ1. H NMR: (300 MHz, C6D6):
13C NMR: (75 MHz, C6D6):
d
137.8, 129.2
1
Iodide 10: d 7.73–7.67 (m, 2H), 7.19–7.05 (m, 3H),
4.35 (dd, J = 2.5, 1.5 Hz, 1H), 4.19 (dd, J = 2.5,
1.5 Hz, 1H), 3.91 (dd, J = 2.5 Hz), 3.90 (s, 5H). Separate
signals of phenylferrocene 11: 4.47 (dd, J = 2.0 Hz, 2H),
4.06 (dd, J = 2.0 Hz, 2H), 3.85 (s, 5H). 13C NMR:
(75 MHz, C6D6): d 137.8, 130.0 (CH), 128.1, 127.2
(CH), 89.4, 76.5 (CH), 72.7 (CH), 69.5 (CH), 68.3
(CH), 43.4. EI MS: (70 eV): m/z (%) = 388 (100) [M+],
(CH), 128.4, 126.6 (CH), 87.9, 85.5, 70.9 (CH),
70.2 (CH), 70.1 (CH), 67.6 (CH), 59.9 (CH2). EI
MS: (70 eV): m/z (%) = 292 (100) [M+], 154 (64),
12
135 (25). HR EI MS: for
292.0551, found: 292.0535.
C
1H1656Fe16O: calcd:
17
5.2.4.
(SFc)-[2-(1-Isoquinolinyl)ferrocen-1-yl]diphenyl-
phosphine borane complex 7a. A pre-cooled solution
of sulfoxide 5a (715 mg, 1.58 mmol) in THF (20 mL)
was added to a solution of PhLi (3.17 mmol)21 at
ꢀ78 °C. After 10 min a solution of Ph2PClÆBH3 is
added. This solution had been prepared by adding bor-
ane in THF (1 M, 4.8 mL, 4.8 mmol) to a solution of
chlorodiphenylphosphine (0.87 mL, 1.05 g, 4.75 mmol)
in diethyl ether (3 mL) at rt and by stirring for 30 min.
The mixture was then stirred for 5 min at ꢀ78 °C and
then for 60 min at 22 °C. Water (0.3 mL) and triethyl-
amine (0.25 mL) were added and the mixture was evap-
orated under reduced pressure. The remaining red oil
was dissolved in CH2Cl2 (5 mL) and filtered through a
pad of silica gel (50 mL) with n-pentane/CH2Cl2 (1:1).
Evaporation of the filtrate afforded the crude product
which was purified by flash chromatography (n-pen-
tane/diethyl ether 7:1) to yield 7a as a red crystalline
solid (69%, 555 mg, 1.09 mmol).
260 (15), 203 (24), 139 (15). HR EI MS: for
12
C
16
1H13127I56Fe: calcd: 387.9411, found: 387.9412.
5.2.2. (2-Iodo-4-methylphenyl)(4-methylphenyl)sulfoxide
13. A pre-cooled solution of sulfoxide 9 (292 mg,
0.729 mmol) in THF (4 mL) was added to a solution
of p-TolLi in diethyl ether (0.80 mmol)22 at ꢀ78 °C.
After 2 h at 0 °C, a solution of iodine (406 mg,
1.60 mmol) in THF (1 mL) was added and the mixture
stirred for 20 min at 0 °C. A satd soln of Na2S2O3 was
added and the mixture extracted with diethyl ether.
The combined organic phases were washed with brine
and dried over MgSO4. Purification by flash chromato-
graphy (n-pentane/diethyl ether 100:3–1:1) afforded
phenylferrocene 11 in quantitative yield and (2-iodo-
4-methylphenyl)(4-methylphenyl)sulfoxide 13 as second
~
fraction (93 mg, 0.26 mmol, 37%). IR: (KBr): m ¼ 3047
(w), 2921 (m), 2862 (w), 1584 (m), 1456 (m), 1096 (m),
1
1080 (m), 1017 (s), 807 (s) cmꢀ1. H NMR: (300 MHz,
[a]D = +229.3 (c 1.22, THF). Mp: 193–194 °C (decomp.)
8.07 (d, 3J = 8.0 Hz, 1H), 7.74 (d,
IR: (KBr): m ¼ 3051 (w), 2390 (m), 1622 (m), 1436 (w),
~
C6D6):
d
3J = 8.4 Hz, 2H), 7.22 (d, J = 0.9 Hz, 1H), 6.83–6.76
(m, 3H), 1.86 (s, 3H), 1.69 (s, 3H). 13C NMR:
(75 MHz, C6D6): d 146.8, 143.7, 142.9, 141.4, 140.0
(CH), 130.2 (CH), 129.9 (2CH), 126.9 (CH), 126.7
(2CH), 93.7, 21.1 (CH3), 20.4 (CH3). EI MS: (70 eV):
m/z (%) = 356 (100) [M+], 340 (14) [M+ꢀO], 308 (41),
249 (49), 229 (89), 214 (44), 122 (62). HR EI MS: for
1107 (w), 1063 (m), 824 (m), 742 (m), 696 (m) cmꢀ1
.
4
3
1H NMR: (300 MHz, CDCl3): d 8.21 (d, J = 8.3 Hz,
1H), 8.02 (d, J = 5.8 Hz, 1H), 7.71 (d, 3J = 8.3 Hz,
1H), 7.67–7.44 (m, 5H), 7.41–7.29 (m, 6H), 7.24–7.16
(m, 2H), 4.98–4.93 (m, 1H), 4.66–4.71 (m, 1H), 4.47 (s,
5H), 4.40–4.35 (m, 1H), 1.82–0.35 (br s, 3H). 13C
NMR: (75 MHz, CDCl3): d 155.2, 141.3 (CH), 135.9,

122
R. J. Kloetzing, P. Knochel / Tetrahedron: Asymmetry 17 (2006) 116–123
133.1 (CH, J = 8.8 Hz), 132.8 (CH, J = 9.4 Hz), 131.8
(J = 28.5 Hz), 130.8, 130.2 (CH, J = 2.0 Hz), 129.9
(CH, J = 2.4 Hz), 129.2 (CH), 127.9 (CH, J = 9.4 Hz),
127.7 (CH, J = 10.3 Hz), 127.0 (CH), 126.6 (CH),
126.1 (CH), 119.5 (CH), 91.3 (J = 7.6 Hz), 75.3 (CH,
J = 6.1 Hz), 74.9 (CH, J = 8.8 Hz), 71.6 (CH), 71.0
(J = 65 Hz), 70.7 (CH, J = 7.8 Hz). 31P NMR:
(81 MHz, CDCl3): d +17.9 (br s). EI MS: (70 eV): m/z
5.3.2. (SFc)-[2-(8-Quinolinyl)ferrocen-1-yl] diphenyl-
phosphine 1b. 31P NMR: (81 MHz, C6D6): d ꢀ19.4 (s).
5.4. Catalysis
5.4.1. Allylic alkylation. The freshly deprotected ligand
1a (Section 5.3) and allylpalladium(II) chloride (dimer,
1.6 mg, 4.4 lmol, 0.87 mol %) were dissolved in toluene
(3 mL) and stirred for 15 min at rt 3-acetoxy-1,3-diphen-
ylpropene (126 mg, 0.50 mmol) in toluene (1 mL), N,O-
bistrimethylsilylacetamide (0.25 mL, 210 mg, 1.01 mmol),
dimethyl malonate (0.11 mL, 130 mg, 0.96 mmol) and
potassium acetate (2.3 mg, 23 lmol, 4.6 mol %) were
then added. The reaction was followed by thin layer
chromatography (n-pentane/diethyl ether 6:1). After
10 h, satd NH4Cl soln was added and the mixture
extracted with dichloromethane (60 mL). The organic
layers were washed with brine and dried over MgSO4.
The crude product was purified by column chromato-
graphy (n-pentane/diethyl ether 5:1) to obtain pure
product 16 (161 mg, 0.496 mmol, 99%, 86% ee) The
enantiomeric excess was determined by HPLC (OD-H,
97% n-heptane, 3% i-propanol, 0.4 mL/min); retention
time (min): 21.5 (R), 23.1 (S). The spectral properties
were in accordance with the literature.6i
(%) = 511 (0.5) [M+], 497 (40) [M+ꢀBH3], 420
12
(100), 222 (26). HR EI MS: for
C
1H2711B56Fe14N31P:
31
calcd: 511.1324, found: 511.1311.
5.2.5. (SFc)-[2-(8-Quinolinyl)ferrocen-1-yl] diphenylphos-
phine borane complex 7b. Prepared according to the
procedure described above (Section 5.2.3) from sulfoxide
5b (181 mg, 0.400 mmol) in THF (5 mL), PhLi
(0.800 mmol),21 and Ph2PClÆBH3 were added. This solu-
tion had been prepared from borane in THF (1 M,
1.2 mL, 1.2 mmol) and chlorodiphenylphosphine
(0.22 mL, 265 mg, 1.20 mmol). Due to solubility prob-
lems it was not possible to pre-cool the solution of sulf-
oxide 5b to ꢀ78 °C. It was slowly added to the PhLi
solution. Purification by flash chromatography (n-pent-
ane/diethyl ether 5:1) yielded 7b as a red crystalline solid
(38%, 77 mg, 0.15 mmol). [a]D = ꢀ3.7 (c 0.54, THF).
~
Mp: 190–191 °C (decomp.) IR: (KBr): m ¼ 3056 (w),
2398 (m), 1636 (m), 1436 (m), 1107 (m), 1062 (m), 828
5.4.2.
Allylic amination. p-Tosylamin (157 mg,
(m), 792 (m), 742 (s), 700 (s) cmꢀ1
.
1H NMR:
0.917 mmol) or benzoyl hydrazine (125 mg, 0.917 mmol)
was added to a suspension of KH (28.5 mg, 0.711 mmol)
in THF (3 mL) and stirred for 2 h at rt. The freshly
deprotected ligand 1a (Section 5.3) and allylpalla-
dium(II) chloride (dimer, 1.6 mg, 4.4 lmol, 0.87 mol %)
were dissolved in THF (1 mL) and stirred for 15 min at
rt. 3-Acetoxy-1,3-diphenylpropene (126 mg, 0.50 mmol)
in THF (1 mL) and the suspension of potassium amide
were added. The reaction was followed by thin layer
chromatography (n-pentane/diethyl ether 2:1). After
14 h at 40 °C, work-up and purification were performed
according to the procedure described above (Section
5.4.1) and the pure products 19a (151 mg, 0.415 mmol,
83%, 77% ee) or 19b (131 mg, 0.399 mmol, 80%, 83%
ee) obtained. The enantiomeric excess was determined
by HPLC (OD, 19a: 90% n-heptane, 10% i-propanol,
0.5 mL/min); retention time (min): 30.4, 45.2; 19b: 95%
n-heptane, 5% i-propanol, 0.6 mL/min; retention time
(min): 85.2, 104.8. The spectral properties were in accor-
dance with the literature.10
(600 MHz, C6D6): d 8.61–8.57 (m, 1H), 8.33 (d,
J = 7.5 Hz, 1H), 8.05–7.98 (m, 2H), 7.63–7.57 (m, 2H),
7.57–7.52 (m, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.20 (dd,
J = 7.5 Hz, 1H), 7.12–7.07 (m, 3H), 6.91–6.86 (m, 1H),
6.83–6.74 (m, 3H), 4.78–4.75 (m, 1H), 4.53–4.50 (m,
1H), 4.45 (s, 5H), 4.39–4.36 (m, 1H), 2.4–1.8 (br m,
3H). 13C NMR: (151 MHz, C6D6): d 149.1 (CH), 148.5,
135.6 (CH), 135.5, 134.9 (CH), 133.8 (CH, J = 9.3 Hz),
133.6 (CH, J = 10.7 Hz), 132.8 (J = 58 Hz), 131.1
(J = 57 Hz), 130.4 (CH), 130.0 (CH), 128.2–127.4 (m),
125.9 (CH), 120.5 (CH), 92.9 (J = 8.2 Hz), 77.4 (CH,
J = 7.0 Hz), 74.2 (CH, J = 10.4 Hz), 71.7, 71,3 (CH),
70.5 (CH, J = 7.0). 31P NMR: (81 MHz, CDCl3): d
+18.7 (br s). EI MS: (70 eV): m/z (%) = 511 (0.5)
[M+], 497 (100) [M+ꢀBH3], 420 (87), 354 (28), 248
12
(37). HR EI MS: for
C
1H2711B56Fe14N31P: calcd:
31
511.1324, found: 511.1367.
5.3. Deprotection
The borane complexes 7a and 7b (10.2 mg, 40.0 lmol)
were dissolved in diethylamine (1 mL) and stirred at
50 °C. After 30 min, the volatile compounds were evap-
orated under reduced pressure. This procedure was car-
ried out five times. The deprotection was monitored by
31P NMR. The ligand was ready for use for metal catal-
ysis after the final evaporation.
Acknowledgements
R.J.K. thanks the Stiftung Stipendien-Fonds des VCI
(Frankfurt) and the Bundesministerium fur Bildung
¨
und Forschung, for a scholarship. We thank Chemetall
(Frankfurt), for the generous gift of chemicals.
5.3.1.
(SFc)-[2-(1-Isoquinolinyl)ferrocen-1-yl]diphenyl-
phosphine 1a. 1H NMR: (300 MHz, acetone-d6): d
8.77 (d, J = 8.3 Hz, 1H), 8.16 (d, J = 5.5 Hz, 1H), 7.88
(d, J = 8.3 Hz, 1H), 7.75–7.53 (m, 6H), 7.45–7.38 (m,
2H), 7.25–7.09 (m, 5H), 5.13–5.07 (m, 1H), 4.67–4.60
(m, 1H), 4.14 (s, 5H), 4.02–3.95 (m, 1H). 31P NMR:
(81 MHz, CDCl3): d ꢀ18.6 (s).
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21. Prepared by adding n-BuLi (2.0 equiv) to iodobenzene in
diethyl ether (4 mL/mmol iodobenzene) and stirring for
30 min at 0 °C.
22. Prepared by adding n-BuLi (2.0 equiv) to 4-iodotoluene in
diethyl ether (4 mL/mmol 4-iodotoluene) and stirring for
30 min at 0 °C.