Explanation of different regioselectivities in the ortho-lithiation of ferrocenyl(phenyl)methanamines

Article abstract of DOI:10.1002/ejoc.201201325

Diastereoselective ortho-lithiation of ferrocenes is a principal strategy for the synthesis of chiral ferrocene ligands. Dilithiation of (R)-1-(2-bromophenyl)-1-ferrocenyl-N,N-dimethylmethanamine leads to a dilithium intermediate, which can be transformed to a Taniaphos ligand with (R,R _p)-configuration. On the other hand, lithiation of (R)-1-phenyl-1-ferrocenyl-N,N-dimethylmethanamine affords a lithiated product with opposite configuration of the stereogenic plane. Presumably, the second lithium atom attached at the ortho-position of the phenyl ring is responsible for this difference through the intramolecular multicenter arrangement involving both lithium atoms and their adjacent carbon atoms, the iron atom of the ferrocenyl moiety, and the nitrogen atom of the amino group. This hypothesis has been supported also by quantum chemical calculations. Diastereoselective ortho-lithiation of ferrocenyl(phenyl)methanamines was studied by ⁷Li NMR spectroscopy and DFT calculations. The configurations of the phosphane products were confirmed by X-ray crystallography. The different facial selectivities of the lithiation can be explained by the multicenter arrangement of the dilithium transition state, which features also Fe-Li interactions. Copyright

Full text of DOI:10.1002/ejoc.201201325

FULL PAPER
DOI: 10.1002/ejoc.201201325
Explanation of Different Regioselectivities in the ortho-Lithiation of
Ferrocenyl(phenyl)methanamines
[a]
[a]
[b]
[a]
ˇ
ˇ
Ambroz Almássy, Andrea Skvorcová, Branislav Horváth, Filip Bilcík,
[a]
[c]
[a]
ˇ
Vladimír Bariak, Erik Rakovský, and Radovan Sebesta*
Keywords: Directed metalation / Lithiation / Ferrocenes / Regioselectivity / Diastereoselective synthesis / NMR
spectroscopy
Diastereoselective ortho-lithiation of ferrocenes is a principal
strategy for the synthesis of chiral ferrocene ligands. Di-
lithiation of (R)-1-(2-bromophenyl)-1-ferrocenyl-N,N-di-
methylmethanamine leads to a dilithium intermediate, which
can be transformed to a Taniaphos ligand with (R,Rp)-config-
uration. On the other hand, lithiation of (R)-1-phenyl-1-ferro-
cenyl-N,N-dimethylmethanamine affords a lithiated product
with opposite configuration of the stereogenic plane. Pre-
sumably, the second lithium atom attached at the ortho-posi-
tion of the phenyl ring is responsible for this difference
through the intramolecular multicenter arrangement involv-
ing both lithium atoms and their adjacent carbon atoms, the
iron atom of the ferrocenyl moiety, and the nitrogen atom of
the amino group. This hypothesis has been supported also
by quantum chemical calculations.
ylamino group and a bromine–lithium exchange. As Tani-
aphos is one of the most widely used ferrocene ligands,[10]
it is useful to investigate the course of its synthesis. Further-
more, the stereochemical outcome of the dilithiation in the
synthesis of Taniaphos is different from that of the lithi-
ation typically observed in related ferrocenyl methyl-
amines.[11] It seems that the presence of two lithium atoms
in the molecule leads to this particular stereochemical out-
come. We therefore hypothesized that a lithium atom at-
tached at the ortho-position of the phenyl ring forces a dif-
ferent conformation in the transition state through Fe–Li
interaction. Interactions of iron atoms with carbocations,
silylium ions, or metals are known;[12] therefore, it seems
reasonable to suppose that Fe–Li interaction can occur dur-
ing the dilithiation of the Taniaphos precursor.
In this context, we decided to investigate dilithiation of
(R)-1-(2-bromophenyl)-1-ferrocenyl-N,N-dimethylmethan-
amine, which leads to the Taniaphos ligand family, and to
compare it with the lithiation of related model substrates.
Explanations suggested for different stereochemical out-
comes are supported by quantum chemical calculations of
transition states of lithiation.
Introduction
Directed ortho-metalation is a useful strategy for selective
introduction of a large variety of substituents on aromatic
compounds.[1] ortho-Metalation of substituted metallocenes
results in the creation of a stereogenic plane, thus leading
to planar chiral compounds. Planar chiral metallocenes,[2]
ferrocene derivatives in particular, find great use in asym-
metric catalysis.[3] Synthesis of most of them features dia-
stereoselective ortho-lithiation as a crucial step for introduc-
ing important donor atoms stereoselectively.[4] In general,
diastereoselective ortho-lithiation has been carefully studied
by spectroscopic as well as theoretical methods.[5] On the
other hand, considerably less attention has been devoted to
dilithiations.[6] Dilithiations are, in comparison to mono-
lithiations, much rarer, but still interesting for the synthesis
of useful compounds.[7] Among several ferrocene derivatives
that can be made by double lithiation,[8] the Taniaphos fam-
ily of chiral ligands are representative examples.[9] In this
case, the process of dilithiation consists of a stereoselective
ferrocene deprotonation ortho-directed by the dimeth-
[a] Department of Organic Chemistry, Faculty of Natural Sciences,
Comenius University in Bratislava,
Mlynská dolina CH-2, 842 15 Bratislava, Slovakia
Fax: +421-2-60296337
Results and Discussion
E-mail: radovan.sebesta@fns.uniba.sk
Homepage: www.fns.uniba.sk/?sebesta
[b] Institute of Chemistry, Faculty of Natural Sciences, Comenius
University in Bratislava,
The Taniaphos ligand precursor, 2-bromobenzylamine
(R)-1, was prepared by following the original Knochel pro-
cedure.[9b] Lithiation of 2-bromobenzylamine (R)-1 with
tBuLi produced a dilithium intermediate, which, after reac-
tion with chlorodiphenylphosphane, led to Taniaphos li-
gand (R,Rp)-2.[9] The Taniaphos ligand has been, for some
Mlynská dolina CH-2, 842 15 Bratislava, Slovakia
[c] Department of Inorganic Chemistry, Faculty of Natural
Sciences, Comenius University in Bratislava,
Mlynská dolina CH-2, 842 15 Bratislava, Slovakia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201325.
Eur. J. Org. Chem. 2013, 111–116
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FULL PAPER
time, wrongly depicted as having the (R,Sp)-configuration, stituted carbon atoms of the substituted Cp ring have sig-
although the correct X-ray structure of the Rh–Taniaphos nals at 66.5, 68.5, and 70.5 ppm, and in compound d1-3 (see
complex was presented in the original report. Fukuzawa Supporting Information), the corresponding signals are at
and co-workers provided additional proof of the absolute 66.5, 67.2, and 68.5 ppm. Carbon atoms bearing deuterium
configuration of the dilithium intermediate by its oxidative atoms show signals of lower intensity due to splitting to
coupling and thus also corrected the configuration of triplets. Therefore, in compound d2-3 deuterium is in the
Taniaphos.[13] The fact that the lithiation of Ugi-type amine pro-Sp position, while in compound d1-3 deuterium is in the
3 led, through a monolithiated intermediate, to aminophos- pro-Rp position.
phane 4[14] with (R,Sp)-configuration may have contributed
to the original confusion with the designation of proper
configurations of Taniaphos ligands (Scheme 1). At the out-
set of our study, we obtained X-ray-quality crystals of
Taniaphos itself and amino phosphane (R,Sp)-4. Crystal
structure analysis confirmed their absolute configurations
(Scheme 1). For details of X-ray structure determinations
of compounds 2 and 4, see Supporting Information.
Figure 1. Determination of the position of deuterium by HSQC in
deuterated compound d2-3.
Scheme 1.
Therefore an interesting question arises: What will be the
major product of the dilithiation of derivative (R)-5? The
Although X-ray crystallographic analysis provides defi-
lithiation of this compound should also proceed via a di-
nite proof of the configuration, it is time-consuming and
lithiated intermediate, but stabilization through an intramo-
expensive. Furthermore, it depends on the availability of
lecular Fe–Li interaction is not possible in this case. There-
suitable crystalline material. Therefore, we sought a more
fore, we performed the lithiation of amine (R)-5, and
convenient method that would provide insight into the fa-
quenching with CD3OD gave dideuterated product d2-6
cial selectivity of the lithiation. We first investigated lithi-
with a deuterium atom in the pro-Rp position of the Cp ring
ation of amines 1 and 3. Deuterated products, obtained by
(Scheme 3).
quenching lithiated intermediates with CD3OD or D2O,
seem to be suitable for this purpose. Compounds d1-3 and
d2-3, obtained in this way, are almost chemically identical,
but they are distinguishable by using NMR spectroscopy
(Scheme 2).
Scheme 3.
2H NMR spectroscopy can also provide information on
the position of deuterium atoms. 2H NMR spectra of com-
pounds d1-3 and d2-6 show that deuterium atoms on the Cp
ring have the same chemical shift (4.25 ppm). On the other
hand, compound d2-3 has one deuterium signal at
4.13 ppm. These spectra provide additional support to a
different relative configuration and thus different regioselec-
tivity of the lithiation (Figure 2). They also show that the
Scheme 2.
The positions of the deuterium atoms on the cyclopen- lithiation of amine 5 follows the path followed by that of
tadienyl (Cp) ring were unambiguously confirmed by the amine 3 and therefore further support the hypothesis that
gHSQC spectrum (Figure 1). In compound d2-3, the unsub- Fe–Li interaction plays a role in the different regioselecti-
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Eur. J. Org. Chem. 2013, 111–116

Regioselectivity in ortho-Lithiation of Ferrocenyl(phenyl)methanamines
vity of the lithiation of amine (R)-1. The gHSQC spectrum ratio of 2:1 under the same reaction conditions. The sub-
of d2-6 also confirms the suggested stereochemistry (see strate without the amino group was lithiated at –60 °C se-
Supporting Information).
lectively on the phenyl ring by bromine–lithium exchange.
No lithiation on the ferrocenyl moiety was observed in this
case.
The lithiation of substrate 1 with nBuLi at –60 °C with-
out allowing the temperature to rise, followed by quenching
with CD3OD, provided only the phenyl deuterated product,
similarly to the lithiation of 2-bromobenzylferrocene. Selec-
tive phenyl deuteration of compound 5 was achieved even
after its treatment with nBuLi for 1 h at 0 °C.
The bromine–lithium exchange on the phenyl ring is
manifested as a broad signal at 1.08–1.16 ppm in 7Li NMR
spectra of the lithiation of amines 1 and 5 (Figure 3, spectra
of 7 and 9). This signal is missing in the spectrum for the
lithiation of amine 3 (Figure 3, spectrum of 8). Increasing
the temperature above 0 °C resulted in a resonance at
1.49 ppm corresponding to the lithium atom at the ortho-
position of the substituted Cp ring (Figure 3, spectra of 7
and 8).
2
Figure 2. H NMR spectra (92 MHz, [D6]acetone, 20 °C, TMS) of
the deuterated products.
7Li NMR spectroscopy can provide direct insight into
the nature of lithium intermediates. For practical reasons,
7
the Li NMR spectroscopic study was carried out in [D8]-
THF and nBuLi instead of [D10]Et2O and tBuLi. The lithi-
ation of substrate 1 consists of two steps. The first step,
bromine–lithium exchange, proceeds quickly even at low
temperature. The lithiation was usually completed within
20 min after treatment with nBuLi at –60 °C. The second
step, diastereoselective ortho-lithiation of the substituted Cp
ring directed by the dimethylamino group, requires higher
temperatures. In the 1H NMR spectrum, two broad singlets
appear at 1.98 and 1.90 ppm (3 H each) corresponding to
the chemically nonequivalent methyl groups of the dimeth-
ylamino group. The coordination of the lithium atom at the
ortho-position of the Cp ring with the nitrogen atom from
the amino group restrains free rotation around the C–N
bond. In the case of compound 1, we obtained almost com-
plete regio- and stereoselectivity of the lithiation with
nBuLi.
7
Figure 3. Li NMR spectra of lithium intermediates 7–9.
With the help of quantum chemical calculations at the
The lithiation of substrates 3 and 5 occurs on the oppo- DFT level BP-86/6-31G*,[15] we identified possible transi-
site ortho-position of the substituted Cp ring and partially tion states for the Cp ring lithiation of amine (R)-1 leading
on the unsubstituted Cp ring. The diastereoselectivity of the to both diastereomers of Taniaphos (Figure 4). Interest-
ortho-lithiation with nBuLi at 5 °C decreases in the order 1 ingly, both transition states show Fe–Li interaction, which
Ͼ 5 Ͼ 3. The lithiation and subsequent deuteration of sub- is therefore probably not the main reason for the observed
strate 5 provided dideuterated amine d2-6 with the dia- diastereoselectivity of the lithiation. However, transition
stereomeric ratio 3:1. Substrate 5, upon treatment with state (Rp)-TS1, leading to the major diastereomer of
nBuLi in Et2O, formed an orange precipitate as the tem- Taniaphos, features additional quasidimeric arrangement of
perature rose above 0 °C. The precipitate was soluble in organolithium fragments. This quasidimeric arrangement is
THF. This suggests the formation of intermolecular clath- not possible in diastereomeric transition state (Sp)-TS1, be-
rates stabilizing the dilithiated intermediate. Amine 3 pro- cause the phenyl group bearing the second lithium is too
vided monodeuterated product d1-3 with a diastereomeric distant.
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Figure 6. DFT (BP-86/6-31G*) calculated diastereomeric transition
states for the lithiation of amine 3.
Figure 4. Structures of diastereomeric transition states in the lithi-
ation of amine 1 calculated by DFT (BP-86/6-31G*).
Calculated molecular orbitals of (Rp)-TS1 offer insight
into the bonding in the transition state. HOMO-3 indicates
the formation of the organolithium dimer, and HOMO-4
represents the Fe–Li interaction. The distance between the
iron atom and the lithium atom on the phenyl ring is
2.72 Å, which corresponds roughly to the sum of the cova-
lent radii of the two metal atoms (2.60 Å).[16] Figure 5 de-
picts molecular orbitals and orbital energies for transition
state (Rp)-TS1.
Conclusions
With X-ray structural analysis of Taniaphos and amino
phosphane 4 we have confirmed their absolute configura-
tions. NMR spectroscopic investigations of deuterated
products provided readily applicable proofs of the direction
7
of the lithiation. Li NMR spectroscopy showed that a di-
lithium intermediate was indeed formed. Dilithiation of
amine 5 proceeded with same facial selectivity as the mono-
lithiation of amine 3, therefore supporting the hypothesis
that Fe–Li interaction and the dimeric arrangement of
organolithium fragments are responsible for the different
outcomes of the lithiation. Finally, with the help of quan-
tum chemical calculations, a model explaining the course of
the lithiation was developed.
Experimental Section
General: All reactions were carried out in an inert atmosphere of
Ar or N2. Solvents were dried and purified by standard methods
before use.[17] NMR spectra were recorded with Varian Mercury
1
2
plus (300 MHz for H, 46 MHz for H, 75 MHz for 13C, 121 MHz
for 31P) and Varian NMR System 600 (600 MHz for H, 92 MHz
1
for H, 150 MHz for 13C, 233 MHz for Li) instruments. Chemical
2
7
shifts (δ) are given relative to tetramethylsilane for 1H and 13C
NMR spectroscopy. A unified chemical shift scale was used for 31
P
NMR (85% H3PO4 as secondary standard) and 7Li NMR (LiCl in
D2O as secondary standard) spectroscopy. Specific optical rota-
tions were measured with a Perkin–Elmer instrument and are given
in degcm3 g–1 dm–1. Melting points were measured in an open capil-
lary tube.
Typical Procedure for Dilithiations: tBuLi (1.6 M in pentane,
400 μL, 0.63 mmol) was added at –70 °C to a solution of amine
(R)-1 (118 mg, 0.37 mmol) in anhydrous Et2O (3 mL). The mixture
was stirred for 80 min while the temperature was raised to room
temp. It was then cooled down to –70 °C and PPh2Cl (120 μL,
0.67 mmol) was added. The resulting mixture was stirred at room
temp. for 16 h. NH4Cl (sat. soln., 6 mL) and Et2O (5 mL) were
added. The organic layer was separated, and the aqueous layer was
extracted with Et2O (3ϫ 10 mL). The combined organic layers
were washed with water (2ϫ 10 mL) and brine (1ϫ 10 mL), dried
with Na2SO4, and the solvents were evaporated. Products were iso-
lated by column chromatography [SiO2, hexane/Et2O (3:1) + 1%
Et3N].
Figure 5. Molecular orbitals and orbital energies for (Rp)-TS1.
Calculated transition states of the lithiation of amine
(R)-3 show only steric interaction of the phenyl group with
the unsubstituted Cp ring of the ferrocene. This gives pref-
erence for the Sp-configuration of the newly formed
stereogenic plane (Figure 6).
The difference between transition states TS1 and TS2 is
that TS1 features additional stabilizing Fe–Li interaction.
Furthermore, preferred transition state (Rp)-TS1 is also sta-
bilized with multicenter arrangement of organolithium
fragments.
For characterization data of amino phosphanes 2 and 4 see Sup-
porting Information.
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Regioselectivity in ortho-Lithiation of Ferrocenyl(phenyl)methanamines
Characterization Data for Deuterated Products
the result of the project implementation 26240120025 supported by
the Research & Development Operational Programme funded by
the European Regional Development Fund (ERDF). NMR spec-
troscopy measurements were provided by the Slovak State Pro-
gramme project no. 2003SP200280203. We also thank the Struc-
tural Funds, Interreg IIIA for the financial support for purchasing
the diffractometer.
(R,Rp)-1-(2-Deuterioferrocenyl)-N,N-dimethyl-1-phenylmethan-
amine: 2H NMR (92 MHz, [D6]acetone, 20 °C, TMS): δ = 4.25 (D-
CFc) ppm. MS: m/z = 276.2 [M – NMe2]+.
(R,Sp)-1-(2-Deuterioferrocenyl)-1-(2-deuteriophenyl)-N,N-dimethyl-
methanamine: 2H NMR (46 MHz, [D6]acetone, 20 °C, TMS): δ =
7.58 (D-CPh), 4.13 (D-CFc) ppm. MS: m/z = 277.2 [M – NMe2]+.
(R,Rp)-1-(2-Deuterioferrocenyl)-1-(4-deuteriophenyl)-N,N-dimethyl-
methanamine: 2H NMR (92 MHz, [D6]acetone, 20 °C, TMS): δ =
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Computational Details: Guess structures for transition states were
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All transition states were characterized by one imaginary frequency.
For coordinates of all calculated structures, see Supporting Infor-
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Eur. J. Org. Chem. 2013, 111–116
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Received: October 8, 2012
Published Online: November 20, 2012
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