A Planar-Chiral Phosphino(alkenyl)ferrocene for Suzuki-Miyaura C-C Coupling Reactions

Article abstract of DOI:10.1002/ejoc.201402861

Planar-chiral phosphinoferrocene [Fe(η⁵-C₅H₃-1-PPh₂-2-(E)-CH=CHPh)(η⁵-C₅H₅)] (4) was applied in the presence of palladium in Suzuki-Miyaura couplings for the synthesis of sterically congested biaryls. The catalytic activity arises from homogeneous palladium phosphine complexes, of which the potential pre-catalyst [Pd(4)₂Cl₂] was characterized structurally. The catalytic system is excellently suited for the synthesis of tri-ortho-substituted biaryls under mild conditions (0.1 mol-%, 50-100 C), whereas its application towards the synthesis of tetra-ortho-substituted biaryls is quite limited. Comparing the performance of the reaction with 4 as catalyst and a range of substrates with differing ortho substituents suggests that transmetalation is rate determining. Complex (S_p)-4 was used in atropselective couplings, wherein enantioenrichments of up to 36 % were achieved. The stereoselectivity depends to some extent on the steric properties of the boronic acids; however, slight changes at the aryl halides influence the enantioselectivity.

Full text of DOI:10.1002/ejoc.201402861

FULL PAPER
DOI: 10.1002/ejoc.201402861
A Planar-Chiral Phosphino(alkenyl)ferrocene for Suzuki–Miyaura C–C
Coupling Reactions
Dieter Schaarschmidt,[a] Martin Grumbt,[a] Alexander Hildebrandt,[a] and Heinrich Lang*[a]
Dedicated to Professor Dr. Dr. h.c. mult. Dietmar Seyferth on the occasion of his 85th birthday
Keywords: Sandwich complexes / Homogeneous catalysis / Asymmetric catalysis / C–C Coupling / Palladium
Planar-chiral phosphinoferrocene [Fe(η5-C5H3-1-PPh2-2-(E)-
CH=CHPh)(η5-C5H5)] (4) was applied in the presence of pal-
ladium in Suzuki–Miyaura couplings for the synthesis of
sterically congested biaryls. The catalytic activity arises from
homogeneous palladium phosphine complexes, of which the
potential pre-catalyst [Pd(4)2Cl2] was characterized structur-
ally. The catalytic system is excellently suited for the synthe-
sis of tri-ortho-substituted biaryls under mild conditions
(0.1 mol-%, 50–100 °C), whereas its application towards the
synthesis of tetra-ortho-substituted biaryls is quite limited.
Comparing the performance of the reaction with 4 as catalyst
and a range of substrates with differing ortho substituents
suggests that transmetalation is rate determining. Complex
(Sp)-4 was used in atropselective couplings, wherein enantio-
enrichments of up to 36% were achieved. The stereoselec-
tivity depends to some extent on the steric properties of the
boronic acids; however, slight changes at the aryl halides in-
fluence the enantioselectivity.
Introduction
The synthesis of sterically congested biaryls and atrop-
selective biaryl couplings by a Suzuki–Miyaura reaction are
almost exclusively considered as individual topics. To the
best of our knowledge there are only two examples reported
of catalysts exhibiting superior activity for the synthesis of
tri- and tetra-ortho-substituted biaryls that have been devel-
oped further towards a successful application in the asym-
metric variant of these couplings.[6,7] As a consequence, a
number of phosphines and N-heterocyclic carbenes have
been presented in the last decade allowing the synthesis of
sterically congested biaryls at comparatively low catalyst
loadings (Յ 1 mol-%) and in the temperature range of 20
to 100 °C within hours. However, the major drawback is
either the complete absence of chirality or the lack of an
enantioselective synthesis.[8] Enantiomerically pure catalysts
have been applied in atropselective couplings, however,
these systems often suffer from the required use of high
catalyst loadings (typically 5 mol-%) and long reaction
times (typically in the range of days).[9] This discrepancy
can be strikingly illustrated by comparing the synthesis of
2,2Ј-dimethyl-1,1Ј-binaphthyl using two ferrocenyl-based
phosphines. As can be seen from Scheme 1, planar-chiral
(R,Sp)-1-[2-(diphenylphosphanyl)ferrocenyl]-N,N-dimeth-
ylethanamine[10] gives the coupling product in a good enan-
tiomeric purity, however, compared with racemic N-[1-(1-
naphthyl)ethyl]-1Ј-(di-tert-butylphosphanyl)ferrocenyl-
methanimine, which was prepared by Hor and co-
workers,[8o] a much higher palladium and phosphine load-
ing as well as a longer reaction time is necessary to achieve
similar yields.
In the last decades, carbon–carbon bond-formation reac-
tions have emerged as an extremely powerful tool in syn-
thetic chemistry, because they allow the preparation of
complex molecules from simple precursors.[1] Among these
transformations, the Suzuki–Miyaura C–C cross-coupling
is undoubtedly of major importance; this is attributed to
the stability of the substrate organoboron compounds
towards oxygen and water as well as because of the toler-
ance of the reaction to a broad range of functional
groups.[2] As a result of rational catalyst design, the Suzuki–
Miyaura coupling can now be performed under mild reac-
tion conditions (low catalyst loading, room temperature)
and is applicable to a variety of substrates, including less
reactive chloroarenes.[2,3] The synthesis of sterically con-
gested biaryls, i.e., compounds bearing three or four substit-
uents ortho to the biaryl axis, however, remains a challeng-
ing task. If such biaryls possess at the very most C2 sym-
metry and if the substituents hinder the rotation about the
C–C single bond, these compounds will become axial-
chiral. This structural motif is present in many natural
products (e.g., Vancomycin)[4] as well as a in a few chiral
auxiliaries (e.g., BINAP)[5] and it has a key role in many
biological or technological fields.
[a] Faculty of Natural Science, Institute of Chemistry, Inorganic
Chemistry, Technische Universität Chemnitz,
09107 Chemnitz, Germany
E-mail: heinrich.lang@chemie.tu-chemnitz.de
http://www.tu-chemnitz.de/chemie/anorg/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402861.
6676
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6676–6685

A Chiral Phosphino(alkenyl)ferrocene for Suzuki–Miyaura Coupling
successfully applied in asymmetric transformations, for ex-
ample, in hydrogenations, conjugate additions, and allylic
substitutions.[19]
Results and Discussion
The title compound, (diphenylphosphino)[2-(E)-phenyl-
vinyl]ferrocene (4), is accessible starting from commer-
cially available formylferrocene in a three-step reaction se-
quence (Scheme 2). The aldehyde functionality required
protection with propylene glycol prior to ortho-directed li-
thiation and subsequent treatment with ClPPh2. After acid-
catalyzed acetal cleavage, racemic aldehyde 3 was converted
into phosphino(alkenyl)ferrocene 4 by means of a Horner–
Wadsworth–Emmons reaction with benzyl diethyl phos-
phonate. All reactions proceeded in good to excellent yields,
and the intermediates and products were purified by
recrystallization from toluene. Furthermore, the synthesis
Scheme 1. Synthesis of 2,2Ј-dimethyl-1,1Ј-binaphthyl by using two
ferrocenyl-based phosphines.[8o,10]
The ferrocenyl moiety represents a framework that is ex- could be conducted on a multigram scale. Chiral ferrocene
cellently suited for the design of chiral Suzuki–Miyaura cat- 3 was obtained almost enantiomerically pure (Sp/Rp = 99:1)
alysts, because phosphinoferrocenes are well established as when (S)-(–)-1,2,4-butanetriol was used for the protection
auxiliaries for C–C cross-couplings[11,12] and, due to its 3D of 1, as demonstrated by Kagan and co-workers.[20] It
nature, 1,2- and 1,3-heterodisubstituted derivatives are in- should be noted that (Sp)-4 has been synthesized by
ˇ
trinsically chiral. Planar-chiral ferrocenes show very good Steˇpnicˇka and co-workers before, who studied its coordina-
enantioselectivities in a variety of asymmetric transforma- tion behavior toward different transition metals and its
tions[13] and a plethora of pathways are known with which catalytic performance in asymmetric allylic alkylation reac-
to access such compounds in enantiomerically pure tions.[19i,19j]
form.[14] In addition to the above mentioned ferrocenyl-
The phosphorus atom in 4 readily coordinates to palla-
based phosphines derived from Ugi’s amine and derivatives dium, forming the two diastereomeric complexes 5 in a 7:3
thereof,[10,15] only three planar-chiral ferrocenes have been ratio (rac/meso) as evidenced by 31P{1H} NMR spectro-
applied in atropselective Suzuki–Miyaura reactions so scopic analysis (δ = 18.0, 17.2 ppm; Scheme 3). Conse-
far.[16]
quently, when (Sp)-4 was applied in this transformation,
We recently reported on chiral P,O-substituted ferrocenes only one resonance signal was observed for (Sp,Sp)-5 (δ =
and their use in the synthesis of sterically congested bi- 18.0 ppm). Single crystals of meso-5 could be obtained by
aryls.[17] However, the application of these ferrocenes in slow diffusion of n-hexane into a saturated solution of 5 in
atropselective couplings was not successful, likely because chloroform at 25 °C. Its molecular structure is depicted in
the interaction between the chiral alkoxy moiety and the Figure 1; selected bond lengths [Å] and angles [°] are listed
catalytically active palladium atom was too weak. To over- in the caption of Figure 1. The crystal and structure refine-
come this issue, we decided to use planar-chiral alkenylfer- ment data are summarized in the Exp. Section. Complex
rocenes with an adjacent phosphino moiety for further in- meso-5 crystallizes in the tetragonal space group I41/a with
vestigations. Interactions between palladium and alkenes a crystallographically imposed inversion symmetry at Pd1.
are commonly claimed and observed in catalytic transfor- A square-planar geometry around palladium is set up by
mations including the Suzuki–Miyaura cross-coupling.[18] two chlorine and two phosphorus atoms in a trans-arrange-
Furthermore, phosphine olefin ligands have already been ment [P1–Pd1–Cl1 91.72(6), P1–Pd1–Cl1A 88.28(6), P1–
Scheme 2. Synthesis of planar-chiral phosphino(alkenyl)ferrocene 4. Reagents and conditions: (i) pTsOH, toluene, reflux, 12 h (88%);
(ii) 1. sBuLi, THF, –78 °C, 1 h; 2. ClPPh2; 3. p-TsOH, CH2Cl2/H2O, reflux, 3 h (61%); (iii) 1. nBuLi, THF, –78 °C, 1 h; 2. 3, 60 °C, 12 h
(86%).
Eur. J. Org. Chem. 2014, 6676–6685
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6677

H. Lang et al.
FULL PAPER
Scheme 3. Synthesis of palladium complexes 5 [cod = (Z,Z)-1,5-cyclooctadiene].
Figure 1. ORTEP diagram (30% probability level) of the molecular structure of meso-5 with the atom-numbering scheme. All hydrogen
atoms have been omitted for clarity. Symmetry generated atoms are indicated by the suffix A; symmetry code: –x, –y + 1, –z. Selected
bond lengths [Å], angles [°]: C1–P1 1.809(6), C2–C11 1.472(10), C11–C12 1.332(10), C12–C13 1.480(10), C19–P1 1.833(7), C25–P1
1.828(7), P1–Pd1 2.3375(16), Cl1–Pd1 2.3041(16), D1–Fe1 1.6513(11), D2–Fe1 1.6575(11); C1–P1–C19 105.1(3), C1–P1–C25 105.4(3),
C1–P1–Pd1 112.8(2), C2–C11–C12 122.0(7), C11–C12–C13 127.7(7), C19–P1–C25 104.9(3), C19–P1–Pd1 119.9(2), C25–P1–Pd1 107.6(2),
P1–Pd1–Cl1 91.72(6), P1–Pd1–Cl1A 88.28(6), P1–Pd1–P1A 180.00(8), D1–Fe1–D2 175.45(8) (D1 denotes the centroid of C5H3; D2
denotes the centroid of C5H5).
Pd1–P1A 180.00(8)°]. Due to the inversion symmetry, the formed by the reaction of [Pd2(dba)3] and 4 accounts for
two ferrocene moieties point in different directions and are the catalytic activity in the Suzuki–Miyaura C–C coupling
rotated by 58.2(2)° out of the plane around Pd1. The ferro- of 1-bromo-2,4,6-triisopropylbenzene and (2-tolyl)boronic
cenyl moiety adopts a conformation between eclipsed and acid.
staggered, with a dihedral angle of –13.2(5)°.
The planar-chiral phosphino(alkenyl)ferrocene 4 was ap-
plied in the Suzuki–Miyaura coupling for the synthesis of
sterically congested biaryls. The catalytically active species
was generated in situ by the reaction of [Pd2(dba)3] (dba =
dibenzylideneacetone) and 4 in a molar ratio of 1:4.[21] Fig-
ure 2 shows the reaction profile of the conversion of 1-
bromo-2,4,6-triisopropylbenzene and (2-tolyl)boronic acid
at 70 °C monitored by GC analysis with acenaphthene as
internal standard. It can be seen that full conversion was
reached within 1 h, irrespective of whether cross-linked
poly(4-vinylpyridine) (PVPy) was added in excess
(Ͼ 500 equiv. based on Pd) or not. In the presence of metal-
lic mercury, however, the catalytic reaction collapses com-
pletely after 10 min, accompanied by a color change of the
solution from slightly yellow to black.[22] As the reaction
profiles are almost identical within the first 10 min, this be-
havior may be traced to an undesired reaction between mer-
cury and the palladium phosphine complex.[9u] If palladium
particles were the catalytically active species, hardly any
conversion of the aryl halide should take place in the pres-
ence of metallic mercury or PVPy.[23,24] In the absence of
Figure 2. Reaction profile of the conversion of 1-bromo-2,4,6-tri-
isopropylbenzene and (2-tolyl)boronic acid at 70 °C; Reaction con-
ditions: aryl halide (0.5 mmol), boronic acid (0.75 mmol),
K3PO4·H2O (1.5 mmol), toluene (3 mL), 0.05 mol-% [Pd2(dba)3],
0.2 mol-% rac-4. PVPy and Hg were added at 0 min.
Phosphino(alkenyl)ferrocene 4 was used for the synthesis
either the palladium source or the phosphine, virtually no of a wide range of di- and tri-ortho-substituted biaryls
conversion of the aryl halide was observed within 2 h. (Figure 3) at 50–100 °C with catalyst loadings of
These experiments show that a homogeneous catalyst 0.1–0.5 mol-%. Full conversion of the aryl halide was
6678
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6676–6685

A Chiral Phosphino(alkenyl)ferrocene for Suzuki–Miyaura Coupling
usually achieved within 24 h; the desired coupling product anthracenyl)boronic acid behave in a similar way. In some
could be isolated after aqueous work-up and subsequent cases the isolated yields of the biaryls derived from poly-
flash chromatography in good to excellent yields.[25] When cyclic aromatic-based boronic acids are lower than those of
(diphenylphosphino)ferrocene was applied instead of 4 in the phenyl-based boronic acids, which may be due to the
the synthesis of biaryl 8n, both higher catalyst loading (0.5 poorer solubility of the former (e.g., 8v,w vs. 8u; 8ad,ae vs.
vs. 0.1 mol-%) and higher reaction temperature (70 vs. 8ac). In contrast, (2-methoxyphenyl)boronic acid often re-
50 °C) were necessary to achieve a similar yield (85 vs. quired a higher reaction temperature than (2-tolyl)boronic
94%). Likewise, Xiao and co-workers reported on the use acid to achieve full conversion of the aryl halide (e.g., 8a
of (diphenylphosphino)ferrocene in the coupling of 1- vs. 8d, 8n vs. 8s, 8y vs. 8ab). Interestingly, (2-fluorophenyl)-
bromo-2-methoxynaphthalene and (1-naphthyl)boronic boronic acid gave somewhat better results when
acid giving the respective product 8q in just 8% yield,[16b] K3PO4·3H2O was used instead of K3PO4·H2O (8e: 87 vs.
whereas the use of 4 allowed for the isolation of biaryl 8q 59%, 8m: 94 vs. 84%, 8t: 91 vs. 82%). It is well documented
in 88% yield by applying only one-tenth of the amount of that the addition of stoichiometric amounts of water in Su-
palladium (Figure 3). Clearly, the presence of the alkenyl zuki–Miyaura reactions, which influences the equilibrium
moiety significantly enhances the catalytic performance of between free boronic acid and its trimeric anhydride borox-
this ferrocene.
ine, may cause a significant increase of the catalytic ac-
It is worth mentioning that the catalytic system presented tivity.[29] However, electron-poor boronic acids are less
here can be used for the efficient conversion of sterically prone to boroxine formation.[30] Consequently, the observed
hindered aryl halides, including 2-bromo-1,3,5-tri- increase in catalytic productivity in case of using
phenylbenzene and 1-bromo-N,N-dimethylnaphthalen-2- K3PO4·3H2O as base must be due to a different reason. The
amine, which have rarely been applied to Suzuki–Miyaura increased amount of water results in a higher OH– concen-
C–C couplings.[26] The structures of biaryls 8b, 8g, 8i, 8n, tration and, consequently, in an increased OH–-to-boronic
8y, 8z, 8am, and 8an in the solid state were determined by acid ratio, which in turn affects the rate of the transmet-
single-crystal X-ray diffraction; further details can be found alation. Amatore et al. have shown that, for a boronic acid
in the Supporting Information.
featuring an electron-donor group, the maximum transmet-
The electronic and steric nature of the ortho-substituents alation rate is reached at a lower OH–-to-boronic acid ratio
at the aryl halides governs the reaction temperature that is than for phenylboronic acid.[31] Hence, because (2-fluoro-
necessary to achieve full consumption of the starting mate- phenyl)boronic acid is the least electron-rich boron com-
rials. Whereas activated 2-bromo-3,5-dimethylbenzaldehyde pound used in this study, the increased OH–-to-boronic acid
and nonactivated 2-(2-bromo-3,5-dimethylphenyl)-1,3-di- ratio may serve as an explanation for the higher catalytic
oxane are coupled at 50 °C, the introduction of sterically productivity when K3PO4·3H2O is used as the base.
more demanding (iPr, Ph) or electron-donating substituents
The formation of biaryls 8a–an was accompanied by
(OMe) necessitates higher reaction temperatures. The same hydrodehalogenation of the aryl halide, hydrolytic de-
holds true for the comparison of 1-bromo-2-methoxy- boronation of the boronic acid and its homocoupling as
naphthalene and 1-bromo-2-phenylnaphthalene, which are side reactions (usually much less than 5% based on GC
both smoothly coupled at 50 °C, and 1-bromo-N,N-dimeth- analysis). The appearance of these by-products likely origi-
ylnaphthalen-2-amine, which requires 70 °C to be fully con- nates from the presence of water and oxygen because most
sumed. In contrast, deactivated 1-bromo-2-methoxynaphth- of the reactions were performed in air without degassing of
alene (50 °C) is more easily converted than nonactivated 1- the solvent toluene. The fact that good to excellent yields
bromo-2-methylnaphthalene (70 °C), which has also been of the respective biaryls could be achieved by performing
observed by Hor and co-workers.[8o] Clearly, the oxidative the catalytic transformations on the bench illustrates the
addition of the aryl halide towards palladium(0) is for these robustness of the catalytic system presented here. In case
substrates not rate determining. A comparison of the syn- of 8b, column chromatographic separation of the biphenyl
thesis of 8n and 8x leads to the conclusion that transmet- formed by hydrolytic deboronation of the respective
alation is rate determining. The respective intermediately boronic acid was difficult. However, when the Suzuki–
formed diaryl palladium complexes, which undergo re- Miyaura C–C coupling was performed under argon, the
ductive elimination to give biaryls 8n and 8x, carry both a aforementioned side reactions were suppressed, thus cir-
methyl and a methoxy group at the aryl moieties and are cumventing any difficulties in the purification of 8b. It has
therefore electronically as well as sterically similar. Conse- to be noted that, for certain combinations of aryl halides
quently, the activation barrier for the C–C bond formation and boronic acids, side reactions could not be prevented
should be almost identical.[27] This is consistent with the even by applying Schlenk techniques. In the course of the
observation that for the conversion of sterically hindered conversion of 2-(2-bromo-3,5-dimethylphenyl)-1,3-dioxane
substrates in Suzuki–Miyaura C–C couplings, phosphines and (1-naphthyl)boronic acid, 2-(3,5-dimethylphenyl)-
with smaller Tolman cone angles are beneficial, indicating 1,3-dioxane was formed, due to hydrodebromination in ap-
a significant contribution of the transmetalation towards proximately 10%. Separation of the latter from 2-[3,5-di-
the overall rate of this catalytic transformation.[6a,8l,8m,17c,28] methyl-2-(naphthalen-1-yl)phenyl]-1,3-dioxane by column
A comparison of the different boronic acids applied re- chromatography was unsuccessful. However, transforma-
veals that (2-tolyl)-, (2-biphenyl)-, (1-naphthyl)-, and (9- tion into the respective aldehydes by proton-catalyzed
Eur. J. Org. Chem. 2014, 6676–6685
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6679

H. Lang et al.
FULL PAPER
Figure 3. Synthesis of di- and tri-ortho-substituted biaryls 8a–an. Reagents and conditions: aryl halide (1.0 mmol), boronic acid
(1.5 mmol), K3PO4·H2O (3.0 mmol), toluene (3 mL), 0.05 mol-% [Pd2(dba)3], 0.2 mol-% rac-4, 24 h. Reaction times were not minimized,
yields based on isolated material (average of two runs). [a] 0.25 mol-% [Pd2(dba)3], 1.0 mol-% rac-4, toluene (5 mL). [b] K3PO4·3H2O
used as base. [c] 0.1 mol-% [Pd2(dba)3], 0.4 mol-% rac-4, boronic acid (2.0 mmol), K3PO4·H2O (4.0 mmol), toluene (6 mL). [d] Synthesized
starting from 2-(2-bromo-3,5-dimethylphenyl)-1,3-dioxane with subsequent acetal cleavage. [e] 2-Chloro-3-nitrotoluene used as aryl
halide.
6680
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6676–6685

A Chiral Phosphino(alkenyl)ferrocene for Suzuki–Miyaura Coupling
acetal cleavage allowed for their convenient separation. For ance of [Pd2(dba)3]/4 for these challenging transformations
the coupling of 2-bromo-3,5-dimethylbenzaldehyde or 2- showed that changing the solvent from toluene to 1,4-di-
chloro-3-nitrotoluene with (2-tolyl)- or (1-naphthyl)boronic oxane was beneficial. This contrasts with our observation
acid, incomplete conversions of the starting materials were for the coupling of 2-bromo-1,3,5-triphenylbenzene and (2-
observed. Moreover, a considerable amount of aromatic tolyl)boronic acid, for which 1,4-dioxane gave a lower con-
compounds arising from hydrodehalogenation of the aryl versionandconsequentlyaloweryieldofbiaryl8hthantoluene
halide and boronic acid homocoupling were formed. These (Ͻ 20 vs. 82%). A possible explanation for this behavior
transformations were conducted in an argon atmosphere might be a better stabilization of certain palladium species
with carefully degassed toluene, therefore, another pathway when 1,4-dioxane is used as the solvent, which may on the
for boronic acid homocoupling must be operating apart one hand result in reduced catalytic activity but, on the
from the reaction with palladium(II)peroxo compounds in- other hand, may increase the long-term stability and there-
termediately formed by oxidation of palladium(0) with oxy- fore the productivity of the catalyst.
gen.[32] Regarding the boronic acids applied, distinct differ-
ences become clear. Both aryl halides give complete conver-
sion with (2-methoxyphenyl)boronic acid and very good
isolated yields of the respective biaryls 8ah and 8ak without
any need for exclusion of air. When changing to (2-tolyl)-
boronic acid, the conversion of the aryl halide dropped to
approximately 70–80% accompanied by the formation of
2,2Ј-dimethyl-1,1Ј-biphenyl and the respective hydrodehalo-
genated aryl halide. In the case of 2,2Ј-dimethyl-6-nitro-
1,1Ј-biphenyl, 3-nitrotoluene, which also formed, could not
be separated. For the coupling of 2-bromo-3,5-dimethyl-
benzaldehyde and (1-naphthyl)boronic acid, the cross-
coupled biaryl is only formed in approximately 10% based
on GC analysis. Clearly, the steric bulk of the boronic acid
plays a crucial role in successful Suzuki–Miyaura C–C cou-
pling, which once again indicates rate determination by the
transmetalation step. One might consider that the difficult-
ies in the conversion of these two aryl halides may arise
from a limited tolerance of functionalities (CHO, NO2) of
the catalyst discussed here. However, both aryl halides are
smoothly coupled with (2-methoxyphenyl)boronic acid, and
GC analysis of the reaction mixtures did not give any hints Reagents and conditions: aryl halide (1.0 mmol), boronic
towards an undesired reaction with the aldehyde or nitro
group. Nevertheless, protection of the aldehyde as its acetal
both prevented the occurrence of side reactions and in-
(average of two runs).
creased the yield of the desired biaryl (52 vs. 95% for 8ag
Figure 4. Synthesis of tetra-ortho-substituted biaryls 8ao–au.
acid (1.5 mmol), K3PO4·H2O (3.0 mmol), 1,4-dioxane (5 mL),
0.5 mol-% [Pd2(dba)3], 2.0 mol-% rac-4, 100 °C, 48 h. Reaction
times were not minimized, yields based on isolated material
and 8ai, respectively). This may not necessarily be related
Enantiomerically pure (Sp)-4 has been applied in the
to a possible incompatibility towards the aldehyde function- atropselective synthesis of tri-ortho-substituted biaryls. Typ-
ality but might be due to the different electronic properties ically there is a significant dependency of the enantio-
of both aryl halides affecting all elementary steps in the selectivity of this transformation on the reaction conditions;
catalytic cycle.
therefore, the influence of different bases, solvents and pal-
The results of the formation of tetra-ortho-substituted bi- ladium sources has been studied by using the example of
aryls are summarized in Figure 4. Comparing the coupling the synthesis of 8n (see the Supporting Information,
of 2-bromo-1,3-dimethoxybenzene with (2-tolyl)- and (2,6- Table S-5). The C–C coupling of 1-bromo-2-methoxy-
dimethylphenyl)boronic acid to give 8j and 8ao, respec- naphthalene and (2-tolyl)boronic acid reaches, in most
tively, it becomes clear that, despite a considerable increase base/solvent combinations, yields of 90% or more at 50 °C.
of the catalyst loading from 0.1 to 1.0 mol-%, the yield de- The enantioselectivity of this C–C coupling is clearly influ-
creases from 93 to 52%. This example illustrates that ferro- enced by the base and the solvent, however, compared with
cene 4 is better suited for the efficient synthesis of tri-ortho- other reported examples, this dependency is less pro-
substituted biaryls. As already discussed for the coupling nounced.[33] The highest selectivity was observed for
of certain aryl halides with mono-ortho-substituted boronic K3PO4·H2O in toluene (27%ee), which was therefore used
acids, all examples depicted in Figure 4 are characterized for all other atropselective coupling reactions. In contrast,
by an incomplete conversion of the starting materials along the enantioselectivity was neither affected by the palladium
with the formation of side products due to hydrode- precursor used ([Pd2(dba)3], [Pd(OAc)2], (Sp,Sp)-5) nor the
bromination of the aryl bromides and boronic acid homo- molar palladium/phosphine ratio (1:1, 1:2, 1:4). Further-
coupling, respectively. Attempts to improve the perform- more, stopping the reactions after 6 h gave the same
Eur. J. Org. Chem. 2014, 6676–6685
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6681

H. Lang et al.
FULL PAPER
enantioselectivity for 8n (27%ee), which shows that in each Table 1. Atropselective synthesis of tri-ortho-substituted biaryls 8n–
v, 8x–ab, and 8ag–an.[a]
case the same catalytically active species is formed and is
Entry
Compd.
ee [%][b]
Entry
Compd.
ee [%][b]
present throughout the reaction.
The results of the atropselective biaryl couplings by a
Suzuki–Miyaura C–C bond formation are summarized in
Table 1. The yields of the respective biaryls 8n–v, 8x–ab, and
8ag–an are identical to those depicted in Figure 3. The
enantioselectivities obtained are at best modest, but they
are in the same range as for other planar-chiral ferrocenes
described elsewhere.[16] For different combinations of aryl
halides and arylboronic acids, the enantioselectivities range
from 0 (Table 1, entries 7 and 20) to 36% (entry 18). The
use of (2-methoxyphenyl)boronic acid almost exclusively re-
sulted in the formation of a nearly racemic product
(Table 1, entries 6, 14, 16, 19, and 21), in fact a significant
degree of enantioselectivity (22%ee) was only observed for
8x (entry 10). For (2-tolyl)boronic acid, the enantioenrich-
ment of the biaryls was highly dependent on the aryl halide
applied. For naphthalene-based aryl bromides, for example,
an ortho methoxy (entry 1) or methyl group (entry 8) gave
dramatically better enantiomeric excesses (27 and 21%ee)
than observed for substrates with an ortho phenyl (entry 11)
or dimethylamino group (entry 20), where the respective bi-
aryls 8y and 8al were formed as a racemate. Likewise, a
comparison of the coupling of 2-bromo-3,5-dimethylbenz-
aldehyde or its trimethylene glycol acetal with (2-tolyl)-
boronic acid (entries 15 and 17) demonstrates the sensitivity
of the enantioselectivity (35 and 1%ee) to slight changes at
the aryl halide. In contrast to the two aforementioned
boronic acids, (1-naphthyl)boronic acid gave a significant
enantioenrichment in the respective biaryls with all aryl hal-
ides in this study (19–36%ee; Table 1, entries 4, 9, 12, 18,
and 22). Further insights into the influence of the ortho
substituent of the aromatic boronic acid on the enantio-
selectivity of the Suzuki–Miyaura C–C coupling could be
gained by analyzing the conversion of 1-bromo-2-methoxy-
naphthalene with different boronic acids (Table 1, entries 1–
1
2
3
4
5
6
7
8
8n
8o
8p
8q
8r
8s
8t
8u
8v
8x
8y
27
9
12
24
21
2
12
13
14
15
16
17
18
19
20
21
22
8z
8aa
8ab
8ag
8ah
8ai
28
23
2
35
2
1
36
4
0
8aj
21
27
22
1
8ak
8al
8am
8an
9
10
11
0
5
19
[a] Reaction conditions were identical to those reported in Figure 3
with the exception of replacing rac-4 by (Sp)-4. [b] Enantiomeric
excesses were determined by HPLC analysis with a Chiralcel OD-
H or OJ-H column.
ence of π···π interactions between the phenyl moiety and
the boronic acid on the enantioselectivity. Inspection of the
enantioenrichment of biaryls 8y–ab, showed that a change
from phenylboronic acids (entries 11 and 14) to boronic
acids with an extended π-system (entries 12 and 13) in-
creased the stereoselectivity; this may suggest a positive in-
fluence of π···π interactions. However, a comparison of the
results obtained with 1-bromo-2-methoxy- and 1-bromo-2-
methylnaphthalene with these two π-extended boronic acids
showed no significant increase in the stereoselectivity (cf. 28
vs. 24% for 8z/8q, 23 vs. 23% for 8v/8aa, and 21 vs. 28%
for 8r/8w). These results might indicate the necessity for the
presence of a polarized group such as a carbonylbenzo-
oxazolidinone or
a bis(2-oxo-3-oxazolidinyl)phosphinyl
unit to significantly increase the stereoinduction.[6b,6c]
Conclusions
Planar-chiral (diphenylphosphino)[2-(E)-phenylvinyl]fer-
7). The following order of enantioenrichment in the biaryls rocene (4) has been applied in the presence of [Pd2(dba)3]
8n–t could be established: C6H4-2-Me Ͼ 1-naphthyl Ͼ 9- (dba = dibenzylideneacetone) as a ligand in Suzuki–Mi-
phenanthryl Ͼ C6H4-2-Ph Ͼ C6H4-2-iPr Ͼ C6H4-2-OMe Ͼ yaura C–C coupling reactions for the synthesis of sterically
C6H4-2-F. Clearly, there is a certain dependency on the congested biaryls. Ferrocene 4 promotes the coupling of di-
steric bulk of the ortho substituents, because the boronic verse aryl halides and arylboronic acids to give biaryls with
acids functionalized with the smallest substituents (OMe, up to four ortho substituents. The system [Pd2(dba)3]/4 is
F) give almost no enantioselectivity. However, in consider- especially well suited for the efficient synthesis of tri-ortho-
ation of the significantly lower degree of stereoinduction substituted biaryls, with turnover numbers of up to 1,000
obtained by using (2-isopropylphenyl)boronic acid (9%ee, achieved even at 50 °C. Without doubt, ferrocene 4 enriches
entry 2) compared with the methyl derivative (27%ee, the limited selection of catalysts available for the challeng-
entry 1), sole consideration of the steric characteristics of ing synthesis of multiply ortho-substituted biaryl deriva-
the boronic acids cannot be decisive.
tives. Comparing the performance of [Pd2(dba)3]/4 for the
Recently, Tang et al. reported on a highly asymmetric synthesis of biaryls containing ortho substituents with a
Suzuki–Miyaura C–C coupling reaction, and they con- range of electronic and steric properties leads to the conclu-
cluded that the stereoselectivity is promoted by π···π inter- sion that transmetalation is rate determining. This is consis-
actions between the extended π-system of the boronic acid tent with reported evidence that phosphines with smaller
and a carbonylbenzooxazolidinone moiety of the aryl hal- Tolman cone angles are beneficial for the synthesis of steri-
ide component at diarylpalladium(II) complexes prior to cally congested biaryls.[6a,8l,8m,17c,28]
reductive elimination.[6b,6c] We therefore studied the cou-
Enantiomerically pure planar-chiral 4 has been used for
pling of 1-bromo-2-phenylnaphthalene with different aryl- atropselective C–C couplings. Tri-ortho-substituted biaryls
boronic acids (Table 1, entries 11–14) to evaluate the influ- could be obtained in up to 36%ee, which is in the same
6682
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6676–6685

A Chiral Phosphino(alkenyl)ferrocene for Suzuki–Miyaura Coupling
lated as an orange solid material in a ratio of rac/meso = 7:3. Ap-
plying this synthesis protocol to [Pd(cod)Cl2] (45 mg, 0.16 mmol,
1.0 equiv.) and (Sp)-4 (150 mg, 0.32 mmol, 2.0 equiv.) afforded
(Sp,Sp)-5 {152 mg, 0.14 mmol, 85% based on [Pd(cod)Cl2]}.
C60H50Cl2Fe2P2Pd (1122.00): calcd. C 64.23, H 4.49; found C
63.83, H 4.54. 31P{1H} NMR (202.5 MHz, CDCl3, 25 °C, H3PO4):
δ = 18.0 (s, major), 17.2 (s, minor) ppm. HRMS: m/z calcd. for
C60H50ClFe2P2Pd [M – Cl]+ 1085.0826; found 1085.0761. Single
crystals of meso-5 that were suitable for X-ray diffraction analysis
were obtained by slow diffusion of n-hexane into a saturated solu-
range as reported for other planar-chiral ferrocenes. Clearly,
there is the need for further optimization of the ligand
structure to combine both the efficient synthesis of these
biaryls under mild conditions within a reasonable time and
a high degree of stereoinduction. The stereoselectivity of
the Suzuki–Miyaura coupling depends to some extent on
the steric properties of the boronic acids; however, slight
changes at the aryl halides applied may dramatically influ-
ence the enantioselectivity. This emphasizes the need for
further studies to gain more insight into the effects of ortho tion of 5 in chloroform at room temperature. Crystal data for meso-
5: C60H50Cl2Fe2P2Pd; Mr = 1121.94 gmol–1; tetragonal; I41/a; λ =
substituents on the conformation of diarylpalladium(II)
complexes and the transition states of the reductive elimi-
nation step.
1.54184 Å, a = 27.1161(13), c = 12.9597(7) Å; V = 9529.0(8) Å3; Z
= 8; ρcalcd. = 1.564 gcm–3; μ = 9.811 mm–1; T = 101(2) K; θ range
3.26–65.50°, reflections collected: 9597, independent: 4032 (Rint
0.0681), R1 = 0.0588, wR2 = 0.1431 [IϾ2σ(I)].
=
General Procedure for Suzuki–Miyaura C–C Coupling: To a 4 mL
vial, containing a magnetic stirring bar, were added aryl halide
(1.0 mmol), boronic acid (1.5 mmol), K3PO4·H2O (691 mg,
3.0 mmol) or K3PO4·3H2O (799 mg, 3.0 mmol) and solutions of
[Pd2(dba)3] (1 mL, 0.5 mm) and 4 (2 mL, 1 mm) in anhydrous tolu-
ene. The vial was sealed with a PTFE-lined screw-cap and heated at
the given temperature for 24 h. After cooling to 25 °C, the reaction
mixture was diluted with diethyl ether (25 mL) and washed with
water (2ϫ 50 mL). The organic phase was filtered through a pad
of alumina and concentrated under reduced pressure. The crude
product obtained was purified by flash chromatography. For the
synthesis of 8b, 8h, 8i, 8ag, 8ai, 8aj, and 8al–8au exclusion of oxy-
gen was achieved by performing the reaction in an oven-dried
Schlenk tube; the reaction mixture was degassed prior to heating.
For C–C couplings at catalyst loadings higher than 0.2 mol-% (8b,
8ao–8au), [Pd2(dba)3] and 4 were added as solid materials.
Experimental Section
General Methods: All air-sensitive manipulations were carried out
under an atmosphere of argon by using standard Schlenk tech-
niques. If necessary, solvents were dried and deoxygenated by stan-
dard procedures. NMR spectra were recorded with a Bruker
Avance III 500 spectrometer (500.3 MHz for 1H, 125.7 MHz for
13C{1H}, and 202.5 MHz for 31P{1H} spectra). Chemical shifts are
reported in δ units (parts per million) downfield from tetramethyl-
silane (δ = 0.00 ppm) with the solvent as reference signal [1H NMR:
CHCl3, δ = 7.26; 13C(1H) NMR: CDCl3, δ = 77.00; 31P(1H) NMR:
standard external rel. 85% H3PO4, δ = 0.0; P(OMe)3, δ = 139.0].
Elemental analyses were measured with a Thermo FlashEA 1112
instrument. High-resolution mass spectra (HRMS) were recorded
with a Bruker Daltonik micrOTOF-QII spectrometer. HPLC
analyses were performed with a Knauer system consisting of a
HPLC Pump K-500 and an UV Detector K-2000 operating at
Supporting Information (see footnote on the first page of this arti-
cle): Description of the experimental and spectroscopic details in-
cluding the X-ray structures of 8b, 8g, 8i, 8n, 8y, 8z, 8am, and 8an.
245 nm equipped with
(4.6ϫ250 mm). GC-MS was performed with
a
Chiralcel OD-H or OJ-H column
Varian Star
a
3400CX gas chromatograph coupled with a Varian Saturn 3 mass
spectrometer using electron impact ionization. Data for single-crys-
tal X-ray diffraction analyses were collected with an Oxford Dif-
fraction Gemini S diffractometer with graphite monochromated
Cu-Kα radiation (λ = 1.54184 Å) or Mo-Kα radiation (λ =
0.71073 Å). The structures were solved by direct methods and re-
fined by full-matrix least-squares procedures on F2.[34] All non-
hydrogen atoms were refined anisotropically, and a riding model
was employed in the treatment of the hydrogen atom positions.
Acknowledgments
The authors are grateful to the Fonds der Chemischen Industrie for
generous financial support. D. S. thanks the Fonds der Chemischen
Industrie for a Chemiefonds fellowship.
[1] a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed. (Eds.: A.
de Meijere, F. Diederich), Wiley-VCH, Weinheim, Germany,
2004; b) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem.
Int. Ed. 2005, 44, 4442–4489; Angew. Chem. 2005, 117, 4516–
4563; c) Modern Arylation Methods (Ed.: L. Ackermann),
Wiley-VCH, Weinheim, Germany, 2009; d) X.-F. Wu, P. Anba-
rasan, H. Neumann, M. Beller, Angew. Chem. Int. Ed. 2010,
49, 9047–9050; Angew. Chem. 2010, 122, 9231–9234.
[2] a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–2483; b)
A. Suzuki, in: Modern Arene Chemistry (Ed.: D. Astruc),
Wiley-VCH, Weinheim, Germany, 2002, p. 53–106; c) A. Su-
zuki, Angew. Chem. Int. Ed. 2011, 50, 6723–6737; Angew.
Chem. 2011, 123, 6855–6869; d) A. Suzuki, Y. Yamamoto,
Chem. Lett. 2011, 40, 894–901.
All chemicals were purchased from commercial suppliers and used
without further purification except where otherwise noted. (2,6-Di-
methylphenyl)boronic acid was filtered through a pad of silica (n-
hexane/Et2O, 2:1 v/v) prior to use. Rac-4,[35] (Sp)-4,[36] [Pd(cod)-
Cl2],[37] 2-bromo-1,3,5-triphenylbenzene,[38] 2-bromo-1,3-dimeth-
oxybenzene,[39] 1-bromo-2-methoxynaphthalene,[40] 1-bromo-2-
methylnaphthalene,[41] 1-bromo-2-phenylnaphthalene,[42] 9-bromo-
anthracene,[43] 2-bromo-3,5-dimethylbenzaldehyde,[44] (2-meth-
oxyphenyl)boronic acid,[45] (2-isopropylphenyl)boronic acid,[46]
mesitylboronic acid,[47] (2-methylnaphthalen-1-yl)boronic acid,[48]
and (2,6-dimethoxyphenyl)boronic acid[49] were synthesized ac-
cording to previously published procedures.
[3] a) A. F. Littke, G. C. Fu, Angew. Chem. Int. Ed. 2002, 41, 4176–
4211; Angew. Chem. 2002, 114, 4350–4386; b) W. A. Herrmann,
Angew. Chem. Int. Ed. 2002, 41, 1290–1309; Angew. Chem.
2002, 114, 1342–1363; c) M. Miura, Angew. Chem. Int. Ed.
2004, 43, 2201–2203; Angew. Chem. 2004, 116, 2251–2253; d)
R. B. Bedford, C. S. J. Cazin, D. Holder, Coord. Chem. Rev.
2004, 248, 2283–2321; e) E. A. B. Kantchev, C. J. O’Brien,
M. G. Organ, Angew. Chem. Int. Ed. 2007, 46, 2768–2813; An-
Bis{diphenylphosphino-[2-(E)-phenylvinyl]ferrocene}palladium Di-
chloride (5): Dichloromethane (15 mL) was added to [Pd(cod)Cl2]
(30 mg, 0.11 mmol, 1.0 equiv.) and rac-4 (100 mg, 0.21 mmol,
2.0 equiv.). After stirring at 25 °C for 1 h, the clear red solution
was evaporated to dryness. The residue obtained was washed with
diethyl ether (5ϫ 15 mL) and n-hexane (15 mL), and the title com-
pound {96 mg, 0.09 mmol, 81% based on [Pd(cod)Cl2]} was iso-
Eur. J. Org. Chem. 2014, 6676–6685
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6683

H. Lang et al.
FULL PAPER
gew. Chem. 2007, 119, 2824–2870; f) R. Martin, S. L. Buch-
wald, Acc. Chem. Res. 2008, 41, 1461–1473; g) N. Marion, S. P.
Nolan, Acc. Chem. Res. 2008, 41, 1440–1449; h) G. A. Mo-
lander, B. Canturk, Angew. Chem. Int. Ed. 2009, 48, 9240–9261;
Angew. Chem. 2009, 121, 9404–9425.
a) G. Bringmann, C. Günther, M. Ochse, O. Schupp, S. Tasler,
in: Progress in the Chemistry of Organic Natural Products, vol.
82 (Eds.: W. Herz, H. Falk, G. W. Kirby, R. E. Moore),
Springer, Vienna, Austria, 2001, p. 1–249; b) G. Bringmann, T.
Gulder, T. A. M. Gulder, M. Breuning, Chem. Rev. 2011, 111,
563–639.
a) R. Noyori, H. Takaya, Acc. Chem. Res. 1990, 23, 345–350;
b) Y. Chen, S. Yekta, A. K. Yudin, Chem. Rev. 2003, 103, 3155–
3211; c) J. M. Brunel, Chem. Rev. 2005, 105, 857–897; d) M.
Berthod, G. Mignani, G. Woodward, M. Lemaire, Chem. Rev.
2005, 105, 1801–1836; e) Y.-M. Li, F.-Y. Kwong, W.-Y. Yu,
A. S. C. Chan, Coord. Chem. Rev. 2007, 251, 2119–2144.
a) W. Tang, A. G. Capacci, X. Wei, W. Li, A. White, N. D.
Patel, J. Savoie, J. J. Gao, S. Rodriguez, B. Qu, N. Haddad,
B. Z. Lu, D. Krishnamurthy, N. K. Yee, C. H. Senanayake, An-
gew. Chem. Int. Ed. 2010, 49, 5879–5883; Angew. Chem. 2010,
122, 6015–6019; b) W. Tang, N. D. Patel, G. Xu, X. Xu, J. Sa-
voie, S. Ma, M.-H. Hao, S. Keshipeddy, A. G. Capacci, X. Wei,
Y. Zhang, J. J. Gao, W. Li, S. Rodriguez, B. Z. Lu, N. K. Yee,
C. H. Senanayake, Org. Lett. 2012, 14, 2258–2261; c) G. Xu,
W. Fu, G. Liu, C. H. Senanayake, W. Tang, J. Am. Chem. Soc.
2014, 136, 570–573.
Bhayana, S. L. Buchwald, J. Am. Chem. Soc. 2010, 132, 11278–
11287; d) A. Bermejo, A. Ros, R. Fernández, J. M. Lassaletta,
J. Am. Chem. Soc. 2008, 130, 15798–15799; e) A. Ros, B. Es-
tepa, A. Bermejo, E. Alvarez, R. Fernández, J. M. Lassaletta,
J. Org. Chem. 2012, 77, 4740–4750; f) Y. Uozumi, Y. Matsuura,
T. Arakawa, Y. M. A. Yamada, Angew. Chem. Int. Ed. 2009,
48, 2708–2710; Angew. Chem. 2009, 121, 2746–2748; g) S.-S.
Zhang, Z.-Q. Wang, M.-H. Xu, G.-Q. Lin, Org. Lett. 2010, 12,
5546–5549; h) X. He, S. Zhang, Y. Guo, H. Wang, G. Lin,
Organometallics 2012, 31, 2945–2948; i) T. Kamei, A. H. Sato,
T. Iwasawa, Tetrahedron Lett. 2011, 52, 2638–2641; j) S. Wang,
J. Li, T. Miao, W. Wu, Q. Li, Y. Zhuang, Z. Zhou, L. Qiu, Org.
Lett. 2012, 14, 1966–1969; k) W. Wu, S. Wang, Y. Zhou, Y. He,
Y. Zhuang, L. Li, P. Wan, L. Wang, Z. Zhou, L. Qiu, Adv.
Synth. Catal. 2012, 354, 2395–2402; l) Y. Zhou, S. Wang, W.
Wu, Q. Li, Y. He, Y. Zhuang, L. Li, J. Pang, Z. Zhou, L. Qiu,
Org. Lett. 2013, 15, 5508–5511; m) G. Shigeng, J. Tang, D.
Zhang, Q. Wang, Z. Chen, L. Weng, J. Organomet. Chem.
2012, 700, 223–229; n) T. Takemoto, S. Iwasa, H. Hamada,
K. Shibatomi, M. Kameyama, Y. Motoyama, H. Nishiyama,
Tetrahedron Lett. 2007, 48, 3397–3401; o) V. R. Jumde, A. Iuli-
ano, Tetrahedron: Asymmetry 2011, 22, 2151–2155; p) G.
Grach, G. Pieters, A. Dinut, V. Terrasson, R. Medimagh, A.
Bridoux, V. Razafimahaleo, A. Gaucher, S. Marque, J. Marrot,
D. Prim, R. Gil, J. G. Planas, C. Viñas, I. Thomas, J.-P. Roblin,
Y. Troin, Organometallics 2011, 30, 4074–4086; q) T. Yamam-
oto, Y. Akai, Y. Nagata, M. Suginome, Angew. Chem. Int. Ed.
2011, 50, 8844–8847; Angew. Chem. 2011, 123, 9006–9009; r)
P. Kasák, K. Mereiter, M. Widhalm, Tetrahedron: Asymmetry
2005, 16, 3416–3426; s) L. Sun, W.-M. Dai, Tetrahedron 2011,
67, 9072–9079; t) M. Mesˇková, M. Putala, Tetrahedron: Asym-
metry 2013, 24, 894–902; u) O. N. Gorunova, M. V. Livantsov,
Y. K. Grishin, M. M. Ilyin Jr., K. A. Kochetkov, A. V. Chu-
rakov, L. G. Kuz’mina, V. N. Khrustalev, V. V. Dunina, J. Or-
ganomet. Chem. 2013, 737, 59–63; v) T. Wang, X.-Q. Hao, J.-J.
Huang, K. Wang, J.-F. Gong, M.-P. Song, Organometallics
2014, 33, 194–205; w) L. Benhamou, C. Besnard, E. P. Kündig,
Organometallics 2014, 33, 260–266.
[4]
[5]
[6]
[7]
[8]
a) L. Wu, E. Drinkel, F. Gaggia, S. Capolicchio, A. Linden, L.
Falivene, L. Cavallo, R. Dorta, Chem. Eur. J. 2011, 17, 12886–
12890; b) L. Wu, A. Salvador, A. Ou, M. W. Shi, B. W. Skelton,
R. Dorta, Synlett 2013, 24, 1215–1220.
a) J. Yin, M. P. Rainka, X.-X. Zhang, S. L. Buchwald, J. Am.
Chem. Soc. 2002, 124, 1162–1163; b) G. Altenhoff, R. God-
dard, C. W. Lehmann, F. Glorius, Angew. Chem. Int. Ed. 2003,
42, 3690–3693; Angew. Chem. 2003, 115, 3818–3821; c) G. Al-
tenhoff, R. Goddard, C. W. Lehmann, F. Glorius, J. Am. Chem.
Soc. 2004, 126, 15195–15201; d) O. Navarro, R. A. Kelly III,
S. P. Nolan, J. Am. Chem. Soc. 2003, 125, 16194–16195; e) R.
Singh, M. S. Viciu, N. Kramareva, O. Navarro, S. P. Nolan,
Org. Lett. 2005, 7, 1829–1832; f) A. Chartoire, M. Lesieur, L.
Falivene, A. M. Z. Slawin, L. Cavallo, C. S. J. Cazin, S. P. No-
lan, Chem. Eur. J. 2012, 18, 4517–4521; g) G. Bastug, S. P. No-
lan, Organometallics 2014, 33, 1253–1258; h) T. Hoshi, T. Nak-
azawa, I. Saitoh, A. Mori, T. Suzuki, J.-i. Sakai, H. Hagiwara,
Org. Lett. 2008, 10, 2063–2066; i) T. Hoshi, I. Saitoh, T. Naka-
zawa, T. Suzuki, J.-i. Sakai, H. Hagiwara, J. Org. Chem. 2009,
74, 4013–4016; j) T. Hoshi, T. Honma, A. Mori, M. Konishi,
T. Sato, H. Hagiwara, T. Suzuki, J. Org. Chem. 2013, 78,
11513–11524; k) L. Ackermann, H. K. Potukuchi, A. Alt-
hammer, R. Born, P. Mayer, Org. Lett. 2010, 12, 1004–1007; l)
C. M. So, W. K. Chow, P. Y. Choy, C. P. Lau, F. Y. Kwong,
Chem. Eur. J. 2010, 16, 7996–8001; m) S. C. To, F. Y. Kwong,
Chem. Commun. 2011, 47, 5079–5081; n) A. Schmidt, A. Rah-
imi, Chem. Commun. 2010, 46, 2995–2997; o) S. Teo, Z. Weng,
T. S. A. Hor, J. Organomet. Chem. 2011, 696, 2928–2934; p) D.-
H. Lee, M.-J. Jin, Org. Lett. 2011, 13, 252–255; q) T. Tu, Z.
Sun, W. Fang, M. Xu, Y. Zhou, Org. Lett. 2012, 14, 4250–4253;
r) G.-Q. Li, Y. Yamamoto, N. Miyaura, Synlett 2011, 1769–
1773; s) M. G. Organ, S. Çalimsiz, M. Sayah, K. H. Hoi, A. J.
Lough, Angew. Chem. Int. Ed. 2009, 48, 2383–2387; Angew.
Chem. 2009, 121, 2419–2423; t) C. Valente, S. Çalimsiz, K. H.
Hoi, D. Mallik, M. Sayah, M. G. Organ, Angew. Chem. Int.
Ed. 2012, 51, 3314–3332; Angew. Chem. 2012, 124, 3370–3388;
u) Q. Zhao, C. Li, C. H. Senanayake, W. Tang, Chem. Eur. J.
2013, 19, 2261–2265; v) S. M. Raders, J. N. Moore, J. K. Parks,
A. D. Miller, T. M. Leißing, S. P. Kelley, R. D. Rogers, K. H.
Shaughnessy, J. Org. Chem. 2013, 78, 4649–4664.
M. Genov, A. Almorín, P. Espinet, Chem. Eur. J. 2006, 12,
[10]
9346–9352.
ˇ
[11] Ferrocenes: ligands, materials and biomolecules (Ed.: P. Steˇp-
nicˇka), Wiley, Chichester, UK, 2008.
[12] For selected examples, see: a) A. Jakob, B. Milde, P. Ecorchard,
C. Schreiner, H. Lang, J. Organomet. Chem. 2008, 692, 3821–
3830; b) D. Schaarschmidt, H. Lang, Catal. Commun. 2010,
11, 581–583; c) M. Lamac, J. Tauchman, S. Dietrich, I. Cisa-
rova, H. Lang, P. Stepnicka, Appl. Organomet. Chem. 2010, 24,
ˇ
326–331; d) P. Steˇpnicˇka, J. Schulz, T. Klemann, U. Siemeling,
I. Císarˇová, Organometallics 2010, 29, 3187–3200; e) A. Hilde-
brandt, N. Wetzold, P. Ecorchard, B. Walfort, T. Rüffer, H.
ˇ
Lang, Eur. J. Inorg. Chem. 2010, 3615–3627; f) P. Steˇpnicˇka, I.
Císarˇová, J. Schulz, Organometallics 2011, 30, 4393–4403; g) S.
Dietrich, A. Nicolai, H. Lang, J. Organomet. Chem. 2011, 696,
739–747; h) B. Milde, M. Lohan, C. Schreiner, T. Rüffer, H.
Lang, Eur. J. Inorg. Chem. 2011, 5437–5449; i) B. Milde, D.
Schaarschmidt, P. Ecorchard, H. Lang, J. Organomet. Chem.
2012, 706–707, 52–65; j) B. Milde, T. Rüffer, H. Lang, Inorg.
Chim. Acta 2012, 387, 338–345; k) M. Lohan, B. Milde, S.
Heider, J. M. Speck, S. Krauße, D. Schaarschmidt, T. Rüffer,
ˇ
H. Lang, Organometallics 2012, 31, 2310–2326; l) P. Steˇpnicˇka,
B. Schneiderová, J. Schulz, I. Císarˇová, Organometallics 2013,
32, 5754–5765; m) J.-C. Hierso, A. Fihri, R. Amardeil, P.
Meunier, H. Doucet, M. Santelli, B. Donnadieu, Organometal-
lics 2003, 22, 4490–4499; n) J.-C. Hierso, A. Fihri, R. Amardeil,
P. Meunier, H. Doucet, M. Santelli, Tetrahedron 2005, 61,
9759–9766; o) J.-C. Hierso, M. Beaupérin, P. Meunier, Eur. J.
Inorg. Chem. 2007, 3767–3780; p) D. Roy, S. Mom, M. Beaupé-
rin, H. Doucet, J.-C. Hierso, Angew. Chem. Int. Ed. 2010, 49,
6650–6654; Angew. Chem. 2010, 122, 6800–6804; q) D. Roy, S.
Mom, D. Lucas, H. Cattey, J.-C. Hierso, H. Doucet, Chem.
Eur. J. 2011, 17, 6453–6461; r) D. Roy, S. Mom, S. Royer, D.
[9]
a) A. N. Cammidge, K. V. L. Crépy, Chem. Commun. 2000,
1723–1724; b) J. Yin, S. L. Buchwald, J. Am. Chem. Soc. 2000,
122, 12051–12052; c) X. Shen, G. O. Jones, D. A. Watson, B.
6684
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6676–6685

A Chiral Phosphino(alkenyl)ferrocene for Suzuki–Miyaura Coupling
Lucas, J.-C. Hierso, H. Doucet, ACS Catal. 2012, 2, 1033–
[24] a) W. J. Sommer, K. Yu, J. S. Sears, Y. Ji, X. Zheng, R. J. Davis,
C. D. Sherrill, C. W. Jones, M. Weck, Organometallics 2005, 24,
4351–4361; b) D. J. M. Snelders, G. van Koten, R. J. M.
Klein Gebbink, J. Am. Chem. Soc. 2009, 131, 11407–11416.
[25] For comparison, 8a: 0.1 mol-% [Pd], 100 °C, 24 h, 95%;[50] 8b:
3 mol-% [Pd], 100 °C, 18 h, 93%;[50] 8c: 0.1 mol-% [Pd], 100 °C,
12 h, 96%;[50] 8n, 8p, 8q, 8s, 8t: 0.5 mol-% [Pd], 80 °C, 24 h,
79–99%;[8q] 8ac: 0.05 mol-% [Pd], 110 °C, 24 h, 97%;[8m] 8ad,
8af: 0.1 mol-% [Pd], 110 °C, 24 h, 84–95%.[8m]
[26] For the use of 1-bromo-N,N-dimethylnaphthalen-2-amine in
Suzuki–Miyaura C–C couplings, see: K. Mikami, T. Miyam-
oto, M. Hatano, Chem. Commun. 2004, 2082–2083.
[27] See, for example: J. F. Hartwig, Inorg. Chem. 2007, 46, 1936–
1947.
1041.
[13]
a) R. Gómez Arrayás, J. Adrio, J. C. Carretero, Angew. Chem.
Int. Ed. 2006, 45, 7674–7715; Angew. Chem. 2006, 118, 7836–
7878; b) Chiral Ferrocenes, in: Asymmetric Catalysis (Eds.: L.-
X. Dai, X.-L. Hou), Wiley-VCH, Weinheim, Germany, 2010;
ˇ
c) M. Drusan, R. Sebesta, Tetrahedron 2014, 70, 759–786.
[14]
[15]
For a recent review, see: D. Schaarschmidt, H. Lang, Organo-
metallics 2013, 32, 5668–5704.
a) A.-S. Castanet, F. Colobert, P.-E. Broutin, M. Obringer, Tet-
rahedron: Asymmetry 2002, 13, 659–665; b) A. N. Cammidge,
K. V. L. Crépy, Tetrahedron 2004, 60, 4377–4386; c) K. Mi-
kami, T. Miyamoto, M. Hatano, Chem. Commun. 2004, 2082–
2083; d) M. Genov, A. Almorín, P. Espinet, Tetrahedron:
Asymmetry 2007, 18, 625–627.
[28] A. F. Littke, C. Dai, G. C. Fu, J. Am. Chem. Soc. 2000, 122,
4020–4028.
[16]
[17]
a) J. F. Jensen, M. Johannsen, Org. Lett. 2003, 5, 3025–3028;
b) D. Vinci, N. Martins, O. Saidi, J. Bacsa, A. Brigas, J. Xiao,
Can. J. Chem. 2009, 87, 171–175; c) N. Debono, A. Labande,
E. Maoury, J.-C. Daran, R. Poli, Organometallics 2010, 29,
1879–1882; d) P. Loxq, N. Debono, S. Gülcemal, J.-C. Daran,
E. Manoury, R. Poli, B. Çetinkayac, A. Labande, New J. Chem.
2014, 38, 338–347.
a) D. Schaarschmidt, H. Lang, Eur. J. Inorg. Chem. 2010, 4811–
4821; b) H. Lang, D. Schaarschmidt, Technische Universität
Chemnitz, Germany, DE 102010001364A1, 2010; c) D.
Schaarschmidt, H. Lang, ACS Catal. 2011, 1, 411–416; d) M.
Korb, D. Schaarschmidt, H. Lang, Organometallics 2014, 33,
2099–2108.
[29] M. an der Heiden, H. Plenio, Chem. Eur. J. 2004, 10, 1789–
1797.
[30] A. L. Korich, P. M. Iovine, Dalton Trans. 2009, 39, 1423–1431.
[31] C. Amatore, A. Jutand, G. Le Duc, Chem. Eur. J. 2011, 17,
2492–2503.
[32] A. J. J. Lennox, G. C. Lloyd-Jones, Chem. Soc. Rev. 2014, 43,
412–443.
[33] Fujihara and co-workers observed enantiomeric excesses of 18–
69% for the coupling of 1-bromo-2-methoxynaphthalene and
(1-naphthyl)boronic acid, depending on the base applied. For
details, see: K. Sawai, R. Tatumi, T. Nakahodo, H. Fujihara,
Angew. Chem. Int. Ed. 2008, 47, 6917–6919; Angew. Chem.
2008, 120, 7023–7025.
[18] For an overview, see: I. J. S. Fairlamb, Org. Biomol. Chem.
2008, 6, 3645–3656.
[34] G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112–122.
[35] D. Schaarschmidt, A. Hildebrandt, S. Bock, H. Lang, J. Or-
ganomet. Chem. 2014, 751, 742–753.
[19] For selected examples, see: a) P. Maire, S. Deblon, F. Breher, J.
Geier, C. Böhler, H. Rüegger, H. Schönberg, H. Grützmacher,
Chem. Eur. J. 2004, 10, 4198–4205; b) E. Piras, F. Läng, H.
Rüegger, D. Stein, M. Wörle, H. Grützmacher, Chem. Eur. J.
2006, 12, 5849–5858; c) R. Shintani, W.-L. Duan, T. Nagano,
A. Okada, T. Hayashi, Angew. Chem. Int. Ed. 2005, 44, 4611–
4614; Angew. Chem. 2005, 117, 4687–4690; d) R. Shintani, W.-
L. Duan, K. Okamoto, T. Hayashi, Tetrahedron: Asymmetry
2005, 16, 3400–3405; e) W.-L. Duan, H. Iwamura, R. Shintani,
T. Hayashi, J. Am. Chem. Soc. 2007, 129, 2130–2138; f) T. Ni-
shimura, Y. Maeda, T. Hayashi, Org. Lett. 2011, 13, 3674–3677;
ˇ
[36] P. Steˇpnicˇka, M. Lamacˇ, I. Císarˇová, J. Organomet. Chem.
2008, 693, 446–456.
[37] D. Drew, J. R. Doyle, A. G. Shaver, in: Inorganic Syntheses:
Reagents for Transition Metal Complex and Organometallic
Syntheses, vol. 28 (Ed.: R. J. Angelici), John Wiley & Sons,
Inc., Hoboken, NJ, USA, 1990, p. 346–349.
[38] L. Hintermann, T. T. Dang, A. Labonne, T. Kribber, L. Xiao,
P. Naumov, Chem. Eur. J. 2009, 15, 7167–7179.
[39] M. Sauer, C. Yeung, J. H. Chong, B. O. Patrick, M. J.
MacLachlan, J. Org. Chem. 2006, 71, 775–788.
g) P. Kasák, V. B. Arion, M. Widhalm, Tetrahedron: Asym- [40] B. Andersh, D. L. Murphy, R. J. Olson, Synth. Commun. 2000,
metry 2006, 17, 3084–3090; h) Z. Liu, H. Du, Org. Lett. 2010,
30, 2091–2098.
ˇ
12, 3054–3057; i) P. Steˇpnicˇka, I. Císarˇová, Inorg. Chem. 2006,
[41] R. Adams, L. O. Binder, J. Am. Chem. Soc. 1941, 63, 2773–
ˇ
45, 8785–8798; j) P. Steˇpnicˇka, M. Lamacˇ, I. Císarˇová, J. Or-
2776.
ganomet. Chem. 2008, 693, 446–456; k) R. T. Stemmler, C. [42] A. C. Spivey, F. Zhu, M. B. Mitchell, S. G. Davey, R. L.
Bolm, Synlett 2007, 1365–1370; l) J. Csizmadiová, M. Mecˇia-
Jarvest, J. Org. Chem. 2003, 68, 7379–7385.
[43] H. Hock, F. Ernst, Chem. Ber. 1959, 92, 2732–2740.
[44] J. N. Moorthy, S. Samanta, J. Org. Chem. 2007, 72, 9786–9789.
[45] Y. Fu, S. Laurent, R. N. Muller, Eur. J. Org. Chem. 2002, 3966–
3973.
ˇ
rová, E. Rakovský, B. Horváth, R. Sebesta, Eur. J. Org. Chem.
2011, 6110–6116; m) Z. Cao, Y. Liu, Z. Liu, X. Feng, M. Zhu-
ang, H. Du, Org. Lett. 2011, 13, 2164–2167; n) Y. Liu, Z. Cao,
H. Du, J. Org. Chem. 2012, 77, 4479–4483.
[20] a) O. Riant, O. Samuel, H. B. Kagan, J. Am. Chem. Soc. 1993, [46] D. Zehm, W. Fudickar, M. Hans, U. Schilde, A. Kelling, T.
115, 5835–5836; b) O. Riant, O. Samuel, T. Flessner, S. Taud-
ien, H. B. Kagan, J. Org. Chem. 1997, 62, 6733–6745.
[21] The assay of [Pd2(dba)3] was determined by 1H NMR spec-
troscopy with respect to: S. S. Zalesskiy, V. P. Ananikov, Orga-
nometallics 2012, 31, 2302–2309.
[22] The reaction mixture was vigorously stirred to ensure sufficient
dispersion of mercury and the organic phase.
[23] For an overview on the discrimination between true homogen-
eous and metal-particle-assisted heterogeneous catalysis, see for
example: a) J. A. Widegren, R. G. Finke, J. Mol. Catal. A 2003,
198, 317–341; b) N. T. S. Phan, M. van der Sluys, C. W. Jones,
Adv. Synth. Catal. 2006, 348, 609–679; c) R. H. Crabtree,
Chem. Rev. 2012, 112, 1536–1554.
Linker, Chem. Eur. J. 2008, 14, 11429–11441.
[47] J. Morgan, J. T. Pinhey, J. Chem. Soc. Perkin Trans. 1 1990,
715–720.
[48] A. N. Cammidge, K. V. L. Crépy, Tetrahedron 2004, 60, 4377–
4386.
[49] I. Sircar, K. S. Gudmundsson, R. Martin, J. Liang, S. Nomura,
H. Jayakumar, B. R. Teegarden, D. M. Nowlin, P. M. Cardar-
elli, J. R. Mah, S. Connell, R. C. Griffith, E. Lazarides, Bioorg.
Med. Chem. 2002, 10, 2051–2066.
[50] T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J.
Am. Chem. Soc. 2005, 127, 4685–4696.
Received: July 4, 2014
Published Online: August 22, 2014
Eur. J. Org. Chem. 2014, 6676–6685
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6685