Exogenous-Base-Free Palladacycle-Catalyzed Highly Enantioselective Arylation of Imines with Arylboroxines

Article abstract of DOI:10.1002/anie.201501846

Enantiomerically pure benzylic amines are important for the development of new drugs. A readily accessible planar-chiral ferrocene-derived palladacycle is shown to be a highly efficient catalyst for the formation of N-substituted benzylic stereocenters; t

Full text of DOI:10.1002/anie.201501846

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501846
German Edition: DOI: 10.1002/ange.201501846
1,2-Additions
Exogenous-Base-Free Palladacycle-Catalyzed Highly Enantioselective
Arylation of Imines with Arylboroxines**
Carmen Schrapel and RenØ Peters*
Abstract: Enantiomerically pure benzylic amines are impor-
tant for the development of new drugs. A readily accessible
planar-chiral ferrocene-derived palladacycle is shown to be
a highly efficient catalyst for the formation of N-substituted
benzylic stereocenters; this catalyst accelerates the 1,2-addition
of arylboroxines to aromatic and aliphatic imines with excep-
tional levels of enantioselectivity. Using aldimines an exoge-
nous base was not necessary for the activation of the boroxines,
when acetate was used as an anionic ligand. Common
problems such as aryl–aryl homocouplings and imine hydro-
lysis were fully overcome, the latter even in the absence of
molecular sieves.
catalysts for this transformation.[8,9] In general, the PdII-
catalyzed additions of arylboronic acids to aldimines are
plagued by a competing imine hydrolysis and require the use
of molecular sieves to achieve acceptable yields.[8a,b,f] So far
the catalytic proficiency of Pd catalysts has not been
comparable to that of the best Rh catalysts in terms of
enantioselectivity and activity.[8] Pd catalysts with a compara-
ble efficiency would provide an attractive alternative, as Rh is
more expensive than Pd.[10]
Herein, we report that a readily available planar-chiral
ferrocene imidazoline palladacycle (FIP) previously devel-
oped by our group[11a,b] has been identified as an attractive Pd
catalyst for the arylation of imines with arylboroxines,
providing a variety of benzylic amines in almost enantiomer-
ically pure form. Important for the high performance is the
use of acetate as anionic ligand, which makes it possible to run
the reaction without stoichiometric amounts of an exogenous
base, which is often required to promote the transmetalation
of the aryl residue from boron to palladium.[12]
C
hiral a-branched benzylic amines constitute an important
structural motif in active pharmaceutical ingredients (APIs)
like Cetirizine[1] and Sertraline (both from Pfizer, Figure 1).[2]
Driven by the application of enantiopure benzylic amines as
APIs, the arylation of aldimines has been established as an
To our knowledge, all Pd complexes previously described
as catalysts in enantioselective arylations of imines using
arylboronic acid derivatives made use of neutral bidentate
ligands coordinating to a PdII center.[8,9] Besides imine
hydrolysis as a general problem, the undesired formation of
bisaryl homocoupling products (Ar–Ar) has been frequently
reported, which is explained by the formation of neutral
bisaryl–PdII intermediates[8] and subsequent reductive elimi-
nation. Pd0 is thus formed and this corresponds to the loss of
active catalyst. The use of palladacycle catalysts instead, in
which PdII is coordinated by a monoanionic C,N-ligand,[13]
might impede the formation of an undesired bisaryl–PdII
intermediate, as a second transmetalation should be less
favorable due to the formation of an anionic Pd center.
C,N-Palladacycles offer the additional advantage that the
position of different ligands can often be controlled since
neutral ligands (substrates) prefer the position trans to the N-
donor, whereas anionic ligands bind trans to the C-donor.[13]
Using a planar-chiral palladacycle we expected that this
preference might contribute to high enantioselectivity.[14] To
prove these hypotheses the addition of Ph-B(OH)2 (2a) to N-
tosylimine 1a was studied (Table 1). Product 4a has previ-
ously been shown to be a valuable precursor of Cetirizine.[7g]
Metallocene-derived imidazoline palladacycles have been
reported by our research group to be efficient catalysts for
various types of catalytic reactions.[11,15,16] With [{FIP-Cl}2]
(6 mol%)—activated by AgOTf (12 mol%) through removal
Figure 1. Examples for approved chiral benzylic amine drugs.
attractive strategy to set up N-substituted benzylic stereocen-
ters. Various types of arylmetal species including zinc,[3]
titanium,[4] and tin[5] reagents have been successfully
employed. The use of arylboronic acid derivatives has also
been intensively studied owing to the stability of these
reagents, their compatibility with a large number of functional
groups, their straightforward preparation, commercial avail-
ability, and relatively low cost.[6] Rhodium complexes have
emerged as the most versatile catalysts for the asymmetric
arylation of aldimines by arylboronic acids.[6,7] In addition,
several reports have described the use of palladium(II)
[*] Dipl.-Chem. C. Schrapel, Prof. Dr. R. Peters
Universität Stuttgart, Institut für Organische Chemie
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
E-mail: rene.peters@oc.uni-stuttgart.de
[**] This work was financially supported by the Deutsche Forschungs-
gemeinschaft (DFG, PE 818/4-1 and PE 818/4-2). We thank Dr.
Wolfgang Frey (Institut für Organische Chemie, Universität Stutt-
gart) for the X-ray crystal structure analyses.
of the Cl bridges to facilitate substrate coordination[11]
—
product 4a was formed in almost enantiomerically pure form
(Table 1, entry 1). This initial reaction was performed at 208C
in toluene in the presence of activated 4 Š molecular sieves
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501846.
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Table 1: Development of the title reaction.
solvent led to slightly improved reactivity. Under
otherwise identical conditions the product was
formed in nearly quantitative yield and with
> 99% ee at 658C (Table 1, entry 7).[21]
We then applied these optimized conditions to
the reactions of other imine and boroxine substrates
(Table 2). In general, imine hydrolysis was largely
avoided in all 21 examples, while products were
usually formed in good to excellent yields. In most
examples the products were nearly enantiomerically
pure with ee values exceeding 99%. Exceptions were
found for only entries 11 and 20 (both 99% ee) and
17 (98% ee). Ortho, meta, and para substituents on
the aromatic residues R1 and R2 of the imine and the
boroxine substrates, respectively, were accommo-
dated under the reaction conditions. The efficiency
when an ortho residue is present on the boroxine is of
particular note (Table 2, entry 7), as these substrates
are usually quite challenging. Electronic effects
No.
X
Y
2a or 3a
(equiv)
Base[a] Additive
T
Yield
Hydro-
ee 4a
[8C] 4a [%][b] lysis [%][b] [%][c]
1
2
3
4
6
1
1
1
1
1
1
OTf 2a (2)
OTf 2a (2)
–
OAc 3a (1)
OAc 3a (1)
OAc 3a (1)
OAc 3a (1)
KF
KF
4Š MS 20
4Š MS 20
92
74
3
13
>99
>99
>99
>99
n.d.
2a/3a (2) KF
4Š MS 20 <1–92 <1–7
NaOAc
–
–
–
–
20
20
70
65
25
2
99
99
<1
<1
<1
<1
5
–
–
–
6
>99
>99
7[d]
[a] 1 equiv was used. [b] Determined by 1H NMR analysis of the crude product using
mesitylene as internal standard. [c] Determined by HPLC. [d] The reaction was
performed in chlorobenzene as solvent. OTf=F3CSO3.
(MS) and with KF as a stoichiometric base.[17] With a preca-
Table 2: Application of the optimized reaction conditions to various
talyst loading of 1 mol% hydrolysis was not fully suppressed
(Table 1, entry 2). This problem seemed to be solved initially
by the direct use of [FIP-Cl]2 (1 mol%), that is, without
catalyst activation by a silver salt. Using boronic acid 2a the
product was formed in high yield and in nearly enantiopure
form (Table 1, entry 3).
substrates.
However, we noticed that the reactivity strongly
depended on the purity of the boronic acid. Analysis of
different new batches of 2a from different commercial
suppliers revealed that 2a is very often contaminated by
large quantities of the corresponding boroxine. Sometimes
commercial batches labeled as boronic acid 2a were in fact
mainly boroxine 3a and resulted in no product under the
conditions of Table 1, entry 3, while in general yields
decreased with increasing proportion of 3a.[18] The use of
pure 3a gave no reaction at all, even when the catalyst loading
was increased to 6 mol%. Still, the development of a method
making use of arylboroxines appeared to be more desirable in
order to avoid reproducibility problems caused by the varying
composition of commercial boronic acids.
As 3a was found to be significantly less reactive than 2a,
the transmetalation was expected to be less efficient with the
former. We were speculating that it might be facilitated by an
anionic ligand at the Pd center which would offer sufficient
Lewis basicity for additional coordination to the boroxine
(similar to the “oxo–palladium pathway”).[17,19] Promising
results were obtained with acetate as ligand.[20] At 208C in the
presence of stoichiometric NaOAc some reactivity was
noticed towards 4a which was formed in nearly enantiomer-
ically pure form (Table 1, entry 4). In the absence of NaOAc
this reactivity disappeared (Table 1, entry 5); however, 4a
could be obtained in quantitative yield at higher temperatures
(Table 1, entry 6). A survey of different silver salts for
chloride removal showed that the nature of the anionic
ligand is crucial for the observed reactivity. With less Lewis
basic anions like triflate and trifluoroacetate, little or no
product was formed (not shown). The use of chlorobenzene as
No.
4
R1
R2
SO2R Yield [%][a] ee [%][b]
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
2-ClC6H4
Ph
Ph
Ts
Ts
Ts
Ts
99
84
98
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
99
>99
>99
>99
>99
>99
98
4-MeOC6H4
4-PhC6H4
3,4-F2C6H4
70[c,d]
50[d]
95
4-MeO2CC6H4 Ts
3-MeOC6H4
2-MeOC6H4
4-MeOC6H4
Ph
4-PhC6H4
4-MeOC6H4
4-PhC6H4
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
96
99
91
85
98
99
86
85
10 4j
11 4k
12 4l
Ph
13 ent-4k 4-MeOC6H4 Ph
14 4m
15 4n
16 4o
17 4p
18 4q
19 4r
20 4s
21 4a’
4-O2NC6H4
4-MeC6H4
2-naphthyl
thiophen-2-yl Ph
Cy
iPr
Ph(CH2)2
4-ClC6H4
4-PhC6H4
Ph
Ph
96
91
55[c,d]
95[c,d]
92[c,d]
32[d,e]
Ph
Ph
Ph
Ph
>99
>99
99
pNs 91[d]
>99
[a] Yield of isolated product. [b] Determined by HPLC. [c] Reaction
temperature: 808C. [d] 2 mol% of [FIP-Cl]2. [e] Determined by 1H NMR
analysis using an internal standard (pTs =4-MeC6H4SO2, pNs=4-
O2NC6H4SO2).
caused by substituents on R1 did not significantly affect the
product yields. Both s-donors (Table 2, entry 15) and s-
acceptors (entries 1–10) as well as p-donors (entry 13) and p-
acceptors (entry 14) were all well tolerated on the aromatic
rings. In addition, good to high yields were obtained for
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imines in which R1 is either a polycyclic aromatic hydrocarbon
(Table 2, entry 16), an electron-rich heterocycle (entry 17), or
an a-branched alkyl residue (entries 18 and 19). Imines with
an a-unbranched alkyl residue, which are challenging due to
the imine/enamine equilibrium, also react with high enantio-
selectivity, but side reactions were noticed and the product
decomposed during its purification (Table 2, entry 20). Grat-
ifyingly, the title reaction is also applicable to imines with
other N-sulfonyl residues besides tosyl. This is shown in
Table 2, entry 21 for a para-nosyl residue, which is well known
as a very versatile N-protecting group that is readily
removable under mild reaction conditions.[22]
Also the boroxine residues R2 can be equipped with
functional groups displaying electron-withdrawing or -donat-
ing effects. Still relatively good reactivity was found, for
example, with a less nucleophilic boroxine carrying two
fluorine atoms on R2, albeit a higher temperature and catalyst
loading were required to obtain a useful yield of 4d (Table 2,
entry 4). A useful yield was also obtained for the difficult case
of a boroxine carrying ester moieties as p-acceptors (Table 2,
entry 5).
Entries 11 and 13 in Table 2 demonstrate that both
possible product enantiomers are accessible on demand in
almost enantiomerically pure form with an identical catalyst
batch by simply switching the imineꢀs and boroxineꢀs sub-
stitution patterns. The absolute configurations of products 4a
and 4k were unambiguously determined by X-ray crystal
structure analysis.[23]
Scheme 1. Possible explanations of the catalytic key steps: a) acetate-
promoted transmetalation of R2 from boroxines to PdII; b) working
model to rationalize the stereochemical outcome of the 1,2-addition
reaction; c) product decomplexation and regeneration of a Pd–OAc
moiety.
Preliminary studies have shown that the formation of N-
substituted quaternary stereocenters[9] is also possible with
high yield and enantioselectivity using our palladacycle
catalyst [Eq. (1)].[24] Starting from ketimine 5, a base (here
KOAc, 2 equiv) was necessary though for high efficiency in
terms of reactivity and enantioselectivity which are otherwise
moderate.
ferrocenyl core to minimize repulsive steric interactions.[25]
Product decomplexation should be possible by reaction of 11
with 9 and would be accompanied by acetate transfer to the
PdII center, thus regenerating catalyst 12 (Scheme 1c).
Mechanistic support for the acetate-promoted transmeta-
lation was obtained by ESI-HRMS examination of a solution
in which activated catalyst (2 mol%) and boroxine 3a were
stirred for 1 h in chlorobenzene at 658C in the absence of an
exogenous base. As dominant Pd-containing species the Pd–
Ph adduct 8 was detected (R2 = Ph, no ligand L present, mass
found: m/z = 742.0552; calculated: m/z = 742.0579). In con-
trast, in the presence of additional imine 1a (1 equiv) complex
8 was not detectable under otherwise identical conditions, but
a species with a mass that would fit to either 10 or 11 (mass
found: m/z = 1060.0725; calculated: m/z = 1060.0745).
In conclusion, we report a highly enantioselective asym-
metric arylation of N-sulfonylimines catalyzed by a readily
available planar-chiral palladacycle (prepared in three steps
starting from FcCONH2[11a,b]). Arylboroxines were initially
found to be unreactive. High efficiency could be achieved by
use of acetate as an anionic ligand for the catalytically active
PdII center. The latter should facilitate the transmetalation
step and an exogenous stoichiometric base could thus be
avoided allowing for mild reaction conditions. In addition,
imine hydrolysis could be fully suppressed even in the absence
of molecular sieves, which is necessary for other Pd catalysts,
while aryl–aryl homocouplings are avoided probably as
a result of the anionic nature of the C,N-ligand.
Our current understanding of the title reaction is illus-
trated in Scheme 1. We propose that a PdII-bound acetate
ligand activates the boroxine by an additional coordination to
give intermediate 7 thus enabling a shift of R2 (Scheme 1a). In
this scenario the acetate would be trapped by a boron atom to
give 9 (the other R2 groups in 9 might also be replaced then).
The stereochemical outcome of the addition reaction is
explained by the working model 10 (Scheme 1b). Based on
the typical coordination behavior of C,N-palladacycles,[11e] we
assume that neutral imines preferably coordinate trans to the
N donor, whereas the anionic residue R2 adopts the cis
position. The very efficient face differentiation of the imine is
expected to be supported by a reactive conformation in which
the sulfonyl moiety of the imine points away from the
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2010, 5, 1726; d) R. Peters, D. F. Fischer, S. Jautze, Top.
Organomet. Chem. 2011, 33, 139.
Keywords: 1,2-additions · boronic acids · ketimines ·
metallocene · transmetalation
[14] Selected alternative addition reactions of arylboronic acids (or
derivatives) to non-imine electrophiles: a) J. Wong, K. Gan, H. J.
Chen, S. A. Pullarkat, Adv. Synth. Catal. 2014, 356, 3391; b) A. L.
Gottumukkala, J. Suljagic, K. Matcha, J. G. de Vries, A. J.
Minnaard, ChemSusChem 2013, 6, 1636; c) A. L. Gottumukkala,
K. Matcha, M. Lutz, J. G. de Vries, A. J. Minnaard, Chem. Eur. J.
2012, 18, 6907; d) F. J. Williams, E. R. Jarvo, Angew. Chem. Int.
Ed. 2011, 50, 4459; Angew. Chem. 2011, 123, 4551; e) Y. Suzuma,
S. Hayashi, T. Yamamoto, Y. Oe, T. Ohta, Y. Ito, Tetrahedron:
Asymmetry 2009, 20, 2751; f) Q. Zhang, J. Chen, M. Liu, H. Wu,
J. Cheng, C. Qin, W. Su, J. Ding, Synlett 2008, 935; g) T.-K.
Zhang, D.-L. Mo, L.-X. Dai, X.-L. Hou, Org. Lett. 2008, 10, 3689;
h) Y.-X. Liao, C.-H. Xing, P. He, Q.-S. Hu, Org. Lett. 2008, 10,
2509; i) P. He, Y. Lu, C.-G. Dong, Q.-S. Hu, Org. Lett. 2007, 9,
343; j) T. Yamamoto, T. Ohta, Y. Ito, Org. Lett. 2005, 7, 4153;
k) P. He, Y. Lu, Q.-S. Hu, Tetrahedron Lett. 2007, 48, 5283; l) Y.
Suzuma, T. Yamamoto, T. Ohta, Y. Ito, Chem. Lett. 2007, 36, 470;
m) F. Gini, B. Hessen, A. J. Minnaard, Org. Lett. 2005, 7, 5309;
n) T. Nishikata, Y. Yamamoto, N. Miyaura, Angew. Chem. Int.
Ed. 2003, 42, 2768; Angew. Chem. 2003, 115, 2874.
[15] Selected studies using ferrocenyl bisimidazolines: a) M. Weber,
W. Frey, R. Peters, Adv. Synth. Catal. 2012, 354, 1443; b) M.
Weber, S. Jautze, W. Frey, R. Peters, Chem. Eur. J. 2012, 18,
14792; c) M. Weber, W. Frey, R. Peters, Chem. Eur. J. 2013, 19,
8342; d) M. Weber, W. Frey, R. Peters, Angew. Chem. Int. Ed.
2013, 52, 13223; Angew. Chem. 2013, 125, 13465; e) T. Hellmuth,
S. Rieckhoff, M. Weiss, K. Dorst, W. Frey, R. Peters, ACS Catal.
2014, 4, 1850; f) M. Weiss, R. Peters, ACS Catal. 2015, 5, 310.
[16] Selected applications of imidazolines as chiral ligands: a) S.
Nakamura, K. Hyodo, Y. Nakamura, N. Shibata, T. Toru, Adv.
Synth. Catal. 2008, 350, 1443; b) H. Liu, D.-M. Du, Adv. Synth.
Catal. 2010, 352, 1113; c) M. Ohara, S. Nakamura, N. Shibata,
Adv. Synth. Catal. 2011, 353, 3285; d) K. Hyodo, S. Nakamura, K.
Tsuji, T. Ogawa, Y. Funahashi, N. Shibata, Adv. Synth. Catal.
2011, 353, 3385; e) K. Hyodo, S. Nakamura, N. Shibata, Angew.
Chem. Int. Ed. 2012, 51, 10337; Angew. Chem. 2012, 124, 10483;
f) K. Hyodo, M. Kondo, Y. Funahashi, S. Nakamura, Chem. Eur.
J. 2013, 19, 4128; g) S. Nakamura, K. Hyodo, M. Nakamura, D.
Nakane, H. Masuda, Chem. Eur. J. 2013, 19, 7304.
How to cite: Angew. Chem. Int. Ed. 2015, 54, 10289–10293
Angew. Chem. 2015, 127, 10428–10432
[1] D. A. Pflum, D. Krishnamurthy, Z. Han, S. A. Wald, C. H.
Senanayake, Tetrahedron Lett. 2002, 43, 923.
[2] W. M. Welch, A. R. Kraska, R. Sarges, K. B. Koe, J. Med. Chem.
1984, 27, 1508.
[3] N. Hermanns, S. Dahmen, C. Bolm, S. Bräse, Angew. Chem. Int.
Ed. 2002, 41, 3692; Angew. Chem. 2002, 114, 3844.
[4] T. Hayashi, M. Kawai, N. Tokunaga, Angew. Chem. Int. Ed. 2004,
43, 6125; Angew. Chem. 2004, 116, 6251.
[5] M. Hayashi, M. Ishigedani, J. Am. Chem. Soc. 2000, 122, 976.
[6] Review: C. S. Marques, A. J. Burke, ChemCatChem 2011, 3, 635.
[7] Selected examples: a) T. Nishimura, A. Noishiki, Y. Ebe, T.
Hayashi, Angew. Chem. Int. Ed. 2013, 52, 1777; Angew. Chem.
2013, 125, 1821; b) T. Nishimura, A. Noishiki, G. C. Tsui, T.
Hayashi, J. Am. Chem. Soc. 2012, 134, 5056; c) T. Korenaga, A.
Ko, K. Uotani, Y. Tanaka, T. Sakai, Angew. Chem. Int. Ed. 2011,
50, 10703; Angew. Chem. 2011, 123, 10891; d) R. Shintani, M.
Takeda, T. Tsuji, T. Hayashi, J. Am. Chem. Soc. 2010, 132, 13168;
e) R. B. C. Jagt, P. Y. Toullec, D. Geerdink, J. G. de Vries, B. L.
Feringa, A. J. Minnaard, Angew. Chem. Int. Ed. 2006, 45, 2789;
Angew. Chem. 2006, 118, 2855; f) N. Tokunaga, Y. Otomaru, K.
Okamoto, K. Ueyama, R. Shintani, T. Hayashi, J. Am. Chem.
Soc. 2004, 126, 13584; g) N. Kuriyama, T. Soeta, X. Hao, Q.
Chen, K. Tomioka, J. Am. Chem. Soc. 2004, 126, 8128.
[8] a) G.-N. Ma, T. Zhang, M. Shi, Org. Lett. 2009, 11, 875; b) Z. Liu,
M. Shi, Tetrahedron 2010, 66, 2619; c) C. S. Marques, A. J. Burke,
Eur. J. Org. Chem. 2010, 1639; d) J. Chen, X. Lu, W. Lou, Y. Ye,
H. Jiang, W. Zeng, J. Org. Chem. 2012, 77, 8541; e) H. Dai, M.
Yang, X. Lu, Adv. Synth. Catal. 2008, 350, 249; f) H. Dai, X. Lu,
Tetrahedron Lett. 2009, 50, 3478.
[9] For very efficient Pd-catalyzed methods employing ketimines,
see: a) G. Yang, W. Zhang, Angew. Chem. Int. Ed. 2013, 52, 7540;
Angew. Chem. 2013, 125, 7688; b) C. Jiang, Y. Lu, T. Hayashi,
Angew. Chem. Int. Ed. 2014, 53, 9936; Angew. Chem. 2014, 126,
10094; c) M. Quan, G. Yang, F. Xie, I. D. Gridnev, W. Zhang,
Org. Chem. Front. 2015, 2, 398.
[10] Engelhard Industrial Bullion (EIB) Prices for one troy ounce
(data for November 19, 2014): Rh: $ 1190; Pd: $ 786 (source:
http://apps.catalysts.basf.com/apps/eibprices/mp/).
[17] Review about the transmetalation of boronic acids or deriva-
tives: A. J. J. Lennox, G. C. Lloyd-Jones, Angew. Chem. Int. Ed.
2013, 52, 7362; Angew. Chem. 2013, 125, 7506.
[11] Selected studies using ferrocenyl imidazoline monopalladacy-
cles: a) M. E. Weiss, D. F. Fischer, Z.-q. Xin, S. Jautze, W. B.
Schweizer, R. Peters, Angew. Chem. Int. Ed. 2006, 45, 5694;
Angew. Chem. 2006, 118, 5823; b) D. F. Fischer, A. Barakat, Z.-q.
Xin, M. E. Weiss, R. Peters, Chem. Eur. J. 2009, 15, 8722; c) R.
Peters, Z.-q. Xin, F. Maier, Chem. Asian J. 2010, 5, 1770; d) S. H.
Eitel, M. Bauer, D. Schweinfurth, N. Deibel, B. Sarkar, H. Kelm,
H.-J. Krüger, W. Frey, R. Peters, J. Am. Chem. Soc. 2012, 134,
4683; e) M. Weber, R. Peters, J. Org. Chem. 2012, 77, 10846;
f) S. H. Eitel, S. Jautze, W. Frey, R. Peters, Chem. Sci. 2013, 4,
2218; g) J. M. Bauer, W. Frey, R. Peters, Angew. Chem. Int. Ed.
2014, 53, 7634; Angew. Chem. 2014, 126, 7764; h) T. Hellmuth,
W. Frey, R. Peters, Angew. Chem. Int. Ed. 2015, 54, 2788; Angew.
Chem. 2015, 127, 2829.
[18] The different commercial suppliers were not able to solve this
purity problem after we informed them about this issue. Our
own attempts to prepare suitable pure boronic acids also failed,
because a completely anhydrous batch is required to avoid any
imine hydrolysis and upon removal of water the formation of
varying amounts of boroxine was usually observed.
[19] During the course of these studies a stoichiometric transmeta-
lation has been reported from a Pd – OAc species: A. R. Kapdi,
G. Dhangar, J. L. Serrano, J. PØrez, L. Garcia, I. J. S. Fairlamb,
Chem. Commun. 2014, 50, 9859.
[20] Very recently it was shown that acetate-bridged palladacycle
dimers exist in solution in equilibrium with their monomers: K.
Panchal, J. Amin, F. X. Roca, M. Motevalli, P. N. Horton, S. J.
Coles, C. J. Richards, J. Organomet. Chem. 2015, 775, 12.
[21] In toluene at 658C the yield of 4a was 92%. In ClC6H5 at 658C,
lower catalyst loadings resulted in reduced yields. With
0.5 mol% and 0.05 mol%, product yields of 73% (> 99% ee)
and 6% (ee n.d.) were noticed.
[12] For other methods where stoichiometric bases were not neces-
sary for the transmetalation from a boronic acid to palladium,
see e.g.: a) Ref. [9a]; b) Ref. [9b]; c) K. Kikushima, J. C. Holder,
M. Gatti, B. M. Stoltz, J. Am. Chem. Soc. 2011, 133, 6902;
d) ref. [8e]; e) S. Lin, X. Lu, Org. Lett. 2010, 12, 2536.
[22] P. G. M. Wuts, T. W. Greene, Greene’s Protective Groups in
Organic Synthesis, 4th ed., Wiley-Interscience, 2006.
[23] CCDC 1050456 (4a) and 1050457 (4k) contain the supplemen-
tary crystallographic data for this paper. These data can be
[13] a) J. Dupont, M. Pfeffer, Palladacycles, Wiley-VCH, Weinheim,
2008; b) C. J. Richards in Chiral Ferrocenes in Asymmetric
Catalysis (Eds.: L.-X. Dai, X.-L. Hou), Wiley-VCH, Weinheim,
2010, pp. 337 – 368; c) H. Nomura, C. J. Richards, Chem. Asian J.
10292 www.angewandte.org
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Angew. Chem. Int. Ed. 2015, 54, 10289 –10293

Angewandte
Chemie
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[24] The absolute configuration of 6 was assigned by comparison to
literature. See Ref. [7b].
[25] Ferrocene reviews: Chiral Ferrocenes in Asymmetric Catalysis
(Eds. L.-X. Dai, X.-L. Hou), Wiley-VCH, Weinheim, 2010.
Received: February 26, 2015
Revised: April 30, 2015
Published online: June 18, 2015
Angew. Chem. Int. Ed. 2015, 54, 10289 –10293
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 10293