Synthesis of gold complexes bearing sterically highly encumbered, chiral carbene ligands

Article abstract of DOI:10.1021/om101192k

The synthesis of chiral carbene ligands derived from bis(tetrahydroisoquinoline) bearing sterically highly demanding, rigid substituents is described. Their corresponding gold complexes were structurally elucidated and successfully employed as catalysts for the desymmetrization of 1,4-diynamides.

Full text of DOI:10.1021/om101192k

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pubs.acs.org/Organometallics
Synthesis of Gold Complexes Bearing Sterically Highly Encumbered,
Chiral Carbene Ligands
Kristina Wilckens, Dieter Lentz,† and Constantin Czekelius*
Institut f€ur Chemie und Biochemie, Freie Universit€at Berlin, Takustrasse 3, D-14195 Berlin, Germany
S Supporting Information
b
ABSTRACT: The synthesis of chiral carbene ligands derived
from bis(tetrahydroisoquinoline) bearing sterically highly de-
manding, rigid substituents is described. Their corresponding
gold complexes were structurally elucidated and successfully
employed as catalysts for the desymmetrization of 1,4-diyna-
mides.
ince the first reports of N-heterocyclic carbenes1 (NHCs) this
compound class has become a major area of research,
induction. In this paper we describe the synthesis of sterically
highly encumbered, chiral carbene ligands derived from bis-
(tetrahydroisoquinoline)11 and the preparation and structure
of the corresponding gold complexes, as well as their application
in the desymmetrization of 1,4-diynamides.
S
focusing on their application as organocatalysts or in catalytically
active transition-metal complexes.2 Carbene complexes comple-
ment and sometimes exceed the properties of catalysts incorpor-
ating phosphine ligands with respect to higher thermal stability
and resistance toward oxidation. However, while a wealth of
chiral phosphines is known and has been successfully employed
in highly enantioselective catalytic processes, the applications of
related chiral carbene ligands are far more limited in number.3,4
This may be explained by the different geometries of the two
compound classes. Phosphines with a stereogenic phosphorus
atom, which is very close to the metal center, as well as bidentate
phosphine ligands with a chiral backbone are readily prepared
and the corresponding metal complexes synthesized by simple
mixing with a metal salt in the majority of cases. NHC ligands
permit the placement of the stereogenic moiety only at some
distance from the metal center, causing the catalytically active
complex to be spatially more open. In addition, only a few
bidentate carbene complexes have been reported for successful
application in enantioselective catalysis.5
Recently, we reported a gold(I)-catalyzed desymmetrization
of 1,4-diynes employing optically active gold carbene
complexes.6 Gold-catalyzed transformations have attracted in-
creasing interest over the last few years.7 Especially, activation of
alkynes, allenes, and alkenes followed by nucleophilic addition of
O-,8 N-,9 or C-nucleophiles10 were found to proceed with high
efficiency and under mild reaction conditions. Herein, different
phosphine or carbene ligands permit the tuning of the Au(I)
catalyst reactivity and selectivity, also with respect to enantiose-
lective transformations. Due to the linear coordination geometry
of Au(I) and the assumed anti addition of a nucleophile to the
activated multiple bond, ligands bound to the metal center need
to exhibit a significant size and steric bulk for effective chiral
Our synthetic strategy for the preparation of the desired
substituted bis(tetrahydroisoquinoline) derivatives was inspired
by a ligand synthesis published by Herrmann and co-workers
(Chart 1, 8a).11c An extension of this methodology should allow
for a late-stage derivatization of the ligand scaffold in order to
easily obtain a variety of structurally diverse compounds which
could be screened in the gold-catalyzed desymmetrization.
Therefore, the parent phenyl substituent was replaced by a p-
bromophenyl group. This moiety serves as a convenient handle
for cross-coupling, allowing the incorporation of various biaryl
substituents which should provide sufficient rigidity in a structu-
rally well-defined scaffold.12 The synthesis of diamine 5 is
depicted in Scheme 1. Phenylacetyl chloride was reacted
with bromobenzene under Friedel-Crafts conditions to give
ketone 2.13 This was transformed into the secondary amine rac-3
by a reductive amination reaction. It is worth noting that only
employment of ammonium acetate and sodium cyanoborohy-
dride in a mixture of methanol and THF proved efficient for this
step. Herein, addition of THF was shown to be essential to
suppress simple ketone reduction and the formation of the
dibenzylamine derivative. Trials to apply Leuckart-Wallach
conditions or to reduce the corresponding ketone oxime by
hydrogenation or with zinc/formic acid provided no satisfying
results. Resolution of the secondary amine rac-3 was achieved by
treatment with tartaric acid and fractional crystallization of
the corresponding ammonium salt from ethanol/2-propanol.
Received: December 22, 2010
Published: March 01, 2011
r
2011 American Chemical Society
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Chart 1. Sterically Encumbered Carbene Ligand Precursors with Biphenyl or Terphenyl Substitution
rather slow for the sterically more demanding ligands.20 In
contrast, deprotonation of the imidazolinium salts 8 with KOtBu
and subsequent treatment with Me2SAuCl led to the desired
products 9, which were stable enough to be purified by silica gel
chromatography and were obtained as white solids.21
Scheme 1. Synthesis of Chiral Bis(tetrahydroisoquinoline) 5
Single crystal X-ray diffraction of the gold complex 9c
permitted structural insight and the determination of the abso-
lute configuration (Figure 1). The tetragonal unit cell has
significant size (a = 26.152(15), c = 12.237(7) Å, V = 8369(7) Å3)
and contains four pairs of two independent molecules. The Au-
C distance (1.995(7) Å) and the linearity of the C-Au-Cl
bonds (177.3 and 179.2°) are in good agreement with those in
related known complexes.22 The gold atoms form a continuous
right-handed helical chain according to Sohnke space group P43
with Au-Au distances of 3.194(2) and 3.258(2) Å, respectively.
These distances are in the typical range for aurophilic interac-
tions found in gold carbene complexes.23 Interestingly, the
trifluoromethyl groups at the ligand substituents are in close
proximity in the crystal, presumably by a stabilizing interaction
similar to interactions in fluorous phases (Figure 2).24
Mass spectroscopic studies indicated the possibility of the
formation of gold bis-carbene complexes. When gold carbene
complex 9i was treated with sodium tetraphenylborate in dichloro-
methane/methanol and submitted to ESI-MS, the formation of the
Bischler-Napieralski cyclization of the formylated amine gave
the optically active 3-aryldihydroisoquinoline 4 in a yield of
72%.14 Reductive dimerization with zinc and Me3SiCl provided
chiral diamine 5 as a single diastereomer in 76% yield.15 Gratify-
ingly, in this reaction no debromination by zinc was observed.
At this point the stage was set for diversifying the ligand
structure by palladium-catalyzed cross-coupling reactions.16,17
Suzuki coupling18 provided access to a variety of different
sterically encumbered ligands bearing a biphenyl or terphenyl
motif19 (Scheme 2). Despite the significant size of the substit-
uents, the cross-coupling reactions proceeded in useful yields of
44-84%. Treatment of the diamines 7 with triethyl orthofor-
mate gave the corresponding imidazolinium salts 8 as precursors
for the carbene ligands (Chart 1).
þ
AuL2 cation with very good agreement of experimental and
calculated isotope distributions was observed (Supporting Informa-
tion). Whether such intermediates play a significant role in catalytic
processes in solution, where the chloride ligand is often replaced by a
weakly coordinating anion such as tetrafluoroborate, will be the
subject of future studies.
The catalytic activity of the new chiral gold carbene complexes
was evaluated in the desymmetrization of diynesulfonamide 10.
The cyclization of this compound class had proven difficult with
gold phosphine complexes (i.e., [Cy3P]AuCl), leading to fast
catalyst inactivation.6b Gold complexes 9a-i were premixed
with substoichiometric quantities of silver tetrafluoroborate in
toluene to form the catalytically active species. We were pleased
to find that the catalysts remained active over the course of the
reaction and the enamide product 11 was obtained in yields up
to 77% (Table 1, entry 6). The highest enantioselectivity
(51% ee) was observed with a catalyst bearing the most bulky
In order to test the new class of ligands with respect to their
behavior in asymmetric catalysis, the corresponding gold com-
plexes were synthesized. It was found that transmetalation from
the silver carbene complexes (obtained by using Ag2O) was
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Scheme 2. Synthesis of the Carbene Ligand Precursors
Table 1. Gold-Catalyzed Desymmetrization of Diynesulfon-
amide 10
Figure 1. Molecular structure (Diamond 3.125) of complex 9c.
entry
gold complex
time/h
yield/%
ee/%
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9f
20
3
53
18
22
45
34
39
51
30
40
traces
52
14
6
36
7
37
9g
9h
9i
3
77
6
50
14
63
gold phosphine catalysts known for this transformation. The
straightforward synthesis, the late-stage diversification, and their
structural rigidity should cause the depicted ligand class to be
candidates also for related transition-metal complexes and applica-
tions in asymmetric catalysis when high steric restriction is intended.
Studies aiming in this direction are currently in progress, and the
results will be reported in due course.
’ ASSOCIATED CONTENT
S
Supporting Information. Text and figures giving experi-
b
mental procedures, characterization data, and NMR spectra for
new compounds and a CIF file giving X-ray crystallographic data
for compound 9c. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 2. Unit cell (ViewerLite) of complex 9c, viewed along the 001
axis (hydrogen atoms omitted for clarity).
ligand (9g), which is comparable to the best enantioselec-
tivity of 60% ee that was obtained using the chiral gold
phosphine complex [MeOBiPHEP(AuCl)2]. In this respect
it is worth mentioning that examples of gold-catalyzed
desymmetrizations of alkynes are very rare.6 In these trans-
formations the stereochemical control is quite challenging
and only a few examples with moderate enantioselectivities have
been reported so far.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: cczekeli@chemie.fu-berlin.de. Tel: þ49 (0)30 838
52625. Fax: þ49 (0)30 838 53625.
Notes
†Responsible for X-ray crystal structure determination.
Summarizing, a new class of sterically highly encumbered carbene
ligands with a tetrahydroisoquinoline backbone and their corre-
sponding gold complexes have been synthesized. Crystal structure
analysis of one complex revealed continuous AuI-AuI contacts in
the solid state. The catalytic activity of the complexes was demon-
strated in the desymmetrization reaction of a diynesulfonamide.
Herein, catalysts incorporating ligands with high steric demand led
to enantioselectivities which were comparable to those of the best
’ ACKNOWLEDGMENT
This work was generously supported by the Fonds der
chemischen Industrie e.V. by a Liebig fellowship and by the
DFG in the context of the Emmy-Noether program (CZ-183/1-1).
Thomas Kolrep (FU Berlin) is kindly acknowledged for ESI-MS
measurements.
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