Enantioselective palladium-catalyzed direct arylations at ambient temperature: access to indanes with quaternary stereocenters

Article abstract of DOI:10.1002/anie.200905060

Tadaa: The title reaction proceeds under essentially neutral reaction conditions at ambient temperature with a taddol-based phosphoramidite ligand L allowing the creation of indanes with quaternary stereogenic centers in high enantiomeric excess (see sche

Full text of DOI:10.1002/anie.200905060

Angewandte
Chemie
DOI: 10.1002/anie.200905060
Asymmetric Catalysis
Enantioselective Palladium-Catalyzed Direct Arylations at Ambient
Temperature: Access to Indanes with Quaternary Stereocenters**
Martin R. Albicker and Nicolai Cramer*
The selective catalytic activation and functionalization of
mechanistic picture of the palladium-catalyzed direct aryla-
tion reactions recently became clearer as a result of intense
investigations.[7] Several mechanistic models have been dis-
cussed, and the one proposed by Maseras, Echavarren and co-
workers, and by Fagnou and co-workers, in which a carbonate/
carboxylate acts in an intramolecular fashion as an ancillary
base initiating a concerted deprotonation/metalation of the
aryl group, is supported by most experimental and theoretical
evidence.[8] As illustrated by the anticipated intermediate 3
(Scheme 1), this would leave one coordination site on the
À
carbon–hydrogen (C H) bonds by transition-metal com-
plexes has broad synthetic potential because of its economic
and ecological benefits.[1] The recent impressive progress of
this vibrant and fast advancing research area opens unima-
ginable opportunities of more efficient strategic disconnec-
tions and streamlined syntheses.[2] Despite its enormous
dormant potential, efficient enantioselective catalytic reac-
À
tions are still a largely unsolved challenge in C H activa-
tions.[3] A main issue remaining is the identification of a
suitable set of external ligands which efficiently control the
stereoselectivity of the insertion event, without obstructing
the general activity of the whole catalyst system. To our
knowledge—except for a pioneering study from Yu and co-
workers describing chiral N-Boc amino acids as ligands for
2
[4]
À
directed C(sp ) H activations —there are no examples of
2
À
enantioselective aromatic C(sp ) H functionalizations using
palladium catalysts.[5] For example, it would be of significant
synthetic value to selectively address one of the enantiotopic
aromatic substituents of a symmetrical substrate by a metal-
ation and subsequent functionalization [Eq. (1)]. Such a
À
Scheme 1. Mechanistic model for the enantioselective C H functional-
2
À
ization of one of the prochiral C(sp ) H bonds of 1a. Tf=trifluorome-
thanesulfonyl, Bn=benzyl, Solv=solvent.
process should also be well-suited to the construction of
congested quaternary stereogenic centers[6] as the transfor-
mation occurs remotely from the tetrasubstituted carbon
atom.
Herein, we report our initial results exploiting a palla-
dium(0)-catalyst ligated by a designed taddol-based phos-
phoramidite to access indanes with quaternary stereogenic
centers in excellent enantioselectivities. The fundamental
palladium atom for the required external steering ligand. We
therefore turned our attention to bulky monodentate phos-
phines that would favor monoligated palladium species or
enable facile dissociation to ensure high reactivity of the
catalyst. The good overall reactivity of alkenyl triflates in
direct arylation reactions has been reported by Willis and co-
workers[9] and their ease of accessibility from ketones make
them an attractive substrate class. Furthermore, the assumed
cationic palladium(II) intermediate 2, formed upon oxidative
addition, should undergo rapid association with a carboxylate
or carbonate anion of the bulk base to form—according to the
current model—the crucial complex 3 for the metalation
process. Reductive elimination of the arising six-membered
palladacycle 4 ultimately releases the cyclized product 5a.
A brief initial survey of some phosphines confirmed that
monodentate ligands indeed showed the highest activity
towards the desired arylation reaction. As exemplified for the
cyclohexyl-mop ligand L1 (Table 1, entry 1), most of the
screened ligands provided nearly no differentiation of the two
aryl groups. Pleasingly, phosphoramidites such as Monophos
[*] M. R. Albicker, Dr. N. Cramer
Laboratory of Organic Chemistry, ETH Zurich
Wolfgang-Pauli-Strasse 10, HCI H 304 8093 Zurich, Switzerland
Fax: (+41)446-321-328
E-mail: Nicolai.cramer@org.chem.ethz.ch
Homepage: http://www.cramer.ethz.ch
[**] We thank O. A. Roth and L. Schneider for initial studies and Dr. W. B.
Schweizer for X-ray crystallographic analysis of compound 5j. We
gratefully acknowledge ETH Zurich (ETH-16 08-3) and Fonds der
Chemischen Industrie (Liebig-Fellowship to N.C.) for funding. We
thank Prof. Dr. E. M. Carreira for generous support and Prof. Dr. D.
Seebach for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905060.
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Table 1: Selected optimization studies.[a]
completed in three hours at ambient temperature. A carbon-
ate base is essential and, remarkably, the milder NaHCO3 can
replace K2CO3 or Na2CO3 to give identical results, whereas
Cs2CO3 significantly slows down the reaction.
As solvents, dimethylacetamide (DMAc) provides the
highest ee value (Table 1, entry 10), whereas acetonitrile,
ethyl acetate, and DMSO were detrimental for the selectivity
(Table 1, entries 11–13). With the optimized parameters in
hand, we turned our attention to the development of a more
selective phosphoramidite. Changing the acetal bridge of the
taddol had little impact or even a slightly negative influence
on the enantioselectivity. Replacement of the phenyl sub-
stituents by bulkier aryl groups (2-naphthyl, 1-naphthyl and
m-xylyl) resulted in poorly reactive catalyst systems (data not
shown). Modifications of the amine portion with cyclic
(pyrrolidine or piperidine; Table 1, entries 7 and 8), and
a- or b-branched secondary amines substituents gave ligands
of poorer performance than the parent ligand L8. However, a
L* Yield [%][b] ee [%][c] substitution of the dimethylamido group with its diethyl
congener increased the ee value from 78% to 81% (Table 1,
Entry Solvent Base
T [8C] [Pd]
1
2
3
4
toluene K3PO4
toluene K3PO4
toluene K3PO4
toluene K3PO4
toluene K3PO4
toluene K2CO3
DMAc K2CO3
DMAc K2CO3
toluene K3PO4
DMAc K2CO3
100
100
100
100
100
100
23
[Pd2(dba)3] L1
86
63
89
85
88
91
85
87
77
98
72
86
80
95
92
90
93
93
3
51
56
52
60
66
63
59
69
78
29
49
19
81
86
81
93
93
entry 14). Furthermore, n-butyl chains gave an even better
selectivity of 86% ee (Table 1, entry 15). Longer dialkylamido
chains (e.g., the n-hexyl homologue L11; Table 1, entry 16)
provided no further enhancement, instead the selectivity fell
to that obtained with the diethylamino variant L9. The n-butyl
substitution pattern of the nitrogen atom seems to be optimal,
and when combined with the para-tert-butylphenyl taddol
congener a ligand (L12) with an optimal reactivity/selectivity
profile resulted, promoting the arylation reaction in 93%
yield and with an ee value of 93% (Table 1, entries 17 and 18).
Next, we explored the scope of the palladium-catalyzed
arylation. In general, under the aforementioned optimized
reaction conditions different aromatic substitution patterns
are well tolerated in the reaction (Table 2). Ortho- and para-
substitution has little impact upon the reaction rate and the
enantioselectivity (Table 2, entries 1 and 2). Electron-rich
substrates bearing an either an ortho- or para-methoxy group
as well as one having a meta-triisopropylsiloxy group, furnish
the indanes in comparable selectivities and yields (Table 2,
entries 3–5). Substrates with electron-poor aromatic substitu-
ents are more reactive and, notably, 1i which has a meta-
fluorine substituent reacts almost in a completely regioselec-
tive manner to provide the depicted isomer 5i in greater than
20:1 regioselectivity (Table 2, entry 8).[12] Chlorinated aro-
matics remain untouched during the reaction and could be
functionalized subsequently (Table 2, entry 7). Heteroaro-
matics, exemplified by the thiophene substrate 1j, react in an
analogous manner; furthermore, the absolute configuration
of the cyclized product 5j was determined to be R by using the
X-ray crystallographic analysis.[13] Substrates deriving from
4-piperidones maintain the selectivity and provide access to
fused tetrahydropyridines 5k and 5l (Table 2, entries 10 and
11). A vinyl palladium species not embedded within a cyclic,
conformationally restricted environment, such as the one
generated from the acyclic derivative 1m, reacts less selec-
tively and furnishes the product 5m in 45% ee, thereby
requiring additional ligand improvements.
[Pd2(dba)3] L2
[Pd2(dba)3] L3
[Pd2(dba)3] L4
[Pd2(dba)3] L5
Pd2(dba)3 L5
Pd(OAc)2 L6
Pd(OAc)2 L7
[Pd2(dba)3] L8
Pd(OAc)2 L8
Pd(OAc)2 L8
Pd(OAc)2 L8
Pd(OAc)2 L8
Pd(OAc)2 L9
Pd(OAc)2 L10
Pd(OAc)2 L11
Pd(OAc)2 L12
Pd(OAc)2 L12
5
6[d]
7
8
9
10
23
100
23
23
23
23
23
23
23
11[d] CH3CN K2CO3
12[d] DMSO K2CO3
13[d] EtOAc K2CO3
14
15
16
17
18
DMAc Na2CO3
DMAc Na2CO3
DMAc Na2CO3
DMAc Na2CO3
23
DMAc NaHCO3 23
[a] Reaction conditions: 1a (0.1 mmol), base (3 equiv), 0.10m in the
indicated solvent, 3 h. [b] Yield of isolated product. [c] The ee values were
determined by HPLC analysis using a chiral stationary phase. [d] 12 h.
dba=(E,E)-dibenzylideneacetone, DMSO=dimethylsulfoxide.
(L2), the Feringa ligands L3 and L4, and the phosphorami-
dite-olefin ligand L5[10] gave rise to promising enantioselec-
tivities (Table 1, entries 1–6). However, the amine portion of
the phosphoramidite seems to have little influence on the
selectivity of this reaction. We therefore chose the taddol-
based phosphoramidite L8 as the lead structure as it provided
comparable results (Table 1, entry 9), and its highly modular
nature would allow facile modifications with regard to the
acetal backbone, the aryl groups, and the substituents of the
nitrogen atom.[11] Ligand L8 was used in our initial examina-
tion of the reaction conditions, and we found a pronounced
dependence of the enantioselectivity upon the palladium
source, the base, and the solvent (Table 1, entries 10–13).
Apart from the first set of reaction conditions ([Pd2(dba)3]/
K3PO4/toluene/100 8C) the reaction proceeds in a higher
selectivity using palladium acetate and a carbonate base in a
polar solvent. Under these conditions, the arylation is
In summary, we demonstrated a very mild intramolecular
direct arylation of vinyl triflates which proceeds with excel-
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Chemie
Table 2: Scope of the enantioselective arylation reaction.[a]
with a rubber septum, and flushed with
nitrogen. After the addition of 1.0 mL of
dry dimethylacetamide, the reaction
mixture was stirred at 23 8C until com-
plete conversion (3 h) was determined
by TLC analysis. The reaction mixture
was extracted with pentanes, and
washed with water and brine. The
organic layer was dried (MgSO4) and
evaporated in vacuo. The residue was
purified on silica gel (pentanes, Rf =
0.30) giving 24.3 mg (93%, 93% ee) of
5a as a colorless viscous oil.
Entry Product[b]
Yield [%][c] ee [%][d]
Entry Product[b]
Yield [%][c] ee [%][d]
1
2
5b
96
94
93
91
5c
99
98
97
86
Received: September 9, 2009
Published online: October 26, 2009
3
4
Keywords: asymmetric catalysis ·
.
À
C H activation · direct arylation ·
5d
5e
palladium · stereocenters
5
6
À
5 f[e]
70
96
98
93
5g
97
82
87
94
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Communications
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