New chiral N-heterocyclic carbene ligands in palladium-catalyzed α-arylations of amides: Conformational locking through allylic strain as a device for stereocontrol

Article abstract of DOI:10.1002/chem.201000031

New Enders/Herrmann-type chiral N-heterocyclic carbene (NHC) ligands have been developed and applied in asymmetric palladium-catalyzed intramolecular α-arylations of amides. The best ligands feature the bulky tert-butyl group and ortho-substituted aryl gr

Full text of DOI:10.1002/chem.201000031

DOI: 10.1002/chem.201000031
New Chiral N-Heterocyclic Carbene Ligands in Palladium-Catalyzed
a-Arylations of Amides: Conformational Locking through Allylic Strain
as a Device for Stereocontrol
Yi-Xia Jia, Dmitry Katayev, Gꢀrald Bernardinelli, Thomas M. Seidel, and
E. Peter Kꢁndig*[a]
Dedicated to Professor Reinhard W. Hoffmann
Abstract: New Enders/Herrmann-type
chiral N-heterocyclic carbene (NHC)
ligands have been developed and ap-
plied in asymmetric palladium-cata-
lyzed intramolecular a-arylations of
amides. The best ligands feature the
bulky tert-butyl group and ortho-substi-
tuted aryl groups at the stereogenic
centers. Aryl bromides readily react at
room temperature and aryl chlorides at
508C. The highly enantiomerically en-
riched (up to 96% ee) 3-alkyl-3-arylox-
indole products were obtained in gen-
erally high yields (>95%) except in
cases of steric congestion. The critical
roles both of the bulky alkyl group and
of the ortho-aryl substituent at the ste-
reogenic center of the ligand were re-
vealed in the crystal structure of a [Pd-
ACHUTNGRENUNG ACHTUNGTERNN(UGN NHC-L*)(I)] complex. The
(h3-allyl)
Keywords: arylation · asymmetric
ligand aryl location and orientation is
fixed by conformational locking that
minimizes A1,3-strain and enables opti-
mal transfer of chiral information.
catalysis
·
carbene ligands
·
N-heterocyclic carbenes · oxindoles ·
palladium
Introduction
Isolable and stable N-heterocyclic carbenes (NHCs) were
first reported by Arduengo et al. in 1991.[1] As ligands for
transition metals, NHCs are strong s-donors and weak p-ac-
ꢀ
ceptors and they form robust carbon metal bonds. These
characteristics have led to their rapid emergence as a new
and important class of ligands for homogeneous catalysis.[2,3]
Chiral NHC ligands are also receiving growing attention[4]
with approaches centered on the strategies depicted in
Scheme 1: a) chiral N-substituents (stereogenic centers[5]
chiral biaryls, planar chiral units),[6] b) chiral N-heterocy-
cles,[7] or c) a combination of the above strategies.[8]
A large number of chiral NHC ligands based on these de-
signs have been developed and some of them have been suc-
cessfully applied in reactions such as ruthenium-catalyzed
asymmetric metathesis,[6c,7,9] rhodium-catalyzed asymmetric
Scheme 1. Strategies for the development of chiral N-heterocyclic car-
bene ligands.
hydrosilylation,[6d,10] rhodium-[11] and copper[12]-catalyzed
conjugated additions, and iridium-catalyzed asymmetric hy-
drogenation.[5d,13] Despite the successes in this field, highly
enantioselective applications of chiral NHC ligands in catal-
ysis are still rare in relation to those involving chiral N-, O-,
and P-ligands. New efficient chiral NHC ligands for asym-
metric catalysis are needed along with insight into their
modes of asymmetry transfer. This article focuses on this
quest.
[a] Dr. Y.-X. Jia, D. Katayev, Dr. G. Bernardinelli, Dr. T. M. Seidel,
Prof. E. P. Kꢀndig
Department of Organic Chemistry, University of Geneva
30 Quai Ernest Ansermet, 1211, Geneva 4 (Switzerland)
Fax : (+41)22-379-3215
Pioneered by the groups of Herrmann[5a] and Enders,[5b]
chiral NHC ligands derived from chiral phenethylamine and
its analogues (Figure 1) have become one of the most im-
portant types of chiral ligands. Most efforts in their develop-
E-mail: peter.kundig@unige.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000031.
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FULL PAPER
ment have focused on the
modification of the aromatic
group and the N-heterocyclic
ligand backbone, whereas little
attention has been paid to
with enantioselectivities not exceeding 76% there remained
room for improvement. Efforts directed towards improving
these results by other groups did not meet with success,[18b,c]
although after our communications[17] Glorius and co-work-
ers were very recently also successful in this endeavor.[19l]
Figure 1. Enders/Herrmann-
type chiral NHC ligands.
modification of the alkyl
R
group (R=Me in almost all
cases).[5a,b,8] We felt that the in-
Results and Discussion
troduction of sterically more demanding R groups at the
ligand stereogenic centers might be beneficial to asymmetric
induction and show here that this hypothesis proved correct.
We had previously reported the efficient synthesis of the
chiral ortho-substituted a-alkylbenzylamines 1a–c (Figure 2)
and shown their applications as chiral auxiliaries,[14] starting
materials for chiral dibenzoazepines,[15] and as building
blocks for chiral bidentate benzoxazine P/N ligands.[16] We
have now turned our attention to the synthesis of chiral
NHC ligands starting from these amines. In doing this, a
new family of bulky Enders/Herrmann-type chiral NHC li-
gands containing alkyl groups of different steric demand at
their chiral benzylic positions were generated. In addition
we have probed the effect of ortho-substituents on the aryl
groups. As shown below, they play a crucial role in asym-
metric induction.
Synthesis of ligand precursors: The first series of ligands
synthesized were the unsaturated imidazolium salts 5, from
the starting chiral ortho-substituted a-alkylbenzylamines 1–3
(Figures 2 and 3). The imidazolium tetrafluoroborarate salt
(R,R)-5a was synthesized by a standard one-pot procedure
in 87% yield (Scheme 2).[27] This proved inefficient for
Scheme 2. General procedures for the synthesis of imidazolium and dihy-
droimidazolium ligand precursors. The R amine precursors are depicted.
Figure 2. Chiral amines for the synthesis of imidazolium and dihydroimi-
dazolium salts.
(R,R)-5b and completely failed in the synthesis of (R,R)-5c
with a bulky tBu group at the benzylic position. Compounds
(R,R)-5b and (R,R)-5c were therefore synthesized by a
method involving diimine formation, ring-closure, and
anion-exchange (Scheme 2). In the ring-closing step, the
method based on chloromethyl pivalate and AgOTf worked
well,[18b] giving the imidazolium triflates in moderate yields.
Anion-exchange of TfOꢀ for Iꢀ allowed us to obtain solid
products instead of oily salts, greatly facilitating purification.
Overall it is a simple process and no purification of the in-
termediates was needed. Product yields were moderate
(Scheme 2). Similarly, the imidazolium iodides (R,R)-5d and
(S,S)-5e were obtained in 14 and 49% yields from (R)-2a
and (S)-2b, respectively.
The reaction that we chose for testing of the ligands was
the palladium-catalyzed asymmetric intramolecular a-aryla-
tion of amides. Initial results of this study have been the
object of preliminary communications.[17]
Pioneered by Hartwig and co-workers, intramolecular a-
arylation of amides provides efficient and direct access to
chiral 3,3-disubstituted oxindoles.[18] These represent
a
common structural motif found in many natural products
with a variety of significant biological activities, making
them interesting and challenging targets for chemical syn-
thesis.[19]
Other asymmetric transition-metal-catalyzed routes to
enantiomerically enriched 3,3-disubstituted oxindoles in-
clude palladium-catalyzed intramolecular Heck reactions,[20]
allylation of oxindoles,[21] domino Heck/cyanation reac-
tions,[22] cyanoamidation reactions,[23] fluorination of oxin-
doles,[24] rhodium-catalyzed addition to isatin,[25] and zinc-
catalyzed hydroxylation of oxindoles.[26]
Hartwigꢂs group screened a large number of chiral phos-
phine and NHC ligands. Chiral phosphines generally per-
formed poorly and bulky chiral NHC ligands were best, but
The dihydroimidazolium salts 5h–l were synthesized by a
four-step procedure that involved diimine formation fol-
lowed by reduction (NaBH4) to the diamines, ring-closure,
and anion metathesis (Scheme 2). Ring-closure of diamines
was carried out with NH4BF4 and triethyl orthoformate.
Subsequent anion exchange afforded the dihydroimidazoli-
um iodide salts 5h–l in good to excellent yields (Scheme 2).
The ligand heterocyclic ring was further modified to
access the structurally diverse ligand precursors (R,R)-5 f,
(S,S)-5g (with a benzoimidazolium ring), and (R,R)-5m
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P. Kꢀndig et al.
Scheme 4. Synthesis of (R,R)-5m.
NH4BF4 and HCACHTNUTRGNEUNG(OEt)3, followed by anion metathesis with
NaI, afforded (R,R)-5m in 70% yield.
Oxindole synthesis: The reaction conditions of Hartwig and
Lee were initially applied for comparison of results (Table 1,
entry 1).[18a] Ligand (R,R)-5a with Me groups at the stereo-
genic benzylic centers afforded the oxindole 7a in accepta-
ble yield but very low enantiomeric excess (entry 2). The
presence of increasing bulk at the stereogenic center (en-
tries 3 and 4) resulted in products of higher enantiomeric
purity.
Figure 3. New chiral NHC ligands.
(with a six-membered N-heterocycle). In an application of
the Buchwald–Hartwig amination procedure,[28] reactions
between (R)-1c or (S)-2b and 1,2-dibromobenzene were
carried out with PdACHTNUTRGNE(UGN OAc)2 (5 mol%), PtBu3 (15%), and
Table 1. Asymmetric intramolecular arylation of amides to form enan-
tioenriched oxindoles 7.[a]
NaOtBu (4 equiv) in xylene at 1508C over 16 h to give the
chiral amines (R,R)-4a and (S,S)-4b in 84 and 96% yield,
respectively (Scheme 3). Chiral HPLC showed that no race-
Entry
1[d]
L*
Yield [%][a]
74
ee [%][b]
Config.[c]
n.d.
57
2[e]
3[e]
4[e]
N
72
93
96
16
77
87
S
S
S
[a] Isolated yield. [b] Determined by chiral HPLC (Chiralcel OD-H).
[c] The absolute configuration was assigned on the basis of the X-ray
structure of (ꢀ)-(S)-18. [d] Ref. [18a]. Best result with 6a. n.d=not deter-
mined. [e] Conditions: 6a (0.25 mmol, 0.05m in the indicated solvent),
base (1.5 equiv), 24 h.
Scheme 3. Synthesis of the benzoimidazolium iodide salts (R,R)-5 f and
(S,S)-5g.
With these results to hand, optimization of the reaction in
the presence of (S,S)-5c was undertaken (Table 2). Changing
from DME to dioxane and THF resulted in only minor de-
creases in the ee of the product, but in a sharp drop in yield
in the case of THF (entries 2 and 3). In toluene the reaction
was characterized by low conversion and a further erosion
of asymmetric induction (entry 4), whereas in benzene the
reaction did not take place at all at room temperature, al-
though complete conversion was achieved upon heating to
758C, which led to a modest product ee of 67% (entry 5).
Starting material was recovered in dichloromethane
(entry 6).
Of the bases tested, NaOtBu was the best, as already indi-
cated in the literature.[18a] With NaH as base only a 14% ee
was obtained (entry 7), whereas NaHMDS and LiOtBu did
not promote the reaction (entries 8 and 9). The yield was
lower when KOtBu was used instead of NaOtBu (entry 10).
mization had occurred during this process. The ring-closing
method used for the synthesis of dihydroimidazolium salts
5h–l with NH4BF4 and HCACTHNUGTRNE(UNG OEt)3 failed when applied to
the syntheses of (R,R)-5 f and (S,S)-5g. However, treatment
of the chiral amines 4 with concentrated HCl in triethyl or-
thoformate as solvent at 808C gave the requisite benzoimi-
dazolium chloride salts in low yields. Through recovery of
the starting materials 4 and rerunning the reactions four
times, followed by anion-exchange of Clꢀ for Iꢀ by treat-
ment with NaI, the products (R,R)-5 f and (S,S)-5g were ob-
tained in 48 and 33% yield, respectively.
The six-membered N-heterocycle product (R,R)-5m was
synthesized by a four-step procedure (Scheme 4).[29] Treat-
ment of (R)-1c with acrolein and subsequent in situ reduc-
tion gave the 1,3-diamine; cyclization by treatment with
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New Chiral N-Heterocyclic Carbene Ligands
FULL PAPER
Table 2. Variation of solvent, temperature, and base in the Pd/ACTHUNRGTNE(NUG S,S)-5c-
performance and their synthesis is more efficient. The
same trend (o-Me > o-OMe) in asymmetric induction
was found in this series: 5i > 5h (entries 8 and 7).
Larger o-substituents as in 5j (OPr) and 5k (OiPr) gave
lower product ee values.
catalyzed reaction 6a ! (S)-7a.
Entry [Pd]
Solvent Base
(dba)2] DME NaOtBu
(dba)2] dioxane NaOtBu
T [8C] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
N
23
23
23
23
75
40
23
96
94
10
20
96
0[d]
65
0[d]
0[d]
76
98
90
87
85
86
73
67
–
ACHTUNGTRENNUNG
A
NaOtBu
4) Modification of the ligand core structure as in 5 f, 5g,
and 5m led to poorer performance (entries 5, 6, and 12).
5) The only ligand bearing an aryl group with two substitu-
ents that was tested was 5l (entry 11). Induction was
high but did not reach those achieved with 5i and 5e.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
G
NaH
NaHMDS 23
LiOtBu
KOtBu
14
–
9
E
23
23
23
50
–
10
11
12[e]
C
88
87
84
Pd
Pd
U
NaOtBu
NaOtBu
Substrate scope: We next probed the scope and limitations
of the reaction with the ligand precursor (S,S)-5e under the
conditions established above (Table 3, entry 3). The sub-
strates 6a–6j were synthesized from the corresponding ani-
lines and acid chlorides and the oxindoles (S)-7a–j were ob-
tained with good to excellent enantioselectivities and in high
yields (Table 4). An exception is the attempted conversion
of 6c (entry 3), which did not afford the oxindole product,
[a] Conditions: 6a (0.25 mmol, 0.05m in the indicated solvent), [Pd]
(5 mol%), (S,S)-5c (5 mol%), base (1.5 equiv), 24 h. The absolute config-
uration was assigned on the basis of the X-ray structure of (ꢀ)-(S)-18.
[b] Isolated yield. [c] Determined by chiral HPLC (Chiralcel OD-H).
[d] No reaction. [e] 14 h.
The reader is reminded that in this reaction the base has a
double role: it generates both the carbene ligand and the
enolate in the catalytic cycle. Finally, switching from [Pd-
ꢀ
showing that the presence of a free N H bond in the sub-
strate is incompatible with this transformation. The N-
benzyl-protected substrate 6b afforded the oxindole (S)-7b
(entry 2) and hydrogenolysis with Li/NH3 afforded (S)-7c.
Reactions with substrates incorporating ortho-aryl substitu-
ents were sluggish and led to products in modest (entry 9)
to good (entries 6, 7) yields. In these cases the ligand precur-
sor (S,S)-5c performed better than (S,S)-5e (entries 7, 9, and
11).
ACHTUNGTRENNUNG(dba)2] to PdACHTUNGTRENNUNG(OAc)2 gave an identically high yield of highly
enantiomerically enriched product 7a (entry 11). Increasing
the temperature from RT to 508C reduced reaction time but
also product ee (entry 12).
Next, the modified NHC ligands 5d–m were investigated
and the results are shown in Table 3. Pertinent features are:
Table 3. Chiral NHC ligands in the Pd-catalyzed a-arylation of 6a to
give 7a.[a]
Table 4. Palladium-catalyzed a-arylation of substrates 6a–j.[a]
Entry
Ligand precursor
(S,S)-5c
(R,R)-5d
(S,S)-5e
(S,S)-5e
(R,R)-5 f
(S,S)-5g
(R,R)-5h
(S,S)-5i
(R,R)-5j
(R,R)-5k
(R,R)-5l
(R,R)-5m
t [h]
Yield [%][b]
ee [%][c]
1
2
3
U
24
24
24
24
48
48
14
48
14
14
14
48
96
98
99[d]
51
67
65
98
55
98
98
98
60
87 (S)
57 (R)
94 (S)
96 (S)
80 (R)
91 (S)
88 (R)
92 (S)
75 (R)
71 (R)
88 (R)
68 (R)
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
4[e]
5
ACHTUNGTRENNUNG
Entry
Product
R
Ar
t [h]
Yield [%][b]
ee [%][c]
ACHTUNGTRENNUNG
6
7
8
9
10
11
12
ACHTUNGTRENNUNG
1[d]
2
(S)-7a
(S)-7b
(S)-7c
(S)-7d
(S)-7e
(S)-7 f
(S)-7 f
(S)-7g
(S)-7h
(S)-7i
(S)-7i
(S)-7j
Me
Bn
H
Ph
Ph
Ph
4-tol
3-tol
2-tol
2-tol
4-MeO-Ph
2-MeO-Ph
1-naphth
1-naphth
2-naphth
24
24
24
24
24
24
36
14
36
36
24
36
99
94
0[f]
99
99
98
98
98
42
72
98
96
94
84
–
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
3
ACHTUNGTRENNUNG
4[d]
5[d]
6
Me
Me
Me
Me
Me
Me
Me
Me
Me
93
93
86
89
93
84
79
84
95
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
7[e]
8
[a] Same reaction conditions as shown in entry 1 of Table 1 for 14–24 h.
[b] Isolated yield. [c] Determined by chiral HPLC (Chiralcel OD-H).
[d] 1 mmol scale. [e] At 108C for 24 h. [f] 48 h.
9[e]
10
11[e]
12
1) A bulky tBu group at the stereogenic benzylic center is
essential, but not sufficient, for high asymmetric induc-
tion (compare entries 2–4 in Table 1).
2) Equally important is the presence of an ortho-aryl sub-
stituent (compare entries 1–3 in Table 3). The best per-
former was the ligand 5e with an o-Me group (entry 3),
followed by 5c with an o-OMe group (entry 1). Both
give much better inductions than the ligand 5d (entry 2).
3) The dihydroimidazolium-derived N-heterocyclic carbene
ligands came close to the imidazoline carbene ligands in
[a] Substrate in DME (0.05m, 0.2 mmol); absolute configurations were
assigned by comparison of the circular dichroism (CD) spectra with that
of (S)-7b. [b] Isolated yield. [c] Determined by chiral HPLC [d] 1 mmol
scale. [e] With (S,S)-5c as ligand precursor. [f] No reaction.
Table 5 lists the results for the reactions of substrates 8
with different alkyl groups at their benzylic positions. In-
creasing the size of the R groups in 8 led to sluggish reac-
tions and lower enantioselectivities (Table 5). This is particu-
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P. Kꢀndig et al.
Table 5. Palladium-catalyzed a-arylation of substrate 8.[a]
(S)-11c and (S)-11g were thus obtained with 25 and 72% ee,
respectively (entries 3 and 7).
Incorporation of C(7) substitution into a six-membered
ring structure reestablished very high product ees, as shown
for substrate 12 (Scheme 5), which yielded the tricyclic oxin-
Entry
1
Product
t [h]
Yield [%][b]
82
ee [%][c]
(S)-9a
48
90
2
3
(S)-9b
(S)-9c
(S)-9d
48
48
80
86
52
89
Scheme 5. Asymmetric synthesis of oxindoles (S)-13 and (S)-15.
4
0.9
1.5
98
98
55
59
5[d]
dole (S)-13 in 87% yield and with 94% ee. Each of the 22
examples above involves an oxindole with an aryl group at
the newly formed stereogenic center. An exception is sub-
strate 14, which yielded the oxindole 15 (Scheme 5), albeit
with a very modest ee of 40%, attesting to the fact that the
search for catalytic systems for this and a wider range of
substrates is by no means over.
[a] Substrate in DME (0.05m, 0.2 mmol); absolute configurations were
assigned by analogy and are tentative. [b] Isolated yield. [c] Determined
by chiral HPLC. [d] ꢀ208C.
Finally, attention was turned to the aryl chloride sub-
strates 16 (Table 7). Mechanistic studies showed that the re-
action involves rate-limiting oxidative addition of aryl hali-
de.[18a] In accord with literature precedence, slightly higher
reaction temperatures are required for aryl chlorides.[18a,19l]
Gratifyingly, at 508C reactions occurred smoothly and al-
though asymmetric induction is lower than with the bromo
analogues, values are still in the range between 84 and
94% ee.
larly striking with R=iPr (8b) and the indanyl substrate 8d,
for which the product ees for (S)-9b and (S)-9d were in the
modest 50–60% ee range (entries 2, 4, 5). In contrast with
the reactions in entries 1–3, which required up to 2 d to go
to completion, the reaction of 8d, to afford the spirocyclic
oxindole 9d, was complete in <1 h at RT and in 1.5 h at
ꢀ208C (entries 4 and 5).
Table 6 lists the results for the reactions of substrates with
different substituents in the aniline component. Yields and
enantioselectivities were generally very high for substrates
with either electron-donating or electron-withdrawing sub-
stituents at C(5) or at C(6). Erosion of asymmetric induction
was observed for C(7)-substituted substrates; the oxindoles
Table 7. Palladium-catalyzed a-arylation of chloride-substrates 16.[a]
Table 6. Palladium-catalyzed a-arylation of substrate 10.[a]
Entry
R
Ar
Product t [h] Yield [%][b] ee [%][c]
1
16a Me Ph
16a Me Ph
16b Me 4-tol
(S)-7a
(S)-7a
(S)-7d
24
48
24
24
24
24
98
21
98
98
98
97
90
94
91
91
84
85
2[d]
3
4
5
6
16c Me 2-naphth (S)-7j
16d Et
Ph
(S)-9a
(S)-9c
Entry
Product
R
t [h]
Yield [%][b]
ee [%][c]
16e Bn Ph
[a] Substrate in DME (0.05m, 0.2 mmol); absolute configurations were
assigned by analogy and were tentative. [b] Isolated yield. [c] Determined
by chiral HPLC. [d] At room temperature.
1
2
3
4
5
6
7d
(S)-11a
(S)-11b
(S)-11c
(S)-11d
(S)-11e
(S)-11 f
(S)-11g
C5-Me
C5-iPr
C5,7-Me
C6-CF3
C6-F
24
24
24
48
48
24
24
98
98
82
98
96
98
96
95
92
26
95
94
95
72
C6-OMe
C7-F
Determination of the absolute configuration of (S)-7b: The
absolute configuration of product (S)-7b was determined
through an X-ray crystal structure analysis of compound
(S)-17, which was obtained from (S)-7b by hydrogenolysis
[a] Substrate in DME (0.05m, 0.2 mmol); absolute configurations were
assigned by analogy and were tentative. [b] Isolated yield. [c] Determined
by chiral HPLC. [d] At 508C.
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New Chiral N-Heterocyclic Carbene Ligands
FULL PAPER
and bromination (Scheme 6). The X-ray structure of 17
showed it to have the S configuration (Figure 4). Assign-
ment of other enantiomerically enriched oxindole products
was by analogy (comparison of CD spectra) and is tentative.
by different rates of deprotonation of the two diastereomers
A.[30]
Asymmetric induction: The ligand screening (Table 3) at-
tests to the importance of the bulky tBu and the o-toluyl or
o-anisyl groups at the stereogenic center. In a search for a
rationale for this finding, the complex [[Pd
5e)(I)] (18) was synthesized from [Pd
N
ACHTUNGTRENNUNG((S,S)-
AHCTUNGTRENNUNG
Scheme 6. Derivatization of (S)-7b to (S)-17 for the determination of the
absolute stereochemistry through its X-ray structure.
(NHC)Cl] complexes,[33] the structure of 18 is that
[PdACTHNUGRTENNUG(allylACHTUGNTRENNUGN
of a distorted square-planar PdII complex with one carbon
of the h3-allyl group trans to the iodide and the other trans
ꢀ
to the NHC ligand. The Pd Callyl bond trans to the NHC
ligand is 2.207 ꢃ and that opposite the iodide is 2.145 ꢃ.
ꢀ
The Pd CNHC bond is 2.044 ꢃ. These values are in the typi-
cal range for those previously found in closely analogous
complexes.[33]
Figure 4. ORTEP structure of (S)-17.[17a]
Mechanism: The mechanism proposed by Hartwig is shown
in Scheme 7. Although the Pd-C enolate B could not be ob-
served, a phosphine complex of the palladacycle A was iso-
lated, spectroscopically fully characterized, and shown to
yield the oxindole product when treated with base.[18a] We
found that, as expected, a 1:1 mixture of two diastereomers
of A was formed when 5e was used in this reaction. Chiral
induction from this intermediate could occur during the Pd-
O-enolate to Pd-C-enolate rearrangement (A!B) or during
reductive elimination. The process may also be influenced
Figure 5. ORTEP structure of [PdACTHNUGRTNENUG ACHUTNGTREN(NUNG S,S-5e)(I)]] [(S,S)-18].
(h3-allyl)
Our interest then focused on the chiral ligand and the
role of the different ligand elements in generating the chiral
site that led to high asymmetric induction. Figure 6 shows
ꢀ
the ligand geometry with respect to the Pd ACTHUNRTGNEUNG(S,S-5e) bond.
For clarity, the allyl and iodide moieties have been left out.
Also note that the descriptor 5e is used for both the com-
plexed carbene ligand and the ligand precursor (imidazo-
lium iodide). The large groups at the stereogenic centers en-
ꢀ
ꢀ
force coplanarity of the CACTHNUTRGENUGN(ligand) Pd bond/C H bond of
ꢀ
the stereogenic center. Rotation around the N C(stereogen-
ic center) bond would lead to allylic strain.[34] This fixes the
aryl groups in space; their orientations are determined by
the aryl o-substituents. Again, minimization of A1,3-strain is
ꢀ
in operation and, as can be seen in Figure 6, the C(Ar) CH3
ꢀ
bond is coplanar with the C H bond of the stereogenic
center. Note that rotating the aryl groups by 1808 would
lead to a situation in which the Me groups would be in con-
flict with the tBu groups.
Scheme 7. Hartwigꢂs proposed catalytic cycle.[18a]
Chem. Eur. J. 2010, 16, 6300 – 6309
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6305

P. Kꢀndig et al.
Conclusion
We have developed a new family of Enders/Herrmann-type
chiral N-heterocyclic carbene ligands. These were very suc-
cessfully applied in the asymmetric palladium-catalyzed a-
arylation of amides, affording 3,3-disubstituted oxindoles
with high enantiomeric excesses. It was confirmed experi-
mentally that the asymmetric induction provided by the
metal-ligand system is strongly linked to the presence in the
ligand both of a bulky tert-butyl group and of an ortho-aryl
substituent at the stereogenic benzylic centers. The critical
role of the ortho-aryl substituent has been shown by an X-
ray analysis of a crystal structure of a PdII
ACTHNUGRTENUNG(allyl)(NHC
Figure 6. Stereochemical arrangement of key elements in Pd-(S,S-5e)
(from the X-ray structure of complex 18).
ligand) iodide complex. The place and orientation of the
ligand aryl groups are fixed by the minimization of A1,3
strain. Further development of chiral NHC ligands by this
principle, their application in organic and organometallic
catalysis, and detailed mechanistic studies of chiral induction
in oxindole synthesis are in progress in our laboratory.
Overall, the ligand, when coordinated to PdII, adopts a C2
chiral structure. Although it is tempting to use Figure 6 and
the knowledge of the absolute stereochemistry of the oxin-
dole products 7 to settle on B as a model (Scheme 7) and to
hypothesize on the origin of asymmetric induction, we
would prefer to collect more data (e.g., an X-ray structure
of A) rather than to speculate at this stage.[30]
Experimental Section
We note that the X-ray structure of the imidazolium salt
(R,R)-5e is different in that both tBu groups are in one
hemisphere and the aryl groups in the other (Figure 7). The
H atoms at the stereogenic centers are again coplanar with
the imidazolium ring, but in the absence of the large Pd two
orientations are possible and the one adopted in the solid-
state structure is shown here.
General: Solvents were purified by filtration on drying columns with a
Solvtekꢁ system or by distillation over Na/benzophenone. Reactions and
manipulations involving organometallic or moisture-sensitive compounds
were carried out under purified nitrogen in glassware dried by heating
under high vacuum. M.p.: Bꢀchi 510. GC: Hewlett–Packard 6890 gas
chromatograph with FID detection on
a Permabond OV-1701–0.25
column (25 m ꢄ 0.32 mm ID). HPLC: Agilent 1100 series chromatograph.
NMR: Bruker AMX 500, AMX 400, or AMX 300 FT; internal D-lock.
IR spectra: Perkin–Elmer Spectrum One. Neat liquids; Golden Gate ac-
cessory. HRMS: +TOF mode, ESI-MS mode, Applied Biosystems/Scix
(Q-STA) spectrometer. [a]D: Perkin–Elmer 241 polarimeter, quartz cell
(l=10 cm), Na high-pressure lamp (l=589 nm). CD spectra: Jasco J-715,
quartz cell (l=1 cm).
Amines: Synthesis and spectroscopic and analytical details of the chiral
precursor amines have been reported as indicated: (R)-1a,[36] (S)-1b,[37]
(S)-1c,[37] (R)-2a,[17a] (S)-2b,[17a] and (R)-3.[17b]
Chiral carbene ligand precursors: For details of the synthesis of and data
for the chiral carbene precursors see the experimental sections and the
supporting information in the references indicated: (R,R)-5a,[17a] (S,S)-
5b,[17a] (S,S)-5c,[17a] (R,R)-5d,[17a] (S,S)-5e,[17a] and (R,R)-5l.[17b] For X-ray
structure details of (S)-18 and imidazolium salt (R,R)-5e, see ref. [17a].
a) Synthesis of diamines
General procedure for the synthesis of dihydroimidazolium iodide salts—
a) Synthesis of diamines: Aq. glyoxal (n mmol) was introduced into
CH2Cl2 (5 mL per mmol glyoxal) and vigorously stirred with freshly de-
hydrated Na2SO4 (2.0 g per mmol glyoxal). After addition of formic acid
(7 mol%) and chiral amine (2n mmol), the mixture was stirred at RT
until completion of the reaction (monitored by TLC). The mixture was
then filtered, and volatiles were removed in vacuo to yield the diimine,
which was dissolved in MeOH (15 mL per mmol glyoxal) and cooled to
08C. NaBH4 (2.5n mmol) was added to the solution of diimine in MeOH
and the resulting mixture was stirred overnight. After evaporation of
MeOH, the residue was filtered through a short SiO2 pad with ether to
give the diamine as a light oil for further use without purification.
Figure 7. X-ray structure of (R,R)-5e (iodide omitted).[17a]
The buried volume (%Vbur) for ligand 5e is 37.4%.[35] The
ligand is thus bulkier than common NHC ligands (such as
IMes). but its %Vbur value is far below the value of ~50%
recently reported for chiral NHC ligands by Gloriusꢂs group,
which provided excellent results in the enantioselective ary-
lation of amides.[19l] We conclude that exceptional bulk may
help but it is not a necessary requirement. Less bulky li-
gands can give high asymmetric induction provided that
their stereodirecting groups are placed judiciously. Our re-
sults with ligands 5e and 5i attest to this.
b) Synthesis of imidazolium iodides: HCACTHNUTRGENUG(N OEt)3 (5 mL per mmol di-
amine) was introduced into the mixture of the above diamine (n mmol)
and NH4BF4 (n mmol), and the mixture was stirred under N2 at 1258C
for 8 h. After cooling to RT and evaporation to dryness, the residue was
dissolved in acetone and then NaI (5.0n mmol) was added. After the
system had been stirred at RT for 12 h, acetone was removed, CH2Cl2
6306
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Chem. Eur. J. 2010, 16, 6300 – 6309

New Chiral N-Heterocyclic Carbene Ligands
FULL PAPER
was added, and the solution was then filtered though cotton. This BF4ꢀ/Iꢀ
exchange was repeated once more. After evaporation of acetone, the res-
idue was purified by flash chromatography to give the dihydroimidazoli-
um iodide salt as a yellow powder.
1279, 1235, 1098, 1054, 951, 776, 731, 696 cmꢀ1; HRMS (EI): m/z: calcd
for C16H14FNO [M+H]+: 256.1131; found: 256.1123.
Compound (S)-13: A dried Schlenk tube was charged under N2 with [Pd-
AHCTUNGRTEG(NNNU dba)2] (5.7 mg, 0.01 mmol), (S,S)-5e (5.2 mg, 0.01 mmol), and NaOtBu
Compound (R,R)-5h: 95% yield; m.p. 99–1018C; [a]2D0 =ꢀ40.6 (c=0.5 in
CH2Cl2); 1H NMR (300 MHz, CDCl3): d=1.21 (s, 18H), 3.78–3.85 (m,
2H), 3.91 (s, 6H), 3.97–4.04 (m, 2H), 5.36 (s, 2H), 7.01 (dd, J=7.5,
15.2 Hz, 4H), 7.38 (t, J=7.5 Hz, 2H), 7.53 (d, J=7.6 Hz, 2H), 9.29 ppm
(s, 1H); 13C NMR (100 MHz, CDCl3): d=28.2, 36.2, 49.4, 55.9, 64.4,
111.5, 120.5, 122.4, 129.6, 130.2, 157.4, 158.9 ppm; IR (ATR diam.): n˜ =
2960, 2838, 1620, 1600, 1584, 1490, 1461, 1438 cmꢀ1; HRMS (EI): m/z:
calcd for C27H39N2O2 [MꢀI]+: 423.3006; found: 423.3029.
(28.8 mg, 0.3 mmol). DME (1 mL) was added and the mixture was stirred
for 10 min. Compound 12 (71.6 mg, 0.2 mmol) was then added as a solu-
tion in DME (3 mL). The reaction mixture was stirred at RT for 48 h and
was then quenched with aq. NH4Cl and extracted with diethyl ether. The
combined organic phases were washed with water and brine and dried
over MgSO4. Flash chromatography over SiO2 afforded (S)-13 (48.3 mg,
87%). HPLC (Chiralcel OD-H) showed (S)-13 to have been formed with
94% ee. Oil; [a]2D0 =ꢀ109.2 (c=1.0 in CH2Cl2), HPLC [Chiracel OD-H
column, n-hexane/iPrOH 99:1, 1.0 mLminꢀ1
, 254 nm; tR =24.33 min
Compound (S,S)-5i: 83% yield; m.p. 220–2228C; [a]2D0 =+45.7 (c=0.5 in
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=1.22 (s, 18H), 2.63 (s, 6H),
3.79–3.91 (m, 2H), 3.98–4.08 (m, 2H), 5.47 (s, 2H), 7.27–7.35 (m, 6H),
7.49 (m, J=7.1 Hz, 2H), 10.83 ppm (s, 1H); 13C NMR (100 MHz,
CDCl3): d=22.0, 28.1, 37.3, 48.8, 65.7, 125.9, 128.1, 128.7, 132.0, 132.4,
138.6, 159.2 ppm; IR (ATR diam.): n˜ =2958, 2909, 2871, 1623, 1479,
(major) and 31.36 min (minor)]; 1H NMR (400 MHz, CDCl3): d=1.84 (s,
3H), 2.05–2.1 (m, 2H), 2.38 (s, 3H), 2.84 (t, J=8 Hz, 2H), 3.78 (q, J=
4.8 Hz, 2H), 6.93 (d, J=10 Hz, 2H), 7.27–7.35 ppm (m, 5H); 13C NMR
(100 MHz, CDCl3): 21.4, 23.7, 24.6, 39.1, 53.5, 120.1, 122.6, 126.7, 127.1,
127.3, 128.5, 131.7, 133.4, 136.6, 141.0, 178.3 ppm; IR (neat): n˜ =3021,
2928, 2868, 1703, 1626, 1491, 1432 cmꢀ1; HRMS (EI): m/z: calcd for
C19H19NO [M+H]+: 278.1539; found: 278.1538.
1462 cmꢀ1
found: 391.3114.
;
HRMS (EI): m/z: calcd for C27H39N2 [MꢀI]+: 391.3107;
Procedures and spectral and analytical data for oxindoles (S)-9a–d, (S)-
Procedures and spectral and analytical data for ligand precursors (R,R)-
5 f and for (S,S)-5g, (R,R)-5j, (R,R)-5k, and (R,R)-5m are given in the
Supporting Information.
11a–g, (S)-13, (S,E)-15 and for [PdACHTNUTRGENNUG AHCTUNGTREN(NGUN S,S-5e)·I] [(S,S)-19] are given
(h3-allyl)
in the Supporting Information.
Substrates: The synthesis of and spectroscopic and analytical details for
the oxindole precursors 6a–j have been reported.[17a]
Procedures and spectral and analytical data for the bromo and chloro
precursors 8a–d, 10a–g, 12, 14, and 16a–e to the oxindoles are given in
the Supporting Information.
Acknowledgements
We thank the Swiss National Science Foundation and the University of
Geneva for financial support.
Catalytic asymmetric intramolecular a-arylation reactions
The synthesis of and spectroscopic and analytical details for the following
oxindoles have been reported: (S)-7a–j,[17a] rac-9a,[38] rac-9c and rac-
9d.[38]
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and the mixture was stirred for 10 min. Compound 10d (77.2 mg,
0.2 mmol) was then added as a solution in DME (3 mL). The reaction
mixture was stirred at RT for 48 h and then quenched with aq. NH4Cl
and extracted with diethyl ether. The combined organic phases were
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H) showed (S)-11d to have been formed with 95% ee. Oil; [a]2D0 =ꢀ66.54
(c=1.0 in CH2Cl2), HPLC [Chiracel OD-H column, n-hexane/iPrOH
99:1, 1.0 mLminꢀ1
, 254 nm; tR =18.87 min (major) and 27.57 min
1
(minor)]; H NMR (400 MHz, CDCl3): d=1.86 (s, 3H), 3.34 (s, 3H), 7.18
(s, 1H), 7.29–7.45 ppm (m, 7H); 13C NMR (100 MHz, CDCl3): 23.5, 26.6,
52.2, 105.0, 105.1, 119.8, 119.9, 124.4, 127.6, 130.5, 130.9, 138.7, 139.8,
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;
HRMS (EI): m/z: calcd for C17H14F3NO [M+H]+: 306.1100; found:
306.1086.
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Compound (S)-11g: A dried Schlenk tube was charged under N2 with
[PdACHTUNGTRENNUNG(dba)2] (5.7 mg, 0.01 mmol), (S,S)-5e (5.2 mg, 0.01 mmol), and
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6.95–7.15 (m, 3H), 7.28–7.41 ppm (m, 5H); 13C NMR (75 MHz, CDCl3):
d=14.2, 23.8, 28.9, 29.0, 52.4, 60.4, 115.9, 116.1, 120.0, 120.1, 123.3,
123.35, 125.4, 126.5, 127.4, 128.6, 129.9, 137.7, 140.3, 146.6, 149.0,
179.1 ppm; IR (neat): n˜ =3057, 2973, 1717, 1631, 1631, 1480, 1366, 1334,
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6308
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 6300 – 6309

New Chiral N-Heterocyclic Carbene Ligands
FULL PAPER
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Received: January 6, 2010
Published online: April 21, 2010
Chem. Eur. J. 2010, 16, 6300 – 6309
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6309