The synthesis of a new class of chiral pincer ligands and their applications in enantioselective catalytic fluorinations and the Nozaki-Hiyama-Kishi reaction

Article abstract of DOI:10.1002/chem.201102375

A new class of chiral tridentate N-donor pincer ligands, bis(oxazolinylmethylidene)isoindolines (boxmi), was synthesized in three steps starting from readily available phthalimides. Their reaction with ethyl (triphenylphosphoranylidene)acetate by means of

Full text of DOI:10.1002/chem.201102375

DOI: 10.1002/chem.201102375
The Synthesis of a New Class of Chiral Pincer Ligands and Their
Applications in Enantioselective Catalytic Fluorinations and the Nozaki–
Hiyama–Kishi Reaction
Qing-Hai Deng, Hubert Wadepohl, and Lutz H. Gade*[a]
Abstract: A new class of chiral triden-
tate N-donor pincer ligands, bis(oxazo-
linylmethylidene)isoindolines (boxmi),
was synthesized in three steps starting
from readily available phthalimides.
Their reaction with ethyl (triphenyl-
phosphoranylidene)acetate by means
of a key-step Wittig reaction gave the
ligand backbones, which were con-
densed with amino alcohols and then
cyclized to obtain the corresponding li-
gands. These ligands were subsequently
applied in the nickel(II)-catalyzed
enantioselective fluorination of oxin-
doles and b-ketoesters to obtain the
corresponding products with enantiose-
lectivities of up to >99% ee and high
yields. Application of the chiral pincer
ligands in the chromium-catalyzed
enantioselective Nozaki–Hiyama–Kishi
reaction of aldehydes gave the corre-
sponding alcohols with an optimal
enantioselectivity of 93%.
Keywords: asymmetric catalysis
·
fluorination · ligand design · nickel ·
Nozaki–Hiyama–Kishi reaction
Introduction
Meridionally coordinating chiral tridentate ligands, fre-
quently referred to as “pincers,”[1] provide the structural
platform for the construction of efficient stereodirecting mo-
lecular environments. Although many of the known chiral
systems of the pincer-type perform relatively poorly in enan-
tioselective catalysis due to certain lack of control of sub-
strate orientation, the assembly from rigid heterocyclic units
recently has given rise to several highly enantioselective cat-
alysts.[2] These ligand systems, such as bis(oxazolinyl)phenyl
(phebox),[3] bis(oxazolinyl)carbazole,[4] and chiral bis(pyridyl-
imino)isoindole (bpi) derivatives[5] have been proven to act
as efficient stereodirecting ligands in a variety of applica-
tions in molecular catalysis.
Scheme 1. Structure of the protio
opener BMS 204352.
ACHUTGTNRENlNUG iACTHUGNTRENNUgG and boxmi 1 and the maxi-K channel
the N-Boc-protected (Boc=t-butyloxycarbonyl) Maxipost
derivative in Scheme 1 was obtained with moderate selectiv-
ity (71% ee).[10a] Thus, the development of new catalyst sys-
tems for the asymmetric fluorination of oxindoles and other
substrates continues to be of considerable interest.
Oxindoles possess structural motifs found in many natural
products[6] and biologically active compounds.[7] In particu-
lar, 3-fluorooxindoles were found to have broad applications
in medicinal chemistry. One such example is BMS 204352
(MaxiPost) (Scheme 1), an effective opener of maxi-K chan-
nels and a potential agent for the treatment of stroke.[7e,f]
Whereas several catalytic systems for the asymmetric fluori-
nation of other nucleophiles[8,9] have been developed, there
are only few reports on catalytic asymmetric fluorination of
oxindoles[10] to obtain chiral 3-fluorooxindoles. Notably, the
only example of a catalytic enantioselective preparation of
The Nozaki–Hiyama–Kishi (NHK) reaction, first reported
in the late 1970s,[11] has become a powerful synthetic tool for
À
the formation of carbon carbon bonds under mild condi-
tions.[12] In 1996, Fꢀrstner et al. reported a catalytic redox
system that used manganese as the reducing agent, which
successfully reduced the quantity of CrII species, thereby
making these reactions more valuable and environmentally
benign.[13] Since the first catalytic enantioselective NHK re-
action using a commercially available salen (salen=(R,R)-
N,N’-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediam-
AHCTUNGTRENNUNG
ine) ligand was reported by Cozzi and co-workers,[14] several
new chiral ligands for the NHK reaction have been devel-
oped.[4,15]
[a] Dr. Q.-H. Deng, Prof. Dr. H. Wadepohl, Prof. Dr. L. H. Gade
Anorganisch-Chemisches Institut
Herein we report the synthesis of a new class of chiral N3
pincer
(boxmi, 1), which are readily accessible in a modular three-
step synthesis. In an evaluation of their potential in enantio-
selective catalysis, these were found to induce very high ste-
reoselectivity in Ni-catalyzed enantioselective fluorination
Universitꢁt Heidelberg, Im Neuenheimer Feld 270
69120 Heidelberg (Germany)
Fax : (+49)6221-545-609
ligands,
bis(oxazolinylmethylidene)isoindolines
E-mail: lutz.gade@uni-hd.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102375.
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Chem. Eur. J. 2011, 17, 14922 – 14928

FULL PAPER
of oxindoles and b-ketoesters,
and Cr-catalyzed enantioselec-
tive NHK reactions of alde-
hydes.
Results and Discussion
Scheme 3. Synthesis of the nickel complexes 10a and 10b.
Synthesis of bis(oxazolinylme-
thylidene)isoindolines and their
coordination to nickel(II): The
To establish the structural details of this new class of ste-
reodirecting ligands, single-crystal X-ray structure analyses
of the protioACTHUNTGRENNUGliCAHTUGTNRENNUGgand 1i (Figure 1a) and the chloronickel com-
bis(oxazolinylmethylidene)isoindoline protioligands were
prepared in three steps starting from easily available phthal-
imides 3 (Scheme 2). The backbones of the pincer ligands
plex [Ni(L)Cl] (10a) (Figure 1b) were carried out. The well-
defined C2-chiral molecular shape and preorganized orienta-
tion of the N-donor functions is apparent in the molecular
structure of 1i, the gross features of which are retained in
its metalated form as evidenced by the almost ideally
square-planar nickel complex 10a. It is notable that the usu-
ally observed difference in N–metal bond lengths for neutral
and anionic N donors appears to be evened out in the struc-
À
ture of 10a (the isoindolato Ni N(1) is 1.904(1) ꢃ, whereas
Scheme 2. Synthesis of ligands 1. i) PhB(OH)2, [PdACHTUNGTRNE(NUG PPh3)4], Cs2CO3,
DME, H2O, reflux.
(4a–d) were prepared according to improved Wittig proce-
dures[16] (combined with a subsequent Suzuki coupling[17] for
4d). Compounds 5a–j were synthesized in high yields by
melting 4 with the corresponding amino alcohols in the pres-
ence of a catalytic amount of NaH,[18] and the desired li-
gands 1a–j were obtained from 5 using a Ph3P/CCl4/Et3N
cyclization protocol[19] (for the detailed screening conditions
of the ligand synthesis, see the Supporting Information)
Deprotonation of 1a with two molar equivalents of NaH
and subsequent stirring with NiCl2 yielded the nickel(II)
complex 10a as a black red solid (Scheme 3, reaction a).
The alternative methods to obtain nickel complex, direct
Figure 1. Molecular structure of a) ligand 1i and b) [Ni(L)Cl] (10a); hy-
drogen atoms omitted for clarity. Selected bond lengths [ꢃ] and angles
À
À
À
[8] of [Ni(L)Cl] (10a): Ni N(1) 1.904(1), Ni N(2) 1.911(1), Ni N(3)
complexation of 1a with NiACHTNUGRTENUNG(OAc)2 in methanol at room
temperature, gave the corresponding nickel(II)–acetato
complex 10b (Scheme 3, reaction b).
À
1.911(1), Ni Cl 2.1927(9); N(1)-Ni-N(2), 91.34(5), N(1)-Ni-N(3),
91.78(5), N(2)-Ni-N(3) 176.64(5), N(1)-Ni-Cl 174.33(4), N(2)-Ni-Cl
88.52(4), N(3)-Ni-Cl 88.49(4).
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14923

L. H. Gade et al.
À
À
Table 2. Substrate scope for the enantioselective fluorination of oxindo-
les.[a]
Ni N(2) 1.911(1), Ni N(3) 1.911(1) ꢃ were found for the
two oxazoline donors). This is thought to be a consequence
of the delocalized p system that connects the donor atoms
in this type of pincer ligand.
Enantioselective catalytic fluorination: The fluorination of
oxindole 6a was initially carried out using boxmi derivative
1a as stereodirecting ligand and N-fluorobenzenesulfon-
ACHTUNGTRENNUNG
amide (NFSI) as fluorinating agent.[10b] Solvent screening
showed ethyl ether to be the most suitable solvent; it raised
the enantioselectivity for this transformation to >99% ee
(Table 1, entries 1–4). Other Lewis acidic metals were also
screened (entries 5–7), and Ni and Zn complexes prepared
in situ were found to give the fluorination product with high
enantioselectivity (entries 4 and 5), whereas cobalt and mag-
nesium complexes proved to be less efficient (entries 6 and
7). Finally, a screening of a series of boxmi ligands was car-
ried out and, in general, the highest selectivities were ob-
tained with derivatives that contained 4-phenyloxazolinyl
units at the “wing tips” of the pincer ligand (ligands 1a, 1d,
and 1h; entries 4, 10, and 14).
7a
7b
95% yield
99% ee
7c
95% yield
>99% ee (S)
89% yield
>99% ee
7d
7e
7 f
94% yield
98% ee (S)
91% yield
>99% ee
93% yield
99% ee
With the optimized conditions in hand, we focused on the
substrate scope and generality of the reaction. The introduc-
tion of electron-donating and -withdrawing groups on both
the oxindole core and the 3-aryl group provided products
with excellent enantioselectivity toward the S enantiomer
(Table 2, 7a–j). With a 3-methyl-substituted oxindole as a
substrate, the reaction affords the product with 91% yield
and 95% ee (Table 2, 7k). It is notable that the R isomer of
7g
7h
92% yield
98% ee
7i
91% yield
>99% ee (S)
92% yield
99% ee (S)
Table 1. Optimization of the fluorination reaction conditions.[a]
7j
7k
7l
93% yield
>99% ee (S)
91% yield
95% ee
90% yield
99% ee (R)
[a] Reaction conditions: 6 (0.1 mmol, 1.0 equiv), NFSI (1.2 equiv), 1a
(12 mol%), Ni(ClO4)2·6H2O (10 mol%), 4 ꢃ MS (50 mg), Et2O (2 mL)
AHCTUNGTRENNUNG
at room temperature under argon. Yields refer to isolated products.
Enantiomeric excess was determined by chiral HPLC analysis. Absolute
configuration of the product was determined by comparison with litera-
ture.
Entry Metal(II) salt
L
Solvent t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ni
Ni
Ni
Ni
N
4
6
10
6
5
8
8
6
6
6
6
6
6
6
6
6
94
85
83
95
91
91
88
95
90
91
93
92
89
90
91
89
97 (S)
87 (S)
78 (S)
>99 (S)
87 (S)
29 (S)
11 (S)
42 (S)
21 (S)
>99 (S)
47 (S)
25 (S)
30 (S)
99 (S)
48 (S)
28 (S)
2 was obtained in 90% yield with 99% ee when 1a was em-
ployed as stereodirecting ligand. Compound 7l would be
converted into R enantiomer of MaxiPost by cleavage of the
N-Boc group.[10a] To the best of our knowledge, this is the
highest enantioselectivity for catalytic preparation of N-
Boc-protected Maxipost.
To further demonstrate the synthetic utility of the boxmi/
Ni fluorination system, we also investigated the catalytic
enantioselective fluorination of several cyclic b-ketoesters.
The pharmaceutically important fluorinated b-ketoesters
9a–e[7g] were obtained with high enantioselectivity (Table 3).
[d]
Zn
Co(OAc)2·4H2O 1a Et2O
Mg(ClO4)2 1a Et2O
(ClO4)2·6H2O 1b Et2O
(ClO4)2·6H2O 1c Et2O
(ClO4)2·6H2O 1d Et2O
(ClO4)2·6H2O 1e Et2O
(ClO4)2·6H2O 1 f Et2O
(ClO4)2·6H2O 1g Et2O
(ClO4)2·6H2O 1h Et2O
(ClO4)2·6H2O 1i Et2O
(ClO4)2·6H2O 1j Et2O
N
1a Et2O
R
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
[a] Reaction conditions: 6a (0.1 mmol, 1.0 equiv), NFSI (1.2 equiv),
ligand (12 mol%), MX (10 mol%), 4 ꢃ molecular sieves (MS) (50 mg),
solvent (2 mL) at room temperature under argon. [b] Yield of isolated
products. [c] Determined by chiral HPLC analysis; absolute configuration
of the product was determined by comparison with literature. [d] Tf=
triflate.
Enantioselective catalytic Nozaki–Hiyama–Kishi reaction:
The Nozaki–Hiyama–Kishi allylation of benzaldehyde 11a
with allylic halide catalyzed by 1a/CrCl2 was selected as the
initial test reaction. A variety of solvents, bases, allylic hal-
ides, and chlorosilanes were tested in the model reaction
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Chiral Pincer Ligands
FULL PAPER
Table 3. Substrate scope for the enantioselective fluorination of b-ketoes-
chlorosilane affected the results slightly, and trimethylsilyl
chloride (TMSCl) was found to give the best results (en-
tries 1, 14 and 15).
ters.[a]
The reaction was further optimized by screening the
whole series of ligands (Table 5). As shown, all catalysts that
bore ligands 1a–j exhibited high catalytic activity to afford
the desired product 12a with high yield. Ligand 1e, which
contained 4-isopropyloxazolinyl units and methyl groups in
the backbone, gave the best enantioselectivity (86% ee)
(Table 5, entry 5).
9a
9b
9c
92% yield
97% ee (R)
92% yield
93% ee
93% yield
92% ee
Table 5. Screening the ligands for the Nozaki–Hiyama–Kishi reaction.
9d
9e
93% yield
97% ee
92% yield
95% ee
Entry
L
t [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
12
12
10
10
10
10
12
12
12
12
91
92
91
89
92
93
92
93
91
92
84 (S)
83 (S)
73 (S)
54 (S)
86 (S)
68 (S)
73 (S)
79 (S)
83 (S)
63 (S)
[a] Reaction conditions: 8 (0.1 mmol, 1.0 equiv), NFSI (1.2 equiv), 1a
(12 mol%), Ni(ClO4)2·6H2O (10 mol%), 4 ꢃ MS (50 mg), Et2O (2 mL)
at room temperature under argon. Yields refer to isolated products.
Enantiomeric excess was determined by chiral HPLC analysis. Absolute
configuration of the product was determined by comparison with litera-
ture.
ACHTUNGTRENNUNG
10
1j
and the results are summarized in Table 4. Among a number
of solvents examined, THF was found to be the optimal one
(Table 4, entries 1–7). In addition, the yield and ee values
depended on the bases and N,N-diisopropylethylamine
(DIPEA) turned out to be the best base (entries 1 and 8–
11). The use of allyl bromide gave highest enantioselectivity
and yield compared to allyl chloride or allyl iodide (en-
tries 1, 12, and 13). Finally, we found that the choice of the
[a] Yield of isolated products. [b] Determined by chiral HPLC analysis;
absolute configuration of the product was determined by comparison
with literature.
With the optimal conditions in hand, the substrate scope
was next explored with different aldehydes and bromides
(Table 6). Aromatic and aliphatic aldehydes were all allyl-
AHCTUNGTREGaNNNU ted with 86–88% ee in high yields (Table 6, entry 1–6). This
Table 4. Optimization of the Nozaki–Hiyama–Kishi reaction conditions.
system also catalyzed methallylation of aldehydes by the use
of methallylbromide to obtain the corresponding products
with 75–90% ee (entry 7–10). Furthermore, this enantiose-
lective reaction was successfully extended to crotylations of
aldehydes by the use of crotyl bromide. The crotylation of
benzaldehyde gave the product with a 3.7:1 ratio of anti to
syn in 90% yield with 86% ee (anti form) (entry 11). Nota-
bly, the observed diastereoselectivity of the crotylation of
hydrocinnamaldehyde was high with a 10:1 ratio that fa-
vored the anti product obtained with 93% ee (entry 12).
Entry
X
Base
R3SiCl
Solvent t [h] Yield [%][a] ee [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Br DIPEA TMSCl
Br DIPEA TMSCl
Br DIPEA TMSCl
Br DIPEA TMSCl
Br DIPEA TMSCl
Br DIPEA TMSCl
Br DIPEA TMSCl
THF
MeCN 16
EtCN 16
DMSO 24
12
91
89
86
67
51
47
32
87
91
89
86
80
85
92
90
84 (S)
69 (S)
62 (S)
49 (S)
7 (S)
DMF
24
DME[c] 16
CH2Cl2 24
27 (S)
12 (S)
45 (S)
59 (S)
49 (S)
55 (S)
43 (S)
69 (S)
82 (S)
84 (S)
Br
–
TMSCl
TMSCl
TMSCl
THF
THF
THF
THF
THF
THF
24
24
24
9
12
12
12
12
Conclusion
Br K2CO3
Br Et3N
Br pyridine TMSCl
Cl DIPEA TMSCl
The convenient synthetic access to this new class of triden-
tate ligands boxmi and the stability of their transition-metal
complexes will allow their application in enantioselective
catalysis. Their potential has been demonstrated in Ni-cata-
lyzed enantioselective fluorinations of oxindoles and b-ke-
toesters and the Cr-catalyzed enantioselective NHK reaction
of aldehydes. Further applications are currently being inves-
tigated in our laboratory.
I
DIPEA TMSCl
Br DIPEA TESCl[c] THF
Br DIPEA TIPSCl[c] THF
[a] Yield of isolated products. [b] Determined by chiral HPLC analysis;
absolute configuration of the product was determined by comparison
with literature. [c] DME=dimethoxyethane, TESCl=triethylsilyl chlo-
ride, TIPSCl=triisopropylsilyl chloride.
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L. H. Gade et al.
Table 6. Substrate scope for the Nozaki–Hiyama–Kishi reaction.
ethane (200 mL) and H2O (60 mL). After degassing the mixture, [Pd-
AHCTUNTGREGUN(NN PPh3)4] (711 mg, 0.67 mmol, 0.25 equiv) was added. The resulting sus-
pension was heated at refluxing temperature for two days. After remov-
ing dimethoxyethane under vacuum, the mixture was diluted in dichloro-
methane and washed with water (3ꢄ100 mL), and the separated organic
phase was dried over anhydrous sodium sulfate. Evaporation of the sol-
vent under vacuum and purification by column chromatography (hexane/
ethyl acetate 4:1) to afford 4d (763 mg, 1.74 mmol) in 65% yield. For
characterization data, see the Supporting Information.
Entry R1
R2 R3 t [h] Product Yield [%][a] ee [%][b]
1
2
3
4
5
Ph
H
H
H
H
H
H
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
10
11
11
12
12
12
12
12
12
12
12a
12b
12c
12d
12e
12 f
12g
12h
12i
92
91
93
92
91
90
93
90
86 (S)
88 (S)
88 (S)
86 (S)
86 (S)
87 (R)
86 (S)
90
79 (S)
75 (R)
86 (anti)[e]
35 (syn)[f]
93 (anti)[h]
40 (syn)[i]
General procedure for the synthesis of 5: Compound 4 (1 equiv) and (S)-
amino alcohol (5 equiv) were mixed and melted in a Schlenk tube under
argon. The solid mixture was then rapidly heated to 1208C in a preheated
oil bath. NaH (60%, 20 mol%) was added to the resulting mixture, and
the reaction mixture was stirred under slightly reduced pressure for 7 h.
The reaction mixture turned brown and became highly viscous. After
subsequent cooling to ambient temperature, the crude product was di-
rectly purified by column chromatography (dichloromethane/methanol
from 40:1 to 10:1) to obtain the desired product 5. For characterization
data, see the Supporting Information.
p-MePh
p-MeOPh
p-ClPh
p-BrPh
PhCH2CH2
Ph
6
7
8
9
p-MePh
p-ClPh
94
10
11
PhCH2CH2 Me
Ph
12j
12k
91
H
H
Me 12
90[c,d]
General procedure for the synthesis of 1: PPh3 (12.5 mmol, 5 equiv),
Et3N (12.5 mmol, 5 equiv), and CCl4 (12.5 mmol, 5 equiv) were added to
a solution of 5 (2.5 mmol, 1 equiv) in MeCN (300 mL). The reaction mix-
ture was stirred at room temperature. After completion of the reaction
(monitored by TLC), water (500 mL) was added and the resulting mix-
ture was extracted with CH2Cl2 (300 mLꢄ5). The combined organic
phase was dried over Na2SO4. The solvent was removed under reduced
pressure, and the crude product was purified by flash chromatography on
silica gel (hexane/ethyl acetate 4:1) to give 1 as yellow solid.
12
PhCH2CH2
Me 12
12l
89[c,g]
[a] Yield of isolated products. [b] Determined by chiral HPLC analysis;
absolute configuration of the product was determined by comparison
with literature. [c] Isolated yield of a mixture of anti and syn product
after chromatographic purification; anti/syn ratio determined by
1H NMR spectroscopy of crude product. [d] anti/syn=3.7:1. [e] The abso-
lute configuration was determined to be (1S,2S) by comparison with the
literature.[15g,20] [f] The absolute configuration was determined to be
(1S,2R) by comparison with the literature.[15g,20] [g] anti/syn=10:1. [h] The
absolute configuration was determined to be (1R,2S) by comparison with
the literature.[15g,21] [i] The absolute configuration was determined to be
(1R,2R) by comparison with the literature.[15g,21]
AHCTUNGTERG(NNUN 1Z,3Z)-1,3-Bis{[(S)-4-phenyl-4,5-dihydrooxazol-2-yl]methylene}isoindo-
line (1a): Yield: 66%; 1H NMR (600 MHz, CDCl3): d=11.90 (brs, 1H),
7.72–7.70 (m, 2H), 7.51–7.50 (m, 2H), 7.31–7.27 (m, 8H), 7.24–7.20 (m,
2H), 5.72 (s, 2H), 5.30 (t, J=8.0 Hz, 2H), 4.65 (t, J=8.0 Hz, 2H),
4.06 ppm (t, J=7.4 Hz, 2H); 13C NMR (150 MHz, CDCl3): d=165.2,
147.9, 143.0, 135.0, 130.0, 128.6, 127.3, 126.7, 121.2, 83.1, 73.8, 69.7 ppm;
IR (KBr): n˜ =1643, 1607, 1475, 1167, 1116, 1065, 993, 755 cmÀ1; HRMS
(ESI): m/z calcd for C28H24N3O2+H [M++H]: 434.18630; found:
434.18618; elemental analysis calcd (%) for C28H23N3O2: C 77.58, H 5.35,
N 9.69; found: C 77.30, H 5.29, N 9.73.
Experimental Section
All manipulations were carried out using standard Schlenk line or drybox
techniques under an atmosphere of argon. Solvents were pre-dried over
activated 4 ꢃ molecular sieves and were heated to reflux over magnesi-
um (methanol), sodium (toluene), potassium (hexane), sodium–potassi-
um alloy (tetrahydrofurane, diethyl ether), or calcium hydride (dichloro-
methane) under an argon atmosphere and collected by distillation. 1H
and 13C{1H} NMR spectra were recorded using a Bruker Avance III 600,
Bruker Avance II 400, and Bruker DRX 200 spectrometer. 1H and
13C NMR spectra were referenced internally to residual protio solvent
(1H) or solvent (13C) resonances and are reported relative to tetramethyl-
silane. 19F NMR spectroscopy was measured at 376 MHz, and CFCl3 (d=
0 ppm) was used as an external standard. HPLC analyses using a Thermo
Electron Surveyor chromatograph. Infrared spectra were prepared as
KBr pellets and were recorded using a Varian Excalibur 3100 series
FTIR spectrometer. Optical rotations were measured using a Perkin–
Elmer 241 polarimeter in a 1 dm cuvette. Mass spectra were recorded by
the mass spectrometry service of the University of Heidelberg Organic
Chemistry Laboratory, and the elemental analyses were measured by the
analytical services of the University of Heidelberg. Compounds 3b,[22]
6,[10a,c] and 8[23] were synthesized according to the literature procedures.
All other reagents were commercially available and used as received.
Characterization data for 1b–j: See the Supporting Information.
Procedure for the synthesis of nickel complex 10a: Compound 1a
(86.6 mg, 0.20 mmol) and sodium hydride (98%, 24 mg, 1 mmol, 5 equiv)
were suspended in THF (10 mL) and stirred at room temperature for
two hours. It was then added through a cannula to a suspension of NiCl2
(51.9 mg, 0.40 mmol, 2 equiv) in THF (10 mL). After stirring the reaction
mixture for 8 h, the solvent was removed under vacuum, and the residue
was redissolved in dichloromethane and filtered. The crude reaction
product was recrystallized from dichloromethane/hexane to obtain pure
product (93.7 mg, 0.18 mmol) as a dark-red solid in 89% yield. 1H NMR
(600 MHz, CD2Cl2): d=7.76 (dd, J=3.0, 5.4 Hz, 2H), 7.52 (dd, J=3.0,
5.4 Hz, 2H), 7.37 (t, J=7.2 Hz, 4H), 7.30 (t, J=7.2 Hz, 2H), 7.16 (d, J=
7.2 Hz, 4H), 5.86 (s, 2H), 5.72 (dd, J=3.0, 8.4 Hz, 2H), 4.48 (t, J=
8.4 Hz, 2H), 4.08 ppm (dd, J=3.0, 8.4 Hz, 2H); 13C NMR (150 MHz,
CD2Cl2): d=164.4, 158.6, 144.4, 137.7, 130.1, 128.9, 127.7, 126.6, 120.6,
82.3, 74.8, 67.5 ppm; IR (KBr): n˜ =1614, 1566, 1532, 1301, 1215, 1116,
1036, 761 cmÀ1; HRMS (FAB): m/z calcd for C28H22N3O235L58Ni+1 [M+]:
525.0754; found: 525.0729; elemental analysis calcd (%) for
C28H22N3O2ClNi: C 63.86, H 4.21, N 7.98; found: C 63.89, H 4.05, N 7.92.
Procedure for the synthesis of nickel complex 10b: Compound 1a
(65 mg, 0.15 mmol) was added to a solution of NiII acetate tetrahydrate
(74.6 mg, 0.30 mmol) in methanol (10 mL) and stirred over night. The
deep-red solution was concentrated under vacuum, then the residue dis-
solved in CH2Cl2 (10 mL) and filtered. The crude reaction product was
recrystallized from dichloromethane/hexane to obtain pure product
(70 mg, 0.13 mmol) as a red solid in 85% yield. 1H NMR (600 MHz,
CD2Cl2): d=7.81 (dd, J=3.0, 5.4 Hz, 2H), 7.61 (dd, J=3.0, 5.4 Hz, 2H),
7.38 (t, J=7.2 Hz, 4H), 7.32 (t, J=7.2 Hz, 2H), 7.23 (d, J=7.2 Hz, 4H),
5.62 (d, J=7.2 Hz, 2H), 5.53 (s, 2H), 4.48 (t, J=8.4 Hz, 2H), 4.29 (d, J=
8.4 Hz, 2H), 1.81 ppm (s, 3H); 13C NMR (150 MHz, CD2Cl2): d=170.6,
General procedure for the synthesis of 4a–c: Phthalimides (20–30 mmol)
and (carbethoxymethylene)triphenylphosphorane (5 equiv) were mixed
in a Schlenk tube under argon. Then the solid mixture was stirred in
1408C for 24 h. The crude product was directly purified by column chro-
matography (n-hexane/ethyl acetate 4:1) to obtain the desired product.
For characterization data, see the Supporting Information.
Procedure for the synthesis of 4d: Compound 4c (950 mg, 2.67 mmol,
1 equiv), Cs2CO3 (8.70 g, 26.7 mmol, 10 equiv), and phenylboronic acid
(2.73 g, 21.36 mmol, 8 equiv) were dissolved in a mixture of dimethoxy-
14926
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 14922 – 14928

Chiral Pincer Ligands
FULL PAPER
165.7, 161.5, 146.4, 144.7, 130.6, 129.1, 127.9, 126.0, 121.6, 84.5, 79.4, 71.4,
Acknowledgements
29.7 ppm; IR (KBr): n˜ =1612, 1569, 1535, 1314, 1223, 1115, 952, 738 cmÀ1
;
HRMS (FAB): m/z calcd for C30H25N3O458Ni+1 [M+]: 549.1199; found:
549.1195; elemental analysis calcd (%) for C30H25N3O4Ni: C 65.49, H
4.58, N 7.64; found: C 65.68, H 4.73, N 7.94.
Q.-H.D. acknowledges support by the Alexander von Humboldt Founda-
tion. Funding was provided by the Deutsche Forschungsgemeinschaft
(SFB 623, TP B6).
General procedure for enantioselective catalytic fluorination: Ni-
ACHTUNGTRENNUNG(ClO4)2·6H2O (10 mol%) and ligand 1a (12 mol%) were stirred under
vacuum for 2 h at room temperature, then 4 ꢃ molecular sieves (50 mg)
and dry Et2O (2 mL) were added under argon atmosphere and stirred for
1 h. Then substrate 6 or 8 (0.10 mmol) was added to the catalyst solution.
After stirring for another 30 min, N-fluorobenzenesulfonimide (NFSI;
1.2 equiv) was added directly to the mixture. The reaction was stirred at
room temperature for 6 h, then stopped by the addition of water
(0.5 mL). The reaction mixture was diluted with CH2Cl2, filtered through
Celite and anhydrous Na2SO4. After removal of solvent, the residue was
purified by column chromatography on silica gel (eluent: hexane/AcOEt
10:1 or CH2Cl2 directly) to afford pure product 7 or 9. For further data,
see the Supporting Information.
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General procedure for enantioselective catalytic NHK reaction: Anhy-
drous chromium(II) chloride (6.1 mg, 0.05 mmol), ligand 1e (23.6 mg,
0.06 mmol), and manganese (54.9 mg, 1.00 mmol) were added into a
flame-dried Schlenk tube. Dry THF (2 mL) was added under argon at-
mosphere and stirred for 1 h. DIPEA (26.2 mL, 0.15 mmol) was added.
The mixture was then stirred at room temperature for 30 min prior to the
addition of allyl bromide (1.00 mmol) with the resulting solution being
stirred for a further 1 h. The reaction was then initiated by the addition
of aldehyde (0.50 mmol) and chlorotrimethylsilane (130 mL, 1.00 mmol)
and stirred under an atmosphere of argon at room temperature until the
disappearance of aldehyde (monitored by TLC). The resulting suspension
was quenched with saturated aqueous NaHCO3 (1 mL) and filtered over
a pad of Celite using Et2O as eluent (15 mL). The aqueous phase was ex-
tracted with Et2O (2ꢄ5 mL) and the combined organic layers were then
dried over anhydrous Na2SO4, filtered, and concentrated under vacuum
to give a red residue. The red oil was then dissolved in THF (2 mL) and
tetra-n-butylammonium fluoride (TBAF; 1m in THF, 1.0 mL) was added.
After stirring for another 30 min, the resulting solution was quenched
with saturated aqueous NH4Cl (1 mL), and the resulting aqueous phase
was extracted with Et2O (3ꢄ5 mL). The organic layers were combined,
dried over anhydrous Na2SO4, and concentrated under vacuum to give an
oil. The crude mixture was then purified by flash column chromatogra-
phy on silica gel using CH2Cl2 as the eluent to give the desired alcohols
13. For further data, see the Supporting Information.
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X-ray diffraction study of 1i and 10a: Data collection: Bruker AXS
Smart 1000 CCD diffractometer, MoKa radiation, graphite monochroma-
tor, l=0.71073 ꢃ, T=100(2) K. Lorentz, polarization, and semiempirical
absorption correction.[24a,b] Structure solution: charge flip.[24c] Refinement:
full-matrix least squares based on F2;[24d] all non-hydrogen atoms aniso-
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others at calculated positions (refined riding). Crystals of 1i were 1:1
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electron density attributed to disordered n-pentane was removed from
the structure (and the corresponding Fobsd) with the BYPASS procedur-
e.[24e] Crystal data for 1i: C34H34N3O2; tetragonal, space group P41; a=
[7] a) B. Volk, J. Barkꢅczy, E. Hegedus, S. Udvari, I. Gacsꢆlyi, T. Mezei,
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11.863(1), c=20.149(2) ꢃ; V=2835.7(4) ꢃ3; Z=4; m=0.076 mmÀ1; F000
1100; q range 1.0 to 29.78; reflections measured: 65364, independent:
4120 (Rint =0.0812), observed (I>2s(I)): 3245; final indices (Fo >
=
R
4s(Fo)): R(F)=0.0593, wR(F2)=0.1433; GOF=1.028. Crystal data for
10a: C33H34ClN3NiO2; monoclinic, space group P21; a=14.999(7), b=
6.393(3), c=15.423(6) ꢃ; b=109.328(8)8; V=1395.4(10) ꢃ3; Z=2; m=
0.827 mmÀ1; F000 =628; q range 2.3 to 32.28; reflections measured: 35221,
independent: 9240 (Rint =0.0328), observed (I>2s(I)): 8937; final R indi-
ces (Fo >4s(Fo)): R(F)=0.0284, wR(F2)=0.0776; GOF=1.099; Flack x=
À0.003(6).
CCDC-830007 (1i) and -830008 (10a) contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Chem. Eur. J. 2011, 17, 14922 – 14928
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Received: July 30, 2011
Published online: November 3, 2011
14928
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