SPANphos ligands in palladium-catalyzed asymmetric fluorination

Article abstract of DOI:10.1002/ejoc.201200223

The synthesis of new enantiopure wide-bite-angle diphosphanes is described as well as their use in the palladium-catalyzed asymmetric fluorination of α-cyanoacetates. Enantiomeric excesses up to 93 % were obtained when Pd(OAc)₂-SPANphos was use

Full text of DOI:10.1002/ejoc.201200223

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FULL PAPER
DOI: 10.1002/ejoc.201200223
SPANphos Ligands in Palladium-Catalyzed Asymmetric Fluorination
Olivier Jacquet,[a] Nicolas D. Clément,[a] Carolina Blanco,[a] Marta Martinez Belmonte,[a]
Jordi Benet-Buchholz,[a] and Piet W. N. M. van Leeuwen*[a]
Keywords: Asymmetric catalysis / Ligand design / Palladium / Halogenation / Fluorine
The synthesis of new enantiopure wide-bite-angle diphos-
phanes is described as well as their use in the palladium-
catalyzed asymmetric fluorination of α-cyanoacetates. Enan-
tiomeric excesses up to 93% were obtained when Pd(OAc)2-
SPANphos was used as catalyst for the fluorination of ethyl
2-cyano-2-phenylacetate with N-fluorobenzenesulfonimide
(NFSI).
Introduction
coordinated complexes were isolated. Only a few examples
of trans-coordinating diphosphane ligands have been used
in asymmetric catalysis,[10] the TRAP ligands introduced by
Ito being notable examples.[11] Recently, Ding and co-
workers applied SPANbox in the Zn-catalyzed enantioselec-
tive hydroxylation of β-keto esters;[12] high enantiomeric ex-
cesses were obtained and, in this instance, neither the ligand
nor the metal required trans coordination. We applied the
same SPANbox in Ni-catalyzed fluorination, but no
enantioselectivity was obtained.[3] We therefore aimed to
use our enantiopure SPANphos ligands in the palladium-
catalyzed asymmetric fluorination of α-cyanoacetates,
which would be the first application of a trans-coordinating
ligand for this kind of reaction. Because the reaction
mechanism does not involve insertion reactions or reductive
elimination reactions, which typically require cis coordina-
tion of the bidentate ligand in square-planar complexes, the
fluorination reaction was thought to be a suitable candidate.
The synthesis of enantiopure molecules bearing a fluor-
ine atom at the stereogenic center has generated great inter-
est, both in the field of analytical chemistry and for the
synthesis of biologically active compounds. Since Togni’s
discovery[1] that a chiral titanium complex as a catalyst
could convert β-keto esters into chiral, non-enolizable α-
fluorinated β-keto esters, many examples involving chiral
transition metal complexes have been published, such as
complexes of nickel, copper, and palladium.[2] We recently
applied chiral nitrogen-based 2,2Ј-spirobichroman (SPAN)
derivatives as organocatalysts for the enantioselective fluo-
rination of β-keto esters,[3] and showed that the activity can
be enhanced by the addition of a nickel salt without loss of
enantioselectivity. In this paper we report the use of
enantiopure diphosphane SPANphos derivatives as chiral
ligands for the palladium-catalyzed asymmetric fluorina-
tion of α-cyanoacetates. The fluorinated product can easily
be further derivatized, either at the ester group, or through
the nitrile functionality. Sodeoka first reported the use of
Pd-diphosphane complexes to promote the enantioselective
fluorination of both β-keto esters[4] and β-keto phosphon-
ates[5] and, later, Kim used a similar system with BINAP as
the chiral ligand to efficiently catalyze the fluorination of
α-cyanoacetates[6] and α-cyanophosphonates.[6a,7]
Results and Discussion
Racemic SPANphos ligands were synthesized according
to a procedure similar to that previously reported in our
laboratory,[8a] by mixing 2 equiv. of the corresponding chlo-
rophosphane with 1 equiv. of dilithio compound. In the
case of SPAN(DBP)2 2, the enantiomers were isolated after
separation by semipreparative chiral HPLC. However, this
method was unsuccessful for the other diphosphanes. Race-
mic SPANphos derivatives were oxidized to the phosphane
oxides, all of which were resolved and separated by semipre-
parative HPLC. Enantiopure SPANphos ligands were ob-
tained by subsequent reduction of the oxides with MeOTf/
LiAlH4 (Scheme 1).[13]
Various racemic diphosphane SPANphos ligands have
been synthesized in our group[8] but, until now, only race-
mic ligands were used successfully in catalysis. A dimeric
Rh-SPANphos complex was the most active catalytic sys-
tem for the carbonylation of methanol.[9] It was shown that,
depending on the ligands borne by rhodium, SPANphos
can be a trans-[8a] or cis-coordinating ligand.[8b] In the case
of platinum(II) or palladium(II) complexes, only trans-
For two enantiomeric phosphanes (S)-4 and (R)-6, the
absolute configuration was determined by X-ray diffrac-
tion. Figure 1 nicely shows the spiro character of the li-
gands. As usual, the POP groups in (S)-4 are nearly flat and
[a] Institute of Chemical Research of Catalonia (ICIQ),
Av. Països Catalans 16, 43007 Tarragona, Spain
E-mail: pvanleeuwen@iciq.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200223.
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P. W. N. M. van Leeuwen et al.
FULL PAPER
Scheme 1. Ligand structures and synthesis.
the dihydropyran groups have an envelope conformation in
Complex A exhibits a large bite angle of the phosphane
both (S)-4 and (R)-6. Distances and angles show normal on the palladium atom (P1–Pd–P2: 175.46°) (see the Sup-
values (see the Supporting Information). porting Information), which is 4° larger than that reported
We were also able to isolate single crystals of the trans- for the PtCl2-SPANphos complex 1.[8a]
chelated dichloropalladium complex with racemic We first screened several palladium precursors in the
SPANphos 1 after mixing 1 equiv. of [Pd(cod)Cl2] with presence of enantiopure SPANphos 1 under previously re-
phosphane 1 (Figure 2). ported reaction conditions (5 mol-% catalyst, NFSI as
A
2
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SPANphos Ligands in Asymmetric Fluorination
Table 2. Solvent screening.
Solvent
Conv.[a] (yield[b]) [%]
ee [%][c]
EtOH
MeOH
iPrOH
DME
100 (97)
85 (75)
93
47
88
72
67
83
82
91
100 (92)
100 (88)
100 (95)
100 (95)
100 (91)
100 (92)
Figure 1. ORTEP plots (40%) of complex (R)-6 (left) and (S)-4
(right). Hydrogen atoms have been omitted for clarity.
THF
Toluene
CH2Cl2
MeCN
[a] Determined by 1H NMR analysis on the crude product. [b] Iso-
lated yield. [c] Determined by chiral-phase HPLC analysis of puri-
fied 10a.
Several of our enantiopure SPAN ligands as well as com-
mercially available (R)-BINAP were then tested (Table 3).
In each case, the reaction was performed both at 0 °C and
at room temperature for 18 h, leading to good conversion.
Except in the case of SPANbox 8b, enantiomeric excesses
were higher at 0 °C than at room temperature. SPANphos
1 was the best ligand in the series and provided higher
enantioselectivities than BINAP. The orientation of the
substituents on the phosphorus atom had a dramatic effect
on the enantioselectivity; this was clearly demonstrated in
the case of ligand 2, which provided only racemic products.
Steric hindrance also had an influence, as shown by the
difference in the enantiomeric excess observed with
SPANphos 3 and 4. Previously, we reported that SPANam-
ine 7 gave a high enantiomeric excess for this reaction when
used with Ni salts,[3] but in this catalytic system SPAN ni-
trogen-based derivatives did not lead to appreciable ee val-
ues.
Figure 2. ORTEP plot of complex A. Hydrogen atoms have been
omitted for clarity.
fluorine donor)[6] except that ethanol was used instead of
methanol because of the lack of solubility of 1 in methanol
(Table 1).
Table 1. Palladium precursor screening.
Subsequently, we studied the effect of the ester substitu-
ent of the α-cyanoacetate (Table 4). Replacement of the
ethyl group of the ester by a methyl group led to slightly
lower enantioselectivity, but when the bulkier tert-butyl es-
ter was used both activity and enantioselectivity dropped
considerably. The latter substrate gave the best enantio-
selectivities in Kim’s system.[6]
To study the substrate scope of the new catalysts, we syn-
thesized several ethyl 2-arylcyanoacetates and carried out
their fluorination under the previously optimized condi-
[Pd]
Conv.[a] (yield[b]) [%]
ee [%][c]
[Pd(OAc)2]3
Pd(dba)2
Pd(acac)2
100 (97)
100 (95)
100 (95)
100 (98)
31 (n.d.)
93
67
74
86
32
[Pd(allyl)Cl]2
[Pd(4-CNPh)(Br){P(oTol)3}2]
[a] Determined by 1H NMR analysis of the crude product. [b] Iso-
lated yield. [c] Determined by chiral-phase HPLC analysis of puri-
fied 10a.
After 18 h at 0 °C, palladium acetate trimer provided 10a tions (Scheme 2).
with an excellent 93%ee with full conversion, thus, this pal-
Apart from substrate 9a, the highest enantioselectivities
ladium precursor was used for further studies. The system were obtained using electron-donating para-substituted
1/Pd(OAc)2 could be used to efficiently catalyze the reaction substrates such as 9g and 9i. In contrast, with electron-with-
in almost any solvent, affording fluorinated cyanoacetate drawing substituents the enantiomeric excess dropped to
10a with full conversion and enantiomeric excesses of more 45%, as was the case for substrate 9h. The activity of the
than 70%. Worse results were obtained in methanol, which catalytic system also decreased when ortho-halogenated
may be due to the low solubility of SPANphos 1 ligand in substrates were used, such as 9d and 9e. Most likely this is
this solvent. Complex A is not reported in the table because a steric effect, because the naphthyl derivative 9f also gave
of its insolubility in polar solvents such as alcohols. There a low ee. In the latter molecules the enolate intermediate
is no clear correlation with polarity or protic character of cannot be planar, and this may influence the enantio-
the solvent, and ethers gave only modest results (Table 2).
selectivity.
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Table 3. Substrate screening.
Chiral ligand
T [°C]
Conv.[a] (yield[b]) [%]
ee [%][c]
1
r.t.
0
–20
r.t.
0
100 (97)
100 (97)
100 (94)
100 (93)
95 (89)
78
93
91
0
2
0
3
r.t.
0
r.t.
0
r.t.
0
r.t.
0
r.t.
0
r.t.
0
100 (91)
95 (85)
82 (76)
12
12
36
51
22
29
14
38
4
4
75 (68)
5
100 (89)
100 (79)
100 (94)
100 (92)
98 (90)
80 (78)
100 (95)
92 (86)
6
7
8a
Scheme 2. Substrate screening.
8
6
8
8b
r.t.
0
r.t.
0
100 (88)
95 (90)
100 (94)
100 (94)
38
10
72
78
Table 5. Effect of the halide donor.
(R)-Binap
1
[a] Determined by H NMR analysis of the crude product. [b] Iso-
lated yield. [c] Determined by chiral-phase HPLC analysis of puri-
fied 10a.
Table 4. Influence of the ester group.
Halide donor (X)
Conv.[a] (yield[b]) [%]
ee [%][c]
NFSI (F)
100 (97)
100 (91)
100 (90)
100 (85)[d]
93
32
0
N-Chlorosuccinimide (Cl)
N-Bromosuccinimide (Br)
N-Iodosuccinimide (I)
n.d.
[a] Determined by 1H NMR analysis of the crude product. [b] Iso-
lated yield. [c] Determined by chiral-phase HPLC analysis of puri-
fied 10a. [d] Fully converted into 13 as a 1:1 meso/dl mixture.
Substrate
T [°C]
Conv.[a] (yield[b]) [%]
ee [%][c]
9a
r.t.
0
r.t.
0
r.t.
0
100 (97)
100 (97)
100 (95)
100 (89)
72 (59)
78
93
74
80
10
11
9b
9c
acts with NFSI to release the fluorinated cyanoacetate and
regenerate the catalyst (Scheme 3). We did not attempt to
characterize the intermediates, but they may well be trans
complexes, because this is the preferred structure of
SPANphos complexes in the absence of other cis enforcing
ligands.[8] The P–P distance in the free ligands are 4.979(4)
41 (35)
[a] Determined by 1H NMR analysis of the crude product. [b] Iso-
lated yield. [c] Determined by chiral-phase HPLC analysis of puri-
fied 10a–c.
Our catalytic system was also tested with other halides and 6.184(3) Å for 4 and 6, respectively. The free ligands
donors such as N-halosuccinimides in an attempt to obtain have a clear C2-symmetric twist, but apparently this pro-
enantioenriched α-chloro-, -bromo- and -iodocyanoacetates nounced asymmetry is not always effective in the complex
(Table 5). When the reaction was performed with N-chloro- or in the catalytic reaction. The reason may be that even in
succinimide at 0 °C, substrate 9a was fully converted into 4, which has a distance close to that required for a trans
the chlorinated product 11 with low enantioselectivity, complex, considerable rotation of the phosphorus lone
whereas only racemic 12 was obtained when N-bromosuc- pairs is needed to enable the formation of a trans complex.
cinimide was used in the reaction. No traces of the expected A crystal structure was obtained for only one ligand and
iodinated product was isolated after reaction with N-iodo- PdCl2, rather than the acetate (see Figure 2 and the Sup-
succinimide; substrate 9a was fully converted into its porting Information). The crystal structure of the parent
dimeric adduct (meso/dl) 13, presumably through a radical SPANphos 1 and PdCl2 show a clear C2 symmetry with two
mechanism.
axial and two equatorial phenyl groups. This is also the best
As regards the mechanism, we envisage that a palladium performing ligand and, thus, we suggest that a trans com-
enolate is formed during the catalytic cycle, which then re- plex may be the active species.
4
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SPANphos Ligands in Asymmetric Fluorination
4.6 mm diameter, 5 μm particle size, 1 mL/min, λ = 254 nm). Chiral
separation of the SpanPhos enantiomers was performed with semi-
preparative Waters HPLC equipment (4.7 mL/min) equipped with
a Daicel Chiralpak IC column (250 mm length, 10 mm diameter,
5 μm particle size). HRMS data were recorded at the High-Resolu-
tion Mass Spectrometry Unit of the ICIQ (Tarragona, Spain) with
Waters LCT Premier liquid chromatography equipment coupled
with a time-of-flight mass spectrometer and using a positive elec-
trospray ionization method. Elemental analyses were performed at
the Unidade de Análise Elemental of the Universidade de Santiago
de Compostela (Spain).
X-ray Data: Single crystals suitable for X-ray analysis were grown
by slow diffusion of n-hexane into a CH2Cl2 solution of enantio-
pure (S)-4 or enantiopure (R)-6 at room temp. Crystal structure
determination for (S)-4 was carried out with an Apex DUO Kappa
4-axis goniometer equipped with an APPEX 2 4K CCD area detec-
tor, a Microfocus Source E025 IuS using Mo-Kα radiation, Quazar
MX multilayer Optics as monochromator, and an Oxford Cryosys-
tems low temperature device Cryostream 700 plus (T = –173 °C).
Crystal structure determination for (R)-6 and complex A were car-
ried out with a Bruker-Nonius diffractometer equipped with an
APPEX 2 4K CCD area detector, an FR591 rotating anode with
Mo-Kα radiation, and Montel mirrors as monochromator. Full-
sphere data collection was used with ω and φ scans. Programs used:
Data collection APEX-2,[18] data reduction Bruker Saint[19] V/.60A
and absorption correction SADABS.[20]
Scheme 3. Tentatively proposed mechanism.
Conclusions
We have developed an efficient synthesis of several
enantiopure P-aryl- and P-alkylphosphanes that are ef-
ficient chiral ligands for the palladium-catalyzed fluorina-
tion of α-cyanoacetates. It is the first example of the appli-
cation of trans-chelating ligands for this kind of reaction,
and the behavior of SPANphos-Pd complexes seems to dif-
fer from the previously reported complexes by Sodeoka and
Kim, which are cis-coordinated. Studies are ongoing in our
laboratory to ensure faster, direct syntheses of enantiopure
SPANphos derivatives[14] and to discover new applications
for these ligands.
Structure Solution and Refinement: Crystal structure solution was
achieved by using direct methods as implemented in SHELXTL[21]
and visualized using the program XP. Missing atoms were sub-
sequently located from difference Fourier synthesis and added to
the atom list. Least-squares refinement on F2 using all measured
intensities was carried out using the program SHELXTL. All non-
hydrogen atoms were refined by including anisotropic displacement
parameters.
Experimental Section
General: Unless otherwise specified, materials were obtained from
commercial suppliers and were used without further purification.
All reactions were carried out using standard Schlenk techniques
for the synthesis of the ligands or in 5 mL sealed screw vials for
the catalysis, under dry argon. Glassware was dried with a heat gun
under vacuum prior to use. All solvents were dried using a Solvent
Purification System (SPS) or using standard procedures. Methyl
trifluoromethanesulfonate (98%; Aldrich) was transferred and kept
in a Schlenk vessel under argon. Dimethoxyethane (DME; anhy-
drous, 99.5%; Sigma–Aldrich), was stored over activated 4 Å mo-
lecular sieves and was degassed by bubbling dry argon for 30 min.
Chlorodiphenylphosphane was purchased from Fluka and distilled
under an inert gas prior to use. Chlorodiethylphosphane (min.
95%) and chlorodiisopropylphosphane (min. 98% from Strem)
were stored in a glove box and were used as received. 8,8Ј-Di-
bromo-4,4,4Ј,4Ј,6,6Ј-hexamethyl-2,2Ј-spirobi[chroman],[8a] 2,8-di-
Crystal Data
Sample (S)-4 at 100 K: C51H50O4P2·0.22C6H14; Mr
808.00 gmol–1; rhombohedral; R3;
36.379(4) Å,
36.379(4) Å, c = 9.7332(10) Å; V = 11155.4(19) Å3; Z = 9; ρcalcd.
=
=
=
a
=
b
1.082 Mg/m3; R1 = 0.0618 (all 0.0977), wR2 = 0.1258 (all 0.1443),
for 7077 reflections with IϾ2σ(I) (for 9848 reflections [Rint
=
0.0528] with a total measured of 15327 reflections), goodness-of-
fit on F2 = 1.028, Flack parameter (std) = –0.03(1), largest diff.
peak (hole) = 0.299 (–0.233) eÅ–3. The asymmetric unit of (S)-4 is
made up of the main molecule and a highly disordered n-hexane
molecule. The n-hexane molecule is located in a crystal channel,
and only 22% of its presence could be localized.
Sample (R)-6 at 297 K: C35H54O2P2; Mr = 568.72 gmol–1; mono-
clinic; P21; a = 10.394(2) Å, b = 11.113(3) Å, c = 15.355(3) Å; β =
104.042(5)°, V = 1720.5(7) Å3; Z = 2; ρcalcd. = 1.098 Mg/m3; R1 =
0.0514 (all 0.0741), wR2 = 0.1295 (all 0.1463), for 8156 reflections
with IϾ2σ(I) (for 10550 reflections [Rint = 0.0597] with a total
measured of 36718 reflections), goodness-of-fit on F2 = 1.050,
Flack parameter (std) = –0.11(07), largest diff. peak (hole) = 0.554
(–0.314) eÅ–3.
methyl-10-chlorophenoxaphosphane,[15]
10-chlorophenoxaphos-
phane,[16] and 9-chlorodibenzo[bd]phosphole[17] were prepared ac-
cording to literature procedures. SPANphos 1 can also be pur-
1
chased from Strem. H, 13C, 31P and 19F NMR were recorded in
CDCl3 with a Bruker Avance 400 Ultrashield NMR spectrometer
(400.1 MHz for 1H, 100.6 MHz for 13C, 162.0 MHz for 31P, and
1
377.0 MHz for 19F). Chemical shifts (δ) for H and 13C NMR sig-
nals were referenced to internal solvent resonances and are re-
ported relative to TMS in units of ppm; chemical shifts for 31P
and 19F NMR signals are reported using 85% phosphoric acid and
Complex A at 100 K: C47H46Cl2O2P2Pd; Mr = 882.08 gmol–1; or-
thorombic; Pna21; a = 17.2250(9) Å, b = 13.0500(8) Å, c =
17.5240(9) Å; V = 3939.2(4) Å3; Z = 4; ρcalcd. = 1.487 Mg/m3; R1
= 0.0356 (all 0.0432), wR2 = 0.0868 (all 0.0933), for 16770 reflec-
tions with IϾ2σ(I) (for 15006 reflections [Rint = 0.0315] with a
total measured of 36850 reflections), goodness-of-fit on F2 = 1.044,
Flack parameter (std) = –0.015(14), largest diff. peak (hole) = 1.250
(–0.774) eÅ–3.
1
CFCl3, respectively, as external standards in H-decoupling mode.
Optical rotations were measured with a Jasco-1030 polarimeter.
Chromatographic analyses (resolution of ligands, load studies, en-
antiomeric excesses) were performed with an HPLC Agilent 1100
apparatus, using a Daicel Chiralpak IC column (250 mm length,
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P. W. N. M. van Leeuwen et al.
CCDC-892611 [for (S)-4], -892612 [for (R)-4] and -892613 (for A) (+)- and (–)-4,4,4Ј,4Ј,6,6Ј-Hexamethyl-2,2Ј-spirobi[chroman]-8,8Ј-
FULL PAPER
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
diylbis(9-dibenzo[bd]phosphole) [(+)-2 and (–)-2]: rac-2 was synthe-
sized using the same procedure used for rac-1 and was obtained as
a white solid. Yield 1.18 g (1.68 mmol, 42%). HPLC resolution of
rac-2 (hexane/CH2Cl2, 85:15): tR = 4.9 [(–)-enantiomer], 6.0 [(+)-
enantiomer] min.
Ligand Synthesis and Resolution
(–)-2: [α]2D8 = –106.6 (c = 0.76, CH2Cl2). 1H NMR (CDCl3, 25 °C):
(+)- and (–)-4,4,4Ј,4Ј,6,6Ј-Hexamethyl-2,2Ј-spirobi[chroman]-8,8Ј-
diylbis(diphenylphosphane) [(+)-1 and (–)-1]: A solution of 8,8Ј-
5
δ = 1.41 (s, 6 H, CH3), 1.99 (d, JH,P = 1.4 Hz, 6 H, CH3), 2.0 (s,
2
2
6 H, CH3), 2.29 (d, JH,H = 14.3 Hz, 2 H, CH2), 2.45 (d, JH,H
=
dibromo-4,4,4Ј,4Ј,6,6Ј-hexamethyl-2,2Ј-spirobi[chroman]
(2 g,
3
3
14.3 Hz, 2 H, CH2), 5.88 (dd, JH,H = 7.4, JH,P = 4.5 Hz, 2 ArH,
4.1 mmol) in THF (40 mL) was cooled to –78 °C. nBuLi (2.5 m in
hexanes, 3.7 mL, 9.3 mmol) was then added dropwise, and the solu-
tion was stirred at –78 °C for 3 h. Chlorodiphenylphosphane
(1.97 g, 8.9 mmol) in THF (15 mL) was added, and the solution
was warmed slowly to room temperature over 16 h. The reaction
was quenched with degassed water and then extracted with dichlo-
romethane. The combined organic layers were dried with magne-
sium sulfate, and the solvents were evaporated. The crude product
was washed with methanol (3ϫ 10 mL) and finally dried in vacuo
to afford the racemic SPANphos 1 as a white powder (2.34 g,
3.32 mmol, 82% yield).
3
4
4
CH), 6.04 (ddt, JH,H = 7.4 Hz, JH,H = 0.9 Hz, JH,P = 2.8 Hz, 2
4
3
ArH, CH), 6.19 (dd, JH,H = 1.9 Hz, JH,P = 4.6 Hz, 2 ArH, CH),
3
4
6.95 (dt, JH,H = 7.5 Hz, JH,H = 1.0 Hz, 2 ArH, CH), 7.12 (d,
4JH,H = 1.9 Hz, 2 ArH, CH), 7.33 (ddt, JH,H = 7.4 Hz, JH,H
=
3
4
1.0 Hz, 4JH,P = 2.9 Hz, 2 ArH, CH), 7.46 (dt, 3JH,H = 7.4 Hz, 4JH,H
3
= 1.0 Hz, 2 ArH, CH), 7.70 (d, JH,H = 7.8 Hz, 2 ArH, CH), 7.73
3
3
3
(dd, JH,H = 7.4 Hz, JH,P = 4.4 Hz, 2 ArH, CH), 7.90 (d, JH,H
=
7.7 Hz, 2 ArH, CH) ppm. 13C NMR (CDCl3, 27 °C): δ = 20.8 (s,
4
4
CH3), 30.8 (d, JC,P = 2.2 Hz, Cq), 32.9 (d, JC,P = 13.2 Hz, CH3),
34.0 (s, CH3), 47.5 (s, CH2), 98.8 (s, Cq), 120.6 (s, CHAr), 121.4 (s,
3
CHAr), 124.0 (d, JC,P = 21.9 Hz, Cq), 126.9 (d, JC,P = 7.4 Hz,
Synthesis of the Racemic Bis(phosphane oxide) rac-1-Oxd: Racemic
1 (2 g, 2.84 mmol) was dissolved in CH2Cl2 (100 mL), and hydro-
gen peroxide (30wt.-% in water, 3.3 mL) was then carefully added
at room temp. The mixture was vigorously stirred at room tempera-
ture for 20 min, and water (20 mL) was added. The organic phase
was separated using ammonium chloride salt, further washed with
another portion of water (20 mL), and finally dried with magne-
sium sulfate. The solvent was removed in vacuo to afford the bi-
s(phosphane oxide) as a white powder (1.88 g, 2.56 mmol, 90%
yield).
3
CHAr), 127.3 (d, JC,P = 6.6 Hz, CHAr), 127.6 (s, CHAr), 128.5 (s,
2
CHAr), 129.6 (s, CHAr), 130.1 (d, JC,P = 3.3 Hz, CHAr), 130.7 (d,
2
2JC,P = 21.1 Hz, CHAr), 131.1 (d, JC,P = 21.9 Hz, CHAr), 131.4 (s,
Cq), 131.8 (d, JC,P = 3.0 Hz, Cq), 142.3–142.4 (2ϫ d, Cq), 142.9 (d,
JC,P = 6.6 Hz, Cq), 144.9 (d, JC,P = 3.7 Hz, Cq), 152.0 (d, JC,P
=
19.8 Hz, Cq) ppm. 31P NMR (CDCl3, 25 °C): δ = –22.1 (s) ppm.
HRMS (ESI): calcd. for C47H42O2P2Na [M + Na+] 723.2558;
found 723.2571. C47H42O2P2·(CH2Cl2)0.25 (700.80): calcd. C 78.60,
H 5.95; found C 78.21, H 6.55 (determined on the crystalline
dichloromethane solvates formed when a solution of amorphous 2
in dichloromethane was left to slowly concentrate at room tempera-
ture).
rac-1-Oxd: 31P NMR (CDCl3, 25 °C): δ = 32.7 (s) ppm. HPLC
(CH2Cl2/iPrOH, 90:10): tR = 5.9 [(+)-enantiomer], 7.5 [(–)-enantio-
mer] min. [α]2D9 = –36.9 (c = 0.56, CH2Cl2).
(+)- and (–)-4,4,4Ј,4Ј,6,6Ј-Hexamethyl-2,2Ј-spirobi[chroman]-8,8Ј-
diylbis(10-phenoxaphosphane) [(+)-3 and (–)-3]: rac-3 was synthe-
sized using the same procedure used for rac-1 and was obtained as
a white solid. Yield 1.84 g (2.5 mmol, 65%).
Reduction of (–)-1-Oxd To Give (+)-1: To (–)-1-Oxd (464 mg,
0.63 mmol) dissolved in DME (8 mL) was added, dropwise, methyl
triflate (0.160 mL, 1.4 mmol) at room temperature, and the solu-
tion was stirred for 2 h. The solution was then cooled to 0 °C, and
LiAlH4 (146 mg, 3.8 mmol) was added in one portion. The mixture
was stirred at 0 °C for 7 h, quenched with water, and the solvent
was removed in vacuo. The residue was taken up in chloroform
(10 mL), filtered through a pad of basic alumina, and the solvent
was removed in vacuo. The solid was washed with MeOH and dried
in vacuo to afford enantiopure (+)-1 as a white powder. If necessary
the product could be further purified by filtration through a pad
of silica using chlorinated solvents. Yield: 382 mg (0.54 mmol,
rac-3-Oxd: 31P NMR (CDCl3, 25 °C): δ = 1.3 (s) ppm. HPLC reso-
lution of rac-3-Oxd (CH2Cl2/iPrOH = 84:16): tR = 6.5 [(–)-enantio-
mer], 8.1 [(+)-enantiomer] min. [α]2D9 = +44.1 (c = 0.49, CH2Cl2).
Reduction of (+)-3-Oxd To Give (+)-3: Using (+)-3-Oxd (310 mg,
0.41 mmol) dissolved in DME (4 mL) and applying the same re-
duction procedure used for (–)-1-Oxd afforded (+)-3 as a white so-
lid. Yield 250 mg (0.34 mmol, 84%). [α]2D8 = +111.6 (c = 0.16,
CH2Cl2). 1H NMR (CDCl3, 25 °C): δ = 1.37 (s, 6 H, CH3), 2.00
86%). [α]2D7 = +70.8 (c = 0.94, CH2Cl2). H NMR (CDCl3, 25 °C):
(d, JH,P = 0.9 Hz, 6 H, CH3), 2.09 (s, 6 H, CH3), 2.19 (d, JH,H
=
1
5
2
5
δ = 1.14 (s, 6 H, CH3), 1.41 (s, JH,P = 1.1 Hz, 6 H, CH3), 1.81 (d,
14.1 Hz, 2 H, CH2), 2.36 (d, 2JH,H = 14.1 Hz, 2 H, CH2), 5.66 (ddd,
2
4
3
2JH,H = 14.1 Hz, 2 H, CH2), 1.88 (d, JH,H = 14.1 Hz, 2 H, CH2),
3JH,H = 7.6 Hz, JH,H = 1.6 Hz, JH,P = 9.9 Hz, 2 ArH, CH), 5.84
4
4
3
3
4
4
1.99 (s, 6 H, CH3), 6.05 (ddd, JH,H = 2.1, JH,H = 0.5, JH,P
=
(ddt, JH,H = 7.4 Hz, JH,H = 1.1 Hz, JH,P = 1.2 Hz, 2 ArH, CH),
6.61 (ddd, JH,H = 2.2 Hz, JH,H = 0.6 Hz, JH,P = 3.9 Hz, 2 ArH,
CH), 6.79 (ddd, JH,H = 8.3 Hz, JH,H = 7.2 Hz, JH,H = 1.7 Hz, 2
ArH, CH), 6.87 (ddd, JH,H = 8.2 Hz, JH,H = 1.1 Hz, JH,P
4.7 Hz, 2 ArH, CH), 6.84 (dd, 4JH,H = 2.1, JH,H = 0.5 Hz, 2 ArH,
CH), 6.94–6.98 (m, 7 ArH, CH), 7.00–7.06 (m, 7 ArH, CH), 7.14–
7.19 (m, 6 ArH, CH) ppm. 13C NMR (CDCl3, 25 °C): δ = 21.1 (s,
4
4
4
3
3
3
4
3
4
4
=
4
4
3
4
CH3), 30.3 (d, JC,P = 1.5 Hz, Cq), 32.2 (d, JC,P = 10.3 Hz, CH3), 1.0 Hz, 2 ArH, CH), 7.01 (ddt, JH,H = 7.3 Hz, JH,H = 1.2 Hz,
3
4
33.8 (s, CH3), 47.2 (s, CH2), 98.1 (s, Cq), 123.9 (d, JC,P = 13.2 Hz,
4JH,P = 1.1 Hz, 2 ArH, CH), 7.12 (ddd, JH,H = 8.3 Hz, JH,H
=
Cq), 128.0–128.2 (3ϫ d, CHAr), 128.4 (s, CHAr), 130.3 (s, Cq), 130.6 1.1 Hz, 4JH,P = 1.0 Hz, 2 ArH, CH), 7.12 (dd, 4JH,H = 2.3 Hz, 4JH,H
3
3
(d, JC,P = 2.5 Hz, Cq), 132.3 (s, CHAr), 133.8 (d, JC,P = 19.1 Hz,
= 0.6 Hz, 2 ArH, CH), 7.29 (ddd, JH,H = 8.3 Hz, JH,H = 7.3 Hz,
CHAr), 134.0 (d, JC,P = 20.5 Hz, CHAr), 137.1 (d, JC,P = 11.6 Hz, 4JH,H = 1.7 Hz, 2 ArH, CH), 7.33 (ddd, JH,H = 7.5 Hz, JH,H
=
3
4
Cq), 138.1 (d, JC,P = 11.8 Hz, Cq), 150.8 (d, JC,P = 17.2 Hz, Cq) 1.7 Hz, JH,P = 9.7 Hz, 2 ArH, CH) ppm. 13C NMR (CDCl3,
3
ppm. 31P NMR (CDCl3, 25 °C): δ = –12.6 (s) ppm. HRMS (ESI):
calcd. for C47H47O2P2 [M + H+] 705.3051; found 705.3023.
C47H46O2P2 (704.83): calcd. C 80.09, H 6.58; found C 79.82, H
6.62.
27 °C): δ = 20.8 (s, CH3), 30.6 (d, 4JC,P = 1.5 Hz, Cq), 32.7 (d, 4JC,P
= 13.8 Hz, CH3), 34.2 (s, CH3), 47.2 (s, CH2), 98.4 (s, Cq), 116.5
(s, CHAr), 117.5 (s, CHAr), 117.9 (d, JC,P = 8.9 Hz, Cq), 118.4 (d,
JC,P = 5.9 Hz, Cq), 123.1–123.3 (2ϫ d, CHAr), 128.2 (d, JC,P
=
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20223
/KAP1
Date: 25-07-12 10:25:36
Pages: 10
SPANphos Ligands in Asymmetric Fluorination
28.8 Hz, Cq), 129.3 (s, CHAr), 129.6 (s, CHAr), 130.2 (s, CHAr), (s, 6 H, CH3), 1.47–1.63 (m, 4 H, CH2), 1.79 (s, 6 H, CH3), 2.05
2
2
131.1 (s, Cq), 131.6 (d, JC,P = 2.9 Hz, Cq), 133.6 (d, 2JC,P = 4.2 Hz,
(d, JH,H = 14.2 Hz, 2 H, CH2), 2.18 (d, JH,H = 14.2 Hz, 2 H,
CHAr), 134.2 (d, 2JC,P = 32.6 Hz, CHAr), 134.9 (d, 2JC,P = 34.0 Hz, CH2), 2.26 (s, 6 H, CH3), 6.71–6.74 (m, 2 ArH, CH), 7.07–7.10 (m,
CHAr), 150.8 (d, JC,P = 22.0 Hz, Cq), 153.4 (s, Cq), 155.2 (d, JC,P 2 ArH, CH) ppm. 13C NMR (CDCl3, 27 °C): δ = 9.9 (d, JC,P
=
=
2
2
1
= 1.5 Hz, Cq) ppm. 31P NMR (CDCl3, 25 °C): δ = 68.2 (s) ppm.
11.7 Hz, CH3), 10.3 (d, JC,P = 16.8 Hz, CH3), 16.0 (d, JC,P
1
HRMS (ESI): calcd. for C47H42O4P2Na [M + Na+] 755.2456;
11.8 Hz, CH2), 19.3 (d, JC,P = 12.7 Hz, CH2), 21.1 (s, CH3), 30.5
4
4
found 755.2464. C47H42O4P2 (732.79): calcd. C 77.04, H 5.78; (d, JC,P = 1.5 Hz, Cq), 32.8 (d, JC,P = 12.0 Hz, CH3), 34.1 (s,
found C 76.69, H 6.44.
CH3), 47.1 (s, CH2), 97.9 (s, Cq), 126.3 (d, JC,P = 18.2 Hz, Cq),
127.8 (s, CH), 128.2 (s, CH), 130.4 (s, Cq), 131.2 (d, JC,P = 2.6 Hz,
Cq), 150.7 (d, JC,P = 15.4 Hz, Cq) ppm. 31P NMR (CDCl3, 27 °C):
δ = –26.5 (s) ppm. HRMS (ESI): calcd. for C31H46O2P2Na [M +
Na+] 535.2871; found 535.2858. C31H46O2P2·(CH2Cl2)1.00 (596.25):
calcd. C 64.32, H 8.10; found C 64.16, H 8.01 (determined on the
crystalline dichloromethane solvates formed when a solution of
amorphous 5 in dichloromethane was left to slowly evaporate at
room temperature).
(+)- and (–)-4,4,4Ј,4Ј,6,6Ј-Hexamethyl-2,2Ј-spirobi[chroman]-8,8Ј-
diylbis(2,8-dimethyl-10-phenoxaphosphane) [(+)-4 and (–)-4]: rac-4
was synthesized using the same procedure used for rac-1 and was
obtained as a white powder (2.25 g, 2.85 mmol, 71% yield). Race-
mic bis(phosphane oxide) rac-4-Oxd was synthesized using the
same procedure used for rac-1-Oxd and was obtained as a white
powder (1.81 g, 2.2 mmol, 87% yield).
rac-4-Oxd: 31P NMR (CDCl3, 25 °C): δ = 0.2 (s) ppm. HPLC reso-
lution of rac-4-Oxd (CH2Cl2/iPrOH, 85:15): tR = 5.7 [(+)-enantio-
mer], 8.9 [(–)-enantiomer] min. [α]2D9 = –58.4 (c = 0.48, CH2Cl2).
(+)- and (–)-4,4,4Ј,4Ј,6,6Ј-Hexamethyl-2,2Ј-spirobi[chroman]-8,8Ј-
diylbis(diisopropylphosphane) [(+)-6 and (–)-6]: rac-6 was synthe-
sized using the same procedure used for rac-1 and was obtained as
a white solid. Yield 1.45 g (2.55 mmol, 63%).
Reduction of (–)-4-Oxd To Give (–)/(S)-4: Using (–)-4-Oxd (524 mg,
0.64 mmol) dissolved in DME (4 mL) and applying the same re-
duction procedure used for (–)-1-Oxd afforded enantiopure (–)/(S)-
4 as a white powder. Yield 417 mg (0.53 mmol, 83%). [α]2D9 = –162.5
(c = 0.10, CH2Cl2). 1H NMR (CDCl3, 25 °C): δ = 1.37 (s, 6 H,
rac-6-Oxd: 31P NMR (CDCl3, 25 °C): δ = 54.2 (s) ppm. HPLC
resolution of rac-6-Oxd (THF/Hexane/iPrOH, 92:5:3): tR = 6.1
[(+)-enantiomer] min {[α]2D7 = +3.4 (c = 0.74, CH2Cl2)]}; (–)-
enantiomer tR = 7.3 min.
5
CH3), 1.41 (s, 6 H, CH3), 2.00 (d, JH,P = 0.9 Hz, 6 H, CH3), 2.09
2
Reduction of (+)-6-Oxd To Give (–)/(R)-6: Using (+)-6-Oxd
(284 mg, 0.47 mmol) dissolved in DME (20 mL) and applying the
same reduction procedure used for (–)-1-Oxd afforded (–)/(R)-6 as
(s, 6 H, CH3), 2.20 (d, JH,H = 14.1 Hz, 2 H, CH2), 2.23 (s, 6 H,
2
4
CH3), 2.36 (d, JH,H = 14.1 Hz, 2 H, CH2), 5.87 (dd, JH,H
=
3
4
1.9 Hz, JH,P = 10.7 Hz, 2 ArH, CH), 6.71 (ddd, JH,H = 2.1 Hz,
a white solid. Yield 99 mg (0.17 mmol, 37%). [α]2D7 = –116.0 (c =
3
3
4JH,H = 0.6 Hz, JH,P = 3.8 Hz, 2 ArH, CH), 6.85 (dd, JH,H
=
3
0.090, CH2Cl2). 1H NMR (CDCl3, 27 °C): δ = 0.59 (dd, JH,H
=
4
3
8.5 Hz, JH,H = 2.0 Hz, 2 ArH, CH), 6.91 (d, JH,H = 8.3 Hz, 2
3
3
3
ArH, CH), 6.95 (d, 3JH,H = 8.3 Hz, 2 ArH, CH), 7.01 (dd, JH,H
=
3
7.1 Hz, JH,P = 8.5 Hz, 6 H, CH3), 0.70 (dd, JH,H = 7.1 Hz, JH,P
3
3
8.3 Hz, 4JH,H = 2.0 Hz, 2 ArH, CH), 7.10 (dd, 4JH,H = 1.9 Hz, 3JH,P
= 10.5 Hz, 2 ArH, CH), 7.10–7.12 (m, 2 ArH, CH) ppm. 13C NMR
(CDCl3, 25 °C): δ = 19.6 (s, CH3), 20.6 (s, CH3), 20.9 (s, CH3), 31.0
= 15.1 Hz, 6 H, CH3), 0.78 (dd, JH,H = 6.8 Hz, JH,P = 13.6 Hz,
3
3
6 H, CH3), 0.82 (m, 2 H, CH), 0.96 (dd, JH,H = 6.8 Hz, JH,P
=
13.7 Hz, 6 H, CH3), 1.22 (s, 6 H, CH3), 1.79 (s, 6 H, CH3), 1.94
2
2
4
4
(d, JH,H = 14.1 Hz, 2 H, CH2), 1.99 (m, 2 H, CH), 2.12 (d, JH,H
= 14.1 Hz, 2 H, CH2), 2.18 (s, 6 H, CH3), 6.68–6.71 (m, 2 ArH,
CH), 7.01 (d, 3JH,H = 1.5 Hz, 2 ArH, CH) ppm. 13C NMR (CDCl3,
(d, JC,P = 1.2 Hz, Cq), 32.9 (d, JC,P = 13.3 Hz, CH3), 34.3 (s,
CH3), 47.4 (s, CH2), 98.8 (s, Cq), 116.8 (s, CHAr), 117.1 (s, CHAr),
118.0 (d, JC,P = 5.9 Hz, Cq), 119.3 (d, JC,P = 7.2 Hz, Cq), 128.6 (d,
JC,P = 28.6 Hz, Cq), 129.1 (s, CHAr), 130.7 (s, CHAr), 130.7 (s, Cq),
2
2
27 °C): δ = 16.5 (d, JC,P = 3.7 Hz, CH3), 19.0 (d, JC,P = 20.1 Hz,
CH3), 19.3 (d, 2JC,P = 15.7 Hz, CH3), 19.7 (d, 1JC,P = 14.4 Hz, CH),
130.8 (s, CHAr), 132.2 (d, JC,P = 10.8 Hz, Cq), 132.5 (d, JC,P
=
2
1
2
19.9 (s, CH3), 20.2 (d, JC,P = 19.5 Hz, CH3), 22.7 (d, JC,P
16.0 Hz, CH), 29.4 (d, 4JC,P = 1.5 Hz, Cq), 32.0 (d, 4JC,P = 12.5 Hz,
CH3), 33.3 (s, CH3), 46.1 (s, CH2), 96.7 (s, Cq), 123.4 (d, JC,P
=
3.5 Hz, Cq), 132.9 (d, JC,P = 11.2 Hz, Cq), 133.8 (d, JC,P = 4.7 Hz,
CHAr), 134.7 (d, 2JC,P = 34.5 Hz, CHAr), 135.0 (d, 2JC,P = 35.9 Hz,
CHAr), 150.7 (d, JC,P = 22.7 Hz, Cq), 152.7 (s, Cq), 152.8 (s,
Cq) ppm. 31P NMR (CDCl3, 25 °C): δ = –68.4 (s) ppm. HRMS
(ESI): calcd. for C51H51O4P2 [M + H+], 789.3263; found 789.3284.
C51H50O4P2·(CH2Cl2)1.25 (893.26): calcd. C 70.11, H 5.91; found C
70.18, H 6.13 (determined on the crystalline dichloromethane sol-
vates formed when a solution of amorphous 4 in dichloromethane
was left to slowly evaporate at room temperature).
=
20.1 Hz, Cq), 126.9 (s, CHAr), 128.1 (s, Cq), 129.4 (s, CHAr), 130.0
(d, JC,P = 2.6 Hz, Cq), 150.3 (d, JC,P = 16.3 Hz, Cq) ppm. 31P NMR
(CDCl3, 27 °C): δ = –4.3(s) ppm. HRMS (ESI): calcd. for
C35H55O2P2 [M + H+] 569.3677; found 569.3674. C35H54O2P2
(568.76): calcd. C 73.90, H 9.57; found C 73.48, H 9.89.
Complex A: In a flame-dried flask, 1 (200 mg, 0.284 mmol,
1 equiv.) and [Pd(cod)Cl2] (81 mg, 0.284 mmol) were dissolved in
anhydrous CH2Cl2 (10 mL). The homogeneous yellow mixture was
stirred at room temp. for 2 h, then the solvent was removed under
reduced pressure, and the yellow solid was washed twice with
anhydrous diethyl ether. After drying under vacuum, complex A
(228 mg, 91%) was obtained as a yellow solid. Monocrystals suit-
able for X-ray diffraction could be obtained by slow diffusion of
(+)- and (–)-4,4,4Ј,4Ј,6,6Ј-Hexamethyl-2,2Ј-spirobi[chroman]-8,8Ј-
diylbis(diethylphosphane) [(+)-5 and (–)-5]: rac-5 was synthesized
using the same procedure used for rac-1 and obtained as a white
solid. Yield 1.41 g (2.75 mmol, 68%).
rac-5-Oxd: 31P NMR (CDCl3, 27 °C): δ = 45.0 (s) ppm. HPLC
resolution of rac-5-Oxd (CH2Cl2/Hexane/iPrOH, 65:20:15): tR
=
10.9 [(–)-enantiomer], 12.0 [(+)-enantiomer] min. [α]2D5 = +45.2 (c
hexanes into a solution of complex A in CH2Cl2. 1H NMR (CDCl3,
= 0.70, CH2Cl2).
3
27 °C): δ = 1.38 (s, 6 H, CH3), 1.48 (s, 6 H, CH3), 2.11 (d, JH,H
=
Reduction of (+)-5-Oxd To Give (+)-5: Using (+)-5-Oxd (240 mg,
0.44 mmol) dissolved in DME (18 mL) and applying the same re-
duction procedure used for (–)-1-Oxd afforded (+)-5 as a white so-
12 Hz, 2 H, CH2), 2.12 (s, 6 H, CH3), 2.63 (d, 3JH,H = 12 Hz, 2 H,
CH2), 6.51 (ddd, JH,H = 2.1 Hz, JH,H = 0.5 Hz, JH,P = 4.7 Hz, 2
ArH, CH), 7.11 (dd, JH,H = 2.1 Hz, JH,H = 0.5 Hz, 2 ArH, CH),
4
4
3
4
4
lid. Yield 90 mg (0.18 mmol, 40%). [α]2D7 = +77.6 (c = 0.025,
7.23–7.34 (m, 7 ArH, CH), 7.43–7.54 (m, 7 ArH, CH), 7.98 (dd,
1
CH2Cl2). H NMR (CDCl3, 27 °C): δ = 0.50–0.71 (m, 10 H, CH2/ JH,H = 4.7, 16 Hz, 6 ArH, CH) ppm. 13C NMR (CDCl3, 27 °C): δ
3
3
CH3), 1.01 (dt, JH,H = 7.7 Hz, JH,P = 15.5 Hz, 6 H, CH3), 1.32
= 21.0 (s, CH3), 28.8 (s, Cq), 29.7 (s, CH3), 31.4 (s, CH3), 46.5 (s,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20223
/KAP1
Date: 25-07-12 10:25:36
Pages: 10
P. W. N. M. van Leeuwen et al.
FULL PAPER
CH2), 104.8 (s, Cq), 120.2 (m, Cq), 127.1 (m, CHAr), 127.6 (s, 4.36 (m, 2 H), 7.30 (d, J = 8 Hz, 2 H, ArH), 7.54 (d, J = 8 Hz,
CHAr), 128.4 (m, CHAr), 129.5 (m, CHAr), 129.6 (s, Cq), 131.1 (s, 2 H, ArH) ppm. 13C NMR (CDCl3, 25 °C): δ = 13.8, 21.3, 64.3,
CHAr), 131.4 (s, Cq), 132.5 (s, Cq), 134.3 (m, CHAr), 137.6 (m,
86.2, 114.1, 125.6, 128.5, 128.8, 129.9, 141.7, 163.1 ppm. 19F NMR
CHAr), 151.8 (s, Cq) ppm. 31P NMR (CDCl3, 27 °C): δ = 20.03 (s) (CDCl3, 25 °C): δ = –143.7 ppm. HPLC (Chiralpak IC; hexane/
ppm. HRMS (ESI): calcd. for C47H46Cl2O2P2Pd [M+] 880.1385;
found 880.1515. C47H46Cl2O2P2Pd (882.13): calcd. C 63.99, H 5.26;
found C 63.71, H 5.38.
CH2Cl2, 9:1): tR1 = 12.3, tR2 = 13.8 min.
Ethyl 4-(1-Cyano-2-ethoxy-1-fluoro-2-oxoethyl)benzoate (10h): Yel-
1
3
low oil. H NMR (CDCl3, 25 °C): δ = 1.32 (t, JH,H = 7 Hz, 3 H),
3
3
1.43 (t, JH,H = 7 Hz, 3 H), 4.36 (m, 2 H), 4.42 (q, JH,H = 7 Hz,
2 H), 7.74 (d, 3JH,H = 9 Hz, 2 H, ArH), 8.17 (d, 3JH,H = 9 Hz, 2 H,
ArH) ppm. 13C NMR (CDCl3, 25 °C): δ = 13.8, 14.3, 61.6, 64.7,
87.7, 113.6, 125.4, 130.4, 133.2, 135.6, 162.3, 165.3 ppm. 19F NMR
(CDCl3, 25 °C): δ = –148.6 ppm. HPLC (Chiralpak IC; hexane/
iPrOH, 95:5): tR1 = 8.4, tR2 = 9.1 min.
Typical Catalytic Procedure: Palladium acetate trimer (1.125 mg,
1.67 μmol) and enantiopure (–)-1 (4.2 mg, 6 μmol) were placed in
a tube under an inert gas. Anhydrous and degassed ethanol
(0.5 mL) was added, and the mixture was stirred for 30 min, during
which time the mixture became homogeneous. The cyanoacetate
(0.1 mmol) was diluted in ethanol (0.5 mL) and then added to the
catalyst. NFSI (35 mg, 0.11 mmol) was introduced in one portion,
and the resulting mixture was stirred for the indicated time. The
crude mixture was then filtered through a short pad of Celite, and
ethanol was removed under reduced pressure. The pure product
was obtained as a colorless oil after silica gel column chromatog-
raphy (diethyl ether/pentane, 5%). The conversion was determined
Ethyl 2-Cyano-2-fluoro-2-(4-methoxyphenyl)acetate (10i): Colorless
oil. 1H NMR (CDCl3, 25 °C): δ = 1.33 (t, 3JH,H = 7 Hz, 3 H), 3.87
(s, 3 H), 4.37 (m, 2 H), 7.00 (d, J = 9 Hz, 2 H, ArH), 7.58 (d, J =
9 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3, 25 °C): δ = 13.8, 55.5,
64.2, 87.9, 114.0, 114.3, 123.3, 127.4, 161.8, 163.1 ppm. 19F NMR
(CDCl3, 25 °C): δ = –140.4 ppm. HPLC (Chiralpak IC; hexane/
CH2Cl2, 9:1): tR1 = 21, tR2 = 23 min.
1
by H NMR analysis of the crude product, and the enantiomeric
excess by HPLC analysis on the pure product with a Chiralpak IC
column.
Ethyl 2-Chloro-2-cyano-2-phenylacetate (11): Colorless oil. 1H
3
NMR (CDCl3, 25 °C): δ = 1.32 (t, JH,H = 7 Hz, 3 H),4.36 (m, 2
Ethyl 2-Cyano-2-fluoro-2-phenylacetate (10a): Colorless oil. 1H
H), 7.49 (m, 3 H, ArH), 7.75 (m, 2 H, ArH) ppm. 13C NMR
(CDCl3, 25 °C): δ = 13.7, 60.0, 65.1, 115.2, 126.5, 129.2, 130.6,
132.9, 163.2 ppm. HPLC (Chiralpak IC; hexane/CH2Cl2, 9:1): tR1
= 19.5, tR2 = 20.8 min.
3
NMR (CDCl3, 25 °C): δ = 1.33 (t, JH,H = 7 Hz, 3 H), 4.37 (m, 2
H), 7.52 (m, 3 ArH), 7.66 (m, 2 ArH) ppm. 13C NMR (CDCl3,
25 °C): δ = 13.8, 63.4, 86.1, 88.1, 125.5, 129.2, 131.3, 131.7,
162.8 ppm. 19F NMR (CDCl3, 25 °C): δ = –145.8 ppm. HPLC
(Chiralpak IC; hexane/CH2Cl2, 9:1): tR1 = 11.5, tR2 = 12.4 min.
Ethyl 2-Bromo-2-cyano-2-phenylacetate (12): Colorless oil. 1H
3
NMR (CDCl3, 25 °C): δ = 1.35 (t, JH,H = 7 Hz, 3 H), 4.37 (m, 2
Methyl 2-Cyano-2-fluoro-2-phenylacetate (10b): Colorless oil. 1H
NMR (CDCl3, 25 °C): δ = 3.92 (s, 3 H), 7.52 (m, 3 ArH), 7.66 (m,
2 ArH) ppm. 13C NMR (CDCl3, 25 °C): δ = 54.6, 86.1, 114.1,
125.5, 129.3, 131.3, 131.5, 162.9 ppm. 19F NMR (CDCl3, 25 °C): δ
H), 7.47 (m, 3 H, ArH), 7.80 (m, 2 H, ArH) ppm. 13C NMR
(CDCl3, 25 °C): δ = 13.7, 45.4, 65.1, 115.5, 127.3, 129.2, 130.5,
132.8, 163.2 ppm. HPLC (Chiralpak IC; hexane/CH2Cl2, 9:1): tR1
= 19.8, tR2 = 22.3 min.
= –145.6 ppm. HPLC (Chiralpak IC; hexane/CH2Cl2, 9:1): tR1
14.4, tR2 = 15.5 min.
=
meso/dl Diethyl 2,3-dicyano-2,3-diphenylsuccinate (13): NMR spec-
troscopic data are in accordance with those reported in the litera-
ture.[22]
tert-Butyl 2-Cyano-2-fluoro-2-phenylacetate (10c): NMR and
HPLC data are in accordance with those described by Kim.[6b]
Supporting Information (see footnote on the first page of this
article): 1H and 13C NMR spectra of ligands, complex A and
fluorinated products.
Ethyl 2-(2-Chlorophenyl)-2-cyano-2-fluoroacetate (10d): Colorless
oil. 1H NMR (CDCl3, 25 °C): δ = 1.38 (t, 3JH,H = 7 Hz, 3 H), 4.44
3
(q, JH,H = 7 Hz, 2 H), 7.47 (m, 3 ArH), 7.79 (d, J = 8 Hz, 1 ArH)
ppm. 13C NMR (CDCl3, 25 °C): δ = 13.7, 64.7, 85.8, 127.5, 128.5,
128.6, 129.5, 129.8, 131.1, 132.3, 162.0 ppm. 19F NMR (CDCl3,
25 °C): δ = –147.8 ppm. HPLC (Chiralpak IC; hexane/CH2Cl2,
9:1): tR1 = 19.9, tR2 = 21.2 min.
Acknowledgments
This work was supported by grants from the Spanish Ministerio de
Ciencia e Innovación (MICINN) (Project CTQ2005-03416; Project
CTQ2008-00683) and Consolider Ingenio 2010 Intecat (CSD2006-
0003). We thank Dr. Carmen Claver for stimulating discussions.
Ethyl 2-(2-Bromophenyl)-2-cyano-2-fluoroacetate (10e): Colorless
oil. 1H NMR (CDCl3, 25 °C): δ = 1.39 (t, 3JH,H = 7 Hz, 3 H), 4.44
3
(q, JH,H = 7 Hz, 2 H), 7.40 (ddd, J = 2, 8, 8 Hz, 1 H, ArH), 7.52
(ddd, J = 2, 8, 8 Hz, 1 H, ArH), 7.66 (d, J = 8 Hz, 1 H, ArH), 7.79
(d, J = 8 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3, 25 °C): δ = 15.6,
66.5, 87.7, 129.3, 130.4, 130.5, 131.4, 131.6, 133.0, 134.2,
163.8 ppm. 19F NMR: δ = –146.1 ppm. HPLC (Chiralpak IC; hex-
ane/CH2Cl2, 9:1): tR1 = 23, tR2 = 25 min.
[1] L. Hintermann, A. Togni, Angew. Chem. 2000, 112, 4530; An-
gew. Chem. Int. Ed. 2000, 39, 4359–4362.
[2] For reviews, see: a) S. France, A. Weatherwax, T. Lectka, Eur.
J. Org. Chem. 2005, 475–479; b) M. Oestreich, Angew. Chem.
2005, 117, 2376; Angew. Chem. Int. Ed. 2005, 44, 2324–2327;
c) G. K. S. Prakash, P. Beier, Angew. Chem. 2006, 118, 2228;
Angew. Chem. Int. Ed. 2006, 45, 2172–2174; d) C. Bobbio, V.
Gouverneur, Org. Biomol. Chem. 2006, 4, 2065–2075; e) N. Shi-
bata, T. Ishimaru, S. Nakamura, T. Toru, J. Fluorine Chem.
2007, 128, 469–483; f) V. A. Brunet, D. O’Hagan, Angew.
Chem. 2008, 120, 1198; Angew. Chem. Int. Ed. 2008, 47, 1179–
1182; g) J.-A. Ma, D. Cahard, Chem. Rev. 2008, 108, PR1–
PR43; h) M. Ueda, T. Kano, K. Maruoka, Org. Biomol. Chem.
2009, 7, 2005–2012; i) D. Cahard, X. Xu, S. Couve-Bonnaire,
X. Pannecoucke, Chem. Soc. Rev. 2010, 39, 558–568; j) Y. K.
Kang, D. Y. Kim, Curr. Org. Chem. 2010, 14, 917–927; k) S.
Ethyl 2-Cyano-2-fluoro-2-(naphthalen-1-yl)acetate (10f): Yellowish
oil. 1H NMR (CDCl3, 25 °C): δ = 1.25 (t, 3JH,H = 7 Hz, 3 H), 4.36
(m, 2 H), 7.61 (m, 3 H, ArH), 7.97 (m, 3 H, ArH), 8.23 (m, 1 H,
ArH) ppm. 13C NMR (CDCl3, 25 °C): δ = 13.7, 64.6, 89.9, 101.9,
123.8, 124.7, 126.8, 127.0, 127.1, 127.8, 129.2, 132.5, 134.2,
162.8 ppm. 19F NMR (CDCl3, 25 °C): δ = –142.2 ppm. HPLC
(Chiralpak IC; hexane/CH2Cl2, 9:1): tR1 = 16.5, tR2 = 17.8 min.
Ethyl 2-Cyano-2-fluoro-2-p-tolylacetate (10g): Colorless oil. 1H
NMR (CDCl3, 25 °C): δ = 1.32 (t, 3JH,H = 7 Hz, 3 H), 2.4 (s, 3 H),
8
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SPANphos Ligands in Asymmetric Fluorination
Lectard, Y. Hamashima, M. Sodeoka, Adv. Synth. Catal. 2010,
352, 2708–2732; l) G. Valero, X. Companyó, R. Rios, Chem.
Eur. J. 2011, 17, 2018–2037; m) A. M. R. Smith, K. K. Hii,
Chem. Rev. 2011, 111, 1637–1656.
O. Jacquet, N. D. Clément, Z. Freixa, A. Ruiz, C. Claver,
P. W. M. N. van Leeuwen, Tetrahedron: Asymmetry 2011, 22,
1490–1498.
Uemura, M. Saitoh, Y. Ito, Tetrahedron Lett. 1999, 40, 1327–
1330; p) R. Kuwano, Y. Ito, J. Org. Chem. 1999, 64, 1232–1237;
q) R. Kuwano, H. Miyazaki, Y. Ito, J. Organomet. Chem. 2000,
603, 18–29; r) R. Kuwano, M. Sawamura, Y. Ito, Bull. Chem.
Soc. Jpn. 2000, 73, 2571–2578; s) R. Kuwano, M. Sawamura,
J. Shirai, M. Takahashi, Y. Ito, Bull. Chem. Soc. Jpn. 2000, 73,
485–486; t) R. Kuwano, K. Sato, T. Kurokawa, D. Karube, Y.
Ito, J. Am. Chem. Soc. 2000, 122, 7614–7615; u) R. Kuwano,
T. Uemura, M. Saitoh, Y. Ito, Tetrahedron: Asymmetry 2004,
15, 2263–2271; v) R. Kuwano, K. Kaneda, T. Ito, K. Sato, T.
Kurokawa, Y. Ito, Org. Lett. 2004, 6, 2213–2215; w) R. Ku-
wano, M. Kashiwabara, Org. Lett. 2006, 8, 2653–2655; x) R.
Kuwano, M. Kashiwabara, K. Sato, T. Ito, K. Kaneda, Y. Ito,
Tetrahedron: Asymmetry 2006, 17, 521–535; y) R. Kuwano, M.
Kashiwabara, M. Ohsumi, H. Kusano, J. Am. Chem. Soc. 2008,
130, 808–809;R. Kuwano, M. Kashiwabara, M. Ohsumi, H.
Kusano, J. Am. Chem. Soc. 2011, 133, 9136–9136; z) R. Ku-
wano, N. Kameyama, R. Ikeda, J. Am. Chem. Soc. 2011, 133,
7312–7315.
[3]
[4]
[5]
Y. Hamashima, K. Yagi, H. Takano, L. Tamás, M. Sodeoka,
J. Am. Chem. Soc. 2002, 124, 14530–14531.
Y. Hamashima, T. Suzuki, Y. Shimura, T. Shimizu, N. Umebay-
ashi, T. Tamura, N. Sasamoto, M. Sodeoka, Tetrahedron Lett.
2005, 46, 1447–1450.
a) H. R. Kim, D. Y. Kim, Tetrahedron Lett. 2005, 46, 3115–
3117; b) S. M. Kim, Y. K. Kang, M. J. Cho, J. Y. Mang, D. Y.
Kim, Bull. Korean Chem. Soc. 2007, 28, 2435–2441.
[6]
[7] Y. K. Kang, M. J. Cho, S. M. Kim, D. Y. Kim, Synlett 2007,
1135–1138.
[8] a) Z. Freixa, M. S. Beentjes, G. D. Batema, C. B. Dieleman,
G. P. F. van Strijdonck, J. N. H. Reek, P. C. J. Kamer, J.
Fraanje, K. Goubitz, P. W. N. M. van Leeuwen, Angew. Chem.
2003, 115, 1322; Angew. Chem. Int. Ed. 2003, 42, 1284–1287;
b) C. Jiménez-Rodríguez, F. X. Roca, C. Bo, J. Benet-Buchholz,
E. C. Escudero-Adán, Z. Freixa, P. W. N. M. van Leeuwen,
Dalton Trans. 2006, 268–278.
[12] J. Li, G. Chen, Z. Wang, R. Zhang, X. Zhang, K. Ding, Chem.
Sci. 2011, 2, 1141–1144.
[13] T. Imamoto, S.-I. Kikuchi, T. Miura, Y. Wada, Org. Lett. 2001,
3, 87–90.
[14] While this work was in progress, an effective and interesting
enantioselective route to bis(chromane) ligands, including
SPANphos, was published: X. Wang, Z. Han, Z. Wang, K.
Ding, Angew. Chem. Int. Ed. 2012, 51, 936–940.
[15] J. Herwig, H. Bohnen, P. Skutta, S. Sturm, P. W. N. M.
van Leeuwen, R. Bronger, (Celanese Chemicals Europe
GmbH), Patent WO 02068434 A1, 2002.
[9] Z. Freixa, P. C. J. Kamer, M. Lutz, A. L. Spek, P. W. N. M.
van Leeuwen, Angew. Chem. 2005, 117, 4459; Angew. Chem.
Int. Ed. 2005, 44, 4385–4388.
[10] Z. Freixa, P. W. N. M. van Leeuwen, Coord. Chem. Rev. 2008,
252, 1755–1786.
[11] a) M. Sawamura, H. Hamashima, Y. Ito, Tetrahedron: Asym-
metry 1991, 2, 593–596; b) M. Sawamura, H. Hamashima, Y.
Ito, J. Am. Chem. Soc. 1992, 114, 8295–8296; c) M. Sawamura,
R. Kuwano, Y. Ito, Angew. Chem. 1994, 106, 92; Angew. Chem.
Int. Ed. Engl. 1994, 33, 111–113; d) M. Sawamura, H. Hamash-
ima, Y. Ito, Tetrahedron 1994, 50, 4439–4454; e) M. Sawamura,
H. Hamashima, M. Sugawara, R. Kuwano, Y. Ito, Organome-
[16] L. A. van der Veen, P. C. J. Kamer, P. W. N. M. van Leeuwen,
Organometallics 1999, 18, 4765–4777.
[17] H. T. Teunissen, F. Bickelhaupt, Phosphorus, Sulfur, Silicon Re-
lat. Elem. 1996, 118, 309–312.
[18] Data collection with: APEX II, versions v1.0-22, v2009.1-0 and
v2009.1-02, Bruker AXS Inc., Madison, Wisconsin, USA,
2007.
tallics 1995, 14, 4549–4558; f) M. Sawamura, H. Hamashima, [19] Data reduction with: SAINT, versions V.2.10, V/.60A and
H. Shinoto, Y. Ito, Tetrahedron Lett. 1995, 36, 6479–6482; g)
R. Kuwano, M. Sawamura, J. Shirai, M. Takahashi, Y. Ito,
Tetrahedron Lett. 1995, 36, 5239–5242; h) Y. Ito (NIPPON OIL
Co.), EP 0,663,382, 1995; i) R. Kuwano, M. Sawamura, Y. Ito,
Tetrahedron: Asymmetry 1995, 6, 2521–2526; j) M. Sawamura,
R. Kuwano, Y. Ito, J. Am. Chem. Soc. 1995, 117, 9602–9603;
k) M. Sawamura, M. Sudoh, Y. Ito, J. Am. Chem. Soc. 1996,
118, 3309–3310; l) R. Kuwano, M. Sawamura, S. Okuda, T.
Asai, Y. Ito, M. Redon, A. Krief, Bull. Chem. Soc. Jpn. 1997,
70, 2807–2822; m) R. Kuwano, H. Miyazaki, Y. Ito, Chem.
Commun. 1998, 71–72; n) Y. Ito, R. Kuwano, Phosphorus Sul-
fur Silicon Relat. Elem. 1999, 146, 469–472; o) R. Kuwano, T.
V7.60A, Bruker AXS Inc., Madison, Wisconsin, USA, 2003/
2007.
[20] SADABS, V.2.10, V2008 and V2008/1, Bruker AXS Inc., Madi-
son, Wisconsin, USA, 2003/2001, see: R. H. Blessing, Acta
Crystallogr., Sect. A 1995, 51, 33–38.
[21] SHELXTL, versions V6.12 and 6.14: G. M. Sheldrick, Acta
Crystallogr., Sect. A 2008, 64, 112–122.
[22] a) R. P. Kozyrod, J. Morgan, J. T. Pinhey, Aust. J. Chem. 1991,
44, 369–376; b) D. Villemin, A. B. Alloum, Synth. Commun.
1992, 22, 3169–3179.
Received: February 24, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O20223
/KAP1
Date: 25-07-12 10:25:36
Pages: 10
P. W. N. M. van Leeuwen et al.
FULL PAPER
Asymmetric Fluorination
A
trans-coordinating diphosphane in
O. Jacquet, N. D. Clément, C. Blanco,
M. M. Belmonte, J. Benet-Buchholz,
P. W. N. M. van Leeuwen* ............... 1–10
asymmetric fluorination catalysis? New
enantiopure wide-bite-angle diphosphanes
were synthesized and used in the pal-
ladium-catalyzed asymmetric fluorination
of α-cyanoacetates. Enantiomeric excesses
up to 93% were obtained using Pd(OAc)2-
SPANphos as the catalyst for the fluorin-
ation of ethyl 2-cyano-2-phenylacetate with
N-fluorobenzenesulfonimide (NFSI).
SPANphos Ligands in Palladium-Cata-
lyzed Asymmetric Fluorination
Keywords: Asymmetric catalysis / Ligand
design / Palladium / Halogenation / Fluor-
ine
10
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