Electronegativity governs enantioselectivity: Alkyl-aryl cross-coupling with fenchol-based palladium-phosphorus halide catalysts

Article abstract of DOI:10.1002/adsc.201100924

A series of bulky, modular, monodentate, fenchol-based phosphites has been employed in an intramolecular palladium-catalyzed alkyl-aryl cross-coupling reaction. This enantioselective α-arylation of N-(2-bromophenyl)-N-methyl- 2-phenylpropanamide is accomplished with [Pd(C₃H₅)(BIFOP- X)(Cl)] as precatalysts, which are based on biphenyl-2,2'-bisfenchol phosphites (BIFOP-X, X=F, Cl, Br, etc.). The phosphorus fluoride BIFOP-F gives the highest enantioselectivity and good yields (64% ee, 88%). Lower selectivities and yields are found for BIFOP halides with heavier halogens (Cl: 74%, 47% ee, Br: 63%, 20% ee). NMR studies on catalyst complexes reveal two equilibrating diastereomeric complexes in equal proportions. In all cases, the phosphorus-halogen moiety remains intact, pointing to its remarkable stability, even in the presence of nucleophiles. The increasing enantioselectivity of the catalysts with the phosphorus halide ligands correlates with the rising electronegativity of the halide (bromine

Full text of DOI:10.1002/adsc.201100924

FULL PAPERS
DOI: 10.1002/adsc.201100924
Electronegativity Governs Enantioselectivity: Alkyl-Aryl
Cross-Coupling with Fenchol-Based Palladium-Phosphorus
Halide Catalysts
Roberto Blanco Trillo,a Matthias Leven,a Jçrg M. Neudçrfl,a and Bernd Goldfussa,*
a
Department of Chemistry, Universitꢀt zu Kçln, Greinstr. 4, 50939 Kçln. Germany
Fax : (+49)-221-470-5057; e-mail: goldfuss@uni-koeln.de
Received: December 13, 2011; Revised: February 10, 2012; Published online: May 15, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201100924.
Abstract: A series of bulky, modular, monodentate, plexes reveal two equilibrating diastereomeric com-
fenchol-based phosphites has been employed in an plexes in equal proportions. In all cases, the phos-
intramolecular palladium-catalyzed alkyl-aryl cross- phorus-halogen moiety remains intact, pointing to its
coupling reaction. This enantioselective a-arylation remarkable stability, even in the presence of nucleo-
of
A
N-(2-bromophenyl)-N-methyl-2-phenylpropan- philes. The increasing enantioselectivity of the cata-
(C3H5)(BIFOP- lysts with the phosphorus halide ligands correlates
N
ACHTUNGTRENNUNG
X)(Cl)] as precatalysts, which are based on biphenyl- with the rising electronegativity of the halide (bro-
2,2’-bisfenchol phosphites (BIFOP-X, X=F, Cl, Br, mine<chlorine<fluorine), as can be rationalized
etc.). The phosphorus fluoride BIFOP-F gives the from structural parameters and DFT computations.
highest enantioselectivity and good yields (64% ee,
88%). Lower selectivities and yields are found for
BIFOP halides with heavier halogens (Cl: 74%, 47% Keywords: alpha-arylation; cross couplings; enantio-
ee, Br: 63%, 20% ee). NMR studies on catalyst com- selective catalysis; fenchol; palladium; phosphites
Introduction
tions.[13b] Surprisingly, the halogen phosphites BIFOP-
Cl 2 and BIFOP-Br 3 were air-stable and proved to
Palladium-catalyzed cross-couplings[1] are powerful
tools for organic syntheses, for example, to generate
quaternary carbon stereocenters.[2] The normally com-
plicated selective a-quaternation of carbonyl com-
pounds can be effectively achieved via palladium cat-
alyzed a-arylations (Scheme 1).[3,4]
While a broad range of phosphines,[5], N-heterocy-
clic carbenes (NHCs)[6] or even secondary phosphine
chlorides[7] are used in Pd-catalyzed cross-couplings,
a much more limited set of NHC and P ligands was
applied in enantioselective a-arylations.[3,4] The high-
est enantioselectivities were found for NHC ligands
(up to 97% ee),[8] with H8-BINAP as the most success-
ful P ligand up to 68% ee were achieved.[9] The most
selective monodentate P ligand accomplished 53%
ee.[5]
Fenchol-based[10] (Scheme 2) reagents and catalysts
were recently reported with applications in chiral or-
ganolithium aggregates[11] and in enantioselective or-
ganozinc catalysts.[12] The sterically highly hindered
BIFOP ligands were employed in Cu-catalyzed 1,4-
Scheme 1. Catalytic cycle of an intramolecular, Pd-catalyzed
additions[13a] and in Pd-catalyzed allylic substitu- a-arylation yielding chiral oxindoles.
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Results and Discussion
Synthesis of Ligands
The biphenyl bisfenchol phoshines (BIFOPs) 1–15
were synthesized by lithiation of BIFOL 1 and subse-
quent reaction with PCl3 or PBr3 (Scheme 3).[13] In-
stead of using PF3, a halide substitution from BIFOP-
Cl 2 with AgF was chosen in order to obtain the anal-
ogous fluorophosphite BIFOP-F 5. All BIFOP halides
(2, 3, and 5) are air stable and very reluctant to un-
dergo reactions with various nucleophilic reagents
(Table 1 and Table 3).[13]
Different nucleophiles were used to substitute the
chloride from 2 to get the ligands 4–15. The same pro-
cedure was used to modify the Benfop 16 system
(Scheme 3).
The BIFOP ligands were isolated in yields of 40–
77%, while the BENFOP-based ligands could be iso-
lated only with yields of 5 to 8%. These were stable
at room temperature and mostly stable to hydrolysis.
X-ray structures for all BIFOP derivatives (Figure 2
and Figure 3)[13] reveal the rigid structure of the
Scheme 2. Fenchol-based P ligands, i.e., FENOPs, BEN-
FOPs and BIFOPs.
be efficient ligands for the Pd catalyst, even in the ligand-backbone with identical conformation for the
presence of a nucleophilic reagent. biaryl-axis while BENFOP derivatives were only iso-
Herein, we discuss the synthesis and applications of lated as oils.
fenchol-based P ligands (Scheme 2) for the enantiose-
lective intramolecular Pd-catalyzed a-arylation and
report the control of enantioselectivity by halide elec- Enantioselective Intramolecular a-Arylation
tronegativity in new halophosphite ligands.
The first set of experiments is performed with
10 mol% of [PdACHTNUGRTENUNG(allyl)Cl]2 and of the chiral ligand in
Scheme 3. Synthesis of the BIFOP- and BENFOP-based library. Reaction conditions: (a) lithiation followed by addition of
PCl3 or, respectively, PBr3 (b) halide substitution.
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Electronegativity Governs Enantioselectivity: Alkyl-Aryl Cross-Coupling
toluene at 1008C for 12 h.[8,9] These conditions give
Table 1. Pd-catalyzed cyclization of 21 via intramolecular a-
arylation.[a]
good yields (>84%) for all BIFOP-based ligands but
hardly any enantioselectivities while the BENFOP
(17, 18) and FENOP (19) ligands give poor selectivi-
ties (Table 1). For the in situ generated lithium phos-
phite BIFOP-Li 14 no conversion is detected.
In order to obtain information on the formation of
the in situ formed catalyst, NMR studies with BIFOP-
Cl 2 and [PdACHTNUTRGNENG(U allyl)Cl]2 were carried out (Figure 1).
Even after 1.5 h at 1008C a solution of BIFOP-Cl 2
and [PdC3H5)Cl]2 in toluene still contains large
amounts of free ligand
Figure 1). It takes as long as 5 h until all free BIFOP-
Ligand
Yield[b] [%]
ee[c] [%]
2
(31P NMR, d=154.4,
BIFOP-Cl[d] (2)
BIFOP-H[d] (4)
BIFOP-F[d] (5)
84
86
90
82
0
33
49
28
n.d.
>2 (S)
>2 (S)
n.d.
Cl 2 is bound in the [Pd(2)ACTHNUTRGNE(UNG C3H5)Cl] complex
(31P NMR, d=137.3 and 138.0,Figure 1). Hence, this
NMR analysis (Figure 1) shows that the bulky ligand
reacts only slowly with the palladium species to form
the catalyst, which is obviously caused by the high
steric strain caused by the embedding fenchane
units.[13]
BIFOP-Me[d] (6)
BIFOP-Li (14)
BENFOP-Me (17)
BENFOP-Ph (18)
FENOP-Ph (20)
–
7 (R)
8 (R)
15 (S)
[a]
Reaction conditions: 10 mol% [PdACTHUNTRGNEU(GN allyl)Cl]2, 10 mol%
These NMR results are now employed to improve
the catalytic procedure. For an optimized method, the
catalysts are formed by equilibration for 5 h prior to
catalysis. Indeed, both yields and enantioselectivities
are substantially improved for all catalysts (Table 2).
The best enantioselectivity was achieved with BIFOP-
L*, 3 mL toluene, 1008C, 0.3 mmol amide, 0.9 mmol
NaO-t-Bu, 1008C, 12 h.
Isolated yield.
Determinated by HPLC.
First heating of L* with [Pd
catalytic procedure.
[b]
[c]
[d]
ACHTUNGTRENN(NUG allyl)Cl]2 for 5 h then the
Figure 1. 31P NMR (CDCl3; 125.5 MHz) of BIFOP-Cl 2 with [Pd
d) 5 h, 0.038 mmol, 3 mL toluene.
ACHTUNGTREN(NGNU allyl)Cl]2 after heating at 1008C for a) 0 h; b) 2,5 h; c) 3 h;
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Table 2. Optimized, Pd-catalyzed cyclization of 21 via intra-
molecular a-arylation.[a]
Table 3. Stability of BIFOP-F 5 against NaO-t-Bu to form
BIFOP-O-t-Bu 15.
Ligand
Yield[b] [%]
ee[c] [%]
BIFOP-Cl[d] (2)
74
63
88
88
63
66
79
54
84
69
76
80
0
47 (S)
20 (S)
25 (S)
64 (S)
13 (S)
23 (S)
14 (S)
4 (S)
15 (S)
17 (S)
27 (S)
29 (S)
–
BIFOP-Br[d] (3)
BIFOP-H[d] (4)
BIFOP-F[d] (5)
BIFOP-Me[d] (6)
BIFOP-Et[d] (7)
Entry Reagent
Conditions
Conversion[a]
BIFOP-n-Bu[d] (8)
BIFOP-t-Bu[d] (9)
BIFOP-Ph[d] (10)
BIFOP-OPh[d] (11)
BIFOP-NEt2[d] (12)
BIFOP-(2)-anisole[d] (13)
BIFOPLi (14)
1
2
3
4
5
6
NaO-t-Bu toluene, 1008C, 24 h
NaO-t-Bu MTBE, 508C, 24 h
NaO-t-Bu THF, 608C, 12 h
NaO-t-Bu TMEDA, 1008C, 12 h >5%
NaO-t-Bu TMEDA, 1008C, 5 d
KO-t-Bu toluene, 1008C, 12 h
–
–
–
50%
decomposition
BIFOP-Ot-Bu[d] (15)
BENFOP-Me (17)
BENFOP-Ph (18)
FENOP-Ph (20)
70
91
83
28
9 (S)
[a]
Determined by 31P NMR.
7 (R)
8 (R)
15 (S)
Table 4. Optimization of Pd source, solvent and temperature
in the intramolecular a-arylation with BIFOP-F 5.[a]
[a]
Reaction conditions: 10 mol% [PdACTHUNTRGNEU(GN allyl)Cl]2, 10 mol%
L*, 3 mL toluene, 1008C, 5 h; then 0.3 mmol amide,
0.9 mmol NaO-t-Bu, 1008C, 12 h.
Isolated yield.
BIFOP-F Pd
Solvent T [8C] Yield[b] ee[c]
[b]
[c]
[d]
10 mol% [Pd
10 mol% [Pd
2.5 mol% [Pd
2.5 mol% [Pd
10 mol% [Pd
10 mol% [Pd
G
100
100
50
76
93
69
93
50
73
53
93
92
90
56 (S)
64 (S)
49 (S)
57 (S)
50 (S)
53 (S)
48 (S)
45 (S)
15 (S)
60 (S)
Determinated by HPLC.
First heating of L* with [Pd
catalytic procedure.
ACHTUNGTRENN(NUG allyl)Cl]2 for 5 h then the
F 5 as ligand with 64% ee (Table 2). Remarkably, its
activity and selectivity are significantly higher than 2.5 mol% [Pd
50
2.5 mol% [PdACHTUNTGRNE(UGN allyl)Cl2] toluene 50
for BIFOP-Cl 2 (47% ee), which itself is superior to
BIFOP-Br 3 (20% ee, Table 2). In all cases, BIFOP
derivatives were used, and the corresponding ligands
could be recovered almost completely (80–90%) after
the performed catalysis.
To test the stability of the BIFOP halides 2, 3 and 5
against nucleophilic substitution with the employed
base NaO-t-Bu, several experiments with different
bases and solvents were performed (Table 3). All
BIFOP halides have similar reactivity with the men-
10 mol% Pd
N
10 mol% PdAHCUTGNTR(EUNNNG OAc)2
[a]
Reaction conditions: 10 mol% [PdACTHNUTRGNEG(NU allyl)Cl2], L*, 3 mL
solvent, 1008C, 5 h, then 0.3 mmol amide, 0.9 mmol
NaO-t-Bu heat 12 h.
Isolated yield.
[b]
[c]
Determined by HPLC.
tioned base and for the abridgement only BIFOP-F 5 ysis.[8] Two different catalyst loadings, i.e., 2.5 mol%
as best ligand is listed (Table 3). The phosphorus fluo- and 10 mol%, at different temperatures, i.e., 508C
ride 5 reacts with NaO-t-Bu neither under catalytic and 1008C, and different sources of palladium, i.e.,
conditions (entry 1) nor in more polar solvents. Only ([Pd
with TMEDA as solvent and under high temperature ployed. The results (Table 4) show that the combina-
for long time, is conversion of BIFOP-F 5 apparent tion of 10 mol% of [Pd(allyl)Cl]2 and toluene as sol-
ACHTUNGTRENGNU(N allyl)Cl2], Pd2ACHTUNTRGEG(NNUN dba)3 and PdACHTUNGTREN(NNGU OAc)2) are em-
AHCTUNGTRENNUNG
(Table 3, entries 4 and 5). If BIFOP-O-t-Bu 15 was vent at 1008C gives the best selectivity and reactivity
applied as ligand in the catalysis, only 9% ee (Table 2) (88%, 64% ee, Table 4). This optimized procedure
are achieved. This catalytic performance of 15, rela- was employed in the foregoing screening of the li-
tive to BIFOP-F 5, additionally proves that the phos- gands (Table 2).
phorus fluoride 5 is the active ligand system during
the catalysis rather than the phosphite 15.
In order to further improve the reaction conditions, Geometrical Comparisons of BIFOP Ligands
a series of experiments was conducted in which the
solvent and the amount of ligand are varied. For this The results of the catalytic cross coupling (Table 2) in-
purpose, the effects of different solvents are studied dicate that enantioselectivity is strongly influenced by
which were tested successfully previously in this catal- the ligand structures. Especially intriguing is the influ-
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Electronegativity Governs Enantioselectivity: Alkyl-Aryl Cross-Coupling
Table 5. Geometries based on X-ray structure of BIFOP-X systems and calculated buried volumes.[a]
X
BAA [8][b]
Angle sum at P [8][c]
FAA-lp [8][d]
FAA [8][d]
Vbur at P (%)[a]
F (5)
À94.5
À91.3
À91.7
À98.2
À96.9
À91.1
À93.3
À98.2
300.5
305.2
306.6
301.4
309.5
309.2
300.0
303.6
34.9
38.9
38.9
30.0
38.7
35.8
34.5
31.4
32.8
37.1
36.9
29.7
31.9
35.1
44.8
34.5
77.8
44.2
46.8
21.8
41.5
31.5
61.4
17.7
Cl (2)[e]
Br (3)[e]
H (4)[e]
Ph (10)
NEt2 (12)[e]
OPh (11)[e]
n-Bu (8)[e]
[a]
The calculations used SambVca[15] with the following parameters: radius of sphere, 3.5 ꢂ; distance from sphere, 2.28 ꢂ;
mesh step, 0.05 ꢂ.
Biaryl dihedral angle (BAA) between C1 C2 C3 C4 atoms in degrees.
Angle sum at phosphorus atom (pyramydality) in degrees.
[b]
[c]
[d]
À
À
À
À
À
À
Fenchyl-aryl dihedral angles (C1 C2 C3 O1) on the lone pair-side of phosphorus (FAA-lp) and at the substituent side
(FAA) of the biaryl axis.
[e]
Already published, see ref.[13]
Figure 2. X-ray crystal structure of P-BIFOP-F 5, with Plus-
conformation of the biaryl axis, ellipsoids are shown with
50% probality.
Figure 3. X-ray crystal structure of P-BIFOP-Ph 10, with
Plus-conformation of the biaryl axis, ellipsoids are shown
with 50% probality.
ence of the halide in the phosphorus ligands BIFOP-
Hal (Hal=Br, Cl, F) on the catalytic selectivities
(Table 1). Hence, the crystal structures of all three
BIFOP-halides 2, 3, 5 are compared to determine the
structural effect of the halide. The geometries of all ty at the phosphorus atoms in BIFOPs, which distorts
BIFOP derivatives are remarkable with respect to the inherent C2-symmetry of the biphenyl bisfenchol
their biaryl angles (BAA), the fenchyl aryl angles units towards C1-asymmetry. This is small for BIFOP-
(FAA, FAA-lp), the pyramidality at the phosphorus H 4 and all BIFOP halides (2, 3, 5), but large for the
atom as well as the positions of the phosphorus atom BIFOP-aryls (10, 13) (Table 5). The phosphorus
in the hydrophobic fenchane cavities (Table 5; atoms, essential for coordination to transition metals,
Figure 2, Figure 3). All BIFOPs exhibit Plus-biaryl exhibit slightly different degrees of pyramidality, the
axes with dihedral angles varying from À918 to À998 angle sums at phosphorus vary from 3008 to 3098
(Table 5, Figure 2, Figure 3). The fenchyl aryl dihedral (Table 5).
angles (FAA and FAAlp) are crucial for the bite of
To quantify the steric demand characterizing these
the chiral diol and are between 308 and 408, similar to ligands, the amount of volume of a sphere centered
fenchyl aryl angles previously analyzed in lithium fen- on the metal (buried volume[14]), using SambVca was
cholates.[12] The difference between the two dihedral calculated.[15] The volume of this sphere represents
angles is a measure for the BIFOP asymmetry. The the space around the metal atom that must be shared
rate of the asymmetry is controlled by the pyramidali- by the different ligands upon coordination. To have
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ACTHNUTRGNEUNG
Figure 4. (a) 31P NMR (125.5 MHz) of free ligand P-BIFOP-F 5, d=125.5 [1J(31P-19F)=1214 Hz]; (b) 31P NMR (251 MHz) of
the complex [PdACHTUNGTRENNUNG ACHUTNGTRENNGUN
(C3H5)(5)(Cl)] 23, d=117.5 [1J(31P-19F)=1240 Hz].
an estimate of the bulkiness of the various ligands, by reaction of the ligands with 0.5 equivalents of the
the crystal structures of the free ligands are examined. corresponding [Pd
(allyl)Cl]2 dimer.[18]
The putative metal atom is positioned 2.28 ꢂ from
The 31P NMR signal of free BIFOP-F 5 (d=125.5,
the coordinating P atom and the radius of the sphere Figure 4, a) is shifted upfield in its [Pd(allyl)(5)Cl]-
was chosen to be 3 ꢂ. The computation of the buried complex 23 (d =117.5, Figure 4, b). The J
volume is presented in Table 5. Whereas BIFOP-Cl 2 coupling of free 5 (1214 Hz) is increased to 1240 Hz
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
1
AHCTUNGTRENNUNG
(31P-19F)
1
and BIFOP-Br 3 exhibit a buried volume comparable in the Pd allyl complex 23 (Figure 4). This J
N
À
to those of the prominent ligands TADDOL or coupling proves that the P F unit remains intact in
BINAP, they exceed the buried volume of P
A
(%Vbur =26.7).[14b] However, the steric demand of as the increased 31P-19F coupling in complex [Pd-
BIFOP-F 5 (%Vbur =77.8) exceeds that of the other (allyl)(5)Cl] 23 relative to free BIFOP-F 5 parallels
AHCTUNGTRENNUNG
ligands, its buried volume is among the largest report- NMR spectroscopic investigations of Ru com-
ed so far for a monodentate ligand.[14b] This high plexes.[19]
buried volume is caused by the short P F distance, so
The 31P NMR-spectrum of the Pd
ACTHNGUTERNNU(G allyl)Cl-complex
À
that the size of the chiral pocket is reduced.[17] This 23 (Figure 4) shows two additional resonances with
provides a rough explanation for the high enantiose- almost equal intensities (1:0.9, Figure 4, b), which
lectivity of BIFOP-F 5, relative to the chloride 2 and point to an equilibration of two diastereomers with
the bromide 3.
endo (23a) and exo (23b) orientations of the allyl
The relatively high enantioselectivity of the catalyst fragment (Figure 5).
with ligand 5 is remarkable (Table 2), as the asymme-
Assignment of the exo 23a and endo 23b isomers
try of 5, measured as the difference of its fenchyl-aryl by 2D NMR experiments was not possible because of
angles, is rather small (DFAA =2.18, Table 5). In com- the overlapping of the resonances arising from the
parison to the other ligands 2–4 with similar asymme- protons of the fenchyl and terminal allyl groups. The
try (DFAA =0.38 to 2.08), the phosphorus atom in 5 is 1H-1H NOESY and 19F-1H NOESY experiments show
by far more encapsulated by the fenchane moieties the absence of any cross-peaks between the two iso-
(Table 5, 77.8%).
mers. The 19F-1H NOESY experiment shows interac-
tion between the P-bonded fluoride of both isomers
1
and all allylic protons (Figure 6) while the H-31P cor-
Characterization of Pd-BIFOP Halide Catalysts
relation NMR spectrum shows cross-peaks between
phosphorus and the central proton Hc (d=4.43) but
To investigate the coordination behaviour of the no interaction could be detected to both terminal
bulky BIFOP halides 2 to palladium more in detail, allyl protons Ha (d=2.45) and Hb (d=3.37, Figure 7).
1
Pd-p-allyl-complexes with ligands BIFOP-Cl 2, In the H-31P correlation NMR spectrum two addi-
5
BIFOP-Br 3 and BIFOP-F 5, respectively, are studied tional unusual high J
N
by NMR spectroscopy. These complexes are obtained between the phosphorus atom and a methyl group of
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Electronegativity Governs Enantioselectivity: Alkyl-Aryl Cross-Coupling
Figure 5. Equilibrating isomers of [PdACTHNUTRGNEUNG
(allyl)(5)Cl] 23 with NOE interactions according to 19F-1H NOESY and 31P-1H correla-
tion experiments.
Figure 6. Relevant NOE contacts from the 19F-1H NOESY experiment of the [Pd
ACTHNUTRGNE(NUG allyl)(5)(Cl)] 23 isomers.
the fenchane backbone. Unreacted [Pd
could not be detected [1H NMR (CDCl3) d=3.03 computations (Figure 8) show that the endo isomer of
(2Hterm, d), 4.10 (2Hterm, d), 5.45 (1Hcen, m)] in solu- [Pd(allyl)(5)(Cl)] 23a is slightly favoured by 0.6 kcal
tion.
molÀ1 over exo 23b (Figure 5). This is in good agree-
Hence, these NMR data prove the structure of ment with the equilibrium distribution of 1:0.9 ob-
complex [Pd
(allyl)(5)(Cl)], which serves as a model served by 31P NMR spectroscopy (Figure 4). The pref-
(C3H5)(Cl)]2 complexes and bulky calyx[4]arene ligands.[18c] DFT
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
for the active catalyst: BIFOP-F coordinates via the erence of the endo isomer 23b can be explained by its
À
phosphorus atom to palladium, while the P F unit re- favoured anti periplanar orientation of the central
mains intact.
proton of the allylic moiety relative to the halide
A variable temperature NMR study of the complex atom bound to phosphorus atom (Figure 8).
[Pd Like the BIFOP-F 5 containing [Pd(C3H5)(5)(Cl)]
(allyl)(5)(Cl)] 23, between À40 and +308C, re-
veals that ligand 5 or complex 23 do not undergo any 23, the analogous BIFOP-Cl containing
significant structural changes in solution, the spectra [Pd
(C3H5)(2)(Cl)] gives rise to two 31P NMR signals
remain identical in this temperature range. A similar at d=137.3 and 138.0 for both its endo and exo dia-
thermal stability is documented for [Pd(allyl)(Cl)]2 stereomers (Figure 9). Likewise, the BIFOP-Br 3 con-
A
ACHTUNGTRENNUNG
2
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
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Figure 7. 1H-31P correlation NMR spectra of the catalyst [Pd
ACTHNUTRGNEUNG(allyl)(5)(Cl)] 23.
taining complex [PdACTHNURGTNE(UNG C3H5)(3)(Cl)] shows two arrangements and with pro-S or pro-R configured ste-
31P NMR signals d=119.9 and 118.0 for the two dia- reocenters. For each structure, the ONIOM (B3LYP/
stereomers (Figure 9). Like the isomers 23a and 23b, 6-31G:UFF) two layer approach is employed to scan
the two resonances have almost equal intensities for the lowest energy conformation by rotation of the
À
(1:0.9) and no significant change can be observed in P Pd axis in 108 steps. Subsequent geometry optimi-
1
the H NMR spectrum or in the 31P NMRspectrum zations yield the four most stable isomers of the
upon variation of the temperature.
BIFOP-F 5 containing diorganopalladium intermedi-
ates [Pd(21)(5)] 24 (Figure 10).
These computations show that the energetically
most favoured intermediate is pro-S (24a), which
competes with the pro-R intermediate (24b, Table 6).
Origin of Enantioselectivity
The catalytic cyclizations of substrate 21 with BIFOP This pro-S preference agrees with the experimentally
phosphite (Erel =0.0 molÀ1) halides 2, 3 and 5 show favoured S-configured product (Table 2). Further-
that yields and enantioselectivities are strongly affect- more, replacement of F by Cl or Br in BIFOP-Hal re-
ed by the type of halide present in the ligand and in- duces the preference of pro-S vs. pro-R structures
crease in the order Br<Cl<F: BIFOP-Br 3 (63% continuously:
Erel(F)=6.0 kcalmolÀ1,
Erel(Cl)=
yield, 20% ee, S) BIFOP-Cl 2 (74% yield, 47% ee, S) 1.4 kcalmolÀ1, Erel(Br)=0.1 kcalmolÀ1 (Table 6). This
and BIFOP-F 5 (88% yield, 64% ee, S, Table 2). To is in agreement with the experimentally observed de-
explore the origins of these intriguingly increasing creased enantioselectivities, i.e., F: 64% ee>Cl: 47%
enantioselectivities, the diorganopalladium intermedi- ee>Br: 20% ee for BIFOP-Hal, Table 1).
ates [Pd(L)R2], with
R1/2 =21, L=BIFOP-Hal,
What are the origins for the S-enantiomeric product
Scheme 1) were computationally analyzed as models 22 yielding increasing enantioselectivities in the order
for the transition structures of the enantioselective Br<Cl<F for BIFOP-X (X=halide) ligands? As it
step, i.e., the foregoing transmetalation. T-shape geo- is apparent for the computed diorganopalladium in-
metries are well documented for such PdR2L com- termediates [Pd(L)R2], the energetic differentiation
plexes.[21] Hence, four [Pd(BIFOP-Hal)R2] intermedi- between the favoured pro-S and the disfavoured pro-
ates have to be considered with trans or cis P-Pd-aryl R structures increases with decreasing phosphorus-
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Electronegativity Governs Enantioselectivity: Alkyl-Aryl Cross-Coupling
Figure 8. Computed structures of (a) the catalyst exo-[PdACTHNUTRGENN(UG C3H5)(5)(Cl] 23a and (b) endo-[PdACHTUNTGREN(NGUN C3H5)(5)(Cl] 23b
[BP86/def-SV(P)].
the contact to the chiral cavity, the higher is the ener-
getic differentiation of pro-S and pro-R structures
(Table 6). This agrees with the increasing experimen-
tal enantioselectivities in the order Br<Cl<F
(Table 2). Bentꢃs rule[22] explains this electronegativity
effect: As the more electronegative substituent indu-
ces more p-character at phosphorus in its bond to the
P atom, more s-character, and hence a shorter bond
À
distance results for the P Pd coordination. The
higher the electronegativity of the attached halogen
À
atom, the shorter is the P Pd bond.
Another proof for electronegativity-induced distor-
tions is the pyramidality of the coordinating phospho-
rus atom, measured by its angle sum. X-ray crystal
structures of the free BIFOP-X ligands show that this
pyramidality increases with increasing electronegativi-
ty of the halide, in agreement with Bentꢃs rule,[22] i.e.,
angle sums are BIFOP-Br: 306.68>BIFOP-Cl:
305.28>BIFOP-F: 300.58 (Table 5). The same in-
creased pyramidality at phosphorus with increased
electronegativity of the attached halogen atom is ap-
parent in the computed diorganopalladium intermedi-
ates (Figure 10, Table 6). Hence, the electronegativity
of the halogen atoms attached to the coordinating P
atom strongly influences the geometry of the inter-
Figure 9. 31P NMR spectra (251 MHz, CDCl3) of catalyst
[Pd
ACHTUNGTRENNUNG
(C3H5)(2)(Cl)] (a) d31P=137.3 and 138.0; (b)
[Pd
ACHTUNGTRENNUNG
(C3H5)(3)(Cl)] d31P=119.9 and 118.0.
palladium distances, i.e., pro-S/R from 3 (Br) 2.40/ mediates and transition structures and governs the
2.36 ꢂ, over 2 (Cl) 2.39/2.35 ꢂ to 5 (F) 2.37/2.32 ꢂ enantioselectivity of the catalyst.
(Table 6). Hence, in the order Br<Cl<F, the PdR2
unit becomes more and more drawn into the chiral
environment of the BIFOP halides. The distances be- Conclusions
tween the halogen atoms (X) and the hydrogen atom
H(C1) at the aryl ortho-position shorten with increasing New modular, fenchol-based, monodentate phosphine
electronegativity of X (Table 6, Figure 10). The closer ligands provide in the Pd-catalyzed a-arylation of
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Figure 10. Computed structures of the diorganopalladium intermediate [Pd(5)R2] 24 [BP86/def-SV(P)]. The repulsive inter-
action between F and C(1)-H is shown for the two most stable structures (24a and 24b, X=F).
amide 21 up to 88% yield and 64% ee (Table 2). Sur- cleophiles, which might be attributed to the strong
prisingly, fluorophosphite BIFOP-F (5) is identified as steric shielding by the fenchane units. NMR experi-
À
the superior ligand, in spite of its potentially labile P
F function. Under the reaction conditions, the P F dination to palladium, which is necessary to form the
group proves to be stable, even in the presence of nu- active catalyst. The different electronegativities of the
ments show that this shielding does not prevent coor-
À
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Electronegativity Governs Enantioselectivity: Alkyl-Aryl Cross-Coupling
Table 6. Computed relative energies and geometric parameters of diorgano palladium intermediates [PdACTHNUTRGNEUNG
(2,3,5)R2].[a]
X
F (pro-S/R)
Cl (pro-S/R)
Br (pro-S/R)
[a]
Erel
À
6.0/0.0
1.4/0.0
0.1/0.0
[a]
P Pd distance (ꢂ)
2.37/2.32
2.63/2.99
113.6/110.7
302.4/301.0
2.39/2.35
2.92/3.18
107.6/111.2
306.8/304.8
2.40/2.36
2.98/3.25
106.3/111.6
308.5/306.2
X HC(1) (ꢂ)[a]
À
[a]
À À
X P Pd (deg.)
angle sum at P (deg.)[a]
[a]
Erel in [kcalmolÀ1] for the two most stable [Pd(L)R2] structures [BP86/def-SV(P)]. D values show the geometric differen-
ces of pro-S and pro-R isomers.
less crystals; yield: 0.78 g (1.6 mmol, 69%); mp 138.38C;
halogen atoms in BIFOP-F, as well as its homologues
BIFOP-Cl and BIFOP-Br, alter the geometries of li-
gands, catalysts, intermediates and transition struc-
[a]2D0: 18.29 (2.8M in hexane). 31P NMR (125.5 MHz,
CDCl3): d=171.3; 1H NMR (300 MHz, CDCl3): d=0.89–
0.68 (6H, m), 0.96 (3H, s), 1.00 (1H, t), 1.05 (3H, s), 1.17
(1H, t), 1.28 (3H, s), 1.43 (3H, s), 1.49–1.51 (1H, m), 1.85–
1.66 (2H, m), 7.19–7.15 (1H, d), 7.37–7.26 (2H, m), 7.47
(1H, d); 13C NMR (75 MHz, CDCl3): d=14.54, 15.68, 23.08,
24.35, 24.53, 25.79, 26.80, 27.34, 32.01, 33.07, 33.40, 37.39,
38.75, 42.88, 49.20, 51.34, 124.34, 126.22, 132.26, 134.28,
134.78, 144.22.
À
tures to a different degree. Especially the shorter P
Pd contact, induced by the highly electonegative fluo-
rine and the resulting more intensive substrate-ligand
interaction, rationalizes the significantly higher enan-
tioselectivity of BIFOP-F relative to its heavier homo-
logues BIFOP-Cl and BIFOP-Br. This demonstrates
the effect of electronegativity on the enantioselectivi-
ty in a Pd-catalyzed cross-coupling cyclization.
BIFOP-F (5)
To a solution of 1.0 g (2.2 mmol) P-BIFOP-Cl 2 in 15 mL
absolute MeCN were added 792 mg (2.4 mmol) AgF. The
mixture was stirred at room temperature for 12 h. Purifica-
tion by flash chromatography (cyclohexane/Et2O, 4:1) and
recrystallization from Et2O/CH2Cl2 furnished compound 5
as coloorless crystals; yield: 0.79 g (1.7 mmol, 77%); mp
120.88C; [a]2D0: À48.53 (4.5M in hexane). 31P NMR
19F NMR (282.4 MHz, CDCl3): d=À53.1; 1H NMR
(300 MHz, CDCl3): d=0.0 (3H, s, CH3), 0.34 (3H, s, CH3),
0.61 (3H, s, CH3), 0.80 (3H, s, CH3), 1.18–1.40 (6H, m), 1.45
(1H, m), 1.48 (2H, d), 1.50 (2H, s), 1.57 (2H, d), 2.08 (2H,
m), 2.27 (1H, d, CH3), 2.32 (1H, d, CH3), 6.64 (1H, d), 6.66
(1H, t), 7.27–7.36 (2H,m), 7.41 (1H, t), 7.53 (1H, d);
13C NMR (75 MHz, CDCl3): d=15.26, 23.93, 24.11, 25.37,
26.40, 32.65, 38.33, 42.46, 46.95, 48.77, 49.51, 123.93, 125.81,
131.81, 133.85, 133.87, 133.37, 143.80; X-ray crystal data:
C32H40F1O2P1; Mr =506.61 gmolÀ1; space group: P212121; a=
Experimental Section
BIFOP-Cl (2)
To a solution of 1.05 g (2.3 mmol) P-BIFOL 1 in 10 mL ab-
solute THF, 2.81 mL (3 mmol) tert-butyllithium in hexanes
(1.6M,) were added slowly at À208C. The mixture was
stirred for 30 min, at À208C then for 1 h at room tempera-
ture. After recooling to À208C 0.3 mL (2.3 mmol) of freshly
distilled PCl3 were added slowly and the reaction mixture
was stirred for 48 h at room temperature. Purification by
flash chromatography (cyclohexane/Et2O, 4:1) and recrystal-
lization from Et2O/CH2Cl2 furnished compound 1 as colour-
less crystals; yield: 0.76 g (1.5 mmol, 64%); mp 130.88C;
[a]2D0: 74.31 (4.5M in hexane). 31P NMR (125.5 MHz,
CDCl3): d=154.4; 1H NMR (300 MHz, CDCl3): d=0.07
(3H, s), 0.30 (3H, s), 0.65 (3H, s), 0.83 (3H, s), 1.10–1.61
(10H, m), 1.72 (3H, m), 2.24 (1H, d), 2.41 (1H, d), 2.48–
2.67 (2H, m), 6.68 (1H, d), 6.97 (1H, t), 7.14–7.22 (2H, m),
7.50 (1H, d), 7.62 (1H, d); 13C NMR (CDCl3): d=15.2, 16.1,
22.2, 22.7, 23.5, 23.9, 24.1, 25.4, 26.4, 26.7, 32.6, 38.3, 42.4,
42.6, 48.8, 49.0, 58.3, 58.7, 123.9, 125.8, 131.8, 133.9, 134.4,
143.8.
(125.5 MHz, CDCl3): d=125.5 [1J
(P-F)=À1214 Hz];
8.1774(2),
b=13.9194(5),
c=23.1395(8) ꢂ;
V=
2633.84(15) ꢂ3; Z=4; 1=1.278 gmLÀ3; T=100(2) K; l=
0.71073; m=0.140 mmÀ1; total reflections: 14335; unique re-
flections: 5764; observed: 4714 [I>2s(I)]; parameters re-
fined: 331; R1=0.0473, wR2=0.1208; GOF=1.042;
H
atoms bound to oxygen were refined, the positions of the H
atoms bound to carbon were calculated. CCDC 865225 con-
tains 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.a-
c.uk/data_request/cif.
BIFOP-Br (3)
To a solution of 1.05 g (2.3 mmol) P-BIFOL 2 in 10 mL abs-
solute THF, 2.81 mL (3 mmol) tert-butyllithium in hexanes
(1.6M,) were added slowly at À208C. The mixture was
stirred for 30 min, at À208C then for 1 h at room tempera-
ture. After recooling to À208C 0.3 mL (2.3 mmol) of freshly
distilled PBr3 were added slowly and the reaction mixture
was stirred for 48 h at room temperature. Purification by
flash chromatography (cyclohexane/Et2O, 4:1) and recrystal-
lization from Et2O/CH2Cl2 furnished compound 3 as colour-
BIFOP-Me (6)
To a solution of 0.5 g (1.1 mmol) P-BIFOP-Cl 2 in 10 mL
MTBE, 1.1 mL (1.1 mmol) methyllithium in hexanes were
added slowly. The mixture was refluxed for 12 h, then the
solvent was removed under vacuum. The residue was taken
up in 10 mL of toluene, the suspension was stirred for 1 h
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Roberto Blanco Trillo et al.
FULL PAPERS
and then LiCl was filtered off through celite. The product 6
was obtained after crystallization in diethyl ether forming
colourless needles; yield: 0.37 g, (0.9 mmol, 65%); mp
1.029; H atoms bound to oxygen were refined, the positions
of the H atoms bound to carbon were calculated. CCDC
865224 contains the supplementary crystallographic 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.
135.88C; [a]2D0: 55.36 (4.5M in hexane). 31P NMR
1
(125.5 MHz, CDCl3): d=158.4 [2J
C
(300 MHz, CDCl3): d=0.81 (3H, s), 0.71 (6H, s), 1.11–0.97
(10H, m), 1.37–1.24 (4H, m), 1.71–1.56 (4H, m), 2.22–2.15
(2H, m), 2.39 (1H, d), 2.43 (1H, d), 2.85 (3H, d) 7.09–7.04
(2H, m), 7.15–7.11 (2H, m), 7.24 (1H, d), 7.28 (1H, t), 7.44
(2H, t), 7.51 (1H, d); 13C NMR (75 MHz, CDCl3): d=19.67,
21.22, 23.71, 30.05, 34.05, 42.53, 42.92, 45.29, 46.49, 49.20,
54.72, 61.36, 69.16, 71.21, 86.14, 91.36, 124.36, 124.77, 129.94,
133.22, 142.25, 146.38.
BIFOP-Anisole (13)
To a solution of 1.0 g (2.2 mmol) BIFOP-Cl 2 in 20 mL
hexane, 1.4 mL (1.9 mmol) Li-anisole [formed from anilsole
and tert-butyllithium in hexanes (1.6M, 3 mmol)] were
added slowly. The mixture was stirred for 5 h at room tem-
perature and then refluxed for 12 h. The solvent was re-
moved under vacuum. The residue was taken up in 20 mL
of toluene, the suspension was stirred for 1 h and then LiCl
was filtered off through celite. The product 13 was obtained
after crystallization in Et2O/CH2Cl2 forming colourless nee-
dles; yield: 0.21 g (0.4 mmol, 43%); mp 143.88C; [a]2D0:
À74.31 (4.5M in hexane). 31P NMR (125.5 MHz, CDCl3):
BIFOP-t-Bu (9)
To a solution of 0.5 g (1.1 mmol) BIFOP-Cl 2 in 10 mL
MTBE, 1.9 mL (1.1 mmol) tert-butyllithium in hexanes
(1.6M) were added slowly. The mixture was refluxed for
16 h, then the solvent was removed under vacuum. The resi-
due was taken up in 20 mL of toluene, the suspension was
stirred for 1 h and then LiCl was filtered off through celite.
The product 9 was obtained after crystallization in Et2O/
CH2Cl2 forming colourless needles; yield: 0.36 g, (0.9 mmol,
ACTHNUTRGNEUNG
d=154.3 [2J(P-H)=6.5 Hz]; 1H NMR (300 MHz, CDCl3):
d=0.00 (3H, s, CH3), 0.32 (3H, s, CH3), 0.67 (3H, s, CH3),
0.85 (3H, s), 1.13–1.41 (7H, m), 1.47 (3H, m), 1.56 (2H, m),
1.62 (2H, m), 2.26 (1H, d), 2.43 (1H, d), 2.50–2.70 (2H, m),
3.08 (0.H, s, OH), 6.71 (1H, dd, CHar), 6.85–6.94 (4H, m,
CHar), 6.99 (1H, t, CHar), 7.52 (1H, t, CHar), 7.64 (1H, t,
CHar); 13C NMR (75 MHz, CDCl3): d=19.54, 21.09, 22.48,
23.05, 23.49, 37.04, 36.21, 39.58, 45.34, 46.53, 48.29, 51.35,
53.85, 56.51, 123.96, 124.29, 124.60, 125.15, 126.70, 127.55,
128.66, 130.13, 131.39, 132.40, 134.51, 135.29, 137.63, 140.27,
143.02, 156.44.
76%); mp 139.98C; [a]D20: 69.53 (4.5M in hexane). 31P NMR
1
(CDCl3): d=174.2 [3J
C
CDCl3): d=0.85–0.74 (6H, m), 1.29–0.98 (12H ,m), 1.47–
1.40 (4H, m), 1.67–1.54 (8H, m), 1.84–1.78 (4H, m), 2.03
(3H,d), 4.86 (2H,d), 7.09–7.04 (2H,m), 7.15–7.11 (2H, m),
7.24 (1H, d), 7.28 (1H, d), 7.44 (1H, d), 7.47 (1H, d);
13C NMR (CDCl3): d=13.61, 20.61, 21.37, 22.05, 22.37,
22.59, 23.43, 23.65, 26.88, 27.29, 27.64, 28,39, 29.63, 33.27,
38.72, 42.68, 45.10, 45.42, 49.43, 51.25, 52.25, 63.26, 106.10,
123.940, 124.16, 124.88, 125.04, 132.87, 133.01, 133.16,
133.68, 136.43, 145.83, 160.62.
BIFOP-O-t-Bu (15)
To a solution of 1.0 g BIFOP-Cl 2 (1.9 mmol) in 20 mL
hexane, 1.4 mL (1.9 mmol) Li-anisole [formed from anilsole
and tert-butyllithium in hexanes (1.6M, 3 mmol)] were
added slowly. The mixture was stirred for 5 days at 1008C
and then refluxed for 12 h. The solvent was removed under
vacuum. The residue was taken up in 20 mL of toluene, the
suspension was stirred for 1 h and then LiCl was filtered off
through celite. The product 15 was obtained after crystalliza-
tion in diethyl ether forming colourless needles; yield:
BIFOP-Ph (10)
To a solution of 0.5 g (1.1 mmol) BIFOP-Cl 2 in 10 mL
MTBE, 0.8 mL (1.5 mmol) phenyllithium in diethyl ether
(2.0M,) were added slowly. The mixture was refluxed for
12 h, then the solvent was removed under vacuum. The resi-
due was taken up in 20 mL of toluene, the suspension was
stirred for 1 h and then LiCl was filtered off through celite.
The product 10 was obtained after crystallization in diethyl
ether forming colorless needles; yield: 0.30 g (0.4 mmol,
40%); mp: 144.88C; [a]2D0: À59.66 (4.5M in hexane).
0.763 g (74%). 31P NMR (125.5 MHz, CDCl3): d=176.2 [2J-
1
N
0.64 (1H, m), 0.83 (3H, s), 0.94–0.92 (4H, m), 1.02–0.99
(4H, m), 1.08 (3H, s), 1.51–1.20 (8H, m), 1.80–1.62 (3H, m),
2.00–1.90 (1H, m), 2.20–2.14 (1H, m), 2.55–2.28 (2H, m),
31P NMR (125.5 MHz, CDCl3): d=139.9 [2J
ACHTNUTRGNEUNG(P-H)=11.4 Hz];
1H NMR (300 MHz, CDCl3): d=0.31 (2H, s), 0.41 (3H, s),
0.61 (3H, s), 0.65 (3H, s), 0.79 (3H, s), 0.79 (3H, s),0.86
(1H, m), 1.12–1.47 (8H, m), 1.61 (2H, m), 1.79 (3H, m),
2.03 (1H, m), 2.10 (1H, d), 2.50 (1H, d), 6.99 (1H, d), 7.06
(1H, dd), 7.10–7.24 (5H, m), 7.36 (1H, m), 7.70 (2H, m);
13C NMR (75 MHz, CDCl3): d=20.04, 20.59, 22.48, 23.65,
23.84, 36.04, 36.21, 37.66, 45.24, 45.93, 49.09, 50.05, 53.45,
54.84, 123.96, 124.29, 124.60, 125.15, 126.70, 128.70, 129.06,
130.13, 131.32, 133.80, 134.51, 135.29, 135.97, 144.27, 144.42,
2.79ACTHNUGRTENNUG(1H, d), 7.08–7.00ACHTUGNTREN(NUGN 3H, m), 7.32–7.15 (6H, m), 7.56 (1H,
d), 7.67 (1H, d), 8.42 (1H, d); 13C NMR (75 MHz, CDCl3):
d=15.30, 16.07, 18.22, 22.36, 23.17, 23.97, 24.15, 25.40, 26.44,
26.46, 33.03, 36.01, 38.37, 42.35, 42.49, 44.13, 48.81, 49.54,
52.12, 53.71, 123.84, 123.96, 124.38, 125.28, 125.84, 126.54,
129.37, 131.87, 133.03, 133.44, 133.69, 134.39, 135.16, 137.59,
143.17, 143.89.
Benfop-Me (17)
146.44. X-ray crystal data: C38H45O2P1; Mr =564.71 gmolÀ1
space group: P212121; a=11.5272(3), b=13.2225(3), c=
;
To a solution of 1.0 g (3.04 mmol) benzylfenchol in 10 mL
THF at À788C 4.2 mL (3.7 mmol) n-butyllithium in hexanes
(1.6M) were added slowly. The mixture was stirred for
30 min at À788C then for 1 h at room temperature. After re-
cooling to 08C 0.3 mL (2.3 mmol) of freshly distilled PCl3
19.9847(6) ꢂ; V=3046.04(14) ꢂ3; Z=4; 1=1.231 gmLÀ3
;
T=100(2) K; l=0.71073; m=0.123 mmÀ1; total reflections:
20541; unique reflections: 6639; observed: 5577 [I>2s(I)];
parameters refined: 376; R1=0.0393, wR2=0.0878; GOF=
1462
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Adv. Synth. Catal. 2012, 354, 1451 – 1465

Electronegativity Governs Enantioselectivity: Alkyl-Aryl Cross-Coupling
were added slowly and the reaction mixture was stirred for
16 h at room temperature. After cooling the mixture again
to À788C 2.4 mL (4.6 mmol, 1.2 equiv.) methyllithium (2M)
were added dropwise. The solvent was removed under
vacuum, the residue was taken up in 8 mL n-hexane and this
mixture was stirred for 1 h. Filtration through celite to
remove LiCl furnished compound 17 as a yellow oil 60 mg;
yield: 0.86 mmol (5%); [a]2D0: À28.85 (4.5M in hexane).
6.68 (1H, d), 7.06 (1H, t), 7.30–7.34 (2H, m), 7.38 (1H, t),
7.63 (1H, d); 13C NMR (150 MHz, CDCl3): d=19.28, 23.34,
23.90, 28.11, 28.66, 29.79, 36.38, 45.28, 45.44, 48.62, 48.85,
50.39, 52.00, 53.40, 74.93, 106.24, 124.81, 126.91, 128.53,
128.64, 133.73, 137.73, 140.83, 141.96.
BIFOP-Cl-Palladium Allylate (22)
31P NMR (125.5 MHz, CDCl3): d=139.2 [2J
ACHTNUTRGNEUNG(P-H)=10.0 Hz];
39.2 mg
(0.075 mmol)
BIFOP-Cl
2
and
13.8 mg
1H NMR (300 MHz, CDCl3): d=0.50 (3H, s, CH3), 1.20
(3H, s, CH3), 1.29 (12H, s, 4CH3), 1.37 (1H, dd, 3J=1.5,
1.2 Hz, CH), 1.52–1.44 (1H, m, CH), 1.77–1.69 (3H, m, CH,
CH2), 2.20–2.10 (1H, m, CH), 2.43–2.39 (2H, m, CH2), 6.99–
6.93 (1H, t, Har), 7.19–7.13 (1H, t, Har), 7.50 u. 7.48 (1H, dd,
3J=1.2, 1.5 Hz, Har), 7.19–7.13 (1H, t, Har), 8.34 u. 8.31 (1H,
(0.038 mmol) allylpalladium chloride dimer were stirred in
3 mL toluene and heated at 1008C for 5 h. A yellow solid
precipitated from solution. The solid was washed with Et2O
and then dried under vacuum. Recrystallization from
CH2Cl2 gave 22 as a yellow solid; yield: 51 mg (0.068 mmol).
1
31P NMR (251 MHz, CDCl3): d=138.0 and 137.3; H NMR
3
dd, J=1.5, 1.2 Hz, Har), 10.43 (1H, br. s, NH); 13C NMR
(600 MHz, CDCl3): d=0.07 (3H, s, CH3), 0.42 (3H, s, CH3),
0.73 (3H, s, CH3), 0.95 (3H, s, CH3), 1.29 (2H, s, CH2), 1.53
(3H, m), 1.61 (5H, m), 1.68–1.78 (6H, m), 2.49 (1H, d,
allyl), .3.41 (1H, d, allyl), 4.50 (1H, s, allyl), 6.68 (1H, d),
7.06 (1H, t), 7.30–7.34 (2H, m), 7.38 (1H, t), 7.63 (1H, d);
13C NMR (150 MHz, CDCl3): d=19.48, 21.61, 23.10, 24.18,
28.03, 28.59, 28.39, 37.39, 42.54, 48.68, 50.32, 52.24, 63.18,
125.36, 126.29, 127.22, 128.30, 128.49, 128.84, 129.10, 129.78,
131.02, 133.90 137.39, 141.19, 142.92.
(75 MHz, CDCl3): d=15.54, 17.72, 23.04, 25.26, 29.46, 30.69,
41.57, 46.49, 48.68, 52.58, 54, 87.57, 121, 122.76, 126.91, 128,
131, 139.30, 176.65; IR: n=3322 (m); 2961 (s); 1650 (s);
1579 (s); 1519 (m); 1438 (m); 1307 (m); 1046 (w); 913 (w);
795 (m); 615 cmÀ1 (m).
BenfoP-Ph (18)
To a solution of 1.0 g (3.04 mmol) benzylfenchol in 10 mL
THF at À788C 4.2 mL (3.7 mmol) n-butyllithium in hexanes
(1.6M) were added slowly. The mixture was stirred for
30 min at À788C then for 1 h at room temperature. After re-
cooling to 08C 0.3 mL (2.3 mmol) of freshly distilled PCl3
were added slowly and the reaction mixture was stirred for
16 h at room temperature. After cooling the mixture again
to À788C 2.4 mL (4.6 mmol, 1.2 equiv.) phenyllithium (2M)
were added dropwise. The solvent was removed under
vacuum, the residue was taken up in 8 mL n-hexane and this
mixture was stirred for 1 h. Filtration through celite to
remove LiCl furnished compound 18 as a yellow oil; yield:
71 mg (0.93 mmol, 8%); [a]2D0: À35.38 (4.5M in hexane).
31P NMR (125.5 MHz, CDCl3): d=129.0; 1H NMR
(300 MHz, CDCl3): d=0.74 (3H, s, CH3), 0.82 (3H, s, CH3),
BIFOP-Br-Palladium Allylate (23)
42.6 mg (0.075 mmol) BIFOP-Br
3
and 13.8 mg
(0.038 mmol) allylpalladium chloride dimer were stirred in
3 mL toluene and heated at 1008C for 5 h. A yellow solid
precipitated from solution. The solid was washed with Et2O
and then dried under vacuum. Recrystallization from
CH2Cl2 gave 23 as
a
yellow solid; yield: 38.5 mg
(0.055 mmol). 31P NMR (251 MHz, CDCl3): d=119.9 and
119.3; 1H NMR (600 MHz, CDCl3): d=0.08 (3H, s, CH3),
0.44 (3H, s, CH3), 0.77 (3H, s, CH3), 0.99 (3H, s, CH3), 1.23
(2H, s, CH2), 1.41 (3H, m), 1.49 (2H, m), 1.63 (3H, m),
1.71–1.82 (6H, m), 2.52 (1H, d, allyl), 3.49 (1H, d, allyl),
4.49 (1H, s, allyl), 6.73 (1H, d), 7.09 (1H, t), 7.32–7.36 (2H,
m), 7.39 (1H, t), 7.67 (1H, d); 13C NMR (150 MHz, CDCl3):
d=19.40, 23.49, 23.97, 28.28, 28.79, 29.84, 36.46, 45.32, 45.60,
48.49, 48.97, 50.60, 51.99, 53.53, 74.01, 106.41, 124.97, 127.10,
128.74, 128.80, 133.92, 137.88, 140.95, 142.18.
3
1.09 (3H, s, CH3), 1.91 (1H, td, J=1.5, 1.2 Hz, CH), 1.20
(2H, d), 1.32 (1H, m), 1.54 (1H, d), 1.79 (1H, d), 1.92 (2H,
m), 4.97 (2H, dd), 7.25 (2H, m), 7.37 (2H, m); 13C NMR
(75 MHz, CDCl3): d=17.76, 23.07, 25.24, 29.47, 30.63, 41.54,
46.13, 48.61, 52.54, 71.60, 98.86, 120.58, 125.17, 125.83,
126.65, 128.47, 128.72, 133.64, 133.9, 140.5, 141.7; IR: n=
2956 (m), 2926 (s), 2870 (m), 2843 (w), 1458 (s), 1435 (s),
1519 (m), 1438 (m), 1112 (m), 1056 (s), 1026 (m), 1010 (w),
956 (w), 748 (s), 719 (w), 696 cmÀ1 (m).
Asymmetric Synthesis of (S)-1,3-Dimethyl-3-
phenylindolin-2-one (20)
PdACTHNUGTRNE(NUG allyl)Cl]2 (5 mol%), ligand (10 mol%), NaO-t-Bu (43 mg,
0.45 mmol, 3 equiv.) and the starting material (0.3 mmol)
were combined with 3 mL toluene and stirred at 1008C until
all starting material was consumed (GC/MS). After comple-
tion the mixture was filtered through a short plug of silica,
diluted with 50 mL EtOAc and the solvents were evaporat-
ed. The crude material was dissolved in a small amount of
CH2Cl2, adsorbed on silica and purified by flash chromatog-
raphy (silica, pentane/EtOAc=10:1) as a pale oil; Rf (pen-
tane/EtOAc, 5:1): 0.26. 1H NMR (300 MHz, CDCl3): d=
1.81 (s, 3H), 3.25 (s, 3H), 6.93 (d, J=7.8 Hz, 1H), 7.11 (dt,
J=7.5 Hz, J=1.0 Hz, 1H), 7.19–7.36 (m, 7H); 13C NMR
(75 MHz, CDCl3): d=23.7, 26.4, 52.1, 108.2, 122.7, 124.1,
126.6, 127.1, 128.0, 128.4, 134.7, 140.7, 143.2, 179.3; GC-MS
(method 50–300M): tR =9.31 min; MS-EI: m/z (%)=237
(96), 222 (100), 207 (12), 194 (20), 165 (12), 152 (9); ESI-
BIFOP-F-Palladium Allylate (21)
38.0 mg (0.075 mmol) BIFOP-F 5 and 13.8 mg (0.038 mmol)
allylpalladium chloride dimer were stirred in 3 mL toluene
and heated at 1008C for 5 h. A yellow solid precipitated
from the solution. The solid was washed with Et2O and then
dried under vacuum. Recrystallization from CH2Cl2 gave 21
as a yellow solid; yield: 36.0 mg (0.052 mmol). 31P NMR
(251 MHz, CDCl3): d=118.1 and 117.0 [1J
ACTHNUTRGNE(NUG P-F)=
À1240 Hz]; 19F (546.8 MHz, CDCl3): d=À40.0; 1H NMR
(600 MHz, CDCl3): d=0.06 (3H, s, CH3), 0.40 (3H, s, CH3),
0.70 (3H, s, CH3), 0.93 (3H, s, CH3), 1.25 (2H, s, CH2), 1.39
(3H, m), 1.47 (2H, m), 1.57 (3H, m), 1.62–1.70 (6H, m),
2.45 (1H, d, allyl), .3.37 (1H, d, allyl), 4.43 (1H, s, allyl),
Adv. Synth. Catal. 2012, 354, 1451 – 1465
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1463

Roberto Blanco Trillo et al.
FULL PAPERS
MS: m/z=260.1040, calcd. for [C16H15NONa]+: 260.1046.
The enantiomeric excess was determined by HPLC analysis
with a chiral column (Chiral Diacel OD-H; 25 cmꢄ0.46 cm;
hexane/i-PrOH=98/2, UV-vis: l=254 nm). The analysis
gave two separate peaks (flow rate: 1.0 mLminÀ1): tr =
12.86 min [S(À)-20a], 15.36 min [R(+)-20b].
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Acknowledgements
We are grateful to the Fonds der Chemischen Industrie for fi-
nancial support. We also thank the Deutsche Forschungsge-
meinschaft (DFG) for funding as well as Bayer AG, BASF
AG, Wacker AG, Evonic AG, Raschig GmbH, Symrise
GmbH, Solvay GmbH and the OMG group for generous
support. We thank the Regionales Rechenzentrum zu Kçln
(RRZK), especially Dr. Lars Packschies, for the maintenance
of the HPLC systems and Prof. Dr. Luigi Cavallo for the fast
addition of the Br parameters to the SambVca database.
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1465