Synthesis, properties and applications of BICAP: A new family of carbazole-based diphosphine ligands

Article abstract of DOI:10.1002/adsc.200303241

A new family of bidentate phosphine ligands based on the biscarbazole backbone has been synthesized and applied in the ruthenium- and rhodium-catalyzed asymmetric hydrogenations of methyl acetoacetate and dimethyl itaconate. The nitrogen atoms in these BICAP ligands allow facile introduction of substituents providing structurally similar, but electronically different ligands, which were used to fine-tune these reactions to 98% and 55% ee, respectively.

Full text of DOI:10.1002/adsc.200303241

FULL PAPERS
Synthesis, Properties and Applications of BICAP: a New Family
of Carbazole-Based Diphosphine Ligands
¬
Peter N. M. Botman, Jan Fraanje, Kees Goubitz, Rene Peschar, Jan W. Verhoeven,
Jan H. van Maarseveen, HenkHiemstra*
Van×t Hoff Institute of Molecular Sciences, University of Amsterdam, Nieuwe Achtergracht 129,
1018 WS Amsterdam, The Netherlands
Fax: (þ31)-20-525-5670, e-mail: hiemstra@science.uva.nl
Received: December 23, 2003; Accepted: March 30, 2004
Dedicated to Joe P. Richmond on the occasion of his 60th birthday.
Abstract: A new family of bidentate phosphine li- but electronically different ligands, which were used
gands based on the biscarbazole backbone has been to fine-tune these reactions to 98% and 55% ee, re-
synthesized and applied in the ruthenium- and rhodi- spectively.
um-catalyzed asymmetric hydrogenations of methyl
acetoacetate and dimethyl itaconate. The nitrogen
atoms in these BICAP ligands allow facile introduc- Keywords: asymmetric catalysis; atropisomerism;
tion of substituents providing structurally similar, enantioselectivity; hydrogenation; P ligands
Introduction
Since the introduction of BINAP 1 by Noyori,[1] the field
of asymmetric homogenous catalysis has been enriched
with a multitude of different C2-symmetric biaryl li-
gands.[2] The large structural variety of these ligands is
mainly responsible for the high level of sophistication
this area has reached nowadays.[3] The optimization,
however, of the many transition metal-catalyzed asym-
metric transformations is still often a matter of trial
and error because small changes in the geometric, steric,
and electronic properties of the ligands can have dra-
matic effects on the outcome of the reactions.
To circumvent the often laborious syntheses of ligand
analogues for fine-tuning catalysis, the availability of a
biaryl scaffold in which diversity can be easily intro-
duced in the last synthesis step would be desirable. Sev-
eral approaches in this direction have been published
over the years. An obvious approach is variation of the
phosphine substituents on a known biaryl backbone.[4] an moiety is the high regioselectivity in the sulfonation
Another striking example are the Tunaphos ligands 2, of BIFAP to give the water-soluble analogue BIFAPS
developed by Zhang and co-workers.[5] This set of biar- 4 in 98%, due to the para-directing furan oxygen. A sim-
yl-type bidentate ligands, in which the bite angle can ilar selectivity in electrophilic substitutions may be ex-
be altered by connection of the atropisomeric parts via pected when the backbone is constructed from two car-
a bridging tether with variable length, proved to be use- bazole moieties. The BICAP ligands 5 thus obtained can
ful for a systematic study of transition metal-catalyzed be further functionalized using the carbazole nitrogen.
asymmetric reactions.
We envisaged that the parent BICAP 5a is a versatile
Our studies towards a more widely applicable skele- synthon to synthesize a new set of ligands in a facile
ton led to the development of the BIFAP diphosphine way, with the same steric environment but with a differ-
ligand 3 in 1999.[6] An advantage of using the dibenzofur- ent electronic behaviour. In this way asymmetric cata-
Adv. Synth. Catal. 2004, 346, 743 754
DOI: 10.1002/adsc.200303241
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Peter N. M. Botman et al.
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lytic reactions can be optimized by using different li-
gands which all originate from a single backbone.
Results and Discussion
Synthesis of Diphosphine Ligands
Scheme 1. Synthesis of BIFAP using HPPh2.
The diphosphine BICAP 5a was prepared from the diol
BICOL 6. We recently published the synthesis and reso-
lution of this latter configurationally stable diol, which our satisfaction, treatment of BIFOL-derived dinona-
can be performed on a multigram scale.[7] Our first at- flate 10 with diphenylphosphine in the presence of
tempts to convert BICOL 6 into BICAP 5a proceeded Pd(OAc)2/dppe and DABCO yielded BIFAP in one
via the corresponding dinonaflate in order to apply a step in a 35% yield (Scheme 1). This procedure simpli-
transition metal-catalyzed cross-coupling reaction for fied the synthesis of BIFAP dramatically compared to
the introduction of the diphenylphosphine moieties.[8a]
The cross-coupling reactions were tested in model
our earlier work.[6]
Diastereomerically pure 11, obtained in the resolution
nonaflates 7a c, which were synthesized from commer- of BICOL,[7] was used for the synthesis of dinonaflate 12
cially available 2-hydroxydibenzofuran and readily pre- (Scheme 2). This N-tosyl protected precursor for the
pared 3-hydroxycarbazole.[9] The most promising results phosphination reactions was obtained after a three-
for the synthesis of phosphines 8a c were obtained us-
[8b]
ing the combination of Ni(dppe)Cl2
or Pd(OAc)2/
dppe with HPPh2 as nucleophile and DABCO as base
(Table 1). The dibenzofuran-derived phosphine 8a
could be isolated in high yield by applying both methods
(entries 1 and 2). The synthesis of the carbazole-derived
phosphine proved to be more problematic (entry 3). The
use of a different phosphine source, such as HPPh2 ¥
[8c]
BH3
or the combination of ClPPh2 and metallic
zinc,[8d] gave no improvement. Protection of the carba-
zole nitrogen as a tosylate proved to be important for
the yield of the reactions (entries 4 and 5).
We then went on to extend the positive results of the
monomeric substrates to the dimeric cases. Much to
Table 1. Cross-coupling reactions using HPPh2.
[a]
For details, see Experimental Section.
All products isolated as phosphine oxide after treatment
[b]
with H2O2.
[c]
Substantial amounts of NH-carbazole were obtained.
The reduced (3H)-carbazole was also isolated in 22%
[d]
yield.
Scheme 2. Synthesis of Ts-BICAP.
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Synthesis, Properties and Applications of BICAP
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step sequence involving N-tosylation of 11, reductive re- Characterization and Properties of the BICAP
moval of the chiral menthol auxiliary using LiAlH4, fol- Ligands
lowed by sulfonylation of the bisphenol using F-SO2C4F9
and Et3N. In contrast to BIFAP 3, all attempts to synthe- The electronic differences of the BICAP ligands seemed
size Ts-BICAP 5b in one step from 12 by the use of a pal- to be reflected in the 31P NMR data (Table 2). The signal
ladium- or nickel-catalyzed cross-coupling with HPPh2 ranged from À14.0 ppm for the most electron-poor Nf-
failed.
BICAP 5c to À17.9 ppm for the most electron-rich Me-
For the synthesis of BICAP we then relied on a step- BICAP 5d.
wise procedure involving the successive introduction
The electron-deficient (S)-Nf-BICAP showed re-
of two diphenylphosphine oxide moieties with a reduc- markably complex NMR spectra, indicating slow dy-
tion step in between.[10] The first diphenylphosphine ox- namic processes on the NMR timescale. Increasing the
ide group could be successfully introduced in 12 by the temperature during the measurements clearly sharp-
use of Pd(OAc)2 and dppb to produce 13 followed by re- ened the signals, although even at 1508C the signals
duction to the phosphine by stirring the substrate in phe- were still not as sharp as the signals obtained in the
nylsilane at a temperature of 1148C in an excellent over- NMR spectra of the other BICAP members. As the phe-
all yield of 94% (Scheme 2). At higher temperatures nomenon was only observed with Nf-BICAP 5c, model
considerable over-reduction to 16 was observed. The in- substrate 17 (Figure 1) was synthesized from (Æ)-BI-
troduction of the second phosphine was carried out us- COL in order to investigate the behaviour in more de-
ing the same sequence to give (S)-Ts-BICAP 5b. The tail.
1
formation of by-product 16 in the second cross-coupling
could not be avoided completely.
The H NMR spectrum of a symmetric bicarbazole
skeleton normally shows six signals, which belong to
To allow diversification of the BICAP backbone the the six pairs of equivalent protons. The 1H NMR of tet-
tosyl groups were removed from 5b by treatment with ratriflate 17 showed the same splitting pattern as ob-
KOH in MeOH.[11] The resulting parent BICAP 5a served for Nf-BICAP. Every signal seemed to be split
([a]2D0: À147 (c 0.49), mp 328 3298C) proved to be an into four; one large signal, two smaller signals of the
ideal precursor for the direct synthesis of a series of an- same intensity and one even smaller signal. The ratio
alogues by alkylation of the nitrogen atoms with several is fixed at roughly 1:0.4:0.4:0.1 (Figure 1a, proton 1).
1
different electrophiles (Scheme 3). Treating BICAP When the H NMR spectrum was measured at higher
with NaH and methyl iodide, for example, yielded the temperatures (Figure 1b e), coalescence was reached
electron-rich Me-BICAP 5d in 71% yield. Treating 5a (T¼708C). Further heating sharpened the signals to
with NaH and F-Nf, on the other hand, yielded the elec- the ™normal∫ six doublets and triplets (T¼1008C).
tron-deficient Nf-BICAP 5c (75% yield). Finally, TBS-
The origin of this fluxional behaviour had to be in the
Cl in combination with NaH provided TBS-BICAP 5e sulfonamide part of the molecules. The X-ray crystal
in a yield of 65%. In this way a series of ligands was ob- structure of 17 (Figure 2) showed that the bonds at the
tained which are sterically alike, but feature different nitrogen atom are in the same plane as the planar carba-
electronic properties of the phosphine groups.
zole moiety. This planarity ruled out an inversion of pyr-
amidal nitrogen and so a hindered rotation about the
À
N S bond is suggested as the cause of the multiplicity
of the NMR spectra.[12] The strongly electron-withdraw-
ing character of the fluorinated groups apparently in-
À
creases the double-bond character of the N S bond
causing a higher rotational barrier. The hindered rota-
tion of the sulfonamide is most likely enhanced by the
two ortho-hydrogens of the carbazole. The bulky CF3
Table 2. 31P NMR data of the BICAP family.
[a]
Measured in CDCl3.
Major signal.
[b]
Scheme 3. Creation of the BICAP family.
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Peter N. M. Botman et al.
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group will position above or below the carbazole plane.
Due to steric hindrance, the C2-symmetric backbone di-
vides the two possible orientations of the CF3 group into
a favoured exo position (the tail is pointing away from
the other carbazole moiety) and an unfavoured endo po-
sition (the CF3 group points towards the other carbazole
moiety). The observed four isomers in the NMR spectra
are thus:
The most abundant species has the two CF3 groups
pointing in the exo-direction just like the situation
found in the solid state (Figure 2). This implies C2 sym-
metry resulting in a single signal for H1.
The least abundant isomer has both CF3 groups in an
endo position, which again implies C2 symmetry.
In the third isomer one CF3 is exo and the other endo.
This implies loss of symmetry and as a result for H1
two signals of equal intensity are found.
To ascertain the structure of the ligands and in order to
compare the structural features of BICAP with BIFAP 3
and BINAP 1, the crystal structures of both (S)-Me-BI-
CAP 5d and ((S)-Me-BICAP)PdCl2 18 were deter-
mined by X-ray diffraction (Figures 3 and 4, respective-
ly). Close examination led to the conclusion that BIFAP
and Me-BICAP have similar geometries reflecting the
À
central C C bonds (1.512 ä and 1.511 ä, respectively)
À
and the P P distances (3.891 ä and 4.139 ä, respective-
ly). Slightly different are the dihedral angles between
the two planar moieties in the biaryls: 81.48 for the angle
of the dibenzofuran units in BIFAP and 88.58 for the an-
gle between the two carbazole parts. In both ligands the
two phenyl rings at each phosphorus atom are non-
equivalent as usual.
Because the crystal structures of the BINAP[13] and
BIFAP[6] palladium dichloride complexes are known,
they can be compared to 18. In all three complexes the
palladium atom adopts a distorted square-planar coor-
Figure 1. 1H NMR spectra of 17 at different temperatures (in
DMF-d7).
Figure 3. ORTEP drawing of the crystal structure of (S)-Me-
BICAP 5d.
Figure 2. ORTEP drawing of the crystal structure of 17.
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acetoacetate 21 (Table 3).[15] This ruthenium-catalyzed
reaction was carried out in a stainless steel autoclave, us-
ing methanol as the solvent at a hydrogen pressure of
100 bar. The behaviour of the BICAP family proved to
be comparable with those of BINAP and BIFAP[6] (en-
tries 5 and 6). The conversions and the stereochemical
outcome of the hydrogenations proved to be excellent
and the absolute configuration of products 22 was the
same for all reactions. We observed a small but signifi-
cant drop in the enantiomeric excess when using the
more electron-rich H-BICAP and Me-BICAP (entries 3
and 4).
To study the behaviour of the BICAP ligands in more
detail we searched for an asymmetric hydrogenation in
which the product was expected to be obtained with
Figure 4. ORTEP drawing of the crystal structure of [(S)-Me- high conversions, but with lower ees. Dimethyl itaconate
BICAP]PdCl2 18.
(23) was found to be a suitable substrate for this pur-
pose.[16] The rhodium-catalyzed hydrogenations of this
olefin provided succinate 24 in quantitative yields
À
dination, with central C C bond lengths of the two when applying any of the BICAP members, but the
connecting carbon atoms of 1.484 ä (18), 1.48 ä enantioselectivities differed dramatically (Table 4).
[(BINAP)PdCl2] and 1.499 ä [(BIFAP)PdCl2]. The When the most electron-deficient Nf-BICAP was
À
À
P1 Pd P2 bite angle in complex 18 (92.2058) is similar used, there was hardly any asymmetric induction (en-
to those of (BINAP)PdCl2 (92.698) and (BIFAP)PdCl2 try 1). The ee increased for the more electron-rich Ts-
(94.398). The last observation from the crystal structures BICAP, TBS-BICAP and H-BICAP (entries 2 4) and
is that the free Me-BICAP ligand has to squeeze more the highest ee was obtained with the most electron-
than the free BIFAP ligand in order to chelate to the pal- rich Me-BICAP (entry 5). The 55% ee of this last reac-
ladium. The torsion angles decreases from 88.58 in Me- tion is close to the result found for BINAP (entry 6).
BICAP to 71.68 in 18, compared to a change from 81.4
in BIFAP to 73.4 in (BIFAP)PdCl2.
Thus, for the hydrogenation of methyl acetoacetate
(21) a more electron-deficient BICAP-catalyst is desira-
Before testing the ligands in asymmetric hydrogena- ble, while the more electron-rich BICAP-catalysts per-
tions, the enantiopurity of the ligands was checked by form better in the hydrogenation of dimethyl itaconate
examination of the 31P NMR spectra of the diastereo- (23). The changes in stereocontrol are most likely
meric complexes 20, obtained after the reaction be- caused by variations in the coordination strengths of
tween the enantiopure palladium dimer 19 and the li- the different BICAP/metal complexes to the substrate,
gands[14] (Scheme 4). All spectra showed only two sets influencing the outcome of the reactions.
of doublets, indicating that the enantiopurity of the
backbone is retained in the reaction sequence from BI-
COL to BICAP.
Table 3. Asymmetric hydrogenation of methyl acetoacetate.
Asymmetric Hydrogenations with the BICAP Family
The performance of the new BICAP family was first in-
vestigated in the asymmetric hydrogenation of methyl
[a]
Ratio substrate :Ru :ligand¼100: 0.1: 0.11.
[b]
[c]
1
Determined by H NMR.
Determined by chiral HPLC of the benzoyl ester.
Scheme 4. Checking the enantiopurity of the BICAP ligands.
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Peter N. M. Botman et al.
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Table 4. Asymmetric hydrogenation of dimethyl itaconate.
ian Inova-500 (202.4 MHz). Chemical shifts are given in ppm
downfield from external 85% H3PO4. Mass spectra were meas-
ured using a JEOL JMS SX/SX102A four-sector mass spec-
trometer, coupled to a JEOL MS-MP7000 data system. Melt-
ing points are uncorrected.
1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonic Acid
Dibenzofuran-2-yl Ester (7a)
To a solution of 2-hydroxydibenzofuran (2.50 g, 13.6 mmol) in
acetonitrile (70 mL) were added triethylamine (3.0 mL,
21.8 mmol) and FSO2C4F9 (3.66 mL, 20.4 mmol) and the reac-
tion mixture was stirred for 18 h at room temperature. The mix-
ture was diluted with EtOAc (150 mL) and the organic phase
was washed with aqueous 0.5 M NaHSO3 (2Â100 mL) and
brine (1Â75 mL). The organic layer was dried over Na2SO4
and concentrated under vacuum. Purification by column chro-
matography (PE:EtOAc¼5:1) afforded 7a as a white solid;
yield: 6.28 g (13.5 mmol, 99%); mp 73 748C; 1H NMR
(400 MHz): d¼7.96 (d, J¼7.7 Hz, 1H), 7.86 (d, J¼2.6 Hz,
1H), 7.60 (m, 2H), 7.53 (td, J¼7.2, 1.3 Hz, 1H), 7.35 7.41
(m, 2H); 13C NMR (100.6 MHz, due to C-F coupling the fluori-
nated carbons were not visible): d¼157.3, 154.7, 145.2, 128.5,
125.6, 123.3, 123.2, 121.1, 120.0, 113.7, 112.8, 112.0. IR: n¼
1472, 1445, 1428, 1201, 1143, 1034, 912 cmÀ1. HRMS (FABþ):
calcd. for C16F9H8O4S (MþHþ): 467.0000; found: 466.9991.
[a]
Ratio substrate :Rh :ligand¼100: 1: 1.1.
[b]
[c]
1
Determined by H NMR.
Determined by chiral GC.
Conclusions
Enantiopure BICOL can be transformed into a new
family of C2-symmetric bicarbazole-based diphosphine
ligands abbreviated as BICAP. The nitrogen of these li-
gands serves asan ideal handle for the introduction of di-
versity. Thus, BICAP proves to be an excellent scaffold
for the synthesis of a variety of biaryl ligands, which are
sterically alike, but differ in their electronic properties
with respect to the electron density on phosphorus.
This provides an opportunity for the fine-tuning of cata-
lytic asymmetric reactions as has been shown for the
asymmetric hydrogenations of methyl acetoacetate
and an itaconic acid derivative.
1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonic Acid 9-
(Nonafluorobutane-1-sulfonyl)-9H-carbazol-3-yl Ester
(7b)
To a solution of 3-hydroxycarbazole (0.70 g, 3.82 mmol) in ace-
tonitrile (38 mL) were added triethylamine (1.60 mL,
11.5 mmol) and FSO2C4F9 (2.74 mL, 15.3 mmol) and the reac-
tion mixture was stirred for 18 h at room temperature. By add-
ing Et2O (150 mL) the formed precipitate was dissolved and
the organic phase was washed with aqueous 0.5 M NaHSO3
(2Â75 mL) and brine (1Â75 mL). The organic layer was dried
over Na2SO4 and concentrated under vacuum. Purification by
column chromatography (PE:EtOAc¼5:1) afforded 7b as a
white solid; yield: 2.86 g (3.78 mmol, 99%); mp 91 928C;
1H NMR (400 MHz): d¼8.19 (d, J¼9.2 Hz, 1H), 8.13 (d, J¼
8.4 Hz, 1H), 8.02 (d, J¼7.1 Hz, 1H), 7.91 (d, J¼2.5 Hz, 1H),
7.61 (td, J¼7.4, 1.3 Hz, 1H), 7.53 (td, J¼7.7, 0.8 Hz, 1H),
7.42 (dd, J¼9.2, 2.5 Hz, 1H); 13C NMR (125 MHz, due to C-
F coupling the fluorinated carbons were not visible): d¼
147.1, 138.9, 136.9, 129.4, 128.0, 125.9, 125.0, 120.8, 120.7,
116.5, 115.2, 113.4; IR: n¼2815, 1479, 1422, 1353, 1201, 1144,
916, 871, 813 cmÀ1. HRMS (FABþ): calcd. for C20F18H8NO5S2
(MþHþ): 747.9556; found: 747.9551.
Experimental Section
General Information
Unless otherwise noted, materials were purchased from com-
mercial suppliers and used without purification. Diphenyl-
phosphine was freshly distilled before use. Toluene, DMF,
DMSO, MeOH, dichloromethane and acetonitrile were fresh-
ly distilled from calcium hydride. Tetrahydrofuran was freshly
distilled from sodium with benzophenone as indicator. Tri-
ethylamine and DIPEAwere stored over potassium hydroxide
pellets and used as such. All air- and moisture-sensitive reac-
tions were carried out under an inert atmosphere of dry argon.
Column chromatography was performed using Aldrich silica
gel (70 230 mesh, 60 ä). Infrared spectra were recorded on
a Bruker IFS 28 spectrophotometer. H NMR and 13C NMR
1
1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonic Acid 9-
(Toluene-4-sulfonyl)-9H-carbazol-3-yl Ester (7c)
(APT) spectra were determined in CDCl3 (unless states other-
wise) on a Bruker ARX 400 (400 and 100.6 MHz, respectively)
or a Varian Inova-500 (500 and 125 MHz, respectively). Spec-
tra are reported in units of ppm on the d scale, relative to
chloroform (7.26 ppm for 1H NMR and 77.0 ppm for
13C NMR). 31P NMR spectra were recorded in CDCl3 (unless
states otherwise) on a Bruker 300 AMX (121.5 MHz) or a Var-
A solution of 3-hydroxycarbazole (0.25 g, 1.36 mmol) and tri-
ethylamine (0.21 mL, 1.50 mmol) in acetonitrile (13.6 mL)
was stirred for 10 min. at room temperature before adding
FSO2C4F9 (0.39 mL, 2.18 mmol). The mixture was stirred for
another 45 min. The reaction was quenched by addition of wa-
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Synthesis, Properties and Applications of BICAP
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ter (50 mL) and EtOAc (50 mL) and the organic phase was
washed with aqueous 0.5 M NaHSO3 (1Â35 mL) and brine
(1Â40 mL). The organic layer was dried over Na2SO4 and con-
centrated under vacuum. Purification by column chromatogra-
phy (PE:EtOAc¼2.5:1) afforded the mono-nonaflate as a
white solid; yield: 0.58 g (1.24 mmol, 92%); mp 116 1178C;
1H NMR (400 MHz): d¼8.20 (br. s, 1H), 8.07 (d, J¼7.6 Hz,
1H), 7.96 (d, J¼2.4 Hz, 1H), 7.43 7.51 (m, 3H), 7.27 7.34
(m, 2H); 13C NMR (100.6 MHz, acetone-d6, due to C-F cou-
pling the fluorinated carbons were not visible): d¼144.6,
140.6, 142.7, 128.5, 125.2, 124.0, 122.3, 121.1, 120.1, 114.7,
113.5, 113.0; IR: n¼3421, 1428, 1235, 1202, 1144, 1124, 1033,
908 cmÀ1; HRMS (FABþ): calcd. for C16F9H9NO3S (MþHþ):
466.0159; found: 466.0135.
2-(Diphenylphosphinoyl)-dibenzofuran (8a)
Compound 7a (0.15 g, 0.32 mmol) was reacted for 6 h accord-
ing to method A. Purification by column chromatography
(PE:EtOAc¼4:1) afforded 8a as a white solid; yield: 0.11 g
1
(0.30 mmol, 94%); mp 159 1608C; H NMR (400 MHz): d¼
8.40 (d, J¼12.1 Hz, 1H), 7.90 (d, J¼7.7 Hz, 1H), 7.54 7.73
(m, 9H), 7.46 7.50 (m, 5H), 7.34 (t, J¼7.5 Hz, 1H); 31P NMR
(121.5 MHz): d¼30.8; IR: n¼3054, 1469, 1437, 1189,
1117 cmÀ1; HRMS (FABþ): calcd. for C24H18O2P (MþHþ):
369.1044; found: 369.1049.
3-(Diphenylphosphinoyl)-9-(nonafluorobutane-1-
To a solution of the mono-nonaflate (2.75 g, 5.91 mmol) in
CH2Cl2 (30 mL) were added LiHMDS (7.8 mL of a 1 M solu-
tion in THF) and TsCl (1.69 g, 8.87 mmol). After stirring the
mixture for 48 h at room temperature, the reaction was
quenched by addition of water (150 mL) and CH2Cl2
(100 mL) and the organic phase was washed with aqueous
0.5 M NaHSO3 (1Â35 mL). The organic layer was dried over
Na2SO4 and concentrated under vacuum. Purification by col-
umn chromatography (PE:EtOAc¼12:1) afforded 7c as a
white solid; yield: 3.40 g (5.50 mmol, 93%); mp 111 1128C;
1H NMR (400 MHz): d¼8.39 (d, J¼9.1 Hz, 1H), 8.33 (d, J¼
8.4 Hz, 1H), 7.91 (d, J¼7.7 Hz, 1H), 7.80 (d, J¼2.5 Hz, 1H),
7.70 (d, J¼8.4 Hz, 2H), 7.56 (td, J¼7.4, 1.2 Hz, 1H), 7.37
7.43 (m, 2H), 7.15 (d, J¼8.2 Hz, 2H), 2.30 (s, 3H); 13C NMR
(100.6 MHz, due to C-F coupling the fluorinated carbons
were not visible): d¼146.0, 145.5, 139.1, 134.6, 129.9, 128.7,
127.6, 126.5, 125.0, 124.2, 120.5, 120.1, 116.3, 115.2, 112.9,
sulfonyl)-9H-carbazole (8b)
Compound 7b (0.15 g, 0.20 mmol) was reacted for 5 h accord-
ing to method A. Purification by column chromatography
(PE:EtOAc¼1:1!1:3) afforded 8b as a white solid; yield:
67 mg (0.10 mmol, 52%); mp 1538C; 1H NMR (400 MHz):
d¼8.53 (d, J¼11.5 Hz, 1H), 8.17 (dd, J¼8.6, 1.5 Hz, 1H),
8.10 (d, J¼8.4 Hz, 1H), 7.98 (d, J¼7.4 Hz, 1H), 7.44 7.75
(m, 13H); 31P NMR (121.5 MHz): d¼28.6; IR: n¼3417, 1713,
1410, 1353, 1195, 1143, 1120, 1033; HRMS (FABþ): calcd.
for C28H18F9NO3PS (MþHþ): 650.0601; found: 650.0602.
3-(Diphenylphosphinoyl)-9-(toluene-4-sulfonyl)-9H-
carbazole (8c)
Compound 7c (0.15 g, 0.24 mmol) was reacted for 5 h accord-
ing to method B. Purification by column chromatography
(PE:EtOAc¼1:2) afforded 8c as a white solid; yield: 117 mg
21.5. IR: n¼3105, 1476, 1426, 1377, 1202, 1144, 909, 813 cmÀ1
.
HRMS (FABþ): calcd. for C23F9H15NO5S2 (MþHþ):
1
(0.22 mmol, 93%); mp 106 1088C; H NMR (400 MHz): d¼
620.0248; found: 620.0219.
8.39 (d, J¼7.8 Hz, 1H), 8.32 (d, J¼11.8 Hz, 1H), 8.31 (d, J¼
8.4 Hz, 1H), 7.64 7.72 (m, 7H), 7.45 7.57 (m, 8H), 7.34 (t,
J¼7.5 Hz, 1H), 7.11 (d, J¼8.2 Hz, 2H), 2.27 (s, 3H);
31P NMR (121.5 MHz): d¼31.0; IR: n¼1716, 1437, 1373,
1176, 1120, 1006, 974 cmÀ1; HRMS (FABþ): calcd. for
C31H25NO3PS (MþHþ): 522.1293; found: 522.1300.
General Procedures for the Cross-Coupling Reactions
on Nonaflates using HPPh2
Method A: Precisely according the literature procedure,[8b] ex-
cept that the last two portions of phosphine (2Â0.4 equivs.)
were added after 5 and 15 min. The reaction mixtures were stir-
red at 1108C until all the starting materials were consumed
(monitored by TLC). When completed the mixture was diluted
with toluene, whereafter the volatiles were removed under vac-
uum. The mixture was filtered over hyflo (eluted with toluene)
and concentrated again. The crude products were dissolved in
THF and aqueous H2O2 (35%) was added. After stirring for
30 min the mixture was diluted with EtOAc and washed with
water (2Â). The organic layer was dried over Na2SO4 and con-
centrated under vacuum. Purifications were performed by col-
umn chromatography.
Method B: Nonaflate (1.0 equiv.), Pd(OAc)2 (0.02 equivs.),
dppe (0.022 equivs.) and DABCO (2 equivs.) were weighed
into a Schlenktube and after three argon/vacuum cycles
DMF (0.2 mL) was added and the solution was stirred for 1 h
at room temperature upon which the colour changed from yel-
low to orange. After addition of HPPh2 (1.2 equivs.) the solu-
tion was heated to 1208C until all starting materials were con-
sumed (monitored by TLC). The work-up was the same as in
method A.
(Æ)-1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonic
Acid 2’-(Nonafluorobutane-1-sulfonyloxy)-
[1,1’]bi[dibenzofuranyl]-2-yl Ester (10)
To a solution of (Æ)-BIFOL (0.50 g, 1.36 mmol) in acetonitrile
(14 mL) were added triethylamine (0.57 mL, 4.09 mmol) and
FSO2C4F9 (0.98 mL, 5.44 mmol) and the reaction mixture
was stirred at 60 8C for 2 h. The mixture was diluted with
EtOAc (60 mL) and the organic phase was washed with aque-
ous 0.5 M NaHSO3 (2Â75 mL) and brine (1Â75 mL). The or-
ganic layer was dried over Na2SO4 and concentrated under vac-
uum. Purification by column chromatography (PE:EtOAc¼
15:1) afforded 10 as a white solid; yield: 1.24 g (1.33 mmol,
1
98%); mp 148 1498C; H NMR (400 MHz): d¼7.86 (d, J¼
9.0 Hz, 2H), 7.64 (d, J¼9.0 Hz, 2H), 7.57 (d, J¼8.3 Hz, 2H),
7.37 (td, J¼7.8, 1.1 Hz, 2H), 6.91 (t, J¼7.4 Hz, 2H), 6.64 (d,
J¼7.9 Hz, 2H); 13C NMR (100.6 MHz, due to C-F coupling
the fluorinated carbons were not visible): d¼157.4, 154.5,
142.5, 128.7, 125.5, 123.4, 122.4, 121.9, 120.8, 120.3, 113.9,
111.8; IR: n¼3075, 1426, 1206, 1145, 909. HRMS (FABþ):
calcd. for C32H13F18O8S2 (MþHþ): 930.9764; found: 930.9753.
Adv. Synth. Catal. 2004, 346, 743 754
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Peter N. M. Botman et al.
FULL PAPERS
Optimized Synthesis of (Æ)-BIFAP (3)
(S)-1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonic Acid
3’-(Diphenylphosphinoyl)-9,9’-bis(toluene-4-sulfonyl)-
9H,9’H-[4,4’]bicarbazolyl-3-yl Ester (13)
According to cross-coupling method B, using nonaflate 10
(150 mg, 161 mmol), 2.5 equivs. of HPPh2 and stirring the mix-
ture at 1408C for 19 h. The mixture was concentrated under
vacuum and purification by column chromatography
(PE:toluene¼2:1) afforded BIFAP 3 as a white solid; yield:
42 mg (57 mmol, 35%). The spectral data were identical to those
reported in the literature.[6]
To a mixture of 12 (3.10 g, 2.51 mmol), diphenylphosphine ox-
ide (0.71 g, 3.51 mmol), Pd(OAc)2 (56 mg, 0.25 mmol) and
dppb (0.11 g, 0.25 mmol) were added DMSO (12.5 mL) and
DIPEA (1.53 mL, 8.78 mmol). The mixture was stirred at
110 8C for 4 h upon which the colour of the solution changed
from orange to darkpurple. After cooling to room temperature
the reaction mixture was diluted with EtOAc (100 mL) and
washed with aqueous 0.5 M NaHSO3 (2Â100 mL) and brine
(2Â100 mL). The organic layer was dried over Na2SO4 and
concentrated under vacuum. Purification by column chroma-
tography (PE:EtOAc¼1:1!1:2) afforded 13 as a white solid;
yield: 2.80 g (2.46 mmol, 98%); mp 121 1238C; [a]2D0: À11 (c
1.00, CHCl3); 1H NMR (400 MHz): d¼8.58 (dd, J¼8.8,
1.6 Hz, 1H), 8.49 (d, J¼9.2 Hz, 1H), 8.16 (d, J¼8.4 Hz, 1H),
8.10 (d, J¼8.5 Hz, 1H), 7.70 7.76 (m, 3H), 7.59 (d, J¼
8.4 Hz, 2H), 7.52 (d, J¼12.1 Hz, 1H), 7.41 (dd, J¼12.1 Hz,
1.2, 1H), 7.46 (d, J¼9.2 Hz, 1H), 7.41 (td, J¼7.4 Hz, 1.2,
1H), 7.09 7.28 (m, 10H), 7.04 (td, J¼7.5, 1.2 Hz, 1H), 6.81
(t, J¼7.8 Hz, 1H), 6.80 (t, J¼7.7 Hz, 1H), 6.55 (t, J¼7.4 Hz,
1H), 6.54 (t, J¼7.4 Hz, 1H), 5.86 (d, J¼8.1 Hz, 2H), 2.35 (s,
3H), 2.28 (s, 3H); 31P NMR (121.5 MHz): d¼28.0; IR: n¼
(S)-1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonic Acid
3’-(Nonafluorobutane-1-sulfonyloxy)-9,9’-bis(toluene-
4-sulfonyl)-9H,9’H-[4,4’]bicarbazolyl-3-yl Ester (12)
To a solution of 11 (2.39 g, 3.28 mmol) in toluene (33 mL) were
added TsCl (1.56 g, 8.20 mmol), t-Bu4NHSO4 (0.22 g,
0.65 mmol) and aqueous 2.5 N NaOH (66 mL). After stirring
the mixture vigorously at room temperature for 5 h, EtOAc
(150 mL) was added and the organic phase was washed with
water (2Â150 mL). The organic layer was dried over Na2SO4
and concentrated under vacuum. The crude solids were dis-
solved in THF (66 mL) and LiAlH4 (0.87 g, 22.9 mmol) was
added carefully. After stirring at room temperature for
30 min, the reaction was quenched by adding slowly a mixture
of water (80 mL), aqueous 2.0 N HCl (250 mL) and EtOAc
(250 mL). After removal of the organic phase the aqueous lay-
er was extracted with EtOAc (2Â180 mL). The combined or-
ganic layers were dried over Na2SO4 and concentrated under
3120, 1422, 1373, 1239, 1207, 1177, 1143, 972, 915 cmÀ1
;
HRMS (FABþ): calcd. for C54H37F9N2O8PS3 (MþHþ):
1139.1306; found: 1139.1281.
(S)-1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonic Acid
3’-Diphenylphosphanyl-9,9’-bis-(toluene-4-sulfonyl)-
vacuum.
Purification
by
column
chromatography
(PE:EtOAc¼1.5:1!1:1) afforded the free diol as a white sol-
id; yield: 2.09 g (3.11 mmol, 95%); mp 3408C (decomposition); 9H,9’H-[4,4’]bicarbazolyl-3-yl Ester (14)
1
[a]2D0: À3.8 (c 1.00, THF); H NMR (400 MHz, acetone-d6):
A solution of 13 (2.28 g, 2.00 mmol) in phenylsilane (13 mL)
d¼8.38 (d, J¼9.0 Hz, 2H), 8.21 (d, J¼8.4 Hz, 2H), 8.15 (br.
s, 2H), 7.73 (d, J¼8.4 Hz, 4H), 7.32 (d, J¼9.0 Hz, 4H), 7.24
7.30 (m, 4H), 6.70 (t, J¼7.3 Hz, 2H), 6.23 (d, J¼7.9 Hz, 2H),
2.28 (s, 6H); 13C NMR (100.6 MHz, acetone-d6): d¼154.2,
146.8, 140.6, 136.0, 134.0, 131.3, 128.5, 128.2, 128.0, 127.9,
125.2, 122.7, 117.7, 117.7, 116.8, 116.5; IR: n¼3354, 3294,
1365, 1173, 1089, 972 cmÀ1; HRMS (FABþ): calcd. for
C38H29O6N2S2 (MþHþ): 673.1467; found: 673.1458.
was stirred at 1148C for 18 h. After addition of EtOAc
(40 mL) the mixture was concentrated under vacuum. Purifica-
tion by column chromatography (PE:EtOAc¼4:1!3:1) af-
forded 14 as a white solid; yield: 2.15 g (1.92 mmol, 96%); mp
109 1108C; [a]D20: À7.1 (c 1.00, CHCl3); 1H NMR
(400 MHz): d¼8.62 (d, J¼9.2 Hz, 1H), 8.51 (d, J¼8.7 Hz,
1H), 8.15 (d, J¼8.4 Hz, 1H), 8.13 (d, J¼8.5 Hz, 1H), 7.71 (d,
J¼8.3 Hz, 2H), 7.56 7.60 (m, 3H), 7.51 (dd, J¼8.7, 3.0 Hz,
1H), 7.18 7.32 (m, 9H), 7.08 (d, J¼8.1 Hz, 2H), 6.84 (td, J¼
7.2 Hz, 0.9, 1H), 6.65 6.75 (m, 4H), 6.58 (td, J¼8.0, 0.7 Hz,
1H), 6.50 (td, J¼8.0, 0.7 Hz, 1H), 6.06 (d, J¼7.9 Hz, 1H),
5.81 (d, J¼7.8 Hz, 1H), 2.32 (s, 3H), 2.28 (s, 3H); 31P NMR
(121.5 MHz): d¼ À14.0. IR: n¼3056, 1421, 1373, 1240, 1177,
1143, 1091, 972, 914 cmÀ1; HRMS (FABþ): calcd. for
C54H37F9N2O7PS3 (MþHþ): 1123.1357; found: 1123.1307.
A solution of the diol (2.05 g, 3.05 mmol), triethylamine
(1.10 mL, 7.93 mmol) and FSO2C4F9 (1.37 mL, 7.62 mmol) in
acetonitrile (61 mL) was stirred at 60 8C for 3 h. The reaction
was quenched by addition of water (150 mL) and EtOAc
(150 mL) and the organic phase was washed with aqueous 0.5
M NaHSO3 (2Â100 mL) and brine (1Â100 mL). The organic
layer was dried over Na2SO4 and concentrated under vacuum.
Purification by column chromatography (PE:EtOAc¼
4:1!2:1) afforded 12 as
a white solid; yield: 3.55 g
(2.86 mmol, 94%); mp 878C; [a]2D0: þ148 (c 1.03, CHCl3).
1H NMR (400 MHz): d¼8.67 (d, J¼9.2 Hz, 2H), 8.25 (d, J¼
8.5 Hz, 2H), 7.60 (d, J¼8.6 Hz, 4H), 7.60 (d, J¼8.6 Hz, 2H),
7.33 (td, J¼7.9, 1.0 Hz, 2H), 7.11 (d, J¼8.2 Hz, 4H), 6.70 (t,
J¼7.5 Hz, 2H), 6.27 (d, J¼7.9 Hz, 2H), 2.28 (s, 6H);
13C NMR (100.6 MHz, due to C-F coupling the fluorinated car-
bons were not visible): d¼145.4, 143.4, 139.6, 137.7, 134.3,
129.8, 128.7, 127.2, 126.3, 124.4, 124.2, 121.6, 120.5, 120.2,
117.7, 115.1, 21.4; IR: n¼3113, 1423, 1375, 1209, 1144,
919 cmÀ1; HRMS (FABþ): calcd. for C46H27F18N2O10S4 (Mþ
Hþ): 1237.0261; found: 1237.0227.
(S)-3’-Diphenylphosphanyl-3-(diphenylphosphinoyl)-
9,9’-bis(toluene-4-sulfonyl)-9H,9’H-[4,4’]bicarbazolyl
(15)
To mixture of 14 (1.86 g, 1.66 mmol), diphenylphosphine oxide
(0.54 g, 2.65 mmol), Pd(OAc)2 (37 mg, 0.16 mmol) and dppb
(0.71 mg, 0.16 mmol) were added DMSO (8.5 mL) and DI-
PEA (1.00 mL, 5.80 mmol). The mixture was stirred at
110 8C for 4 h upon which the colour of the solution changed
from orange to darkpurple. After cooling to room temperature
750
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis, Properties and Applications of BICAP
FULL PAPERS
the reaction mixture was diluted with EtOAc (100 mL) and
washed with aqueous 0.5 M NaHSO3 (2Â100 mL) and brine
(2Â100 mL). The organic layer was dried over Na2SO4 and
concentrated under vacuum. Purification by column chroma-
tography (PE:EtOAc¼2:1!1:1) afforded first by-product
16 as a white solid (yield: 0.27 g, 0.33 mmol, 20%) followed
by 15 as a white solid; yield: 1.36 g (1.33 mmol, 80%); mp
155 1568C; [a]D: À65 (c 1.00, CHCl3); 1H NMR (400 MHz):
d¼8.55 (dd, J¼8.7, 1.4 Hz, 1H), 8.32 (d, J¼8.7 Hz, 1H), 8.00
(d, J¼8.4 Hz, 1H), 7.96 (d, J¼8.4 Hz, 1H), 7.71 7.78 (m,
7H), 7.60 (dd, J¼8.7, 2.9 Hz, 1H), 7.41 7.46 (m, 3H), 7.19
7.35 (m, 9H), 7.06 7.12 (m, 3H), 6.95 (t, J¼7.5 Hz, 1H), 6.78
(t, J¼7.4 Hz, 1H), 6.68 (t, J¼7.4 Hz, 1H), 6.50 6.59 (m,
4H), 6.45 (t, J¼7.6 Hz, 1H), 6.39 (d, J¼7.3 Hz, 2H), 6.00 (t,
J¼7.6 Hz, 1H), 5.71 (d, J¼7.9 Hz, 1H), 5.09 (d, J¼8.0 Hz,
1H), 2.34 (s, 3H), 2.33 (s, 3H); 31P NMR (121.5 MHz): d¼
27.0, À16.1. IR: n¼3054, 1435, 1420, 1371, 1175, 972,
909 cmÀ1; HRMS (FABþ): calcd. for C62H47N2O5P2S2 (Mþ
Hþ): 1025.2402; found: 1025.2411.
8.0 Hz, 2H), 6.12 (d, J¼8.0 Hz, 2H); 31P NMR (121.5 MHz):
d¼ À17.7; IR: n¼3415, 3052, 2925, 15921466, 1433, 1330,
1257 cmÀ1; HRMS (FABþ): calcd. for C48H35N2P2 (MþHþ):
701.2276; found: 701.2266.
(S)-Nf-BICAP (5c)
NaH (14 mg, 0.35 mmol of a 60% dispersion in mineral oil) was
added to a solution of 5a (70 mg, 0.10 mmol) in 1:1 THF/DMF
(2.0 mL). After stirring the mixture for 15 min, FSO2C4F9
(54 mL, 0.30 mmol) was added and the suspension was heated
to 558C for 5 h. The reaction mixture was diluted with EtOAc
(20 mL) and the organic phase was washed with water (2Â
15 mL), aqueous saturated NH4Cl (20 mL), dried over Na2
SO4 and concentrated under vacuum. Purification by column
chromatography (PE:EtOAc¼20:1!10:1) afforded 5c as a
white solid; yield: 84 mg (75 mmol, 75%); mp 66 678C; [a]2D0:
À37 (c 0.51, CHCl3); 1H NMR (400 MHz, DMSO-d6, 1508C):
d¼8.27 (d, J¼9.0 Hz, 2H), 7.83 (d, J¼8.5 Hz, 2H), 7.67 (d,
J¼8.5 Hz, 2H), 7.24 7.36 (m, 12H), 6.9 (m, 6H), 6.83 6.88
(m, 4H), 6.66 (m, 2H), 5.87 (m, 2H); 31P NMR (202.4 MHz,
DMSO-d6, 1508C): d¼ À13.2; IR: n¼2925, 1411, 1238, 1195,
1144 cmÀ1; HRMS (FABþ): calcd. for C56H33N2P2S2O4F18
(MþHþ): 1265.1070; found: 1265.1095.
By-product 16: mp 136 1388C; [a]2D0: À38 (c 0.95, CHCl3);
1H NMR (400 MHz): d¼8.47 (d, J¼8.4 Hz, 1H), 8.42 (d, J¼
8.7 Hz, 1H), 8.22 (d, J¼8.3 Hz, 1H), 8.21 (d, J¼8.4 Hz, 1H),
7.74 (d, J¼8.3 Hz, 2H), 7.67 (d, J¼8.3 Hz, 2H), 7.43 (t, J¼
8.0 Hz, 1H), 7.74 (dd, J¼8.7, 3.0 Hz, 1H), 7.08 7.32 (m,
12H), 6.89 7.01 (m, 5H), 6.66 (t, J¼7.5 Hz, 1H), 6.59 (t, J¼
7.7 Hz, 1H), 6.03 (d, J¼7.9 Hz, 1H), 5.91 (d, J¼7.9 Hz, 1H),
2.34 (s, 3H), 2.27 (s, 3H); 31P NMR (121.5 MHz): d¼ À14.7.
IR: n¼3054, 1371, 1174, 1090, 973, 909 cmÀ1; HRMS (FABþ):
calcd. for C50H38N2O4PS2 (MþHþ): 825.2011; found: 825.2021.
(S)-Me-BICAP (5d)
NaH (23 mg, 0.58 mmol of a 60% dispersion in mineral oil) was
added to a solution of 5a (0.17 g, 0.24 mmol) in 1:1 THF/DMF
(4.8 mL). After stirring the mixture for 15 min, methyl iodide
(31 mL, 0.50 mmol) was added and the suspension was stirred
for another 30 min. The reaction was diluted with EtOAc
(20 mL) and the organic phase was washed with water (2Â
15 mL), aqueous saturated NH4Cl (20 mL), dried over Na2
SO4 and concentrated under vacuum. Purification by column
chromatography (pentane:Et2O¼2:1!1:2) afforded 5d as a
white solid; yield: 0.12 g (0.17 mmol, 71%); mp 324 3258C;
(S)-Ts-BICAP (5b)
A solution of 15 (0.80 g, 0.78 mmol) in phenylsilane (7 mL) was
stirred at 1258C for 48 h. After addition of EtOAc (40 mL) the
mixture was concentrated under vacuum. Purification by col-
umn chromatography (PE:EtOAc¼5:1!3:1) afforded 5b
as a white solid; yield: 0.74 g (0.73 mmol, 94%); mp 145
1
1478C; [a]2D0: À69 (c 0.61, CHCl3); H NMR (400 MHz): d¼
1
[a]2D0: À86 (c 0.21, CHCl3); H NMR (500 MHz): d¼7.57 (s,
8.46 (d, J¼8.6 Hz, 2H), 8.02 (d, J¼8.4 Hz, 2H), 7.70 (d, J¼
8.3 Hz, 4H), 7.53 (d, J¼8.7 Hz, 2H), 7.17 7.20 (m, 14H),
7.05 (t, J¼7.5 Hz, 2H), 6.80 (t, J¼7.3 Hz, 2H), 6.66 6.72 (m,
4H), 6.58 (d, J¼7.5 Hz, 2H), 6.57 (t, J¼7.6 Hz, 2H), 6.28 (d,
J¼7.7 Hz, 2H), 5.52 (d, J¼7.9 Hz, 2H), 2.31 (s, 6H);
31P NMR (121.5 MHz): d¼ À15.8; IR: n¼3055, 1371, 1175,
971, 908 cmÀ1; HRMS (FABþ): calcd. for C62H47N2O4P2S2
(MþHþ): 1009.2453; found: 1009.2443.
4H), 7.27 (t, J¼8.0 Hz, 2H), 7.21 (t, J¼7.5 Hz, 2H), 7.02
7.09 (m, 6H), 6.90 7.00 (m, 14H), 6.54 (t, J¼7.2 Hz, 2H),
6.13 (d, J¼7.9 Hz, 2H), 3.91 (s, 6H); 31P NMR (202.4 MHz):
d¼ À18.0; IR: n¼3049, 2929, 1579, 1475, 1433, 1259; HRMS
(FABþ): calcd. for C50H39N2P2 (MþHþ): 729.2589; found:
729.2596.
(S)-TBS-BICAP (5e)
n-BuLi (0.10 mL, 0.25 mmol of a 2.5 M solution in THF) was
added to a solution of 5a (40 mg, 57 mmol) in 1:3 THF/toluene
(2.6 mL). After stirring the mixture for 15 min, TBSCl (31 mL,
0.20 mmol) was added and the suspension was stirred for an-
other 5 h. The reaction mixture was diluted with EtOAc
(20 mL) and the organic phase was washed with water (1Â
15 mL), brine (1Â20 mL), dried over Na2SO4 and concentrat-
ed under vacuum. Purification by column chromatography
(PE:EtOAc¼15:1!7:1) afforded 5e as a white solid; yield:
34 mg (37 mmol, 65%); mp 126 1278C; [a]2D0: À103 (c 0.73,
CHCl3); 1H NMR (400 MHz): d¼7.73 (d, J¼8.7 Hz, 2H),
7.38 7.44 (m, 4H), 7.14 7.17 (m, 4H), 7.06 7.10 (m, 6H),
6.87 7.03 (m, 12H), 6.41 (t, J¼7.5 Hz, 2H), 5.94 (d, J¼
(S)-BICAP (5a)
To a solution of 5b (0.50 g, 0.49 mmol) in THF (25 mL) was
added 2 M KOH in MeOH (3.0 mL). The reaction mixture
was stirred at 558C for 3 h, then quenched by addition of water
(30 mL). The product was extracted with EtOAc (2Â60 mL)
and the organic layers were washed with brine (60 mL), dried
over Na2SO4 and concentrated under vacuum. Purification
by column chromatography (toluene) afforded 5a as a white
solid; yield: 0.33 g (0.46 mmol, 95%); mp 328 3298C; [a]2D0:
À147 (c 0.49, THF); 1H NMR (400 MHz, acetone-d6): d¼
10.56 (br. s, 2H), 7.68 (d, J¼8.4 Hz, 2H), 7.45 (d, J¼8.4 Hz,
2H), 7.36 (d, J¼8.1 Hz, 2H), 6.93 7.17 (m, 22H), 6.44 (t, J¼
Adv. Synth. Catal. 2004, 346, 743 754
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751

Peter N. M. Botman et al.
FULL PAPERS
7.9 Hz, 2H), 1.01 (s, 18H), 0.81 (s, 6H), 0.79 (s, 6H); 31P NMR
(202.4 MHz): d¼ À17.4; IR: n¼3050, 2927, 2856, 1569, 1463,
1420, 1271, 966, 822 cmÀ1; HRMS (FABþ): calcd. for C60H63
N2P2Si2 (MþHþ): 929.4005; found: 929.4019.
A colourless crystal (grown from a solution of EtOAc/PE)
with dimensions 0.25Â0.40Â0.40 mm approximately was
used for data collection. A total of 6827 unique reflections
was measured within the range À12ꢀhꢀ13, À15ꢀkꢀ15,
0ꢀl16. Of these, 5030 were above the significance level of
4s(Fobs) and were treated as observed. The range of (sin q)/l
was 0.040 0.626 ä (3.5ꢀqꢀ74.88). Two reference reflections
([1 1 0],[0 1 3]) were measured hourly and showed 6% decrease
during the 92 h collecting time, which was corrected for. Unit
cell parameters were refined by a least-squares fitting proce-
dure using 23 reflections with 40.03ꢀqꢀ41.70. The hydrogen
atoms were calculated. After isotropic refinement of the non-
H atoms O4 and O5 had very high atomic displacement param-
eters. Careful examination of a DF synthesis revealed position-
al disorder for both atoms, so it was decided two split both
atoms into two half-occupied positions and keep the ADP×s
isotropic during further refinement. Full-matrix least-squares
refinement on F, anisotropic for the non-hydrogen atoms iso-
tropic for the hydrogen atoms restraining the latter in such a
way that the distance to their carrier remained constant at ap-
proximately 1.0 ä, converged to R¼0.098, Rw ¼0.089,
(D/s)max ¼0.41, S¼1.01. A weighting scheme w¼[3.5þ
0.01*(s(Fobs))2 þ0.01/(s(Fobs))]À1 was used. The secondary
isotropic extinction coefficient[20] refined to g¼518(48). A fi-
nal difference Fourier map revealed a residual electron density
between À1.33 and 1.49 eäÀ3 in the vicinity of the disordered
atoms. Scattering factors were taken from the International Ta-
bles for X-Ray Crystallography.[21] The anomalous scattering
of S, and F was taken into account.[22] All calculations were per-
formed with XTAL3.7,[23] unless stated otherwise.
(Æ)-Trifluoromethanesulfonic Acid 9,9’-
Bis(trifluoromethanesulfonyl)-3’-
trifluoromethanesulfonyloxy-9H,9’H-
[4,4’]bicarbazolyl-3-yl Ester (17)
To a suspension of (Æ)-BICOL (0.10 g, 0.27 mmol) in CH2Cl2
(3 mL) were added LiHMDS (1.57 mL of a 1 M solution in
THF, 1.57 mmol) and triflic anhydride (0.32 mL, 1.89 mmol)
at À30 8C. The resulting green solution was heated to 40 8C
and stirred for 4 h. The mixture was diluted with CH2Cl2
(20 mL) and the organic phase was washed with aqueous
0.5 M NaHSO3 (2Â30 mL) and brine (1Â30 mL). The organic
layer was dried over Na2SO4 and concentrated under vacuum.
Purification by column chromatography (PE:EtOAc¼15:1)
afforded 17 as a white solid; yield: 73 mg (81 mmol, 30%); mp
1
57 598C; H NMR (400 MHz, DMF-d7): d¼8.64 8.79 (m,
2H), 8.16 8.30 (m, 2H), 7.63 7.67 (m, 2H), 7.10 7.24 (m,
2H), 6.98, 6.92, 6.63, 6.56 (4 d, J¼8.0, 7.9, 8.1, 7.3 Hz, intensity
ratio 1.1:0.4:0.4:0.1, together 2H); 1H NMR (400 MHz,
DMF-d7, T¼130 8C): d¼8.80 (d, J¼9.0 Hz, 2H), 8.25 8.28
(m, 4H), 7.75 (t, J¼7.5 Hz, 2H), 7.30 (t, J¼7.5 Hz, 2H), 6.89
(d, J¼7.0 Hz, 2H); HRMS (FABþ): calcd. for
C28H13O10F12N2S4 (MþHþ): 892.9261; found: 892.9227.
[(S)-Me-BICAP]PdCl2 (18)
Crystal structure of [(S)-Me-BICAP]PdCl2 (18)
To a solution of (S)-Me-BICAP (30.0 mg, 41 mmol) in CH2Cl2
(1.5 mL) was added PdCl2(MeCN)2 (10.1 mg, 39 mmol) and
the resulting solution was stirred for 1 h at room temperature.
After evaporation of the solvent, the crude product was recrys-
tallized from a mixture of CH2Cl2/EtOAc/iPr2O, yielding red
cubic crystals.
C50H38Cl2N2P2Pd, Mr ¼906.2, orthorhombic, P212121, a¼
14.610(1), b¼15.766(1), c¼17.89(3) ä, V¼3837.0(7) ä3,
Z¼4, Dx ¼1.46 g cmÀ3, m(CuKa)¼5.85 mmÀ1, F(000)¼1776,
room temperature, Final R¼0.038 for 4367 observed reflec-
tions.
A red crystal with dimensions 0.25Â0.50Â0.50 mm approx-
imately was used for data collection. A total of 4669 unique re-
flections was measured within the range 0ꢀhꢀ18, 0ꢀkꢀ19,
0ꢀlꢀ22. Of these, 4367 were above the significance level of
4s(Fobs) and were treated as observed. The range of (sin q)/l
was 0.042 0.626 ä (3.7ꢀqꢀ74.78). Two reference reflections
([ 3 0 2 ], [ 0 2 2 ]) were measured hourly and showed no de-
crease during the 80 h collecting time. Unit cell parameters
were refined by a least-squares fitting procedure using 23 re-
flections with 39.95ꢀ2qꢀ41.94. The hydrogen atoms were cal-
culated and kept fixed with U¼0.10 ä2. Full-matrix least-
squares refinement on F, anisotropic for the non-hydrogen
atoms converged to R¼0.038, Rw ¼0.039, (D/s)max ¼0.076,
S¼0.94. A weighting scheme w¼[3.5þ0.01*(s(Fobs))2 þ
0.01/(s(Fobs))]À1 was used. The secondary isotropic extinction
coefficient[20] refined to g¼1183(57). A final difference Fouri-
er map revealed a residual electron density between À0.68 and
0.73 eäÀ3 in the vicinity of the heavy atoms. Scattering factors
were taken from the International Tables for X-Ray Crystal-
lography.[21] The anomalous scattering of Cl, P and Pd was tak-
en into account.[22] All calculations were performed with
XTAL3.7,[23] unless stated otherwise. Refining the inverted
structure converged to R¼0.066, thus confirming the correct
X-Ray Crystallographic Study
All X-ray measurements were carried out on an Enraf-Nonius
CAD-4 diffractometer with graphite-monochromated CuKa
radiation [l(CuKa)¼1.5418 ä] and w-2q scan. Corrections
for Lorentz and polarization effects were applied. Absorption
corrections were performed (for 17 and 18) with the program
PLATON,[17] following the method of North et al.[18] using Y-
scans of five reflections, with coefficients in the range 0.759
0.967 (17) and 0.491 0.977 (18). The structures were solved
by the PATTY option of the DIRDIF-99 program system.[19]
Crystal Structure of BICOLTetratriflate (17)
C28H12F12N2O10S4, Mr ¼892.7, triclinic, Pı≈, a¼10.497(2), b¼
162.542(1), c¼13.426(2) ä, a¼85.35(1), b¼70.97(1(3), g¼
85.838(9)8, V¼1663.5(4) ä3, Z¼2, Dx ¼1.78 g cmÀ3
,
m(CuKa)¼38.19 cmÀ1 , F(000)¼892, À208C, Final R¼0.98
for 5030 observed reflections.
752
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Adv. Synth. Catal. 2004, 346, 743 754

Synthesis, Properties and Applications of BICAP
FULL PAPERS
structure. Phenyl group C31-C36 behaves rather anisotropic
compared with the other three phenyl groups.
ution was stirred at 70 8C for 17 h. After cooling to room tem-
perature the reaction mixture was diluted with CH2Cl2 (30 mL)
and washed with aqueous 0.5 M NaHSO3 (1Â30 mL) and wa-
ter (1Â30 mL). The organic layer was dried over Na2SO4 and
concentrated under vacuum. Purification by column chroma-
tography (PE:CH2Cl2 ¼1:8!1:25) afforded the benzoylated
product, which was used to determine to enantiomeric excess
by chiral HPLC [Daicel OB, heptane:i-PrOH¼9:1, 1.0 mL
minÀ1, UV 254 nm: tR ¼8.56 (R) and 10.6 min. (S)].
Crystal structure of (S)-Me-BICAP (5d)
C50H38N2P2, Mr ¼728.8, orthorhombic, P212121, a¼9.9515(6),
b¼11.4449(8), c¼34.374(3) ä, V¼3915.0(5) ä 3, Z¼4, Dx ¼
1.24 g cmÀ3, m(CuKa)¼1.29 mmÀ1 , F(000)¼1528, room tem-
perature, Final R¼0.056 for 3864 observed reflections.
A white crystal (grown from a mixture of CH2Cl2/PE) with
dimensions 0.15Â0.20Â0.75 mm approximately was used for General Procedure for Asymmetric Hydrogenation of
data collection. A total of 4524 unique reflections was meas-
ured within the range 0ꢀhꢀ12, 0ꢀkꢀ14, 0ꢀlꢀ42. Of these,
3864 were above the significance level of 2.5s(Iobs) and were
treated as observed. In addition 865 ™Friedel∫ reflections
were measured; these were used in the determination of the ab-
solute configuration. The range of (sin q)/l was 0.029 0.626 ä
(2.6ꢀqꢀ74.78). Two reference reflections ([ 2 1 0 ], [ 2 0 4 ])
were measured hourly and showed no decrease during the
80 h collecting time. Unit cell parameters were refined by a
least-squares fitting procedure using 23 reflections with
39.93ꢀ2qꢀ41.84. Full-matrix least-squares refinement on F,
anisotropic for the non-hydrogen atoms, isotropic for the hy-
drogen atoms restraining the latter in such a way that the dis-
tance to their carrier remained constant at approximately
1.0 ä, converged to R¼0.056, Rw ¼0.071, (D/s)max ¼0.11, S¼
1.08. A weighting scheme w¼[4.2þ0.01*(s(Fobs))2 þ0.01/
(s(Fobs))]À1 was used. The secondary isotropic extinction co-
efficient[20] refined to g¼13010(454). A final difference Fouri-
er map revealed a residual electron density between À0.32 and
0.38 eäÀ3. Scattering factors were taken from the International
Tables for X-Ray Crystallography.[21] The anomalous scatter-
ing of P was taken into account.[22] All calculations were per-
formed with XTAL3.7,[23] unless stated otherwise. The Flack
parameter[24] converged to Xabs¼0, thus confirming the cor-
rect structure.
Dimethyl Itaconate (23)
A solution of Rh(nbd)2BF4 (3.0 mg, 8.02 mmol) and ligand
(9.22 mmol) in CH2Cl2 (4 mL) was stirred for 30 min. After
the itaconate (127 mg, 0.80 mmol) was added, a 1 mL sample
was transferred into a glass vial, placed in a stainless-steel au-
toclave and equipped with a stirring bean. The autoclave was
flushed with hydrogen gas (3Â5 bar), before the reaction mix-
ture was stirred at room temperature under hydrogen pressure
(5 bar) for 15 h. The autoclave was depressurized and opened.
The resulting solution was filtered over silica (eluted with CH2
Cl2) and concentrated under vacuum. At this stage the conver-
sion was determined by 1H NMR and the enantiomeric excess
of 24 was checked by chiral GC [Beta-Dex 325 (Supelco), gas
flow settings: carrier gas helium 150 kPa, H2 50 kPa, air
100 kPa, oven temperature program: 70 8C isotherm 40 min.;
30 8C/min up to 190 8C; isotherm 16 min., tR ¼ ꢁ33 min. (R)
and ꢁ34 min. (S)].
Acknowledgements
Prof. P. W. N. M. van Leeuwen, Dr. P. C. J. Kamer, F. Ribaudo,
B. H. G. Swennenhuis, G. C. Schoemaker, R. P. J. Bronger, and
J. A. J. Geenevasen (University of Amsterdam) and A. van den
Hoogenband (Solvay Pharmaceuticals, Weesp, The Nether-
lands) are kindly acknowledged for their support. We thank
the National Research School Combination Catalysis (NRSC-
C) for financial support.
Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementa-
ry publication No. CCDC 225796 (17), No. CCDC 225797 (18),
No. CCDC 225795 (5d). Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road, Cambridge
CB21EZ, UK [Fax: (internat.) þ44 1223/336 033; E-mail:
deposit@ccdc.cam.ac.uk]
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754
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 743 754