Tuning the peri effect for enantioselectivity: Asymmetric hydrogenation of unfunctionalized olefins with the BIPI ligands

Article abstract of DOI:10.1002/adsc.201201104

The modular nature of the BIPI ligands allows for systematic optimization of each ligand region. The development of ligands optimized for asymmetric hydrogenation of the challenging unfunctionalized olefin substrate class is described. The naphthyl peri p

Full text of DOI:10.1002/adsc.201201104

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DOI: 10.1002/adsc.201201104
Tuning the Peri Effect for Enantioselectivity: Asymmetric
Hydrogenation of Unfunctionalized Olefins with the BIPI
Ligands
a,
a
a
a
a
Carl A. Busacca, * Bo Qu, Nicole Gr eˇ t, Keith R. Fandrick, Anjan K. Saha,
a
a
a
a
Maurice Marsini, Diana Reeves, Nizar Haddad, Magnus Eriksson,
a
a
a
a
a
Jiang-Ping Wu, Nelu Grinberg, Heewon Lee, Zhibin Li, Bruce Lu,
Dajun Chen, Yaping Hong, Shengli Ma, and Chris H. Senanayake
Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, USA
E-mail: carl.busacca@boehringer-ingelheim.com
Princeton Global Synthesis LLC, 360 George Patterson Blvd. Suite 206, Bristol, PA 19007, USA
b
b
a
a
a
b
Received: December 18, 2012; Published online: March 20, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201201104.
Abstract: The modular nature of the BIPI ligands
allows for systematic optimization of each ligand
region. The development of ligands optimized for
asymmetric hydrogenation of the challenging un-
functionalized olefin substrate class is described.
The naphthyl peri position, C-8, has been identified
as a critical stereocontrol element in the design of
these ligands. Highly enantioselective ligands suita-
ble for hydrogenation of tri- and tetrasubstituted
olefins are detailed.
these engineered ligands (Figure 1) have been
achieved. The first applications of these systems to
unfunctionalized olefins are described below.
[
7]
[8]
Pfaltz et al. and Buchwald et al. have reported
asymmetric hydrogenations of tri- and tetrasubstitut-
F
ed olefins with cationic iridium BAr and zirconocene
F
catalysts, respectively. The Ir
A
H
U
G
E
N
N
(COD)BAr complex of
BIPI 153 was thus prepared and examined in the AH
of tetrasubstituted olefin 1 (Scheme 1). Full conver-
sion was obtained with 1 bar of H , yet a disappointing
2
er of only 74:26 was observed. This established that
the successful ligands for functionalized alkenes were
unsuitable for the more diffcult substrate class. A sys-
tematic ligand optimization study was therefore initi-
ated.
Keywords: asymmetric hydrogenation; BIPI li-
gands; naphthalenes; peri position; unfunctional-
ized olefins
Asymmetric hydrogenation (AH) is a critical technol-
ogy in the manufacture of pharmaceuticals, agrochem-
icals, fragrances, and many organic building blocks of
[1]
commerce. Significant advances have been realized
in the years since the pioneering work of Kagan,
[
2]
Noyori, Knowles and others, particularly for func-
tionalized olefins in which a carbonyl group acts as
a metal recognition element. Unfunctionalized ole-
fins, however, have remained a more challenging sub-
strate class.
[
3]
Figure 1. BIPI ligands for functionalized olefin AH.
The BIPI ligands are a modular and electronically
[
4]
tunable ligand platform invented in the late 1990s
and designed for ready optimization to enable asym-
metric transformations with differing electronic and
steric requirements. Highly selective asymmetric hy-
[
5]
drogenations of ene-ureas, ene-carbamates, and en-
[6]
amides with the rhodium complexes of a variety of Scheme 1. Failed S Ar reaction.
N
Adv. Synth. Catal. 2013, 355, 1455 – 1463
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Carl A. Busacca et al.
COMMUNICATIONS
[a]
Table 1. AH of dimethylindene 1.
Ligand
% Conversion
er of 2
BIPI 81
BIPI 83
BIPI 84
BIPI 93
BIPI 153
BIPI 201
BIPI 202
BIPI 203
BIPI 205
BIPI 206
BIPI 207
BIPI 210
BIPI 238
8
100
19
57:43
65:35
63:37
89:11
74:26
77:23
81:19
85:15
78:22
84:16
94:6
100
100
100
100
100
100
100
100
100
100
F
Figure 2. Ligands converted to cationic iridium BAr com-
95:5
98:2
plexes.
[a]
F
Ir-COD-BAr complexes, CH Cl , 1 bar H , dr >100:1.
2
2
2
A variety of structurally diverse BIPI ligands
(
Figure 2) were converted to their cationic iridium-
F
A( COD)BAr complexes, and all were purified by silica
C
H
T
U
N
G
T
R
E
N
N
U
N
G
Thus, the advantage of the naphthyl core ligands
gel chromatography. Only N-acyl-containing ligands over the phenyl core, first observed in functionalized
were chosen, as we have previously shown that all olefin hydrogenations, may also be in effect for the
[
5,6,9]
successful AH ligands require this functionality.
unfunctionalized substrates. For the former substrate
There are four subclasses of possible substitution pat- class, strong evidence for the importance of the naph-
[
6]
terns when either aryl or alkyl groups are chosen for thyl peri proton (H-8) was gathered. This may in-
the phosphorus and imidazoline substituents of the volve conformational restriction of the phosphine sub-
ligand. Examples of all four types were thus selected stituents leading to increased selectivity.
so that the different systems could be compared.
Methanol, CH Cl and toluene were examined as hy- the naphthalene core were then undertaken. Fluoro-
Efforts to incorporate a larger peri substituent on
2
2
drogenation solvents for several of these complexes,
ACHTUNGTRENNUiGN midazoline 3 with a methyl group at the peri position
and the highest conversions were consistently ob- was prepared, yet the subsequent S Ar reaction with
N
served in CH Cl . Examination of these ligands in the the anion of dicyclohexylphosphine·borane failed
2
2
asymmetric hydrogenation of dimethylindene 1 was (Scheme 1). The most likely explanation for this is the
then carried out under 1 bar of H in CH Cl . The re- severe steric constraints imposed by 1,8-disubstituted
2
2
2
[
10]
sults for this screening set are shown in Table 1.
The complexes derived from ligands with dialkyl- reduction by the phosphine·borane anion.
phosphines and diarylimidazolines (BIPI 81, 83, and Reducing the size of the peri substituent to fluo-
4) showed low conversion, low selectivity, or both. rine, however, gave a successful S Ar reaction which,
naphthalenes. The higher halogens (Cl, Br) suffered
8
N
Ligands with aryl groups on phosphorus and carbon in turn, led to the 8-fluoro ligand BIPI 238. When the
BIPI 93, 201–203, 205) all gave full conversion, yet iridium complex of this ligand was screened against
the highest selectivity observed was 89:11 er (BIPI olefin 1, full conversion with 98:2 er was obtained.
3). Aryl P-substitution paired with C-alkyl groups The selectivity observed with BIPI 238 is the highest
BIPI 206) gave full conversion yet a diminished er of ever reported for this challenging substrate.
4:16. The fourth subclass, with alkyl substitution for The synthetic limitations described above prevent
(
9
(
8
both elements, proved to be optimum as long as small a complete study of steric and electronic effects of the
alkyl groups (Et, i-Pr) were avoided. BIPI 207, with peri position in this ligand series. A fluorine electron-
a phenyl ligand core and cyclohexyl on phosphorus, ic effect seems unlikely, though, in light of the re-
provided product 2 with full conversion and 94:6 er. duced selectivity seen with less electron-donating P-
When the analogous naphthyl core ligand to BIPI substituents. Our current working hypothesis is thus
2
07, (BIPI 210), was examined, quantitative conver- steric in origin. Fluorine has a larger covalent
[
11]
sion with a slightly higher selectivity (95:5 er) was ob- radius (~60 pm vs. 31 pm), than hydrogen, as well
served.
[
12]
as a larger A value
(0.15 vs. 0.0). The steric de-
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Adv. Synth. Catal. 2013, 355, 1455 – 1463

Tuning the Peri Effect for Enantioselectivity: Asymmetric Hydrogenation of Unfunctionalized Olefins
cult to hydrogenate enantioselectively. The P-aryl/C-
aryl combination was again found to be the poorest
ligand subclass. With substrate 4, only the alkyl/alkyl
substitution pattern led to full conversion with enan-
tioselectivities above 90:10 er. The superiority of the
8-fluoro ligand BIPI 238 was again observed, provid-
ing the target with full conversion and 95:5 er. The
less sterically demanding 8-H ligand, BIPI 210, fur-
nished 5 in 93:7 er. In all cases, only a single diaste-
reomer was observed.
In comparison, the optimzed PHOX ligand gave 5
[
7]
in 89:11 er, although without complete conversion,
[
8]
while the best zirconocene catalyst has been report-
ed to give 5 in 96:4 er, yet this was carried out under
Figure 3. ORTEP diagram of the crystal structure of the almost 200 bar of H2.
zinc complex.
Two additional unfunctionalized olefin substrates
were then studied, using a more reduced list of li-
mands of this substituent may in effect be “magni- gands. As shown in Scheme 2, treatment of (E)-a-
fied” by the unique interactions of 1,8-disubstituted methylstilbene 6 with the iridium complex of either
naphthalenes. Insight into the sterics of these systems BIPI 210 or BIPI 238 under 1 bar of H gave adduct 7
2
was gained through examination of the zinc complex in >99:1 er.
precursor to BIPI 210. The crystal structure is shown
in Figure 3.
Reduction of phenyldihydronaphthalene 8 under
1 bar of H with BIPI 238 (Scheme 3) gave adduct 9
2
The distances from the peri proton (H-3) to the in 96:4 er, while the branched, acyclic-amide ligand
two methine protons of the phosphine cyclohexyl BIPI 235 provided the reduced product with an even
rings (H-26, H-32) are only 1.997 and 2.151 ꢁ, and higher selectivity of 97:3 er.
the peri HÀP distance is just 2.771 ꢁ. All values are
In summary, systematic optimization of the BIPI
ligand platform has led to catalysts capable of asym-
less than the sum of the van der Waals radii.
With several highly enantioselective catalysts in metric hydrogenation of unfunctionalized olefins with
hand, additional unfunctionalized olefin substrates selectivities among the best reported for these diffi-
were then examined. Asymmetric hydrogenation of cult substrates. The importance of the naphthyl peri
dimethyldihydronaphthalene 4 was studied, and the
results are shown in Table 2.
Direct comparisons to the indene substrate 1 reveal
that the dihydronaphthalene 4 is generally more diffi-
Table 2. AH of dimethyldihydronaphthalene 4.
Scheme 2. AH of trisubstituted olefin 6.
Ligand
% Conversion
er of 5
BIPI 81
BIPI 83
BIPI 84
BIPI 93
BIPI 153
BIPI 201
BIPI 202
BIPI 203
BIPI 205
BIPI 206
BIPI 207
BIPI 210
BIPI 238
26
100
47
56:44
54:46
51:49
67:33
54:46
55:45
58:42
65:35
57:43
87:13
90:10
93:7
89
100
100
100
100
100
100
100
100
100
95:5
Scheme 3. AH of olefin 8.
Adv. Synth. Catal. 2013, 355, 1455 – 1463
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Carl A. Busacca et al.
COMMUNICATIONS
position, first observed in the hydrogenation of func- 1N NaOH (500 mL) was added, and the resulting mixture
stirred vigorously. After ~5 min, the product began to pre-
cipitate from the organic phase. After 15 min, the 2-phase
slurry was filtered. The filter cake was washed first with
CH Cl (~150 mL), then with H O (~500 mL). The resultant
damp white solid was then dried on the frit under a flow of
nitrogen for 4 h. As the crop 1 solids were drying, the origi-
nal 2-phase filtrate was processed as follows: the phases
tionalized olefins, has now been seen to operate for
unfunctionalized olefins as well. By judicious choice
of the ligand substituents, multiple classes of sub-
strates can now be hydrogenated by these systems
with excellent selectivity. Further applications of the
naphthyl core BIPI ligands in olefin asymmetric hy-
drogenation are currently in progress.
2
2
2
were separated, and the organic phase washed with H O
2
(
1ꢂ700 mL), dried (MgSO ), and the solvents removed in
4
vacuo to give a yellow solid. This solid was then suspended
in MTBE (~200 mL) and the mixture heated to reflux. The
slurry thus obtained was then filtered hot. The filter cake
was then washed with MeOH (~100 mL) and air-dried on
the frit to give 12.5 g of a light yellow powder. HPLC
showed both crops were completely pure. KF of crop 1 after
Experimental Section
General Remarks
1
13
H and C NMR chemical shifts were calibrated vs. the deu-
1
13
terated solvent used. H and C NMR data in CDCl were
3
4 h drying showed <1000 ppm H O, and 34.4 g of the fluoro-
2
calibrated using 7.24 ppm and 77.0 ppm, C D using 7.20 and
6
6
naphthylimidazoline was obtained as a white powder. The
1
28.0 ppm, CD Cl using 5.32 and 53.5 ppm, and DMSO-d
2 2 6
11
combined yield of both crops was 46.9 g (70%); mp 197–
1
using 2.49 and 39.5 ppm. B NMR chemical shifts are unca-
librated. All NMR spectra were collected on Bruker Avance
1
998C. H NMR (500 MHz, CDCl ): d=8.13 (m, 2H), 7.83
3
(
m, 1H), 7.62 (d, J=9 Hz, 1H), 7.56 (m, 2H), 5.70 (br s,
1
13
spectrometers equipped with a 5 mm BBI probe ( H, C,
1
H), 1.81–1.65 (m, 10H), 1.41 (m, 2H), 1.31–1.00 (m, 10H);
31
19
1
3
3
P) or a 5 mm QNP probe ( F), each with z-gradient, at
C NMR (500 MHz, CDCl ): d=157.8 (s, J =2 Hz), 157.0
3
C,F
1
13
19
31
1
3
08C, unless otherwise indicated. H, C, F, and P NMR
(
s, J =256 Hz), 135.7 (s, JC,F =6 Hz), 127.9 (d), 127.5 (d,
C,F
1
1
3
spectra frequencies were H: 600, 500 or 400 MHz; C: 150,
JC,F =3 Hz), 126.7 (d, JC,F =2 Hz), 126.6 (d, JC,F =4 Hz), 123.6
d, JC,F =4 Hz), 123.5 (s, JC,F =11 Hz), 121.1 (d, JC,F =7 Hz),
12.7 (s, JC,F =9 Hz), 73.6 (d), 64.1 (d), 43.4 (d), 28.9 (t), 28.6
1
9
31
1
1
25, or 100 MHz; F: 471 or 376 MHz; P: 202 or
15
(
62 MHz; N: 51 MHz. Where multiplicity is determined
1
13
1
9
for C NMR data, any multiplicity listed first (s, d, t, q)
(
t), 26.7 (t), 26.4 (t), 26.3 (t); F NMR (471 Hz, CDCl ): d=
3
1
refers to multiplicity with respect to H. If coupling to other
À123.8; HR-MS: m/z=379.2553, calcd. for [C H FN +
2
5
31
2
19
31
11
+
nuclei is present ( F, P, B.), that coupling constant is
listed second, and normally explicitly described. Boron is
a quadrupolar nucleus with spin of 3/2. It therefore causes
H ]: 379.2544 (error=2.36 ppm).
3
1
quadrupolar line broadening of attached nuclei, here P and
BIPI 210, Part 2: S Ar Reaction/Zinc Complex
N
1
H. This is seen in the spectra of all phosphine·borane start-
Formation
ing materials and products.
A 3-neck 2-L flask equipped with a direct argon line and
septa was charged with (S,S)-fluoronaphthylimidazoline
Accurate mass measurements were performed on a time
of flight mass spectrometer (LC/MSD TOF) operating in
a positive electrospray ionization mode with the capillary
voltage of 3 kV. The mass spectrometer was tuned and cali-
brated using a tuning mix prior to sample analysis. Samples
were introduced to the mass spectrometer by flow injection
using an HPLC system. All reagents were used as received
unless stated otherwise.
All free secondary phosphines are pyrophoric and should
be handled with great care. Dicyclohexylphosphine·borane
and di-tert-butylphosphine·borane were purchased and used
as received.
(
(
(
50.0 g, 132 mmol, 1 equiv.), dicyclohexylphosphine·borane
33.6 g, 158 mmol, 1.2 equiv.) and anhydrous DMAc
300 mL) in the order given. Argon sparging beneath the
surface of the white suspension was then started. After
5 min, the flask was placed in an ice bath, then 60% NaH
11.65 g, 290 mmol, 2.2 equiv.) was added in 2 portions,
10 min apart, causing immediate gas evolution and foam-
1
(
~
ing, and giving a yellow reaction mixture. After 15 min, the
ice bath was removed and the mixture allowed to warm to
room temperature. After 20 min at room temperature,
argon sparging was stopped and the white suspension was
stirred vigorously under argon. After stirring 14 h at room
temperature, a dark red solution was present. HPLC
showed that the starting material had been consumed, and
All of the deprotonations with NaH described below
cause (caution!) gas evolution (H ) and foaming to various
degrees. It is therefore best to use an oversize flask or reac-
tor to contain the foams that are generated.
2
~
6:1 ratio of product:de-boronated product was present.
The reaction mixture was cautiously poured onto ice
BIPI 210, Part 1: Fluoronaphthylimidazoline
3
(
500 cm )+saturated NH Cl (300 mL). The resulting mix-
4
A 3-neck 2-L flask was charged with 1-fluoro-2-naphthalde-
hyde (31.0 g, 178 mmol, 1 equiv.), CH Cl (700 mL), and
ture was then extracted with EtOAc (2ꢂ500 mL). The com-
bined organics were then washed with H O (1ꢂ500 mL),
2
2
2
crystalline (S,S)-1,2-dicyclohexylethylenediamine (40.0 g,
78 mmol, 1 equiv.) in the order given. The resulting yellow
solution was stirred under argon at room temperature. After
h at room temprature, the flask was cooled in an ice bath,
then NBS (33.1 g, 187 mmol, 1.05 equiv.) was added neat, at
once. The mixture was then allowed to slowly warm to room
temperature under argon. After 2 h at room temperature,
dried (MgSO ), and the solvents removed under vacuum to
4
1
give a yellow foam. This foam was then dissolved in MTBE
(750 mL) in a 2-L 3-neck flask. To this solution, stirring
under argon at room temperature, was then added 4N HCl/
p-dioxane (33 mL, 132 mmol, 1 equiv.) dropwise via syringe
over ~10 min, giving a thick slurry of the HCl salt. After
3
15 min, the slurry was filtered under N . The solids were
2
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Adv. Synth. Catal. 2013, 355, 1455 – 1463

Tuning the Peri Effect for Enantioselectivity: Asymmetric Hydrogenation of Unfunctionalized Olefins
then pulverized under MTBE on the frit and re-filtered
from The Cambridge Crystallographic Data Centre via
under N . After ~30 min, 88 g (~100%) of crude, dry, phos-
www.ccdc.cam.ac.uk/data_request/cif.
2
phineborane imidazoline HCl salt was obtained as a light
yellow powder. A 3-neck 2-L flask equipped with a direct
argon line, reflux condenser and septum with thermocouple
was charged with free base (S,S)-imidazolinephosphine·bor-
ane [82.7 g, 0.145 mol, from 88 g HCl salt after partitioning
BIPI 210 Part 3: Decomplexation
A 3-neck 100-mL flask equipped with a direct argon line,
inert gas valve and septum was charged with the phosphinoi-
midazoline·zinc chloride complex i-PrOH solvate (1.00 g,
1.33 mmol, 1 equiv.), and CH Cl (15 mL). Argon sparging
between 0.5N NaOH and EtOAc and drying (MgSO )] and
4
190 proof ethanol (450 mL). Argon sparging beneath the
2
2
yellow solution surface was then started. After 10 min,
argon sparging was stopped, and the mixture heated to
gentle reflux under argon. After 45 min at reflux, HPLC
showed that the de-boronation was complete to a longer-re-
tention time peak. The mixture was then cooled to room
temperature while sparging with argon and the solvents
were then removed under vacuum. The residual yellow
semi-solid was then dissolved in THF (500 mL) which had
been de-oxygenated by sparging vigorously with N2 for
beneath the colorless solution surface was then started.
After 10 min, ethylenediamine (0.178 mL, 2.66 mmol,
2 equiv.) was added at once via syringe, causing immediate
formation of a white precipitate. After 15 min, the reaction
mixture was filtered under a vigorous flow of N
a thin Celite pad in a medium-fritted filter funnel into
a 100-mL 1-neck flask, washing the pad with CH Cl (~
through
2
2
2
5 mL). The solvents were then removed under vacuum, and
the residual solids dried under high vacuum to give 0.75 g (~
1
00%) of the free phosphinoimidazoline product as a light
3
0 min prior to use, and placed in a 3-neck 2-L flask
equipped with a direct argon line, inert gas valve, septum
with thermocouple, and graduated 250 mL addition
yellow foam which was used without further purification.
a
funnel. Argon sparging beneath the yellow solution surface
was then started. After 10 min, 1M ZnCl /Et O (145 mL,
BIPI 210 Part 4: Acylation
2
2
0
.145 mol, 1 equiv.) was charged to the addition funnel via
The free phosphinoimidazoline described above was dis-
solved in CH Cl (10 mL) and transferred to a 3-neck 50-mL
cannula under N pressure. While continuing to sparge with
2
2
2
argon, this solution was then added dropwise over ~10 min
flask. The solution was then cooled under argon to ~28C in
an ice bath. TEA (0.37 mL, 2.66 mmol, 2 equiv.) was then
added via syringe, followed after 5 min by CyCOCl
(0.18 mL, 1.33 mmol, 1 equiv.). After a further 5 min, the ice
bath was removed. After 30 min at room temperature,
N,N,N’-trimethylethylenediamine (0.10 mL) was added to
scavenge any unreacted acid chloride. The volatiles were
then removed under vacuum. The residue was partitioned
between EtOAc (20 mL) and 0.5N HCl (20 mL) and the
phases were separated. The organic phase was then washed
with saturatedd NaHCO (1ꢂ20 mL), dried (MgSO ), and
to the well-stirred reaction mixture, causing an exotherm
from 22.48C to 25.38C. When ~60% of the ZnCl solution
2
had been added, the reaction mixture converted from
a clear yellow solution to a white suspension. After 20 min,
the volatiles were removed under vacuum. To the residue, in
a round-bottom flask, was then added i-PrOH (200 mL) and
the mixture heated to reflux under argon. A clear solution
was never obtained, though crystallization occurred in
a slurry-to-slurry conversion. After 10 min at reflux, the
mixture was cooled to room temperature and the resultant
3
4
the solvents removed under vacuum to give a light yellow
foam. This material was then chromatographed on silica gel
slurry filtered under a vigorous flow of N in a medium-frit-
2
ted filter funnel, washing the filter cake with additional i-
PrOH (~50 mL). After 20 min drying on the frit, 73.4 g
under N pressure, eluting with 6:1 hexane: EtOAc, and cap-
2
ping fractions as soon as they were collected to prevent any
oxidation. The active fractions were then combined and con-
centrated under high vacuum to give 0.656 g BIPI 210
(
73%) of the phosphinoimidazoline·zinc chloride complex
was obtained as a dense, white powder, which crystallized as
1
the mono-i-PrOH solvate; mp >2508C. H NMR (500 MHz,
(
74%) as a light yellow foam. Note: Hindered rotation in
DMSO-d ): d=8.48 (br s, 1H), 8.37 (d, J=8 Hz, 1H), 8.20
6
these ligands coupled with many conformations of the five
cyclohexyl rings leads to extreme line broadening in all
nuclei, with peak doubling and broad envelopes of resonan-
ces observed, even with highly purified materials. This NMR
(
(
d, J=8 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.73 (m, 1H), 7.69
m, 2H), 4.34 (d, J=4 Hz, 1H), 4.08 (br s, 1H), 3.78 (m,
1
1
H), 3.60 (m, 1H), 3.50 (m, 1H), 2.96 (br s, 1H), 2.63 (m,
H), 2.12 (m, 1H), 2.04 (m, 1H), 1.89–1.07 (m, 42H), 1.04
behavior has been noted previously (Org. Lett. 2008, 10,
1
3
(
d, J=6 Hz, 6H), 1.02–0.73 (m, 3H); C NMR (125 MHz,
1
3
41, see the Supporting Information). H NMR (500 MHz,
1
DMSO-d ): d=165.9 (s), 136.1 (s, JC,P =21 Hz), 134.7 (s,
6
C D ): d=8.41 (br m, 1H), 7.64–7.47 (m, 3H), 7.38 (t, J=
6
6
JC,P =4 Hz), 133.6 (s), 131.5 (d), 129.2 (d), 127.6 (d, JC,P
=
7
Hz, 1H), 7.21 (t, J=7 Hz, 1H), 4.56 (br m, 1H), 3.87 (br
4
Hz), 127.2 (d), 126.9 (d), 71.4 (d), 67.0 (t), 62.0 (d), 61.1
13
m, 1H), 2.71–0.16 (m, 55H); C NMR (125 MHz, C D ):
6
6
1
(
(
(
(
2
d), 41.9 (d, J =49 Hz), 35.1 (d, JC,P =4 Hz), 34.4 (d), 31.4
C,P
d=174.2 (s), 159.0 (s), 144.5 (s), 137.1 (s), 136.6 (s), 134.6
t), 31.3 (t), 30.6 (t), 29.3 (t), 28.0 (t), 27.9 (t), 27.7 (t), 27.4
t), 26.45 (t), 26.38 (t), 26.27 (t), 26.25 (t), 26.16 (t), 26.12
t), 26.04 (t), 26.00 (t), 25.74 (t), 25.66 (t), 25.63 (t), 25.5 (q),
(
(
s), 134.3 (s), 130.7 (d), 130.2 (d), 127.8 (d), 127.2 (d), 127.1
d), 127.0 (d), 74.1 (d), 73.4 (d), 65.9 (d), 65.3 (d), 43.5 (d),
4
3.1 (d), 38.1 (d), 38.0 (d), 37.2 (d), 37.1 (d), 35.0 (t), 34.8
3
1
5.4 (t), 25.2 (t), 25.1 (t); P NMR (202 MHz, DMSO-d ):
6
(t), 34.2 (t), 34.0 (t), 33.9 (t), 31.4 (t), 31.3 (t), 30.4 (t), 30.1
(t), 29.8 (t), 29.5 (t), 28.2 (t), 28.0 (t), 27.4 (t), 27.3 (t), 27.2
d=À8.94; HR-MS: m/z=557.4014, calcd. for [C H N P+
3
7
53
2
+
31
H ]: 557.4019 (error=0.92 ppm).
(t), 27.1 (t), 26.9 (t), 26.2 (t), 26.0 (t), 25.7 (t); P NMR
The crystal structure data for the complex have been de-
posited with the Cambridge Crystallographic Database
(202 MHz, C D ): d=À0.53 (minor), À4.43 (major); HR-
6
6
+
MS: m/z=667.4759, calcd. for [C H N OP+H ]: 667.4751
4
4
63
2
(
CCDC 915865). These data can be obtained free of charge
(error=1.2 ppm).
Adv. Synth. Catal. 2013, 355, 1455 – 1463
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1459

Carl A. Busacca et al.
COMMUNICATIONS
BIPI 210 Iridium Complex
chromatography on silica gel with pentane as eluent. The
major fraction was again carefully concentrated to give 8.5 g
of a pale pink solution, which contained about 1.1 g 1,8-di-
fluoronaphthalene (~67%) by NMR assay. Complete re-
moval of solvent was avoided because of the volatility of the
A 3-neck 100-mL flask equipped with a direct argon line,
inert gas valve and septum was charged with (S,S)-BIPI 210
(
0.395 g, 0.592 mmol, 1 equiv., weighed in glovebox), [Ir-
ACHTUNGTRENNUNG( COD)Cl] (0.216 g, 0.326 mmol, 0.55 equiv., 1.1 Ir equiv.,
2
desired compound, and the solution was used directly in the
weighed in glovebox), and dry CH Cl (17 mL) was then
added via syringe. Slow argon sparging beneath the surface
2
2
1
subsequent step. H NMR (400 MHz, CDCl ): d=7.59 (H-4,
3
dd, J=0.8, 8.0 Hz, 2H), 7.39 (H-3, tt, J=2.4, 8.0 Hz, 2H),
of the red solution was started immediately. After 5 min,
1
3
F
7.13 (H-2, m, 12 lines, 2H); C NMR (100 MHz, CDCl
):
3
NaBAr (0.571 g, 0.650 mmol, 1.1 equiv.) was added at once.
1
3
d=157.6 (s, C-1, J =259 Hz, J =12 Hz), 137.3 (s, C-4a,
C,F
C,F
After 30 min at room temperature, TLC (CH Cl ) of an ali-
2
2
3,3
3,5
J
=3, 3 Hz), 126.7 (d, C-3, J =3, 3 Hz), 123.4 (d, C-
C,F
,4
C,F
2,2
quot showed the expected very non-polar red spot for the
4
F
4, J =4, 4 Hz), 114.4 (s, C-8a, JC,F =12, 12 Hz), 111.2 (d,
C-2, JC,F =10, 13 Hz); F NMR (471 MHz, CDCl ): d=
C,F
,4
anion-exchanged BAr complex. The volatiles were then re-
2
19
3
moved under vacuum and the residue chromatographed on
silica gel under N pressure eluting with 3:1 CH Cl :hexane,
+
À115.8. GC-MS: 164 (M ), 144, 123.
2
2
2
A 3-neck 100-mL flask equipped with an inert gas valve
and septum with thermocouple was evacuated/argon filled
collecting only the center fractions, to give 0.90 g (83%) of
F
the BIPI 210 iridium BAr complex as a red foam. Note:
(
2ꢂ), then it was charged with dry THF (9.0 mL) via sy-
Hindered rotation in these ligands coupled with different
conformations of the five cyclohexyl rings leads to extreme
line broadening in all nuclei, peak doubling or trebling, and
broad envelopes of resonances observed, even with highly
purified materials. In addition, there is quadrupolar line
ringe, and the solution cooled to À788C under argon. Once
equilibrated, 1.4M sBuLi/cyclohexane (3.70 mL, 5.19 mmol,
1.1 equiv.) was added dropwise via syringe over 10 min
while maintaining the internal temperature below À608C,
giving a yellow reaction mixture. After aging for 15 min,
a solution of 1,8-difluoronaphthalene (0.773 g, 4.71 mmol,
1 equiv.)+pentane (6.0 mL) was added dropwise via syringe
over ~5 min, giving a dark green reaction mixture. The re-
sultant mixture was then aged for 3 h at À788C, at which
point an orange reaction mixture was present. Dry DMF
(0.45 mL, 5.75 mmol, 1.2 equiv.) was then added dropwise
via syringe over ~5 min. After 5 min, the À788C bath was
replaced with a 08C bath. After 15 min at ~08C, TLC
1
91
193
broadening caused by abundant Ir and Ir (both spin
/2). This NMR behavior has been noted previously (Org.
3
Lett. 2008, 10, 341, see the Supporting Information).
1
H NMR (500 MHz, CD Cl ): d=7.77 (s, 9H), 7.61 (s, 5H),
2
2
7
.37 (m, 6H), 5.11–3.77 (m, 2H), 2.84–0.35 (m, 63H);
1
3
2
C NMR (125 MHz, CD Cl ): d=176.0 (s), 162.2 (s, J =
C,F
2
2
4
5
0 Hz), 149.8 (d), 135.2 (d), 129.3 (s, qq, C-B, J =3 Hz,
C,F
1
1
JC,B =32 Hz), 125.0 (s, C-F, J =270 Hz), 117.8 (d, 5 lines,
C,F
J=4 Hz), 93.5 (d, J=9 Hz), 86.4 (d, J=13 Hz), 70.2 (d), 67.6
(
d), 66.8 (d), 63.4 (d), 44.7 (d), 44.3 (d), 42.2 (d), 39.2 (d,
(
hexane) showed clean conversion to a significantly more
JC,P =23 Hz), 37.3 (d, JC,P =4 Hz), 32.5 (d, JC,P =27 Hz), 31.4
polar, brilliantly blue-fluorescing spot. The reaction was
quenched at 08C by the slow addition of 0.5N HCl (10 mL),
(
(
t), 30.8 (t), 30.1 (t), 29.9 (t), 29.7 (t), 29.5 (t), 29.3 (t), 29.2
t), 29.1 (t), 28.3 (t), 27.2–25.3 [broad baseline below 17
then H O (15 mL) and MTBE (25 mL) were added. The
2
31
lines, all (t)]; P NMR (202 MHz, CD Cl ): d=55.5 (major
2
2
phases were then separated and the aqueous phase re-ex-
tracted with MTBE (1ꢂ50 mL). The combined organics
isomer); HR-MS: m/z=943.5173, calcd. for [C H IrN OP]:
5
0
75
2
943.5241 (error=7.2 ppm).
were then dried washed with H O (1ꢂ25 mL), dried
2
(
MgSO ), and the solvents removed under vacuum to give
4
BIPI 238, Part 1: 1,8-Difluoro-2-naphthaldehyde
an orange solid. This material was then fully dissolved in
boiling cyclohexane (~6 mL) and allowed to cool to room
temperature while standing, causing crystallization. The
slurry thus obtained was then filtered, using a small amount
of cyclohexane to transfer the slurry and wash the cake.
After air-drying on the frit ~10 min, 0.420 g (46% first crop
recrystallized yield) of 1,8-difluoro-2-naphthaldehyde was
obtained as a yellow, crystalline solid. The filtrates were
concentrated to give an orange solid, which was then chro-
matographed on silica gel eluting with 10:1 hexane:EtOAc
to give a further 0.20 of the aldehyde as a yellow solid. The
To a 250-mL three-neck flask with magnetic stirring bar,
rubber septum, and low temperature thermometer, was
charged with 1,8-dibromonaphthalene (2.84 g, 10 mmol,
1
equiv.). The reaction flask was evacuated and then refilled
with N (3ꢂ). Anhydrous THF (50 mL) was then added via
2
syringe. The reaction mixture was cooled to À788C by a dry
ice/acetone bath. 1.6M nBuLi/hexane (20 mL, 32 mmol,
3.2 equiv.) was added dropwise via syringe, keeping the in-
ternal temperature below À688C. After the addition was
complete, the reaction mixture was further stirred for 1 h at
À758C. NFSI (9.45 g, 30 mmol, 3 equiv.) was then dissolved
in anhydrous THF (25 mL), and the resultant solution was
added to the reaction mixture via syringe, keeping the inter-
nal temperature below À508C. Without removal of the cool-
ing bath, the reaction mixture was allowed to warm up over-
night and stirred for another 4 h at room temperature the
following day. The reaction mixture was then filtered to
remove insoluble by-products. A sample from the filtrate
was checked by GC-MS, which showed the desired 1,8-di-
fluoronaphthalene as the major component. The filtrate was
carefully concentrated (~208C/100 mm) by rotary evapora-
tion (caution! the product is volatile!), and purified by
1
combined yield was 0.62 g (69%); mp 86–878C. H NMR
(
(
(
500 MHz, C D ): d=10.28 (s, H-9, J =0.7 Hz, 1H), 7.71
dd, H-3, J=6, 9 Hz, 1H), 6.93 (m, H-4+H-5, 2H), 6.82
ddd, H-6, J=5, 8, 8 Hz, 1H), 6.67 (ddd, H-7, J=0.8, 8,
6 6 H,F
1
3
1
2 Hz, 1H); C NMR (125 MHz, C D ): d=185.7 (d, C-9,
6 6
3
3
1
JC,F =10 Hz), 162.3 (s, C-1, J =2 Hz, J =272 Hz), 159.0
C,F
C,F
3
1
3,3
(
s, C-8, J =1.4 Hz, J =260 Hz), 140.1 (s, C-4a, JC,F =2,
C,F
C,F
5
5
,3
,3
4,4
3,5
4 Hz), 130.2 (d, C-6,
5 Hz), 124.1 (d, C-5,
2 Hz), 120.9 (s, C-2,
J
J
J
C,F =2, 8 Hz), 124.4 (d, C-4,
C,F =3, 5 Hz), 123.7 (d, C-3,
J
J
C,F =3,
C,F =2,
J =
C,F
4
,2
2,2
C,F =2, 6 Hz), 114.4 (s, C-8a,
4
,2
19
12, 12 Hz), 112.7 (d, C-7,
JC,F =2, 20 Hz); F NMR
(470 MHz, CDCl ): d=À112.7 (F-8, J =66 Hz), À123.6
3
F,F
1460
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1455 – 1463

Tuning the Peri Effect for Enantioselectivity: Asymmetric Hydrogenation of Unfunctionalized Olefins
(
F-1, JF,F =66 Hz); HR-MS: m/z=210.0724, calcd. for
with EtOAc (2ꢂ25 mL). The combined organics were then
washed with H O (2ꢂ50 mL), dried (MgSO ), and the sol-
+
C H F O+NH ]: 210.0725 (error=0.46 ppm).
11
6
2
4
2
4
vents removed under vacuum to give a yellow oil. This oil
was then fully dissolved in MTBE (25 mL) and transferred
to a 100-mL 3-neck flask equipped with direct argon line,
inert gas valve and septum. To this solution, stirring under
argon at room temperature, was then added 4N HCl/p-diox-
ane (0.41 mL, 1.65 mmol, 1 equiv.) dropwise via syringe over
BIPI 238, Part 2: Difluoronaphthylimidazoline
A 3-neck 50-mL flask was charged with 1,8-difluoro-2-naph-
thaldehyde (0.60 g, 3.12 mmol, 1 equiv.), CH Cl (12 mL),
2
2
and
crystalline
(S,S)-1,2-dicyclohexylethylenediamine
(
0.701 g, 3.12 mmol, 1 equiv.) in the order given. The result-
~
3 min, giving a thick slurry of the HCl salt. After 15 min,
ing yellow solution was stirred under argon at room temper-
ature. After 2.5 h at room temperature, the flask was cooled
in an ice bath, then NBS (0.58 g, 3.28 mmol, 1.05 equiv.) was
added neat, at once. After 15 min at ~28C, the ice bath was
replaced by a cool water bath. After 2 h at room tempera-
ture, 1N NaOH (25 mL) was added, and the resulting mix-
ture stirred vigorously, causing a precipitate to form. After
the slurry was filtered under N . The solids were then pulv-
2
erized under MTBE on the frit and re-filtered under N2.
After ~15 min, 0.98 g (~95%) of the dry HCl salt was ob-
tained as a non-hygroscopic, pale yellow powder. NMR
showed it was a mixture of the phosphine·borane and the
free phosphine, so the mixture was then fully de-protected
as follows: A 3-neck 100-mL flask equpped with a direct
argon line, reflux condenser with inert gas valve and septum
was charged with absolute EtOH (40 mL) and argon sparg-
ing beneath the solution surface was started. After 15 min,
the crude phosphine borane·HCl salt (0.75 g, ~1.20 mmol,
15 min, the slurry was filtered, washing the solids with H O
2
(
1ꢂ25 mL). The solids were then pulverized on the frit
under hexane (~25 mL), then filtered and air-dried on the
frit for 60 min to give 1.2 g of a yellow powder. This solid
was then fully dissolved in boiling n-heptane (60 mL) and al-
lowed to cool to room temperature while standing, causing
crystallization. The resultant slurry was then filtered, and
the solids air-dried on the frit to give 0.687 g (55% 1st crop
1
equiv.) was added, and the flask was placed in a pre-equili-
brated 788C oil bath. Argon sparging was then stopped,
H O was flowed through the condenser, and the light yellow
2
solution was heated at gentle reflux under argon. After
recrystallized yield) of the difluoronaphthylimidazoline as
6
0 min at reflux, HPLC showed complete conversion to
1
a
fluffy, light yellow solid; mp 183–1848C. H NMR
a later-eluting peak. TLC (basic alumina, EtOAc) showed
conversion to a much slower-moving spot. The reaction mix-
ture was cooled, and then the volatiles were removed under
vacuum. The residue was then azeotroped with PhMe at the
Rotovap (1ꢂ50 mL) and finally dried under high vacuum to
give 0.65 g of a yellow solid. This solid was then partitioned
(
500 MHz, C D ): d=8.59 (dd, H-3, J=7, 8 Hz, 1H), 7.17
6 6
(
dd, H-4, J=2.1, 8 Hz, 1H), 7.04 (dd, H-5, J=1.6, 8 Hz,
1
8
3
1
H), 6.85 (ddd, H-6, J=5, 8, 13 Hz, 1H), 6.77 (dd, H-7, J=
, 12 Hz, 1H), 5.48 (br s, N-H, 1H), 3.85 (br s, H-10, 1H),
.21 (br s, H-11, 1H), 2.04 (br s, 1H), 1.89–1.47 (m, 10H),
1
3
.46–0.75 (m, 11H); C NMR (125 MHz, C D ): d=158.2 (s,
6
6
3
1
3
between EtOAc (50 mL) and saturated NaHCO
The phases were separated and the organic phase was dried
(MgSO ), and the solvents removed under vacuum. The resi-
due was then chromatographed under N pressure on basic
3
(50 mL).
C-8, J =2 Hz, J =254 Hz), 157.1 (s, C-9, J =2 Hz),
C,F
C,F
C,F
3
1
1
56.1 (s, C-1, JC,F =2 Hz, JC,F =256 Hz), 138.0 (s, C-4a,
3
,3
5,3
4
JC,F =2.5, 4 Hz), 128.9 (d, C-3, JC,F =1.6, 3.5 Hz), 128.2
4
,4
2
(
d, C-6,), 123.5 (d, C-5,
J
=3, 4.5 Hz), 123.4 (d, C-4,
C,F
4,2
4
3
,4
,3
alumina (Activity I), eluting with EtOAc and capping frac-
tions as soon as they were collected to prevent oxidation.
After concentration under vacuum, the residue was azeo-
troped with cyclohexane (1ꢂ20 mL) at the Rotovap, to give
a yellow foam. This material was then fully dissolved in
JC,F =3, 4 Hz), 115.1 (s, C-2,
JC,F =11, 14 Hz), 111.9 (d, C-7, JC,F =1.6, 21 Hz), 74.2 (d,
J
C,F
4,2
=2, 9 Hz), 114.2 (s, C-8a,
C-11), 64.3 (d, C-10), 44.2 (d), 43.5 (d), 29.7 (t), 29.3 (t), 29.1
1
9
(
(
(
t), 28.4 (t), 27.1 (t), 26.8 (t), 26.4 (t), 26.3 (t); F NMR
470 MHz, CDCl ): d=À114.7 (F-8, J =69 Hz), À117.2
3
F,F
2
.0 mL boiling MeOH and allowed to cool to room temper-
F-1,
J =69 Hz); HR-MS; m/z=397.2445, calcd. for
F,F
+
ature while standing under argon, causing crystallization.
After 30 min at room temperature, the slurry was filtered
[C H F N +H ]: 397.2450.
25 30 2 2
under N to give 530 mg (69%, 0.83 mmol) of the free phos-
2
BIPI 238, Part 3: S Ar Reaction/De-Boronation
N
phinoimidazoline as a pale yellow solid, which crystallized
1
as the bis-methanol solvate; mp 101–1028C. H NMR
A 3-neck 25-mL flask equipped with a direct argon line,
inert gas valve and septum was charged with (S,S)-difluoro-
naphthylimidazoline (0.656 g, 1.65 mmol, 1 equiv.), dicyclo-
hexylphosphine·borane (0.420 g, 1.97 mmol, 1.2 equiv.) and
anhydrous DMAc (5.0 mL) in the order given. Argon sparg-
ing beneath the surface of the thick yellow suspension was
then started. After 15 min, the flask was placed in an ice
bath, then 60% NaH (0.145 g, 3.62 mmol, 2.2 equi.v) was
added at once, causing immediate gas evolution and foam-
ing, and giving a yellow reaction mixture. After 5 min, the
ice bath was removed and the mixture allowed to warm to
room temperature, at which point it was a wine-red color.
After 4 h at room temperature, HPLC (@ 230 nm) showed
(
(
(
500 MHz, C D ): d=7.72 (dd, H-3, J=3, 8 Hz, 1H), 7.50
d, H-5, J=8 Hz, 1H), 7.26 (dd, H-5, J=1, 8 Hz, 1H), 7.00
ddd, H-7, J=1.3, 7.5, 7.5 Hz, 1H), 6.96 (m, H-6, 1H), 5.05
6 6
(br s, N-H, 1H), 3.98 (br s, H-10, 1H), 3.35 (br s, H-11, 1H),
3.08 (s, H-14, 6H), 2.57 (m, H-15 + H-16, 2H), 2.34–0.80
1
3
(m, 42H); C NMR (125 MHz, C
J
D
6
): d=165.6 (s, C-9,
6
3
1
C,P =9 Hz), 160.2 (s, C-8, JC,F =252 Hz), 146.6 (s), 136.9 (s,
C-4a, J=5 Hz), 130.7 (d, C-4), 128.9 (d, C-3, JC,P =11 Hz,
C,F =1 Hz), 126.6 (d, C-7, JC,F =9 Hz), 126.4 (d, C-5, J=
3 Hz), 125.2 (s), 113.3 (d, C-7, JC,F =25 Hz), 77.3 (d, C-10),
3
5
3
J
2
65.7 (d, C-11), 50.4 (q, C-14), 44.7 (d, C-12/13), 43.4 (d, C-
1
12/13), 36.64 (d, C-15, JC,P =54 Hz, JCF =29 Hz), 36.63 (d, C-
1
96% conversion to a peak with significantly longer retention
16, JC,P =52 Hz, JC,F =2 Hz); note: all tꢃs (CH
ꢃs) follow, yet
2
time than the difluoride starting material. The reaction mix-
ture was cautiously poured onto ice (25 cm )+saturated
J values cannot be determined: 34.2 (t), 33.9 (t), 33.6 (t),
33.4 (t), 32.0 (t), 31.9 (t), 31.7 (t), 31.6 (t), 30.8 (t), 30.4 (t),
29.9 (t), 27.9 (t), 27.8 (t), 27.75 (t), 27.70 (t), 27.66 (t), 27.63
3
NH Cl (25 mL). The resulting mixture was then extracted
4
Adv. Synth. Catal. 2013, 355, 1455 – 1463
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1461

Carl A. Busacca et al.
COMMUNICATIONS
(
(
t), 27.57 (t), 27.55 (t), 27.5 (t, br), 27.20 (t), 27.19 (t), 26.99
was then added at once, giving a bright orange solution.
After 10 min, (S,S)-BIPI 238 (0.269 g, 0.393 mmol, 1 equiv.,
weighed in glovebox) was then added at once to the vigo-
rously stirred mixture, giving immediately a dark red solu-
tion. After 20 min, TLC (10:1 hexane:EtOAc) of an aliquot
of the mixture showed a small amount of free ligand re-
mains and there is a major polar spot. After 1.5 h at room
temperature, TLC shows some ligand still remains, so an ad-
ditional 25 mg of the iridium dimer was added. After a fur-
19
t), 26.98 (t); F NMR (376 MHz, C D ): d=À109.31;
6
6
3
1
P NMR (202 MHz, C D ): d=10.74. HR-MS: m/z=
75.3936, calcd. for [C H FN P+H ]: 575.3925 (error=
6
6
+
5
1
37 52 2
.9 ppm).
BIPI 238, Part 4: Acylation
The phosphinoimidazoline bis-methanol solvate (0.500 g,
.78 mmol, 1 equiv.) described above was azeotroped with
F
0
ther 30 min, NaBAr (0.382 g, 0.433 mmol, 1.1 equiv.) was
THF (2ꢂ20 mL) at the Rotovap to remove the methanol
that had co-crystallized. The resultant yellow oil was then
transferred to a 3-neck 50-mL flask equipped with a direct
added neat, at once, to the vigorously stirred reaction mix-
ture. After 30 min, TLC (CH Cl ) shows the reaction is com-
plete to a very non-polar spot. The volatiles were then re-
moved under vacuum to give a red foam. This foam was
2
2
argon line, inert gas valve and septum. CH Cl (12 mL) was
2
2
then added and slow arfon sparging beneath the solution
surface was then started. After 10 min, the flask was placed
in an ice bath, then TEA (0.219 mL, 1.57 mmol, 2 equiv,)
was added via syringe, followed after 2 min by cyclohexane-
carbonyl chloride (0.105 mL, 0.78 mmol, 1 equiv.), added
dropwise via microsyringe over ~2 min. The ice bath was
then removed and the mixture allowed to warm to room
temperature. After 5 min at room temperature, TLC (7:1
hexane:EtOAc) showed the reaction was complete to a non-
polar spot. N,N,N’-Trimethylethylenediamine (0.10 mL) was
then added via syringe to scavenge any unreacted acid chlo-
ride. After 5 min, the volatiles were removed under vacuum
and the residue partitioned between 0.5N HCl (30 mL) and
EtOAc (30 mL). The organic phase was then washed with
then chromatographed on silica gel under N eluting with
2
1
:1 CH Cl :cyclohexane and collecting only the center, pure
2 2
fractions to give a semi-solid. This material was then azeo-
troped with MTBE (1ꢂ40 mL) at the Rotovap and finally
dried under high vacuum to give 0.53 g (73%) of the iridium
complex as a red foam. Note: Hindered rotation in these li-
gands coupled with different conformations of the five cy-
clohexyl rings leads to extreme line broadening in all nuclei,
peak doubling or trebling, and broad envelopes of resonan-
ces observed, even with highly purified materials. In addi-
tion, there is quadrupolar line broadening caused by abun-
1
91
193
dant Ir and Ir (both spin 3/2). This NMR behavior has
been noted previously (Org. Lett. 2008, 10, 341, see the Sup-
1
porting Information). H NMR (500 MHz, CD Cl ): d=
2
2
saturated NaHCO (1ꢂ30 mL), dried (MgSO ), and the sol-
3
4
8.22–7.22 (br m, 5H), 7.64 (s, 11H), 7.47 (s, 5H), 5.01–2.49
13
vents removed under vacuum to give a yellow foam. This
(
br m, 3H), 2.45–0.17 (br m, 60H); C NMR (125 MHz,
2
material was then chromatograhed under N on silica gel
2
CD Cl ): d=162.3 (s, C-CF , J =50 Hz), 135.4 (d), 129.4
2 2 3 C,F
4 1 1
eluting with 7:1 hexane:EtOAc. The pure fractions were col-
lected, and they were capped as soon as they were collected
to prevent oxidation. After concentration under vacuum,
the residue was azeotroped with cyclohexane at the Roto-
vap, and finally dried under high vacuum to give 0.487 g
(
s, qq, C-B, JC,F =3 Hz, JC,B =32 Hz), 125.1 (s, JC,F
=
2
72 Hz), 118.0 (d, 5 lines, J=4 Hz), 63.71 (d, br), 32.1–24.5
1
9
(
br baseline resonances); F NMR (376 MHz, CD Cl ): d=
2 2
31
À62.86; P NMR (202 MHz, CD Cl ): d=40.77, 23.13; HR-
2
2
MS: m/z=985.5083, calcd. for [C H IrN OP]: 985.5147
5
2
74
2
(
91%) of BIPI 238 as a light yellow foam. Note: Hindered
(
error=6.5 ppm).
rotation in these ligands coupled with numerous conforma-
tions of the five cyclohexyl rings leads to extreme line
broadening in all nuclei, with peak doubling and broad en-
velopes of resonances observed, even with highly purified
materials. This NMR behavior has been described previous-
ly (Org. Lett. 2008, 10, 341, see the Supporting Information).
General Procedure. Lab-Scale Screening Asymmetric
Hydrogenations
To a vial were added 29 mg (0.15 mmol) trans-a-methylstil-
1
F
H NMR (500 MHz, C D ): d=7.56 (dd, J=2.5, 8 Hz, 1H),
bene 6, 5.5 mg (0.003 mmol) of Ir-(BIPI-238) AHCTUNETGRNNUN(G COD)BAr
6
6
7.45 (br s, 1H), 7.25 (d, J=8 Hz, 1H), 7.00 (m, 1H), 6.93
and 0.5 mL of degassed CH Cl in the glovebox. The vial
2 2
(
5
m, 1H), 4.55 (br s, 1H), 3.90 (br s, 1H), 2.75–0.40 (m,
was inserted into a HEL CAT 24 autoclave reactor. The au-
toclave was then closed and transferred out of the glovebox.
13
5H); C NMR (125 MHz, DMSO-d ): d=159.7 (s, C-8,
6
1
JC,F =250 Hz), 146.6 (s), 129.9 (d), 129.6 (d), 128.2 (d), 126.4
The reactor was first purged with N (3ꢂ) and then cooled
2
2
(
d), 125.8 (d), 113.0 (d, C-7, J =25 Hz), 73.5 (d), 65.2 (d),
down to 08C followed by a hydrogen purge (3ꢂ). The auto-
C,F
43.2 (d), 42.7 (d), 37.7 (d), 37.6 (d), 37.5 (d), 36.7, 33.5, 31.1,
clave was then pressurized to 1 bar H and stirred at 08C for
2
3
0.3, 29.5, 29.2, 27.3, 27.2, 27.1, 26.8, 26.7, 26.6, 25.7;
20 h. The reactor was then vented, purged with N , and
warmed to room temperature. The% conversion and% ee of
7 were then determined by chiral HPLC.
2
1
3
9
F NMR (471 MHz, DMSO-d ): d=À107.73, À109.30;
6
1
P NMR (162 MHz, DMSO-d ): d=14.97, 10.13; HR-MS:
6
+
m/z=685.4621, calcd. for [C H FN OP+H ]: 685.4657
4
4
62
2
(
error=5.2 ppm).
Enantioselectivity Determinations
BIPI 238 Iridium Complex
2
: Chiral GC, Astec Chiraldex B-PH @ 908C, isothermal;
A 3-neck 50-mL flask equipped with a direct argon line,
inert gas valve and septum was charged with CH Cl
the retention times of the enantiomers are 14.07 min and
14.35 min.
2
2
(
15 mL). Slow argon sparging beneath the solution surface
was then started. After 10 min, [Ir(COD)Cl] (0.145 g,
.216 mmol, 0.55 equiv., 1.10 Ir equiv., weighed in glovebox)
5: Chiral GC, Astec Chiraldex B-PH @ 1208C, isother-
mal; the retention times of the enantiomers are 10.64 min
and 10.96 min.
AHCTUNGTRENNUNG
2
0
1462
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1455 – 1463

Tuning the Peri Effect for Enantioselectivity: Asymmetric Hydrogenation of Unfunctionalized Olefins
7
: Chiral HPLC, Chiralpak OJ-3, 99:1 heptane:EtOH,
lona, C. H. Senanayake, Org. Lett. 2008, 10, 341–344;
b) J. C. Lorenz, C. A. Busacca, X. Feng, N. Grinberg,
N. Haddad, J. Johnson, S. Kapadia, H. Lee, A. Saha, M.
Sarvestani, E. M. Spinelli, R. Varsolona, X. Wei, X.
Zeng, C. H. Senanayake, J. Org. Chem. 2010, 75, 1155–
1161.
À1
2
58C, 1.0 mLmin .; The retention times of the enantiomers
are 2.15 min and 3.20 min.
: Chiral GC, Astec Chiraldex B-PH @ 1508C, isother-
9
mal; the retention times of the enantiomers are 25.28 min
and 26.81 min.
[
6] C. A. Busacca, J. C. Lorenz, A. K. Saha, S. Cheekoori,
N. Haddad, D. Reeves, H. Lee, Z. Li, S. Rodriguez,
C. H. Senanayake, Catal. Sci. Technol. 2012, 2, 2083–
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asc.wiley-vch.de
1463