Enantioselective nickel-catalyzed hydrocyanation of vinylarenes using chiral phosphine-phosphite ligands and TMS-CN as a source of HCN

Article abstract of DOI:10.1002/anie.201208082

Anti-headache chemistry: In the presence of a tailored modular P,P ligand the nickel-catalyzed addition of HCN, generated in situ from TMS-CN, to styrene derivatives proceeds with an unprecedented level of stereocontrol (up to 97 % ee) to give 2-aryl-acetonitriles, for example, the depicted precursor of Ibuprofen. Copyright

Full text of DOI:10.1002/anie.201208082

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Angewandte
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DOI: 10.1002/anie.201208082
Hydrocyanation
Enantioselective Nickel-Catalyzed Hydrocyanation of Vinylarenes
Using Chiral Phosphine–Phosphite Ligands and TMS-CN as a Source
of HCN**
Anna Falk, Anna-Lena Gçderz, and Hans-Gꢀnther Schmalz*
The transition-metal-catalyzed hydrocyanation of alkenes
(Scheme 1) represents a highly attractive synthetic method
from both an industrial and an academic point of view.[1]
vinyl-naphthalene (MVN) with high enantioselectivity
(95% ee) employing a carbohydrate-derived diphosphonite
ligand;[6c] however, all other substrates only gave rise to much
lower selectivities (< 60% ee). Vogt and co-workers tested
(and optimized) chiral Xantphos-derived diphosphites for the
asymmetric Ni-catalyzed hydrocyanation of vinylarenes and
obtained moderate enantioselectivities (with 80% ee for
MVN as the best substrate by far). Noteworthy, the selectiv-
ities reported for styrene as the parent substrate never
exceeded 65% ee.[8,9] In a more recent paper, RajanBabu and
co-workers also reported the hydrocyanation of aryl-1,3-
dienes (up to 78% ee).[10] Thus, the search for reliable
protocols for asymmetric hydrocyanation, which could be
applied also in the context of complex-molecule total syn-
thesis, still represents a challenging research task. We here
disclose the results of a study which has led to the
identification of a superior chiral ligand and the development
of a practical procedure for the Ni-catalyzed hydrocyanation
of various vinylarenes with high enantioselectivity (up to
97% ee).
Our investigation was triggered by the consideration that
Taddol-derived phosphine–phosphites of type 4 might be
suitable ligands for the Ni-catalyzed asymmetric hydrocyana-
tion, because bidentate P,P ligands with a rather large bite
angle promote reductive elimination.[1a] These ligands, which
are accessible from the corresponding phenolic precursors (3)
in only four steps (Scheme 2),[11] had proven their value in
several other metal-catalyzed reactions,[12] and their modular
nature allows a facile structural fine-tuning for individual
applications.
Scheme 1. Hydrocyanation of alkenes.
Starting from simple olefins (1) and HCN, this reaction offers
a fully atom-economical access to nitriles (2a and 2b), which
are of value as polymer building blocks and intermediates for
the synthesis of pharmaceuticals and other functionalized
compounds (such as amines, carboxylic acid derivatives,
aldehydes, ketones, N-heterocycles).[2] The by far most
prominent application is the production of adiponitrile from
1,3-butadiene (> 1000000 tons per year) which exploits two
Ni-catalyzed hydrocyanation steps (homogeneous cataly-
sis).[3] Remarkably, there are almost no examples for the
application of alkene hydrocyanation in the multistep syn-
thesis of more complex organic compounds.
As Scheme 1 illustrates, the hydrocyanation of a terminal
alkene (1) leads either to the (chiral) branched Markovnikov
product 2a or to the linear product 2b. The general possibility
to perform such transformations enantioselectively in the
presence of a chiral ligand was first demonstrated by Elmes
and Jackson in the Pd-catalyzed hydrocyanation of norbor-
nene (30% ee).[4] Since then, only few reports on asymmetric
hydrocyanation have appeared.[5–9] In 1992 RajanBabu and
Casalnuovo succeeded in applying the Ni-catalyzed hydro-
cyanation of vinylarenes (1, R = aryl) in the synthesis of
branched products of type 2a.[6a] After intense optimization,
these authors achieved the hydrocyanation of 2-methoxy-6-
[*] Dipl.-Chem. A. Falk, B. Sc. A.-L. Gçderz, Prof. Dr. H.-G. Schmalz
Department fꢀr Chemie, Universitꢁt zu Kçln
Greinstrasse 4, 50939 Kçln (Germany)
Scheme 2. Modular phosphine–phosphite ligands of type 4.
E-mail: schmalz@uni-koeln.de
Homepage: http://www.schmalz.uni-koeln.de
[**] This work was supported by the Fonds der Chemischen Industrie
(doctoral stipend to A.F.). It was performed within the context of
“SusChemSys”, a program of the State of North Rhine-Westphalia
(Germany), co-financed by the European Union through ERDF
funds. We also thank Carl Dittmer, Kçln, for contributing to the
ligand synthesis. TMS=trimethylsilyl.
In a first series of experiments we tested eight of our
ligands (4a–h) in the hydrocyanation of styrene (5) under
standard conditions (THF, [Ni(cod)2], 708C, 20 h) employing
acetone cyanohydrin as an in situ source of HCN.[13] We were
happy to find that our ligands indeed performed very well and
we obtained only the branched product 6 with a respectable
(at this time unsurpassed) selectivity of up to 68% ee
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208082.
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Table 3: Temperature effect on the Ni-catalyzed hydrocyanation of
styrene using acetone cyanohydrin in MeOH.[a]
(Table 1). Interestingly, the substitution pattern of the ligand
backbone had only little effect on the ligand performance
(which is in contrast to our previous experiences with this
kind of ligand).[12] In this initial screening, ligand 4b was
found to be most selective while 4a with the bulky tert-butyl
substituent as R1 appeared to be most active.
Entry
Ligand
T [8C]
t [h]
Conv. [%][b]
ee [%][b]
1
2
3
4
5
6
4a
4a
4a
4a
4b
4b
70
RT
0
1
1
17
17
1
100
100[c]
31
1
100
65
60
61
64
66
64
69
ꢀ10
70
Table 1: Initial screening of some chiral phosphine–phosphite ligands of
type 4 in the Ni-catalyzed hydrocyanation of styrene (5).[a]
RT
20
[a] Conditions: styrene, 5 mol% preformed catalyst ([Ni(cod)2]/L* 1:1),
1.7 equiv acetone cyanohydrin, MeOH. [b] Determined by GC-FID on
a chiral stationary phase. [c] Yield of the isolated product: 94%.
Entry
Ligand
Substitution pattern
ee [%][b]
1 h even at room temperature using ligand 4a (Table 3,
entry 2). The yield of the isolated pure nitrile 6 (61% ee) was
94% in this case (1 mmol scale). Slightly improved enantio-
selectivities were observed at lower temperatures, however, at
the expense of the reaction rate. The best selectivity (69% ee)
combined with a satisfying conversion was observed for
ligand 4b at room temperature (Table 3, entry 6).
While we had obtained high conversions under mild
conditions, the enantioselectivities (using ligands 4a and 4b,
respectively) were still not satisfying. Thus, we decided to vary
the ligand structure. For this purpose, we applied our modular
synthetic scheme[11a,12e] to prepare a set of eight additional
phosphine–phosphite ligands (7a–d, 8a–d; Figure 1). Because
the backbone substituent(s) had little impact on the selectiv-
ities (compare Table 1) we focused on the variation of the aryl
substituents (Ar2) at the Taddol unit.
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4 f
R1 =tBu; R2 =H; R3 =tBu; R4 =H
R1 =iPr; R2 =H; R3 =H; R4 =H
R1 =Ph; R2 =H; R3 =H; R4 =H
R1 =Me; R2 =H; R3 =H; R4 =H
R1 =iPr; R2 =H; R3 =H; R4 =Me
R1 =tBu; R2 =H; R3 =H; R4 =H
R1 =Me; R2 =H; R3 =H; R4 =Me
R1 =Me; R2 =Me; R3 =H; R4 =H
65
68
67
63
56
64
56
65
4g
4h
[a] Conditions: styrene (1 equiv), 5 mol% of preformed catalyst ([Ni-
(cod)2]/L* 1:1), acetone cyanohydrin (1.7 equiv), THF, 708C, 20 h.
[b] Determined by GC-FID on a chiral stationary phase.
Employing ligands 4a and 4b, we next investigated the
effect of the catalyst loading and the solvent on the reaction
outcome (Table 2). We found that the amount of catalyst
(preformed in toluene) only influenced the conversion rate
while the selectivity was little affected (Table 2, entries 1–3).
Using 5 mol% of catalyst we then screened a variety of
(anhydrous) solvents. While the enantioselectivities remained
almost unchanged, only the reactions in toluene and MeOH
gave full conversions after 20 h (Table 2, entries 4, 7, 9, and
10).
Table 2: Ni-catalyzed hydrocyanation of styrene (5) to 6: variation of
catalyst amount and solvent.[a]
Entry Ligand (L*) Cat. loading Solvent
[mol%]
Conv. [%][b] ee [%][b]
Figure 1. A second set of phosphine–phosphite ligands tested.
1
2
3
4
5
6
7
8
9
10
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
2
5
10
5
5
5
5
5
5
5
THF
THF
THF
toluene
n-hexane
DMSO
MeOH
THF
25
57
88
100
43
86
100
38
95
62
64
65
60
60
52
60
68
63
64
Testing these ligands in the Ni-catalyzed hydrocyanation
of styrene revealed that the structural modification of the
Taddol unit indeed led to dramatic changes in the outcome of
the reactions. Ligands 7c and 8a gave very good enantiose-
lectivities (up to 82% ee) with the non-fluorinated ligand 8a
being much more active (Table 4, entries 3 and 5). Apparently
the steric effect of the additional substituents in meta position
of the Taddol aryl units is important for the superior
performance of ligands 7c and 8a. Again, variation of the
backbone substituent R1 (ligands 8b–8d) had little impact on
the selectivities; only ligand 8d with a bulky tert-butyl group
in this position was significantly less selective and active. We
therefore used ligand 8a for the final optimization.
toluene
MeOH
100
[a] Conditions: styrene (1 equiv), preformed catalyst ([Ni(cod)2]/L* 1:1),
acetone cyanohydrin (1.7 equiv), 708C, 20 h. [b] Determined by GC-FID
on a chiral stationary phase (n-dodecane as internal standard).
Having identified MeOH as a promising solvent, we
examined the influence of the temperature. As Table 3
indicates, high conversions could be achieved within only
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Table 4: Performance of new phosphine–phosphite ligands (Figure 1) in
TMS-CN solution was added over a period of 5 h (Table 5,
entry 3).[16]
the asymmetric hydrocyanantion of styrene.[a]
Using ligand 8a we finally succeeded in achieving the
hydrocyanation of styrene with 86% ee at full conversion
(Table 5, entry 4). The key to this success was to switch back
to THF as a solvent (which had furnished slightly better ee
values in the initial screening, see Table 3) and to slowly add
a solution of TMS-CN in THF/MeOH (which actually
represents a dilute solution of HCN in THF).[17] A THF/
MeOH ratio of 14:1 and an initial TMS-CN concentration of
0.125m proved to be optimal for achieving high conversion (at
a catalyst concentration of 0.006m). The ideal addition time
was 2 h at room temperature. At lower temperatures even
somewhat higher enantioselectivities were obtained, how-
ever, with incomplete conversion (Table 5, entries 4–6).
The applicability of the developed standard protocol was
then probed by employing various substituted arylalkenes
(Table 6). Much to our delight, good conversions and high to
excellent enantioselectivities (up to 97% ee) were obtained in
almost all cases. Electron-withdrawing and electron-donating
substituents were tolerated, and even styrenes with a b sub-
stituent could be reacted (Table 6, entries 8–11).[18] All
reactions proceeded very cleanly and with complete regiose-
lectivity within the analytical limits (GC, NMR).
To demonstrate the preparative usefulness of the devel-
oped methodology we applied it in a gram-scale synthesis of
the nitrile 10, which is a precursor of the antiinflammatory
drug Ibuprofen (11) (Scheme 3). We employed 1 g of
substrate 9[19] and the Ni-catalyzed hydrocyanation proceeded
smoothly under the established conditions (with ligand 8a) to
afford pure 10 in quantitative yield with an enantiomeric
excess of 92%. No traces of the linear regioisomer (of type
2b) could be detected by GC or NMR analysis.
To determine the absolute configuration, a sample of 10
was hydrolyzed by treatment with a 3:3:1 mixture of sulfuric
acid, acetic acid, and water at 1208C. The resulting product
showed a positive optical rotation and thus proved to be (S)-
(+)-Ibuprofen (11). Consequently, the absolute configuration
of nitrile 10 (and probably also the other structurally related
hydrocyanation products obtained with ligand 8a) could be
assigned as S. Noteworthy, the [a]D value of 11 corresponded
to an enantiomeric purity of only 30% ee which indicates
partial racemization under the harsh conditions of the nitrile
hydrolysis.[20] Nevertheless, we would like to point out that the
nitrile 10 (92% ee) should be converted efficiently into
enantiomerically pure (S)-(+)-Ibuprofen (11) with the help
of a suitable nitrilase (completion of the enantioselectivity
through kinetic resolution or recrystallization).[21]
Entry
Ligand (L*)
Conv. [%][b]
ee [%][b]
1
2
3
4
5
6
7
8
7a
7b
7c
7d
8a
8b
8c
8d
22
43
8
64
69
82
n.d.
81
81
0
100
73
86
14
81
74
[a] Conditions: styrene (1 equiv), 5 mol% of preformed catalyst ([Ni-
(cod)2]/L* 1:1), acetone cyanohydrin (1.7 equiv), MeOH, RT, 20 h.
[b] Determined by GC-FID on a chiral stationary phase.
Using 4b as a reference and 8a as the most promising
ligand, we finally investigated the source of HCN as a reaction
parameter we had not yet addressed. While industry does not
hesitate to use HCN on a larger scale, our goal was to employ
safe reagents that are easy to handle in a normal laboratory. In
the experiments described above we used acetone cyanohy-
drin (added in one portion), which disintegrates during the
reaction to form HCN and acetone. As an alternative, we
envisioned that commercially available trimethylsilyl cyanide
(TMS-CN) in the presence of a protic solvent such as MeOH
could serve to generate HCN in situ in a controllable fash-
ion.[14] To test this, we diluted TMS-CN with toluene and
added it by means of a syringe pump to a solution of styrene
and catalyst ([Ni(cod)2]/4b) in MeOH at 208C. As the results
shown in Table 5 (entries 1–3) indicate, product 6 was reliably
formed with an enantioselectivity of 69% ee while the
conversion of styrene was highly dependent on the addition
time. Interestingly, too slow addition leads to a breakdown of
the conversion, which indicates that the catalyst dies in the
absence of enough fresh HCN. On the other hand, it is known
that higher HCN concentrations have to be avoided to
prevent the formation of catalytically inactive [NiL*CN2]
complexes.[3b,6b,15] Full conversion was achieved when the
Table 5: Enantioselective hydrocyanation of styrene using TMS-CN in
the presence of MeOH as a source of HCN.[a]
Entry Solvent Addition T [8C] Ligand (L*) Conv. [%][b] ee [%][b]
To conclude, we have devised a practical protocol for the
asymmetric Ni-catalyzed hydrocyanation of vinylarenes.
Using styrene (5), a hitherto “difficult” substrate, we suc-
ceeded in identifying the modular phosphine–phosphite 8a as
a tailored chiral ligand, which is available in both enantio-
meric forms. We also showed that the handling of toxic HCN
can be circumvented by employing TMS-CN as a safe reagent
in the presence of MeOH. The developed method opens
a reliable and scalable access to a broad spectrum of chiral
nitriles with high levels of enantioselectivity. We are opti-
mistic that these results form a valid basis for the future
time [h]
1
2
3
4
5
6
MeOH
MeOH
MeOH
THF
THF
THF
20
10
5
2
2
20
20
20
20
0
4b
4b
4b
8a
8a
8a
2
27
100
100
65
69
69
69
86
89
91
2
ꢀ20
14
[a] Conditions: styrene, 5mol% of preformed catalyst ([Ni(cod)2]/L*
1:1), slow addition of TMS-CN (1.5 equiv) either as a 0.25m solution in
toluene (entries 1–3) or in THF/MeOH (14:1; entries 4–6). [b] Deter-
mined by GC-FID on a chiral stationary phase.
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Table 6: Enantioselective hydrocyanation of various arylalkenes under
the optimized conditions using ligand 8a.[a]
Experimental Section
Enantioselective hydrocyanation of 4-isobutylstyrene: Synthesis of
(S)-(ꢀ)-2-(4-isobutylphenyl)propanenitrile (10): A round-bottomed
Schlenk flask was charged with ligand 8a (289.3 mg, 0.312 mmol,
0.05 equiv), [Ni(cod)2] (85.8 mg, 0.312 mmol, 0.05 equiv), and toluene
(6.2 mL). The mixture was stirred for 5 min and the solvent was
removed on the Schlenk vacuum line. The residue was dried in vacuo
for 20 min before it was re-dissolved in THF (52.0 mL), and 1-
isobutyl-4-vinylbenzene (1.0 g, 6.24 mmol, 1.0 equiv) was added. A
separate Schlenk flask was charged with THF (69.9 mL), MeOH
(5.0 mL), and TMS-CN (1.17 mL, 9.36 mmol, 1.5 equiv) and the
resulting solution was then slowly transferred to the stirred catalyst/
substrate solution by means of a syringe pump over 2 h. When the
addition was finished, the solvent was removed under reduced
pressure. (Caution: This operation must be performed in a fume
hood.) The residue was purified by column chromatography (SiO2,
Entry
Substrate
Product
Conv. [%][b] ee [%][b]
1
100
100
86
92
2
3
100
90
89
91
4
cyclohexane/ethyl acetate 20:1) to afford product 10 (1.17 g,
20
6.24 mmol, 100%) as
a
colorless liquid. ½aꢁ589¼ꢀ16.48,
20
20
20
½aꢁ546¼ꢀ20.58, ½aꢁ405¼ꢀ43.18, ½aꢁ365¼ꢀ60.58 (c = 0.5 in CHCl3). Fur-
ther analytical data are given in the Supporting Information.
5
6
7
100
73
80
97
90
Received: October 8, 2012
Published online: December 20, 2012
Keywords: asymmetric catalysis · nickel · nitriles ·
.
phoshite ligands · trimethylsilyl cyanide
34
8[c]
15
28
83
70
81
84
83
67
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(cod)2]/8a 1:1), THF, RT, slow addition (2 h) of TMS-CN (1.5 equiv) in
THF/MeOH (14:1, 0.125m); b) H2SO4/AcOH/H2O (3:3:1), 1208C.
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[14] To the best of our knowledge, TMS-CN has never been used as
a HCN source in the metal-catalyzed hydrocyanation of alkenes;
for an application in the Pd-catalyzed silylcyanation of alkynes,
see a) N. Chatani, T. Hanafusa, J. Chem. Soc. Chem. Commun.
1985, 838 – 839; b) N. Chatani, T. Takeyasu, N. Horiuchi, T.
Hanafusa, J. Org. Chem. 1988, 53, 3539 – 3548; see also c) S. Arai,
[15] Addition of pure TMS-CN in one portion to substrate and
catalyst in MeOH, toluene, THF, or mixtures of these led to
conversions of less than 3%.
[16] This method was also used to synthesize racemic reference
samples of various nitrile products (Table 6). See the Supporting
Information for details.
[17] When the substrate and the catalyst were dissolved in THF/
MeOH (14:1) and TMS-CN was added as a diluted solution in
pure THF, a selectivity of 81% ee was observed, which is the
same as that found for the reaction in pure MeOH.
[18] The fact that only the E isomer of the starting alkenes was
detected (incomplete conversion) indicates that the Z isomers
have significantly higher reactivity.
[19] Compound 9 was prepared from the corresponding aldehyde
through Wittig olefination (see the Supporting Information for
details).
[20] H. Kakeya, N. Sakai, T. Sugai, H. Ohta, Tetrahedron Lett. 1991,
32, 1343 – 1346.
[21] R. Kourist, P. Domꢁnguez de Marꢁa, K. Miyamoto, Green Chem.
2011, 13, 2607 – 2618.
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