Enantioselective Nickel-Catalyzed Hydrocyanation using Chiral Phosphine-Phosphite Ligands: Recent Improvements and Insights

Article abstract of DOI:10.1002/adsc.201500644

The asymmetric hydrocyanation of vinylarenes was investigated using hydrogen cyanide (HCN) in the presence of 5 mol% of a catalyst prepared from a phenol-derived chiral phosphine-phosphite ligand and bis(cyclooctadiene)nickel [Ni(cod)₂]. The reactions were performed in tetrahydrofuran (THF) at room temperature to give exclusively the branched nitriles with superior enantioselectivities of 88-99% ee for vinylarenes and 74-94% ee for vinylheteroarenes, respectively. Using styrene as a model substrate it was shown that the catalyst loading could be decreased to 0.42 mol% without any loss of selectivity (88% ee). The structure of the pre-catalyst, i.e., a tetrahedral Ni(0)(P,P-chelate)(cod) complex, was proven by X-ray and NMR analysis. Additional insight into the reaction course was gained by monitoring the hydrocyanation of styrene-d₈ by means of ²D NMR spectroscopy.

Full text of DOI:10.1002/adsc.201500644

UPDATES
DOI: 10.1002/adsc.201500644
Enantioselective Nickel-Catalyzed Hydrocyanation using Chiral
Phosphine-Phosphite Ligands: Recent Improvements and Insights
Anna Falk,a Alberto Cavalieri,a Gary S. Nichol,a Dieter Vogt,a,*
and Hans-Günther Schmalzb,*
a
EaStCHEM, University of Edinburgh, School of Chemistry, David Brewster Road, Edinburgh, EH9 3FJ, U.K.
E-mail: d.vogt@ed.ac.uk
University of Cologne, Department of Chemistry, Greinstr. 4, 50939 Kçln, Germany
b
Fax: (+49)-(0)221-470-3064; phone: (+49)-(0)221-470-3063; e-mail: schmalz@uni-koeln.de
Received: July 5, 2015; Revised: August 7, 2015; Published online: October 14, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500644.
Abstract: The asymmetric hydrocyanation of vinyl-
arenes was investigated using hydrogen cyanide
(HCN) in the presence of 5 mol% of a catalyst pre-
pared from a phenol-derived chiral phosphine-phos-
achieved by RajanBabu and Casalnuovo who showed
that the conversion of 2-methoxy-6-vinylnaphthalene
(MVN) proceeds with high enantioselectivity
(95% ee) in the presence of a carbohydrate-derived
diphosphinite ligand.[3] Later, the same authors also
reported the hydrocyanation of aryl-1,3-dienes with
up to 78% ee.[4] While important mechanistic insights
into the Ni-catalyzed (asymmetric) hydrocyanation
were reported by Vogt and co-workers,[5] selectivities
for most substrates remained unsatisfactory (e.g., ex-
ceeded ꢀ60% ee for styrene).[6]
phite
ligand
and
bis(cyclooctadiene)nickel
[Ni(cod)2]. The reactions were performed in tetra-
hydrofuran (THF) at room temperature to give ex-
clusively the branched nitriles with superior enan-
tioselectivities of 88–99% ee for vinylarenes and
74–94% ee for vinylheteroarenes, respectively.
Using styrene as a model substrate it was shown
that the catalyst loading could be decreased to
0.42 mol% without any loss of selectivity (88% ee).
The structure of the pre-catalyst, i.e., a tetrahedral
Ni(0)(P,P-chelate)(cod) complex, was proven by X-
ray and NMR analysis. Additional insight into the
reaction course was gained by monitoring the hy-
Recently, we disclosed a first general protocol for
the highly enantioselective (up to 97% ee) Ni-cata-
lyzed hydrocyanation of various vinylarenes employ-
ing the chiral phosphine-phosphite ligand 3 and
TMSCN/MeOH as an in situ source of HCN
(Scheme 1).[7] Modular ligands of this type are accessi-
ble in only a few steps[8] and have proven their utility
already in numerous transition metal-catalyzed reac-
tions.[9] While the in situ generation of HCN is attrac-
tive for small-scale laboratory applications, especially
regarding safety aspects, the use of HCN itself as an
atom-economic and much less expensive reagent is
preferable for larger or even industrial scales. We
2
drocyanation of styrene-d8 by means of D NMR
spectroscopy.
Keywords: asymmetric synthesis; hydrocyanation;
hydrogen cyanide (HCN); nickel; phosphine-phos-
phites
The hydrocyanation, that is, the conversion of alkenes
into saturated nitriles, is widely known as the industri-
al production of adiponitrile from 1,3-butadiene in-
volves two consecutive homogeneously Ni-catalyzed
hydrocyanation steps.[1] Nevertheless, the hydrocyana-
tion has found virtually no application in the synthesis
of more complex products (e.g., in natural product
synthesis) so far. A reason for this might be the lack
of reliable general protocols especially with respect to
stereocontrol. After some initial reports on asymmet-
ric hydrocyanation,[2] a singular breakthrough was Scheme 1. Asymmetric hydrocyanation of styrenes.
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Anna Falk et al.
Table 2. Hydrocyanation of hydroxy-substituted styrenes
here report the results of an extended study which
demonstrates that the asymmetric Ni-catalyzed hydro-
cyanation of vinylarenes with HCN in the presence of
ligand 3 leads to even improved selectivities and can
be applied to a spectrum of synthetically relevant sub-
strates (Scheme 1).
and vinylheteroarenes.[a]
In a first series of experiments we picked three dif-
ferent vinylarenes to probe whether the reaction out-
come using HCN is comparable with the one using
TMSCN/MeOH.[7] For this purpose, the substrate was
added to a solution of the catalyst (5 mol%) in THF
under argon followed by addition of a solution of
HCN in THF at room temperature over a period of
2 h. After chromatographic purification the selectivity
was determined by means of GC on a chiral station-
ary phase.[10] Noteworthy, all three reactions (Table 1)
reached full conversion after 2 h and proceeded with
slightly improved enantioselectivities. This may be
due to the complete absence of MeOH, which has
been shown to give lower ees than THF (the best per-
forming solvent) alone in previous experiments.[7] No
traces of the linear regioisomers could be detected.
Encouraged by these initial results and to probe the
scope of the methodology we investigated the hydro-
cyanation of a number of additional substrates using
HCN. As Table 2 reveals, substrates 1d and 1e con-
taining a free hydroxy function in para or meta posi-
tions are well tolerated, while 1f with an ortho OH
substituent showed no conversion at all. Remarkably,
1d afforded the product (2d) with the highest selectiv-
[a]
Reaction conditions: substrate, 5 mol% of preformed cat-
alyst [Ni(cod)2/3=1/1] in THF, slow addition (2 h) of
HCN (1.5 equiv.) in THF (0.125M), room temperature.
Determined by GC-FID on a chiral stationary phase, the
[b]
absolute configuration of the products was not deter-
mined.
n.c.=no conversion.
Table 1. Comparison of results using HCN instead of
TMSCN/MeOH.
[c]
ity (>99% ee) ever observed for this kind of transfor-
mation.
The heteroaromatic vinylarenes 4, 6, and 8 also af-
forded the corresponding nitriles (5, 7, and 9, respec-
tively) with high to excellent levels of selectivity
under the standard conditions (Table 2, entries 4 and
5). These types of products had never been prepared
by asymmetric hydrocyanation and are of potential
interest as fine chemicals or intermediates in pharma-
ceutical chemistry. Again, all three reactions were
found to proceed with complete regioselectivity and
the pure products were isolated in good to excellent
yields after column chromatography. In the case of 5
the lower yield results from incomplete conversion.
For the asymmetric hydrocyanation of styrene (1a
to 2a), the reaction was followed over time by taking
samples, which were analyzed by GC. The obtained
reaction profile indicated a rapid initial conversion
(see the Supporting Information, Graph S1). Accord-
ingly, the HCN addition time could either be short-
ened to 15 min or the catalyst loading could be de-
creased to 0.42 mol% (2 h) without loss of selectivity
[a]
Reaction conditions: 0.25 mmol substrate, 5 mol% of pre-
formed catalyst [Ni(cod)2/3=1/1] in THF, slow addition
(2 h) of TMSCN (1.5 equiv.) in THF/MeOH=14/
1 (0.125M), room temperature.
Slow addition (2 h) of HCN (1.5 equiv.) in THF
(0.125M).
Determined by GC-FID on a chiral stationary phase, the
absolute configuration of the products was not deter-
mined, unless otherwise indicated.
[b]
[c]
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Enantioselective Nickel-Catalyzed Hydrocyanation
Table 3. Further optimization of styrene hydrocyanation.[a]
THF): d=130.23 (d, J=44.5 Hz), 25.25 (d, J=
43.8 Hz) indicated a 1:1 Ni to ligand ratio with both
phosphorus atoms coordinated to the metal center, as
a significant shift for both signals of the two P moiet-
ies (phosphine and phosphite) occurred (see the Sup-
porting Information, Figure S1-3).
By slow diffusion of n-pentane into a solution of
the isolated complex in THF under an inert atmos-
phere we were able to grow crystals of the complex
Ni(3)(cod) suitable for X-ray single crystal analysis.[12]
The structure of the complex (Figure 1) clearly resem-
bles the assumed structure (I) with a tetrahedral coor-
dination mode of the Ni(0) center.
Catalyst loading
[mol%]
HCN addition Conversion ee[b]
time
[%]
[%]
5
1.25
0.42
15 min
30 min
2 h
100
100
100
88
88
88
[a]
Reaction conditions: substrate, preformed catalyst
[Ni(cod)2/3=1/1] in THF, slow addition of HCN
(1.5 equiv.) in THF (0.125M), room temperature.
[b]
Determined by GC-FID on a chiral stationary phase.
(at full conversion) (Table 3, see the Supporting Infor-
mation, Graph S2).
The generally accepted and to quite some extent
proven catalytic cycle for the Ni-catalyzed hydrocya-
nation of vinylarenes is shown in Scheme 2. After for-
mation of the catalytically active complex (I), sub-
strate and HCN addition lead, after hydrogen inser-
tion, to the allyl-complex (V). The corresponding ni-
trile product is set free in a reductive elimination,
which was proven to be the rate-, as well as the enan-
tioselectivity-determining step.[2e,5,11]
Part of our investigations was also to prove the as-
sumed catalyst structure (I). The comparison of
31P NMR data of the free ligand (122 MHz, CDCl3):
d=149.57 (d, J=73.3 Hz), À18.72 (d, J=73.3 Hz)
with those of the Ni(3)(cod) complex (162 MHz,
Figure 1. Molecular structure of the catalyst precursor
Ni(3)(cod) in the crystal. Displacement ellipsoids are dis-
played at the 50% probability level. All hydrogen atoms
and THF molecules in the crystal are omitted for clarity. Se-
lected bond lengths (Š) and angles (deg) with standard un-
À
À
certainties given in parentheses: Ni P(1)=2.0766(17), Ni
P(2)=2.1265(18), Ni C(1)=2.081(7), Ni C(2)=2.092(7),
À
À
À
À
À À
Ni C(5)=2.074(6), Ni C(6)=2.101(7), P(1) Ni P(2)=
91.98(7).
We were also able to follow the conversion of deu-
2
terated styrene-d8 by D NMR (Figure 2). The com-
parison of the spectra of the free substrate (trace 1)
compared to the one after addition of the catalyst
(trace 2) proves the existence of a complex like (II),
where the starting material is coordinated to the Ni
center. After the addition of HCN we recorded the
product spectrum (trace 3). Notably, no deuterium
scrambling occurred, which suggests that formation of
the intermediate allyl-complex (V) is irreversible or
at least reversible to a very low extent.
To conclude, we could show that the previously
used TMSCN/MeOH mixture can easily be replaced
with HCN, which even improves the reaction out-
Scheme 2. Proposed catalytic cycle for the hydrocyanation
of styrene.[5]
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Acknowledgements
This work was supported by the Fonds der Chemischen In-
dustrie (doctoral stipend to A.F.) and by SusChemSys, a pro-
gramme of the state of North Rhine-Westphalia, Germany,
co-financed by the European Union through ERDF funds.
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Experimental Section
General Procedure for the Ni-Catalyzed
Enantioselective Hydrocyanation with HCN
A
Schlenk flask was charged with Ni(cod)2 (3.4 mg,
0.0125 mmol, 0.05 equiv.), ligand (11.6 mg, 0.0125 mmol) and
toluene (0.25 mL). The mixture was stirred for 5 min at
room temperature and the toluene was removed under
vacuum directly on the Schlenk line to yield the air-sensitive
catalytically active complex. To this were added THF
(2.0 mL) and the corresponding substrate (0.25 mmol,
1.0 equiv.). HCN (10.1 mg, 0.015 mL, 0.375 mmol, 1.5 equiv.)
was dissolved in THF (3.0 mL) and immediately added to
the substrate-containing mixture over a 2 h period by means
of a syringe pump at room temperature. After completion
of the addition, argon was bubbled through the reaction
mixture for 10 min to remove traces of HCN. The solvents
were removed under reduced pressure and the residue was
submitted to column chromatography to yield the pure ni-
triles.
CAUTION! Hydrogen cyanide is very volatile and
highly toxic. Distilled HCN is prone to very exothermic oli-
gomerization when heated and should be stored at tempera-
tures well below its melting point. Sensible precautions in-
clude working in a well ventilated fume hood equipped
with HCN sensors (inside and outside the fume hood), and
proper first aid cyanide kit and procedures should be in
place. Excess HCN may be disposed by addition to aqueous
sodium hypochlorite (which converts it to cyanate).
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