A robust nickel catalyst for cyanomethylation of aldehydes: Activation of acetonitrile under base-free conditions

Article abstract of DOI:10.1002/anie.201302613

Nick of time: The nickel cyanomethyl complex 1 catalyzes the room temperature coupling of aldehydes with acetonitrile under base-free conditions. The catalytic system is long-lived and remarkably efficient with high turnover numbers (TONs) and turnover fr

Full text of DOI:10.1002/anie.201302613

Angewandte
Chemie
Communications
Homogeneous Catalysis
S. Chakraborty, Y. J. Patel, J. A. Krause,
H. Guan*
&&&& — &&&&
A Robust Nickel Catalyst for
Cyanomethylation of Aldehydes:
Activation of Acetonitrile under Base-Free
Conditions
Nick of time: The nickel cyanomethyl
complex 1 catalyzes the room temper-
ature coupling of aldehydes with aceto-
nitrile under base-free conditions. The
catalytic system is long-lived and
numbers (TONs) and turnover frequen-
cies (TOFs) achieved. The mild reaction
conditions allow a wide variety of alde-
hydes, including base-sensitive ones, to
catalytically react with acetonitrile.
remarkably efficient with high turnover
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Communications
DOI: 10.1002/anie.201302613
Homogeneous Catalysis
A Robust Nickel Catalyst for Cyanomethylation of Aldehydes:
Activation of Acetonitrile under Base-Free Conditions**
Sumit Chakraborty, Yogi J. Patel, Jeanette A. Krause, and Hairong Guan*
Nucleophilic addition of a-cyano carbanions to carbonyl
substrates is a synthetically important process as it provides
easy access to a large variety of pharmaceutically important
compounds through the resultant b-hydroxy nitriles.[1] This
method is straightforward and avoids the use of highly toxic
cyanide salts (for the ring-opening of epoxides), but is often
limited to activated nitriles (e.g., a-arylnitriles, pKa values of
ca. 22 in DMSO) with increased acidity of the a-CH protons.[2]
Utilization of unactivated simple alkylnitriles, such as aceto-
nitrile (pKa = 31.3 in DMSO), is challenging as it generally
requires a strong base to generate the desired carbanions.[3]
The employed reaction conditions are incompatible with
base-sensitive substrates, and in some cases, lead to the loss of
the hydroxy group by dehydration.[2a–c,3a] For cyanomethyla-
tion of carbonyl substrates in particular, efforts have been
made to circumvent the deprotonation of acetonitrile by
catalytically activating Me3SiCH2CN using a base,[4] fluo-
ride,[5] or N-heterocyclic carbene (NHC).[6]
trile in the presence of DBU (DBU = 1,8-diazabicyclo-
[5.4.0]undec-7-ene) as the base.[7] Ozerov et al. have devel-
oped a catalytic system involving a cationic nickel complex
supported by a diarylamido-based PNP pincer ligand.[8] They
have proposed a mechanism similar to the one depicted in
Scheme 1 (BD = DBU). We surmised that cyanomethylation of
aldehydes could be catalyzed by a transition-metal complex
without an added base. The key is to synthesize a cyanomethyl
complex which is sufficiently nucleophilic to attack aldehydes
(Scheme 2). Although the pKa value of a secondary alcohol is
Scheme 2. Activation of CH3CN by the relief of dp–pp repulsion.
Transition-metal catalysis has offered an alternative
solution to cyanomethylation of carbonyl substrates, in
which a relatively weak base can be used to deprotonate
acetonitrile. The working hypothesis (Scheme 1) is that
expected to be lower than that of a typical alkylnitrile,[9] the
activation of CH3CN could be driven by the relief of dp–pp
repulsion between an occupied metal d orbital and the oxygen
lone pair.[10] Conceivably, the catalytic reactions can also be
initiated by an appropriate metal alkoxide or hydroxide. It is
interesting to note that cyanomethylation of aldehydes has
been reported to be catalyzed by 10 mol% of CuOtBu[5d,11] or
1 mol% of [{Rh(OCH3)(cod)}2]/PCy3 (cod = 1,5-cycloocta-
diene),[12] although a Lewis-acidic metal center (CuI or RhIII)
has been suggested to be responsible for the observed
catalytic activity. Herein we report an inexpensive, air- and
moisture-stable nickel cyanomethyl complex capable of
catalyzing the coupling of aldehydes and acetonitrile without
adding any base or additive. The catalytic turnover numbers
(TONs up to 82000) are the highest ever for such a trans-
formation. A preliminary mechanistic study is consistent with
the mode of activation of acetonitrile as outlined in Scheme 2.
We have recently reported catalytic reduction of alde-
hydes and CO2 promoted by square-planar nickel hydride
complexes bearing a bis(phosphinite)-based pincer ligand,
Scheme 1. Activation of CH3CN by a Lewis-acidic metal center.
a Lewis-acidic metal center would lower the pKa value of
acetonitrile substantially once it is coordinated. Guided by
this hypothesis, Shibasaki and co-workers have identified
[CpRu(PPh3)(CH3CN)2]PF6 (Cp = cyclopentadienyl) as an
effective catalyst for the coupling of aldehydes and acetoni-
À
[*] Dr. S. Chakraborty, Y. J. Patel, Dr. J. A. Krause, Prof. H. Guan
Department of Chemistry, University of Cincinnati
P. O. Box 210172, Cincinnati, OH 45221-0172 (USA)
E-mail: hairong.guan@uc.edu
and have highlighted the importance of Ni H hydricity
enhanced by the strongly trans-influencing pincer ligand.[13]
We therefore anticipated that a nickel cyanomethyl complex
with the same ligand system should result in a nucleophilic
CH2CN moiety. After reacting with an aldehyde, the filled–
filled repulsion between nickel and oxygen orbitals in the
resultant nickel alkoxide species is expected for the square-
planar geometry, thereby facilitating the activation of aceto-
nitrile. To begin our study we treated Zargarianꢀs nickel
complex (1)[14] with LiCH2CN [Eq. (1); THF = tetrahydro-
Homepage: http://homepages.uc.edu/~guanhg/index.html
[**] We thank the U.S. National Science Foundation (CHE-0952083) for
support of this research. X-Ray data were collected on a Bruker
SMART6000 diffractometer which was purchased with funding
provided by an NSF-MRI grant (CHE-0215950).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302613.
2
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Table 1: Cyanomethylation of aldehydes catalyzed by 2.[a]
Entry
2 (mol%)
RCHO
t [h] Yield [%][b]
1
2
3
4
5
6
7
8
1
0.01
1
0.01
1
1
1
1
1
PhCHO (3a)
PhCHO (3a)
6
72
2
36
2
4
4
4
4
91
83[c]
93
90[c]
88
95
89
85
84
77
71
79
furan]. The obtained product 2 was found to be air- and
moisture-stable in both solid state and solution (toluene). The
most characteristic resonance in the 1H NMR spectrum of 2 in
p-CF3C6H4CHO (3b)
p-CF3C6H4CHO (3b)
p-NO2C6H4CHO (3c)
o-FC6H4CHO (3d)
m-FC6H4CHO (3e)
p-FC6H4CHO (3 f)
p-MeOC(O)-C6H4CHO (3g)
p-MeOC6H4CHO (3h)
o-MeC6H4CHO (3i)
m-MeC(O)-C6H4CHO (3j)
[D8]THF is a triplet centered at d = 0.78 ppm (3JP-H
=
9.2 Hz),[15] thus suggesting that 2 is a C-bound cyanomethyl
complex. The methylene carbon resonance of 2 (in CD2Cl2)
was observed at d = À23.91 ppm as a triplet (2JP-C = 13.0 Hz),
thus confirming the coordination mode of the CH2CN ligand.
9
10
11
12
1
1
1
48
36
8
The IR spectrum of 2 (in CH2Cl2) revealed a strong band at
À1
ꢀ
n = 2185 cm , which falls in the range for n(C N) of a C-
bound cyanomethyl complex.[16] The structure of 2 was further
13
1
4
87
established by X-ray crystallography (Figure 1).[17] The Ni-
14
1
4
90
15
16
1
1
24
8
73
95
17
18
1
1
12
12
88
86
19
1
2
90
[a] Unless noted otherwise, 25 mmol of 2 and 2.5 mmol of RCHO were
mixed in 3 mL of CH3CN. All reactions were monitored by 1H NMR
spectroscopy to ensure quantitative conversion of RCHO. [b] Yield of
isolated product. [c] 6.8 mmol of 2 and 68 mmol of RCHO were mixed in
15 mL of CH3CN.
Figure 1. Molecular structure of 2. Thermal ellipsoids shown at the
50% probability level. Hydrogen atoms except those on the cyano-
methyl ligand are omitted for clarity. Selected bond lengths [ꢀ] and
angles [deg]: Ni–C1 1.9101(18), Ni–C19 2.0123(19), C19–C20 1.438(3),
C20–N1 1.149(3); Ni-C19-C20 110.39(14), C19-C20-N1 178.0(2), C1-
Ni-C19 177.69(8).
within 72 hours with a TON of 10000. This catalytic system is
remarkably active and robust as the catalyst loading can be
further reduced close to the ppm level. We found that stirring
the mixture consisting of 138 mL of PhCHO (1.36 mol),
150 mL of CH3CN (2.87 mol), and only 3.0 mg of 2 (5 ppm
catalyst loading) for 72 hours produced 4a with 41% of
PhCHO converted, thus giving a TON of 82000 and
a turnover frequency of 1139 hÀ1. It should be mentioned
that both PhCHO and CH3CN were used without drying and
degassing. Control experiments showed no reaction in the
absence of 2 and no inhibition with added mercury (150 equiv
with respect to 2).
Next, we examined the scope of this cyanomethylation
reaction with other aldehydes, and typically we used 1 mol%
of 2 for the catalytic studies. As shown in Table 1, the catalytic
system is amenable to a wide variety of aldehydes including
substituted benzaldehydes (entries 3–12), as well as hetero-
aromatic (entries 13, 14, and 19), a,b-unsaturated (entry 15),
and aliphatic aldehydes (entries 16–18). In general, benzal-
dehydes bearing an electron-withdrawing group (entries 3–9)
react faster than PhCHO, which in turn reacts faster than
those bearing an electron-donating group (entries 10 and 11).
Simple ketones such as acetophenone are unreactive under
our catalytic conditions, and in fact for m-acetylbenzaldehyde
CH2CN bond distance was found to be 2.0123(19) ꢁ, which is
longer than the one reported by Ritleng, Chetcuti, and co-
workers for their [Cp(NHC)Ni(CH2CN)] complex
[1.961(2) ꢁ],[16b] but comparable to Jonesꢀ [Ni(dippe)-
(CH2CN)Cl] (dippe = 1,2-bis(diisopropylphosphino)ethane)
complex [2.0135(14) ꢁ].[16d] The elongation of the Ni C
À
bond in 2 is likely due to the strong trans influence of the
pincer aromatic ring.
With the nickel cyanomethyl complex in hand, we decided
to test its catalytic activity by adding 1 mol% of 2 (with
respect to aldehyde) into a 0.77m solution of PhCHO in
acetonitrile. At room temperature, the reaction was complete
within 6 hours, thus providing the b-hydroxy nitrile product
4a (Table 1) quantitatively, as judged by NMR spectroscopy.
When the catalyst loading was reduced to 0.01 mol% and the
concentration of PhCHO was increased to approximately
3.1m (entry 2),[18] a quantitative conversion was achieved
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(entry 12), cyanomethylation takes place exclusively at the
aldehyde functionality. For the a,b-unsaturated substrate 3m,
only the 1,2-product was obtained. Dehydration of b-hydroxy
nitrile products, self-aldol condensation of aldehydes (for 3n–
p), and transesterification of 3g (or 4g) are potential side
reactions which usually occur under basic conditions. Gratify-
ingly, none of those were observed in our studies. For
CH3CH2CN, which contains even less acidic a-CH protons
(pKa = 32.5 in DMSO), its coupling with PhCHO can also be
effectively catalyzed by 2 [Eq. (3)], albeit with low diastereo-
selectivity.
Scheme 3. Proposed catalytic cycle.
To probe the mechanism for the cyanomethylation
process, we first monitored the catalytic reaction of PhCHO
in CD3CN (with 10 mol% of 2) by NMR spectroscopy.
Throughout the catalysis, the only observed nickel species was
[D2]-2. The incorporation of deuterium into the nickel
complex is, as confirmed in a separate experiment, due to
rapid H/D exchange between 2 and CD3CN. If indeed the
mechanism in Scheme 2 is operating, the insertion of PhCHO
Scheme 4. Deprotonation of acetonitrile by a nickel alkoxide species.
pp repulsion between nickel and oxygen centers, which
disappears upon the formation of 2. Further study using
1 mol% of 6 for the coupling of PhCHO and CH3CN showed
similar catalytic activity to complex 2, thus suggesting the
possibility of entering the catalytic cycle through a nickel
hydride or alkoxide species. As a control experiment, we
dissolved 6 in CD3CN and did not observe the formation of
[D2]-2, thus confirming that the cyanomethyl catalyst must be
produced by the route shown in Scheme 4.
À
into the Ni C bond of 2 should be the rate-determining step.
As anticipated, the stoichiometric reaction between 2 and
PhCHO in CD3CN [Eq. (4)] yielded [D2]-2 and the deute-
rium-labeled 4a without the observation of the proposed
The group of Naota has shown that ruthenium cyano-
methyl complexes undergo interconversion between C-bound
and N-bound isomers through sliding the metal along the
cyanomethyl ligand skeleton.[16a] Ritleng, Chetcuti, and co-
workers have proposed a similar isomerization process which
À = =
À
ꢀ
nickel alkoxide intermediate. Replacing the NMR solvent
with [D8]THF, however, showed no aldehyde insertion. We
suspected that the insertion step might be reversible. Con-
sistent with this hypothesis, the reaction of 1 and the sodium
alkoxide derived from 4a afforded 2 and PhCHO [Eq. (5)].
converts [Cp(NHC)Ni N C CH2] to [Cp(NHC)Ni CH2C
N].[16b,c] Thus, our catalytic system may involve rate-limiting
isomerization of 2 to the N-bound isomer, which converges
with the steps proposed for Lewis acid catalysis
(Scheme 1).[7,8,11,12] Attempts to generate the N-bound
nickel cyanomethyl complex by deprotonating the cationic
acetonitrile complex 8[14b,20] were unsuccessful [Eq. (6)].
Analogous to the observations for other nickel systems,[8,16b,c]
only the C-bound isomer 2 formed. Nevertheless, the N-
bound isomer is not likely to be involved in our catalytic
system. We noticed that catalytic cyanomethylation of
PhCHO was very sensitive to the change of phosphorus
substituents on the nickel pincer catalysts. For example,
replacing the iPr groups in 2 with more bulky tBu groups
completely shut down the catalysis. Steric alterations near the
nickel center are likely to have little effect on the C-to-N
In view of the above-mentioned NMR results, we propose
a catalytic cycle (Scheme 3) for the cyanomethylation reac-
tions. The insertion of an aldehyde into 2 to generate 5 is
kinetically feasible but thermodynamically uphill (as con-
firmed by the NMR studies described above). However, the
unfavorable equilibrium is shifted by the deprotonation of
CH3CN with 5. To mimic the step regenerating the catalyst 2,
we prepared the nickel benzyloxide 7 (in C6D6) in situ from
the hydride 6 and PhCHO according to our previously
reported procedure.[13a] Evaporating C6D6 and subsequent
treatment of the residue with CD3CN led to an immediate
formation of [D2]-2 and PhCH2OD (Scheme 4). Given the
fact that PhCH2OÀ itself is not basic enough to deprotonate
CH3CN,[19] the observed reactivity probably arises from dp–
À ꢀ
isomerization across the linear C C N moiety as well as the
electrophilic attack on the remote carbon end of [Ni] N C
CH2. In contrast, steric environment around nickel is
expected to strongly influence the insertion of PhCHO into
the Ni C bond of 2. More definitive evidence arguing against
rate-limiting C-to-N isomerization came from the experi-
ments measuring half-lives of PhCHO during catalytic
cyanomethylation reactions. When the catalyst concentration
À = =
À
4
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In conclusion, we have shown an incredibly robust nickel
catalyst for the cyanomethylation of aldehydes under base-
free conditions with unprecedentedly high turnover numbers
and frequencies. Mechanistic studies have suggested rever-
sible insertion of aldehydes into a C-bound cyanomethyl
complex and subsequent activation of acetonitrile with the
resulting nickel alkoxide intermediate. We have ascribed the
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Received: March 28, 2013
Published online: && &&, &&&&
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À
Keywords: aldol reaction · C H bond activation · nickel ·
phosphane ligands · synthetic methods
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