Iron-Catalyzed Alkylation of Nitriles with Alcohols

Article abstract of DOI:10.1002/chem.201803762

A general, efficient iron-catalyzed α-alkylation of nitriles with primary alcohols through a hydrogen-borrowing pathway has been developed, allowing a wide variety of alkylated nitriles to be readily accessible. Detailed mechanistic studies suggest that the reaction proceeds via an olefin intermediate with the turnover rate limited by the hydrogenation of the olefin with an iron hydride. Apart from participating in the alkylation, the nitrile is found to play an important role in promoting the formation of and stabilizing the active catalytic species.

Full text of DOI:10.1002/chem.201803762

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Title: Iron-catalyzed alkylation of nitriles with alcohols
Authors: Wei Ma, Suiya Cui, Huamin Sun, Weijun Tang, Dong Xue,
Chaoqun Li, Juan Fan, Jianliang Xiao, and Chao Wang
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To be cited as: Chem. Eur. J. 10.1002/chem.201803762
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Iron-catalyzed alkylation of nitriles with alcohols
Wei Ma,[a] Suiya Cui,[a] Huamin Sun,[a] Weijun Tang,[a] Dong Xue,[a] Chaoqun Li,[a] Juan Fan,[a] Jianliang
Xiao*[a,b] and Chao Wang*[a]
Abstract: A general, efficient iron-catalyzed α-alkylation of nitriles
with primary alcohols via a hydrogen-borrowing pathway has been
developed, allowing a wide variety of alkylated nitriles to be readily
accessible. Detailed mechanistic studies suggest that the reaction
proceeds via an olefin intermediate with the turnover rate limited by
the hydrogenation of the olefin with an iron hydride. Apart from
participating in the alkylation, the nitrile is found to play an important
role in promoting the formation of and stabilizing the active catalytic
species.
Nitriles are versatile building blocks in organic synthesis. They
can be easily transformed into a plethora of compounds, e.g.
amides, carboxylic acids, ketones and oxazolines (Scheme 1).[1]
Moreover, there are many drugs and natural products containing
cyano groups.[2] Amongst the methods for the synthesis of nitrile
compounds, the α-alkylation of alkylnitriles with alcohols via a
hydrogen borrowing or hydrogen auto transfer strategy[3]
provides an environmentally benign route, with water as the only
by-product. Transition metal complexes, including Ru,[4] Os,[5]
Rh,[6] Ir[7] and Pd,[8] have been reported to be effective catalysts
for this reaction. Despite the progress, the replacement of noble-
metal catalysts with those derived from earth-abundant base
metals is attractive, as it offers additional economic and
ecological benefits.[9] Recently, Milstein and co-workers reported
Scheme 1. The importance of nitrile compounds and past/present work on α-
alkylation of nitriles with alcohols.
a remarkable example of Mn-catalyzed α-olefination of nitriles
with alcohols via acceptorless dehydrogenation.[10] However, to
the best of our knowledge, the α-alkylation of nitriles with
Iron complexes 1-4 were prepared and initially examined as
alcohols catalyzed by base metals has not been reported.
catalyst candidates for the model alkylation of phenylacetonitrile
6 with 4-methylbenzyl alcohol 5 (Scheme 2). After screening a
variety of conditions including these and other metal compounds
(see SI for details), complex 3, with cyclohexyl substituents on
Herein, we present the first examples of iron-catalyzed α-
alkylation of nitriles with primary alcohols through a hydrogen-
borrowing strategy (Scheme 1). The iron pincer catalyst showed
even better performance than some of the noble metal catalysts
the phosphorus, was found to be most effective in catalyzing the
in terms of substrate scope and catalytic activity.
model reaction. Thus, under the catalysis of 3 (1 mol%) in the
Iron pincer complexes with PNP ligands have proven to be
presence of the activating NaBHEt3 (2 mol%) and NaOH (1
efficient catalysts for dehydrogenation[11] and hydrogenation[12] of
equivalent), 7a was obtained in an NMR yield of 99% in toluene
a range of substrates. The dehydrogenation and hydrogenation
abilities of these complexes render them possible candidates for
at 130 oC under Ar in 6 h, and the substrate to catalyst ratio
could be raised to 500 (Scheme 2). Slightly lower activities were
hydrogen-borrowing catalysts. However, iron complexes,[9] and
observed by replacing the cyclohexyl substituent of 3 with
particularly the pincer variants,[9e] have rarely been used as
catalysts in hydrogen borrowing reactions. With these
observations in mind, we examined Fe-PNP complexes for the
alkylation of nitriles with alcohols, a reaction requiring both
phenyl (2) or isopropyl (4) variants. Complex 1, without the CO
ligand, was essentially inactive. The structures of 1 and 3 were
confirmed by X-ray diffraction.
With the optimized reaction conditions in hand, the scope of
dehydrogenation and hydrogenation abilities of the catalyst.
the alkylation reaction was explored (Scheme 3). The α-
alkylation of 6 with various alcohols was first examined with 3 as
catalyst (1 mol%), NaBHEt3 (2 mol%) as activating agent and
[a]
[b]
W. Ma, S. Y. Cui, Dr. H. M. Sun, Prof. Dr. W. J. Tang, Prof. Dr. D.
Xue, Prof. Dr. C. Q. Li, J. Fan, Prof. Dr. J. L. Xiao, Prof. Dr. C. Wang
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry
of Education, Department of Chemistry and Chemical Engineering,
Shaanxi Normal University, Xi’an, 710119, (China)
E-mail: c.wang@snnu.edu.cn
NaOH as base (1 equivalent). In general, both benzylic and
aliphatic alcohols reacted well to afford the corresponding
alkylated products in good to excellent yields. For benzylic
alcohols, electron-donating substituents tend to impart slightly
better activity than electron-withdrawing ones (7a-7k), and good
yields were still obtained for sterically bulky substrates (7d, 7e).
The presence of a morpholine moiety on the phenyl ring of
benzyl alcohol is tolerated (7k). Aliphatic alcohols generally gave
lower yields of the desired α-alkylated products (7l-7v) and
Prof. Dr. J. L. Xiao
Department of Chemistry, University of Liverpool
Liverpool, L69 7ZD, (UK)
Supporting information for this article is given via a link at the end of
the document.
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Scheme 2. Fe-PNP complexes catalyzed α-Alkylation of nitriles with primary
alcohols and the X-ray structures of 1 and 3. See SI for detailed conditions.
further optimization of reaction conditions was required in some
cases (7l, 7m, 7n, 7t). Despite extensive effort of optimization,
the yield for the reaction of methanol with 2-naphthylacetonitrile
was only 26% (7l); however, significantly higher yields were
obtained with longer chain aliphatic alcohols (7m-7o).
Interestingly, complex 2 gave better results than 3 for some of
aliphatic alcohols (7n, 7t). These results indicate that fine tuning
of the steric and electronic properties of the catalyst is
necessary to suit reactivity of different substrates in hydrogen
borrowing reactions, which require a subtle balance of the
dehydrogenation/hydrogenation abilities of catalysts. Sterically
bulkier aliphatic alcohols could also react (7p-7r), affording albeit
a lower yield in the case of cyclopropylmethanol (7q). Notably,
both unsaturated and amino alcohols are viable substrates, with
the C=C double bond and amino unit remaining intact in the
product (7u-7v). 7v could be hydrolyzed to an amino acid 7w in
high yield (see SI), which is a unique gamma-aminobutyric-acid
derivative and may find applications in biological studies.[13]
The scope of the reaction was further examined by reacting
other nitrile compounds with 5 (Scheme 3). A variety of
arylacetonitriles containing both electron-withdrawing and
donating substituents were successfully alkylated with 5 in good
to excellent yields (8a-8g). 2-(Phenylsulfonyl)acetonitrile was
also a viable substrate, the product of which (8h) could be
further functionalized.[14] However, aliphatic nitriles, such as
acetonitrile and phenylpropanenitrile, gave poor yields in the
alkylation reaction (8i, 8j), probably as a result of the high pKa
values of the protons adjacent to the cyano group (pKa = 31 for
acetonitrile vs 22 for phenylacetonitrile in DMSO).
Scheme 3. α-Alkylation of nitriles (black) with primary alcohols (red). See SI
for detailed conditions.
typical of a sequential reaction (Scheme 4). Based on the
information gained from this scheme and the literature[4-8], the
alkylation is proposed to proceed via the dehydrogenation of 5 to
give 4-methylbenzaldehyde, which condenses with 6 under
basic conditions to form 10, hydrogenation of which affords 7a.
As the alkylation is performed under a nitrogen atmosphere, the
formation of 10 indicates that hydrogen gas is released. Indeed,
hydrogen gas was detected from the head gas of the reaction of
5 with 6 catalyzed by 3 (See section 5.2 in the SI). Together with
the faster initial rates for the formation of 10 than for 7a, the
accumulation of 10 suggests that the turnover rate of the
alkylation may be limited by the step of hydrogenation.
The proposition above is supported by further experiments.
Thus, the isolated olefin intermediate 10’ was reduced by benzyl
alcohol or H2 under the catalysis of 3, affording 7b as expected
from the intermediary role of 10’ (See section 5.3 in the SI).
Comparing the alkylation of 6 by benzyl alcohol with that by αα-
Another appealing feature of the Fe-catalyzed system is that
heterocyclic substrates are well tolerated (Scheme 3). Thus,
unprotected indole (9a-9d), furan (9e) and pyridine (9f-9i) were
all proved to be viable. These substrates are problematic even
for some noble metal catalysts.[4-8]
The remarkable ability of the iron complexes in catalyzing
the alkylation prompted us to look into the reaction mechanism.
Monitoring of the alkylation of 6 with 5 catalyzed by complexes
2-4 revealed an olefin intermediate 10 and a kinetic profile
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d2-benzyl alcohol revealed a significant kinetic isotope effect for
the formation of 7b, but only an insignificant one for that of its
olefin intermediate (See section 5.4 in the SI), corroborating
olefin hydrogenation as rate limiting step. Interestingly, it is noted
that whilst the complexes 2-4 show similar initial rates in forming
7a, 2 appears to be significantly less active in catalyzing the
dehydrogenation of 5 from which 7a results. Thus, the lower
alkylation yield observed with 2 in Scheme 2 can be ascribed to
its lower activity in alcohol dehydrogenation.
spectrum, a new CO stretching peak was observed at 1902 cm-1
(Scheme S12). We tentatively attribute these observations to
complex 15 resulting from the protonation of 12 by 5 (Scheme 5).
However, the corresponding HRMS only showed peaks
assignable to 12 and 13, presumably due to the instability of 15.
Remarkably, introducing the nitrile 6, instead of 5, led to the
formation of only one observable species 14, according to the 1H
NMR (δ -19.1 ppm), 31P NMR (δ 86.2 ppm), IR (1920 cm-1) and
HRMS ([M+H]+, 667.3595) (See Sections 5.5.1-5.5.4, SI).[17]
Further 1H NMR, 31P NMR and HRMS experiments confirmed
that addition of 6 to the mixture of 11a/11b, 12, 13, 18 and free
ligand, formed upon treatment of 3 with NaBHEt3, resulted in the
disappearance of all these species, affording 14 (See Section
5.5.5, SI). Being the only observable species in the presence of
substrates, 14 could be the catalyst resting state. These
observations indicate that coordinating substrates, particularly
the nitriles, stabilize the iron-hydride intermediate and enhance
its concentration. We note that this stabilizing effect of
substrates has not been reported before in iron-catalyzed
hydrogenation and dehydrogenation, which may have
implications in the design and application of Fe-PNP catalysts.
Scheme 4. Kinetic profiles for the reaction of 5 with 6 catalyzed by the Fe-
PNP complexes 2, 3 and 4. See SI for detailed conditions.
A key mechanistic question is what happened to the Fe
complex during the reaction. Toward this end, we carried out
extensive studies by using NMR, IR and HRMS. In the catalytic
reaction, the Fe catalyst was first activated by NaBHEt3. As
shown in Scheme S12 (SI), dissolving 3 in toluene afforded a
clear blue solution, which gave an absorption peak at 1944 cm-1
-
in the IR spectrum, corresponding to the stretching absorption of
CO ligand, and a single peak at δ 60.7 ppm in the 31P NMR
spectrum. Addition of 2 equivalents of NaBHEt3 to this solution
led to an immediate color change from blue to red. In the 1H
NMR spectrum, two sets of hydride signals were detected at δ -
9.3 ppm (multiplet) and -25.1 ppm (Scheme S13, SI); the 31P
NMR spectrum showed peaks at δ 106.5, 106.3 and 105.9 ppm.
Based on the study of Hazari, Schneider[15] and Jones[11c] and
their co-workers, these resonances can be tentatively assigned
to the complexes 11a, 11b and 12 (Scheme 5). The 31P NMR
spectrum also revealed a peak at δ 98.0 ppm, assignable to
13[15], and a signal from the free ligand. IR and HRMS provided
further support for the structures. Thus, the absorptions at 1795
and 1850 cm-1 in the IR spectrum (Scheme S12) fit with the
previously reported data for CO stretching in 13,[16] and peaks
corresponding to 12 and 13 were detected by HRMS. In addition,
HRMS indicated the formation of the species 18. Clearly,
treatment of 3 with NaBHEt3 affords a complex mixture.
Scheme 5. Proposed mechanism for the alkylation of nitriles, including various
spectroscopically detected species (Ar = p-methylphenyl).
The mechanism of how 13 and 18 are formed is not yet clear.
A tentative pathway is shown in Scheme 5. 11b may undergo
reductive elimination of H2 to afford a zero-valent complex 17,
disproportionation of which would result in 13 and 18. The latter
is not expected to be stable, decomposing to the free ligand and
undefined iron species. On the other hand, the hydride in
11a/11b could be protonated by the neighboring N-H proton,
affording 12. All these species are likely to be in equilibrium, and
More insightful observations were made upon introduction of
the substrates. Thus, addition of alcohol 5, after mixing 3 with
NaBHEt3 for 15 min in d8-toluene, gave rise to only a major
1
hydride peak at δ -23.3 ppm in the H NMR spectrum (Scheme
S13); the 31P NMR showed a peak at δ 84.8 ppm. In the IR
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primary alcohols via a hydrogen borrowing pathway has been
developed. The catalytic system shows broad substrate scope
and high activity. Mechanistic studies showed that the reaction
proceeds sequentially, involving the intermediary of an olefin.
Significantly, the commonly adopted procedure of catalyst
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Acknowledgements
This research was supported by the National Natural Science
Foundation of China (21473109, 21773145), Science and
Technology Program of Shaanxi Province (2016KJXX-26),
Projects for the Academic Leaders and Academic Backbones,
Shaanxi Normal University (16QNGG008), the Program for
Changjiang Scholars and Innovative Research Team in
University (IRT_14R33), and the 111 project (B14041).
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Keywords: iron catalysis • alkylation • nitrile • alcohol •
hydrogen transfer
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W. Ma, S. Y. Cui, H. M. Sun, W. J. Tang,
D. Xue, C. Q. Li, J. Fan, J. L. Xiao,* C.
Wang*
Page No. – Page No.
Fe catalyzed alkylation of nitriles with
alcohols
A Fe-PNP pincer complex catalyzes efficient α-alkylation of nitriles with primary
alcohols via a hydrogen-borrowing pathway, with the turnover rate limited by the
reduction of the olefin intermediate. The nitriles are important - not only being a
substrate but also stabilizing active Fe-H species.
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