Chlorophosphines as auxiliary ligands in ruthenium-catalyzed nitrile hydration reactions: Application to the preparation of β-ketoamides

Article abstract of DOI:10.1039/c5cy02142a

The catalytic hydration of nitriles into amides, in water under neutral conditions, has been studied using a series of arene-ruthenium(ii) complexes containing commercially available chlorophosphines as auxiliary ligands, i.e. compounds [RuCl₂(η⁶-p-cymene)(PR₂Cl)] (R = aryl, heteroaryl or alkyl group). In the reaction medium, the coordinated chlorophosphines readily undergo hydrolysis to generate the corresponding phosphinous acids PR₂OH, which are well-known "cooperative" ligands for this catalytic transformation. Among the complexes employed, best results were obtained with [RuCl₂(η⁶-p-cymene){P(4-C₆H₄F)₂Cl}]. Performing the catalytic reactions at 40 °C with 2 mol% of this complex, a large variety of organonitriles could be selectively converted into the corresponding primary amides in high yields and relatively short times. The application of [RuCl₂(η⁶-p-cymene){P(4-C₆H₄F)₂Cl}] in the preparation of synthetically useful β-ketoamides is also presented.

Full text of DOI:10.1039/c5cy02142a

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DOI: 10.1039/C5CY02142A
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ARTICLE
Chlorophosphines as auxiliary ligands in ruthenium-catalyzed
nitrile hydration reactions: Application to the preparation of -
ketoamides
Received 00th January 20xx,
Accepted 00th January 20xx
Rebeca González-Fernández,a Pedro J. González-Liste,a Javier Borge,b Pascale Crochet*a and
DOI: 10.1039/x0xx00000x
Victorio Cadierno*a
www.rsc.org/
The catalytic hydration of nitriles into amides, in water under neutral conditions, has been studied using a series of arene-
ruthenium(II) complexes containing commercially available chlorophosphines as auxiliary ligands, i.e. compounds
[RuCl2(η6-p-cymene)(PR2Cl)] (R
= aryl, heteroaryl or alkyl group). In the reaction medium, the coordinated
chlorophosphines readily undergo hydrolysis to generate the corresponding phosphinous acids PR2OH, which are well-
known “cooperative” ligands for this catalytic transformation. Among the complexes employed, best results were obtained
with [RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}]. Performing the catalytic reactions at 40 ᵒC with 2 mol% of this complex, a large
variety of organonitriles could be selectively converted into the corresponding primary amides in high yields and relatively
short times. The application of [RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] in the preparation of synthetically useful -ketoamides
is also presented.
have made it the catalyst of choice to promote the hydration
of C≡N bonds in a huge number of synthetic approaches to
Introduction
Hydration of nitriles (RC≡N) to the corresponding primary
structurally complex natural products and biologically active
molecules.9 Very recently, van Leeuwen and co-workers also
amides (RC(=O)NH2) is a valuable reaction in academia and
industry. Amides are used, not only as intermediates in organic
synthesis, but also for a wide variety of applications in the
production of polymers, lubricants, pharmaceuticals,
herbicides, and detergents.1 Traditional methods to hydrate
nitriles involve the use of strong acids and bases as
promoters.2 However, these reactions suffer from harsh
conditions, low yields and selectivity due to the over-hydrolysis
of the amides into carboxylic acids, a kinetically favoured
process,3 and have a significant environmental footprint. To
circumvent these problems, several catalytic processes have
been devised utilizing enzymes,4 transition metal complexes,5
heterogeneous catalysts,6 and metal nanoparticles.7 In this
context, among the different catalysts currently known, the
described the successful application of
a
related
[PtH{(PR2O)2H}(PR2OH)] (R2 = chiral binaphthyl unit) complex in
the kinetic resolution of racemic nitriles.10
Fig 1 Structure of the platinum(II) complex [PtH{(PMe2O)2H}(PMe2OH)] (A).
The utility of phosphinous acid PR2OH ligands in this
catalytic transformation was further demonstrated by the
group of Tyler and ours with the ruthenium derivatives B-D
(Fig. 2).11 In particular, complexes
B and C showed a
Pt(II) complex [PtH{(PMe2O)2H}(PMe2OH)]
(A in Fig. 1),
remarkable activity under unusually mild conditions
(temperatures below 80 ᵒC),11a,c,d being even able to hydrate
challenging cyanohydrins,11a,c substrates for which the Parkins
developed by Parkins, is probably who has attained the greater
success.8 As a matter of fact, the remarkable activity,
selectivity, and functional group compatibility of this derivative
catalyst
A
was completely inoperative.12
a.Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al
CSIC), Centro de Innovación en Química Avanzada (ORFEO-CINQA), Departamento
de Química Orgánica e Inorgánica, IUQOEM, Universidad de Oviedo, Julián
Clavería 8, E-33006 Oviedo, Spain. E-mail: crochetpascale@uniovi.es (P.C.),
vcm@uniovi.es (V.C.); Fax: +(34) 985103446; Tel.: +(34) 985103453.
b.Departamento de Química Física y Analítica, Centro de Innovación en Química
Avanzada (ORFEO-CINQA), Universidad de Oviedo, Julián Clavería 8, E-33006
Oviedo, Spain.
† Electronic Supplementary Information (ESI) available: Copies of the NMR spectra
of complexes 2b, 3 and 4b, and all the amides generated in this work. CCDC
1415870 (2g) and 1415871 (4c). See DOI: 10.1039/x0xx00000x
Fig 2 Structure of the ruthenium hydration catalysts B-D
.
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DFT calculations performed by our group with the arene- secondary phosphine oxides,
ruthenium(II) complexes
a
large number of
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DOI: 10.1039/C5CY02142A
B
unravelled the key role played by chlorophosphines are currently commercially available at
the PR2OH ligands in these catalytic reactions. Thus, as shown relatively low prices. To confirm this possibility, we decided to
in Scheme 1, the hydration process involves the initial addition synthesize, and evaluate the catalytic behaviour, of a series of
of the OH group of the ligand on the coordinated nitrile, and ruthenium(II) complexes of general composition [RuCl2(η6-p-
subsequent hydrolysis of the resulting five-membered cymene)(PR2Cl)] (R = aryl, heteroaryl or alkyl group). As a result
metallacycle.11d This reaction pathway, initially proposed of this study, we present herein a new catalytic system, i.e.
without any evidence by Parkins for complex A,8 contrasts with complex [RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}], able to promote
the general assumption that the metal-catalyzed hydration of the selective hydration of nitriles to amides in pure water, at
nitriles must involve the direct addition of the water molecule low metal loadings (2 mol%) and under mild conditions (40 ᵒC).
(or the OH- group if basic conditions are employed) on the The application of this complex in the preparation of
metal-coordinated nitrile.5
synthetically useful
-ketoamides, by hydration of the
corresponding -ketonitriles, is also discussed.

Results and discussion
Our research began with the preparation of a diverse family of
half-sandwich [RuCl2(η6-p-cymene)(PR2Cl)] complexes 2a-h
through the treatment of the dimeric precursor [{RuCl(µ-Cl)(η6-
p-cymene)}2] (1) with 2.1 equivalents of different commercially
available chlorophosphines (see Scheme 4). As expected, the
chloride bridges cleavage reactions proceeded quickly in
tetrahydrofuran at room temperature, affording complexes
2a-h as orange-red solids in moderate to excellent yields (58-
98%) after appropriate work-up (see details in the
Scheme 1 The role of PR2OH ligands in the catalytic hydration of nitriles.
On the other hand, the method most commonly employed
in the literature to synthesize transition metal complexes with
phosphinous acid PR2OH ligands involves the reaction of the
corresponding metallic precursor with a secondary phosphine
oxide R2P(=O)H.13,14 For example, complexes A-C were
obtained from the reactions of [Pt(PPh3)4], [{RuCl(µ-Cl)(η6-
Experimental
Section).
Compound
[RuCl2(η6-p-
cymene)(PPh2Cl)]
( )
2a was previously described in the
literature.18 Following the same approach, complex [RuCl2(η6-
arene)}2] and [{RuCl(µ-Cl)(η3:η3-C10H16)}2] (C10H16
= 2,7-
p-cymene)(PPhCl2)] (3) could be synthesized in 75% yield from
the reaction of dimer
(Scheme 4).
1 with dichlorophenylphosphine
dimethylocta-2,6-diene-1,8-diyl), respectively, with R2P(=O)H
(R = Me, Ph).8,11a,c,d In solution, the secondary phosphine
oxides exist as a tautomeric mixture of penta-, i.e. R2P(=O)H,
and trivalent, i.e. PR2OH, isomers, with the pentavalent one
predominating under ambient conditions.15 In the presence of
a metal this equilibrium is driven towards the PR2OH tautomer
via coordination (Scheme 2).13
Scheme 2 General procedure to obtain metal complexes with PR2OH ligands.
Although comparatively much less employed, an
alternative procedure to synthesize metal complexes with
phosphinous acid PR2OH ligands is by hydrolysis of coordinated
chlorophosphines (Scheme 3).16,17
Scheme 4 Synthesis of the arene-ruthenium(II) complexes 2a-h and 3.
Compounds 2a-h and
3 were characterized by means of
elemental analyses and multinuclear NMR spectroscopy
1
(31P{1H}, H, 13C{1H} and 19F{1H}), all data being fully consistent
with the proposed formulations (details are given in the
Experimental Section). In this regard, the most noticeable
aspect is that, while for 2a-h the expected deshielding of the
phosphorus resonance with respect to that of the
corresponding free chlorophosphine (Δδ = 14-38 ppm) was
observed in their 31P{1H} NMR spectra, the opposite trend was
Scheme 3 Alternative procedure to generate complexes with PR2OH ligands.
This fact opens the possibility, previously unexplored, of
using chlorophosphine-metal complexes as pre-catalysts for
nitrile hydration reactions, since in aqueous medium they
would readily generate the cooperative PR2OH ligands. This
point would be of high practical interest because, unlike the
found for [RuCl2(η6-p-cymene)(PPhCl2)] (
3) (δP = 145.6 ppm vs
165.0 ppm for free PPhCl2). The stronger π-accepting nature of
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dichloro PRCl2 vs monochloro PR2Cl phoshines may be behind Cl)(η6-p-cymene)}2]
ARTICLE
(1
)
with 2.2 equivalenVtiesw Aroticfle Ontlhinee
this behaviour.19
corresponding secondary phosphine oxide R2P(=O)H (Scheme
DOI: 10.1039/C5CY02142A
In addition, the structure of complex [RuCl2(η6-p- 5). We must note in this point that formation of [RuCl2(η6-p-
cymene)(PCy2Cl)] (2g) could be unambiguously confirmed by cymene)(PPh2OH)] (4a) by hydrolysis of 2a 18b
as well as by
means of X-ray diffraction methods. X-ray quality crystals were direct reaction of
with Ph2P(=O)H,11b was previously
obtained by slow diffusion of diethyl ether into a saturated described in the literature. In the case of complexes [RuCl2(η6-
solution of 2g in dichloromethane. An ORTEP view of the p-cymene)(PCy2Cl)] (2g) and [RuCl2(η6-p-cymene)(PPhCl2)] (
),
molecule, along with selected structural parameters, is shown hydrolysis of the chlorodicyclohexylphosphine and
,
1
3
in Fig. 3. The complex features the expected three-legged dichlorophenylphosphine ligands also takes place in the
“piano-stool” geometry, with the ruthenium atom surrounded presence of water, but the process is accompanied by an
by the η6-bonded p-cymene ligand, two chlorides, and the extensive decoordination of the ligand, as assessed by the
phosphorus atom of PCy2Cl. The phosphine ligand, in which appearance of additional signals in the 31P{1H} NMR spectra at
both cyclohexyl groups adopt a chair conformation, is linked to δP 50 and 20 ppm corresponding to Cy2P(=O)H14e and
ruthenium with a Ru-P1 bond length of 2.3377(8) Å, very PhP(=O)H(OH),21 respectively. Although we have no definitive
similar to that found in the crystal structure of the related explanation for these results, we assume that the partial
complex [RuCl2(η6-benzene)(PCy2Cl)] (Ru-P = 2.3247(4) Å).20 As decoordination of the in-situ generated ligands Cy2POH and
observed for [RuCl2(η6-benzene)(PCy2Cl)], the chlorine atom of PhP(OH)2 may be associated with the higher thermodynamic
the PCy2Cl ligand points toward the η6-arene to minimize the stability of their pentavalent tautomers Cy2P(=O)H and
steric repulsions of the latter with the bulky cyclohexyl groups. PhP(=O)H(OH).
Fig
3 ORTEP-type view of the structure of complex 2g showing the
crystallographic labelling scheme. Hydrogen atoms have been omitted for clarity.
Thermal ellipsoids are drawn at 30% probability level. Selected bond distances
(Å): Ru-P1 2.3377(8), Ru-Cl1 2.4125(9), Ru-Cl2 2.4035(8), Ru-C* 1.7197(2), P1-Cl3
2.086(1), P1-C11 1.849(3), P1-C17 1.847(3). Selected bond angles (˚): Cl1-Ru-Cl2
85.31(3), Cl1-Ru-P1 88.37(3), Cl1-Ru-C* 124.64(3), Cl2-Ru-P1 91.32(3), Cl2-Ru-C*
123.98(3), P1-Ru-C* 130.17(3), Ru-P1-Cl3 112.02(4), Ru-P1-C11 123.6(1), Ru-P1-
C17 116.4(1), C11-P1-Cl3 97.5(1), C11-P1-C17 103.6(2), C17-P1-Cl3 99.8(1). C*
denotes the centroid of the p-cymene ring (C1, C2, C3, C4, C5 and C6).
Scheme 5 Synthesis of the arene-ruthenium(II) complexes 4a-f,h
.
The novel phosphinous acid complexes [RuCl2(η6-p-
cymene)(PR2OH)] (R = 4-C6H4F (4b), 4-C6H4CF3 (4c), 4-C6H4Me
(4d), 4-C6H4OMe (4e), 2-furyl (4f), Et (4h)) were characterized
by elemental analyses, IR and multinuclear NMR spectroscopy,
the data obtained being in fully accord with the proposed
formulations (details are given in the Experimental Section). In
addition, the molecular structure of 4c could be confirmed
through a single-crystal X-ray diffraction study (see Fig. 4). An
interesting aspect of the structure is that, unlike what
happened with complex [RuCl2(η6-p-cymene)(PCy2Cl)] (2g) (Fig.
3), the bulkier substituents of the phosphorus atom are now
oriented on the same side of the p-cymene ligand (torsion C*-
Ru-P1-C11 and C*-Ru-P1-C18 angles of 45.45ᵒ and 79.43ᵒ,
respectively), while the OH group points in the opposite
Prior to study the catalytic behaviour of complexes 2a-h
and
3, we first explored their reactivity towards water.
Experiments performed in NMR tube with CD2Cl2 solutions of
these complexes confirmed that, upon addition of one drop of
water, the chlorophosphine ligands undergo hydrolysis of the
P-Cl bonds. In the case of complexes [RuCl2(η6-p-
cymene)(PR2Cl)] (R = Ph (2a) 4-C6H4F (2b), 4-C6H4CF3 (2c), 4-
C6H4Me (2d), 4-C6H4OMe (2e), 2-furyl (2f), Et (2h)) a clean
transformation into the corresponding phosphinous acid
derivatives
[RuCl2(η6-p-cymene)(PR2OH)]
(
4a-f,h
)
was
observed, the hydrolysis process being faster with 2b and 2c
containing the more electron-poor phosphines (Scheme 5).
The identity of the products formed in these NMR tube
reactions was confirmed by comparison of the 31P{1H} NMR
data with those of pure samples of 4a-f,h synthesized by the
conventional route, i.e. through the reaction of dimer [{RuCl(µ-
direction (C*-Ru-P1-O1
= 162.80ᵒ). This conformation,
unexpected on the basis of steric grounds, may be imposed by
the intramolecular H-bond that the OH group establishes with
one of the chloride ligands, albeit this interaction is relatively
weak (O1-H1o = 0.82 Å, H1o-Cl2 = 2.327 Å, O1-Cl2 = 2.99 Å and
O1-H1o-Cl2 = 138.34ᵒ).22
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formed phosphinous acid ligands. Regarding 2f, its unexpected
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DOI: 10.1039/C5CY02142A
low activity does not seem to be associated with the
decoordination of P(2-furyl)2OH since complex [RuCl2(η6-p-
cymene){P(2-furyl)2OH}] (4f) was found to be perfectly stable
in solution. The presence of the potentially coordinating 2-
furyl units in the ligand, which could compete with the nitrile
for binding the metal, may be behind the negative result
observed in this case.23a For the rest of complexes, a direct
relationship between their catalytic activities and the
electronic nature of the substituents of the P-donor ligands
could not be drawn (entries 1-5 and 8). Taking into account
that compounds [RuCl2(η6-p-cymene)(PR2OH)] are the active
species in the hydration process, two antagonistic effects
Fig
4 ORTEP-type view of the structure of complex 4c showing the
crystallographic labelling scheme. Hydrogen atoms, except that on O1, have
been omitted for clarity. Thermal ellipsoids are drawn at 30% probability level. come into play: (i) the formation of [RuCl2(η6-p-
cymene)(PR2OH)] by hydrolysis of [RuCl2(η6-p-cymene)(PR2Cl)],
that occurs faster when electron-withdrawing substituents are
Selected bond distances (Å): Ru-P1 2.316(2), Ru-Cl1 2.388(2), Ru-Cl2 2.424(2),
Ru-C* 1.7112(5), P(1)-O1 1.604(4), P1-C11 1.829(6), P1-C18 1.814(6). Selected
bond angles (˚): Cl1-Ru-Cl2 87.66(6), Cl1-Ru-P1 83.14(6), Cl1-Ru-C* 126.59(5),
Cl2-Ru-P1 84.29(6), Cl2-Ru-C* 125.52(5), P1-Ru-C* 134.09(5), Ru-P1-O1 112.9(2), present in the chlorophosphine (see above), and (ii) the
Ru-P1-C11 116.0(2), Ru-P1-C18 117.5(2), C11-P1-O1 102.1(3), C11-P1-C18
104.8(3), C18-P1-O1 101.5(3). C* denotes the centroid of the p-cymene ring (C1,
C2, C3, C4, C5 and C6).
nucleophilic addition of the P-OH unit to the coordinated
benzonitrile molecule, to generate the five-membered
metallacyclic intermediate depicted in Scheme 1, that would
be favoured when electron-donating substituents are present
The ability of complexes [RuCl2(η6-p-cymene)(PR2Cl)] (2a-h
and [RuCl2(η6-p-cymene)(PPhCl2)] (
) to promote the catalytic
)
in the phosphinous acid ligand. Apparently, the catalytic
activity observed seems to be governed by a subtle balance
between these two factors. From this initial screening,
complex [RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (2b) emerged as
the most active, being able to generate benzamide in 98% GC-
yield after only 30 min (entry 2; > 99% after 1 h).23b
Remarkably, the in-situ-generated precatalyst, obtained by
3
hydration of nitriles was subsequently explored employing
benzonitrile as model substrate. In a typical experiment, the
corresponding complex (2 mol% of Ru) was added under argon
atmosphere to a 0.33 M aqueous solution of benzonitrile, and
the mixture heated in an oil bath at 80 ᵒC for 2 h. The course of
the reactions was monitored by GC, analyzing aliquots every
30 min. Selected results are collected in Table 1.
mixing the dimeric precursor [{RuCl(µ-Cl)(η6-p-cymene)}2] (
1)
(1 mol%) with P(4-C6H4F)2Cl (2 mol%), presents the same
catalytic performance than that of the isolated complex
Table
1 Catalytic hydration of benzonitrile using the ruthenium(II)
complexes
[RuCl2(η6-p-cymene)(PR2Cl)]
(2a-h)
and
[RuCl2(η6-p-
[RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}]
(2b) (99% GC-yield of
cymene)(PPhCl2)] (3)a
benzamide after 1 h). This convenient one-pot procedure,
based on the use of two commercial reagents, without the
need of any purification, may be particularly attractive for
application by non-expert organometallic chemists.
Entry Catalyst
t (h)
Yield (%)b
t (h)
Yield (%)b
Table 2 Catalytic hydration of benzonitrile using the ruthenium(II) complex
[RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (2b): Effect of the metal loading and
temperaturea
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
3
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
90
98
30
84
59
5
14
89
1
2
2
2
2
2
2
2
2
2
> 99
> 99
93
> 99
86
7
40
> 99
3
Entry
% of Ru
T (ᵒC)
t (h)
Yield (%)b
1
2
3
4
5
6
7
2 mol%
1 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
80
80
70
60
50
40
r.t.
1
8
1
1.5
3
> 99
95
> 99
> 99
> 99
> 99
> 99
a
Reactions were performed under Ar atmosphere starting from 1 mmol of
benzonitrile (0.33 M in water). b Determined by GC (uncorrected GC areas).
With the exception of [RuCl2(η6-p-cymene){P(2-furyl)2Cl}]
4
10
(
2f), [RuCl2(η6-p-cymene)(PCy2Cl)]
(2g
)
and [RuCl2(η6-p-
cymene)(PPhCl2)]
(
3
)
which showed only a residual or
a
Reactions were performed under Ar atmosphere starting from 1 mmol of
benzonitrile (0.33 M in water). b Determined by GC (uncorrected GC areas).
mederate activity (entries 6, 7 and 9), the rest of complexes
were able to generate the desired benzamide as the unique
reaction product in ≥ 86% GC-yield after 2 h (in no case
benzoic acid was detected by GC). The low reactivity of 2g and
With the isolated complex 2b we conducted additional
studies at lower metal loadings and temperatures (Table 2).
Thus, while the reduction of the catalyst loading from 2 to 1
mol% resulted in a significant drop in activity (entry 2 vs 1), a
decrease in temperature had not a dramatic effect on the
3
is consistent with the NMR tube experiments discussed
above, showing the extensive decoordination of the in situ
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effectiveness of the process (entries 3-6). For example, a large variety of heterocycles, such as lactams,27 pyrans,28
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DOI: 10.1039/C5CY02142A
performing the reaction at 40 ᵒC, quantitative conversion was oxocyclohexenes,29
isoquinolines,30
pyrroloquinolines,31
reached in 4 h (entry 6). To our delight the reaction could also naphthyridines,32 nicotinamides,33 or 3-acyltetramic acids,34 to
be completed at r.t. in a reasonable time (10 h; entry 7). We name a few. In addition, they can also be easily converted, via
would like to point here that such a remarkable reactivity at
low temperatures is unprecedented for ruthenium
catalysts.24,25,26
a zinc-carbenoid mediated chain-extension, into their -keto
homologues, which are compounds related with a number of
biologically relevant systems.35 Another interesting aspect in
To define the scope of this catalytic transformation, other
aromatic and heteroaromatic nitriles were subjected to the
the chemistry of
-ketoamides is their use as precursors of
chiral -hydroxyamides, which are useful building blocks for

action of complex [RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (2b
)
the synthesis of pharmacological molecules, through the
asymmetric hydrogenation of the C=O unit.36 As a result of all
this, considerable efforts have been directed towards the
development of synthetic methodologies giving access to this
(entries 2-16 in Table 3). Thus, we were pleased to find that all
the substrates tested could be selectively converted into the
corresponding primary amides in high yield (≥ 89% by GC; ≥
75% isolated) and, in general, short times at 40 ᵒC. Several
electron-withdrawing and electron-donating functional groups
in the ortho, meta and para positions of the aromatic rings
were tolerated, and no over-hydrolysis to carboxylic acids was
observed. As shown in entries 17-21, complex 2b was also
effective in the hydration of vinylic and non-conjugated
nitriles, thus confirming its general applicability and the
synthetic potential of this reaction. However, we must note
that, due probably to its low solubility in water, with the purely
aliphatic heptanenitrile an increase in temperature (100 ᵒC)
was needed to obtain the desired hexanamide in high yield
(entry 20).
class of compounds. In this regard, the aminolysis of
-
ketoesters,37 the addition of amines to -acylketenes38 and

diketenes,39 the

-acylation of amides,40 the addition of
enolates to isocyanates,41 and the catalytic oxidation of N-
hydroxy-propargylamines,42 are among the most popular
methods currently employed for the preparation
ketoamides.43 However, in most cases, these methods are only
appropriate for secondary and tertiary -ketoamides, the N-
unsubstituted ones being hardly obtainable or non-accessible.
The hydration of
entry to primary
systems described so far in the literature for this
transformation are enzymatic.44 Chemocatalytic reactions are
unknown.45
-


-ketonitriles enables, in principle, a simple

-ketoamides. However, the only catalytic
Table 3 Catalytic hydration of nitriles using the ruthenium(II) complex
[RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (2b)a
Table 4 Catalytic hydration of -ketonitriles using the ruthenium(II) complex
[RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (2b)a
Entry Nitrile
t (h)
Yield (%)b
1
2
3
4
5
6
7
8
R = Ph
R = 2-C6H4F
R = 4-C6H4F
R = C6F5
R = 3-C6H4Cl
R = 4-C6H4Cl
R = 2-C6H4Br
R = 4-C6H4Br
R = 4-C6H4C(=O)Me
R = 4-C6H4C(=O)H
R = 4-C6H4C(=O)OEt
R = 4-C6H4OMe
R = 4-C6H4SMe
R = 1,3-benzodioxole-5-yl
R = 5-Me-2-furyl
R = 3-thienyl
R = CH2Cl
R = CH2OPh
R = CH2-2-thienyl
R = n-C6H13
4
5
2
> 99 (93)
> 99 (93)
> 99 (79)
92 (85)
> 99 (89)
98 (83)
97 (78)
98 (91)
96 (80)
99 (77)
89 (75)
98 (90)
98 (91)
96 (85)
> 99 (92)
99 (89)
99 (93)
> 99 (96)
> 99 (92)
99 (83)
99 (95)
Entry
Temp. (ᵒC)
Yield (%)b K/E ratioc
-Ketonitrile
10
1.5
9.5
8
5.5
3.5
3.5
8
1
2
3
4
5
6
7
8
R = Ph
R = 4-C6H4F
40
40
40
40
40
60
40
40
60
60
60
40
60
80
77
88
75
80
89
83
79
84
80
79
90
81
73
71
1.6:1
2.2:1
1:1.8
1.1:1
1.3:1
1:1
1.1:1
1.6:1
2.2:1
4:1
1:1.9
4.9:1
9.9:1
2.2:1
R = 2-C6H4Cl
R = 3-C6H4Cl
R = 4-C6H4Cl
R = 3,4-C6H3Cl2
R = 3-C6H4CF3
R = 3-C6H4Me
R = 4-C6H4Me
R = 4-C6H4OMe
R = 2-Br-5-C6H3OMe
R = 2-Furyl
9
10
11
12
13
14
15
16
17
18
10
20c
21
6
9
6.5
24
0.5
2
1
2
2
6
8
10
11
12
13
14
R = 3-Thienyl
R = tBu
a
Reactions were performed under Ar atmosphere starting from 1 mmol of
the corresponding nitrile (0.33 M in water). b Isolated yield. c Keto/enol ratio
determined by 1H NMR spectroscopy in DMSO-d6.
R = (E)-CH=CHPh
a
Reactions were performed under Ar atmosphere starting from 1 mmol of
b
As shown in Table 4, employing 2 mol% of complex 2b and
the corresponding nitrile (0.33
M
in water).
Determined by GC
(uncorrected GC areas); Isolated yields after work-up are given in brackets. c
performing the catalytic reactions in a temperature range of
40-80 ᵒC for 14 h,46 a diverse family of

-ketonitriles could be
Reaction performed at 100 ᵒC.
converted into the corresponding
-ketoamides, in high
The outstanding performance of complex [RuCl2(η6-p-
cymene){P(4-C6H4F)2Cl}] (2b) was further exploited in the
isolated yields (71-90%), regardless of the nature of the
substituent present in the keto group. As expected, the NMR
spectra obtained for these amide products showed in all cases
the presence of a tautomeric mixture of their keto and enol
forms (see ESI).47
catalytic synthesis of
ketonitriles (Table 4). At this point, we would like to stress that
-ketoamides are versatile intermediates in the preparation of
-ketoamides by hydration of -

This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Catalysis Science & Technology
Page 6 of 12
ARTICLE
Journal Name
Finally we must note that inspection by 31P{1H} NMR Synthesis of [RuCl2(η6-p-cymene)(PR2Cl)] (R = Ph (2a), 4-C6H4F
spectroscopy of the crude reaction mixtures (after solvent (2b), 4-C H CF (2c), 4-C H Me (2d), 4-C H OMeVi(e2weA)r,tic2le-Ofunrlinyel
DOI: 10.1039/C5CY02142A
6 4
6
4
3
6
4
removal) of some of the catalytic reactions included in Tables 3 (2f), Cy (2g), Et (2h))
and 4 confirms that, during the catalytic events, complex
A suspension of the dimeric precursor [{RuCl(µ-Cl)(η6-p-
cymene)}2] ( ) (0.165 g, 0.27 mmol) in tetrahydrofuran (15 mL)
[RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}]
(2b
)
is completely
1
converted into the active compound [RuCl2(η6-p-cymene){P(4-
C6H4F)2OH}] (4b), the spectra showing a major resonance at δP
was treated, at room temperature, with the appropriate
chlorophosphine (0.57 mmol) for 1 h. The solvent was then
removed under reduced pressure, and the resulting orange-
red solid residue washed with hexanes (3 x 20 mL), and dried
in vacuo. (2a):18 Yield: 0.230 g (81%). 31P{1H} NMR (CD2Cl2): δ =
96.6 (s) ppm. 1H NMR (CD2Cl2): δ = 7.97-7.44 (m, 10H, Ph), 5.41
=
106 ppm. A minor singlet signal at δP = 18 ppm,
corresponding to (4-C6H4F)2P(=O)H,15e is additionally observed
in the spectra indicating that partial dissociation of the P-
donor ligand is also taking place.
3
and 5.36 (d, 2H each, JHH = 6.0 Hz, CH of cym), 2.84 (sept, 1H,
3
3JHH = 6.0 Hz, CHMe2), 2.02 (s, 3H, Me), 1.21 (d, 6H, JHH = 6.0
Conclusions
Hz, CHMe2) ppm. 13C{1H} NMR (CD2Cl2): δ = 135.9 (d, 1JPC = 36.2
Hz, Cipso of Ph), 132.9 (d, JPC = 12.1 Hz, CHortho or CHmeta of Ph),
131.4 (s, CHpara of Ph), 127.9 (d, JPC = 10.1 Hz, CHortho or CHmeta
In summary, we have demonstrated that simple, commercially
available, and inexpensive chlorophosphines can be used as
effective auxiliary ligands in metal-catalyzed nitrile hydration
2
of Ph), 110.8 and 98.4 (s, C of cym), 91.6 (d, JPC = 5.0 Hz, CH of
reactions. In aqueous
medium, the
coordinated
cym), 88.3 (d, 2JPC = 6.0 Hz, CH of cym), 30.5 (s, CHMe2), 21.7 (s,
CHMe2), 17.6 (s, Me) ppm. Elemental analysis calcd. (%) for
C22H24Cl3PRu: C 50.16, H 4.59; found: C 50.27, H 4.69. (2b):
Yield: 0.264 g (87%). 31P{1H} NMR (CD2Cl2): δ = 94.4 (s) ppm. 1H
NMR (CD2Cl2): δ = 7.93 and 7.19 (m, 4H each, C6H4F), 5.43 and
chlorophosphines readily undergo hydrolysis to generate the
corresponding phosphinous acids PR2OH, which are well-
known “cooperative” ligands for this catalytic transformation.
In particular, using the arene-ruthenium(II) complex [RuCl2(η6-
p-cymene){P(4-C6H4F)2Cl}]
(2b) we could develop a new
3
3
5.36 (d, 2H each, JHH = 6.0 Hz, CH of cym), 2.86 (sept, 1H, JHH
protocol for the high-yield and selective conversion of nitriles
into primary amides, in pure water as a solvent, and at
unusually low temperatures. The synthetic utility of the
methodology reported herein was fully validated with the
3
= 6.9 Hz, CHMe2), 2.03 (s, 3H, Me), 1.22 (d, 6H, JHH = 6.9 Hz,
CHMe2) ppm. 13C{1H} NMR (CD2Cl2): δ = 164.0 (dd, JFC = 253.4
1
Hz, 4JPC = 2.5 Hz, C of C6H4F), 135.5 (dd, 2JPC = 13.4 Hz, 3JFC = 8.8
1
4
Hz, CH of C6H4F), 131.2 (dd, JPC = 39.3 Hz, JFC = 3.4 Hz, C of
C6H4F), 115.8 (dd, JFC = 21.6 Hz, JPC = 12.1 Hz, CH of C6H4F),
111.2 and 98.8 (s, C of cym), 91.4 (d, JPC = 4.6 Hz, CH of cym),
preparation of a diverse family of
-ketoamides, representing
2
3
the first chemocatalytic route reported in the literature to
access to this relevant class of compounds from -ketonitriles.
2
2
88.4 (d, JPC = 6.4 Hz, CH of cym), 30.6 (s, CHMe2), 21.6 (s,
CHMe2), 17.6 (s, Me) ppm. 19F{1H} NMR (CD2Cl2): δ = -108.2 (d,
4JPF
= 2.3 Hz) ppm. Elemental analysis calcd. (%) for
Experimental
C22H22Cl3F2PRu: C 46.95, H 3.94; found: C 46.82, H 4.02. (2c):
Yield: 0.207 g (58%). 31P{1H} NMR (CD2Cl2): δ = 93.5 (s) ppm. 1H
3
3
General methods
NMR (CD2Cl2): δ = 8.09 (dd, 4H, JPH = 10.5 Hz, JHH = 8.6 Hz,
3
4
C6H4CF3), 7.70 (dd, 4H, JHH = 8.6 Hz, JPH = 1.8 Hz, C6H4CF3),
The manipulations were performed under argon atmosphere
using vacuum-line and standard Schlenk or sealed-tube
techniques. All reagents were obtained from commercial
5.50 and 5.42 (d, 2H each, 3JHH = 6.1 Hz, CH of cym), 2.87 (sept,
3
3
1H, JHH = 6.9 Hz, CHMe2), 2.06 (s, 3H, Me), 1.23 (d, 6H, JHH
=
=
6.9 Hz, CHMe2) ppm. 13C{1H} NMR (CD2Cl2): δ = 139.1 (d, JPC
1
suppliers and used as received, with the exception of
2
48
compounds [{RuCl(µ-Cl)(η6-p-cymene)}2] (
1
)
and [RuCl2(η6-p-
34.9 Hz, C of C6H4CF3), 133.5 (d, JPC = 12.0 Hz, CH of C6H4CF3),
132.8 (q, 2JFC = 32.7 Hz, C of C6H4CF3), 124.8 (dq, JPC = 10.8 Hz,
3
11b
cymene)(PPh2OH)] (4a
)
which were prepared following the
3JFC = 3.7 Hz, CH of C6H4CF3), 123.5 (q, JFC = 272.5 Hz, CF3),
1
method reported in the literature. GC measurements were
performed with a Hewlett-Packard HP6890 equipment using a
Supelco Beta-DexTM 120 column (30 m length; 250 µm
diameter). Elemental analyses were provided by the Analytical
Service of the Instituto de Investigaciones Químicas (IIQ-CSIC)
of Seville. Infrared spectra were recorded on a Perkin-Elmer
1720-XFT spectrometer. NMR spectra were recorded on
Bruker DPX-300 or AV400 instruments. The chemical shift
values (δ) are given in parts per million and are referred to the
residual peak of the deuterated solvent employed (1H and 13C),
to an external 85% aqueous H3PO4 solution (31P), or to the
CFCl3 standard (19F). DEPT experiments have been carried out
for all the compounds reported.
2
111.6 and 99.5 (s, C of cym), 91.3 (d, JPC = 4.4 Hz, CH of cym),
2
88.7 (d, JPC = 6.0 Hz, CH of cym), 30.6 (s, CHMe2), 21.6 (s,
CHMe2), 17.7 (s, Me) ppm. 19F{1H} NMR (CD2Cl2): δ = -63.5 (s)
ppm. Elemental analysis calcd. (%) for C24H22F6Cl3PRu: C
43.49, H 3.35; found: C 43.60, H 3.42. (2d): Yield: 0.228 g
(76%). 31P{1H} NMR (CD2Cl2): δ = 97.3 (s) ppm. 1H NMR
(CD2Cl2): δ = 7.78 (dd, 4H, 3JPH = 11.4 Hz, 3JHH = 8.3 Hz, C6H4Me),
3
4
7.25 (dd, 4H, JHH = 8.3 Hz, JPH = 2.4 Hz, C6H4Me), 5.39 and
3
3
5.34 (d, 2H each, JHH = 6.3 Hz, CH of cym), 2.84 (sept, 1H, JHH
= 6.9 Hz, CHMe2), 2.41 (s, 6H, C6H4Me), 2.02 (s, 3H, Me), 1.21
(d, 6H, JHH = 6.9 Hz, CHMe2) ppm. 13C{1H} NMR (CD2Cl2): δ =
3
142.1 (s, C of C6H4Me), 132.9 (d, JPC = 12.0 Hz, CH of C6H4Me),
1
132.5 (d, JPC = 38.2 Hz, C of C6H4Me), 128.5 (d, JPC = 11.0 Hz,
2
CH of C6H4Me), 110.6 and 98.2 (s, C of cym), 91.5 (d, JPC = 4.4
2
Hz, CH of cym), 88.2 (d, JPC = 6.2 Hz, CH of cym), 30.5 (s,
6 | J. Name., 2012, 00, 1-3
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Page 7 of 12
Catalysis Science & Technology
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Journal Name
ARTICLE
CHMe2), 21.7 (s, CHMe2), 21.2 (s, C6H4Me), 17.6 (s, Me) ppm. with diethyl ether (3 x 20 mL), and dried in vacuoV.ieYwieAlrdtic:le0O.1nl9in6e
31
1
1
DOI: 10.1039/C5CY02142A
Elemental analysis calcd. (%) for C24H28Cl3PRu: C 51.95, H g (75%). P{ H} NMR (CD2Cl2): δ = 145.6 (s) ppm. H NMR
5.09; found: C 51.80, H 5.22. (2e): Yield: 0.310 g (98%). 31P{1H} (CD2Cl2): δ = 8.13-7.51 (m, 5H, Ph), 5.36 (br, 4H, CH of cym),
NMR (CD2Cl2): δ = 96.6 (s) ppm. 1H NMR (CD2Cl2): δ = 7.86-7.79 2.89 (sept, 1H, 3JHH = 6.0 Hz, CHMe2), 2.13 (s, 3H, Me), 1.25 (d,
(m, 4H, C6H4OMe), 6.94 (dd, 4H, JHH = 9.0 Hz, JPH = 1.4 Hz, 6H, 3JHH = 6.0 Hz, CHMe2) ppm. 13C{1H} NMR (CD2Cl2): δ = 138.1
3
4
C6H4OMe), 5.39 and 5.33 (d, 2H each, 3JHH = 6.3 Hz, CH of cym), (d, JPC = 20.1 Hz, Cipso of Ph), 132.6 (s, CHpara of Ph), 131.4 (d,
1
3
3.87 (s, 6H, OMe), 2.85 (sept, 1H, JHH = 6.9 Hz, CHMe2), 2.02 JPC = 13.1 Hz, CHortho or CHmeta of Ph), 127.9 (d, JPC = 12.1 Hz,
(s, 3H, Me), 1.22 (d, 6H, JHH = 6.9 Hz, CHMe2) ppm. 13C{1H} CHortho or CHmeta of Ph), 112.2 and 100.3 (s, C of cym), 92.7 (d,
3
NMR (CD2Cl2): δ = 162.0 (s, C of C6H4OMe), 134.8 (d, JPC = 13.3 2JPC = 6.0 Hz, CH of cym), 89.2 (d, 2JPC = 7.0 Hz, CH of cym), 30.7
1
Hz, CH of C6H4OMe), 126.9 (d, JPC = 41.9 Hz, C of C6H4OMe), (s, CHMe2), 21.5 (s, CHMe2), 17.8 (s, Me) ppm. Elemental
113.2 (d, JPC = 11.9 Hz, CH of C6H4OMe), 110.6 and 98.0 (s, C of analysis calcd. (%) for C16H19Cl4PRu: C 39.61, H 3.95; found: C
2
2
cym), 91.4 (d, JPC = 4.4 Hz, CH of cym), 88.1 (d, JPC = 6.2 Hz, 39.51, H 4.08.
CH of cym), 55.4 (s, OMe), 30.5 (s, CHMe2), 21.6 (s, CHMe2),
17.6 (s, Me) ppm. Elemental analysis calcd. (%) for
Synthesis of [RuCl2(η6-p-cymene)(PR2OH)] (R = 4-C6H4F (4b), 4-
C6H4CF3 (4c), 4-C6H4Me (4d), 4-C6H4OMe (4e), 2-furyl (4f), Et
(4h))
The dimeric precursor [{RuCl(µ-Cl)(η6-p-cymene)}2] (
1) (0.165
C24H28Cl3O2PRu: C 49.12, H 4.81; found: C 49.27, H 4.82. (2f):
Yield: 0.235 g (86%). 31P{1H} NMR (CD2Cl2): δ = 55.6 (s) ppm. 1H
3
NMR (CD2Cl2): δ = 7.79 (br, 2H, CH of furyl), 7.25 (d, 2H, JHH
=
3.6 Hz, CH of furyl), 6.58 (m, 2H, CH of furyl), 5.70 and 5.64 (d,
2H each, 3JHH = 6.0 Hz, CH of cym), 2.84 (sept, 1H, 3JHH = 7.1 Hz,
g, 0.27 mmol) was added, at room temperature, to a
tetrahydrofuran solution (15 mL) containing the appropriate
secondary phosphine oxide R2P(=O)H, generated in situ by
reacting the corresponding chlorophosphine PR2Cl (0.59 mmol)
with H2O (17 µL, 0.092 mmol) for 1 h.17 The resulting mixture
was stirred at room temperature for 1 h. The solvent was then
removed under reduced pressure, and the resulting orange-
red solid residue washed with hexane (3 x 20 mL; complexes
4c-e,h) or a mixture diethyl ether/hexane (1:1 v/v; 3 x 20 mL;
complexes 4b,f), and dried in vacuo. Complexes 4d and 4h
required further purification by column chromatography over
SiO2, employing CH2Cl2 as the eluent. (4b): Yield: 0.250 g (85%).
IR (KBr): v = 3145 (w, O-H) cm-1. 31P{1H} NMR (CD2Cl2): δ =
106.1 (s) ppm. 1H NMR (CD2Cl2): δ = 7.70 and 7.23 (m, 4H each,
3
CHMe2), 2.08 (s, 3H, Me), 1.18 (d, 6H, JHH = 7.1 Hz, CHMe2)
3
ppm. 13C{1H} NMR (CD2Cl2): δ = 148.3 (d, JPC = 6.3 Hz, CH of
1
2
furyl), 145.9 (d, JPC = 65.6 Hz, C of furyl), 125.1 (d, JPC = 19.1
3
Hz, CH of furyl), 111.5 (d, JPC = 7.3 Hz, CH of furyl), 111.0 and
99.1 (s, C of cym), 91.8 (d, 2JPC = 5.8 Hz, CH of cym), 88.2 (d, 2JPC
= 7.0 Hz, CH of cym), 30.5 (s, CHMe2), 21.4 (s, CHMe2), 17.6 (s,
Me) ppm. Elemental analysis calcd. (%) for C18H20Cl3O2PRu: C
42.66, H 3.98; found: C 42.80, H 4.16. (2g): Yield: 0.227 g
(78%). 31P{1H} NMR (CD2Cl2): δ = 155.7 (s) ppm. 1H NMR
3
(CD2Cl2): δ = 5.47 (br, 4H, CH of cym), 2.97 (sept, 1H, JHH = 7.5
Hz, CHMe2), 2.80-2.60 (m, 2H, CH of Cy), 2.14 (s, 3H, Me), 1.90-
3
1.60 (m, 14H, CH2), 1.30-1.26 (m, 6H, CH2), 1.26 (d, 6H, JHH
=
7.5 Hz, CHMe2) ppm. 13C{1H} NMR (CD2Cl2): δ = 106.6 and 98.5
3
2
2
C6H4F), 5.40 and 5.30 (d, 2H each, JHH = 5.7 Hz, CH of cym),
(s, C of cym), 90.6 (d, JPC = 5.0 Hz, CH of cym), 89.5 (d, JPC
=
2.53 (sept, 1H, 3JHH = 6.9 Hz, CHMe2), 2.01 (s, 3H, Me), 1.03 (d,
2
4.0 Hz, CH of cym), 40.7 (d, JPC = 9.0 Hz, CH of Cy), 29.9 (s,
CHMe2), 27.1 and 25.8 (s, CH2), 26.6 (d, JPC = 13.0 Hz, CH2), 26.5
(d, JPC = 11.0 Hz, CH2), 25.9 (d, JPC = 3.0 Hz, CH2), 21.7 (s,
CHMe2), 17.5 (s, Me) ppm. Elemental analysis calcd. (%) for
C22H36Cl3PRu: C 49.03, H 6.73; found: C 48.93, H 6.90. (2h):
Yield: 0.188 g (81%). 31P{1H} NMR (CD2Cl2): δ = 135.7 (s) ppm.
6H, 3JHH = 6.9 Hz, CHMe2) ppm; OH signal not observed. 13C{1H}
1
NMR (CD2Cl2): δ = 164.5 (d, JFC = 250.3 Hz, C of C6H4F), 133.9
2
3
1
(dd, JPC = 13.1 Hz, JFC = 8.6 Hz, CH of C6H4F), 133.2 (d, JPC
=
62.6 Hz, C of C6H4F), 115.6 (dd, 2JFC = 21.4 Hz, 3JPC = 11.8 Hz, CH
of C6H4F), 109.0 and 97.3 (s, C of cym), 89.3 (d, 2JPC = 4.5 Hz, CH
of cym), 87.1 (d, 2JPC = 5.4 Hz, CH of cym), 30.4 (s, CHMe2), 21.5
(s, CHMe2), 17.6 (s, Me) ppm. 19F{1H} NMR (CD2Cl2): δ = -108.6
3
1H NMR (CD2Cl2): δ = 5.56 and 5.54 (d, 2H each, JHH = 6.9 Hz,
CH of cym), 2.88 (sept, 1H, 3JHH = 6.9 Hz, CHMe2), 2.62-2.32 (m,
4
3
(d, JPF = 2.0 Hz) ppm. Elemental analysis calcd. (%) for
4H, CH2), 2.14 (s, 3H, Me), 1.25 (d, 6H, JHH = 6.9 Hz, CHMe2),
3
3
1.23 (dt, JPH = 18.0 Hz, JHH = 7.5 Hz, CH2CH3) ppm. 13C{1H}
C22H23Cl2F2OPRu: C 48.54, H 4.26; found: C 48.40, H 4.11.
(4c): Yield: 0.181 g (52%). IR (KBr): v = 3185 (w, O-H) cm-1.
2
NMR (CD2Cl2): δ = 108.1 and 97.6 (s, C of cym), 90.1 (d, JPC
5.1 Hz, CH of cym), 87.8 (d, JPC = 5.7 Hz, CH of cym), 30.4 (s,
CHMe2), 25.5 (d, JPC = 18.2 Hz, CH2), 21.7 (s, CHMe2), 17.8 (s,
Me), 7.8 (d, JPC = 5.0 Hz, CH2CH3) ppm. Elemental analysis
=
1
31P{1H} NMR (CD2Cl2): δ = 105.9 (s) ppm. H NMR (CD2Cl2): δ =
2
3
1
7.88-7.79 (m, 8H, C6H4CF3), 5.46 and 5.32 (d, 2H each, JHH
=
3
2
5.8 Hz, CH of cym), 2.50 (sept, 1H, JHH = 6.9 Hz, CHMe2), 2.05
3
(s, 3H, Me), 1.02 (d, 6H, JHH = 6.9 Hz, CHMe2) ppm; OH signal
calcd. (%) for C14H24Cl3PRu: C 39.04, H 5.62; found: C 39.15, H
5.74.
not observed. 13C{1H} NMR (CD2Cl2): δ = 141.2 (d, JPC = 54.6
1
2
Hz, C of C6H4CF3), 132.8 (q, JFC = 31.6 Hz, C of C6H4CF3), 131.8
(d, 2JPC = 12.0 Hz, CH of C6H4CF3), 125.3 (dq, 3JPC = 10.8 Hz, 3JFC
=
Synthesis of [RuCl2(η6-p-cymene)(PPhCl2)] (3)
A suspension of the dimeric precursor [{RuCl(µ-Cl)(η6-p-
3.7 Hz, CH of C6H4CF3), 123.7 (q, 1JFC = 272.9 Hz, CF3), 109.2 and
98.0 (s, C of cym), 89.4 (d, 2JPC = 4.6 Hz, CH of cym), 87.5 (d, 2JPC
= 5.3 Hz, CH of cym), 30.5 (s, CHMe2), 21.4 (s, CHMe2), 17.7 (s,
Me) ppm. 19F{1H} NMR (CD2Cl2): δ = -63.4 (s) ppm. Elemental
analysis calcd. (%) for C24H23F6Cl2OPRu: C 44.74, H 3.60;
found: C 44.63, H 3.53. (4d): Yield: 0.165 g (57%). IR (KBr): v =
cymene)}2] (
was treated,
1
) (0.165 g, 0.27 mmol) in tetrahydrofuran (15 mL)
at room temperature, with
dichlorophenylphosphine (0.077 mL, 0.57 mmol) for 15 min.
The orange solid precipitated formed was filtered, washed
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Journal Name
3037 (w, O-H) cm-1. 31P{1H} NMR (CD2Cl2): δ = 106.8 (s) ppm. 1H introduced into a Teflon-capped sealed tube, andVitehweArrtieclaecOtniloinne
3
3
DOI: 10.1039/C5CY02142A
NMR (CD2Cl2): δ = 7.58 (dd, 4H, JPH = 10.8 Hz, JHH = 8.0 Hz, mixture stirred at 40 °C for the indicated time (see Table 3).
3
4
C6H4Me), 7.33 (dd, 4H, JHH = 8.0 Hz, JPH = 1.8 Hz, C6H4Me), The course of the reaction was monitored regularly taking
5.38 and 5.27 (d, 2H each, 3JHH = 5.6 Hz, CH of cym), 2.50 (sept, samples of ca. 20 µL, which, after extraction with CH2Cl2 (3
3
1H, JHH = 6.9 Hz, CHMe2), 2.45 (s, 6H, C6H4Me), 1.99 (s, 3H, mL), were analyzed by GC. Once the reaction finished, the hot
3
Me), 1.02 (d, 6H, JHH = 6.9 Hz, CHMe2) ppm; OH signal not mixture was allowed to reach room temperature, and then
observed. 13C{1H} NMR (CD2Cl2): δ = 141.6 (d, 4JPC = 2.3 Hz, C of kept in an ice bath for 4 h. This led to the complete
1
C6H4Me), 134.3 (d, JPC = 59.8 Hz, C of C6H4Me), 131.4 (d, JPC
=
crystallization of the corresponding primary amide, which was
12.0 Hz, CH of C6H4Me), 128.9 (d, JPC = 11.0 Hz, CH of C6H4Me), separated, recrystallized from hot water, washed with hexane
2
108.4 and 99.6 (s, C of cym), 89.3 (d, JPC = 5.0 Hz, CH of cym), (2 × 5 mL) and vacuum-dried (in some cases an additional
2
86.8 (d, JPC = 5.8 Hz, CH of cym), 30.6 (s, CHMe2), 21.5 (s, purification by column chromatography over silica gel was
CHMe2), 21.2 (s, C6H4Me), 17.5 (s, Me) ppm. Elemental analysis needed). The identity of the isolated amides was assessed by
calcd. (%) for C24H29Cl2OPRu: C 53.74, H 5.45; found: C 53.61, comparison of their NMR spectroscopic data with those
H 5.50. (4e): Yield: 0.301 g (98%). IR (KBr): v = 3196 (w, O-H) reported in the literature (copies of the NMR spectra obtained
cm-1. 31P{1H} NMR (CD2Cl2): δ = 105.9 (s) ppm. 1H NMR (CD2Cl2): are giving in the ESI file).
3
3
δ = 7.63 (dd, 4H, JPH = 10.2 Hz, JHH = 8.0 Hz, C6H4OMe), 7.03
(dd, 4H, 3JHH = 8.6 Hz, 4JPH = 1.5 Hz, C6H4OMe), 5.38 and 5.28 (d,
2H each, JHH = 5.7 Hz, CH of cym), 3.89 (s, 6H, OMe), 2.55
3
General procedure for the catalytic hydration of -
ketonitriles with [RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (2b)
3
(sept, 1H, JHH = 6.9 Hz, CHMe2), 1.99 (s, 3H, Me), 1.03 (d, 6H,
3JHH = 6.9 Hz, CHMe2) ppm; OH signal not observed. 13C{1H}
NMR (CD2Cl2): δ = 161.9 (s, C of C6H4OMe), 133.5 (d, JPC = 13.0
The corresponding -ketonitrile (1 mmol), water (3 mL), and
the ruthenium(II) complex 2b (0.011 g, 0.02 mmol; 2 mol%)
were introduced into a Teflon-capped sealed tube, and the
reaction mixture stirred at 40-80 °C for 14 h (see Table 4).
Precipitation of the-ketoamide formed along the reaction
was observed. After that time, the hot mixture was allowed to
1
Hz, CH of C6H4OMe), 128.9 (d, JPC = 62.9 Hz, C of C6H4OMe),
113.6 (d, JPC = 11.7 Hz, CH of C6H4OMe), 108.4 and 96.4 (s, C of
2
2
cym), 89.3 (d, JPC = 4.6 Hz, CH of cym), 86.8 (d, JPC = 5.6 Hz,
CH of cym), 55.5 (s, OMe), 30.4 (s, CHMe2), 21.5 (s, CHMe2),
17.6 (s, Me) ppm. Elemental analysis calcd. (%) for
C24H29O3Cl2PRu: C 50.71, H 5.14; found: C 50.56, H 5.12. (4f):
Yield: 0.224 g (85%). IR (KBr): v = 3125 (w, O-H) cm-1. 31P{1H}
reach room temperature, the precipitated
-ketoamide was
filtered, washed with water (3 × 5 mL) and hexane (2 × 5 mL),
and vacuum-dried. The identity of the isolated amides was
assessed by comparison of their NMR spectroscopic data with
those reported in the literature (copies of the NMR spectra
obtained are giving in the ESI file).
1
NMR (CD2Cl2): δ = 78.1 (s) ppm. H NMR (CD2Cl2): δ = 7.70 (br,
2H, CH of furyl), 7.05 (d, 2H, 3JHH = 3.0 Hz, CH of furyl), 6.63 (br,
3
2H, CH of furyl), 5.57 (br, 4H, CH of cym), 2.65 (sept, 1H, JHH
=
3
6.9 Hz, CHMe2), 2.03 (s, 3H, Me), 1.10 (d, 6H, JHH = 7.1 Hz,
CHMe2) ppm; OH signal not observed. 13C{1H} NMR (CD2Cl2): δ
X-Ray crystal structure determination of complexes 2g and 4c
1
3
= 150.0 (d, JPC = 90.3 Hz, C of furyl), 147.6 (d, JPC = 6.7 Hz, CH
2
3
Crystals of 2g and 4c suitable for X-ray diffraction analysis were
obtained by slow diffusion of diethyl ether and n-hexane,
respectively, into saturated solutions of the complexes in
dichloromethane. The most relevant crystal and refinement
data are collected in Table 5. In both cases, data collection was
performed with an Oxford Diffraction Xcalibur Nova single
crystal diffractometer using Cu-Kα radiation (λ = 1.5418 Å).
Images were collected at a fixed crystal-to-detector distance of
62 mm for complex 2g and 63 mm for 4c, using the oscillation
method with 1ᵒ oscillation and 1.5-5.0 s variable exposure time
per image for 2g, and 3.0-20.0 s for 4c. Data collection strategy
was calculated with the program CrysAlis Pro CCD.49 Data
reduction and cell refinement was performed with the
program CrysAlis Pro RED.49 An empirical absorption correction
was applied using the SCALE3 ABSPACK algorithm as
implemented in the program CrysAlis Pro RED.49
In both cases, the software package WINGX was used for
space group determination, structure solution, and
refinement.50 For 2g the structure was solved by a charge
flipping iterative algorithm using SUPERFLIP,51 and for 4c the
structure was solved by Patterson interpretation and phase
expansion using DIRDIF2008.52 Isotropic least-squares
refinement on F2 using SHELXL97 was performed.53 During the
of furyl), 121.4 (d, JPC = 15.9 Hz, CH of furyl), 111.2 (d, JPC
=
=
2
6.7 Hz, CH of furyl), 108.7 and 97.3 (s, C of cym), 90.1 (d, JPC
2
5.4 Hz, CH of cym), 86.9 (d, JPC = 6.3 Hz, CH of cym), 30.6 (s,
CHMe2), 21.4 (s, CHMe2), 17.8 (s, Me) ppm. Elemental analysis
calcd. (%) for C18H21O3Cl2PRu: C 44.28, H 4.33; found: C 44.37,
H 4.45. (4h): Yield: 0.129 g (58%). IR (KBr): v = 3180 (w, O-H)
cm-1. 31P{1H} NMR (CD2Cl2): δ = 126.6 (s) ppm. 1H NMR (CD2Cl2):
3
δ = 5.54 and 5.50 (d, 2H each, JHH = 5.8 Hz, CH of cym), 2.76
(sept, 1H, 3JHH = 7.2 Hz, CHMe2), 2.28-2.21 (m, 4H, CH2), 2.09 (s,
3H, Me), 1.26 (d, 6H, 3JHH = 7.2 Hz, CHMe2), 1.23 (dt, 3JPH = 16.2
Hz, 3JHH = 7.6 Hz, CH2CH3) ppm; OH signal not observed. 13C{1H}
2
NMR (CD2Cl2): δ = 106.8 and 95.0 (s, C of cym), 89.2 (d, JPC
=
2
4.5 Hz, CH of cym), 85.6 (d, JPC = 5.4 Hz, CH of cym), 30.8 (s,
CHMe2), 25.2 (d, JPC = 33.9 Hz, CH2), 21.8 (s, CHMe2), 18.1 (s,
Me), 6.7 (d, JPC = 3.7 Hz, CH2CH3) ppm. Elemental analysis
1
2
calcd. (%) for C14H25Cl2OPRu: C 40.78, H 6.11; found: C 40.61,
H 6.27.
General procedure for the catalytic hydration of nitriles with
[RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (2b)
The corresponding nitrile (1 mmol), water (3 mL), and the
ruthenium(II) complex 2b (0.011 g, 0.02 mmol; 2 mol%) were
8 | J. Name., 2012, 00, 1-3
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ARTICLE
final stages of the refinements, all the positional parameters This work was supported by the Spanish MINECO (projects
View Article Online
and the anisotropic temperature factors of all non-H atoms CTQ2013-40591-P and CTQ2014-519D1O2-I:R1E0D.1C03)9/Ca5nCdY021t4h2Ae
were refined. Complex 4c contains two highly disordered Gobierno del Principado de Asturias (project GRUPIN14-006).
trifluoromethyl groups. Although SHELXL97 provides two
possible sites for each of the fluorine atoms, the anisotropic
motion of the atoms on a single position leads to a better
Notes and references
description of this positional disorder. The H atoms were
geometrically located and their coordinates were refined
riding on their parent atoms. The final position of the
hydrogen atom H1o (complex 4c) was obtained after a rotating
group refinement (the initial torsion angle is derived from a
difference Fourier synthesis). The function minimized was
1
(a) The Chemistry of Amides, ed. J. Zabicky, Wiley-
Interscience, New York, 1970; (b) The Amide Linkage:
Structural Significance in Chemistry, Biochemistry and
Materials Science, ed. A. Greenberg, C. M. Breneman and J.
F. Liebman, John Wiley & Sons, New York, 2000; (c)
Polyesters and Polyamides, ed. B. L. Deopura, B. Gupta, M.
Joshi and R. Alagirusami, CRC Press, Boca Raton, 2008; (d) I.
Johansson, in Kirk-Othmer Encyclopedia of Chemical
Technology, John Wiley & Sons, New York, 2004, vol. 2, pp.
442-463.
See, for example: (a) Methoden Org. Chem. (Houben Weyl),
ed. D. Dopp and H. Dopp, Thieme Verlag, Stuttgart, 1985,
vol. E5(2), pp. 1024-1031; (b) P. D. Bailey, T. J. Mills, R.
Pettecrew and R. A. Price, in Comprehensive Organic
Functional Group Transformations II, ed. A. R. Katritzky and
R. J. K. Taylor, Elsevier, Oxford, 2005, vol 5, pp 201-294.
C. P. Wilgus, S. Downing, E. Molitor, S. Bains, R. M. Pagni and
G. W. Kabalka, Tetrahedron Lett., 1995, 36, 3469.
2 2
2 2
2
{

[

(Fo2 - Fc ) ]/

[

(Fo ) ]}1/2 where

= 1/[2(Fo ) + (aP)2 + bP]
2
(a and b values are collected in Table 5) with

(Fo ) from
2
2
counting statistics and P = [Max (Fo ,0) + 2Fc ]/3. Atomic
scattering factors were taken from International Tables for X-
ray Crystallography.54 Geometrical calculations were made
with PARST.55 The crystallographic plots were made with
ORTEP3.50
2
3
4
Table 5 Crystal data and structure refinement for compounds 2g and 4c
2g
4c
For selected reviews, see: (a) M. Kobayashi and S. Shimizu,
Curr. Opin. Chem. Biol., 2000, 4, 95; (b) I. Endo, M. Nojori, M.
Empirical formula
Formula weight
Temperature/K
Wavelength/Å
Crystal system
Space group
Crystal size/mm
a/Å
b/Å
c/Å
α (ᵒ)
β (ᵒ)
C22H36Cl3PRu
538.90
293(2)
1.54184
Triclinic
P-1
0.19 x 0.09 x 0.03
7.6344(3)
10.5128(3)
15.3514(6)
103.182(3)
92.237(3)
90.962(3)
2
C24H23F6Cl2OPRu
644.36
293(2)
Tsujimura, M. Nakasako, S. Nagashima, M. Yohda and M.
Odaka, J. Inorg. Biochem., 2001, 83, 247; (c) J. A. Kovacs,
Chem. Rev., 2004, 104, 825; (d) G. De Santis and R. Di
Cosimo, in Biocatalysis for the Pharmaceutical Industry:
Discovery, Development and Manufacturing, ed. J. Tao, G.-Q.
Lin and A. Liese, Wiley-VCH, Weinheim, 2009, pp 153-181;
(e) S. Prasad and T. C. Bhalla, Biotechnol. Adv., 2010, 28, 725;
(f) M.-X. Wang, Acc. Chem. Res., 2015, 48, 602.
For selected reviews, see: (a) V. Y. Kukushkin and A. J. L.
Pombeiro, Chem. Rev., 2002, 102, 1771; (b) V. Y. Kukushkin
and A. J. L. Pombeiro, Inorg. Chim. Acta, 2005, 358, 1; (c) T. J.
Ahmed, S. M. M. Knapp and D. R. Tyler, Coord. Chem. Rev.,
2011, 255, 949; (d) R. García-Álvarez, P. Crochet and V.
Cadierno, Green Chem., 2013, 15, 46; (e) R. García-Álvarez, J.
Francos, E. Tomás-Mendivil, P. Crochet and V. Cadierno, J.
Organomet. Chem., 2014, 771, 93; (f) P. Crochet and V.
Cadierno, Top. Organomet. Chem., 2014, 48, 81.
1.54184
Monoclinic
P21/c
0.52 x 0.04 x 0.04
6.8231(1)
11.2772(2)
33.5183(6)
90
91.031(1)
90
4
2578.66(8)
1.660
7.961
5
6
γ (ᵒ)
Z
Volume/Å3
Calculated density/g cm-3
µ/mm-1
1198.29(8)
1.494
9.030
F(000)
θ range/°
Index ranges
556
1288
4.32-69.68
-8 ≤ h ≤ 9
-12 ≤ k ≤ 9
-17 ≤ l ≤ 18
97.5%
4.14-69.49
-5 ≤ h ≤ 8
-13 ≤ k ≤ 13
-40 ≤ l ≤ 40
99.3%
For selected examples, see: (a) M. Tamura, H. Wakasugi, K.-I.
Shimizu and A. Satsuma, Chem. Eur. J., 2011, 17, 11428; (b)
Y. Gangarajula and B. Gopal, Chem. Lett., 2012, 41, 101; (c)
G. K. S. Prakash, S. B. Munoz, A. Papp, K. Masood, I.
Bychinskaya, T. Mathew and G. A. Olah, Asian J. Org. Chem.,
Completeness to θmax
No. of reflns. collected
No. of unique reflns.
No. of parameters/restraints
Refinement method
Goodness-of-fit on F2
Weight function (a, b)
R1 [I > 2σ(I)]a
9679
21368
2012,
Catal. Sci. Technol., 2013,
Hawkins and S. V. Ley, Org. Lett., 2014, 16, 1060; (f) Y.
Gangarajula and B. Gopal, Appl. Catal. A: Gen., 2014, 475
211; (g) M. Tamura, K. Sawabe, K. Tomishige, A. Satsuma and
K.-I. Shimizu, ACS Catal., 2015, , 20; (h) B. Sarmah, R.
Srivastava, P. Manjunathan and G. V. Shanbhag, ACS
Sustainable Chem. Eng., 2015, , 2933.
1
, 146; (d) M. Tamura, A. Satsuma and K.-I. Shimizu,
4410 (Rint = 0.040) 4804 (Rint = 0.038)
244/0 317/0
Full-matrix least-squares on F2
1.060
0.0480, 0.0973
0.0335
0.0842
3
, 1386; (e) C. Battilocchio, J. M.
,
1.170
0.0203, 12.0241
0.0528
0.1227
5
wR2 [I > 2σ(I)]a
3
R1 (all data)
0.0388
0.0560
7
8
For a review, see: E. L. Dows and D. R. Tyler, Coord. Chem.
Rev., 2014, 280, 28.
R2 (all data)
0.0920
0.1241
0.78, -0.57
Largest diff. peak and hole/e Å-3 0.65, -0.77
(a) T. Ghaffar and A. W. Parkins, Tetrahedron Lett., 1995, 36
,
a R1 = ∑(|Fo|-|Fc|)/∑|Fo|; wR2 = {∑[w(Fo2-Fc2)2]/∑[w(Fo2)2]}1/2
8657; (b) T. Ghaffar and A. W. Parkins, J. Mol. Catal. A:
Chem., 2000, 160, 249.
9
For a recent review on the synthetic applications of complex
[PtH{(PMe2O)2H}(PMe2OH)] (
2015, , 380.
10 H. Gulyás, I. Rivilla, S. Curreli, Z. Freixa and P. W. N. M. van
Leeuwen, Catal. Sci. Technol., 2015, , 3822.
A), see: V. Cadierno, Appl. Sci.,
Acknowledgements
5
5
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11 (a) S. M. M. Knapp, T. J. Sherbow, R. B. Yelle, J. J. Juliette and 21 D. Yakhvarov, E. Trofimova, O. Sinyashin, O. Kataeva, Y.
View Article Online
D. R. Tyler, Organometallics, 2013, 32, 3744; (b) E. Tomás-
Budnikova, P. Lönnecke, E. Hey-Hawkins, A. Petr, Y.
DOI: 10.1039/C5CY02142A
Mendivil, L. Menéndez-Rodríguez, J. Francos, P. Crochet and
Krupskaya, V. Kataev, R. Klingeler and B. Büchner, Inorg.
Chem., 2011, 50, 4553.
V. Cadierno, RSC Adv., 2014, 4, 63466; (c) E. Tomás-Mendivil,
F. J. Suárez, J. Díez and V. Cadierno, Chem. Commun., 2014, 22 For a discussion about the strength of hydrogen bonds, see:
50 9661; (d) E. Tomás-Mendivil, V. Cadierno, M. I. T. Steiner, Angew. Chem. Int. Ed., 2002, 41, 48.
Menéndez and R. López, Chem. Eur. J., 2015, 21, 16874; (e) 23 (a) Employing directly complex [RuCl2(η6-p-cymene){P(2-
,
Ruthenium complexes with pyrazolyl ligands have also
shown good efficiency and selectivity in the catalytic
hydration of nitriles at 80 °C: Í. Ferrer, J. Rich, X. Fontrodona,
M. Rodríguez and I. Romero, Dalton Trans., 2013, 42, 13461;
Í. Ferrer, X. Fontrodona, M. Rodríguez and I. Romero, Dalton
Trans., 2016, in press (DOI: 10.1039/C5DT04376J).
furyl)2OH}] (4f) as catalyst, under identical experimental
conditions, benzamide was formed in 13% after 2 h; (b)
Employing directly complex [RuCl2(η6-p-cymene){P(4-
C6H4F)2OH}] (4b) as catalyst, under identical experimental
conditions, benzamide was formed in 96% after 30 min.
24 Although different ruthenium complexes have shown some
activity in water at temperatures ≤ 40 ᵒC, they require of
extremely long reaction times (2-4 days) to generate the
amides in good yields. See, references 11a,c and: (a) S. M. M.
Knapp, T. J. Sherbow, J. J. Juliette and D. R. Tyler,
Organometallics, 2012, 31, 2941; (b) S. M. M. Knapp, T. J.
Sherbow, R. B. Yelle, L. N. Zakharov, J. J. Juliette and D. R.
Tyler, Organometallics, 2013, 32, 824; (c) R. García-Álvarez,
M. Zablocka, P. Crochet, C. Duhayon, J.-P. Majoral and V.
Cadierno, Green Chem., 2013, 15, 2447.
12 T. J. Ahmed, B. R. Fox, S. M. M. Knapp, R. B. Yelle, J. J. Juliette
and D. R. Tyler, Inorg. Chem., 2009, 48, 7828.
13 For selected reviews covering the coordination chemistry of
secondary phosphine oxides, see: (a) D. M. Roundhill, R. F.
Sperline and W. B. Beaulieu, Coord. Chem. Rev., 1978, 26
263; (b) B. Walther, Coord. Chem. Rev., 1984, 60, 67; (c) T.
Appleby and J. D. Woollins, Coord. Chem. Rev., 2002, 235
,
,
121; (d) L. Ackermann, Synthesis, 2006, 1557; (e) T. M.
Shaikh, C.-M. Weng and F. E. Hong, Coord. Chem. Rev., 2012,
256, 771.
25 Very recently, an efficient copper-based catalytic system
able to hydrate nitriles in water at 35 ᵒC has been
communicated: P. Marcé, J. Lynch, A. J. Blacker and J. M. J.
Williams, Chem. Commun., 2016, 52, 1436.
14 Concerning the preparation of the secondary phosphine
oxides, several methods have been described in the
literature. However, the one used more frequently is the
addition of Grignard, or related organometallic reagents, to 26 The rhodium-based systems [{Rh(μ-OMe)(cod)}2]/PCy3 (cod =
H-phosphonates. See, for example: (a) T. L. Emmick and R. L.
Letsinger, J. Am. Chem. Soc., 1968, 90, 3459; (b) H. R. Hays, J.
Org. Chem., 1968, 33, 3690; (c) A. Leyris, J. Bigeault, D. Nuel,
L. Giordano and G. Buono, Tetrahedron Lett., 2007, 48, 5247;
1,5-cyclooctadiene) and [RhBr(PIN)(cod)] (PIN = 1-isopropyl-
3-(5,7-dimethyl-1,8-naphthyrid-2-yl)imidazol-2-ylidene) are
known to hydrate nitriles under ambient conditions.
However, they operate in organic media with only small
amounts of water, and the latter requires the help of a base:
(a) A. Goto, K. Endo and S. Saito, Angew. Chem. Int. Ed.,
2008, 47, 3607; (b) P. Daw, A. Sinha, S. M. W. Rahaman, S.
Dinda and J. K. Bera, Organometallics, 2012, 31, 3790.
(d) Q. Xu, C.-Q. Zhao, L.-B. Han, J. Am. Chem. Soc., 2008, 130
,
12648; (e) T. Achard, L. Giordano, A. Tenaglia, Y. Gimbert and
G. Buono, Organometallics, 2010, 29, 3936.
15 For studies and discussions of the factors affecting this
equilibrium, see: (a) J. Chatt and B. T. Heaton, J. Chem. Soc. 27 (a) J. Cossy and C. Leblanc, Tetrahedron Lett., 1989, 30, 4531;
A, 1968, 2745; (b) H. J. Brass, R. A. Di Prete, J. O. Edwards, R.
G. Lawler, R. Curci and G. Modena, Tetrahedron, 1970, 26
4555; (c) B. Hoge, S. Neufeind, S. Hettel, W. Wiebe and C.
Thösen, J. Organomet. Chem., 2005, 690, 2382; (d) B. Hoge,
(b) J. Cossy, D. Belotti, N. K. Cuong and C. Chassagnard,
Tetrahedron, 1993, 49, 7691; (c) C.-Y. Zhou and C.-M. Che, J.
Am. Chem. Soc., 2007, 129, 5828; (d) Z.-X. Xu, Y.-X. Tan, H.-R.
Fu, J. Liu and J. Zhang, Inorg. Chem., 2014, 53, 12199.
,
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10 | J. Name., 2012, 00, 1-3
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46 The low solubility of the
-ketoamide products in the
reaction medium precluded the monitoring of the reactions
by GC. That is why they were all performed at a fixed, and
relatively long, time to ensure a high conversion.
47 For a recent study on the keto-enol equilibrium in
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DOI: 10.1039/C5CY02142A
For Graphical Abstract use only
The utility of chlorophosphines as auxiliary ligands in metal-catalyzed nitrile hydration
reactions has been demonstrated, along with their application in the preparation of β-
ketoamides.