Selective nucleophilic oxygenation of palladium-bound isocyanide ligands: Route to imine complexes that serve as efficient catalysts for copper-/phosphine-free sonogashira reactions

Article abstract of DOI:10.1021/om4000665

Metal-mediated reactions between cis-[PdCl₂(CNR)₂] (R = Xy (1), Cy (2), tBu (3), C₆H₃(Cl-2)Me-6 (4)) and the ketonitrones Ph₂C=N(O)C₆H₄R′ (R′ = Me (5), Cl (6)) proceed in a 1:1 m

Full text of DOI:10.1021/om4000665

Article
pubs.acs.org/Organometallics
Selective Nucleophilic Oxygenation of Palladium-Bound Isocyanide
Ligands: Route to Imine Complexes That Serve as Efficient Catalysts
for Copper-/Phosphine-Free Sonogashira Reactions
Andreii S. Kritchenkov,† Konstantin V. Luzyanin,†,‡ Nadezhda A. Bokach,† Maxim L. Kuznetsov,§
Vladislav V. Gurzhiy,∥ and Vadim Yu. Kukushkin*,†,⊥
†Department of Chemistry, Saint Petersburg State University, Universitetsky Pr. 26, 198504 Stary Petergof, Russian Federation
‡Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, United Kingdom
§
́
́ ́
Centro de Quımica Estrutural, Complexo I, Instituto Superior Tecnico, Universidade Tecnica de Lisboa, Av. Rovisco Pais, 1049-001
Lisbon, Portugal
∥Department of Geology, Saint Petersburg State University, Universitetskaya Nab. 7/9, 199034 Saint Petersburg, Russian Federation
⊥Saint Petersburg State Forest Technical University, Institutskii per. 5, 194021 Saint Petersburg, Russian Federation
S
* Supporting Information
ABSTRACT: Metal-mediated reactions between cis-
[PdCl2(CNR)2] (R = Xy (1), Cy (2), tBu (3), C6H3(Cl-2)
Me-6 (4)) and the ketonitrones Ph2CN(O)C6H4R′ (R′ =
Me (5), Cl (6)) proceed in a 1:1 molar ratio as selective
nucleophilic oxygenations and provide the imine−isocyanide
complexes [PdCl2{N(C6H4R′)CPh2}(CNR)] (7−14: R′ =
Me, R = Xy (7), Cy (8), tBu (9), C6H3(Cl-2)Me-6 (10); R′ =
Cl, R = Xy (11), Cy (12), tBu (13), C6H3(Cl-2)Me-6 (14)) in
excellent yields (90−94%), while the reaction of the cis-
[PdCl2(CNR)2] complexes with aldonitrones proceeds as 1,3-dipolar cycloaddition, giving carbene adducts which then convert
to the imine complexes. Theoretical calculations at the DFT level indicate that, in the case of aldonitrones, formation of the imine
complexes occurs preferably via a cycloaddition/splitting pathway, including the generation of a cycloadduct, while, in the case of
ketonitrones, both the cycloaddition/splitting route and the direct oxygen atom transfer pathway are equally plausible from a
kinetic viewpoint. Complexes 7−14 were characterized by elemental analyses (C, H, N), by high-resolution ESI+-MS, IR, and 1H
and 13C{1H} NMR spectroscopy, and also by X-ray diffraction (for 8). The catalytic activity study conducted for 7−14, taken as
the catalysts in the Cu-/phosphine-free Sonogashira reaction, was evaluated for a typical model system comprising 4-
methoxyiodobenzene and phenylacetylene and affording 1-methoxy-4-(phenylethynyl)benzene. The obtained data indicate that 7−
14 exhibit a high catalytic activity (yields up to 95%, TONs up to 15000), and these catalysts are among the best studied so far.
of the isocyanide C atom toward attack by an O-nucleophile
that can be achieved by (i) application of metal-free electrophiles
(sulfur tetrafluoride,10a halogen, acid,12 and trifluoracetic
anhydride catalyzed10b oxidations by DMSO, iodine catalyzed
oxygenation by amine N-oxides13) or (ii) a metal-mediated route
when metal centers bind the isocyanide C atom and act as elec-
trophilic activators, thus facilitating nucleophilic oxygenations
of RNC ligands (e.g., Au0,8 MoIV, or WIV catalyzed9 and CuI-
mediated nucleophilic oxygenations14).
Previously, two of us reported that aldonitrones, Ar(H)C
N(O)Alk, react with one isocyanide in cis-[PdCl2(CNR)2] to
form a cyclic carbene ligand formed via 1,3-dipolar cycloaddi-
tion (Scheme 1).15 The reactions of such poorly studied dipoles
as ketonitrones,16 Ar2CN(O)Ar, with isocyanide ligands in
their metal complexes were not studied, although we recently
INTRODUCTION
■
In carbonyl chemistry, the nucleophilic oxygenation of carbon
monoxide is a classic issue, and it has been thoroughly studied
under both metal-mediated1 and metal-free conditions.2 Many
of these oxidations proceed as a nucleophilic oxygenation (see
reviews3 and recent works1f,4), and they are particularly useful
in synthetic chemistry for conducting oxidative substitution of
metal-bound CO,3b liberation of organic ligands,1a,3b oligomeri-
zation of mononuclear metal carbonyl derivatives,5 intramolecular
ligand displacement,6 and deinsertion reactions.7
Isocyanides are isoelectronic with the CO molecule, and it
would seem that they have to undergo the same type oxidation.
Surprisingly, despite the wealth of isocyanide chemistry, the
conversion of RNC to RNCO has still been much less investi-
gated than similar oxygenations of CO. The reported examples
of such reactions include the nucleophilic oxygenation of an
isocyanide by amine N-oxides,8 N2O,9 DMSO,10 and ozone.11
In the vast majority of cases, these processes require an activation
Received: January 29, 2013
© XXXX American Chemical Society
A
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dichloromethane or benzene solutions, and they lead to the
generation of imine−isocyanide palladium(II) complexes 7−14.
These reactions were studied at different temperatures, in
different solvents, and using various ratios of the reactants. The
obtained results are disclosed in sections that follow.
Scheme 1. Different Reactivity of Aldo- and Ketonitrones
toward PdII-Bound Isocyanides
When the reactions between 5 (or 6) and 1−4, in all possible
combinations, in CH2Cl2 or C6H6 in molar ratios ranging from
1:1 to 1:2 were performed at ca. 5 °C for 4 h and then the
reaction mixtures were stirred at room temperature for 5 h, we
observed a selective oxygenation of the isocyanide ligands to
give the corresponding uncomplexed isocyanates and gen-
eration of imine−isocyanide complexes 7−14; the latter were
isolated in excellent yields (90−94%). The formation of the
RNCO isocyanates was unambiguously established by (i) the
IR monitoring of the reaction mixtures (ca. 2260 cm−1; lit.10b
2257 cm−1 ν(CNO))) and (ii) by the treatment of the
reaction mixtures with Et2NH followed by isolation of the
substituted ureas Et2NC(O)NHR generated via the reported
addition of Et2NH to the isocyanates.10b Identification of
Et2NC(O)NHR was based on comparison of their melting
points with those for the known species.18
verified their reactivity toward various platinum- and palladium-
activated nitrile, RCN, species.16,17 In contrast to the previous
cycloaddition study involving aldonitrones,15 we now observe
that an isocyanide ligand in cis-[PdCl2(CNR)2] reacts with the
ketonitrones Ph2CN(O)C6H4R′ (R′ = Me, Cl) and
undergoes facile and selective oxygenation to give free
isocyanates and mixed imine−isocyanide palladium(II) com-
plexes (Scheme 1).
In this work (i) we compare the reactivity of the RNC ligands in
cis-[PdCl2(CNR)2] toward aldo- and ketonitrones and suggest an
efficient route to oxygenate metal-activated RNC species by
ketonitrones, (ii) as a result of the observed oxygenation we
synthesize and characterize a series of mixed imine−isocyanide
palladium(II) complexes, and (iii) we test these species as catalysts
in copper-/phosphine-free Sonogashira cross-coupling and it
appears that they exhibit a great efficiency in this reaction. All
these results are consistently disclosed in this work.
When the reactions between 5 (or 6) and 1−4, in 1:1 or 1:2
ratios, in CH2Cl2 were performed at −30 °C, only the decrease
of the reaction rate was observed. At room temperature in
either CH2Cl2 or C6H6, the reaction lost its selectivity, resulting
in a broad mixture of products, where we detected imine−
isocyanide complexes 7−14 (ca. 20−25% based on the 1H NMR
integration of the meta protons of the p-R′C6H4 group) and the
corresponding isocyanates RNCO (identified by HRESI-MS)
along with many other as yet unidentified species.
It has previously been reported15 (Scheme 3) that the acyclic
aldonitrones R3C(H)N(O)R1 (R3 = 4-CH3C6H4; R1 = Me,
Scheme 3. Reaction of PdII-Bound Isocyanides with
Aldonitrones
RESULTS AND DISCUSSION
■
Palladium(II)-Mediated Nucleophilic Oxygenation of
Isocyanide Ligands by Ketonitrones. In the current work,
the isocyanide complexes cis-[PdCl2(CNR)2] (R = Xy (1), Cy
(2), tBu (3), C6H3(Cl-2)Me-6 (4)), on one hand, and the
ketonitrones Ph2CN(O)C6H4R′ (R′ = Me (5), Cl (6)), on
the other hand, were employed as the partners for the reactivity
study (Scheme 2 and Table 1).
Scheme 2. Studied Oxygenations
CH2Ph) react with 1−4 (molar ratio 1:1, at ca. 5 °C in C6H6)
to give stable carbene−isocyanide complexes A (ca. 60%),
which are formed via 1,3-dipolar cycloaddition; they decompose
only upon heating (C6H6, 60 °C; CHCl3, room temperature) to
give the corresponding isocyanates RNCO and imine−isocyanide
complexes B.
Table 1. Compound Numbering for Scheme 2
R
In contrast to the cycloaddition study,15 no evidence for
generation of the carbene cycloadducts originating from 1−4
and ketonitrones 5 (or 6) were detected by both HRESI-MS
5, R′ = Me
6, R′ = Cl
Xy
1
2
3
4
7
11
12
13
14
Cy
8
1
tBu
9
and H NMR spectroscopy, even at −30 °C. Furthermore,
C6H3(Cl-2)Me-6
10
imine−isocyanide complexes 7−14 originating from the
deoxygenation of the ketonitrones, proved to be stable even
in refluxing toluene (24 h), while imine−isocyanide species B
(Scheme 3) are unstable and were not isolated in analytically
The reactions between 5 and 6 and the isocyanide ligands
RNC in their palladium(II) complexes 1−4 were performed in
B
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pure form and were characterized in their CDCl3 solutions by
HRESI-MS and H NMR.
1,3-dipolar cycloaddition (CA), which then splits into the imine
and the isocyanate (route A, Scheme 5). This route is operating
in the case of aldonitrones, as was proved by previous experimental15
and theoretical19 studies. The second route includes the direct
oxygen atom transfer from the nitrone to the isocyanide ligand
(route B, Scheme 5), which may occur either in a concerted or
in a stepwise manner. The experimentally observed imine complex
IV and free isocyanate are formed as a result of the substitution of
OCNR for the imine in the coordination sphere of complex III.
1. Route A. The mechanism of generation of complex IV via
route A was previously theoretically studied in detail by one of
us for the reaction of the aldonitrone PhC(H)N(O)Me with
the complex [PdCl2(CNMe)2] (I).19f It was shown that the
cycloadduct IIaldo is formed in a stepwise manner via the acyclic
intermediate INTaldo. Cycloadduct IIaldo then undergoes split-
ting via the concerted cleavage of the N(2)−C(3) and N(4)−
O(5) bonds. This process is accompanied by the spontaneous
recoordination of the isocyanate and formation of complex III,
featuring the O-bound OCNMe ligand. Subsequent ligand sub-
stitution affords final product IValdo via a dissociative mechanism
with a small activation barrier of 8.4 kcal/mol, while the rate-
determining step of the whole reaction is the first CA.
1
It should be pointed out that nitrones 5 and 6 do not react
with the uncomplexed isocyanides RNC even under drastic
conditions (125 h, reflux in the RNC media). The latter obser-
vation means that the oxygenation of the isocyanides by the
ketonitrones is palladium(II)-mediated. The processes involv-
ing metal-mediated oxygenations of isocyanides to give iso-
cyanates (Scheme 4) have been poorly studied, and they are
Scheme 4. Metal-Catalyzed Oxygenations
Taking into account that in this work CH2Cl2 was employed
as a solvent instead of the benzene applied previously,15 we re-
calculated the activation and reaction energies of the reaction
between PhC(H)N(O)Me and I along route A with dichloro-
methane as the solvent (Table 2) (previously published values19f
were obtained for a benzene solution).
Within this work, the same mechanistic route A was cal-
culated for the reaction between the ketonitrone Ph2C
N(O)Ph and I. The calculations demonstrated that in this case
CA also occurs via the stepwise pathway, including the for-
mation of acyclic intermediate INTketo. The first step, viz. the
formation of INTketo via TS1keto (Figure 1), is the rate-determining
step, while the energy of TS2keto of the second step is 5.8 kcal/mol
lower than the energy of TS1keto. The overall activation barrier
of CA involving the ketonitrone is higher by 1.7 kcal/mol in
comparison to that involving the aldonitrone (Figure 2).
CA of the aldonitrone is slightly exoergonic with a ΔGs value
of −0.8 kcal/mol, whereas the reaction with the ketonitrone
is clearly endoergonic by 3.0 kcal/mol. This difference in the
represented by amine N-oxide Au0-catalyzed oxygenation8 and
MoII- or WII-catalyzed oxidation by N2O.9 Plausible mechanisms of
these transformations include the nucleophilic addition of R3NO or
N2O to metal-coordinated isocyanides followed by formation of
R3N or N2, respectively, and generation of π-coordinated iso-
cyanate, which is then substituted by RNC (Scheme 4).
With regard to noncatalytic metal-mediated processes, only
one example of oxidation of an isocyanide ligand to furnish iso-
cyanate was reported, and it includes the reaction of (RNC)CuI
−
species with t-BuCO3 . It is believed that this transformation
also proceeds via the nucleophilic oxygenation of the isocyanide
14
−
ligand by t-BuCO3 .
Theoretical Mechanistic Study. With the aim of under-
standing the reasons for the different chemical behaviors of keto-
nitrones and aldonitrones toward PdII-bound isocyanides, quantum
chemical calculations of the reaction mechanisms have been
performed. There are two plausible routes leading to imines and
isocyanates upon the reaction between nitrones and isocyanides.
The first involves the initial formation of the cycloadduct, via
Scheme 5. Mechanisms of Formation of Imine Complexes and Isocyanates upon the Reaction of Nitrones with Palladium-
Bound Isocyanides
C
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the conversion of both INTketo and INTaldo into the CA product
requires an even smaller activation energy (1.7 and 3.7 kcal/mol,
respectively).
Table 2. Calculated Gibbs Free Energies of Activation and
Reaction for CH2Cl2 Solution (in kcal/mol)
reaction
ΔGs⧧
ΔGs
An inspection of Figure 2 indicates three principal differences
in the energy profiles for the reactions of the aldonitrone and
the ketonitrone with I, i.e., (i) the rate-limiting step of route B
is the INTaldo → III step for the aldonitrones, while it is the
Ph2CN(O)Ph + I → INTketo step for the ketonitrone, (ii)
cycloadduct IIaldo is slightly exoergonic relative to the starting
reactants, whereas the cycloadduct IIketo is endoergonic, and
(iii) the activation barrier of the II decomposition into III is
lower for the ketonitrone than for the aldonitrone by 3.3 kcal/mol.
Considering these features, the following conclusions may be
formulated. First, for the aldonitrone, the generation of the
oxygen atom transfer product IValdo occurs via formation of
cycloadduct IIaldo as the intermediate (route A), while route B
is clearly less favorable. This conclusion is coherent with the
experiment,15 where the cycloadducts were isolated. Second, for
the ketonitrone, both routes of the IVketo formation (A and B)
are equally plausible. The generation of the cycloadduct IIketo is
also expected. However, its accumulation should be less effi-
cient compared to that of IIaldo due to the positive ΔGs values
of IIketo formation and a lower activation barrier to its decomposition.
Note that the difference of 3.3 kcal/mol between the activation
barriers of the IIaldo and IIketo decompositions corresponds to
the difference in the reaction rates by a factor of ca. 280.
Additionally, an extensive search of the potential energy surface
was carried out with the aim of locating transition states for the
one-step concerted I → III oxygen transfers. However, we were
unable to find TSs that would allow the rejection of the possibility
of this route.
PhC(H)N(O)Me + I → INTaldo via TS1aldo
26.0
3.7
21.7
−22.5
−36.0
−58.6
−14.2
20.2
INTaldo → IIaldo via TS2aldo
IIaldo → III + MeNC(H)Ph via TS3aldo
INTaldo → III + MeNC(H)Ph via TS4aldo
III + MeNC(H)Ph → IValdo + OCNMe
Ph2CN(O)Ph + I → INTketo via TS1keto
INTketo → IIketo via TS2keto
IIketo → III + PhNCPh2 via TS3keto
INTketo → III + PhNCPh2 via TS4keto
III + PhNCPh2 → IVketo + OCNMe
25.7
7.1
27.7
1.7
−17.2
−47.8
−65.0
−8.1
22.3
5.1
thermodynamic stabilities of the CA products is crucial for the
comparison of the reactivity of these two types of nitrones toward
isocyanide ligands (see below).
Splitting of IIketo to furnish III and Ph2CNPh occurs in a
concerted mode via TS3keto. The calculated activation energy of
the IIketo splitting is lower by 3.3 kcal/mol than that of the IIaldo
splitting (the ΔGs⧧ values are 22.3 and 25.7 kcal/mol, respec-
tively; Figure 2).
2. Route B. Route B starts with the formation of the
intermediate INT, which then is directly converted to III via
TS4. In the case of the aldonitrone PhCHN(O)Me, the rate-
limiting step for route B is the second one (decomposition of
INTaldo), while for the ketonitrone Ph2CN(O)Me the rate-
determining step is the first one (formation of INTketo). The
activation barrier of the INTketo decomposition into III is lower
than that of INTaldo (5.1 vs 7.1 kcal/mol, respectively). However,
Figure 1. Equilibrium structures of transition states.
D
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Figure 3. Molecular structure of 8 with the atomic numbering scheme.
Thermal ellipsoids are drawn at the 50% probability level. Selected bond
lengths (Å) and angles (deg): Pd−C(1) = 1.922(4), Pd−N(2) = 2.053(3),
Pd−Cl(1) = 2.3003(9), Pd−Cl(2) = 2.3052(9), C(1)−N(1) = 1.147(5),
N(1)−C(3) = 1.465(5), N(2)−C(2) = 1.302(4), N(2)−C(21) =
1.434(4); C(1)−Pd−N(2) = 176.64(13), C(1)−Pd−Cl(1) = 86.98(11),
N(2)−Pd−Cl(1) = 89.82(7), Cl(1)−Pd−Cl(2) = 175.30(3), C(2)−
N(2)−C(21) = 120.3(3), C(2)−N(2)−Pd = 123.2(2), C(21)−N(2)−
Pd = 116.41(19), N(1)−C(1)−Pd = 175.6(3), C(1)−N(1)−C(3) =
170.7(4).
square planar environment around the metal center. The CN
bond length (N2−C2 = 1.302(4) Å) is in the range that is
typical of double-bond values and agrees with that reported for
the related complex [PdCl2{N(Me)C(H)C6H4Me-4}(CNC6H4-
OMe-4)].15 In the isocyanide moiety, the CN triple-bond
length (C1−N1 = 1.147(5) Å) is equal, within 3σ, to those in
cis-[PdCl2(CNR)2] (R = Cy, 1.128−1.142 Å; R = 2,6-Me2C6H3,
1.128−1.142 Å; R = tBu, 1.108−1.149 Å).20
Application of 7−14 as Catalysts for Sonogashira
Coupling. The Sonogashira reaction has been proven to be a
very powerful method for carbon−carbon bond formation. It
has been widely employed in fine chemical synthesis: in particular,
in medicinal chemistry and natural product preparation.21−25 The
conventional protocol for Sonogashira cross-coupling runs under
anaerobic conditions and requires a homogeneous palladium
catalyst and copper(I) cocatalyst.26 However, the latter can lead
to undesired side reactions (e.g., oxidative homocoupling of the
terminal acetylene to give a diyne) and to a drop in the selec-
tivity of the main cross-coupling process.
Figure 2. Energy profiles of the reactions of the aldonitrone PhC(H)
N(O)Me (i) and the ketonitrone Ph2CN(O)Ph (ii) with complex I.
Relative energies are indicated in kcal/mol; route A is shown in red and
route B in blue.
Characterization of 7−14. Complexes 7−14 were
obtained as yellow solids and characterized by elemental analyses
1
(C, H, N), by HRESI+-MS, IR, and H and 13C{1H} NMR
spectroscopy, and also by X-ray diffraction (for 8). All palladium
species gave satisfactory microanalyses. In the ESI+-MS, the typical
ions that were detected were [M + H]+, [M + Na]+, and [M + K]+
with the characteristic isotopic distribution. A comparison of the
IR spectra of the products with those of starting 1−4 indicated
intense ν(CN) vibrations in the range between 1630 and
1639 cm−1 along with ν(CN) bands at ca. 2240 cm−1.
Numerous modifications to the Sonogashira reaction,27−31
aiming at increasing the selectivity of the process, have been
reported to date. Despite the success of some systems, the vast
majority of them still require anaerobic conditions, high catalyst
loadings (up to 5 mol %), and long reaction times (up to 24 h),
hence the search for new alternative, more efficient systems for
Sonogashira coupling.
In this work, we evaluated the catalytic activity of 7−14 in
Cu-/phosphine-free Sonogashira reactions. For this study we
addressed the reaction of 4-methoxyiodobenzene (4-iodoani-
sole) with phenylacetylene, affording 1-methoxy-4-(phenylethynyl)-
benzene, a typical model reaction for studying Sonogashira coupling.
We conducted the preliminary optimizations of the catalytic
system and found that the most appropriate are the conditions
described previously by some of us for palladium−aminocarbene
1
In the H NMR spectra of 7−14, signal integrations give
evidence that the reaction between any of the cis-[PdCl2(CNR)2]
complexes and any of the ketonitrones proceeds in a 1:1
1
ratio. Both H and 13C{1H} NMR spectra of 7−14 exhibit
signals from the imine and the isocyanide ligands; the re-
sonances of the isocyanide ligands are shifted slightly to low
field in comparison to those in starting 1−4. In the 13C{1H}
NMR spectra, peaks from the imine C atom (163.0−165.3
ppm) were recognized.
Complex 8 was characterized by a single-crystal X-ray dif-
fraction study (Figure 3). In 8, the chlorides are mutually trans
(Cl1−Pd−Cl2 = 175.30(3)°) and the C1 atom of the isocyanide
and the N2 atom of the imine ligand complete a slightly distorted
E
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Table 3. Catalytic Properties of 7−14 in the Model Sonogashira System
1 × 10−8 mol of catalyst
1 × 10−9 mol of catalyst
catalyst
entry
yield, %
TON
TOF, min−1
entry
yield, %
TON
TOF, min−1
7
1
2
3
4
5
6
7
8
94
92
94
93
90
95
92
93
9400
9200
9400
9300
9000
9500
9200
9300
157
153
157
155
150
158
153
155
9
14
14
13
12
12
12
15
12
14000
14000
13000
12000
12000
12000
15000
12000
233
233
217
200
200
200
250
200
8
10
11
12
13
14
15
16
9
10
11
12
13
14
complexes: viz., nondistilled ethanol as a solvent, potassium
carbonate as a base, in air. The reaction proceeds in reflux-
ing EtOH, and full conversion of the starting materials is
achieved within 1 h. The obtained results are summarized in
Table 3.
analytically pure form, in contrast to similar species derived
from aldonitrones, which were unstable and were characterized
only in CDCl3 solutions by HRESI-MS and 1H NMR
spectroscopy.
Third, complexes 7−14 were tested as catalysts in copper-/
phosphine-free Sonogashira reactions and demonstrated high
catalytic activity in the model coupling of 4-methoxyiodoben-
zene (4-iodoanisole) with phenylacetylene (yields 90−95%,
TONs up to 15000, and TOFs up to 250 min−1), and these
results are among the best so far reported in the field of Cu-/
phosphine-free Sonogashira coupling. As a continuation of this
work, we intend to enhance the range of nucleophilic oxygen donors,
which could convert isocyanide ligands in their palladium(II)
complexes into isocyanate followed by substitution of RNCO
by other ligands; this project is underway in our group.
With 1 × 10−8 mol of 7−14 as catalysts, the yields of the
target product were nearly quantitative (90−95%, entries 1−8
of Table 3). Decreasing the concentration of any of 7−14 to
10−9 resulted in a drop in the yield of the cross-coupling system
to 12−15% (entries 9−16 of Table 3). In contrast to the
iodides, when aryl bromides and chlorides were used as the
substrates, the yields of the cross-coupling product were less
that 20% (for chlorides) or 44% (for bromides) under any of
the attempted conditions (temperature 80−110 °C, time 1−48
h, catalyst loading 10−8−10−5 mol, bases Cs2CO3, Et3N, and t-
BuOK, cocatalysts CuI and PPh3).
In conclusion, all imine−isocyanide palladium(II) complexes
7−14 exhibit high catalytic activity in the model cross-coupling
system. The yields of the cross-coupling product were up to
95%, with TONs up to 15000 and TOFs up to 250 min−1. These
results are among the best reported so far32b,33 in the field of
Cu-/phosphine-free Sonogashira coupling. To the best of our
knowledge, the most efficient Cu-/phosphine-free systems that
provide ca. 90% yields of the coupling products are based on
palladium complexes, and they are characterized by TONs that
range from 8600 to 9950.32b,33
Final Remarks. The results obtained in this work could be
considered from a few perspectives. First, we found that the
isocyanide ligands in their palladium(II) complexes undergo
rapid and selective metal-mediated nucleophilic oxygenation by
ketonitrones. The interaction of palladium(II)-bound isocya-
nides with ketonitrones proceeds as at least overall nucleophilic
oxygenation of RNC ligands independent of the molar ratio of
reactants and the solvent employed, while the interactions of
PdII-bound isocyanides with aldonitrones provide cycloadducts,
which only after upon heating convert to corresponding imine−
isocyanide complexes. The theoretical calculations indicate that,
in the case of aldonitrones, formation of the imine complexes
occurs preferably via a CA/splitting pathway, including the
generation of a cycloadduct, while in the case of ketonitrones
both the CA/splitting route and the direct oxygen atom transfer
pathway are equally plausible from a kinetic viewpoint. In
addition, the cycloadduct derived from CA of the ketonitrone is
less stable and more easily splits into the imine and the isocyanate,
in comparison with the cycloadduct derived from the aldonitrone.
These features allow the explanation of the experimentally observed
difference in the behavior of keto- and aldonitrones toward the
metal-bound isocyanides.
EXPERIMENTAL SECTION
■
Materials and Instrumentation. Solvents, PdCl2, and all iso-
cyanides were obtained from commercial sources and used as received,
with the exception of benzene and chloroform, which were purified by
conventional distillation over sodium/benzophenone and calcium chloride,
respectively. Complexes 1−4 were prepared as previously reported.34
Ketonitrones 5 and 6 were obtained according to the previously
described protocol by the reaction of aryl nitroso compounds with
diphenyldiazomethane in diethyl ether at room temperature (60−85%).35
C, H, and N elemental analyses were carried out by the Department of
Organic Chemistry of Saint Petersburg State University on a Hewlett-
Packard 185B Carbon Hydrogen Nitrogen Analyzer. Electrospray
ionization mass spectra were obtained on a Bruker micrOTOF spectrom-
eter equipped with an electrospray ionization (ESI) source. The instru-
ment was operated in both positive and negative ion modes using an m/z
range of 50−3000. The capillary voltage of the ion source was set at
−4500 V (ESI+-MS) and the capillary exit at (70−150) V. For ESI
species were dissolved in MeCN; NaBF4 or formic acid was used as an
additional ionization agent. In the isotopic pattern, the most intense
peak is reported. TLC was performed on Merck 60 F254 SiO2 plates.
Infrared spectra (4000−400 cm−1) were recorded on a Shimadzu
FTIR-8400S instrument as KBr pellets. 1H and 13C{1H} NMR spectra
were recorded on Bruker Avance II+ 400 MHz (UltraShield Magnet)
and Avance II+ 500 MHz (UltraShield Plus Magnet) spectrometers at
ambient temperature in CD2Cl2.
X-ray Diffraction Study. Crystals of 8 suitable for an X-ray study
were obtained by slow evaporation of a CH2Cl2 solution at room
temperature. For the single-crystal X-ray diffraction experiment, a
crystal of 8 was fixed on a micro mount, placed in a Bruker Kappa
APEX II DUO diffractometer, and measured at 100 K using mono-
chromated microfucused Mo Kα radiation. The unit cell parameters
(Table S1; see the Supporting Information) were refined by least-
squares techniques using 24619 reflections in the 2θ range of 3.28−
70.16°. The structure was solved by direct methods and refined to
R1 = 0.052 (wR2 = 0.122) for 8558 unique reflections with |Fo| ≥ 4σF
by means of the SHELXL-97 program36 incorporated in the OLEX2
program package.37 Positions of H atoms were modeled using the
Second, the obtained imine−isocyanide complexes 7−14
were found to be unexpectedly stable and were isolated in an
F
dx.doi.org/10.1021/om4000665 | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
“riding” model. Absorbance correction was applied using the SADABS
program.38 Positions of H atoms were modeled using the “riding”
model, except for OH, where the H atoms were localized objectively
and kept fixed during refinement. Supplementary crystallographic data
for this paper have been deposited at the Cambridge Crystallographic
Data Centre (CCDC 921202) and can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif.
standard conditions (1000 mL/mol). The enthalpies and Gibbs free
energies in solution (Hs and Gs) were estimated using eqs 5 and 6,
Hs = Es(6‐311+G(d, p)) − Eg(6‐311+G(d, p))
+ Hg(6‐31G(d))
(5)
Computational Details. A full geometry optimization of all
structures and transition states (TS) has been carried out at the DFT/
HF hybrid level of theory using Becke’s three-parameter hybrid ex-
change functional in combination with the gradient-corrected cor-
relation functional of Lee, Yang, and Parr (B3LYP)39 with the help of
the Gaussian-03 program package. No symmetry operations were
applied. The geometry optimization was carried out using a quasi-
relativistic Stuttgart pseudopotential that described 60 core electrons
and the appropriate contracted basis set40 for the palladium atoms
and the 6-31G(d) basis set for other atoms. Then, single-point
calculations were performed on the basis of the equilibrium geo-
metries found using the 6-311+G(d,p) basis set for nonmetal atoms.
As was shown by some of us previously,19a−e this approach is
sufficiently accurate for the description of the nucleophilic additions
and cycloadditions to the CN bond, providing results close to
those obtained by such methods as MP2, MP4, CCSD(T), CBS-Q,
and G3B3.
Gs = Hs − TSs
(6)
where Es, Eg, and Hg are the total energies in solution and in the gas
phase and the gas-phase enthalpy calculated at the corresponding level,
respectively.
Synthetic Work. Synthesis of Imine−Isocyanide Complexes 7−
14 (General Procedure). A solution of any of 1−4 (0.1 mmol) in
CH2Cl2 (1 mL) was added at ca. 5 °C to a solution of ketonitrone 5
or 6 (0.1 mmol) in CHCl3 (1 mL). The system was kept at this
temperature for approximately 4 h, whereupon it was gradually heated
to 20−25 °C (ca. 15 min) and stirred at room temperature for 5 h.
The yellow solution that formed was evaporated under vacuum at
room temperature, and the oily residue obtained was extracted with
Et2O (three 3 mL portions). The solvent was evaporated under
vacuum at 20−25 °C to give yellow powders of 7−14, which were
dried in air at room temperature.
The Hessian matrix was calculated analytically for the optimized struc-
tures in order to prove the location of correct minima (no imaginary
frequencies) or saddle points (only one imaginary frequency) and to
estimate the thermodynamic parameters, the latter being calculated at
25 °C. The nature of all transition states was investigated by the
analysis of vectors associated with the imaginary frequency and by the
calculations of the intrinsic reaction coordinates (IRC) using the
Gonzalez−Schlegel method.41 Sometimes, the IRC calculations failed
due to the low imaginary frequency of a transition state. In these cases,
the analysis of the TS nature was performed in accord with the
following procedure. First, the atoms of TS were shifted from the
equilibrium positions along the vectors corresponding to the imaginary
frequency, in both directions. Then, geometry optimization with small
size of an optimization step was carried out.
Solvent effects (δEs) were taken into account in the single-point
calculations on the basis of gas-phase geometries at the CPCM-
B3LYP/6-311+G(d,p)//gas-B3LYP/6-31G(d) level of theory using
the polarizable continuum model in the CPCM version42 with CH2Cl2
as solvent. The UAKS model was applied for the molecular cavity. The
entropic term in solution (Ss) was calculated according to the pro-
cedure described by Wertz43 and Cooper and Ziegler44 using eqs 1−4,
7 (54 mg, 94%). Anal. Found: C, 60.03; H, 4.56; N, 4.85. Calcd
for C29H26N2Cl2Pd: C, 60.07; H, 4.52; N, 4.83. High-resolution ESI+:
m/z 601.0403 ([M + Na]+ requires 601.0406); Rf = 0.37 (eluent
CHCl3/n-hexane, 5/1, v/v). νmax(KBr)/cm−1: 2933 m (C−H), 2247 m
(CN), 1630 s (NC). δH (400.130 MHz, CD2Cl2): 2.30 (3H, s, CH3
from p-tol), 2.43 (6H, s, CH3 from Xyl) 7.11−8.25 (17H, 5 m, Haromatic).
δC (100.613 MHz, CD2Cl2): 16.2 (CH3 from p-tol), 21.3 (CH3 from
Xyl), 127.2−140.2 (Caromatic), 165.0 (CN); the CN carbon was not
detected. Complex 7 has no specific melting point. On heating it gradually
decomposes starting from 155 °C to furnish a dark brown residue.
8 (51 mg, 92%). Anal. Found: C, 58.10; H, 5.02; N, 5.02. Calcd for
C27H28N2Cl2Pd: C, 58.13; H, 5.06; N, 5.05. High-resolution ESI+: m/z
557.0744 ([M + H]+ requires 557.0743). Rf = 0.41 (eluent CHCl3/
n-hexane, 5/1, v/v). νmax(KBr)/cm−1: 2939 m (C−H), 2244 m (C
N), 1633 s (NC). δH (400.130 MHz, CD2Cl2): 1.14−1.80 (10H, m,
CH2 from Cy), 2.31 (3H, s, CH3 from p-tol), 3.93 (1H, br m, CH
from Cy), 7.13−8.28 (14H, 4 m, Haromatic). δC (100.613 MHz,
CD2Cl2): 20.4 (CH3 from p-tol), 24.4, 31.3, and 34.0 (CH2 from Cy),
127.7−140.0 (Caromatic), 163.0 (CN); the CN carbon was not
detected. Complex 8 has no specific melting point. On heating it gradually
decomposes starting from 148 °C to furnish a dark brown residue.
9 (48 mg, 90%). Anal. Found: C, 56.50; H, 4.91; N, 5.25. Calcd for
C25H26N2Cl2Pd: C, 56.46; H, 4.93; N, 5.27. High-resolution ESI+: m/z
553.0408 ([M + Na]+ requires 553.0406). Rf = 0.36 (eluent CHCl3/n-
hexane, 5/1, v/v). νmax(KBr)/cm−1: 2933 m (C−H), 2244 m (CN),
1639 s (NC). δH (400.130 MHz, CD2Cl2): 1.44 (9H, s, CH3 from
tBu), 2.31 (3H, s, CH3 from p-tol), 7.15−8.28 (14H, 5 m, Haromatic). δC
(100.613 MHz, CD2Cl2): 16.2 (CH3 from p-tol), 31.3 and 30.4
(C from tBu), 127.5−140.0 (Caromatic), 164.0 (CN); the CN carbon
was not detected. Complex 9 has no specific melting point. On heating it
gradually decomposes starting from 153 °C to furnish a dark brown residue.
10 (54 mg, 94%). Anal. Found: C 56.06; H, 3.84; N, 4.66. Calcd for
C28H23N2Cl3Pd: C, 56.02; H, 3.86; N, 4.67. High-resolution ESI+: m/z
620.9855 ([M + Na]+ requires 620.9859). Rf = 0.33 (eluent CHCl3/
n-hexane, 5/1, v/v). νmax(KBr)/cm−1: 2929 m (C−H), 2244 m (C
N), 1637 s (NC). δH (100.613 MHz, CD2Cl2): 2.31 (3H, s, CH3
from p-tol), 2.52 (3H, s, CH3 from C6H3(Cl)CH3) 7.10−8.22 (17H, 5
m, Haromatic). δC (75.5 MHz, CD2Cl2): 18.2 (CH3 from p-tol), 22.6
(CH3 from C6H3(Cl)CH3), 127.2−140.8 (Caromatic), 165.1 (CN);
the CN carbon was not detected. Complex 10 has no specific
melting point. On heating it gradually decomposes starting from 155 °C
to furnish a dark brown residue.
ΔS1 = R ln Vsm,liq/Vm,gas
(1)
ΔS2 = R ln V◦m/Vs
m,liq
(2)
(3)
S◦s − (S◦s + R ln Vsm,liq/Vm,gas
)
liq
gas
α =
(S◦s + R ln Vsm,liq/Vm,gas
)
gas
Ss = Sg + ΔSsol
= Sg + [ΔS1 + α(Sg + ΔS1) + ΔS2]
=Sg+[(−11.80 cal/(mol K))− 0.21(Sg − 11.80 cal/(mol K))
+ 5.45 cal/(mol K)]
(4)
where Sg is the gas-phase entropy of the solute, ΔSsol is the solvation
entropy, S°sliq, S°sgas, and Vsm,liq are the standard entropies and molar
volume of the solvent in liquid and gas phases, respectively (173.84
and 270.28 J/(mol K) and 64.15 mL/mol, respectively, for CH2Cl2),
Vm,gas is the molar volume of the ideal gas at 25 °C (24450 mL/mol),
and V°m is the molar volume of the solution corresponding to the
11 (56 mg, 93%). Anal. Found: C, 56.03; H, 3.90; N, 4.66. Calcd for
C25H23N2Cl3Pd: C, 56.02; H, 3.86; N, 4.67. High-resolution ESI+: m/z
584.9862 ([M + Na]+ requires 584.9859). Rf = 0.35 (eluent CHCl3/
n-hexane, 5/1, v/v). νmax(KBr)/cm−1: 2932 m (C−H), 2243 m
G
dx.doi.org/10.1021/om4000665 | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(CN), 1636 s (NC). δH (400.130 MHz, CD2Cl2): 2.43 (6H, s,
CH3 from Xyl) 7.14−8.31 (17H, 5 m, Haromatic). δC (100.613 MHz,
CD2Cl2): 21.4 (CH3 from Xyl), 128.0−141.3 (Caromatic), 165.2
(CN); the CN carbon was not detected. Complex 11 has no
specific melting point. On heating it gradually decomposes starting from
155 °C to furnish a dark brown residue.
12 (52 mg, 90%). Anal. Found: C, 54.02; H, 4.39; N, 4.88. Calcd for
C26H25N2Cl3Pd: C, 54.00; H, 4.36; N, 4.84. High-resolution ESI+: m/z
559.0012 ([M + Na]+ requires 559.0016). Rf = 0.39 (eluent CHCl3/n-
hexane, 5/1, v/v). νmax(KBr)/cm−1: 2933 m (C−H), 2241 m (CN),
1635 s (NC). δH (400.130 MHz, CD2Cl2): 1.14−1.81 (10H, m,
CH2 from Cy), 3.93 (1H, br m, CH from Cy), 7.15−8.32 (14H, 4 m,
Haromatic). δC (100.613 MHz, CD2Cl2): 24.4, 31.3, and 34.1 (CH2 from
Cy), 127.5−142.3 (Caromatic), 164.5 (CN); the CN carbon was
not detected. Complex 12 has no specific melting point. On heating it
gradually decomposes starting from 141 °C to furnish a dark brown
residue.
ACKNOWLEDGMENTS
■
We thank the Russian Fund for Basic Research (Grants 11-03-
00262, 12-03-33071, and 12-03-00076) and Federal Grant-in-Aid
Program “Human Capital for Science and Education in Innovative
Russia” for 2009−2013, Agreement No. 14.B37.21.0794 from
03.09.2012. We acknowledge Saint Petersburg State University
for research grants (2011−2013, 12.37.133.2011 and 2013−
2015, 12.38.781.2013) and a grant for applied study (2012−2013,
12.39.1050.2012). The work was also supported by the FCT of
Portugal (projects PTDC/QUI-QUI/119561/2010 and PTDC/
QUI-QUI/109846/2009). M.L.K. thanks the FCT and IST for a
̂
research contract with the Ciencia 2007 program. NMR studies were
performed at the Centre for Magnetic Resonance, while X-ray
diffraction experiments were carried out at the X-ray Diffraction
Centre (Saint Petersburg State University).
13 (48 mg, 93%). Anal. Found: C, 52.17; H, 4.19; N, 5.05. Calcd for
C24H23N2Cl3Pd: C, 52.20; H, 4.20; N, 5.07. High-resolution ESI+: m/z
551.0044 ([M + H]+ requires 551.0040). Rf = 0.38 (eluent CHCl3/n-
hexane, 5/1, v/v). νmax(KBr)/cm−1: 2931 m (C−H), 2244 m (CN),
1633 s (NC). δH (400.130 MHz, CD2Cl2): 1.43 (9H, CH3 from
tBu), 7.19−8.32 (14H, 5 m, Haromatic). δC (100.613 MHz, CD2Cl2):
31.3 and 30.4 (C from tBu), 127.3−142.5 (Caromatic), 164.7 (CN);
the CN carbon was not detected. Complex 13 has no specific
melting point. On heating it gradually decomposes starting from 150 °C
to furnish a dark brown residue.
14 (59 mg, 90%). Anal. Found: C, 52.28; H, 3.28; N, 4.52. Calcd for
C27H20N2Cl4Pd: C, 52.25; H, 3.25; N, 4.51. High-resolution ESI+: m/z
642.9285 ([M + Na]+ requires 642.9284). Rf = 0.37 (eluent CHCl3/
n-hexane, 5/1, v/v). νmax(KBr)/cm−1: 2921 m (C−H), 2238 m (C
N), 1633 s (NC). δH (400.130 MHz, CD2Cl2): 2.54 (3H, s, CH3
from C6H3(Cl)CH3), 7.14−8.24 (17H, 5 m, Haromatic). δC (100.613
MHz, CD2Cl2): 18.0 (CH3 from p-tol), 22.6 (CH3 from C6H3(Cl)-
CH3), 127.4−142.2 (Caromatic), 165.2 (CN); the CN carbon was
not detected. Complex 14 has no specific melting point. On heating it
gradually decomposes starting from 155 °C to furnish a dark brown
residue.
Catalytic Studies: General Procedure for the Catalytic
Sonogashira Cross-Coupling. A 10 mL vial was charged with
potassium carbonate (2.5 × 10−4 mol, 2.5 equiv), the aryl iodide (1.0 ×
10−4 mol, 1.0 equiv), phenylacetylene (1.5 × 10−4 mol, 1.5 equiv), and
a solution of the catalyst (1 × 10−8 mol) in EtOH (1 mL) and
equipped with a Teflon-coated magnetic bar. The vial was closed with
a septum and an aluminum crimp seal and kept in the oil bath at 80 °C
for 1 h with vigorous stirring. After it was cooled to room temperature,
the reaction mixture was evaporated to dryness under a stream of di-
nitrogen and 1,2-dimethoxyethane (1 equiv; used as a NMR internal
standard) was added. The content of the vial was extracted with three
0.20 mL portions of CDCl3; all fractions were combined and analyzed
by 1H NMR spectroscopy. The product peak assignments were based
on the published data,45 while quantifications were performed upon
integration of the selected peaks of the product with those of the standard.
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H
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dx.doi.org/10.1021/om4000665 | Organometallics XXXX, XXX, XXX−XXX